TY - JOUR AU - Sieswerda, Elske AU - Boer, Mark G. J. de AU - Bonten, M. AU - Boersma, Wim G. AU - Jonkers, Rene E. AU - Aleva, Roel M. AU - Kullberg, B.J. AU - Schouten, J.A. AU - Prins, J.M. AU - Joost Wiersinga, W. PY - 2021 UR - https://hdl.handle.net/2066/228673 TI - Recommendations for antibacterial therapy in adults with COVID-19-an evidence based guideline EP - 66 SN - 1198-743X IS - iss. 1 SP - 61 JF - Clinical Microbiology and Infection VL - vol. 27 DO - https://doi.org/10.1016/j.cmi.2020.09.041 ER - TY - JOUR AU - Bolt, S.H. AU - Witjes, M. AU - Ende, B. van den PY - 2020 UR - https://hdl.handle.net/2066/221410 AB - This article investigates the emergence of a growing demand in the Netherlands: the wish of organ donor families and organ recipients to establish contact. Such direct contact transgresses both the anonymity and privacy long considered by many to be fundamental to organ donation. Legislation prescribes that privacy should be safeguarded, but the parties involved increasingly manage to find each other. Research is needed to provide insight into the ramifications of direct contact, which may inform mourning counseling and psychosocial support. Drawing on qualitative interviews with donor's relatives, we analyze the reasons for the desire to have direct contact. We seek to understand how meanings are constructed and contested through organs at the margins of life and death in the individualized and secularized society of the Netherlands. We find that relatives struggle with persistent restless feelings after postmortem organ donation and may develop a level of personal attachment and assign inalienability to human body parts. TI - Restless feelings: Desiring direct contact after postmortem organ donation EP - 82 SN - 0030-2228 IS - iss. 1 SP - 62 JF - Omega : Journal of Death and Dying VL - vol. 82 PS - 21 p. DO - https://doi.org/10.1177/0030222818800207 ER - TY - JOUR AU - Weiss, S.L. AU - Peters, M.J. AU - Alhazzani, W. AU - Agus, M.S.D. AU - Flori, H.R. AU - Inwald, D.P. AU - Nadel, S. AU - Schlapbach, L.J. AU - Tasker, R.C. AU - Argent, A.C. AU - Brierley, J. AU - Carcillo, J. AU - Carrol, E.D. AU - Carroll, C.L. AU - Cheifetz, I.M. AU - Choong, K. AU - Cies, J.J. AU - Cruz, A.T. AU - Luca, D. De AU - Deep, A. AU - Faust, S.N. AU - Oliveira, C.F. De AU - Hall, M.W. AU - Ishimine, P. AU - Javouhey, E. AU - Joosten, K.F. AU - Joshi, P. AU - Karam, O. AU - Kneyber, M.C.J. AU - Lemson, J. AU - MacLaren, G. AU - Mehta, N.M. AU - Møller, M.H. AU - Newth, C.J. AU - Nguyen, T.C. AU - Nishisaki, A. AU - Nunnally, M.E. AU - Parker, M.M. AU - Paul, R.M. AU - Randolph, A.G. AU - Ranjit, S. AU - Romer, L.H. AU - Scott, H.F. AU - Tume, L.N. AU - Verger, J.T. AU - Williams, E.A. AU - Wolf, J. AU - Wong, H.R. AU - Zimmerman, J.J. AU - Kissoon, N. AU - Tissieres, P. PY - 2020 UR - https://hdl.handle.net/2066/220775 TI - Executive summary: surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children EP - 9 SN - 0342-4642 IS - iss. Suppl 1 SP - 1 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-019-05877-7 ER - TY - JOUR AU - Weiss, S.L. AU - Peters, M.J. AU - Alhazzani, W. AU - Agus, M.S.D. AU - Flori, H.R. AU - Inwald, D.P. AU - Nadel, S. AU - Schlapbach, L.J. AU - Tasker, R.C. AU - Argent, A.C. AU - Brierley, J. AU - Carcillo, J. AU - Carrol, E.D. AU - Carroll, C.L. AU - Cheifetz, I.M. AU - Choong, K. AU - Cies, J.J. AU - Cruz, A.T. AU - Luca, D. De AU - Deep, A. AU - Faust, S.N. AU - Oliveira, C.F. De AU - Hall, M.W. AU - Ishimine, P. AU - Javouhey, E. AU - Joosten, K.F. AU - Joshi, P. AU - Karam, O. AU - Kneyber, M.C.J. AU - Lemson, J. AU - MacLaren, G. AU - Mehta, N.M. AU - Møller, M.H. AU - Newth, C.J. AU - Nguyen, T.C. AU - Nishisaki, A. AU - Nunnally, M.E. AU - Parker, M.M. AU - Paul, R.M. AU - Randolph, A.G. AU - Ranjit, S. AU - Romer, L.H. AU - Scott, H.F. AU - Tume, L.N. AU - Verger, J.T. AU - Williams, E.A. AU - Wolf, J. AU - Wong, H.R. AU - Zimmerman, J.J. AU - Kissoon, N. AU - Tissieres, P. PY - 2020 UR - https://hdl.handle.net/2066/220773 TI - Executive Summary: Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children EP - 195 SN - 1529-7535 IS - iss. 2 SP - 186 JF - Pediatric Critical Care Medicine VL - vol. 21 DO - https://doi.org/10.1097/PCC.0000000000002197 ER - TY - JOUR AU - Stolk, R.F. AU - Kox, M. AU - Pickkers, P. PY - 2020 UR - https://hdl.handle.net/2066/220815 TI - Noradrenaline drives immunosuppression in sepsis: clinical consequences EP - 1248 SN - 0342-4642 IS - iss. 6 SP - 1246 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-020-06025-2 ER - TY - JOUR AU - Smit, L. AU - Trogrlić, Z. AU - Devlin, J.W. AU - Osse, R.J. AU - Ponssen, H.H. AU - Slooter, A.J. AU - Hunfeld, N.G. AU - Rietdijk, W.J.R. AU - Boogaard, M. van den AU - Gommers, D. AU - Jagt, M. van der PY - 2020 UR - https://hdl.handle.net/2066/225437 AB - INTRODUCTION: Delirium in critically ill adults is associated with prolonged hospital stay, increased mortality and greater cognitive and functional decline. Current practice guideline recommendations advocate the use of non-pharmacological strategies to reduce delirium. The routine use of scheduled haloperidol to treat delirium is not recommended given a lack of evidence regarding its ability to resolve delirium nor improve relevant short-term and longer-term outcomes. This study aims to evaluate the efficacy and safety of haloperidol for the treatment of delirium in adult critically ill patients to reduce days spent with coma or delirium. METHODS AND ANALYSIS: EuRIDICE is a prospective, multi-centre, randomised, double-blind, placebo-controlled trial. Study population consists of adult intensive care unit (ICU) patients without acute neurological injury who have delirium based on a positive Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU) assessment. Intervention is intravenous haloperidol 2.5 mg (or matching placebo) every 8 hours, titrated daily based on ICDSC or CAM-ICU positivity to a maximum of 5 mg every 8 hours, until delirium resolution or ICU discharge. Main study endpoint is delirium and coma-free days (DCFD) up to 14 days after randomisation. Secondary endpoints include (1) 28-day and 1-year mortality, (2) cognitive and functional performance at 3 and 12 months, (3) patient and family delirium and ICU experience, (4) psychological sequelae during and after ICU stay, (4) safety concerns associated with haloperidol use and (5) cost-effectiveness. Differences in DCFDs between haloperidol and placebo group will be analysed using Poisson regression analysis. Study recruitment started in February 2018 and continues. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam (MEC2017-511) and by the Institutional Review Boards of the participating sites. Its results will be disseminated via peer-reviewed publication and conference presentations. TRIAL REGISTRATION: NCT03628391. TI - Efficacy of halopeRIdol to decrease the burden of Delirium In adult Critically ill patiEnts (EuRIDICE): study protocol for a prospective randomised multi-centre double-blind placebo-controlled clinical trial in the Netherlands SN - 2044-6055 IS - iss. 9 JF - BMJ Open VL - vol. 10 DO - https://doi.org/10.1136/bmjopen-2019-036735 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/225437/225437.pdf?sequence=1 ER - TY - JOUR AU - Witjes, M. AU - Jansen, N.E. AU - Dongen, J. Van AU - Herold, I.H.F. AU - Otterspoor, L. AU - Haase-Kromwijk, B. AU - Hoeven, J.G. van der AU - Abdo, W.F. PY - 2020 UR - https://hdl.handle.net/2066/225441 AB - BACKGROUND: One of the most important bottlenecks in the organ donation process worldwide is the high family refusal rate. AIMS AND OBJECTIVES: The main aim of this study was to examine whether family guidance by trained donation practitioners increased the family consent rate for organ donation. DESIGN: This was a prospective intervention study. METHODS: Intensive and coronary care unit nurses were trained in communication about donation (ie, trained donation practitioners) in two hospitals. The trained donation practitioners were appointed to guide the families of patients with a poor medical prognosis. When the patient became a potential donor, the trained donation practitioner was there to guide the family in making a well-considered decision about donation. We compared the family consent rate for donation with and without the guidance of a trained donation practitioner. RESULTS: The consent rate for donation with guidance by a trained donation practitioner was 58.8% (20/34), while the consent rate without guidance by a trained donation practitioner was 41.4% (41/99, P = 0.110) in those patients where the family had to decide on organ donation. CONCLUSIONS: Our data suggest that family guidance by a trained donation practitioner could benefit consent rates for organ donation. RELEVANCE TO CLINICAL PRACTICE: Trained nurses play an important role in supporting the families of patients who became potential donors to guide them through the decision-making process after organ donation request. TI - Appointing nurses trained in organ donation to improve family consent rates EP - 304 SN - 1362-1017 IS - iss. 5 SP - 299 JF - Nursing in Critical Care VL - vol. 25 DO - https://doi.org/10.1111/nicc.12462 ER - TY - JOUR AU - Muilwijk, E.W. AU - Lange, D.W. de AU - Schouten, J.A. AU - Wasmann, R.E. AU - Heine, R. ter AU - Burger, D.M. AU - Colbers, A. AU - Haas, P.J. AU - Verweij, P.E. AU - Pickkers, P. AU - Brüggemann, R.J.M. PY - 2020 UR - https://hdl.handle.net/2066/225354 AB - Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.). TI - Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time To Rethink Dosing SN - 0066-4804 IS - iss. 10 JF - Antimicrobial Agents and Chemotherapy VL - vol. 64 DO - https://doi.org/10.1128/AAC.00984-20 ER - TY - JOUR AU - Birgand, G. AU - Schouten, J.A. AU - Ruppé, E. PY - 2020 UR - https://hdl.handle.net/2066/225471 TI - Less contact isolation is more in the ICU: con EP - 1734 SN - 0342-4642 IS - iss. 9 SP - 1732 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-019-05887-5 ER - TY - JOUR AU - Valburg, M.K. van AU - Termorshuizen, F. AU - Brinkman, S. AU - Abdo, W.F. AU - Bergh, W.M. van den AU - Horn, J. AU - Mook, W. van AU - Siegerink, B. AU - Slooter, A.J. AU - Wermer, M.J. AU - Geerts, B.F. AU - Arbous, M.Sesmu PY - 2020 UR - https://hdl.handle.net/2066/225472 AB - OBJECTIVES: Assessment of all-cause mortality of intracerebral hemorrhage and ischemic stroke patients admitted to the ICU and comparison to the mortality of other critically ill ICU patients classified into six other diagnostic subgroups and the general Dutch population. DESIGN: Observational cohort study. SETTING: All ICUs participating in the Dutch National Intensive Care Evaluation database. PATIENTS: All adult patients admitted to these ICUs between 2010 and 2015; patients were followed until February 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of all 370,386 included ICU patients, 7,046 (1.9%) were stroke patients, 4,072 with ischemic stroke, and 2,974 with intracerebral hemorrhage. Short-term mortality in ICU-admitted stroke patients was high with 30 days mortality of 31% in ischemic stroke and 42% in intracerebral hemorrhage. In the longer term, the survival curve gradient among ischemic stroke and intracerebral hemorrhage patients stabilized. The gradual alteration of mortality risk after ICU admission was assessed using left-truncation with increasing minimum survival period. ICU-admitted stroke patients who survive the first 30 days after suffering from a stroke had a favorable subsequent survival compared with other diseases necessitating ICU admission such as patients admitted due to sepsis or severe community-acquired pneumonia. After having survived the first 3 months after ICU admission, multivariable Cox regression analyses showed that case-mix adjusted hazard ratios during the follow-up period of up to 3 years were lower in ischemic stroke compared with sepsis (adjusted hazard ratio, 1.21; 95% CI, 1.06-1.36) and severe community-acquired pneumonia (adjusted hazard ratio, 1.57; 95% CI, 1.39-1.77) and in intracerebral hemorrhage patients compared with these groups (adjusted hazard ratio, 1.14; 95% CI, 0.98-1.33 and adjusted hazard ratio, 1.49; 95% CI, 1.28-1.73). CONCLUSIONS: Stroke patients who need intensive care treatment have a high short-term mortality risk, but this alters favorably with increasing duration of survival time after ICU admission in patients with both ischemic stroke and intracerebral hemorrhage, especially compared with other populations of critically ill patients such as sepsis or severe community-acquired pneumonia patients. TI - Long-Term Mortality Among ICU Patients With Stroke Compared With Other Critically Ill Patients EP - e883 SN - 0090-3493 IS - iss. 10 SP - e876 JF - Critical Care Medicine VL - vol. 48 DO - https://doi.org/10.1097/CCM.0000000000004492 ER - TY - JOUR AU - François, B. AU - Wittebole, X. AU - Ferrer, R. AU - Mira, J.P. AU - Dugernier, T. AU - Gibot, S. AU - Derive, M. AU - Olivier, A. AU - Cuvier, V. AU - Witte, S. AU - Pickkers, P. AU - Vandenhende, F. AU - Garaud, J.J. AU - Sánchez, M. AU - Salcedo-Magguilli, M. AU - Laterre, P.F. PY - 2020 UR - https://hdl.handle.net/2066/225478 AB - PURPOSE: Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients. METHODS: This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations. RESULTS: Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points. CONCLUSION: No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker. TI - Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial EP - 1437 SN - 0342-4642 IS - iss. 7 SP - 1425 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-020-06109-z ER - TY - JOUR AU - Radke, R.M. AU - Frenzel, T. AU - Baumgartner, H AU - Diller, G.P. PY - 2020 UR - https://hdl.handle.net/2066/225292 AB - Adults with congenital heart disease (ACHD) may be at high risk in the case of COVID-19. Due to the heterogeneity of ACHD and secondary complications, risk profiles are, however, not uniform. This document aims to give an overview of relevant data and outline our pragmatic approach to disease prevention and management. Based on anatomy and additional physiological factors including symptoms, exercise capacity, heart failure, pulmonary hypertension and cyanosis, we propose a pragmatic approach to categorising patients into low-risk, intermediate-risk and high-risk groups. We regard especially patients with complex cyanotic conditions, those with palliated univentricular hearts, heart failure, severe valvular disease or pulmonary hypertension as high-risk patients. To avoid infection, we recommend self-isolation and exemption from work for these cohorts. Infected ACHD patients with low or moderate risk and without signs of deterioration may be remotely followed and cared for at home while in self isolation. High-risk patients or those with signs of respiratory or cardiovascular impairment require admission ideally at a tertiary ACHD centre. Especially patients with complex, cyanotic disease, heart failure and arrhythmias require particular attention. Treatment in patients with cyanotic heart disease should be guided by the relative degree of desaturation compared with baseline and lactate levels rather than absolute oxygen saturation levels. Patients with right heart dilatation or dysfunction are potentially at increased risk of right heart failure as mechanical ventilation and acute respiratory distress syndrome can lead to increase in pulmonary arterial pressures. TI - Adult congenital heart disease and the COVID-19 pandemic EP - 1309 SN - 1355-6037 IS - iss. 17 SP - 1302 JF - Heart VL - vol. 106 DO - https://doi.org/10.1136/heartjnl-2020-317258 ER - TY - JOUR AU - Bestebreurtje, P. AU - Koning, B.A.E. de AU - Roeleveld, N. AU - Knibbe, C.A.J. AU - Tibboel, D. AU - Groen, B. van AU - Ven, C.P. van de AU - Plötz, F.B. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225501 AB - BACKGROUND AND OBJECTIVE: Omeprazole is a proton pump inhibitor that is used in acid suppression therapy in infants. Infants cannot swallow the oral tablets or capsules. Since, infants require a non-standard dose of omeprazole, the granules or tablets are often crushed or suspended in water or sodium bicarbonate, which may destroy the enteric coating. In this study we explore the efficacy and pharmacokinetics of rectally administered omeprazole in infants with gastroesophageal reflux disease (GERD) due to esophageal atresia (EA) or congenital diaphragmatic hernia (CDH) and compare these with orally administered omeprazole. METHODS: Infants (6-12 weeks postnatal and bodyweight > 3 kg) with EA or CDH and GERD were randomized to receive a single dose of 1 mg/kg omeprazole rectally or orally. The primary outcome was the percentage of infants for whom omeprazole was effective according to predefined criteria for 24-h intraesophageal pH. Secondary outcomes were the percentages of time that gastric pH was < 3 or < 4, as well as the pharmacokinetic parameters. RESULTS: Seventeen infants, 4 with EA and 13 with CDH, were included. The proportion of infants for whom omeprazole was effective was 56% (5 of 9 infants) after rectal administration and 50% (4 of 8 infants) after oral administration. The total reflux time in minutes and percentages and the number of reflux episodes of pH < 4 decreased statistically significantly after both rectal and oral omeprazole administration. Rectal and oral administration of omeprazole resulted in similar serum exposure. CONCLUSIONS: A single rectal omeprazole dose (1 mg/kg) results in consistent increases in intraesophageal and gastric pH in infants with EA- or CDH-related GERD, similar to an oral dose. Considering the challenges with existing oral formulations, rectal omeprazole presents as an innovative, promising alternative for infants with pathological GERD. CLINICAL TRIAL REGISTER: ClinicalTrials.gov Identifier: NCT00226044. TI - Rectal Omeprazole in Infants With Gastroesophageal Reflux Disease: A Randomized Pilot Trial EP - 643 SN - 0378-7966 IS - iss. 5 SP - 635 JF - European Journal of Drug Metabolism and Pharmacokinetics VL - vol. 45 DO - https://doi.org/10.1007/s13318-020-00630-8 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Zanden, T.M. van der AU - Bussel, L.P.M. van AU - Hoop-Sommen, M. de AU - Russel, F.G.M. AU - Johnson, T.N. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225414 AB - As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control coronavirus disease 2019 (COVID-19) experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing World Health Organization (WHO) dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best-evidence to inform pediatric CHQ doses for children infected with COVID-19. A previously developed physiologically-based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID-19 recommended adult dosage regimen of 44 mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in area under the concentration-time curve from zero to 70 hours (AUC(0-70h) ) the optimal CHQ dose was determined in children of different ages compared with adults. Revised doses were re-introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body-weight based dose is given. As such, we propose the following total cumulative doses: 35 mg/kg (CHQ base) for children 0-1 month, 47 mg/kg for 1-6 months, 55 mg/kg for 6 months-12 years, and 44 mg/kg for adolescents and adults, not to exceed 3,300 mg in any patient. Our study supports age-adjusted CHQ dosing in children with COVID-19 in order to avoid suboptimal or toxic doses. The knowledge-driven, model-informed dose selection paradigm can serve as a science-based alternative to recommend pediatric dosing when pediatric clinical trial data is absent. TI - Chloroquine Dosing Recommendations for Pediatric COVID-19 Supported by Modeling and Simulation EP - 252 SN - 0009-9236 IS - iss. 2 SP - 248 JF - Clinical Pharmacology and Therapeutics VL - vol. 108 DO - https://doi.org/10.1002/cpt.1864 ER - TY - JOUR AU - Bestebreurtje, P. AU - Roeleveld, N. AU - Knibbe, C.A.J. AU - Sorge, A.A. van AU - Plötz, F.B. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225422 AB - BACKGROUND AND OBJECTIVE: Omeprazole is a proton pump inhibitor (PPI) that is used in acid suppression therapy in infants. In this study we aimed to develop a pediatric omeprazole suppository, with good physical and chemical stability, suitable for pharmaceutical batch production. METHODS: The composition of the suppository consisted of omeprazole, witepsol H15 and arginine (L) base. To achieve evenly distributed omeprazole suspension suppositories, the temperature, stirring rate, and arginine (L) base amount were varied. A previously validated quantitative high-performance liquid chromatography-ultraviolet method was modified and a long-term stability study was performed for one year. RESULTS: Evenly distributed omeprazole suspension suppositories were obtained by adding 100 mg arginine (L) base and pouring at a temperature of 34.7 °C and a stirring speed of 200 rpm. The long-term stability study showed no signs of discoloration and a stable omeprazole content between 90 and 110% over 1 year if stored in the dark at room temperature. CONCLUSION: We developed a pediatric omeprazole suppository. This formulation may provide a good alternative to manipulated commercial or extemporaneously compounded omeprazole oral formulations for infants. Clinical studies are needed to establish efficacy and safety in this young population. TI - Development and Stability Study of an Omeprazole Suppository for Infants EP - 633 SN - 0378-7966 IS - iss. 5 SP - 627 JF - European Journal of Drug Metabolism and Pharmacokinetics VL - vol. 45 DO - https://doi.org/10.1007/s13318-020-00629-1 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Hattem, A.C. van AU - Pertijs, J.C.L.M. AU - Jongh, C.A. de AU - Verdijk, R.M. AU - Smeets, B. AU - Koenderink, J.B. AU - Russel, F.G.M. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225424 AB - When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9-39 weeks), 17 neonates (GA range 24.6-41.3 weeks, PNA range 0.004-3.5 weeks), 8 children (PNA range 0.1-3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not detected in BBB or BCSFB. In conclusion, human BBB and BCSFB ABC membrane transporters show brain location and transporter-specific maturation. TI - Developmental patterns in human blood-brain barrier and blood-cerebrospinal fluid barrier ABC drug transporter expression EP - 273 SN - 0948-6143 IS - iss. 3 SP - 265 JF - Histochemistry and Cell Biology VL - vol. 154 DO - https://doi.org/10.1007/s00418-020-01884-8 ER - TY - JOUR AU - Bus, L. De AU - Depuydt, P. AU - Steen, J. van der AU - Dhaese, S. AU - Smet, K. De AU - Tabah, A. AU - Akova, M. AU - Cotta, M.O. AU - Pascale, G. De AU - Dimopoulos, G. AU - Fujitani, S. AU - Garnacho-Montero, J. AU - Leone, M. AU - Lipman, J. AU - Ostermann, M. AU - Paiva, J.A. AU - Schouten, J.A. AU - Sjövall, F. AU - Timsit, J.F. AU - Roberts, J.A. AU - Zahar, J.R. AU - Zand, F. AU - Zirpe, K. AU - Waele, J.J. De PY - 2020 UR - https://hdl.handle.net/2066/225430 AB - PURPOSE: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. METHODS: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. RESULTS: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60-1.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14-1.64). CONCLUSION: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely. TI - Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study EP - 1417 SN - 0342-4642 IS - iss. 7 SP - 1404 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-020-06111-5 ER - TY - JOUR AU - Kooistra, E.J. AU - Waalders, N.J.B. AU - Kox, M. AU - Pickkers, P. PY - 2020 UR - https://hdl.handle.net/2066/225435 TI - Effect of anakinra in COVID-19 EP - e524 SN - 2665-9913 IS - iss. 9 SP - e523 JF - The Lancet. Rheumatology VL - vol. 2 DO - https://doi.org/10.1016/S2665-9913(20)30235-6 ER - TY - JOUR AU - Beunders, R. AU - Groenendael, R. van AU - Leijte, G.P. AU - Kox, M. AU - Pickkers, P. PY - 2020 UR - https://hdl.handle.net/2066/225495 AB - BACKGROUND: The assessment of renal function in clinical practice remains challenging. Using creatinine to assess the glomerular filtration rate (GFR) is notoriously inaccurate, and determination of the true GFR, e.g., using inulin or iohexol, is laborious and not feasible in daily practice. Proenkephalin (PENK) is a novel candidate biomarker for kidney function that is filtrated in the glomerulus, has shown to represent steady-state GFR in patients with different severities of renal insufficiency. In this pilot study in non-steady-state critically ill patients, we compared plasma PENK concentrations with creatinine-based GFR assessments and validated both against the "true GFR" measured using a gold standard method: iohexol plasma clearance. METHODS: Twenty-three critically ill patients with septic shock were included. Kidney function was determined using the Modification of Diet in Renal Disease formula (eGFRMDRD), Endogenous Creatinine Clearance (GFRECC), and iohexol plasma clearance (GFRiohexol) during a 6-h window. Plasma PENK concentrations were measured using the penKid immunoassay. RESULTS: The eGFRMDRD and GFRECC correlated with the GFRiohexol (R = 0.82, P < 0.0001 and R = 0.82, P < 0.0001 respectively); however, bias and variability were considerable: the eGFRMDRD overestimated the true GFR with 31 ± 35% (95% limits of agreement: -37% to 100%) and the GFRECC with 37 ± 49% (95% limits of agreement: -59% to 133%). Plasma PENK concentrations showed a very strong inverse correlation with the GFRiohexol (R = 0.90, P < 0.0001) which tended to be better compared with the correlation of eGFRMDRD (P = 0.06) and GFRECC (P = 0.08) with the GFRiohexol. CONCLUSIONS: In this pilot study in non-steady-state critically ill sepsis patients, GFR appears to be more accurately reflected by plasma PENK concentrations compared to conventional creatinine-based methods. Therefore, PENK holds promise as an accurate and feasible biomarker to determine kidney function during non-steady-state conditions in the critically ill. TI - Proenkephalin Compared to Conventional Methods to Assess Kidney Function in Critically Ill Sepsis Patients EP - 314 SN - 1073-2322 IS - iss. 3 SP - 308 JF - Shock VL - vol. 54 DO - https://doi.org/10.1097/SHK.0000000000001510 ER - TY - JOUR AU - Boeschoten, S.A. AU - Boehmer, A.L.M. AU - Merkus, P.J.F.M. AU - Rosmalen, J. van AU - Jongste, J.C. de AU - Fraaij, P.L. AU - Molenkamp, R. AU - Heisterkamp, S.G.J. AU - Woensel, J.B. van AU - Kapitein, B. AU - Haarman, E.G. AU - Asperen, R.M. Wösten-van AU - Kneyber, M.C.J. AU - Lemson, J. AU - Hartman, S.J.F. AU - Waardenburg, D.A. van AU - Bunker-Wiersma, H.E. AU - Brouwer, C.N.M. AU - Ewijk, B.E. van AU - Landstra, A.M. AU - Verwaal, M. AU - Vaessen-Verberne, A.A. AU - Hammer, S. AU - Buysse, C.M. AU - Hoog, M. de PY - 2020 UR - https://hdl.handle.net/2066/225146 AB - RATIONALE: Severe acute asthma (SAA) can be fatal, but is often preventable. We previously observed in a retrospective cohort study, a three-fold increase in SAA paediatric intensive care (PICU) admissions between 2003 and 2013 in the Netherlands, with a significant increase during those years of numbers of children without treatment of inhaled corticosteroids (ICS). OBJECTIVES: To determine whether steroid-naïve children are at higher risk of PICU admission among those hospitalised for SAA. Furthermore, we included the secondary risk factors tobacco smoke exposure, allergic sensitisation, previous admissions and viral infections. METHODS: A prospective, nationwide multicentre study of children with SAA (2-18 years) admitted to all Dutch PICUs and four general wards between 2016 and 2018. Potential risk factors for PICU admission were assessed using logistic regression analyses. MEASUREMENTS AND MAIN RESULTS: 110 PICU and 111 general ward patients were included. The proportion of steroid-naïve children did not differ significantly between PICU and ward patients. PICU children were significantly older and more exposed to tobacco smoke, with symptoms >1 week prior to admission. Viral susceptibility was not a significant risk factor for PICU admission. CONCLUSIONS: Children with SAA admitted to a PICU were comparable to those admitted to a general ward with respect to ICS treatment prior to admission. Preventable risk factors for PICU admission were >7 days of symptoms without adjustment of therapy and exposure to tobacco smoke. Physicians who treat children with asthma must be aware of these risk factors. TI - Risk factors for intensive care admission in children with severe acute asthma in the Netherlands: a prospective multicentre study SN - 2312-0541 IS - iss. 3 JF - ERJ Open Research VL - vol. 6 DO - https://doi.org/10.1183/23120541.00126-2020 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/225146/225146.pdf?sequence=1 ER - TY - JOUR AU - Rood, P.J.T. AU - Boogaard, M. van den PY - 2020 UR - https://hdl.handle.net/2066/218592 TI - Response to the Letter: Can delirium subtypes predict differences in 90-day mortality in the intensive care unit? - The authors reply SN - 0883-9441 SP - 314 JF - Journal of Critical Care VL - vol. 56 DO - https://doi.org/10.1016/j.jcrc.2020.01.002 ER - TY - JOUR AU - Weiss, S.L. AU - Peters, M.J. AU - Alhazzani, W. AU - Agus, M.S.D. AU - Flori, H.R. AU - Inwald, D.P. AU - Nadel, S. AU - Schlapbach, L.J. AU - Tasker, R.C. AU - Argent, A.C. AU - Brierley, J. AU - Carcillo, J. AU - Carrol, E.D. AU - Carroll, C.L. AU - Cheifetz, I.M. AU - Choong, K. AU - Cies, J.J. AU - Cruz, A.T. AU - Luca, D. De AU - Deep, A. AU - Faust, S.N. AU - Oliveira, C.F. De AU - Hall, M.W. AU - Ishimine, P. AU - Javouhey, E. AU - Joosten, K.F. AU - Joshi, P. AU - Karam, O. AU - Kneyber, M.C.J. AU - Lemson, J. AU - MacLaren, G. AU - Mehta, N.M. AU - Moller, M.H. AU - Newth, C.J. AU - Nguyen, T.C. AU - Nishisaki, A. AU - Nunnally, M.E. AU - Parker, M.M. AU - Paul, R.M. AU - Randolph, A.G. AU - Ranjit, S. AU - Romer, L.H. AU - Scott, H.F. AU - Tume, L.N. AU - Verger, J.T. AU - Williams, E.A. AU - Wolf, J. AU - Wong, H.R. AU - Zimmerman, J.J. AU - Kissoon, N. AU - Tissieres, P. PY - 2020 UR - https://hdl.handle.net/2066/218601 AB - OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 52 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 49 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research. TI - Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children EP - e106 SN - 1529-7535 IS - iss. 2 SP - e52 JF - Pediatric Critical Care Medicine VL - vol. 21 DO - https://doi.org/10.1097/PCC.0000000000002198 ER - TY - JOUR AU - Waele, J.J. De AU - Schouten, J.A. AU - Beovic, B. AU - Tabah, A. AU - Leone, M. PY - 2020 UR - https://hdl.handle.net/2066/218605 AB - Antimicrobial de-escalation (ADE) is defined as the discontinuation of one or more components of combination empirical therapy, and/or the change from a broad-spectrum to a narrower spectrum antimicrobial. It is most commonly recommended in the intensive care unit (ICU) patient who is treated with broad-spectrum antibiotics as a strategy to reduce antimicrobial pressure of empirical broad-spectrum therapy and prevent antimicrobial resistance, yet this has not been convincingly demonstrated in a clinical setting. Even if it appears beneficial, ADE may have some unwanted side effects: it has been associated with prolongation of antimicrobial therapy and could inappropriately be used as a justification for unrestricted broadness of empirical therapy. Also, exposing a patient to multiple, sequential antimicrobials could have unwanted effects on the microbiome. For these reasons, ADE has important shortcomings to be promoted as a quality indicator for appropriate antimicrobial use in the ICU. Despite this, ADE clearly has a role in the management of infections in the ICU. The most appropriate use of ADE is in patients with microbiologically confirmed infections requiring longer antimicrobial therapy. ADE should be used as an integral part of an ICU antimicrobial stewardship approach in which it is guided by optimal specimen quality and relevance. Rapid diagnostics may further assist in avoiding unnecessary initiation of broad-spectrum therapy, which in turn will decrease the need for subsequent ADE. TI - Antimicrobial de-escalation as part of antimicrobial stewardship in intensive care: no simple answers to simple questions-a viewpoint of experts EP - 244 SN - 0342-4642 IS - iss. 2 SP - 236 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-019-05871-z ER - TY - JOUR AU - Guidet, B. AU - Lange, D.W. de AU - Boumendil, A. AU - Leaver, S. AU - Watson, X. AU - Boulanger, C. AU - Szczeklik, W. AU - Artigas, A. AU - Morandi, A. AU - Andersen, F. AU - Zafeiridis, T. AU - Jung, C. AU - Moreno, R. AU - Walther, S. AU - Oeyen, S. AU - Schefold, J.C. AU - Cecconi, M. AU - Marsh, B. AU - Joannidis, M. AU - Nalapko, Y. AU - Elhadi, M. AU - Nollet, J.L. AU - Fjolner, J. AU - Flaatten, H. PY - 2020 UR - https://hdl.handle.net/2066/218610 AB - PURPOSE: Premorbid conditions affect prognosis of acutely-ill aged patients. Several lines of evidence suggest geriatric syndromes need to be assessed but little is known on their relative effect on the 30-day survival after ICU admission. The primary aim of this study was to describe the prevalence of frailty, cognition decline and activity of daily life in addition to the presence of comorbidity and polypharmacy and to assess their influence on 30-day survival. METHODS: Prospective cohort study with 242 ICUs from 22 countries. Patients 80 years or above acutely admitted over a six months period to an ICU between May 2018 and May 2019 were included. In addition to common patients' characteristics and disease severity, we collected information on specific geriatric syndromes as potential predictive factors for 30-day survival, frailty (Clinical Frailty scale) with a CFS > 4 defining frail patients, cognitive impairment (informant questionnaire on cognitive decline in the elderly (IQCODE) with IQCODE >/= 3.5 defining cognitive decline, and disability (measured the activity of daily life with the Katz index) with ADL 90% of human genes and may be triggered by developmental signals. As concentrations of several endogenous OATP1B1 substrates change during growth and development, with this exploratory study we investigated age-dependent alternative splicing of SLCO1B1 mRNA in 97 postmortem livers (fetus-adolescents). Twenty-seven splice variants were detected; 10 were confirmed by additional bioinformatic analyses and verified by quantitative polymerase chain reaction, and selected for detailed analysis based on relative abundance, association with age, and overlap with an adjacent gene. Two splice variants code for reference OATP1B1 protein, and eight code for truncated proteins. The expression of eight isoforms was associated with age. We conclude that alternative splicing of SLCO1B1 occurs frequently in children; although the functional consequences remain unknown, the data raise the possibility of a regulatory role for alternative splicing in mediating developmental changes in drug disposition. TI - Alternative Splicing of the SLCO1B1 Gene: An Exploratory Analysis of Isoform Diversity in Pediatric Liver EP - 519 SN - 1752-8054 IS - iss. 3 SP - 509 JF - Cts-Clinical and Translational Science VL - vol. 13 DO - https://doi.org/10.1111/cts.12733 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220573/220573.pdf?sequence=1 ER - TY - JOUR AU - Wagener, F.A.D.T.G. AU - Pickkers, P. AU - Peterson, S.J. AU - Immenschuh, S. AU - Abraham, N.G. PY - 2020 UR - https://hdl.handle.net/2066/220555 AB - SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill and show lung injury and hemolysis. Heme is a prosthetic moiety crucial for the function of a wide variety of heme-proteins, including hemoglobin and cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement activation, thrombosis, and fibrosis. Heme can be degraded by the anti-inflammatory enzyme heme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, and carbon monoxide. We therefore postulate that free heme contributes to many of the inflammatory phenomena witnessed in critically ill COVID-19 patients, whilst induction of HO-1 or harnessing heme may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative and anti-inflammatory properties. Until a vaccine against SARS-CoV-2 becomes available, we need to explore novel strategies to attenuate the pro-inflammatory, pro-thrombotic, and pro-fibrotic consequences of SARS-CoV-2 leading to morbidity and mortality. The heme-HO system represents an interesting target for novel "proof of concept" studies in the context of COVID-19. TI - Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections SN - 2076-3921 IS - iss. 6 JF - Antioxidants VL - vol. 9 DO - https://doi.org/10.3390/antiox9060540 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220555/220555.pdf?sequence=1 ER - TY - JOUR AU - Schrier, L. AU - Hadjipanayis, A. AU - Stiris, T. AU - Ross-Russell, R.I. AU - Valiulis, A. AU - Turner, M.A. AU - Zhao, W. AU - Cock, P. De AU - Wildt, S.N. de AU - Allegaert, K. AU - Anker, J. van den PY - 2020 UR - https://hdl.handle.net/2066/220512 AB - Health-care professionals who prescribe medicines have the professional duty to choose medicines that are in the best interest of their individual patient, irrespective if that patient is an adult or a child. However, the availability of medicines with an appropriate label for pediatric use is lagging behind those for adults, and even available pediatric drugs are sometimes not suitable to administer to children. Consequently, health-care professionals often have no other option than to prescribe off-label medicines to children. An important reason for use of off-label medicines is to improve access to (innovative) treatments or to address medical needs and preferences of patients, especially when no other options are available. However, off-label use of medicines is in general not supported by the same level of evidence as medicines licensed for pediatric use. This may result in increased uncertainty on efficacy as well as the risk for toxicity and other side effects. In addition, liability may also be of concern, counterbalanced by professional guidelines.Conclusion: The purpose of this joint EAP/ESDPPP policy statement is to offer guidance for HCPs on when and how to prescribe off-label medicines to children and to provide recommendations for future European policy. TI - Off-label use of medicines in neonates, infants, children, and adolescents: a joint policy statement by the European Academy of Paediatrics and the European society for Developmental Perinatal and Pediatric Pharmacology EP - 847 SN - 0340-6199 IS - iss. 5 SP - 839 JF - European Journal of Pediatrics VL - vol. 179 DO - https://doi.org/10.1007/s00431-019-03556-9 ER - TY - JOUR AU - Schijvens, A.M. AU - Wildt, S.N. de AU - Schreuder, M.F. PY - 2020 UR - https://hdl.handle.net/2066/220522 AB - In children, the main causes of chronic kidney disease (CKD) are congenital diseases and glomerular disorders. CKD is associated with multiple physiological changes and may therefore influence various pharmacokinetic (PK) parameters. A well-known consequence of CKD on pharmacokinetics is a reduction in renal clearance due to a decrease in the glomerular filtration rate. The impact of renal impairment on pharmacokinetics is, however, not limited to a decreased elimination of drugs excreted by the kidney. In fact, renal dysfunction may lead to modifications in absorption, distribution, transport, and metabolism as well. Currently, insufficient evidence is available to guide dosing decisions on many commonly used drugs. Moreover, the impact of maturation on drug disposition and action should be taken into account when selecting and dosing drugs in the pediatric population. Clinicians should take PK changes into consideration when selecting and dosing drugs in pediatric CKD patients in order to avoid toxicity and increase efficiency of drugs in this population. The aim of this review is to summarize known PK changes in relation to CKD and to extrapolate available knowledge to the pediatric CKD population to provide guidance for clinical practice. TI - Pharmacokinetics in children with chronic kidney disease EP - 1172 SN - 0931-041X IS - iss. 7 SP - 1153 JF - Pediatric Nephrology VL - vol. 35 DO - https://doi.org/10.1007/s00467-019-04304-9 ER - TY - JOUR AU - Winter, B.C. de AU - Hoog, M. de AU - Vet, N.J. AU - Dunk-Craaijo, J.H. AU - Koch, B.C. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/220653 TI - Finger-Prick Blood Sampling for Therapeutic Drug Monitoring: Be Aware of Skin Contamination by Nebulized Drugs EP - 513 SN - 0163-4356 IS - iss. 3 SP - 512 JF - Therapeutic Drug Monitoring VL - vol. 42 DO - https://doi.org/10.1097/FTD.0000000000000746 ER - TY - JOUR AU - Winter, D.A. AU - Joosse, M.E. AU - Wildt, S.N. de AU - Taminiau, J. AU - Ridder, L. AU - Escher, J.C. PY - 2020 UR - https://hdl.handle.net/2066/220523 AB - OBJECTIVES: Infliximab (IFX), a monoclonal antibody directed against tumor necrosis factor alpha is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic characteristics and immunogenicity of IFX in children. The objective was to provide a systematic overview of current literature on pharmacokinetic and immunogenicity of IFX in children with IBD, to assess the validity of current adult to pediatric dosing extrapolation. METHODS: A literature search identified publications up to October 2018. Eligibility criteria were study population consisting of children and/or adolescents with IBD, report of IFX trough levels and/or antibodies-to IFX, full text article or abstract, article in English, and original data. RESULTS: Initial electronic search yielded 2360 potentially relevant articles, with 1831 remaining after removal of duplicates. An additional search yielded another 202 potentially relevant articles. Of the 2033 retrieved articles, 2000 articles were excluded based on title, abstract, or eligibility criteria. Clearance of IFX was increased in young children and children with extensive disease, leading to lower trough levels after extrapolated dosing of 5 mg/kg, antibodies-to IFX emergence, and subsequent reduced efficacy. CONCLUSIONS: Adult to pediatric weight-based dosing extrapolation is often inadequate. We provide several considerations for optimal dosing of IFX in children and adolescents with IBD. TI - Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease: A Systematic Review and Revised Dosing Considerations EP - 776 SN - 0277-2116 IS - iss. 6 SP - 763 JF - Journal of Pediatric Gastroenterology and Nutrition VL - vol. 70 DO - https://doi.org/10.1097/MPG.0000000000002631 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Koenderink, J.B. AU - Johnson, T.N. AU - Wildt, S.N. de AU - Russel, F.G.M. PY - 2020 UR - https://hdl.handle.net/2066/220524 AB - Developmental changes in children can affect the disposition and clinical effects of a drug, indicating that scaling an adult dose simply down per linear weight can potentially lead to overdosing, especially in very young children. Physiologically-based pharmacokinetic (PBPK) models are compartmental, mathematical models that can be used to predict plasma drug concentrations in pediatric populations and acquire insight into the influence of age-dependent physiological differences on drug disposition. Pediatric PBPK models have generated attention in the last decade, because physiological parameters for model building are increasingly available and regulatory guidelines demand pediatric studies during drug development. Due to efforts from academia, PBPK model developers, pharmaceutical companies and regulatory authorities, examples are now available where clinical studies in children have been replaced or informed by PBPK models. However, the number of pediatric PBPK models and their predictive performance still lags behind that of adult models. In this review we discuss the general pediatric PBPK model principles, indicate the challenges that can arise when developing models, and highlight new applications, to give an overview of the current status and future perspective of pediatric PBPK modeling. TI - Physiologically-based pharmacokinetic models for children: Starting to reach maturation? SN - 0163-7258 JF - Pharmacology and Therapeutics. Part A: Chemotherapy, Toxicology and Metabolic Inhibitors VL - vol. 211 DO - https://doi.org/10.1016/j.pharmthera.2020.107541 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220524/220524.pdf?sequence=1 ER - TY - JOUR AU - Suessenbach, F.K. AU - Makowski, N. AU - Feickert, M. AU - Gangnus, T. AU - Wildt, S.N. de AU - Tins, J. AU - Burckhardt, B.B. PY - 2020 UR - https://hdl.handle.net/2066/220641 AB - While the role of plasma renin activity (PRA) in heart failure has been widely studied in adults, comprehensive data on pediatric heart failure remain lacking. This drawback is increasingly being addressed by academic research. Nevertheless, such pediatric investigations are commonly conducted only once due to ethical constraints. Therefore, the quality of bioanalytical data must be ensured to acquire meaningful insights into maturing humoral parameters. However, appropriate post-validation assessment of bioanalytical runs is currently underrepresented by regulatory guidance. Thus, for applications in an academic environment, an easy-to-handle six-step bioanalytical quality control system was designed based on regulatory guidelines (e.g. U.S. Food and Drug Administration) combined with international recommendations (e.g. Clinical and Laboratory Standards Institute) and current scientific discussion. Its applicability to an enzyme-linked immunosorbent assay for determination of PRA was investigated within three pediatric trials of the EU-funded "Labeling of Enalapril in Neonates up to Adolescents" project. This quality control system identified 15 % bioanalytical runs as non-compliant to the predefined specifications and ensured the reliable quantification of 940 pharmacodynamic samples. The inter-run assessment of quality controls was able to demonstrate the comparability of the study results. Furthermore, 86 % of incurred sample reanalysis pairs complied with regulatory requirements (>67 %), thus underlining the long-term reproducibility of the utilized ligand-binding assay. Successful participation in interlaboratory testing confirmed the accuracy of the applied method throughout the entire study period. Further investigations showed no notable differences between the five applied lots of the PRA assay. The applicability of this quality control system was proven in an academic environment and ensured reliable results for PRA over the entire 24-month study period. TI - A quality control system for ligand-binding assay of plasma renin activity: Proof-of-concept within a pharmacodynamic study SN - 0731-7085 JF - Journal of Pharmaceutical and Biomedical Analysis VL - vol. 181 DO - https://doi.org/10.1016/j.jpba.2019.113090 ER - TY - JOUR AU - Thilly, Nathalie AU - Pereira, O. AU - Schouten, J.A. AU - Hulscher, M.E.J.L. AU - Pulcini, C. PY - 2020 UR - https://hdl.handle.net/2066/221560 TI - Proxy indicators to estimate appropriateness of antibiotic prescriptions by general practitioners: a proof-of-concept cross-sectional study based on reimbursement data, north-eastern France 2017 EP - 16 SN - 1025-496X IS - iss. 27 SP - 7 JF - Euro Surveillance VL - vol. 25 DO - https://doi.org/10.2807/1560-7917.ES.2020.25.27.1900468 ER - TY - JOUR AU - Koeken, V.A.C.M. AU - Pasch, Eva S. van der AU - Leijte, G.P. AU - Mourits, V.P. AU - Bree, L.C.J. de AU - Moorlag, S.J.C.F.M. AU - Kox, M. AU - Laarhoven, A. van AU - Netea, M.G. AU - Crevel, R. van PY - 2020 UR - https://hdl.handle.net/2066/221589 TI - The effect of BCG vaccination on alveolar macrophages obtained from induced sputum from healthy volunteers SN - 1043-4666 JF - Cytokine VL - vol. 133 DO - https://doi.org/10.1016/j.cyto.2020.155135 ER - TY - JOUR AU - Ali, M AU - Tins, J. AU - Wildt, S.N. de AU - Burckhardt, B.B. PY - 2020 UR - https://hdl.handle.net/2066/220782 AB - The LENA collaborator list below was not included in the original article.s. TI - Fit-for-Purpose Quality Control System in Continuous Bioanalysis during Long-Term Pediatric Studies SN - 1550-7416 IS - iss. 2 JF - Aaps Journal VL - vol. 22 DO - https://doi.org/10.1208/s12248-020-0415-x ER - TY - JOUR AU - Milton, A. AU - Schandl, A. AU - Soliman, I. AU - Joelsson-Alm, E. AU - Boogaard, M. van den AU - Wallin, E. AU - Brorsson, C. AU - Östberg, U. AU - Latocha, K. AU - Savilampi, J. AU - Paskins, S. AU - Bottai, M. AU - Sackey, P. PY - 2020 UR - https://hdl.handle.net/2066/220789 AB - BACKGROUND: Methods to identify patients at risk for incomplete physical recovery after intensive care unit (ICU) stay are lacking. Our aim was to develop a method for prediction of new-onset physical disability at ICU discharge. METHODS: Multinational prospective cohort study in 10 general ICUs in Sweden, Denmark, and the Netherlands. Adult patients with an ICU stay ≥12 hours were eligible for inclusion. Sixteen candidate predictors were analyzed with logistic regression for associations with the primary outcome; new-onset physical disability 3 months post-ICU, defined as a ≥10 score reduction in the Barthel Index (BI) compared to baseline. RESULTS: Of the 572 included patients, follow-up data are available on 78% of patients alive at follow-up. The incidence of new-onset physical disability was 19%. Univariable and multivariable modeling rendered one sole predictor for the outcome: physical status at ICU discharge, assessed with the five first items of the Chelsea critical care physical assessment tool (CPAx) (odds ratio 0.87, 95% confidence interval (CI) 0.81-0.93), a higher score indicating a lower risk, with an area under the receiver operating characteristics curve of 0.68 (95% CI 0.61-0.76). Negative predictive value for a low-risk group (CPAx score >18) was 0.88, and positive predictive value for a high-risk group (CPAx score ≤18) was 0.32. CONCLUSION: The ICU discharge assessment described in this study had a moderate AUC but may be useful to rule out patients unlikely to need physical interventions post-ICU. For high-risk patients, research to determine post-ICU risk factors for an incomplete rehabilitation is mandated. TI - ICU discharge screening for prediction of new-onset physical disability-A multinational cohort study EP - 797 SN - 0001-5172 IS - iss. 6 SP - 789 JF - Acta Anaesthesiologica Scandinavica VL - vol. 64 DO - https://doi.org/10.1111/aas.13563 ER - TY - JOUR AU - Heesakkers, H. AU - Devlin, J.W. AU - Slooter, A.J. AU - Boogaard, M. van den PY - 2020 UR - https://hdl.handle.net/2066/220796 AB - PURPOSE: To determine the correlation and discriminative value of the E-PRE-DELIRIC and PRE-DELIRIC scores with delirium exposure to evaluate the prognostic value of both models. METHODS: A secondary analysis of a randomized clinical trial enrolling 1506 delirium-free, critically ill adults with an anticipated ICU stay of ≥2 days. Days spent with delirium (≥1 positive CAM-ICU) or coma (≥1 RASS ≤-4) in the 28-days after ICU admission were calculated. Patients were categorized into four groups: no delirium, short-exposure (1 delirium day), moderate-exposure (2-5 delirium days), and long- exposure (≥6 delirium days) to determine the correlation and discriminative value of the E-PRE-DELIRIC and the PRE-DELIRIC with days spent with delirium. RESULTS: The correlation between the overall E-PRE-DELIRIC and PRE-DELIRIC scores and days spent with delirium were: R = 0.08 (P = .005) and R = 0.26 (P < .001), respectively. The correlation between both prediction scores and days spent with coma or delirium were R = 0.21 (P < .0001) and R = 0.46 (P < .0001), respectively. The highest Area Under the Receiver Operating Characteristic for both E-PRE-DELIRIC [0.57 (95% CI:0.51-0.62)] and PRE-DELIRIC [0.58 (95% CI:0.53-0.62)] was found in the long delirium exposure group. CONCLUSION: The E-PRE-DELIRIC and PRE-DELIRIC model each poorly correlate and discriminate with days spent with delirium in the 28 days after ICU admission. TI - Association between delirium prediction scores and days spent with delirium EP - 9 SN - 0883-9441 SP - 6 JF - Journal of Critical Care VL - vol. 58 DO - https://doi.org/10.1016/j.jcrc.2020.03.008 ER - TY - JOUR AU - Makowski, N. AU - Ciplea, A.M. AU - Ali, M AU - Burdman, I. AU - Wildt, S.N. de AU - Bartel, A. AU - Burckhardt, B.B. PY - 2020 UR - https://hdl.handle.net/2066/220451 AB - Aim: Clinical research in pediatrics is progressively initiated by academia. As the reliability of pharmacodynamic measures is closely linked to the quality of bioanalytical data, bioanalytical quality assurance is crucial. However, clear guidance on comprehensive bioanalytical quality monitoring in the academic environment is lacking. Methods & results: By applying regulatory guidelines, international recommendations and scientific discussions, a five-step quality control system for monitoring the bioanalysis of aldosterone by immunoassay was developed. It comprised performance qualification, calibration curve evaluation, analysis of the intra- and inter-run performance via quality control samples, incurred sample reanalysis and external quality assessment by interlaboratory testing. A total of 55 out of 70 runs were qualified for the quantification of aldosterone in the study sample enabling the evaluation of 954 pediatric samples and demonstrating reliability over the 29-month bioanalysis period. Conclusion: The bioanalytical quality control system successfully monitored the aldosterone assay performance and proved its applicability in the academic environment. TI - A comprehensive quality control system suitable for academic research: application in a pediatric study EP - 333 SN - 1757-6180 IS - iss. 5 SP - 319 JF - Bioanalysis VL - vol. 12 DO - https://doi.org/10.4155/bio-2019-0242 ER - TY - JOUR AU - Hartman, S.J.F. AU - Orriens, L.B. AU - Zwaag, S.M. AU - Poel, T. AU - Hoop, M. de AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225119 AB - BACKGROUND: The Dutch Pediatric Formulary (DPF) increasingly bases its guidelines on model-based dosing simulations from pharmacokinetic studies. This resulted in nationwide dose changes for vancomycin, gentamicin, and tobramycin in 2015. OBJECTIVE: We aimed to evaluate target attainment of these altered, model-based doses in critically ill neonates and children. METHODS: This was a retrospective cohort study in neonatal intensive care unit (NICU) and pediatric ICU (PICU) patients receiving vancomycin, gentamicin, or tobramycin between January 2015 and March 2017 in two university hospitals. The first therapeutic drug monitoring concentration for each patient was collected, as was clinical and dosing information. Vancomycin and tobramycin target trough concentrations were 10-15 and ≤ 1 mg/L, respectively. Target gentamicin trough and peak concentrations were < 1 and 8-12 mg/L, respectively. RESULTS: In total, 482 patients were included (vancomycin [PICU] n = 62, [NICU] n = 102; gentamicin [NICU] n = 97; tobramycin [NICU] n = 221). Overall, median trough concentrations were within the target range for all cohorts but showed large interindividual variability, causing nontarget attainment. Trough concentrations were outside the target range in 66.1%, 60.8%, 14.7%, and 23.1% of patients in these four cohorts, respectively. Gentamicin peak concentrations were outside the range in 69% of NICU patients (term neonates 87.1%, preterm infants 57.1%). Higher creatinine concentrations were associated with higher vancomycin and tobramycin trough concentrations. CONCLUSION: This study illustrates the need to validate model-based dosing advice in the real-world setting as both sub- and supratherapeutic concentrations of vancomycin, gentamicin, and tobramycin were very prevalent. Our data underline the necessity for further individualization by addressing the high interindividual variability to improve target attainment. TI - External Validation of Model-Based Dosing Guidelines for Vancomycin, Gentamicin, and Tobramycin in Critically Ill Neonates and Children: A Pragmatic Two-Center Study EP - 444 SN - 1174-5878 IS - iss. 4 SP - 433 JF - Paediatric Drugs VL - vol. 22 DO - https://doi.org/10.1007/s40272-020-00400-8 ER - TY - JOUR AU - Tabah, A. AU - Bassetti, M. AU - Kollef, M.H. AU - Zahar, J.R. AU - Paiva, J.A. AU - Timsit, J.F. AU - Roberts, J.A. AU - Schouten, J.A. AU - Giamarellou, H. AU - Rello, J. AU - Waele, J. De AU - Shorr, A.F. AU - Leone, M. AU - Poulakou, G. AU - Depuydt, P. AU - Garnacho-Montero, J. PY - 2020 UR - https://hdl.handle.net/2066/218616 AB - BACKGROUND: Antimicrobial de-escalation (ADE) is a strategy of antimicrobial stewardship, aiming at preventing the emergence of antimicrobial resistance (AMR) by decreasing the exposure to broad-spectrum antimicrobials. There is no high-quality research on ADE and its effects on AMR. Its definition varies and there is little evidence-based guidance for clinicians to use ADE in the intensive care unit (ICU). METHODS: A task force of 16 international experts was formed in November 2016 to provide with guidelines for clinical practice to develop questions targeted at defining ADE, its effects on the ICU population and to provide clinical guidance. Groups of 2 experts were assigned 1-2 questions each within their field of expertise to provide draft statements and rationale. A Delphi method, with 3 rounds and an agreement threshold of 70% was required to reach consensus. RESULTS: We present a comprehensive document with 13 statements, reviewing the evidence on the definition of ADE, its effects in the ICU population and providing guidance for clinicians in subsets of clinical scenarios where ADE may be considered. CONCLUSION: ADE remains a topic of controversy due to the complexity of clinical scenarios where it may be applied and the absence of evidence to the effects it may have on antimicrobial resistance. TI - Antimicrobial de-escalation in critically ill patients: a position statement from a task force of the European Society of Intensive Care Medicine (ESICM) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Critically Ill Patients Study Group (ESGCIP) EP - 265 SN - 0342-4642 IS - iss. 2 SP - 245 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-019-05866-w ER - TY - JOUR AU - Suarez, J.I. AU - Martin, R.H. AU - Bauza, C. AU - Georgiadis, A. AU - Rao, C.P.V. AU - Calvillo, E. AU - Hemphill, J.C.. AU - Sung, G. AU - Oddo, M. AU - Abdo, W.F. AU - Taccone, F.S. AU - LeRoux, P.D. PY - 2020 UR - https://hdl.handle.net/2066/218623 AB - INTRODUCTION: Neurocritical care focuses on the care of critically ill patients with an acute neurologic disorder and has grown significantly in the past few years. However, there is a lack of data that describe the scope of practice of neurointensivists and epidemiological data on the types of patients and treatments used in neurocritical care units worldwide. To address these issues, we designed a multicenter, international, point-prevalence, cross-sectional, prospective, observational, non-interventional study in the setting of neurocritical care (PRINCE Study). METHODS: In this manuscript, we analyzed data from the initial phase of the study that included registration, hospital, and intensive care unit (ICU) organizations. We present here descriptive statistics to summarize data from the registration case report form. We performed the Kruskal-Wallis test followed by the Dunn procedure to test for differences in practices among world regions. RESULTS: We analyzed information submitted by 257 participating sites from 47 countries. The majority of those sites, 119 (46.3%), were in North America, 44 (17.2%) in Europe, 34 (13.3%) in Asia, 9 (3.5%) in the Middle East, 34 (13.3%) in Latin America, and 14 (5.5%) in Oceania. Most ICUs are from academic institutions (73.4%) located in large urban centers (44% > 1 million inhabitants). We found significant differences in hospital and ICU organization, resource allocation, and use of patient management protocols. The highest nursing/patient ratio was in Oceania (100% 1:1). Dedicated Advanced Practiced Providers are mostly present in North America (73.7%) and are uncommon in Oceania (7.7%) and the Middle East (0%). The presence of dedicated respiratory therapist is common in North America (85%), Middle East (85%), and Latin America (84%) but less common in Europe (26%) and Oceania (7.7%). The presence of dedicated pharmacist is highest in North America (89%) and Oceania (85%) and least common in Latin America (38%). The majority of respondents reported having a dedicated neuro-ICU (67% overall; highest in North America: 82%; and lowest in Oceania: 14%). CONCLUSION: The PRINCE Study results suggest that there is significant variability in the delivery of neurocritical care. The study also shows it is feasible to undertake international collaborations to gather global data about the practice of neurocritical care. TI - Worldwide Organization of Neurocritical Care: Results from the PRINCE Study Part 1 EP - 179 SN - 1541-6933 IS - iss. 1 SP - 172 JF - Neurocritical Care VL - vol. 32 DO - https://doi.org/10.1007/s12028-019-00750-3 ER - TY - JOUR AU - Boogaard, M. van den AU - Tilburgs, B. PY - 2020 UR - https://hdl.handle.net/2066/218524 TI - Can we accurately predict ICU delirium? SN - 0964-3397 SP - 102809 JF - Intensive and Critical Care Nursing VL - vol. 57 DO - https://doi.org/10.1016/j.iccn.2020.102809 ER - TY - JOUR AU - Rao, C.P.V. AU - Suarez, J.I. AU - Martin, R.H. AU - Bauza, C. AU - Georgiadis, A. AU - Calvillo, E. AU - Hemphill, J.C., 3rd AU - Sung, G. AU - Oddo, M. AU - Taccone, F.S. AU - LeRoux, P.D. AU - Abdo, W.F. AU - Mora, J.E. AU - Bui, T. PY - 2020 UR - https://hdl.handle.net/2066/218566 AB - BACKGROUND: Neurocritical care is devoted to the care of critically ill patients with acute neurological or neurosurgical emergencies. There is limited information regarding epidemiological data, disease characteristics, variability of clinical care, and in-hospital mortality of neurocritically ill patients worldwide. We addressed these issues in the Point PRevalence In Neurocritical CarE (PRINCE) study, a prospective, cross-sectional, observational study. METHODS: We recruited patients from various intensive care units (ICUs) admitted on a pre-specified date, and the investigators recorded specific clinical care activities they performed on the subjects during their first 7 days of admission or discharge (whichever came first) from their ICUs and at hospital discharge. In this manuscript, we analyzed the final data set of the study that included patient admission characteristics, disease type and severity, ICU resources, ICU and hospital length of stay, and in-hospital mortality. We present descriptive statistics to summarize data from the case report form. We tested differences between geographically grouped data using parametric and nonparametric testing as appropriate. We used a multivariable logistic regression model to evaluate factors associated with in-hospital mortality. RESULTS: We analyzed data from 1545 patients admitted to 147 participating sites from 31 countries of which most were from North America (69%, N = 1063). Globally, there was variability in patient characteristics, admission diagnosis, ICU treatment team and resource allocation, and in-hospital mortality. Seventy-three percent of the participating centers were academic, and the most common admitting diagnosis was subarachnoid hemorrhage (13%). The majority of patients were male (59%), a half of whom had at least two comorbidities, and median Glasgow Coma Scale (GCS) of 13. Factors associated with in-hospital mortality included age (OR 1.03; 95% CI, 1.02 to 1.04); lower GCS (OR 1.20; 95% CI, 1.14 to 1.16 for every point reduction in GCS); pupillary reactivity (OR 1.8; 95% CI, 1.09 to 3.23 for bilateral unreactive pupils); admission source (emergency room versus direct admission [OR 2.2; 95% CI, 1.3 to 3.75]; admission from a general ward versus direct admission [OR 5.85; 95% CI, 2.75 to 12.45; and admission from another ICU versus direct admission [OR 3.34; 95% CI, 1.27 to 8.8]); and the absence of a dedicated neurocritical care unit (NCCU) (OR 1.7; 95% CI, 1.04 to 2.47). CONCLUSION: PRINCE is the first study to evaluate care patterns of neurocritical patients worldwide. The data suggest that there is a wide variability in clinical care resources and patient characteristics. Neurological severity of illness and the absence of a dedicated NCCU are independent predictors of in-patient mortality. TI - Global Survey of Outcomes of Neurocritical Care Patients: Analysis of the PRINCE Study Part 2 EP - 103 SN - 1541-6933 IS - iss. 1 SP - 88 JF - Neurocritical Care VL - vol. 32 DO - https://doi.org/10.1007/s12028-019-00835-z ER - TY - JOUR AU - Geense, W.W. AU - Zegers, M. AU - Boogaard, M. van den AU - Hannink, G.J. PY - 2020 UR - https://hdl.handle.net/2066/218576 TI - Nonpharmacologic Interventions to Prevent or Mitigate Adverse Long-Term Outcomes Among ICU Survivors: Is the ICU Diary Really Important? Reply EP - e266 SN - 0090-3493 IS - iss. 3 SP - e265 JF - Critical Care Medicine VL - vol. 48 DO - https://doi.org/10.1097/CCM.0000000000004195 ER - TY - JOUR AU - Lemasle, Lea AU - Blet, A. AU - Geven, C.B.C.A.G. AU - Cherifa, Menyssa AU - Deniau, Benjamin AU - Hollinger, Alexa AU - Mebazaa, Alexandre AU - Gayat, Etienne PY - 2020 UR - https://hdl.handle.net/2066/214081 TI - Bioactive Adrenomedullin, Organ Support Therapies, and Survival in the Critically Ill: Results from the French and European Outcome Registry in ICU Study EP - 55 SN - 0090-3493 IS - iss. 1 SP - 49 JF - Critical Care Medicine VL - vol. 48 DO - https://doi.org/10.1097/CCM.0000000000004044 ER - TY - JOUR AU - Huis, A. AU - Schouten, J.A. AU - Lescure, D.L.A. AU - Krein, Sarah AU - Ratz, David AU - Saint, Sanjay AU - Hulscher, M. AU - Todd Greene, M. PY - 2020 UR - https://hdl.handle.net/2066/216660 TI - Infection prevention practices in the Netherlands: results from a National Survey SN - 2047-2994 IS - iss. 1 JF - Antimicrobial Resistance and Infection Control VL - vol. 9 DO - https://doi.org/10.1186/s13756-019-0667-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/216660/216660.pdf?sequence=1 ER - TY - JOUR AU - Matic, M. AU - Hoogd, Sjoerd de AU - Wildt, S.N. de AU - Tibboel, D. AU - Knibbe, Catherijne A.J. AU - Schaik, R.H. van PY - 2020 UR - https://hdl.handle.net/2066/216675 TI - OPRM1 and COMT polymorphisms: implications on postoperative acute, chronic and experimental pain after cardiac surgery EP - 193 SN - 1462-2416 IS - iss. 3 SP - 181 JF - Pharmacogenomics VL - vol. 21 DO - https://doi.org/10.2217/pgs-2019-0141 ER - TY - JOUR AU - Blet, A. AU - Roquetaillade, C. de AU - Hartmann, O. AU - Struck, J. AU - Pickkers, P. AU - Mebazaa, A. AU - Chousterman, B.G. PY - 2020 UR - https://hdl.handle.net/2066/218583 TI - Added value of serial bio-adrenomedullin measurement in addition to lactate for the prognosis of septic patients admitted to ICU SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-2794-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218583/218583.pdf?sequence=1 ER - TY - JOUR AU - Verweyen, Emely AU - Holzinger, Dirk AU - Weinhage, Toni AU - Hinze, Claas AU - Wittkowski, Helmut AU - Pickkers, P. AU - Foell, Dirk AU - Kessel, Christoph PY - 2020 UR - https://hdl.handle.net/2066/217416 TI - Synergistic Signaling of TLR and IFN alpha/beta Facilitates Escape of IL-18 Expression from Endotoxin Tolerance EP - 539 SN - 1073-449X IS - iss. 5 SP - 526 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 201 DO - https://doi.org/10.1164/rccm.201903-0659OC ER - TY - JOUR AU - Vliegen, Gwendolyn AU - Kehoe, Kaat AU - Bracke, An AU - Hert, Emilie De AU - Verkerk, Robert AU - Fransen, Erik AU - Peters, E. AU - Pickkers, P. AU - Jorens, Philippe G. AU - Meester, Ingrid De PY - 2020 UR - https://hdl.handle.net/2066/219831 TI - Dysregulated activities of proline-specific enzymes in septic shock patients (sepsis-2) SN - 1932-6203 IS - iss. 4 JF - PLoS One VL - vol. 15 DO - https://doi.org/10.1371/journal.pone.0231555 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/219831/219831.pdf?sequence=1 ER - TY - JOUR AU - Leijte, G.P. AU - Rimmele, Thomas AU - Kox, M. AU - Bruse, N. AU - Monard, Celine AU - Gossez, Morgane AU - Pickkers, P. AU - Venet, F. PY - 2020 UR - https://hdl.handle.net/2066/217647 TI - Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-2830-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/217647/217647.pdf?sequence=1 ER - TY - JOUR AU - Keijzer, H.M. AU - Hoedemaekers, C.W.E. PY - 2020 UR - https://hdl.handle.net/2066/218613 TI - Timing is everything: Combining EEG and MRI to predict neurological recovery after cardiac arrest EP - 242 SN - 0300-9572 SP - 240 JF - Resuscitation VL - vol. 149 DO - https://doi.org/10.1016/j.resuscitation.2020.02.006 ER - TY - JOUR AU - Vet, N.J. AU - Winter, Brenda C.M. de AU - Koninckx, Muriel AU - Boeschoten, Shelley A. AU - Boehmer, Annemie L.M. AU - Verhallen, Jacintha T. AU - Wildt, S.N. de AU - Koch, Birgit C.P. AU - Hoog, M. de PY - 2020 UR - https://hdl.handle.net/2066/217393 TI - Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus EP - 264 SN - 0312-5963 IS - iss. 2 SP - 257 JF - Clinical Pharmacokinetics VL - vol. 59 DO - https://doi.org/10.1007/s40262-019-00811-y ER - TY - JOUR AU - Vincent, J.L. AU - Ferguson, A. AU - Pickkers, P. AU - Jakob, S.M. AU - Jaschinski, Ulrich AU - Almekhlafi, Ghaleb A. AU - Bauer, P.R. AU - Sakr, Y. PY - 2020 UR - https://hdl.handle.net/2066/218996 TI - The clinical relevance of oliguria in the critically ill patient: analysis of a large observational database SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-02858-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218996/218996.pdf?sequence=1 ER - TY - JOUR AU - Madotto, F. AU - Rezoagli, E. AU - Pham, T. AU - Schmidt, M. AU - McNicholas, B. AU - Protti, A. AU - Panwar, R. AU - Bellani, G. AU - Fan, E. AU - Haren, F. van AU - Schouten, J.A. AU - Brochard, L. AU - Laffey, J.G. PY - 2020 UR - https://hdl.handle.net/2066/218568 AB - BACKGROUND: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. METHODS: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 >/= 0.60 during hyperoxemia). RESULTS: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). CONCLUSIONS: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. TRIAL REGISTRATION: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073. TI - Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: insights from the LUNG SAFE study SN - 1466-609X IS - iss. 1 SP - 125 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-2826-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218568/218568.pdf?sequence=1 ER - TY - JOUR AU - Hanskarnp-Sebregts, Mirelle AU - Robben, P.B. AU - Wollersheim, H.C. AU - Zegers, M. PY - 2020 UR - https://hdl.handle.net/2066/217433 TI - Transparency about internal audit results to reduce the supervisory burden: A qualitative study on the preconditions of sharing audit results EP - 223 SN - 0168-8510 IS - iss. 2 SP - 216 JF - Health Policy VL - vol. 124 DO - https://doi.org/10.1016/j.healthpol.2019.11.013 ER - TY - JOUR AU - Vermeulen, E. AU - Karsenberg, K. AU - Lee, J.H. van der AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/218569 TI - Involve Children and Parents in Clinical Studies EP - 13 SN - 1752-8054 IS - iss. 1 SP - 11 JF - Cts-Clinical and Translational Science VL - vol. 13 DO - https://doi.org/10.1111/cts.12696 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218569/218569.pdf?sequence=1 ER - TY - JOUR AU - Zwaag, J. AU - Horst, R. ter AU - Blazenovic, Ivana AU - Stoessel, Daniel AU - Ratter, Jacqueline AU - Worseck, Josephine M. AU - Stienstra, R. AU - Netea, M.G. AU - Pickkers, P. AU - Kox, M. PY - 2020 UR - https://hdl.handle.net/2066/219254 TI - Involvement of Lactate and Pyruvate in the Anti-Inflammatory Effects Exerted by Voluntary Activation of the Sympathetic Nervous System SN - 2218-1989 IS - iss. 4 JF - Metabolites VL - vol. 10 DO - https://doi.org/10.3390/metabo10040148 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/219254/219254.pdf?sequence=1 ER - TY - JOUR AU - Hartman, S.J.F. AU - Bruggemann, R.J.M. AU - Orriens, L. AU - Dia, N. AU - Schreuder, M.F. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/218581 AB - BACKGROUND: Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. METHODS: Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. RESULTS: 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. CONCLUSION: The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible. TI - Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature. EP - 205 SN - 0312-5963 IS - iss. 2 SP - 173 JF - Clinical Pharmacokinetics VL - vol. 59 N1 - 1 februari 2020 DO - https://doi.org/10.1007/s40262-019-00813-w ER - TY - JOUR AU - Zanden, T.M. van der AU - Hoog, M. de AU - Windster, J.D. AU - Rosmalen, J. van AU - Sijs, I.H. van der AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/217631 TI - Does a Dose Calculator as an Add-On to a Web-Based Paediatric Formulary Reduce Calculation Errors in Paediatric Dosing? A Non-Randomized Controlled Study EP - 239 SN - 1174-5878 IS - iss. 2 SP - 229 JF - Paediatric Drugs VL - vol. 22 DO - https://doi.org/10.1007/s40272-020-00386-3 ER - TY - JOUR AU - Hassani, M. AU - Staveren, S. van AU - Grinsven, E. van AU - Bartels, M. AU - Tesselaar, K. AU - Leijte, G.P. AU - Kox, M. AU - Pickkers, P. AU - Vrisekoop, N. AU - Koenderman, L. PY - 2020 UR - https://hdl.handle.net/2066/218545 TI - Characterization of the phenotype of human eosinophils and their progenitors in the bone marrow of healthy individuals EP - e56 SN - 0390-6078 IS - iss. 2 SP - e52 JF - Haematologica VL - vol. 105 DO - https://doi.org/10.3324/haematol.2019.219048 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218545/218545.pdf?sequence=1 ER - TY - JOUR AU - Schuurmans, Jaap AU - Vos, Stephanie AU - Vissers, P. AU - Tilburgs, B. AU - Engels, Y. PY - 2020 UR - https://hdl.handle.net/2066/227451 TI - Supporting GPs around euthanasia requests from people with dementia: a qualitative analysis of Dutch nominal group meetings EP - E842 SN - 0960-1643 IS - iss. 700 SP - E833 JF - British Journal of General Practice VL - vol. 70 DO - https://doi.org/10.3399/bjgp20X713093 ER - TY - JOUR AU - Workum, J.D. AU - Janssen, S.H.V. AU - Touw, H.R.W. PY - 2020 UR - https://hdl.handle.net/2066/218551 AB - Neuromuscular blocking agents are regularly used in the intensive care unit (ICU) to facilitate mechanical ventilation in patients with acute respiratory distress syndrome and patient-ventilator dyssynchronies. However, prolonged neuromuscular blockade is associated with adverse effects like ICU-acquired weakness. Residual neuromuscular blockade is, however, not routinely monitored in the intensive care unit, and as such, this phenomenon might be unrecognized and underreported. We report a case in which an unusual prolonged effect of neuromuscular blockade was seen after cessation of the drug, which illustrates the complexity of neuromuscular blockade in the ICU. We advocate for the use of train-of-four measurements in the ICU, recommend to choose cisatracurium over rocuronium in critically ill patients due to their pharmacokinetics when continuous neuromuscular blockade is considered, and propose a subsequent strategy once the choice has been made to start neuromuscular blockade. TI - Considerations in Neuromuscular Blockade in the ICU: A Case Report and Review of the Literature SN - 2090-6420 SP - 8780979 JF - Case reports in critical care VL - vol. 2020 DO - https://doi.org/10.1155/2020/8780979 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218551/218551.pdf?sequence=1 ER - TY - JOUR AU - Admiraal, M.M. AU - Horn, J. AU - Hofmeijer, J. AU - Hoedemaekers, C.W.E. AU - Kaam, C.R. van AU - Keijzer, H.M. AU - Putten, Michel J.A.M. van AU - Schultz, M.J. AU - Rootselaar, A.F. van PY - 2020 UR - https://hdl.handle.net/2066/225433 AB - OBJECTIVE: To determine the additional value of EEG reactivity (EEG-R) testing to EEG background pattern for prediction of good outcome in adult patients after cardiac arrest (CA). METHODS: In this post hoc analysis of a prospective cohort study, EEG-R was tested twice a day, using a strict protocol. Good outcome was defined as a Cerebral Performance Category score of 1-2 within 6 months. The additional value of EEG-R per EEG background pattern was evaluated using the diagnostic odds ratio (DOR). Prognostic value (sensitivity and specificity) of EEG-R was investigated in relation to time after CA, sedative medication, different stimuli, and repeated testing. RESULTS: Between 12 and 24 hours after CA, data of 108 patients were available. Patients with a continuous (n = 64) or discontinuous (n = 19) normal voltage background pattern with reactivity were 3 and 8 times more likely to have a good outcome than without reactivity (continuous: DOR, 3.4; 95% confidence interval [CI], 0.97-12.0; p = 0.06; discontinuous: DOR, 8.0; 95% CI, 1.0-63.97; p = 0.0499). EEG-R was not observed in other background patterns within 24 hours after CA. In 119 patients with a normal voltage EEG background pattern, continuous or discontinuous, any time after CA, prognostic value was highest in sedated patients (sensitivity 81.3%, specificity 59.5%), irrespective of time after CA. EEG-R induced by handclapping and sternal rubbing, especially when combined, had highest prognostic value. Repeated EEG-R testing increased prognostic value. CONCLUSION: EEG-R has additional value for prediction of good outcome in patients with discontinuous normal voltage EEG background pattern and possibly with continuous normal voltage. The best stimuli were clapping and sternal rubbing. TI - EEG reactivity testing for prediction of good outcome in patients after cardiac arrest EP - e661 SN - 0028-3878 IS - iss. 6 SP - e653 JF - Neurology VL - vol. 95 DO - https://doi.org/10.1212/WNL.0000000000009991 ER - TY - PAT AU - Netea, M.G. AU - Deuren, M. van AU - Meer, H. van der AU - Veerdonk, F.L. van de AU - Mast, Q. de AU - Bruggemann, R.J.M. AU - Hoeven, J.G. van der PY - 2020 UR - https://hdl.handle.net/2066/228267 PB - [S.l. : s.n.] TI - Treatment of ARDS and other parameters related to Covid-19 ER - TY - THES AU - Rood, P.J.T. PY - 2020 UR - https://hdl.handle.net/2066/226627 PB - [S.l. : s.n.] TI - Non pharmacological prevention and treatment of delirium in the intensive care unit N1 - Radboud University, 1 december 2020 N1 - Promotores : Pickkers, P., Vermeulen, H. Co-promotor : Boogaard, M.H.W.A. van den ER - TY - JOUR AU - Made, C.I. van der AU - Simons, A. AU - Schuurs-Hoeijmakers, J.H.M. AU - Heuvel, Guus van den AU - Mantere, T. AU - Kersten, S. AU - Deuren, R.C. van AU - Steehouwer, M. AU - Reijmersdal, S.V. van AU - Jaeger, M. AU - Astuti, G.D. AU - Corominas-Galbany, J. AU - Hoeven, J.G. van der AU - Hagmolen of ten Have, W. AU - Mast, Q. de AU - Bleeker-Rovers, C.P. AU - Joosten, L.A.B. AU - Yntema, H.G. AU - Gilissen, C.F. AU - Nelen, M.R. AU - Meer, J.W.M. van der AU - Brunner, H.G. AU - Netea, M.G. AU - Veerdonk, F.L. van de AU - Hoischen, A. PY - 2020 UR - https://hdl.handle.net/2066/222168 TI - Presence of Genetic Variants Among Young Men With Severe COVID-19 EP - 673 SN - 0098-7484 IS - iss. 7 SP - 663 JF - Jama : Journal of the American Medical Association VL - vol. 324 DO - https://doi.org/10.1001/jama.2020.13719 ER - TY - JOUR AU - Kooistra, E.J. AU - Waalders, N.J.B. AU - Grondman, I. AU - Janssen, N.A.F. AU - Nooijer, A.H. de AU - Netea, M.G. AU - Veerdonk, F.L. van de AU - Hoeven, J.G. van der AU - Kox, M. AU - Pickkers, P. PY - 2020 UR - https://hdl.handle.net/2066/228401 TI - Anakinra treatment in critically ill COVID-19 patients: a prospective cohort study SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-03364-w L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/228401/228401.pdf?sequence=1 ER - TY - JOUR AU - Bersselaar, L.R. van den AU - Brule, J.M.D. van den AU - Hoeven, J.G. van der PY - 2020 UR - https://hdl.handle.net/2066/224862 AB - Acetaminophen and flucloxacillin both interfere with the γ-glutamyl cycle. Long-lasting concomitant use of flucloxacillin and acetaminophen can lead to 5-oxoproline accumulation and severe high anion gap metabolic acidosis. Females and patients with sepsis, impaired kidney and/or liver function, malnutrition, advanced age, congenital 5-oxoprolinase deficiency and supratherapeutic acetaminophen and flucloxacillin dosage are associated with increased risk. Therefore, a critical attitude towards the prescription of acetaminophen concomitant with flucloxacillin in these patients is needed. We present the case of a 79-year-old woman with severe 5-oxoprolinaemia after long-lasting treatment with flucloxacillin and acetaminophen, explaining the toxicological mechanism and risk factors, and we make recommendations for acetaminophen use in patients with long-lasting flucloxacillin treatment. LEARNING POINTS: Although rare, long-lasting treatment with flucloxacillin concomitant with acetaminophen can lead to severe high anion gap metabolic acidosis.When prescribing long-lasting flucloxacillin therapy in combination with acetaminophen, regular blood gas analysis is needed to evaluate pH and the anion gap.In cases of 5-oxoproline-induced high anion gap metabolic acidosis in patients with long-lasting acetaminophen and flucloxacillin therapy, acetaminophen prescription should be stopped immediately. Replacing flucloxacillin with another antibiotic agent should be considered. TI - Acetaminophen Use Concomitant with Long-Lasting Flucloxacillin Therapy: A Dangerous Combination SN - 2284-2594 IS - iss. 7 JF - European Journal of Case Reports in Internal Medicine VL - vol. 7 DO - https://doi.org/10.12890/2020_001569 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/224862/224862.pdf?sequence=1 ER - TY - JOUR AU - Lassche, G. AU - Frenzel, T. AU - Mignot, M.H. AU - Jonker, M.A. AU - Hoeven, H. van der AU - Herpen, C.M.L. van AU - Scheffer, G.J. PY - 2020 UR - https://hdl.handle.net/2066/218323 AB - BACKGROUND: Extracorporeally induced whole-body hyperthermia (eWBH) might be a beneficial treatment in cancer patients. Objectives of this pig study were to assess thermal distribution, (patho-)physiological effects, and safety of eWBH with a new WBH device. METHODS: Fourteen healthy adult pigs were anesthetized, mechanically ventilated, and cannulated; 12 were included in the analysis. Blood was heated in 11 pigs (one pig served as control) using a WBH device (Vither Hyperthermia B.V.) containing two separate fluidic circuits and a heat exchanger. Temperature was monitored on nine different sites, including the brain. Core temperature (average of 4 deep probes) was elevated to 42 degrees C for 2 hr. RESULTS: Elevation of core body temperature to 42 degrees C took on average (+/- standard deviation) 38 +/- 8 min. Initially observed temperature spikes diminished after lowering maximal blood temperature to 45 degrees C. Hereafter, brain temperature spikes never exceeded 42.5 degrees C, mean brain temperature was at highest 41.9 degrees C during maintenance. WBH resulted in increased heart rates and decreased mean arterial pressures. The vast amounts of fluids required to counter hypotension tended to be smaller after corticosteroid administration. Hemodialysis was started in three animals (potassium increase prevention in two and hyperkalemia treatment in one). Severe rhabdomyolysis was observed in all pigs (including the control). All animals survived the procedure until planned euthanasia 1, 6, or 24 hr post procedure. CONCLUSION: Fast induction of eWBH with homogenous thermal distribution is feasible in pigs using the Vither WBH device. Severe hemodynamic disturbances, rhabdomyolysis, and hyperkalemia were observed. TI - Thermal distribution, physiological effects and toxicities of extracorporeally induced whole-body hyperthermia in a pig model SN - 2051-817X IS - iss. 4 JF - Physiological Reports VL - vol. 8 DO - https://doi.org/10.14814/phy2.14366 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218323/218323.pdf?sequence=1 ER - TY - JOUR AU - Duprey, Matthew S. AU - Boogaard, M.H.W.A. van den AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Briesacher, Becky A. AU - Saczynski, Jane S. AU - Griffith, John L. AU - Devlin, John W. PY - 2020 UR - https://hdl.handle.net/2066/218801 TI - Association between incident delirium and 28-and 90-day mortality in critically ill adults: a secondary analysis SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-02879-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218801/218801.pdf?sequence=1 ER - TY - JOUR AU - Kox, M. AU - Frenzel, T. AU - Schouten, J.A. AU - Veerdonk, F.L. van de AU - Hemelaar, P. AU - Beunders, R. AU - Hoeven, J.G. van der AU - Gerretsen, J.J.F. AU - Netea, M.G. AU - Joosten, L.A.B. AU - Janssen, N.A.F. AU - Grondman, I. AU - Nooijer, A.H. de AU - Mast, Q. de AU - Jaeger, M. AU - Kouijzer, I.J.E. AU - Lemmers, H.L.M. AU - Crevel, R. van AU - Maat, J.S. van de AU - Moorlag, S.J.C.F.M. AU - Taks, E.J.M. AU - Debisarun, A. AU - Wertheim, H.F.L. AU - Hopman, J. AU - Rahamat-Langendoen, J.C. AU - Bleeker-Rovers, C.P. AU - Fasse, E. AU - Rijssen, E. van AU - Cranenbroek, B. van AU - Smeets, R.L. AU - Joosten, I. AU - Koenen, H.J. AU - Pickkers, P. PY - 2020 UR - https://hdl.handle.net/2066/220045 TI - COVID-19 patients exhibit less pronounced immune suppression compared with bacterial septic shock patients SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-02896-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220045/220045.pdf?sequence=1 ER - TY - JOUR AU - Jonkman, A.H. AU - Roesthuis, L.H. AU - Boer, E.C. de AU - Vries, H.J.C. de AU - Girbes, Armand R.J. AU - Hoeven, J.G. van der AU - Tuinman, P.R. AU - Heunks, L.M.A. PY - 2020 UR - https://hdl.handle.net/2066/220795 TI - Inadequate Assessment of Patient-Ventilator Interaction Due to Suboptimal Diaphragm Electrical Activity Signal Filtering EP - 144 SN - 1073-449X IS - iss. 1 SP - 141 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 202 DO - https://doi.org/10.1164/rccm.201912-2306LE ER - TY - JOUR AU - Sonnemans, L.J.P. AU - Bayat, A.R. AU - Bruinen, Aniek R.C. AU - Wely, M.H. van AU - Brouwer, M.A. AU - Bosboom, D.G. AU - Hoeven, J.G. van der AU - Prokop, M. AU - Klein, W.M. PY - 2020 UR - https://hdl.handle.net/2066/219245 TI - Comparing thoracoabdominal injuries of manual versus load-distributing band cardiopulmonary resuscitation EP - 201 SN - 0969-9546 IS - iss. 3 SP - 197 JF - European Journal of Emergency Medicine VL - vol. 27 DO - https://doi.org/10.1097/MEJ.0000000000000642 ER - TY - JOUR AU - Roesthuis, L.H. AU - Berg, M.J.W. van den AU - Hoeven, H. van der PY - 2020 UR - https://hdl.handle.net/2066/220518 TI - Advanced respiratory monitoring in COVID-19 patients: use less PEEP! SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-02953-z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220518/220518.pdf?sequence=1 ER - TY - JOUR AU - Loon, L.M. van AU - Stolk, R.F. AU - Hoeven, J.G. van der AU - Veltink, P.H. AU - Pickkers, P. AU - Lemson, J. AU - Kox, M. PY - 2020 UR - https://hdl.handle.net/2066/218558 AB - AIM: Comparing the effects of different vasopressors in septic shock patients is hampered by high heterogeneity and the fact that current guidelines dictate the use of norepinephrine. Herein, we studied the effects of three vasopressor agents, norepinephrine, phenylephrine, and vasopressin, on the macro- and microcirculation during experimental human endotoxemia, a standardized, controlled model of systemic inflammation in humans in vivo. METHODS: We performed a randomized controlled study in which 40 healthy male volunteers were assigned to a 5-h infusion of either 0.05 mug/kg/min norepinephrine (n = 10), 0.5 mug/kg/min phenylephrine (n = 10), 0.04 IU/min vasopressin (n = 10), or saline (n = 10), starting 1 h before intravenous administration of 2 ng/kg lipopolysaccharide (LPS). The macrocirculation was monitored using arterial catheter-derived parameters with additional blood pressure waveform contour analysis (PCA) until 4.5 h following LPS administration. Sublingual microcirculatory density and flow were assessed using a handheld video microscope until 6 h post-LPS. RESULTS: LPS administration affected all macrocirculatory and microcirculatory parameters. The LPS-induced decrease in blood pressure and systemic vascular resistance (SVR) was refractory to low-dose norepinephrine and phenylephrine, and to a lesser extent, to vasopressin. Only vasopressin exerted effects on PCA parameters compared with placebo, by mitigating the LPS-induced decrease in diastolic blood pressure by stabilizing SVR and cardiac output. The endotoxemia-induced decreased indices of microvascular flow and density were not influenced by vasopressor therapy. CONCLUSIONS: In a highly controlled model of systemic inflammation in humans in vivo, a 5-h infusion of various vasopressors revealed distinctive effects on macrohemodynamic variables without affecting the sublingual microcirculation. TI - Effect of Vasopressors on the Macro- and Microcirculation During Systemic Inflammation in Humans In Vivo EP - 174 SN - 1073-2322 IS - iss. 2 SP - 171 JF - Shock VL - vol. 53 DO - https://doi.org/10.1097/SHK.0000000000001357 ER - TY - JOUR AU - Oppersma, Eline AU - Doorduin, J. AU - Roesthuis, L.H. AU - Hoeven, J.G. van der AU - Veltink, Peter H. AU - Heunks, L.M.A. PY - 2020 UR - https://hdl.handle.net/2066/222162 TI - Patient-Ventilator Interaction During Noninvasive Ventilation in Subjects With Exacerbation of COPD: Effect of Support Level and Ventilator Mode EP - 1322 SN - 0020-1324 IS - iss. 9 SP - 1315 JF - Respiratory Care VL - vol. 65 DO - https://doi.org/10.4187/respcare.07159 ER - TY - JOUR AU - IJland, M.M. AU - Lemson, J. AU - Hoeven, H. van der AU - Heunks, L.M.A. PY - 2020 UR - https://hdl.handle.net/2066/223867 TI - The impact of critical illness on the expiratory muscles and the diaphragm assessed by ultrasound in mechanical ventilated children SN - 2110-5820 IS - iss. 1 JF - Annals of Intensive Care VL - vol. 10 DO - https://doi.org/10.1186/s13613-020-00731-2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/223867/223867.pdf?sequence=1 ER - TY - JOUR AU - Gommans, D.H.F. AU - Nas, J. AU - Pinto-Sietsma, S.J. AU - Koop, Y. AU - Konst, R.E. AU - Mensink, F.B. AU - Aarts, G.W.A. AU - Konijnenberg, L.S.F. AU - Cortenbach, K.R. AU - Verhaert, D.V.M. AU - Thannhauser, J. AU - Mol, J.H.Q. AU - Rooijakkers, M.J.P. AU - Vos, J.L. AU - Rumund, A. van AU - Vart, P. AU - Hassing, R.J. AU - Cornel, J.H. AU - Jager, C.P.C. de AU - Heuvel, M. van den AU - Hoeven, J.G. van der AU - Royen, N. van AU - Kimmenade, R.R.J. van PY - 2020 UR - https://hdl.handle.net/2066/224636 TI - Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease EP - 68 SN - 0002-8703 SP - 60 JF - American Heart Journal VL - vol. 226 DO - https://doi.org/10.1016/j.ahj.2020.05.010 ER - TY - JOUR AU - Pickkers, P. AU - Hoeven, H. van der AU - Citerio, G. PY - 2020 UR - https://hdl.handle.net/2066/225389 TI - COVID-19: 10 things I wished I'd known some months ago EP - 1452 SN - 0342-4642 IS - iss. 7 SP - 1449 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-020-06098-z ER - TY - JOUR AU - Stolk, R.F. AU - Pasch, E. van der AU - Naumann, F.V. AU - Schouwstra, J. AU - Bressers, S. AU - Herwaarden, A.E. van AU - Gerretsen, J.J.F. AU - Schambergen, R. AU - Ruth, M.M. AU - Hoeven, J.G. van der AU - Leeuwen, H. van AU - Pickkers, P. AU - Kox, M. PY - 2020 UR - https://hdl.handle.net/2066/225483 AB - Rationale: Sepsis is characterized by a dysregulated immune response to infection. Norepinephrine, the cornerstone vasopressor used in septic shock, may contribute to immune dysregulation and impact host defense.Objectives: To investigate effects of norepinephrine and the alternative vasopressor vasopressin on the immune response and host defense.Methods: Leukocytes from six to nine donors were stimulated in the presence or absence of norepinephrine and vasopressin. A total of 190 C57BL/6J mice received a continuous infusion of norepinephrine or vasopressin via microosmotic pumps and were challenged with LPS or underwent cecal ligation and puncture. Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin, or saline and intravenously challenged with LPS. The relationship between the norepinephrine infusion rate and the use of β-blockers and plasma cytokines was assessed in 195 patients with septic shock.Measurements and Main Results: Norepinephrine attenuated the production of proinflammatory mediators and reactive oxygen species and augmented antiinflammatory IL-10 production both in vitro and in LPS-challenged mice. Norepinephrine infusion during cecal ligation and puncture resulted in increased bacterial dissemination to the spleen, liver, and blood. In LPS-challenged volunteers, norepinephrine enhanced plasma IL-10 concentrations and attenuated the release of the proinflammatory cytokine IFN-γ-induced protein 10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more antiinflammatory cytokine balance, whereas β-blocker use was associated with a more proinflammatory cytokine balance.Conclusions: Norepinephrine dysregulates the immune response in mice and humans and compromises host defense. Therefore, it may significantly contribute to sepsis-induced immunoparalysis, whereas vasopressin does not have untoward immunologic effects. TI - Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis EP - 842 SN - 1073-449X IS - iss. 6 SP - 830 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 202 DO - https://doi.org/10.1164/rccm.202002-0339OC ER - TY - JOUR AU - Veerdonk, F.L. van de AU - Kouijzer, I.J.E. AU - Nooijer, A.H. de AU - Hoeven, H. van der AU - Maas, C. AU - Netea, M.G. AU - Brüggemann, R.J.M. PY - 2020 UR - https://hdl.handle.net/2066/225335 AB - This case-control study examines the association between receipt of the bradykinin 2 (B2) receptor antagonist icatibant and improved oxygenation in patients with coronavirus disease 2019 (COVID-19). TI - Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19 SN - 2574-3805 IS - iss. 8 JF - JAMA Network Open VL - vol. 3 DO - https://doi.org/10.1001/jamanetworkopen.2020.17708 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/225335/225335.pdf?sequence=1 ER - TY - JOUR AU - Kok, N. AU - Hoedemaekers, A. AU - Hoeven, H. van der AU - Zegers, M. AU - Gurp, J.L.P. van PY - 2020 UR - https://hdl.handle.net/2066/225342 TI - Recognizing and supporting morally injured ICU professionals during the COVID-19 pandemic EP - 1654 SN - 0342-4642 IS - iss. 8 SP - 1653 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-020-06121-3 ER - TY - JOUR AU - Nepogodiev, D. AU - Omar, Omar AU - Glasbey, J.C. AU - Li, E. AU - Simoes, J.F.F. AU - Abbott, T. AU - Pickkers, P. AU - Venn, M.L. AU - Bhangu, A. PY - 2020 UR - https://hdl.handle.net/2066/228869 TI - Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans EP - 1449 SN - 0007-1323 IS - iss. 11 SP - 1440 JF - British Journal of Surgery VL - vol. 107 DO - https://doi.org/10.1002/bjs.11746 ER - TY - JOUR AU - Spoormans, E.M. AU - Lemkes, Jorrit S. AU - Janssens, Gladys N. AU - Hoeven, Nina W. van der AU - Jewbali, Lucia S.D. AU - Dubois, Eric A. AU - Blans, Michiel J. AU - Camaro, C. AU - Hoeven, H. van der AU - Appelman, Y. AU - Royen, N. van PY - 2020 UR - https://hdl.handle.net/2066/228692 TI - Data on sex differences in one-year outcomes of out-of-hospital cardiac arrest patients without ST-segment elevation SN - 2352-3409 JF - Data in Brief VL - vol. 33 DO - https://doi.org/10.1016/j.dib.2020.106521 ER - TY - JOUR AU - Singh, Yogen AU - Villaescusa, Javier Urbano AU - Cruz, Eduardo M. da AU - Tibby, S.M. AU - Bottari, Gabriella AU - Saxena, Rohit AU - Boode, W.P. de AU - Lemson, J. PY - 2020 UR - https://hdl.handle.net/2066/228726 TI - Recommendations for hemodynamic monitoring for critically ill children-expert consensus statement issued by the cardiovascular dynamics section of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-03326-2 ER - TY - JOUR AU - Ostermann, M. AU - Zarbock, A. AU - Goldstein, Stuart AU - Kashani, K. AU - Macedo, E. AU - Murugan, Raghavan AU - Pickkers, P. AU - Kellum, J.A. AU - Ronco, C. PY - 2020 UR - https://hdl.handle.net/2066/228727 TI - Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference A Consensus Statement SN - 2574-3805 IS - iss. 10 JF - JAMA Network Open VL - vol. 3 DO - https://doi.org/10.1001/jamanetworkopen.2020.19209 ER - TY - JOUR AU - Mokart, D. AU - Darmon, M. AU - Schellongowski, P. AU - Pickkers, P. AU - Soares, M. AU - Rello, J. AU - Bisbal, Magali AU - Azoulay, E. PY - 2020 UR - https://hdl.handle.net/2066/226266 TI - Acute respiratory failure in immunocompromised patients: outcome and clinical features according to neutropenia status SN - 2110-5820 IS - iss. 1 JF - Annals of Intensive Care VL - vol. 10 DO - https://doi.org/10.1186/s13613-020-00764-7 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/226266/226266.pdf?sequence=1 ER - TY - JOUR AU - Leeuw, T.G. de AU - Zanden, Tjitske van Der AU - Ravera, Simona AU - Felisi, M. AU - Bonifazi, D. AU - Tibboel, D. AU - Kaguelidou, F. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/228523 TI - Diagnosis and Treatment of Chronic Neuropathic and Mixed Pain in Children and Adolescents: Results of a Survey Study amongst Practitioners SN - 2227-9067 IS - iss. 11 JF - Children VL - vol. 7 DO - https://doi.org/10.3390/children7110208 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/228523/228523.pdf?sequence=1 ER - TY - JOUR AU - Binda, F. AU - Tebano, G. AU - Kallen, M.C. AU - Oever, J. ten AU - Hulscher, M.E. AU - Schouten, J.A. AU - Pulcini, C. PY - 2020 UR - https://hdl.handle.net/2066/221547 TI - Nationwide survey of hospital antibiotic stewardship programs in France EP - 422 SN - 0399-077X IS - iss. 5 SP - 414 JF - Médecine et Maladies Infectieuses VL - vol. 50 DO - https://doi.org/10.1016/j.medmal.2019.09.007 ER - TY - JOUR AU - Messika, Jonathan AU - Darmon, M. AU - Mal, Herve AU - Pickkers, P. AU - Soares, M. AU - Canet, Emmanuel AU - Zafrani, Lara AU - Azoulay, E. PY - 2020 UR - https://hdl.handle.net/2066/228532 TI - Etiologies and Outcomes of Acute Respiratory Failure in Solid Organ Transplant Recipients: Insight Into the EFRAIM Multicenter Cohort EP - 2987 SN - 0041-1345 IS - iss. 10 SP - 2980 JF - Transplantation Proceedings VL - vol. 52 DO - https://doi.org/10.1016/j.transproceed.2020.02.170 ER - TY - JOUR AU - Wolbrink, D.R.J. AU - Kolwijck, E. AU - Oever, J. ten AU - Horvath, K.D. AU - Bouwense, S.A.W. AU - Schouten, J.A. PY - 2020 UR - https://hdl.handle.net/2066/218573 AB - BACKGROUND: Severe acute pancreatitis is marked by organ failure and (peri)pancreatic necrosis with local complications such as infected necrosis. Infection of these necrotic collections together with organ failure remain the major causes of admission to an intensive care unit (ICU) in acute pancreatitis. Appropriate treatment of infected necrosis is essential to reduce morbidity and mortality. Overall knowledge of the treatment options within a multidisciplinary team-with special attention to the appropriate use of antimicrobial therapy and invasive treatment techniques for source control-is essential in the treatment of this complex disease. OBJECTIVES: To address the current state of microbiological diagnosis, antimicrobial treatment, and source control for infected pancreatic necrosis in the ICU. SOURCES: A literature search was performed using the Medline and Cochrane libraries for articles subsequent to 2003 using the keywords: infected necrosis, pancreatitis, intensive care medicine, treatment, diagnosis and antibiotic(s). CONTENT: This narrative review provides an overview of key elements of diagnosis and treatment of infected pancreatic necrosis in the ICU. IMPLICATIONS: In pancreatic necrosis it is essential to continuously (re)evaluate the indication for antimicrobial treatment and invasive source control. Invasive diagnostics (e.g. through fine-needle aspiration, FNA), preferably prior to the start of broad-spectrum antimicrobial therapy, is advocated. Antimicrobial stewardship principles apply: paying attention to altered pharmacokinetics in the critically ill, de-escalation of broad-spectrum therapy once cultures become available, and early withdrawal of antibiotics once source control has been established. This is important to prevent the development of antimicrobial resistance, especially in a group of patients who may require repeated courses of antibiotics during the prolonged course of their illness. TI - Management of infected pancreatic necrosis in the intensive care unit: a narrative review EP - 25 SN - 1198-743X IS - iss. 1 SP - 18 JF - Clinical Microbiology and Infection VL - vol. 26 DO - https://doi.org/10.1016/j.cmi.2019.06.017 ER - TY - JOUR AU - Berrevoets, M.A.H. AU - Oever, J. ten AU - Oerlemans, A.J.M. AU - Kullberg, B.J. AU - Hulscher, M.E.J.L. AU - Schouten, J.A. PY - 2020 UR - https://hdl.handle.net/2066/218588 AB - BACKGROUND: Our aim in this study was to develop quality indicators (QIs) for outpatient parenteral antimicrobial therapy (OPAT) care that can be used as metrics for quality assessment and improvement. METHODS: A RAND-modified Delphi procedure was used to develop a set of QIs. Recommendations on appropriate OPAT care in adults were retrieved from the literature using a systematic review and translated into potential QIs. These QIs were appraised and prioritized by a multidisciplinary panel of international OPAT experts in 2 questionnaire rounds combined with a meeting between rounds. RESULTS: The procedure resulted in 33 OPAT-specific recommendations. The following QIs that describe recommended OPAT care were prioritized by the expert panel: the presence of a structured OPAT program, a formal OPAT care team, a policy on patient selection criteria, and a treatment and monitoring plan; assessment for OPAT should be performed by the OPAT team; patients and family should be informed about OPAT; there should be a mechanism in place for urgent discussion and review of emergent clinical problems, and a system in place for rapid communication; laboratory results should be delivered to physicians within 24 hours; and the OPAT team should document clinical response to antimicrobial management, document adverse events, and monitor QIs for OPAT care and make these data available. CONCLUSIONS: We systematically developed a set of 33 QIs for optimal OPAT care, of which 12 were prioritized by the expert panel. These QIs can be used to assess and improve the quality of care provided by OPAT teams. TI - Quality Indicators for Appropriate Outpatient Parenteral Antimicrobial Therapy in Adults: A Systematic Review and RAND-modified Delphi Procedure EP - 1082 SN - 1058-4838 IS - iss. 6 SP - 1075 JF - Clinical Infectious Diseases VL - vol. 70 DO - https://doi.org/10.1093/cid/ciz362 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/218588/218588.pdf?sequence=1 ER - TY - JOUR AU - Vreman, J.T.M. AU - Loon, Lex M. van AU - Biggelaar, Wilma van den AU - Hoeven, J.G. van der AU - Lemson, J. AU - Boogaard, M. van den PY - 2020 UR - https://hdl.handle.net/2066/228518 TI - Contribution of alarm noise to average sound pressure levels in the ICU: An observational cross-sectional study SN - 0964-3397 JF - Intensive and Critical Care Nursing VL - vol. 61 DO - https://doi.org/10.1016/j.iccn.2020.102901 ER - TY - JOUR AU - Khorashadi, Mina AU - Beunders, R. AU - Pickkers, P. AU - Legrand, M. PY - 2020 UR - https://hdl.handle.net/2066/228565 TI - Proenkephalin: A New Biomarker for Glomerular Filtration Rate and Acute Kidney Injury EP - 661 SN - 1660-8151 IS - iss. 12 SP - 655 JF - Nephron VL - vol. 144 DO - https://doi.org/10.1159/000509352 ER - TY - JOUR AU - Loon, Lex M. van AU - Hoeven, H. van der AU - Veltink, Peter H. AU - Lemson, J. PY - 2020 UR - https://hdl.handle.net/2066/227282 TI - The inspiration hold maneuver is a reliable method to assess mean systemic filling pressure but its clinical value remains unclear SN - 2305-5839 IS - iss. 21 JF - Annals of Translational Medicine VL - vol. 8 DO - https://doi.org/10.21037/atm-20-3540 ER - TY - JOUR AU - Beunders, R. AU - Schuetz, Maren J. AU - Groenendael, R. van AU - Leijte, G.P. AU - Kox, M. AU - Eijk, L.T. AU - Pickkers, P. PY - 2020 UR - https://hdl.handle.net/2066/227336 TI - Endotoxemia-Induced Release of Pro-inflammatory Mediators Are Associated With Increased Glomerular Filtration Rate in Humans in vivo SN - 2296-858X JF - Frontiers in Medicine VL - vol. 7 DO - https://doi.org/10.3389/fmed.2020.559671 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/227336/227336.pdf?sequence=1 ER - TY - JOUR AU - Wilson, Christopher M. AU - Li, Qian AU - Gaedigk, R. AU - Bi, C. AU - Wildt, S.N. de AU - Steven Leeder, J. AU - Fridley, B. PY - 2020 UR - https://hdl.handle.net/2066/226265 TI - Ontogeny Related Changes in the Pediatric Liver Metabolome SN - 2296-2360 JF - Frontiers in Pediatrics VL - vol. 8 DO - https://doi.org/10.3389/fped.2020.00549 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/226265/226265.pdf?sequence=1 ER - TY - JOUR AU - Hartman, S.J.F. AU - Zwiers, Alexandra J.M. AU - Water, Nadies E.C. van de AU - Rosmalen, Joost van AU - Struck, Joachim AU - Schulte, Janin AU - Pickkers, P. AU - Beunders, R. AU - Schreuder, M.F. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/226132 TI - Proenkephalin as a new biomarker for pediatric acute kidney injury - reference values and performance in children under one year of age EP - 1919 SN - 1434-6621 IS - iss. 11 SP - 1911 JF - Clinical Chemistry and Laboratory Medicine VL - vol. 58 DO - https://doi.org/10.1515/cclm-2020-0381 ER - TY - JOUR AU - Lopez, Rene AU - Rello, J. AU - Taccone, F.S. AU - Salem, Omar Ben Hadj AU - Bauer, P.R. AU - Seguin, Amelie AU - Pickkers, P. AU - Azoulay, E. AU - Darmon, M. PY - 2020 UR - https://hdl.handle.net/2066/228398 TI - Aminoglycosides in Immunocompromised Critically Ill Patients With Bacterial Pneumonia and Septic Shock: A Post-Hoc Analysis of a Prospective Multicenter Multinational Cohort EP - 737 SN - 1073-2322 IS - iss. 6 SP - 731 JF - Shock VL - vol. 54 DO - https://doi.org/10.1097/SHK.0000000000001553 ER - TY - JOUR AU - Jonkman, Annemijn H. AU - Frenzel, T. AU - McCaughey, Euan J. AU - McLachlan, Angus J. AU - Boswell-Ruys, Claire L. AU - Collins, David W. AU - Kox, M. AU - Pickkers, P. AU - Roesthuis, L.H. AU - Schouten, J.A. AU - Butler, Jane E. AU - Heunks, L.M.A. PY - 2020 UR - https://hdl.handle.net/2066/226753 TI - Breath-synchronized electrical stimulation of the expiratory muscles in mechanically ventilated patients: a randomized controlled feasibility study and pooled analysis SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 24 DO - https://doi.org/10.1186/s13054-020-03352-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/226753/226753.pdf?sequence=1 ER - TY - JOUR AU - Smeets, N.J.L. AU - Litjens, C.H.C. AU - Heuvel, J.M.W. van den AU - Hove, H. AU - Broek, P.H.H. van den AU - Russel, F.G.M. AU - Koenderink, J.B. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225313 AB - BACKGROUND: Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters. METHODS: Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS. RESULTS: Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520-770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters. CONCLUSION: The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug-drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates. TI - Completing the Enalaprilat Excretion Pathway-Renal Handling by the Proximal Tubule SN - 1999-4923 IS - iss. 10 JF - Pharmaceutics VL - vol. 12 DO - https://doi.org/10.3390/pharmaceutics12100935 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/225313/225313.pdf?sequence=1 ER - TY - JOUR AU - Gieling, E.M. AU - Wallenburg, E. AU - Frenzel, T. AU - Lange, D.W. de AU - Schouten, J.A. AU - Oever, J. ten AU - Kolwijck, E. AU - Burger, D.M. AU - Pickkers, P. AU - Heine, R. ter AU - Brüggemann, R.J.M. PY - 2020 UR - https://hdl.handle.net/2066/225325 AB - The objective of the present study was to develop a dosing algorithm for ciprofloxacin based on both renal function and pathogen susceptibility in critically ill patients. In this observational prospective multicenter pharmacokinetic study, a total of 39 adult intensive care unit patients receiving ciprofloxacin were included. On two occasions a total of 531 samples of ciprofloxacin were collected. Renal function is a significant covariate on ciprofloxacin clearance. A dose of 400 mg every 12 hours was sufficient to reach the preestablished target of area under the curve (AUC) in relation to the minimum inhibitory concentration (MIC) (AUC/MIC) > 125 in patients with an estimated glomerular filtration rate (eGFR) < 130 mL/min and an infection caused by a pathogen with an MIC ≤ 0.125 mg/L. For patients with infections caused by pathogens with an MIC ≥ 0.5 mg/L and eGFR> 100 mL/min, doses up to 600 mg four times daily or more were estimated to be required. This study provides a new dosing algorithm for ciprofloxacin in critically ill patients. In order to achieve adequate target attainment, the dosing of ciprofloxacin should be based on renal function and the MIC of the causative pathogen. Higher doses than the standard licensed dose are necessary to obtain target attainment for less susceptible pathogens and patients with high renal clearance. In the setting of impaired renal function, a daily dose of 400 mg (which is currently recommended) will not result in adequate target attainment for less susceptible pathogens. TI - Higher Dosage of Ciprofloxacin Necessary in Critically Ill Patients: A New Dosing Algorithm Based on Renal Function and Pathogen Susceptibility EP - 774 SN - 0009-9236 IS - iss. 4 SP - 770 JF - Clinical Pharmacology and Therapeutics VL - vol. 108 DO - https://doi.org/10.1002/cpt.1855 ER - TY - JOUR AU - Kotsopoulos, A.M.M. AU - Vos, P . de AU - Jansen, N.E. AU - Bronkhorst, E.M. AU - Hoeven, J.G. van der AU - Abdo, W.F. PY - 2020 UR - https://hdl.handle.net/2066/220528 AB - BACKGROUND: Controlled donation after circulatory death (cDCD) is a major source of organs for transplantation. A potential cDCD donor poses considerable challenges in terms of identification of those dying within the predefined time frame of warm ischemia after withdrawal of life-sustaining treatment (WLST) to circulatory arrest. Several attempts have been made to develop models predicting the time between treatment withdrawal and circulatory arrest. This time window determines whether organ donation can occur and influences the quality of the donated organs. However, the selected patients used for these models were not always restricted to potential cDCD donors (eg, patients with cancer or severe infections were also included). This severely limits the generalizability of those data. OBJECTIVE: The objectives of this study are the following: (1) to develop a model predicting time to death within 60 minutes in potential cDCD patients; (2) to validate and update previous prediction models on time to death after WLST; (3) to determine timing and patient characteristics that are associated with prognostication and the decision-making process that leads to initiating end-of-life care; (4) to evaluate the impact of timing of family approach on organ donation approval; and (5) to assess the influence of variation in WLST processes on postmortem organ donor potential and actual postmortem organ donors. METHODS: In this multicenter observational prospective cohort study, all patients admitted to the intensive care unit of 3 university hospitals and 3 teaching hospitals who met the criteria of the cDCD protocol as defined by the Dutch Transplant Foundation were included. The target of enrolment was set to 400 patients. Previously developed models will be refitted in our data set. To further update previous prediction models, we will apply least absolute shrinkage and selection operator (LASSO) as a tool for efficient variable selection to develop the multivariable logistic regression model. RESULTS: This protocol was funded in August 2014 by the Dutch Transplant Foundation. We expect to have the results of this study in July 2020. Patient enrolment was completed in July 2018 and data collection was completed in April 2020. CONCLUSIONS: This study will provide a robust multimodal prediction model, based on clinical and physiological parameters, that can predict time to circulatory arrest in cDCD donors. In addition, it will add valuable insight in the process of WLST in cDCD donors and will fill an important knowledge gap in this essential field of health care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04123275; https://clinicaltrials.gov/ct2/show/NCT04123275. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16733. TI - Prediction Model for Timing of Death in Potential Donors After Circulatory Death (DCD III): Protocol for a Multicenter Prospective Observational Cohort Study SN - 1929-0748 IS - iss. 6 JF - JMIR Research Protocols VL - vol. 9 DO - https://doi.org/10.2196/16733 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220528/220528.pdf?sequence=1 ER - TY - JOUR AU - Roesthuis, L.H. AU - Hoeven, J.G. van der AU - Hees, H.W.H. van AU - Schellekens, W.M. AU - Doorduin, J. AU - Heunks, L.M. PY - 2020 UR - https://hdl.handle.net/2066/220537 AB - BACKGROUND: Inappropriate ventilator assist plays an important role in the development of diaphragm dysfunction. Ventilator under-assist may lead to muscle injury, while over-assist may result in muscle atrophy. This provides a good rationale to monitor respiratory drive in ventilated patients. Respiratory drive can be monitored by a nasogastric catheter, either with esophageal balloon to determine muscular pressure (gold standard) or with electrodes to measure electrical activity of the diaphragm. A disadvantage is that both techniques are invasive. Therefore, it is interesting to investigate the role of surrogate markers for respiratory dive, such as extradiaphragmatic inspiratory muscle activity. The aim of the current study was to investigate the effect of different inspiratory support levels on the recruitment pattern of extradiaphragmatic inspiratory muscles with respect to the diaphragm and to evaluate agreement between activity of extradiaphragmatic inspiratory muscles and the diaphragm. METHODS: Activity from the alae nasi, genioglossus, scalene, sternocleidomastoid and parasternal intercostals was recorded using surface electrodes. Electrical activity of the diaphragm was measured using a multi-electrode nasogastric catheter. Pressure support (PS) levels were reduced from 15 to 3 cmH(2)O every 5 min with steps of 3 cmH(2)O. The magnitude and timing of respiratory muscle activity were assessed. RESULTS: We included 17 ventilated patients. Diaphragm and extradiaphragmatic inspiratory muscle activity increased in response to lower PS levels (36 ± 6% increase for the diaphragm, 30 ± 6% parasternal intercostals, 41 ± 6% scalene, 40 ± 8% sternocleidomastoid, 43 ± 6% alae nasi and 30 ± 6% genioglossus). Changes in diaphragm activity correlated best with changes in alae nasi activity (r(2) = 0.49; P < 0.001), while there was no correlation between diaphragm and sternocleidomastoid activity. The agreement between diaphragm and extradiaphragmatic inspiratory muscle activity was low due to a high individual variability. Onset of alae nasi activity preceded the onset of all other muscles. CONCLUSIONS: Extradiaphragmatic inspiratory muscle activity increases in response to lower inspiratory support levels. However, there is a poor correlation and agreement with the change in diaphragm activity, limiting the use of surface electromyography (EMG) recordings of extradiaphragmatic inspiratory muscles as a surrogate for electrical activity of the diaphragm. TI - Recruitment pattern of the diaphragm and extradiaphragmatic inspiratory muscles in response to different levels of pressure support SN - 2110-5820 IS - iss. 1 JF - Annals of Intensive Care VL - vol. 10 DO - https://doi.org/10.1186/s13613-020-00684-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220537/220537.pdf?sequence=1 ER - TY - JOUR AU - Buijsers, B. AU - Yanginlar, C. AU - Nooijer, A.H. de AU - Grondman, I. AU - Maciej-Hulme, M.L. AU - Jonkman, W.I. AU - Janssen, N.A.F. AU - Rother, N AU - Graaf, M.J.J. de AU - Pickkers, P. AU - Kox, M. AU - Joosten, L.A.B. AU - Nijenhuis, T. AU - Netea, M.G. AU - Hilbrands, L.B. AU - Veerdonk, F.L. van de AU - Duivenvoorden, R. AU - Mast, Q. de AU - Vlag, J. van der PY - 2020 UR - https://hdl.handle.net/2066/226238 TI - Increased Plasma Heparanase Activity in COVID-19 Patients SN - 1664-3224 JF - Frontiers in Immunology VL - vol. 11 DO - https://doi.org/10.3389/fimmu.2020.575047 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/226238/226238.pdf?sequence=1 ER - TY - JOUR AU - Verweij, P.E. AU - Rijnders, B.J.A. AU - Brüggemann, R.J.M. AU - Azoulay, E. AU - Bassetti, M. AU - Blot, S. AU - Calandra, T. AU - Clancy, C.J. AU - Cornely, O.A. AU - Chiller, T. AU - Depuydt, P. AU - Giacobbe, D.R. AU - Janssen, N.A.F. AU - Kullberg, B.J. AU - Lagrou, K. AU - Lass-Flörl, C. AU - Lewis, R.E. AU - Liu, P.W. AU - Lortholary, O. AU - Maertens, J. AU - Martin-Loeches, I. AU - Nguyen, M.H. AU - Patterson, T.F. AU - Rogers, T.R. AU - Schouten, J.A. AU - Spriet, I. AU - Vanderbeke, L. AU - Wauters, J. AU - Veerdonk, F.L. van de PY - 2020 UR - https://hdl.handle.net/2066/225348 AB - PURPOSE: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. METHODS: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. RESULTS: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung. CONCLUSION: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA. TI - Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion EP - 1535 SN - 0342-4642 IS - iss. 8 SP - 1524 JF - Intensive Care Medicine VL - vol. 46 DO - https://doi.org/10.1007/s00134-020-06091-6 ER - TY - JOUR AU - Liesveld, J. AU - Cremers, A.J.H. AU - Meis, J.F.G.M. AU - Kolwijck, E. AU - Schouten, J.A. PY - 2020 UR - https://hdl.handle.net/2066/221432 TI - Atypical and fulminant presentations of pneumococcal infections: A case series in a tertiary intensive care unit EP - 190 SN - 0300-2977 IS - iss. 4 SP - 183 JF - Netherlands Journal of Medicine VL - vol. 78 ER - TY - JOUR AU - Geense, W.W. AU - Zegers, H.W. AU - Dieperink, Peter AU - Vermeulen, H. AU - Hoeven, J.G. van der AU - Boogaard, M. van den PY - 2020 UR - https://hdl.handle.net/2066/214092 TI - Changes in frailty among ICU survivors and associated factors: Results of a one-year prospective cohort study using the Dutch Clinical Frailty Scale EP - 193 SN - 0883-9441 SP - 184 JF - Journal of Critical Care VL - vol. 55 DO - https://doi.org/10.1016/j.jcrc.2019.10.016 ER - TY - JOUR AU - Geense, W.W. AU - Boogaard, M. van den AU - Peters, Marco A. A. AU - Simons, K.S. AU - Ewalds, Esther AU - Vermeulen, H. AU - Hoeven, J.G. van der AU - Zegers, H.W. PY - 2020 UR - https://hdl.handle.net/2066/222163 TI - Physical, Mental, and Cognitive Health Status of ICU Survivors Before ICU Admission: A Cohort Study EP - 1279 SN - 0090-3493 IS - iss. 9 SP - 1271 JF - Critical Care Medicine VL - vol. 48 DO - https://doi.org/10.1097/CCM.0000000000004443 ER - TY - JOUR AU - Taccone, Fabio Silvio AU - Horn, Janneke AU - Storm, C. AU - Cariou, A. AU - Sandroni, C. AU - Friberg, H. AU - Hoedemaekers, C. AU - Oddo, M. PY - 2019 UR - https://hdl.handle.net/2066/202783 TI - Death after awakening from post-anoxic coma: the "Best CPC" project SN - 1466-609X JF - Critical Care VL - vol. 23 DO - https://doi.org/10.1186/s13054-019-2405-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/202783/202783.pdf?sequence=1 ER - TY - JOUR AU - Ingelse, S.A. AU - Geukers, Vincent G. AU - Dijsselhof, Monique E. AU - Lemson, J. AU - Bem, R.A. AU - Woensel, J.B. van PY - 2019 UR - https://hdl.handle.net/2066/214466 TI - Less Is More?-A Feasibility Study of Fluid Strategy in Critically Ill Children With Acute Respiratory Tract Infection SN - 2296-2360 JF - Frontiers in Pediatrics VL - vol. 7 DO - https://doi.org/10.3389/fped.2019.00496 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/214466/214466.pdf?sequence=1 ER - TY - JOUR AU - Maraolo, Alberto Enrico AU - Ong, D.S.Y. AU - Cimen, Cansu AU - Howard, Philip AU - Kofteridis, Diamantis P. AU - Schouten, J.A. AU - Pulcini, Celine AU - Harxhi, Arjan PY - 2019 UR - https://hdl.handle.net/2066/209482 TI - Organization and training at national level of antimicrobial stewardship and infection control activities in Europe: an ESCMID cross-sectional survey EP - 2068 SN - 0934-9723 IS - iss. 11 SP - 2061 JF - European Journal of Clinical Microbiology and Infectious Diseases VL - vol. 38 DO - https://doi.org/10.1007/s10096-019-03648-2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/209482/209482.pdf?sequence=1 ER - TY - JOUR AU - Licciardi, F. AU - Boogaard, M. van den AU - Piane, M. Delle AU - Tovo, P.A. AU - Montin, D. PY - 2019 UR - https://hdl.handle.net/2066/216142 TI - EBV-Related Hodgkin Lymphoma in an ICF2 Patient: Is EBV Susceptibility a Hallmark of This ICF Subtype? EP - 236 SN - 0271-9142 IS - iss. 3 SP - 234 JF - Journal of Clinical Immunology VL - vol. 39 DO - https://doi.org/10.1007/s10875-019-00596-6 ER - TY - JOUR AU - Rood, P.J.T. AU - Zegers, M. AU - Slooter, A.J. AU - Beishuizen, Albertus AU - Simons, K.S. AU - Voort, P.H. van der AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Boogaard, M.H.W.A. van den PY - 2019 UR - https://hdl.handle.net/2066/206245 TI - Prophylactic Haloperidol Effects on Long-term Quality of Life in Critically Ill Patients at High Risk for Delirium Results of the REDUCE Study EP - 335 SN - 0003-3022 IS - iss. 2 SP - 328 JF - Anesthesiology VL - vol. 131 DO - https://doi.org/10.1097/ALN.0000000000002812 ER - TY - JOUR AU - Zwaag, J. AU - Beunders, R. AU - Warle, M.C. AU - Kellum, J.A. AU - Riksen, N.P. AU - Pickkers, P. AU - Kox, M. PY - 2019 UR - https://hdl.handle.net/2066/206254 TI - Remote ischaemic preconditioning does not modulate the systemic inflammatory response or renal tubular stress biomarkers after endotoxaemia in healthy human volunteers: a single-centre, mechanistic, randomised controlled trial EP - 185 SN - 0007-0912 IS - iss. 2 SP - 177 JF - British Journal of Anaesthesia VL - vol. 123 DO - https://doi.org/10.1016/j.bja.2019.03.037 ER - TY - JOUR AU - Verlaat, C.W.M. AU - Wubben, N. AU - Visser, I.H. AU - Hazelzet, J.A. AU - Waardenburg, D. van AU - Dam, Nicolette A. van AU - Hoeven, J.G. van der AU - Lemson, J. AU - Boogaard, M. van den PY - 2019 UR - https://hdl.handle.net/2066/206255 TI - Retrospective cohort study on factors associated with mortality in high-risk pediatric critical care patients in the Netherlands SN - 1471-2431 IS - iss. 1 JF - BMC Pediatrics VL - vol. 19 DO - https://doi.org/10.1186/s12887-019-1646-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206255/206255.pdf?sequence=1 ER - TY - JOUR AU - Groenendael, R. van AU - Kox, M. AU - Leijte, G.P. AU - Koeneman, B. AU - Gerretsen, J. AU - Eijk, L.T. AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/206306 AB - AIMS: EA-230 is a human chorionic gonadotropin hormone-derived linear tetrapeptide, developed for the treatment of systemic inflammation-related disorders. EA-230 has shown promising immunomodulatory and tissue-protective effects in animals and an excellent safety profile in human phase I studies that we performed. The present phase IIa study follows-up on these results by investigating the safety, efficacy and pharmacokinetics of EA-230 under systemic inflammatory conditions induced by experimental human endotoxaemia. METHODS: In this randomized, double blind, placebo-controlled phase IIa study, systemic inflammation was induced by intravenous administration of Escherichia coli-derived lipopolysaccharide (LPS). At t = 0 hours, 36 healthy male volunteers received 2 ng/kg LPS, followed by a 2-hour continuous infusion of EA-230 (15, 45 and 90 mg/kg/h, n = 8 per group) or placebo (n = 12). RESULTS: EA-230 was well tolerated and showed a favourable safety profile. Treatment with the highest dose of EA-230 resulted in a significant attenuation of the LPS-induced increase in plasma levels of inflammatory mediators interleukin (IL)-6, IL-8, IL-1 receptor antagonist, monocyte chemoattractant protein-1, macrophage inflammatory proteins-1alpha and -1beta, and vascular cell adhesion protein-1 (% reduction of 48, 28, 33, 28, 14, 16 and 19 respectively, p < .01), and reduced fever (peak decrease from 1.8 +/- 0.1 degrees C to 1.3 +/- 0.2 degrees C, P < .05) and symptom scores (peak decrease from 7.4 +/- 1.0 to 4.0 +/- 1.2 points, P < .05). EA-230 exhibited a very short elimination half-life and a large volume of distribution in the highest dosage group (geometric mean and 95% confidence interval: 0.17 [0.12-0.24] hours and 2.2 [1.3-3.8] L/kg, respectively). CONCLUSION: Administration of EA-230 is safe and results in attenuation of the systemic inflammatory response in humans. TI - A randomized double-blind, placebo-controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA-230 during experimental human endotoxaemia EP - 1571 SN - 0306-5251 IS - iss. 7 SP - 1559 JF - British Journal of Clinical Pharmacology VL - vol. 85 DO - https://doi.org/10.1111/bcp.13941 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206306/206306.pdf?sequence=1 ER - TY - JOUR AU - Pickkers, P. AU - Poll, T. van der PY - 2019 UR - https://hdl.handle.net/2066/206310 TI - What's new in immunostimulating strategies in the ICU EP - 112 SN - 0342-4642 IS - iss. 1 SP - 110 JF - Intensive Care Medicine VL - vol. 45 DO - https://doi.org/10.1007/s00134-018-5462-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206310/206310.pdf?sequence=1 ER - TY - JOUR AU - Voors, A.A. AU - Kremer, D. AU - Geven, C.B.C.A.G. AU - Maaten, J.M.A.A. van der AU - Struck, J. AU - Bergmann, A. AU - Pickkers, P. AU - Metra, M. AU - Mebazaa, A. AU - Dungen, H.D. AU - Butler, J. PY - 2019 UR - https://hdl.handle.net/2066/206328 AB - Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin-angiotensin-aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio-ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio-ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non-neutralizing ADM-binding antibody with a half-life of 15 days. Adrecizumab binds at the N-terminal epitope of ADM, leaving the C-terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM-binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation. TI - Adrenomedullin in heart failure: pathophysiology and therapeutic application EP - 171 SN - 1388-9842 IS - iss. 2 SP - 163 JF - European Journal of Heart Failure VL - vol. 21 DO - https://doi.org/10.1002/ejhf.1366 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206328/206328.pdf?sequence=1 ER - TY - JOUR AU - Vyvere, T. Vande AU - Wilms, G. AU - Claes, L. AU - Leon, F. Martin AU - Nieboer, D. AU - Verheyden, J. AU - Hauwe, L. van den AU - Pullens, P. AU - Bartels, R.H.M.A. AU - Hoedemaekers, A. AU - Maas, A.I. AU - Parizel, P.M. PY - 2019 UR - https://hdl.handle.net/2066/206372 AB - Observer variability in local radiological reading is a major concern in large-scale multi-center traumatic brain injury (TBI) studies. A central review process has been advocated to minimize this variability. The aim of this study is to compare central with local reading of TBI imaging datasets and to investigate the added value of central review. A total of 2050 admission computed tomography (CT) scans from subjects enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed for seven main CT characteristics. Kappa statistics were used to calculate agreement between central and local evaluations and a center-specific analysis was performed. The McNemar test was used to detect whether discordances were significant. Central interobserver and intra-observer agreement was calculated in a subset of patients. Good agreement was found between central and local assessment for the presence or absence of structural pathology (CT+, CT-, kappa = 0.73) and most CT characteristics (kappa = 0.62 to 0.71), except for traumatic axonal injury lesions (kappa = 0.37). Despite good kappa values, discordances were significant in four of seven CT characteristics (i.e., midline shift, contusion, traumatic subarachnoid hemorrhage, and cisternal compression; p = 0.0005). Central reviewers showed substantial to excellent interobserver and intra-observer agreement (kappa = 0.73 to kappa = 0.96), contrasted by considerable variability in local radiological reading. Compared with local evaluation, a central review process offers a more consistent radiological reading of acute CT characteristics in TBI. It generates reliable, reproducible data and should be recommended for use in multi-center TBI studies. TI - Central versus Local Radiological Reading of Acute Computed Tomography Characteristics in Multi-Center Traumatic Brain Injury Research EP - 1092 SN - 0897-7151 IS - iss. 7 SP - 1080 JF - Journal of Neurotrauma VL - vol. 36 DO - https://doi.org/10.1089/neu.2018.6061 ER - TY - JOUR AU - Lier, D. AU - Geven, C.B.C.A.G. AU - Leijte, G.P. AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/206494 AB - Systemic inflammation plays a pivotal role in a multitude of conditions, including sepsis, trauma, major surgery and burns. However, comprehensive analysis of the pathophysiology underlying this systemic inflammatory response is greatly complicated by variations in the immune response observed in critically ill patients, which is a result of inter-individual differences in comorbidity, comedication, source of infection, causative pathogen, and onset of the inflammatory response. During experimental human endotoxemia, human subjects are challenged with purified endotoxin (lipopolysaccharide) intravenously which induces a short-lived, well-tolerated and controlled systemic inflammatory response, similar to that observed during sepsis. The human endotoxemia model can be conducted in a highly standardized and reproducible manner, using a carefully selected homogenous study population. As such, the experimental human endotoxemia model does not share the aforementioned clinical limitations and enables us to investigate both the mechanisms of systemic inflammation, as well as to evaluate novel (pharmacological) interventions in humans in vivo. The present review provides a detailed overview of the various designs, organ-specific changes, and strengths and limitations of the experimental human endotoxemia model, with the main focus on its use as a translational model for sepsis research. TI - Experimental human endotoxemia as a model of systemic inflammation EP - 106 SN - 0300-9084 SP - 99 JF - Biochimie VL - vol. 159 DO - https://doi.org/10.1016/j.biochi.2018.06.014 ER - TY - JOUR AU - Rood, P.J.T. AU - Schoor, F.R. van de AU - Tertholen, K. van AU - Pickkers, P. AU - Boogaard, M. van den PY - 2019 UR - https://hdl.handle.net/2066/206147 TI - Differences in 90-day mortality of delirium subtypes in the intensive care unit: A retrospective cohort study EP - 124 SN - 0883-9441 SP - 120 JF - Journal of Critical Care VL - vol. 53 DO - https://doi.org/10.1016/j.jcrc.2019.06.007 ER - TY - THES AU - Witjes, M. PY - 2019 UR - https://hdl.handle.net/2066/206200 PB - [S.l. : s.n.] TI - Organ donation in the Netherlands; how to improve donor identification and family consent N1 - Radboud University, 4 september 2019 N1 - Promotor : Hoeven, J.G. van der Co-promotores : Abdo, W.F., Jansen, N.E. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206200/206200.pdf?sequence=1 ER - TY - JOUR AU - Jonkman, Annemijn H. AU - Jansen, D. AU - Gadgil, Suvarna AU - Keijzer, Christiaan AU - Girbes, Armand R.J. AU - Scheffer, G.J. AU - Hoeven, J.G. van der AU - Sinderby, Christer S. AU - Heunks, L.M.A. PY - 2019 UR - https://hdl.handle.net/2066/206223 TI - Monitoring patient-ventilator breath contribution in the critically ill during neurally adjusted ventilatory assist: reliability and improved algorithms for bedside use EP - 271 SN - 8750-7587 IS - iss. 1 SP - 264 JF - Journal of Applied Physiology VL - vol. 127 DO - https://doi.org/10.1152/japplphysiol.00071.2019 ER - TY - JOUR AU - Lowensteyn, Yvette Nicole AU - Jansen, Nicolaas Johannes Georgius AU - Heerde, Marc van AU - Klein, Richard Henryk AU - Kneyber, Martin Christiaan Jacques AU - Kuiper, J. AU - Verlaat, C.W.M. AU - Waardenburg, Dirk Adriaan van AU - Hasselt, Peter Marin van PY - 2019 UR - https://hdl.handle.net/2066/205022 TI - Increasing the dose of oral vitamin K prophylaxis and its effect on bleeding risk EP - 1042 SN - 0340-6199 IS - iss. 7 SP - 1033 JF - European Journal of Pediatrics VL - vol. 178 DO - https://doi.org/10.1007/s00431-019-03391-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/205022/205022.pdf?sequence=1 ER - TY - JOUR AU - Khandelwal, K. AU - Boogaard, M. van den AU - Mehrem, S.L. AU - Gebel, J. AU - Fagerberg, C. AU - Beusekom, E. van AU - Binsbergen, E. van AU - Topaloglu, O. AU - Steehouwer, M. AU - Gilissen, C. AU - Ishorst, N. AU - Rooij, I.A.L.M. van AU - Roeleveld, N. AU - Christensen, K. AU - Schoenaers, J. AU - Berge, S.J. AU - Murray, J.C. AU - Hens, G. AU - Devriendt, K. AU - Ludwig, K.U. AU - Mangold, E. AU - Hoischen, A. AU - Zhou, H. AU - Dotsch, V. AU - Carels, C.E.L. AU - Bokhoven, H. van PY - 2019 UR - https://hdl.handle.net/2066/204872 AB - We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected. TI - Deletions and loss-of-function variants in TP63 associated with orofacial clefting EP - 1112 SN - 1018-4813 IS - iss. 7 SP - 1101 JF - European Journal of Human Genetics VL - vol. 27 DO - https://doi.org/10.1038/s41431-019-0370-0 ER - TY - JOUR AU - Hartman, S.J.F. AU - Boeddha, Navin P. AU - Ekinci, Ebru AU - Koch, Birgit C.P. AU - Donders, R. AU - Hazelzet, Jan A. AU - Driessen, Gertjan J. AU - Wildt, S.N. de PY - 2019 UR - https://hdl.handle.net/2066/205057 TI - Target attainment of cefotaxime in critically ill children with meningococcal septic shock as a model for cefotaxime dosing in severe pediatric sepsis EP - 1260 SN - 0934-9723 IS - iss. 7 SP - 1255 JF - European Journal of Clinical Microbiology and Infectious Diseases VL - vol. 38 DO - https://doi.org/10.1007/s10096-019-03535-w L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/205057/205057.pdf?sequence=1 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Koenderink, J.B. AU - Wildt, S.N. de AU - Russel, F.G.M. PY - 2019 UR - https://hdl.handle.net/2066/206439 AB - Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months-15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92-1.09) and in CSF (range 0.64-1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64-1.66, range AUCo/AUCp CSF: 1.43-1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS. TI - Development of a physiologically-based pharmacokinetic pediatric brain model for prediction of cerebrospinal fluid drug concentrations and the influence of meningitis SN - 1553-7358 IS - iss. 6 SP - e1007117 JF - Plos Computational Biology VL - vol. 15 DO - https://doi.org/10.1371/journal.pcbi.1007117 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206439/206439.pdf?sequence=1 ER - TY - JOUR AU - Loon, L.M. van AU - Hoeven, J.G. van der AU - Lemson, J. PY - 2019 UR - https://hdl.handle.net/2066/206550 AB - The administration of beta-blockers in patients with sepsis is a trending topic in intensive care medicine since the landmark study by Morelli and colleagues, showing a striking decrease in 28-day mortality compared to standard care. While the available evidence suggests that the use of beta-blockers in septic shock is safe, the effects on hemodynamics are controversial. In this paper, we review the effect of beta-blockade in septic shock on hemodynamics from animal models to critically ill patients. TI - Hemodynamic response to beta-blockers in severe sepsis and septic shock: A review of current literature EP - 143 SN - 0883-9441 SP - 138 JF - Journal of Critical Care VL - vol. 50 DO - https://doi.org/10.1016/j.jcrc.2018.12.003 ER - TY - JOUR AU - Martin-Loeches, I. AU - Lemiale, V. AU - Geoghegan, P. AU - McMahon, M.A. AU - Pickkers, P. AU - Soares, M. AU - Perner, A. AU - Meyhoff, T.S. AU - Bukan, R.B. AU - Rello, J. AU - Bauer, P.R. AU - Louw, A. van de AU - Taccone, F.S. AU - Salluh, J. AU - Hemelaar, P. AU - Schellongowski, P. AU - Rusinova, K. AU - Terzi, N. AU - Mehta, S. AU - Antonelli, M. AU - Kouatchet, A. AU - Klepstad, P. AU - Valkonen, M. AU - Landburg, P.P. AU - Barratt-Due, A. AU - Bruneel, F. AU - Pene, F. AU - Metaxa, V. AU - Moreau, A.S. AU - Souppart, V. AU - Burghi, G. AU - Girault, C. AU - Silva, U.V.A. AU - Montini, L. AU - Barbier, F. AU - Nielsen, L.B. AU - Gaborit, B. AU - Mokart, D. AU - Chevret, S. AU - Azoulay, E. PY - 2019 UR - https://hdl.handle.net/2066/206594 AB - BACKGROUND: It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. METHODS: Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. RESULTS: Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90-1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. CONCLUSIONS: Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients. TI - Influenza and associated co-infections in critically ill immunosuppressed patients SN - 1466-609X IS - iss. 1 SP - 152 JF - Critical Care VL - vol. 23 DO - https://doi.org/10.1186/s13054-019-2425-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206594/206594.pdf?sequence=1 ER - TY - JOUR AU - Witjes, M. AU - Jansen, N.E. AU - Hoeven, J.G. van der AU - Abdo, W.F. PY - 2019 UR - https://hdl.handle.net/2066/206616 AB - BACKGROUND: The last decade, there have been many initiatives worldwide to increase the number of organ donors. However, it is not clear which initiatives are most effective. The aim of this study is to provide an overview of interventions aimed at healthcare professionals in order to increase the number of organ donors. METHODS: We systematically searched PubMed, EMBASE, CINAHL, PsycINFO, and the Cochrane Library for English language studies published until April 24, 2019. We included studies describing interventions in hospitals aimed at healthcare professionals who are involved in the identification, referral, and care of a family of potential organ donors. After the title abstract and full-text selection, two reviewers independently assessed each study's quality and extracted data. RESULTS: From the 18,854 records initially extracted from five databases, we included 22 studies in our review. Of these 22 studies, 14 showed statistically significant effects on identification rate, family consent rate, and/or donation rate. Interventions that positively influenced one or more of these outcomes were training of emergency personnel in organ donation, an electronic support system to identify and/or refer potential donors, a collaborative care pathway, donation request by a trained professional, and additional family support in the ICU by a trained nurse. The methodological quality of the studies was relatively low, mainly because of the study designs. CONCLUSIONS: Although there is paucity of data, collaborative care pathways, training of healthcare professionals and additional support for relatives of potential donors seem to be promising interventions to increase the number of organ donors. TRIAL REGISTRATION: PROSPERO, CRD42018068185. TI - Interventions aimed at healthcare professionals to increase the number of organ donors: a systematic review SN - 1466-609X IS - iss. 1 SP - 227 JF - Critical Care VL - vol. 23 DO - https://doi.org/10.1186/s13054-019-2509-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206616/206616.pdf?sequence=1 ER - TY - JOUR AU - Rodriguez Rosales, Y.A. AU - Kox, M. AU - Rijssen, E. van AU - Cranenbroek, B. van AU - Welie, M. van AU - Pickkers, P. AU - Joosten, I. AU - Koenen, H.J.P.M. PY - 2019 UR - https://hdl.handle.net/2066/206650 TI - Long-Term Effects of Experimental Human Endotoxemia on Immune Cell Function: Similarities and Differences With Sepsis. EP - 689 SN - 1073-2322 IS - iss. 6 SP - 678 JF - Shock VL - vol. 51 DO - https://doi.org/10.1097/SHK.0000000000001222 ER - TY - JOUR AU - Leijte, G.P. AU - Pickkers, P. AU - Kox, M. PY - 2019 UR - https://hdl.handle.net/2066/206683 TI - Mitochondrial DNA: Innocent in Plasma, but Guilty in Urine? SN - 1073-2322 IS - iss. 2 SP - 266 JF - Shock VL - vol. 51 DO - https://doi.org/10.1097/SHK.0000000000001142 ER - TY - JOUR AU - Bruse, N. AU - Leijte, G.P. AU - Pickkers, P. AU - Kox, M. PY - 2019 UR - https://hdl.handle.net/2066/206704 AB - INTRODUCTION: In the last decade, the sepsis research field has shifted focus from targeting hyperinflammation to reversing sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis is very heterogeneous: the magnitude and the nature of the underlying immune defects differ considerably between patients, but also within individuals over time. Therefore, a 'one-treatment-fits-all' strategy for sepsis-induced immunoparalysis is bound to fail, and an individualized 'precision medicine' approach is required. Such a strategy is nevertheless hampered by the unsuitability of the currently available markers to identify the many immune defects that can manifest in individual patients. Areas covered: We describe the currently available markers for sepsis-induced immunoparalysis and limitations pertaining to their use. Furthermore, future prospects and caveats are discussed, focusing on 'omics' approaches: genomics, transcriptomics, epigenomics, and metabolomics. Finally, we present a contemporary overview of adjuvant immunostimulatory therapies. Expert opinion: The integration of multiple omics techniques offers a systems biology approach which can yield biomarker profiles that accurately and comprehensively gauge the extent and nature of sepsis-induced immunoparalysis. We expect this development to be instrumental in facilitating precision medicine for sepsis-induced immunoparalysis, consisting of the application of targeted immunostimulatory therapies and follow-up measurements to monitor the response to treatment and to titrate or adjust medication. TI - New frontiers in precision medicine for sepsis-induced immunoparalysis EP - 263 SN - 1744-666X IS - iss. 3 SP - 251 JF - Expert Review of Clinical Immunology VL - vol. 15 DO - https://doi.org/10.1080/1744666X.2019.1562336 ER - TY - JOUR AU - Schetz, M. AU - Jong, A. de AU - Deane, A.M. AU - Druml, W. AU - Hemelaar, P. AU - Pelosi, P. AU - Pickkers, P. AU - Reintam-Blaser, A. AU - Roberts, J. AU - Sakr, Y. AU - Jaber, S. PY - 2019 UR - https://hdl.handle.net/2066/206707 AB - The World Health Organization defines overweight and obesity as the condition where excess or abnormal fat accumulation increases risks to health. The prevalence of obesity is increasing worldwide and is around 20% in ICU patients. Adipose tissue is highly metabolically active, and especially visceral adipose tissue has a deleterious adipocyte secretory profile resulting in insulin resistance and a chronic low-grade inflammatory and procoagulant state. Obesity is strongly linked with chronic diseases such as type 2 diabetes, hypertension, cardiovascular diseases, dyslipidemia, non-alcoholic fatty liver disease, chronic kidney disease, obstructive sleep apnea and hypoventilation syndrome, mood disorders and physical disabilities. In hospitalized and ICU patients and in patients with chronic illnesses, a J-shaped relationship between BMI and mortality has been demonstrated, with overweight and moderate obesity being protective compared with a normal BMI or more severe obesity (the still debated and incompletely understood "obesity paradox"). Despite this protective effect regarding mortality, in the setting of critical illness morbidity is adversely affected with increased risk of respiratory and cardiovascular complications, requiring adapted management. Obesity is associated with increased risk of AKI and infection, may require adapted drug dosing and nutrition and is associated with diagnostic and logistic challenges. In addition, negative attitudes toward obese patients (the social stigma of obesity) affect both health care workers and patients. TI - Obesity in the critically ill: a narrative review EP - 769 SN - 0342-4642 IS - iss. 6 SP - 757 JF - Intensive Care Medicine VL - vol. 45 DO - https://doi.org/10.1007/s00134-019-05594-1 ER - TY - JOUR AU - Bajcetic, M. AU - Wildt, S.N. de AU - Dalinghaus, M. AU - Breitkreutz, J. AU - Klingmann, I. AU - Lagler, F.B. AU - Keatley-Clarke, A. AU - Breur, J.M. AU - Male, C. AU - Jovanovic, I. AU - Szatmari, A. AU - Ablonczy, L. AU - Burckhardt, B.B. AU - Cawello, W. AU - Kleine, K. AU - Obarcanin, E. AU - Spatenkova, L. AU - Swoboda, V. AU - Meulen, M. van der AU - Wagner, P. AU - Walsh, J. AU - Laer, S. PY - 2019 UR - https://hdl.handle.net/2066/206710 AB - Introduction: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. Methods and Analysis: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n=25; 1 month to less than 12 years) or congenital heart disease (CHD) (n=60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naive to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naive patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. Ethics and dissemination: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. Trial registration numbers: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21. TI - Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study SN - 2451-8654 SP - 100393 JF - Contemporary Clinical Trials Communications VL - vol. 15 DO - https://doi.org/10.1016/j.conctc.2019.100393 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206710/206710.pdf?sequence=1 ER - TY - JOUR AU - Pham, T. AU - Neto, A. Serpa AU - Pelosi, P. AU - Laffey, J.G. AU - Haro, C. De AU - Lorente, J.A. AU - Bellani, G. AU - Fan, E. AU - Brochard, L.J. AU - Pesenti, A. AU - Schultz, M.J. AU - Artigas, A. AU - Schouten, J.A. AU - Surbatovic, M. AU - Veljovic, M. PY - 2019 UR - https://hdl.handle.net/2066/206712 AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Hospital mortality in acute respiratory distress syndrome is approximately 40%, but mortality and trajectory in "mild" acute respiratory distress syndrome (classified only since 2012) are unknown, and many cases are not detected WHAT THIS ARTICLE TELLS US THAT IS NEW: Approximately 80% of cases of mild acute respiratory distress syndrome persist or worsen in the first week; in all cases, the mortality is substantial (30%) and is higher (37%) in those in whom the acute respiratory distress syndrome progresses BACKGROUND:: Patients with initial mild acute respiratory distress syndrome are often underrecognized and mistakenly considered to have low disease severity and favorable outcomes. They represent a relatively poorly characterized population that was only classified as having acute respiratory distress syndrome in the most recent definition. Our primary objective was to describe the natural course and the factors associated with worsening and mortality in this population. METHODS: This study analyzed patients from the international prospective Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) who had initial mild acute respiratory distress syndrome in the first day of inclusion. This study defined three groups based on the evolution of severity in the first week: "worsening" if moderate or severe acute respiratory distress syndrome criteria were met, "persisting" if mild acute respiratory distress syndrome criteria were the most severe category, and "improving" if patients did not fulfill acute respiratory distress syndrome criteria any more from day 2. RESULTS: Among 580 patients with initial mild acute respiratory distress syndrome, 18% (103 of 580) continuously improved, 36% (210 of 580) had persisting mild acute respiratory distress syndrome, and 46% (267 of 580) worsened in the first week after acute respiratory distress syndrome onset. Global in-hospital mortality was 30% (172 of 576; specifically 10% [10 of 101], 30% [63 of 210], and 37% [99 of 265] for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively), and the median (interquartile range) duration of mechanical ventilation was 7 (4, 14) days (specifically 3 [2, 5], 7 [4, 14], and 11 [6, 18] days for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively). Admissions for trauma or pneumonia, higher nonpulmonary sequential organ failure assessment score, lower partial pressure of alveolar oxygen/fraction of inspired oxygen, and higher peak inspiratory pressure were independently associated with worsening. CONCLUSIONS: Most patients with initial mild acute respiratory distress syndrome continue to fulfill acute respiratory distress syndrome criteria in the first week, and nearly half worsen in severity. Their mortality is high, particularly in patients with worsening acute respiratory distress syndrome, emphasizing the need for close attention to this patient population. TI - Outcomes of Patients Presenting with Mild Acute Respiratory Distress Syndrome: Insights from the LUNG SAFE Study EP - 283 SN - 0003-3022 IS - iss. 2 SP - 263 JF - Anesthesiology VL - vol. 130 DO - https://doi.org/10.1097/ALN.0000000000002508 ER - TY - JOUR AU - Kashani, K. AU - Rosner, M.H. AU - Haase, M. AU - Lewington, A.J.P. AU - O'Donoghue, D.J. AU - Wilson, F.P. AU - Nadim, M.K. AU - Silver, S.A. AU - Zarbock, A. AU - Ostermann, M. AU - Mehta, R.L. AU - Kane-Gill, S.L. AU - Ding, X. AU - Pickkers, P. AU - Bihorac, A. AU - Siew, E.D. AU - Barreto, E.F. AU - Macedo, E. AU - Kellum, J.A. AU - Palevsky, P.M. AU - Tolwani, A.J. AU - Ronco, C. AU - Juncos, L.A. AU - Rewa, O.G. AU - Bagshaw, S.M. AU - Mottes, T.A. AU - Koyner, J.L. AU - Liu, K.D. AU - Forni, L.G. AU - Heung, M. AU - Wu, V.C. PY - 2019 UR - https://hdl.handle.net/2066/206716 AB - AKI is a global concern with a high incidence among patients across acute care settings. AKI is associated with significant clinical consequences and increased health care costs. Preventive measures, as well as rapid identification of AKI, have been shown to improve outcomes in small studies. Providing high-quality care for patients with AKI or those at risk of AKI occurs across a continuum that starts at the community level and continues in the emergency department, hospital setting, and after discharge from inpatient care. Improving the quality of care provided to these patients, plausibly mitigating the cost of care and improving short- and long-term outcomes, are goals that have not been universally achieved. Therefore, understanding how the management of AKI may be amenable to quality improvement programs is needed. Recognizing this gap in knowledge, the 22nd Acute Disease Quality Initiative meeting was convened to discuss the evidence, provide recommendations, and highlight future directions for AKI-related quality measures and care processes. Using a modified Delphi process, an international group of experts including physicians, a nurse practitioner, and pharmacists provided a framework for current and future quality improvement projects in the area of AKI. Where possible, best practices in the prevention, identification, and care of the patient with AKI were identified and highlighted. This article provides a summary of the key messages and recommendations of the group, with an aim to equip and encourage health care providers to establish quality care delivery for patients with AKI and to measure key quality indicators. TI - Quality Improvement Goals for Acute Kidney Injury EP - 953 SN - 1555-9041 IS - iss. 6 SP - 941 JF - Clinical Journal of the American Society of Nephrology VL - vol. 14 DO - https://doi.org/10.2215/CJN.01250119 ER - TY - JOUR AU - Haren, F. van AU - Pham, T. AU - Brochard, L. AU - Bellani, G. AU - Laffey, J. AU - Dres, M. AU - Fan, E. AU - Goligher, E.C. AU - Heunks, L. AU - Lynch, J. AU - Schouten, J.A. AU - Wrigge, H. AU - McAuley, D. PY - 2019 UR - https://hdl.handle.net/2066/206723 AB - OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required. TI - Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study EP - 238 SN - 0090-3493 IS - iss. 2 SP - 229 JF - Critical Care Medicine VL - vol. 47 DO - https://doi.org/10.1097/CCM.0000000000003519 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206723/206723.pdf?sequence=1 ER - TY - JOUR AU - Bersselaar, L.R. van den AU - Hoeven, J.G. van der AU - Jong, B. De PY - 2019 UR - https://hdl.handle.net/2066/206724 AB - Pesticide self-poisoning is rare in developed countries. We report a suicide case after inhalation of a pyrethrins containing insecticide spray. The patient presented at the emergency department with respiratory failure. Despite mechanical ventilation, he developed severe pulmonary inflammation with a systemic inflammatory response syndrome and died 5 days later. Studies reporting on acute pyrethrins or pyrethroids insecticide poisoning in both occupational and non-occupational cases usually describe mild and self-limiting respiratory symptoms as the predominant symptom. Severe or fatal cases of pyrethrins or pyrethroids poisoning are very rare. Patients with asthma or allergies are apparently more at risk for severe symptoms. In these cases, early and aggressive treatment with bronchodilatators, steroids, antihistamines and epinephrine should be considered. TI - Suicide after inhaling a pyrethrins containing insecticide spray SN - 1757-790X IS - iss. 4 JF - BMJ Case Reports VL - vol. 12 DO - https://doi.org/10.1136/bcr-2018-227936 ER - TY - JOUR AU - Tuinman, P.R. AU - Westerloo, D. van AU - Slot, S. AU - Touw, H.R.W. PY - 2019 UR - https://hdl.handle.net/2066/206726 TI - The 'blinking frog' ultrasound sign establishes the presence of pretracheal vasculature EP - 262 SN - 0342-4642 IS - iss. 2 SP - 261 JF - Intensive Care Medicine VL - vol. 45 DO - https://doi.org/10.1007/s00134-018-5435-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206726/206726.pdf?sequence=1 ER - TY - JOUR AU - Brussee, J.M. AU - Krekels, E.H.J. AU - Calvier, E.A.M. AU - Palic, S. AU - Rostami-Hodjegan, A. AU - Danhof, M. AU - Barrett, J.S. AU - Wildt, S.N. de AU - Knibbe, C.A. PY - 2019 UR - https://hdl.handle.net/2066/206728 AB - Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1-17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information. TI - A Pediatric Covariate Function for CYP3A-Mediated Midazolam Clearance Can Scale Clearance of Selected CYP3A Substrates in Children SN - 1550-7416 IS - iss. 5 SP - 81 JF - Aaps Journal VL - vol. 21 DO - https://doi.org/10.1208/s12248-019-0351-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206728/206728.pdf?sequence=1 ER - TY - JOUR AU - Pickkers, P. AU - Russell, J.A. PY - 2019 UR - https://hdl.handle.net/2066/206754 TI - Treatment with a polymyxin B filter to capture endotoxin in sepsis patients: is there a signal for therapeutic efficacy? EP - 283 SN - 0342-4642 IS - iss. 2 SP - 282 JF - Intensive Care Medicine VL - vol. 45 DO - https://doi.org/10.1007/s00134-018-5481-5 ER - TY - JOUR AU - Essen, T.A. van AU - Boogert, H.F. den AU - Cnossen, M.C. AU - Ruiter, G.C.W. de AU - Haitsma, I. AU - Polinder, S. AU - Steyerberg, Ewout W. AU - Menon, D. AU - Maas, A.I. AU - Lingsma, H.F. AU - Peul, W.C. AU - Bartels, R.H.M.A. AU - Hoedemaekers, A. AU - Sir, O. AU - Ziverte, A. AU - Zumbo, F. PY - 2019 UR - https://hdl.handle.net/2066/206759 AB - The collaborator names are inverted. TI - Variation in neurosurgical management of traumatic brain injury: a survey in 68 centers participating in the CENTER-TBI study EP - 455 SN - 0001-6268 IS - iss. 3 SP - 451 JF - Acta Neurochirurgica VL - vol. 161 DO - https://doi.org/10.1007/s00701-019-03815-6 ER - TY - JOUR AU - Blans, M.J. AU - Bosch, F.H. AU - Hoeven, J.G. van der PY - 2019 UR - https://hdl.handle.net/2066/206870 TI - A practical approach to critical care ultrasound EP - 164 SN - 0883-9441 SP - 156 JF - Journal of Critical Care VL - vol. 51 DO - https://doi.org/10.1016/j.jcrc.2019.01.002 ER - TY - JOUR AU - Leijte, G.P. AU - Kiers, D. AU - Heijden, W.A. van der AU - Jansen, A. AU - Gerretsen, J. AU - Boerrigter, V. AU - Netea, M.G. AU - Kox, M. AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/202958 AB - OBJECTIVE: To investigate immunostimulatory effects of acetylsalicylic acid during experimental human endotoxemia and in sepsis patients. DESIGN: Double-blind, randomized, placebo-controlled study in healthy volunteers and ex vivo stimulation experiments using monocytes of septic patients. SETTING: Intensive care research unit of an university hospital. SUBJECTS: Thirty healthy male volunteers and four sepsis patients. INTERVENTIONS: Healthy volunteers were challenged IV with endotoxin twice, at a 1-week interval, with each challenge consisting of a bolus of 1 ng/kg followed by continuous administration of 1 ng/kg/hr during 3 hours. Volunteers were randomized to acetylsalicylic acid prophylaxis (80 mg acetylsalicylic acid daily for a 14-d period, starting 7 d before the first endotoxin challenge), acetylsalicylic acid treatment (80 mg acetylsalicylic acid daily for the 7-d period in-between both endotoxin challenges), or the control group (receiving placebo). Furthermore, monocytes of sepsis patients were incubated with acetylsalicylic acid preexposed platelets and were subsequently stimulated with endotoxin. MEASUREMENTS AND MAIN RESULTS: Acetylsalicylic acid prophylaxis enhanced plasma tumor necrosis factor-alpha concentrations upon the first endotoxin challenge by 50% compared with the control group (p = 0.02) but did not modulate cytokine responses during the second endotoxin challenge. In contrast, acetylsalicylic acid treatment resulted in enhanced plasma levels of tumor necrosis factor-alpha (+53%; p = 0.02), interleukin-6 (+91%; p = 0.03), and interleukin-8 (+42%; p = 0.02) upon the second challenge, whereas plasma levels of the key antiinflammatory cytokine interleukin-10 were attenuated (-40%; p = 0.003). This proinflammatory phenotype in the acetylsalicylic acid treatment group was accompanied by a decrease in urinary prostaglandin E metabolite levels (-27% +/- 7%; p = 0.01). Ex vivo exposure of platelets to acetylsalicylic acid increased production of tumor necrosis factor-alpha (+66%) and decreased production of interleukin-10 (-23%) by monocytes of sepsis patients. CONCLUSIONS: Treatment, but not prophylaxis, with low-dose acetylsalicylic acid, partially reverses endotoxin tolerance in humans in vivo by shifting response toward a proinflammatory phenotype. This acetylsalicylic acid-induced proinflammatory shift was also observed in septic monocytes, signifying that patients suffering from sepsis-induced immunoparalysis might benefit from initiating acetylsalicylic acid treatment. TI - Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study EP - 516 SN - 0090-3493 IS - iss. 4 SP - 508 JF - Critical Care Medicine VL - vol. 47 DO - https://doi.org/10.1097/CCM.0000000000003630 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/202958/202958.pdf?sequence=1 ER - TY - JOUR AU - Marouane, A. AU - Cornelissen, E.A.M. AU - Nusmeier, A. AU - Bootsma-Robroeks, C.M.H.H.T. PY - 2019 UR - https://hdl.handle.net/2066/202679 TI - Oscillometric and intra-arterial blood pressure in children post-kidney transplantation: Is invasive blood pressure measurement always needed? SN - 1397-3142 IS - iss. 1 JF - Pediatric Transplantation VL - vol. 23 DO - https://doi.org/10.1111/petr.13309 ER - TY - JOUR AU - Groenendael, R. van AU - Beunders, R. AU - Hofland, J. AU - Morshuis, W.J. AU - Kox, M. AU - Eijk, L.T.G.J. van AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/202155 TI - The Safety, Tolerability, and Effects on the Systemic Inflammatory Response and Renal Function of the Human Chorionic Gonadotropin Hormone-Derivative EA-230 Following On-Pump Cardiac Surgery (The EASI Study): Protocol for a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study EP - 68 SN - 1929-0748 IS - iss. 2 SP - 56 JF - JMIR Research Protocols VL - vol. 8 DO - https://doi.org/10.2196/11441 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/202155/202155.pdf?sequence=1 ER - TY - JOUR AU - Westerdijk, K AU - Simons, K.S. AU - Zegers, M.J. AU - Wever, P.C. AU - Pickkers, P. AU - Jager, Cornelis P. C. de PY - 2019 UR - https://hdl.handle.net/2066/202166 TI - The value of the neutrophil-lymphocyte count ratio in the diagnosis of sepsis in patients admitted to the Intensive Care Unit: A retrospective cohort study SN - 1932-6203 IS - iss. 2 JF - PLoS One VL - vol. 14 DO - https://doi.org/10.1371/journal.pone.0212861 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/202166/202166.pdf?sequence=1 ER - TY - JOUR AU - Beumer, M.C. AU - Koch, R.M. AU - Beuningen, D. van AU - Oude Lashof, A.M.L. AU - Veerdonk, F.L. van de AU - Kolwijck, E. AU - Hoeven, J.G. van der AU - Bergmans, D.C. AU - Hoedemaekers, C.W.E. PY - 2019 UR - https://hdl.handle.net/2066/202056 TI - Influenza virus and factors that are associated with ICU admission, pulmonary co-infections and ICU mortality EP - 65 SN - 0883-9441 SP - 59 JF - Journal of Critical Care VL - vol. 50 DO - https://doi.org/10.1016/j.jcrc.2018.11.013 ER - TY - JOUR AU - Kaguelidou, F. AU - Roux, E. Le AU - Mangiarini, L. AU - Lundin, R. AU - Leeuw, T.G. de AU - Pasqua, O. Della AU - Felisi, M. AU - Bonifazi, D. AU - Tibboel, D. AU - Ceci, A. AU - Wildt, S.N. de AU - Alberti, C. PY - 2019 UR - https://hdl.handle.net/2066/203187 AB - INTRODUCTION: Gabapentin is currently used 'off-label' in children and adolescents with chronic neuropathic pain, and reliable evidence of its effects and optimal dosing are lacking. OBJECTIVES: The GABA-1 trial aims to compare the efficacy and safety of gabapentin liquid formulation relative to tramadol and to explore the pharmacokinetics of both drugs in the treatment of chronic, neuropathic or mixed pain in the paediatric population. METHODS AND ANALYSIS: The trial is a multicentre, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial. Participants aged from 3 months to <18 years of age with moderate to severe (>/=4/10 in age-appropriate pain scales) chronic neuropathic or mixed pain will be recruited in 14 clinical sites in eight European countries. A total of 94 subjects will be randomised to receive gabapentin and tramadol placebo or tramadol and gabapentin placebo throughout 16-19 weeks (including 3 weeks of titration [optimisation period], 12 weeks of treatment at a stable dose [maintenance period] and 1-4 weeks of tapering [discontinuation period]). The primary objective is to assess the efficacy of gabapentin relative to tramadol for the treatment of moderate to severe chronic neuropathic or mixed pain by comparing the difference in average pain scores (assessed by age-appropriate pain scales) between intervention arms after 15 weeks of treatment. Secondary objectives include the assessment of the safety, quality of life and global satisfaction with treatment and the description of the pharmacokinetic-pharmacodynamic relationship of gabapentin liquid formulation and tramadol oral drops to validate the recommended paediatric doses. Only rescue pain medication by paracetamol and/or ibuprofen is allowed during the trial. ETHICS AND DISSEMINATION: Ethic approval was obtained in the eight participating countries. Results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. TRIAL REGISTRATION NUMBERS: 2014-004851-30 and NCT02722603. TRIAL STATUS: Ongoing research study, currently recruiting. TI - Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: the GABA-1 trial-a study protocol SN - 2044-6055 IS - iss. 2 SP - e023296 JF - BMJ Open VL - vol. 9 DO - https://doi.org/10.1136/bmjopen-2018-023296 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/203187/203187.pdf?sequence=1 ER - TY - JOUR AU - Diez, C. Castro AU - Khalil, F. AU - Schwender, H. AU - Dalinghaus, M. AU - Jovanovic, I. AU - Makowski, N. AU - Male, C. AU - Bajcetic, M. AU - Meulen, M. van der AU - Wildt, S.N. de AU - Ablonczy, L. AU - Szatmari, A. AU - Klingmann, I. AU - Walsh, J. AU - Laer, S. PY - 2019 UR - https://hdl.handle.net/2066/203191 AB - Objective: To characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting. Methods: A Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology. Results: Out of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I in newborns. Captopril was most frequently selected as first-choice for newborns (73%) and infants and toddlers (66%) and enalapril for children (56%) and adolescents (58%). Reported starting and maintenance doses varied widely. Up to 72% of participants follow formal creatinine increase limits for decision-making when up-titrating; however, heterogeneity in the cut-off points selected existed. ACE-I formulations prescribed by 47% of participants are obtained from more than a single source. Regarding symptomatic HF maintenance therapy, 25 different initial drug combinations were reported, although 79% select a regimen that includes ACE-I and diuretic (thiazide and/or loop), 61% ACE-I and aldosterone antagonist; 44% start with beta-blocker, 52% use beta-blockers as an add-on drug. Of the 89 participants that prescribe pharmacotherapy to asymptomatic patients, 40% do not use ACE-I monotherapy or ACE-I-beta-blocker two-drug only combination. Conclusions: Despite some reluctance to use them in newborns, ACE-I seem key in paediatric HF treatment strategies. Use in single ventricle patients seems frequent, in apparent contradiction with current paediatric evidence. Disparate dosage criteria and potential formulation-induced variability suggest significant differences may exist in the risk-benefit profile children are exposed to. No uniformity seems to exist in the drug regimens in use. The information collected provides relevant insight into real-life clinical practice and may facilitate research to identify the best therapeutic options for HF children. TI - Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: a European survey SN - 2399-9772 IS - iss. 1 SP - e000365 JF - BMJ Paediatrics Open VL - vol. 3 DO - https://doi.org/10.1136/bmjpo-2018-000365 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/203191/203191.pdf?sequence=1 ER - TY - JOUR AU - Badee, J. AU - Fowler, S. AU - Wildt, S.N. de AU - Collier, A.C. AU - Schmidt, S. AU - Parrott, N. PY - 2019 UR - https://hdl.handle.net/2066/203206 AB - Limited understanding of drug pharmacokinetics in children is one of the major challenges in paediatric drug development. This is most critical in neonates and infants owing to rapid changes in physiological functions, especially in the activity of drug-metabolising enzymes. Paediatric physiologically based pharmacokinetic models that integrate ontogeny functions for cytochrome P450 enzymes have aided our understanding of drug exposure in children, including those under the age of 2 years. Paediatric physiologically based pharmacokinetic models have consequently been recognised by the European Medicines Agency and the US Food and Drug Administration as innovative tools in paediatric drug development and regulatory decision making. However, little is currently known about age-related changes in UDP-glucuronosyltransferase-mediated metabolism, which represents the most important conjugation reaction for xenobiotics. Therefore, the objective of the review was to conduct a thorough literature survey to summarise our current understanding of age-related changes in UDP-glucuronosyltransferases as well as associated clinical and experimental sources of variance. Our findings indicate that there are distinct differences in UDP-glucuronosyltransferase expression and activity between isoforms for different age groups. In addition, there is substantial variability between individuals and laboratories reported for human liver microsomes, which results in part from a lack of standardised experimental conditions. Therefore, we provide a number of best practice recommendations for experimental conditions, which ultimately may help improve the quality of data used for quantitative clinical pharmacology approaches, and thus for safe and effective pharmacotherapy in children. TI - The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling EP - 211 SN - 0312-5963 IS - iss. 2 SP - 189 JF - Clinical Pharmacokinetics VL - vol. 58 DO - https://doi.org/10.1007/s40262-018-0681-2 ER - TY - JOUR AU - Lemkes, Jorrit S. AU - Janssens, Gladys N. AU - Hoeven, Nina W. van der AU - Jewbali, Lucia S.D. AU - Dubois, Eric A. AU - Meuwissen, Martijn AU - Stoel, M.A. AU - Camaro, C. AU - Hoeven, H. van der AU - Oudemans-van Straaten, Heleen M. AU - Royen, N. van PY - 2019 UR - https://hdl.handle.net/2066/203311 TI - Coronary Angiography after Cardiac Arrest without ST-Segment Elevation EP - 1407 SN - 0028-4793 IS - iss. 15 SP - 1397 JF - The New England Journal of Medicine VL - vol. 380 DO - https://doi.org/10.1056/NEJMoa1816897 ER - TY - JOUR AU - Voller, Swantje AU - Flint, R.B. AU - Beggah, Fouzi AU - Reiss, Irwin K.M. AU - Andriessen, Peter AU - Zimmermann, L.J. AU - Liem, K.D. AU - Wildt, S.N. de AU - Knibbe, Catherijne A.J. AU - Simons, Sinno H.P. PY - 2019 UR - https://hdl.handle.net/2066/208056 TI - Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model EP - 1308 SN - 0091-2700 IS - iss. 10 SP - 1300 JF - Journal of Clinical Pharmacology and Journal of New Drugs VL - vol. 59 DO - https://doi.org/10.1002/jcph.1429 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208056/208056.pdf?sequence=1 ER - TY - JOUR AU - Teheux, L. AU - Verlaat, C.W. AU - Lemson, J. AU - Draaisma, J.M.T. AU - Fuijkschot, J. PY - 2019 UR - https://hdl.handle.net/2066/208059 TI - Risk stratification to improve Pediatric Early Warning Systems: it is all about the context EP - 1596 SN - 0340-6199 IS - iss. 10 SP - 1589 JF - European Journal of Pediatrics VL - vol. 178 DO - https://doi.org/10.1007/s00431-019-03446-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208059/208059.pdf?sequence=1 ER - TY - JOUR AU - Diez, Cristina C. AU - Khalil, F. AU - Makowski, N. AU - Schwender, Holger AU - Jovanovic, I. AU - Dalinghaus, M. AU - Wildt, S.N. de AU - Laeer, S. PY - 2019 UR - https://hdl.handle.net/2066/208038 TI - Pharmacotherapy in paediatric heart failure: a Delphi process EP - 876 SN - 1047-9511 IS - iss. 7 SP - 869 JF - Cardiology in the Young VL - vol. 29 DO - https://doi.org/10.1017/S1047951119000660 ER - TY - JOUR AU - Bauer, P.R. AU - Chevret, S. AU - Yadav, Hemang AU - Mehta, Sangeeta AU - Pickkers, P. AU - Bukan, R.B. AU - Shah, S. AU - Hemelaar, P. AU - Moralez, Guilliana M. AU - Vinatier, Isabelle PY - 2019 UR - https://hdl.handle.net/2066/207983 TI - Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy SN - 0903-1936 IS - iss. 1 JF - European Respiratory Journal VL - vol. 54 DO - https://doi.org/10.1183/13993003.02442-2018 ER - TY - JOUR AU - Cheung, Kit Wun Kathy AU - Groen, Bianca D. van AU - Burckart, Gilbert J. AU - Zhang, L. AU - Wildt, S.N. de AU - Huang, Shiew-Mei PY - 2019 UR - https://hdl.handle.net/2066/208007 TI - Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters EP - S69 SN - 0091-2700 SP - S56 JF - Journal of Clinical Pharmacology and Journal of New Drugs VL - vol. 59 DO - https://doi.org/10.1002/jcph.1489 ER - TY - JOUR AU - Grondman, I. AU - Arts, R.J.W. AU - Koch, R.M. AU - Leijte, G.P. AU - Gerretsen, J. AU - Bruse, N. AU - Kempkes, R.W.M. AU - Horst, R. ter AU - Kox, M. AU - Pickkers, P. AU - Netea, M.G. AU - Gresnigt, M.S. PY - 2019 UR - https://hdl.handle.net/2066/205267 AB - Secondary infections are a major complication of sepsis and associated with a compromised immune state, called sepsis-induced immunoparalysis. Molecular mechanisms causing immunoparalysis remain unclear; however, changes in cellular metabolism of leukocytes have been linked to immunoparalysis. We investigated the relation of metabolic changes to antimicrobial monocyte functions in endotoxin-induced immunotolerance, as a model for sepsis-induced immunoparalysis. In this study, immunotolerance was induced in healthy males by intravenous endotoxin (2 ng/kg, derived from Escherichia coli O:113) administration. Before and after induction of immunotolerance, circulating CD14(+) monocytes were isolated and assessed for antimicrobial functions, including cytokine production, oxidative burst, and microbial (Candida albicans) killing capacity, as well metabolic responses to ex vivo stimulation. Next, the effects of altered cellular metabolism on monocyte functions were validated in vitro. Ex vivo lipopolysaccharide stimulation induced an extensive rewiring of metabolism in naive monocytes. In contrast, endotoxin-induced immunotolerant monocytes showed no metabolic plasticity, as they were unable to adapt their metabolism or mount cytokine and oxidative responses. Validation experiments showed that modulation of metabolic pathways, affected by immunotolerance, influenced monocyte cytokine production, oxidative burst, and microbial (C. albicans) killing in naive monocytes. Collectively, these data demonstrate that immunotolerant monocytes are characterized by a loss of metabolic plasticity and these metabolic defects impact antimicrobial monocyte immune functions. Further, these findings support that the changed cellular metabolism of immunotolerant monocytes might reveal novel therapeutic targets to reverse sepsis-induced immunoparalysis. TI - Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst EP - 25 SN - 0741-5400 IS - iss. 1 SP - 11 JF - Journal of Leukocyte Biology VL - vol. 106 DO - https://doi.org/10.1002/JLB.5HI0119-018R L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/205267/205267.pdf?sequence=1 ER - TY - JOUR AU - Kiers, D. AU - Eijk, L.T.G.J. van AU - Hoeven, J.G. van der AU - Swinkels, D.W. AU - Pickkers, P. AU - Kox, M. PY - 2019 UR - https://hdl.handle.net/2066/205269 TI - Hypoxia attenuates inflammation-induced hepcidin synthesis during experimental human endotoxemia EP - 232 SN - 0390-6078 IS - iss. 6 SP - 230 JF - Haematologica VL - vol. 104 DO - https://doi.org/10.3324/haematol.2018.202796 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/205269/205269.pdf?sequence=1 ER - TY - JOUR AU - Wassenaar, A. AU - Schoonhoven, L. AU - Devlin, J.W. AU - Haren, F.M. van AU - Slooter, A.J. AU - Jorens, P.G. AU - Jagt, M. van der AU - Simons, K.S. AU - Egerod, I. AU - Burry, L.D. AU - Beishuizen, A. AU - Matos, J. AU - Donders, A.R.T. AU - Pickkers, P. AU - Boogaard, M. van den PY - 2019 UR - https://hdl.handle.net/2066/208358 AB - OBJECTIVES: To externally validate two delirium prediction models (early prediction model for ICU delirium and recalibrated prediction model for ICU delirium) using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. DESIGN: Prospective, multinational cohort study. SETTING: Eleven ICUs from seven countries in three continents. PATIENTS: Consecutive, delirium-free adults admitted to the ICU for greater than or equal to 6 hours in whom delirium could be reliably assessed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The predictors included in each model were collected at the time of ICU admission (early prediction model for ICU delirium) or within 24 hours of ICU admission (recalibrated prediction model for ICU delirium). Delirium was assessed using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. Discrimination was determined using the area under the receiver operating characteristic curve. The predictive performance was determined for the Confusion Assessment Method-ICU and Intensive Care Delirium Screening Checklist cohort, and compared with both prediction models' original reported performance. A total of 1,286 Confusion Assessment Method-ICU-assessed patients and 892 Intensive Care Delirium Screening Checklist-assessed patients were included. Compared with the area under the receiver operating characteristic curve of 0.75 (95% CI, 0.71-0.79) in the original study, the area under the receiver operating characteristic curve of the early prediction model for ICU delirium was 0.67 (95% CI, 0.64-0.71) for delirium as assessed using the Confusion Assessment Method-ICU and 0.70 (95% CI, 0.66-0.74) using the Intensive Care Delirium Screening Checklist. Compared with the original area under the receiver operating characteristic curve of 0.77 (95% CI, 0.74-0.79), the area under the receiver operating characteristic curve of the recalibrated prediction model for ICU delirium was 0.75 (95% CI, 0.72-0.78) for assessing delirium using the Confusion Assessment Method-ICU and 0.71 (95% CI, 0.67-0.75) using the Intensive Care Delirium Screening Checklist. CONCLUSIONS: Both the early prediction model for ICU delirium and recalibrated prediction model for ICU delirium are externally validated using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. Per delirium prediction model, both assessment tools showed a similar moderate-to-good statistical performance. These results support the use of either the early prediction model for ICU delirium or recalibrated prediction model for ICU delirium in ICUs around the world regardless of whether delirium is evaluated with the Confusion Assessment Method-ICU or Intensive Care Delirium Screening Checklist. TI - External Validation of Two Models to Predict Delirium in Critically Ill Adults Using Either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for Delirium Assessment EP - e835 SN - 0090-3493 IS - iss. 10 SP - e827 JF - Critical Care Medicine VL - vol. 47 DO - https://doi.org/10.1097/CCM.0000000000003911 ER - TY - JOUR AU - Geven, C.B.C.A.G. AU - Blet, A. AU - Kox, M. AU - Hartmann, O. AU - Scigalla, P. AU - Zimmermann, J. AU - Marx, G. AU - Laterre, P.F. AU - Mebazaa, A. AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/205501 AB - INTRODUCTION: Sepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist. Adrenomedullin (ADM) is a vasoactive peptide. High plasma concentrations of ADM correlate with worse outcome in sepsis patients. Preclinical work with the non-neutralising ADM-binding antibody adrecizumab showed promising effects in animal models of septic shock, including improved vascular barrier function, reduced vasopressor demand and organ dysfunction and increased survival. Therapeutic use of adrecizumab may therefore improve outcome in critically ill patients with septic shock and high ADM plasma concentrations. Phase I studies in healthy volunteers did not reveal any safety concerns. In this biomarker-guided trial, the safety and efficacy of adrecizumab will be investigated in patients with septic shock. METHODS AND ANALYSIS: We describe a phase II, randomised, double-blind, placebo-controlled, biomarker-guided, proof-of-concept and dose-finding clinical trial in patients with early septic shock and high concentration of circulating ADM. A total of 300 patients will be enrolled at approximately 30 sites within the European Union. Patients are randomised to receive active treatment (2 and 4 mg/kg adrecizumab) or placebo, in a 1:1:2 ratio. Patient selection is guided by clinical parameters, and biomarker-guided by measurement of circulating biologically active ADM concentration at admission. Primary endpoint is safety and tolerability of adrecizumab over a 90-day period. A key secondary endpoint is the Sepsis Severity Index over a 14-day period. ETHICS AND DISSEMINATION: This study is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, the European Medicines Agency guidelines of Good Clinical Practice and all other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT03085758; Pre-results. TI - A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2) SN - 2044-6055 IS - iss. 2 JF - BMJ Open VL - vol. 9 DO - https://doi.org/10.1136/bmjopen-2018-024475 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/205501/205501.pdf?sequence=1 ER - TY - JOUR AU - Pickkers, P. AU - Vassiliou, Timon AU - Liguts, Valdis AU - Prato, Federico AU - Tissieres, Pierre AU - Kloesel, Stephan AU - Goldstein, Jacques AU - Harenski, Kai PY - 2019 UR - https://hdl.handle.net/2066/204053 TI - Sepsis Management with a Blood Purification Membrane: European Experience EP - 44 SN - 0253-5068 SP - 36 JF - Blood Purification VL - vol. 47 DO - https://doi.org/10.1159/000499355 ER - TY - JOUR AU - Monnier, A.A. AU - Schouten, J.A. AU - Tebano, G. AU - Zanichelli, V. AU - Huttner, B.D. AU - Pulcini, C. AU - Hulscher, M.E. AU - Gyssens, I.C.J. PY - 2019 UR - https://hdl.handle.net/2066/204573 TI - Ensuring Antibiotic Development, Equitable Availability, and Responsible Use of Effective Antibiotics: Recommendations for Multisectoral Action EP - 1959 SN - 1058-4838 IS - iss. 11 SP - 1952 JF - Clinical Infectious Diseases VL - vol. 68 DO - https://doi.org/10.1093/cid/ciy824 ER - TY - JOUR AU - Blet, A. AU - Deniau, Benjamin AU - Geven, C.B.C.A.G. AU - Sadoune, M. AU - Caillard, Anais AU - Kounde, Paul-Robert AU - Pickkers, P. AU - Samuel, Jane-Lise AU - Mebazaa, Alexandre PY - 2019 UR - https://hdl.handle.net/2066/203895 TI - Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats SN - 2197-425X JF - Intensive Care Medicine Experimental VL - vol. 7 DO - https://doi.org/10.1186/s40635-019-0255-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/203895/203895.pdf?sequence=1 ER - TY - JOUR AU - Rood, P.J.T. AU - Frenzel, T. AU - Verhage, R. AU - Bonn, M. AU - Hoeven, H. van der AU - Pickkers, P. AU - Boogaard, M. van den PY - 2019 UR - https://hdl.handle.net/2066/204752 TI - Development and daily use of a numeric rating score to assess sleep quality in ICU patients EP - 74 SN - 0883-9441 SP - 68 JF - Journal of Critical Care VL - vol. 52 DO - https://doi.org/10.1016/j.jcrc.2019.04.009 ER - TY - JOUR AU - Admiraal, Marjolein M. AU - Rootselaar, A.F. van AU - Hofmeijer, J. AU - Hoedemaekers, C.W.E. AU - Kaam, C.R. van AU - Keijzer, H.M. AU - Schultz, Marcus J. AU - Horn, Janneke PY - 2019 UR - https://hdl.handle.net/2066/204755 TI - Electroencephalographic reactivity as predictor of neurological outcome in postanoxic coma: A multicenter prospective cohort study EP - 27 SN - 0364-5134 IS - iss. 1 SP - 17 JF - Annals of Neurology VL - vol. 86 DO - https://doi.org/10.1002/ana.25507 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/204755/204755.pdf?sequence=1 ER - TY - JOUR AU - Oppersma, Eline AU - Doorduin, J. AU - Gooskens, Petra J. AU - Roesthuis, L.H. AU - Heijden, E. van der AU - Hoeven, J.G. van der AU - Veltink, Peter H. AU - Heunks, L.M.A. PY - 2019 UR - https://hdl.handle.net/2066/203017 TI - Glottic patency during noninvasive ventilation in patients with chronic obstructive pulmonary disease EP - 57 SN - 1569-9048 SP - 53 JF - Respiratory Physiology & Neurobiology VL - vol. 259 DO - https://doi.org/10.1016/j.resp.2018.07.006 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/203017/203017.pdf?sequence=1 ER - TY - JOUR AU - Ketharanathan, N. AU - Yamamoto, Y. AU - Rohlwink, U.K. AU - Wildschut, E.D. AU - Mathot, R.A.A. AU - Lange, E.C.M. de AU - Wildt, S.N. de AU - Argent, A.C. AU - Tibboel, D. AU - Figaji, A.A. PY - 2019 UR - https://hdl.handle.net/2066/203150 AB - Evidence-based analgosedation in severe pediatric traumatic brain injury (pTBI) management is lacking, and improved pharmacological understanding is needed. This starts with increased knowledge of factors controlling the pharmacokinetics (PK) of unbound drug at the target site (brain) and related drug effect(s). This prospective, descriptive study tested a pediatric physiology-based pharmacokinetic software model by comparing actual plasma and brain extracellular fluid (brainECF) morphine concentrations with predicted concentration-time profiles in severe pTBI patients (Glasgow Coma Scale [GCS], /= 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. DISCUSSION: We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. TRIAL REGISTRATION: EudractCT, 2014-004897-40 . Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012 . Registered on 7 September 2017. TI - Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial SN - 1745-6215 JF - Trials VL - vol. 20 DO - https://doi.org/10.1186/s13063-018-3169-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/203162/203162.pdf?sequence=1 ER - TY - THES AU - Kiers, H.D. PY - 2019 UR - https://hdl.handle.net/2066/200678 PB - [S.l. : s.n.] TI - Oxygen and platelets. Translational studies on therapeutic targets for immunomodulation N1 - Radboud University, 4 februari 2019 N1 - Promotores : Pickkers, P., Scheffer, G.J. Co-promotor : Kox, M. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/200678/200678.pdf?sequence=1 ER - TY - THES AU - Brule, J.M.D. van den PY - 2019 UR - https://hdl.handle.net/2066/200690 PB - [S.l. : s.n.] TI - Cerebral hemodynamics. After cardiac arrest, in sepsis and in the human endotoxemia model N1 - Radboud University, 21 februari 2019 N1 - Promotor : Hoeven, J.G. van der Co-promotor : Hoedemaekers, C.W.E. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/200690/200690.pdf?sequence=1 ER - TY - THES AU - Koch, R.M. PY - 2019 UR - https://hdl.handle.net/2066/207783 PB - [S.l. : s.n.] TI - Differential pathogen-host interactions N1 - Radboud University, 25 oktober 2019 N1 - Promotor : Pickkers, P. Co-promotores : Kox, M., Jonge, M.I. de L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/207783/207783.pdf?sequence=1 ER - TY - JOUR AU - Onland, Wes AU - Cools, Filip AU - Kroon, Andre AU - Rademaker, Karin AU - Merkus, Maruschka P. AU - Dijk, Peter H. AU - Heijst, A.F.J. van AU - Matthijsse, R. AU - Boode, W.P. de AU - Baal, Caroline van AU - Wildt, S.N. de PY - 2019 UR - https://hdl.handle.net/2066/201191 TI - Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation A Randomized Clinical Trial EP - 363 SN - 0098-7484 IS - iss. 4 SP - 354 JF - Jama : Journal of the American Medical Association VL - vol. 321 DO - https://doi.org/10.1001/jama.2018.21443 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/201191/201191.pdf?sequence=1 ER - TY - THES AU - Geven, C.B.C.A.G. PY - 2019 UR - https://hdl.handle.net/2066/201197 PB - [S.l. : s.n.] TI - Targeting adrenomedullin in sepsis N1 - Radboud University, 15 maart 2019 N1 - Promotor : Pickkers, P. Co-promotor : Kox, M. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/201197/201197.pdf?sequence=1 ER - TY - JOUR AU - Schijvens, A.M. AU - Hesteren, Fransje H.S. van AU - Cornelissen, E.A.M. AU - Bootsma-Robroeks, Charlotte M.H.H.T. AU - Bruggemann, R.J.M. AU - Burger, D.M. AU - Wildt, S.N. de AU - Schreuder, M.F. AU - Heine, R. ter PY - 2019 UR - https://hdl.handle.net/2066/201264 TI - The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients EP - 515 SN - 0931-041X IS - iss. 3 SP - 507 JF - Pediatric Nephrology VL - vol. 34 DO - https://doi.org/10.1007/s00467-018-4117-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/201264/201264.pdf?sequence=1 ER - TY - JOUR AU - Dominguez Andres, J. AU - Novakovic, B. AU - Li, Yang AU - Scicluna, B.P. AU - Gresnigt, M.S. AU - Arts, R.J. AU - Oosting, M. AU - Moorlag, S.J.C.F.M. AU - Groh, L.A. AU - Zwaag, J. AU - Koch, R.M. AU - Horst, R. ter AU - Joosten, L.A.B. AU - Kox, M. AU - Pickkers, P. AU - Kumar, V. AU - Stunnenberg, H.G. AU - Netea, M.G. PY - 2019 UR - https://hdl.handle.net/2066/201256 TI - The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity EP - 220 SN - 1550-4131 IS - iss. 1 SP - 211 JF - Cell Metabolism VL - vol. 29 DO - https://doi.org/10.1016/j.cmet.2018.09.003 ER - TY - JOUR AU - Janssen, M.C.H. AU - Koene, S. AU - Laat, P. de AU - Hemelaar, P. AU - Pickkers, P. AU - Spaans, Edwin AU - Beukema, R.J. AU - Beyrath, J.D. AU - Groothuis, J.T. AU - Verhaak, C.M. AU - Smeitink, J. PY - 2019 UR - https://hdl.handle.net/2066/201258 TI - The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders EP - 111 SN - 0009-9236 IS - iss. 1 SP - 101 JF - Clinical Pharmacology and Therapeutics VL - vol. 105 DO - https://doi.org/10.1002/cpt.1197 ER - TY - JOUR AU - Kiers, D. AU - Leijte, G.P. AU - Gerretsen, J. AU - Zwaag, J. AU - Kox, M. AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/201084 TI - Comparison of different lots of endotoxin and evaluation of in vivo potency over time in the experimental human endotoxemia model EP - 45 SN - 1753-4259 IS - iss. 1 SP - 34 JF - Innate Immunity VL - vol. 25 DO - https://doi.org/10.1177/1753425918819754 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/201084/201084.pdf?sequence=1 ER - TY - JOUR AU - Numan, T. AU - Boogaard, M. van den AU - Kamper, A.M. AU - Rood, P.J.T. AU - Schoon, Y. AU - Peelen, L.M. AU - Slooter, A.J. PY - 2019 UR - https://hdl.handle.net/2066/199936 TI - Delirium detection using relative delta power based on 1-minute single-channel EEG: a multicentre study EP - 68 SN - 0007-0912 IS - iss. 1 SP - 60 JF - British Journal of Anaesthesia VL - vol. 122 DO - https://doi.org/10.1016/j.bja.2018.08.021 ER - TY - JOUR AU - Schijvens, A.M. AU - Heine, R. ter AU - Wildt, S.N. de AU - Schreuder, M.F. PY - 2019 UR - https://hdl.handle.net/2066/202596 AB - Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice. TI - Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome EP - 403 SN - 0931-041X IS - iss. 3 SP - 389 JF - Pediatric Nephrology VL - vol. 34 DO - https://doi.org/10.1007/s00467-018-3929-z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/202596/202596.pdf?sequence=1 ER - TY - JOUR AU - Geven, C.B.C.A.G. AU - Kox, M. AU - Blet, A. AU - Mebazaa, Alexandre AU - Schroedter, Mathias AU - Struck, Joachim AU - Bergmann, A. AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/202597 TI - Preclinical safety evaluation of the adrenomedullin-binding antibody Adrecizumab in rodents, dogs and non-human primates EP - 16 SN - 0041-008X SP - 1 JF - Toxicology and Applied Pharmacology VL - vol. 369 DO - https://doi.org/10.1016/j.taap.2019.02.014 ER - TY - JOUR AU - Rubio, I. AU - Osuchowski, M.F. AU - Shankar-Hari, M. AU - Skirecki, T. AU - Winkler, M.S. AU - Lachmann, G. AU - Rosee, P. La AU - Monneret, G. AU - Venet, F. AU - Bauer, M AU - Brunkhorst, F.M. AU - Kox, M. AU - Cavaillon, J.M. AU - Uhle, F. AU - Weigand, M.A. AU - Flohe, S.B. AU - Wiersinga, W.J. AU - Martin-Fernandez, M. AU - Almansa, R. AU - Martin-Loeches, I. AU - Torres, A. Cedillo AU - Giamarellos-Bourboulis, E.J. AU - Girardis, M. AU - Cossarizza, A. AU - Netea, M.G. AU - Poll, T. van der AU - Scherag, A. AU - Meisel, C. AU - Schefold, J.C. AU - Bermejo-Martin, J.F. PY - 2019 UR - https://hdl.handle.net/2066/215595 AB - Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care. TI - Current gaps in sepsis immunology: new opportunities for translational research EP - e436 SN - 1473-3099 IS - iss. 12 SP - e422 JF - Lancet Infectious Diseases VL - vol. 19 DO - https://doi.org/10.1016/S1473-3099(19)30567-5 ER - TY - JOUR AU - Kleiber, N. AU - Calvier, E. AU - Mooij, M.G. AU - Krekels, E.H.J. AU - Vaes, W.H. AU - Tibboel, D. AU - Knibbe, C.A.J. AU - Wildt, S.N. de PY - 2019 UR - https://hdl.handle.net/2066/215611 AB - OBJECTIVES: Decreasing morbidity and mortality by rationalizing drug treatment in the critically ill is of paramount importance but challenging as the underlying clinical condition may lead to large variation in drug disposition and response. New microtracer methodology is now available to gain knowledge on drug disposition in the intensive care. On the basis of studies in healthy adults, physicians tend to assume that oral doses of acetaminophen will be completely absorbed and therefore prescribe the same dose per kilogram for oral and IV administration. As the oral bioavailability of acetaminophen in critically ill children is unknown, we designed a microtracer study to shed a light on this issue. DESIGN: An innovative microtracer study design with population pharmacokinetics. SETTING: A tertiary referral PICU. PATIENTS: Stable critically ill children, 0-6 years old, and already receiving IV acetaminophen. INTERVENTIONS: Concomitant administration of an oral C radiolabeled acetaminophen microtracer (3 ng/kg) with IV acetaminophen treatment (15 mg/kg every 6 hr). MEASUREMENTS: Blood was drawn from an indwelling arterial or central venous catheter up to 24 hours after C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and C concentrations by accelerated mass spectrometry. MAIN RESULTS: In 47 patients (median age of 6.1 mo; Q1-Q3, 1.8-20 mo) the mean enteral bioavailability was 72% (range, 11-91%). With a standard dose (15 mg/kg 4 times daily), therapeutic steady-state concentrations were 2.5 times more likely to be reached with IV than with oral administration. CONCLUSIONS: Microtracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral administration of acetaminophen results in less predictable exposure and higher likelihood of subtherapeutic blood concentration than does IV administration. IV dosing may be preferable to ensure adequate pain relief. TI - Enteral Acetaminophen Bioavailability in Pediatric Intensive Care Patients Determined With an Oral Microtracer and Pharmacokinetic Modeling to Optimize Dosing EP - e983 SN - 0090-3493 IS - iss. 12 SP - e975 JF - Critical Care Medicine VL - vol. 47 DO - https://doi.org/10.1097/CCM.0000000000004032 ER - TY - JOUR AU - Witjes, M. AU - Kotsopoulos, A.M.M. AU - Otterspoor, L. AU - Herold, I.H.F. AU - Simons, K.S. AU - Woittiez, K. AU - Eijkenboom, J.J. AU - Hoeven, J.G. van der AU - Jansen, N.E. AU - Abdo, W.F. PY - 2019 UR - https://hdl.handle.net/2066/215536 AB - BACKGROUND: The aim of this study was to evaluate the implementation process of a multidisciplinary approach for potential organ donors in the emergency department (ED) in order to incorporate organ donation into their end-of-life care plans. METHODS: A new multidisciplinary approach was implemented in 6 hospitals in The Netherlands between January 2016 and January 2018. The approach was introduced during staff meetings in the ED, intensive care unit (ICU), and neurology department. When patients with a devastating brain injury had a futile prognosis in the ED, without contraindications for organ donation, an ICU admission was considered. Every ICU admission to incorporate organ donation into end-of-life care was systematically evaluated with the involved physicians using a standardized questionnaire. RESULTS: In total, 55 potential organ donors were admitted to the ICU to incorporate organ donation into end-of-life care. Twenty-seven families consented to donation and 20 successful organ donations were performed. Twenty-nine percent of the total pool of organ donors in these hospitals were admitted to the ICU for organ donation. CONCLUSIONS: Patients with a devastating brain injury and futile medical prognosis in the ED are an important proportion of the total number of donors. The implementation of a multidisciplinary approach is feasible and could lead to better identification of potential donors in the ED. TI - The Implementation of a Multidisciplinary Approach for Potential Organ Donors in the Emergency Department EP - 2365 SN - 0041-1337 IS - iss. 11 SP - 2359 JF - Transplantation VL - vol. 103 DO - https://doi.org/10.1097/TP.0000000000002701 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215536/215536.pdf?sequence=1 ER - TY - JOUR AU - Blans, M.J. AU - Bosch, F.H. AU - Hoeven, J.G. van der PY - 2019 UR - https://hdl.handle.net/2066/215548 AB - BACKGROUND: In critical care medicine, the use of transthoracic echo (TTE) is expanding. TTE can be used to measure dynamic parameters such as cardiac output (CO). An important asset of TTE is that it is a non-invasive technique. The Probefix is an external ultrasound holder strapped to the patient which makes it possible to measure CO using TTE in a fixed position possibly making the CO measurements more accurate compared to separate TTE CO measurements. The feasibility of the use of the Probefix to measure CO before and after a passive leg raising test (PLR) was studied. Intensive care patients were included after detection of hypovolemia using Flotrac. Endpoints were the possibility to use Probefix. Also CO measurements with and without the use of Probefix, before and after a PLR were compared to the CO measurements using Flotrac. Side effects in terms of skin alterations after the use of Probefix and patient's comments on (dis)comfort were evaluated. RESULTS: Ten patients were included; in eight patients, sufficient recordings with the use of Probefix could be obtained. Using Bland-Altman plots, no difference was found in accuracy of measurements of CO with or without the use of Probefix before and after a PLR compared to Flotrac generated CO. There were only mild and temporary skin effects of the use of Probefix. CONCLUSIONS: In this small feasibility study, the Probefix could be used in eight out of ten intensive care patients. The use of Probefix did not result in more or less accurate CO measurements compared to manually recorded TTE CO measurements. We suggest that larger studies on the use of Probefix in intensive care patients are needed. TI - The use of an external ultrasound fixator (Probefix) on intensive care patients: a feasibility study SN - 2524-8987 IS - iss. 1 SP - 26 JF - The Ultrasound Journal VL - vol. 11 DO - https://doi.org/10.1186/s13089-019-0140-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215548/215548.pdf?sequence=1 ER - TY - JOUR AU - Loon, L.M. van AU - Rongen, G.A.P.J.M. AU - Hoeven, J.G. van der AU - Veltink, P.H. AU - Lemson, J. PY - 2019 UR - https://hdl.handle.net/2066/215563 AB - Clinical data suggests that heart rate (HR) control with selective beta1-blockers may improve cardiac function during septic shock. However, it seems counterintuitive to start beta-blocker infusion in a shock state when organ blood flow is already low or insufficient. Therefore, we studied the effects of HR control with esmolol, an ultrashort- acting beta1-selective adrenoceptor antagonist, on renal blood flow (RBF) and renal autoregulation during early septic shock. In 10 healthy sheep, sepsis was induced by continuous i.v. administration of lipopolysaccharide, while maintained under anesthesia and mechanically ventilated. After successful resuscitation of the septic shock with fluids and vasoactive drugs, esmolol was infused to reduce HR with 30% and was stopped 30-min after reaching this target. Arterial and venous pressures, and RBF were recorded continuously. Renal autoregulation was evaluated by the response in RBF to renal perfusion pressure (RPP) in both the time domain and frequency domain. During septic shock, beta-blockade with esmolol significantly increased the pressure dependency of RBF to RPP. Stopping esmolol showed the reversibility of the impaired renal autoregulation. Showing that clinical diligence and caution are necessary when treating septic shock with esmolol in the acute phase since esmolol reduced RPP to critical values thereby significantly reducing RBF. TI - beta-Blockade attenuates renal blood flow in experimental endotoxic shock by reducing perfusion pressure SN - 2051-817X IS - iss. 23 SP - e14301 JF - Physiological Reports VL - vol. 7 DO - https://doi.org/10.14814/phy2.14301 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215563/215563.pdf?sequence=1 ER - TY - JOUR AU - Buijze, G.A. AU - Jong, H.M.Y. De AU - Kox, M. AU - Sande, M.G. van de AU - Schaardenburg, D. van AU - Vugt, R.M. Van AU - Popa, C. AU - Pickkers, P. AU - Baeten, D.L. PY - 2019 UR - https://hdl.handle.net/2066/215570 AB - OBJECTIVES: The primary objective of this trial was to assess safety and anti-inflammatory effects of an add-on training program involving breathing exercises, cold exposure, and meditation in patients with axial spondyloarthritis. METHODS: This study was an open-label, randomised, one-way crossover clinical proof-of-concept trial. Twenty-four patients with moderately active axial spondyloarthritis(ASDAS >2.1) and hs-CRP >/=5mg/L were included and randomised to an intervention (n = 13) and control group (n = 11) group that additionally received the intervention after the control period. The intervention period lasted for 8 weeks. The primary endpoint was safety, secondary endpoints were change in hs-CRP, serum calprotectin levels and ESR over the 8-week period. Exploratory endpoints included disease activity measured by ASDAS-CRP and BASDAI, quality of life (SF-36, EQ-5D, EQ-5D VAS), and hospital anxiety and depression (HADS). RESULTS: We found no significant differences in adverse events between groups, with one serious adverse event occurring 8 weeks after end of the intervention and judged 'unrelated'. During the 8-week intervention period, there was a significant decline of ESR from (median [interquartile range] to 16 [9-26.5] to 9 [5-23] mm/hr, p = 0.040, whereas no effect was found in the control group (from 14 [8.3-27.3] to 16 [5-37] m/hr, p = 0.406). ASDAS-CRP declined from 3.1 [2.5-3.6] to 2.3 [1.9-3.2] in the intervention group (p = 0.044). A similar trend was observed for serum calprotectin (p = 0.064 in the intervention group versus p = 0.182 in the control group), but not for hs-CRP. CONCLUSIONS: This proof-of-concept study in axial spondyloarthritis met its primary endpoint with no safety signals during the intervention. There was a significant decrease in ESR levels and ASDAS-CRP upon the add-on training program in the intervention group. These findings warrant full-scale randomised controlled trials of this novel therapeutic approach in patients with inflammatory conditions. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02744014. TI - An add-on training program involving breathing exercises, cold exposure, and meditation attenuates inflammation and disease activity in axial spondyloarthritis - A proof of concept trial SN - 1932-6203 IS - iss. 12 JF - PLoS One VL - vol. 14 DO - https://doi.org/10.1371/journal.pone.0225749 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215570/215570.pdf?sequence=1 ER - TY - JOUR AU - Hanskamp-Sebregts, M.E. AU - Zegers, M. AU - Westert, G.P. AU - Boeijen, W.M.J. AU - Teerenstra, S. AU - Gurp, P.J.M. van AU - Wollersheim, H.C. PY - 2019 UR - https://hdl.handle.net/2066/215427 AB - OBJECTIVE: To evaluate the effectiveness of internal auditing in hospital care focussed on improving patient safety. DESIGN, SETTING AND PARTICIPANTS: A before-and-after mixed-method evaluation study was carried out in eight departments of a university medical center in the Netherlands. INTERVENTION(S): Internal auditing and feedback focussed on improving patient safety. MAIN OUTCOME MEASURE(S): The effect of internal auditing was assessed 15 months after the audit, using linear mixed models, on the patient, professional, team and departmental levels. The measurement methods were patient record review on adverse events (AEs), surveys regarding patient experiences, safety culture and team climate, analysis of administrative hospital data (standardized mortality rate, SMR) and safety walk rounds (SWRs) to observe frontline care processes on safety. RESULTS: The AE rate decreased from 36.1% to 31.3% and the preventable AE rate from 5.5% to 3.6%; however, the differences before and after auditing were not statistically significant. The patient-reported experience measures regarding patient safety improved slightly over time (P < 0.001). The SMR, patient safety culture and team climate remained unchanged after the internal audit. The SWRs showed that medication safety and information security were improved (P < 0.05). CONCLUSIONS: Internal auditing was associated with improved patient experiences and observed safety on wards. No effects were found on adverse outcomes, safety culture and team climate 15 months after the internal audit. TI - Effects of patient safety auditing in hospital care: results of a mixed-method evaluation (part 1) EP - 15 SN - 1353-4505 IS - iss. 7 SP - 8 JF - International Journal for Quality in Health Care VL - vol. 31 DO - https://doi.org/10.1093/intqhc/mzy134 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215427/215427.pdf?sequence=1 ER - TY - JOUR AU - Bruintjes, M.H.D. AU - Krijtenburg, P. AU - Martini, Chiara AU - Poyck, P. AU - D'Ancona, F.C.H. AU - Huurman, V.A.L. AU - Jagt, M.F. van der AU - Langenhuijsen, J.F. AU - Nijboer, W.N. AU - Laarhoven, C.J.H.M. van AU - Dahan, A. AU - Warle, M.C. AU - Albers, K.I. AU - Donders, A.R.T. AU - Hilbrands, L.B. AU - Scheffer, G.J. PY - 2019 UR - https://hdl.handle.net/2066/215207 AB - BACKGROUND: Profound neuromuscular blockade (NMB) during anaesthesia has been shown to reduce postoperative pain scores, when compared with a moderate block. We hypothesised that profound NMB during laparoscopic donor nephrectomy (LDN) could also improve the early quality of recovery after surgery. OBJECTIVES: To compare the effectiveness of profound versus moderate NMB during LDN in enhancing postoperative recovery. DESIGN: A phase IV, double-blinded, randomised controlled trial. SETTING: Multicentre trial, from November 2016 to December 2017. PATIENTS: A total of 101 living kidney donors scheduled for LDN were enrolled, and 96 patients were included in the analyses. INTERVENTIONS: Patients were randomised to receive profound (posttetanic count 1 to 3) or moderate (train-of-four count 1 to 3) neuromuscular block. MAIN OUTCOME MEASURES: The primary outcome was the early quality of recovery at postoperative day 1, measured by the Quality of Recovery-40 Questionnaire. Secondary outcomes were adverse events, postoperative pain, analgesic consumption and length-of-stay. RESULTS: The intention-to-treat analysis did not show a difference with regard to the quality of recovery, pain scores, analgesic consumption and length-of-stay. Less intra-operative adverse events occurred in patients allocated to profound NMB (1/48 versus 6/48). Five patients allocated to a profound NMB received a moderate block and in two patients neuromuscular monitoring failed. The as-treated analysis revealed that pain scores were significantly lower at 6, 24 and 48 h after surgery. Moreover, the quality of recovery was significantly better at postoperative day 2 in patients receiving a profound versus moderate block (179.5 +/- 13.6 versus 172.3 +/- 19.2). CONCLUSION: Secondary analysis indicates that an adequately maintained profound neuromuscular block improves postoperative pain scores and quality of recovery. As the intention-to-treat analysis did not reveal a difference regarding the primary endpoint, future studies should pursue whether a thoroughly maintained profound NMB during laparoscopy improves relevant patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02838134. TI - Efficacy of profound versus moderate neuromuscular blockade in enhancing postoperative recovery after laparoscopic donor nephrectomy: A randomised controlled trial EP - 501 SN - 0265-0215 IS - iss. 7 SP - 494 JF - European Journal of Anaesthesiology VL - vol. 36 DO - https://doi.org/10.1097/EJA.0000000000000992 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215207/215207.pdf?sequence=1 ER - TY - JOUR AU - Albers, K.I. AU - Diaz-Cambronero, O. AU - Keijzer, C. AU - Snoeck, M.M.J. AU - Warle, M.C. AU - Fuchs-Buder, T. PY - 2019 UR - https://hdl.handle.net/2066/215225 TI - Revisiting the Classification of Neuromuscular Blockade, Aligning Clinical Practice and Research. EP - e178 SN - 0003-2999 IS - iss. 5 SP - e176 JF - Anesthesia and Analgesia VL - vol. 129 N1 - 1 november 2019 DO - https://doi.org/10.1213/ANE.0000000000004407 ER - TY - JOUR AU - Hoedemaekers, C. PY - 2019 UR - https://hdl.handle.net/2066/214910 AB - With an ageing population, the number of very old patients that are admitted to an intensive care unit (ICU) is also increasing. The possible benefit of ICU admission for these patients should be weighed against the risks of cognitive and functional impairment. Prospective studies are necessary to optimize the triage process and to identify factors, other than age, that are related to long-term outcome in ICU patients. TI - [Elderly patients in the ICU: extending life to the max?] SN - 0028-2162 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 163 ER - TY - JOUR AU - Hanskamp-Sebregts, M.E.C. AU - Zegers, M. AU - Boeijen, W.M.J. AU - Wollersheim, H.C. AU - Gurp, P.J. van AU - Westert, G.P. PY - 2019 UR - https://hdl.handle.net/2066/209687 TI - Process evaluation of the effects of patient safety auditing in hospital care (part 2) EP - 441 SN - 1353-4505 IS - iss. 6 SP - 433 JF - International Journal for Quality in Health Care VL - vol. 31 DO - https://doi.org/10.1093/intqhc/mzy173 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/209687/209687.pdf?sequence=1 ER - TY - JOUR AU - Witjes, M. AU - Kruijff, P.E.V. AU - Haase-Kromwijk, B. AU - Hoeven, J.G. van der AU - Jansen, N.E. AU - Abdo, W.F. PY - 2019 UR - https://hdl.handle.net/2066/208686 AB - BACKGROUND: The aim of this nationwide observational study is to identify modifiable factors in communication about organ donation that influence family consent rates. METHODS: Thirty-two intensivists specialized in organ donation systematically evaluated all consecutive organ donation requests with physicians in the Netherlands between January 2013 and June 2016, using a standardized questionnaire. RESULTS: Out of 2528 consecutive donation requests, 2095 (83%) were evaluated with physicians. The questionnaires of patients registered with consent or objection in the national donor registry were excluded from analysis. Only those questionnaires, in which the family had to make a decision about donation, were analyzed (n = 1322). Independent predictors of consent included: requesting organ donation during the conversation about futility of treatment (OR 1.8; p = 0.004), understanding of the term 'brain death' by the family (OR 2.4; p = 0.002), and consulting a donation expert prior to the donation request (OR 3.4; p < 0.001). CONCLUSIONS: Our study showed that decoupling the organ donation conversation from the conversation about futility of treatment was associated with lower family consent rates. Comprehension of the concept of brain death by the family and consultation with a transplant coordinator before the organ donation request by the physician could positively influence consent rates. TI - Physician Experiences with Communicating Organ Donation with the Relatives: A Dutch Nationwide Evaluation on Factors that Influence Consent Rates EP - 364 SN - 1541-6933 IS - iss. 2 SP - 357 JF - Neurocritical Care VL - vol. 31 DO - https://doi.org/10.1007/s12028-019-00678-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208686/208686.pdf?sequence=1 ER - TY - JOUR AU - Groen, B.D. AU - Vaes, W.H. AU - Park, B.K. AU - Krekels, E.H.J. AU - Duijn, E. van AU - Korgvee, L.T. AU - Maruszak, W. AU - Grynkiewicz, G. AU - Garner, R.C. AU - Knibbe, Catherijne A.J. AU - Tibboel, D. AU - Wildt, S.N. de AU - Turner, M.A. PY - 2019 UR - https://hdl.handle.net/2066/208998 AB - AIMS: Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [(14) C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. METHODS: Preterm to 2-year-old infants admitted to the intensive care unit received [(14) C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [(14) C]midazolam and [(14) C]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. RESULTS: Of 15 infants (median gestational age 39.4 [range 23.9-41.4] weeks, postnatal age 11.4 [0.6-49.1] weeks), 6 received a microtracer and 9 a microdose of [(14) C]midazolam (111 Bq kg(-1) ; 37.6 ng kg(-1) ). In a 2-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [(14) C]1-OH-midazolam/[(14) C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. CONCLUSION: Our data support the dose linearity of the PK of an IV [(14) C]midazolam microdose in children. Hence, a [(14) C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children. TI - Dose-linearity of the pharmacokinetics of an intravenous [(14) C]midazolam microdose in children EP - 2340 SN - 0306-5251 IS - iss. 10 SP - 2332 JF - British Journal of Clinical Pharmacology VL - vol. 85 DO - https://doi.org/10.1111/bcp.14047 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208998/208998.pdf?sequence=1 ER - TY - JOUR AU - Cheung, K.W.K. AU - Groen, B.D. AU - Spaans, E. AU - Borselen, M.D. van AU - Bruijn, A. de AU - Simons-Oosterhuis, Y. AU - Tibboel, D. AU - Samsom, J.N. AU - Verdijk, R.M. AU - Smeets, B. AU - Zhang, L. AU - Huang, S.M. AU - Giacomini, K.M. AU - Wildt, S.N. de PY - 2019 UR - https://hdl.handle.net/2066/209000 AB - Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age. TI - A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization EP - 1092 SN - 0009-9236 IS - iss. 5 SP - 1083 JF - Clinical Pharmacology and Therapeutics VL - vol. 106 DO - https://doi.org/10.1002/cpt.1516 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/209000/209000.pdf?sequence=1 ER - TY - JOUR AU - Groenland, Carline N. AU - Termorshuizen, Fabian AU - Rietdijk, Wim J.R. AU - Brule, J.M. van den AU - Dongelmans, Dave A. AU - Jonge, Evert de AU - Boersma, Eric AU - Uil, Corstiaan A. den PY - 2019 UR - https://hdl.handle.net/2066/209006 TI - Emergency Department to ICU Time Is Associated With Hospital Mortality: A Registry Analysis of 14,788 Patients From Six University Hospitals in The Netherlands* EP - 1571 SN - 0090-3493 IS - iss. 11 SP - 1564 JF - Critical Care Medicine VL - vol. 47 DO - https://doi.org/10.1097/CCM.0000000000003957 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/209006/209006.pdf?sequence=1 ER - TY - JOUR AU - Raymakers-Janssen, Paulien A.M.A. AU - Lilien, Marc R. AU - Tibboel, Dick AU - Kneyber, Martin C.J. AU - Dijkstra, Sandra AU - Woensel, J.B. van AU - Lemson, J. AU - Waardenburg, D. van AU - Roeleveld, P.P. PY - 2019 UR - https://hdl.handle.net/2066/209007 TI - Epidemiology and Outcome of Critically Ill Pediatric Cancer and Hematopoietic Stem Cell Transplant Patients Requiring Continuous Renal Replacement Therapy: A Retrospective Nationwide Cohort Study EP - E901 SN - 0090-3493 IS - iss. 11 SP - E893 JF - Critical Care Medicine VL - vol. 47 DO - https://doi.org/10.1097/CCM.0000000000003973 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/209007/209007.pdf?sequence=1 ER - TY - JOUR AU - Thakkar, R.K. AU - Weiss, S.L. AU - Fitzgerald, J.C. AU - Keele, L. AU - Thomas, N.J. AU - Nadkarni, V.M. AU - Neeleman, C. AU - Lemson, J. AU - Sherring, C. AU - Bushell, T. PY - 2019 UR - https://hdl.handle.net/2066/208556 AB - BACKGROUND: Sepsis is a leading cause of morbidity and mortality after surgery. Most studies regarding sepsis do not differentiate between patients who have had recent surgery and those without. Few data exist regarding the risk factors for poor outcomes in pediatric postsurgical sepsis. Our hypothesis is pediatric postsurgical, and medical patients with severe sepsis have unique risk factors for mortality. METHODS: Data were extracted from a secondary analysis of an international point prevalence study of pediatric severe sepsis. Sites included 128 pediatric intensive care units from 26 countries. Pediatric patients with severe sepsis were categorized into those who had recent surgery (postsurgical sepsis) versus those that did not (medical sepsis) before sepsis onset. Multivariable logistic regression models were used to determine risk factors for mortality. RESULTS: A total of 556 patients were included: 138 with postsurgical and 418 with medical sepsis. In postsurgical sepsis, older age, admission from the hospital ward, multiple organ dysfunction syndrome at sepsis recognition, and cardiovascular and respiratory comorbidities were independent risk factors for death. In medical sepsis, resource-limited region, hospital-acquired infection, multiple organ dysfunction syndrome at sepsis recognition, higher Pediatric Index of Mortality-3 score, and malignancy were independent risk factors for death. CONCLUSIONS: Pediatric patients with postsurgical sepsis had different risk factors for mortality compared with medical sepsis. This included a higher mortality risk in postsurgical patients presenting to the intensive care unit from the hospital ward. These data suggest an opportunity to develop and test early warning systems specific to pediatric sepsis in the postsurgical population. TI - Risk Factors for Mortality in Pediatric Postsurgical versus Medical Severe Sepsis EP - 110 SN - 0022-4804 SP - 100 JF - Journal of Surgical Research VL - vol. 242 DO - https://doi.org/10.1016/j.jss.2019.04.011 ER - TY - JOUR AU - Roesthuis, L.H. AU - Hoeven, H. van der AU - Sinderby, C. AU - Frenzel, T. AU - Ottenheijm, C. AU - Brochard, L. AU - Doorduin, J. AU - Heunks, L. PY - 2019 UR - https://hdl.handle.net/2066/208617 AB - PURPOSE: Respiratory muscle weakness frequently develops in critically ill patients and is associated with adverse outcome, including difficult weaning from mechanical ventilation. Today, no drug is approved to improve respiratory muscle function in these patients. Previously, we have shown that the calcium sensitizer levosimendan improves calcium sensitivity of human diaphragm muscle fibers in vitro and contractile efficiency of the diaphragm in healthy subjects. The main purpose of this study is to investigate the effects of levosimendan on diaphragm contractile efficiency in mechanically ventilated patients. METHODS: In a double-blind randomized placebo-controlled trial, mechanically ventilated patients performed two 30-min continuous positive airway pressure (CPAP) trials with 5-h interval. After the first CPAP trial, study medication (levosimendan 0.2 microg/kg/min continuous infusion or placebo) was administered. During the CPAP trials, electrical activity of the diaphragm (EAdi), transdiaphragmatic pressure (Pdi), and flow were measured. Neuromechanical efficiency (primary outcome parameter) was calculated. RESULTS: Thirty-nine patients were included in the study. Neuromechanical efficiency was not different during the CPAP trial after levosimendan administration compared to the CPAP trial before study medication. Tidal volume and minute ventilation were higher after levosimendan administration (11 and 21%, respectively), whereas EAdi and Pdi were higher in both groups in the CPAP trial after study medication compared to the CPAP trial before study medication. CONCLUSIONS: Levosimendan does not improve diaphragm contractile efficiency. TI - Effects of levosimendan on respiratory muscle function in patients weaning from mechanical ventilation EP - 1381 SN - 0342-4642 IS - iss. 10 SP - 1372 JF - Intensive Care Medicine VL - vol. 45 DO - https://doi.org/10.1007/s00134-019-05767-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208617/208617.pdf?sequence=1 ER - TY - JOUR AU - Leijte, G.P. AU - Kox, M. AU - Pickkers, P. PY - 2019 UR - https://hdl.handle.net/2066/208633 TI - Fever in Sepsis: Still a Hot Topic EP - 264 SN - 1073-449X IS - iss. 2 SP - 263 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 200 DO - https://doi.org/10.1164/rccm.201903-0484LE L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208633/208633.pdf?sequence=1 ER - TY - JOUR AU - Bogaerts, J.M.A. AU - Hoeven, J.G. van der AU - Arts, E.E.A. AU - Kolk, B.M. van der AU - Brosens, L.A.A. PY - 2019 UR - https://hdl.handle.net/2066/208636 TI - Fish scale crystals: an under-recognised cause of intestinal necrosis SN - 0021-9746 IS - iss. 8 SP - 567 JF - Journal of Clinical Pathology : the Journal of the Association of Clinical Pathologists VL - vol. 72 DO - https://doi.org/10.1136/jclinpath-2018-205203 ER - TY - JOUR AU - McNicholas, B.A. AU - Rezoagli, E. AU - Pham, T. AU - Madotto, F. AU - Guiard, E. AU - Fanelli, V. AU - Bellani, G. AU - Griffin, M.D. AU - Schouten, J.A. AU - Ranieri, M. AU - Laffey, J.G. PY - 2019 UR - https://hdl.handle.net/2066/208648 AB - OBJECTIVES: To understand the impact of mild-moderate and severe acute kidney injury in patients with acute respiratory distress syndrome. DESIGN: Secondary analysis of the "Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure", an international prospective cohort study of patients with severe respiratory failure. SETTING: Four-hundred fifty-nine ICUs from 50 countries across five continents. SUBJECTS: Patients with a glomerular filtration rate greater than 60 mL/min/1.73 m prior to admission who fulfilled criteria of acute respiratory distress syndrome on day 1 and day 2 of acute hypoxemic respiratory failure. INTERVENTIONS: Patients were categorized based on worst serum creatinine or urine output into: 1) no acute kidney injury (serum creatinine < 132 micromol/L or urine output >/= 0.5 mL/kg/hr), 2) mild-moderate acute kidney injury (serum creatinine 132-354 micromol/L or minimum urine output between 0.3 and 0.5mL/kg/hr), or 3) severe acute kidney injury (serum creatinine > 354 micromol/L or renal replacement therapy or minimum urine output < 0.3 mL/kg/hr). MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital mortality, whereas secondary outcomes included prevalence of acute kidney injury and characterization of acute respiratory distress syndrome risk factors and illness severity patterns, in patients with acute kidney injury versus no acute kidney injury. One-thousand nine-hundred seventy-four patients met inclusion criteria: 1,209 (61%) with no acute kidney injury, 468 (24%) with mild-moderate acute kidney injury, and 297 (15%) with severe acute kidney injury. The impact of acute kidney injury on the ventilatory management of patients with acute respiratory distress syndrome was relatively limited, with no differences in arterial CO2 tension or in tidal or minute ventilation between the groups. Hospital mortality increased from 31% in acute respiratory distress syndrome patients with no acute kidney injury to 50% in mild-moderate acute kidney injury (p 10% of the brain could differentiate between patients with favourable and unfavourable outcomes on a group level within 1-3 days after cardiac arrest. Advanced imaging techniques such as functional MRI or diffusion tensor imaging show promising results, but need further evaluation. CONCLUSION: CT derived grey-white matter ratio and MRI based measures of diffusivity and connectivity hold promise to improve outcome prediction after cardiac arrest. Prospective validation studies in a multivariable approach are needed to determine the additional value for the individual patient. TI - Brain imaging in comatose survivors of cardiac arrest: Pathophysiological correlates and prognostic properties EP - 136 SN - 0300-9572 SP - 124 JF - Resuscitation VL - vol. 133 DO - https://doi.org/10.1016/j.resuscitation.2018.09.012 ER - TY - JOUR AU - Baarslag, M.A. AU - Ista, E. AU - Leeuw, T. de AU - Rosmalen, J. van AU - Tibboel, D. AU - Dijk, M van AU - Wildt, S.N. de PY - 2018 UR - https://hdl.handle.net/2066/199996 TI - Clinically effective implementation of intravenous paracetamol as primary analgesia after major surgery in neonates and young infants EP - 1169 SN - 0003-9888 IS - iss. 12 SP - 1168 JF - Archives of Disease in Childhood VL - vol. 103 DO - https://doi.org/10.1136/archdischild-2018-315379 ER - TY - JOUR AU - Dekker, Douwe AU - Dorresteijn, M.J. AU - Welzen, M.E.B. AU - Timman, S.T. AU - Pickkers, P. AU - Burger, D.M. AU - Smits, P. AU - Wagener, F.A.D.T.G. AU - Russel, F.G.M. PY - 2018 UR - https://hdl.handle.net/2066/187828 TI - Parenteral bilirubin in healthy volunteers: a reintroduction in translational research EP - 279 SN - 0306-5251 IS - iss. 2 SP - 268 JF - British Journal of Clinical Pharmacology VL - vol. 84 DO - https://doi.org/10.1111/bcp.13458 ER - TY - JOUR AU - Andrews, Louise M. AU - Hesselink, Dennis A. AU - Gelder, Teun van AU - Koch, B.C. AU - Cornelissen, E.A.M. AU - Bruggemann, R.J.M. AU - Wildt, S.N. de AU - Cransberg, Karlien AU - Winter, Brenda C.M. de PY - 2018 UR - https://hdl.handle.net/2066/190117 TI - A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation EP - 489 SN - 0312-5963 IS - iss. 4 SP - 475 JF - Clinical Pharmacokinetics VL - vol. 57 DO - https://doi.org/10.1007/s40262-017-0567-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190117/190117.pdf?sequence=1 ER - TY - JOUR AU - Wassenaar, A. AU - Rood, P.J.T. AU - Boelen, D.H.E. AU - Schoonhoven, L. AU - Pickkers, P. AU - Boogaard, M.H.W.A. van den PY - 2018 UR - https://hdl.handle.net/2066/190118 TI - Feasibility of cognitive training in critically ill patients: a pilot study EP - 135 SN - 1062-3264 IS - iss. 2 SP - 124 JF - American Journal of Critical Care VL - vol. 27 DO - https://doi.org/10.4037/ajcc2018467 ER - TY - JOUR AU - Brussee, J.M. AU - Vet, N.J. AU - Krekels, Elke H.J. AU - Valkenburg, Abraham J. AU - Jacqz-Aigrain, Evelyne AU - Gerven, Joop M.A. van AU - Wildt, S.N. de AU - Knibbe, C.A. PY - 2018 UR - https://hdl.handle.net/2066/190055 TI - Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure EP - 368 SN - 0306-5251 IS - iss. 2 SP - 358 JF - British Journal of Clinical Pharmacology VL - vol. 84 DO - https://doi.org/10.1111/bcp.13459 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190055/190055.pdf?sequence=1 ER - TY - JOUR AU - Irving, S.Y. AU - Daly, B. AU - Verger, J. AU - Typpo, K.V. AU - Brown, A.M. AU - Hanlon, A. AU - Weiss, S.L. AU - Fitzgerald, J.C. AU - Nadkarni, V.M. AU - Neeleman, C. AU - Lemson, J. AU - Thomas, N.J. AU - Srinivasan, V. PY - 2018 UR - https://hdl.handle.net/2066/200437 AB - OBJECTIVES: The impact of nutrition status on outcomes in pediatric severe sepsis is unclear. We studied the association of nutrition status (expressed as body mass index z score) with outcomes in pediatric severe sepsis. DESIGN: Secondary analysis of the Sepsis Prevalence, Outcomes, and Therapies study. Patient characteristics, ICU interventions, and outcomes were compared across nutrition status categories (expressed as age- and sex-adjusted body mass index z scores using World Health Organization standards). Multivariable regression models were developed to determine adjusted differences in all-cause ICU mortality and ICU length of stay by nutrition status. SETTING: One-hundred twenty-eight PICUs across 26 countries. PATIENTS: Children less than 18 years with severe sepsis enrolled in the Sepsis Prevalence, Outcomes, and Therapies study (n = 567). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nutrition status data were available for 417 patients. Severe undernutrition was seen in Europe (25%), Asia (20%), South Africa (17%), and South America (10%), with severe overnutrition seen in Australia/New Zealand (17%) and North America (14%). Severe undernutrition was independently associated with all-cause ICU mortality (adjusted odds ratio, 3.0; 95% CI, 1.2-7.7; p = 0.02), whereas severe overnutrition in survivors was independently associated with longer ICU length of stay (1.6 d; p = 0.01). CONCLUSIONS: There is considerable variation in nutrition status for children with severe sepsis treated across this selected network of PICUs from different geographic regions. Severe undernutrition was independently associated with higher all-cause ICU mortality in children with severe sepsis. Severe overnutrition was independently associated with greater ICU length of stay in childhood survivors of severe sepsis. TI - The Association of Nutrition Status Expressed as Body Mass Index z Score With Outcomes in Children With Severe Sepsis: A Secondary Analysis From the Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study EP - e1039 SN - 0090-3493 IS - iss. 11 SP - e1029 JF - Critical Care Medicine VL - vol. 46 DO - https://doi.org/10.1097/CCM.0000000000003351 ER - TY - JOUR AU - Wassenaar, A. AU - Boogaard, M. van den PY - 2018 UR - https://hdl.handle.net/2066/200452 TI - The authors reply - Integration of an Abbreviated ICU Cognitive Failure Questionnaire Reply SN - 0090-3493 IS - iss. 5 SP - e480 JF - Critical Care Medicine VL - vol. 46 DO - https://doi.org/10.1097/CCM.0000000000003031 ER - TY - JOUR AU - Felten-Barentsz, K.M. AU - Oorsouw, Roel van AU - Haans, Antonius J.C. AU - Staal, J.B. AU - Hoeven, J.G. van der AU - Nijhuis-van der Sanden, M.W.G. PY - 2018 UR - https://hdl.handle.net/2066/197984 TI - Patient views regarding the impact of hydrotherapy on critically ill ventilated patients: A qualitative exploration study EP - 327 SN - 0883-9441 SP - 321 JF - Journal of Critical Care VL - vol. 48 DO - https://doi.org/10.1016/j.jcrc.2018.09.021 ER - TY - JOUR AU - Wijngaart, L.S. van den AU - Geense, W.W. AU - Boehmer, A.L.M. AU - Brouwer, M.L. AU - Hugen, C.A.C. AU - Ewijk, Bart E. van AU - Roukema, J. AU - Merkus, P.J.F.M. PY - 2018 UR - https://hdl.handle.net/2066/197415 TI - Barriers and Facilitators When Implementing Web-Based Disease Monitoring and Management as a Substitution for Regular Outpatient Care in Pediatric Asthma: Qualitative Survey Study SN - 1438-8871 IS - iss. 10 JF - Journal of Medical Internet Research VL - vol. 20 DO - https://doi.org/10.2196/jmir.9245 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/197415/197415.pdf?sequence=1 ER - TY - JOUR AU - Michelson, K.N. AU - Reubenson, G. AU - Weiss, S.L. AU - Fitzgerald, J.C. AU - Ackerman, K.K. AU - Christie, L. AU - Bush, J.L. AU - Nadkarni, V.M. AU - Neeleman, C. AU - Thomas, N.J. AU - Schreiner, M.S. PY - 2018 UR - https://hdl.handle.net/2066/196441 AB - OBJECTIVES: Duplicative institutional review board/research ethics committee review for multicenter studies may impose administrative burdens and inefficiencies affecting study implementation and quality. Understanding variability in site-specific institutional review board/research ethics committee assessment and barriers to using a single review committee (an increasingly proposed solution) can inform a more efficient process. We provide needed data about the regulatory oversight process for the Sepsis PRevalence, OUtcomes, and Therapies multicenter point prevalence study. DESIGN: Survey. SETTING: Sites invited to participate in Sepsis PRevalence, OUtcomes, and Therapies. SUBJECTS: Investigators at sites that expressed interest and/or participated in Sepsis PRevalence, OUtcomes, and Therapies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using an electronic survey, we collected data about 1) logistics of protocol submission, 2) institutional review board/research ethics committee requested modifications, and 3) use of a single institutional review board (for U.S. sites). We collected surveys from 104 of 167 sites (62%). Of the 97 sites that submitted the protocol for institutional review board/research ethics committee review, 34% conducted full board review, 54% expedited review, and 4% considered the study exempt. Time to institutional review board/research ethics committee approval required a median of 34 (range 3-186) days, which took longer at sites that required protocol modifications (median [interquartile range] 50 d [35-131 d] vs 32 d [14-54 d)]; p = 0.02). Enrollment was delayed at eight sites due to prolonged (> 50 d) time to approval. Of 49 U.S. sites, 43% considered using a single institutional review board, but only 18% utilized this option. Time to final approval for U.S. sites using the single institutional review board was 62 days (interquartile range, 34-70 d) compared with 34 days (interquartile range, 15-54 d) for nonsingle institutional review board sites (p = 0.16). CONCLUSIONS: Variability in regulatory oversight was evident for this minimal-risk observational research study, most notably in the category of type of review conducted. Duplicative review prolonged time to protocol approval at some sites. Use of a single institutional review board for U.S. sites was rare and did not improve efficiency of protocol approval. Suggestions for minimizing these challenges are provided. TI - Site Variability in Regulatory Oversight for an International Study of Pediatric Sepsis EP - e188 SN - 1529-7535 IS - iss. 4 SP - e180 JF - Pediatric Critical Care Medicine VL - vol. 19 DO - https://doi.org/10.1097/PCC.0000000000001455 ER - TY - JOUR AU - Douw, G. AU - Huisman-de Waal, G.J. AU - Zanten, A.R.H. AU - Hoeven, J.G. van der AU - Schoonhoven, L. PY - 2018 UR - https://hdl.handle.net/2066/196447 AB - BACKGROUND: Rapid response systems aim to improve early recognition and treatment of deteriorating general ward patients. Sole reliance on deviating vital signs to escalate care in rapid response systems disregards nurses' judgments about a patient's condition based on worry and other indicators of deterioration. To make worry explicit, the Dutch-Early-Nurse-Worry-Indicator-Score was developed, summarising non-quantifiable signs of deterioration in the nine indicators: breathing, circulation, temperature, mentation, agitation, pain, unexpected trajectory, patient indicates not feeling well and nurses' subjective observations. Nurses' worry can be present even when vital signs are largely unchanged, enabling treatment to commence at an early stage. On the other hand, reliance on nurses' worry might lead to unnecessary calls for medical assistance or an overuse of rapid response teams. OBJECTIVES: Explore the occurrence of nurses' worry in real time, determine whether acting on worry leads to unnecessary action and determine the indicators present at different levels of deterioration. DESIGN: A prospective cohort study. SETTING: Three surgical wards in a tertiary, university affiliated teaching hospital. PARTICIPANTS: All nurses participated and adult, surgical, native speaking patients were included in the study. METHODS: A descriptive analysis is performed on one year of data on surgical ward nurses' experience of worry and its underlying indicators in addition to routinely measured vital signs. RESULTS: Out of a total of 46,571 measurements, vital signs were normal 18,727 times, with worry expressed 605 times (3%), resulting in 62 calls (10.2%) to the attending physician. More than half of these calls resulted in necessary interventions. Calls for assistance and subsequent intervention after worry was expressed increase in parallel with early warning scores. The breathing indicator showed the highest increase in frequency with increasing deviation in vital signs. CONCLUSION: This study suggests that worry has potential as an early indicator of deterioration, alerting nurses and encouraging them to start timely interventions. Overuse of medical assistance could not be determined, The Dutch-Early-Nurse-Worry-Indicator-Score objectifies worry when vital signs do not support its presence and systematic assessment of these indicators is recommended. TI - Surgical ward nurses' responses to worry: An observational descriptive study EP - 95 SN - 0020-7489 SP - 90 JF - International Journal of Nursing Studies VL - vol. 85 DO - https://doi.org/10.1016/j.ijnurstu.2018.05.009 ER - TY - JOUR AU - Benic, M.S. AU - Milanic, R. AU - Monnier, A.A. AU - Gyssens, I.C. AU - Adriaenssens, N. AU - Versporten, A. AU - Zanichelli, V. AU - Marechal, M. Le AU - Huttner, B. AU - Tebano, G. AU - Hulscher, M.E. AU - Pulcini, C. AU - Wertheim, H.F.L. AU - Schouten, J.A. AU - Vlahovic-Palcevski, V. PY - 2018 UR - https://hdl.handle.net/2066/193591 AB - Background: Quantifying antibiotic use is an essential element of antibiotic stewardship since it allows comparison between different settings and time windows, and measurement of the impact of interventions. However, quantity metrics (QMs) and methods have not been standardized. Objectives: To propose a set of QMs for antibiotic use in inpatients (IQMs) that are accepted globally by professionals in a range of disciplines. The study was conducted within the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project. Methods: A systematic literature review using MEDLINE identified articles on measuring inpatient antibiotic use, published up to 29 January 2015. A consensually selected list of national and international web sites was screened for additional IQMs. IQMs were classified according to the type of numerator used and presented to a multidisciplinary panel of stakeholders. A RAND-modified Delphi consensus procedure, which consisted of two online questionnaires and a face-to-face meeting, was performed. Results: The systematic literature review and web site search identified 168 eligible articles from which an initial list of 20 IQMs, composed of 20 different numerators and associated denominators was developed. The consensus procedure resulted in a final set of 12 IQMs. Among this final set, DDDs per 100(0) patient-days and days of therapy per patient-days were most frequently found in the review. The panel recommended that antibiotic use should be expressed in at least two metrics simultaneously. Conclusions: Our consensus procedure identified a set of IQMs that we propose as an evidence-based global standard. TI - Metrics for quantifying antibiotic use in the hospital setting: results from a systematic review and international multidisciplinary consensus procedure EP - vi58 SN - 0305-7453 IS - iss. suppl_6 SP - vi50 JF - Journal of Antimicrobial Chemotherapy VL - vol. 73 DO - https://doi.org/10.1093/jac/dky118 ER - TY - JOUR AU - Versporten, A. AU - Gyssens, I.C.J. AU - Pulcini, C. AU - Monnier, A.A. AU - Schouten, J.A. AU - Milanic, R. AU - Benic, M. Stanic AU - Tebano, G. AU - Marechal, M. Le AU - Zanichelli, V. AU - Huttner, B. AU - Vlahovic-Palcevski, V. AU - Goossens, H. AU - Wertheim, H.F.L. AU - Hulscher, M.E. AU - Adriaenssens, N. PY - 2018 UR - https://hdl.handle.net/2066/193592 AB - Background: The international Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving Reinvestment in Research and Development and Responsible Antibiotic Use) aims to develop a global definition of 'responsible' antibiotic use. Objectives: To identify consensually validated quantity metrics for antibiotic use in the outpatient setting. Methods: First, outpatient quantity metrics (OQMs) were identified by a systematic search of literature and web sites published until 12 December 2014. Identified OQMs were evaluated by a multidisciplinary, international stakeholder panel using a RAND-modified Delphi procedure. Two online questionnaires and a face-to-face meeting between them were conducted to assess OQM relevance for measuring the quantity of antibiotic use on a nine-point Likert scale, to add comments or to propose new metrics. Results: A total of 597 articles were screened, 177 studies met criteria for full-text screening and 138 were finally included. Twenty different OQMs were identified and appraised by 23 stakeholders. During the first survey, 14 OQMs were excluded and 6 qualified for discussion. During the face-to-face meeting, 10 stakeholders retained five OQMs and suggestions were made considering context and combination of metrics. The final set of metrics included defined daily doses, treatments/courses and prescriptions per defined population, treatments/courses and prescriptions per defined number of physician contacts and seasonal variation of total antibiotic use. Conclusions: A small set of consensually validated metrics to assess the quantity of antibiotic use in the outpatient setting was obtained, enabling (inter)national comparisons. The OQMs will help build a global conceptual framework for responsible antibiotic use. TI - Metrics to assess the quantity of antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure EP - vi66 SN - 0305-7453 IS - iss. suppl_6 SP - vi59 JF - Journal of Antimicrobial Chemotherapy VL - vol. 73 DO - https://doi.org/10.1093/jac/dky119 ER - TY - JOUR AU - Brussee, J.M. AU - Yu, Huixin AU - Krekels, Elke H.J. AU - Palic, Semra AU - Brill, Margreke J.E. AU - Barrett, Jeffrey S. AU - Wildt, S.N. de AU - Knibbe, C.A. PY - 2018 UR - https://hdl.handle.net/2066/194409 TI - Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach SN - 0724-8741 IS - iss. 9 JF - Pharmaceutical Research VL - vol. 35 DO - https://doi.org/10.1007/s11095-018-2458-6 ER - TY - JOUR AU - Collet, Marie O. AU - Caballero, Jesus AU - Sonneville, Romain AU - Bozza, Fernando A. AU - Nydahl, Peter AU - Schandl, A. AU - Boogaard, M. van den AU - Wetterslev, Jorn AU - Perner, Anders PY - 2018 UR - https://hdl.handle.net/2066/194417 TI - Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study EP - 1089 SN - 0342-4642 IS - iss. 7 SP - 1081 JF - Intensive Care Medicine VL - vol. 44 DO - https://doi.org/10.1007/s00134-018-5204-y ER - TY - JOUR AU - Kiers, D. AU - Wielockx, Ben AU - Peters, E. AU - Eijk, L.T. AU - Gerretsen, J. AU - John, A. AU - Janssen, Emmy AU - Damen, L.A.A. AU - Langereis, J.D. AU - Zomer, A.L. AU - Joosten, L.A. AU - Netea, M.G. AU - Riksen, N.P. AU - Scheffer, G.J. AU - Pickkers, P. AU - Kox, M. PY - 2018 UR - https://hdl.handle.net/2066/194401 TI - Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation EP - 156 SN - 2352-3964 SP - 144 JF - Ebiomedicine VL - vol. 33 DO - https://doi.org/10.1016/j.ebiom.2018.06.021 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194401/194401.pdf?sequence=1 ER - TY - JOUR AU - Barker, C.I.S. AU - Standing, J.F. AU - Kelly, L.E. AU - Faught, L. Hanly AU - Needham, A.C. AU - Rieder, M.J. AU - Wildt, S.N. de AU - Offringa, M. PY - 2018 UR - https://hdl.handle.net/2066/193438 AB - Optimising the dosing of medicines for neonates and children remains a challenge. The importance of pharmacokinetic (PK) and pharmacodynamic (PD) research is recognised both in medicines regulation and paediatric clinical pharmacology, yet there remain barriers to undertaking high-quality PK and PD studies. While these studies are essential in understanding the dose-concentration-effect relationship and should underpin dosing recommendations, this review examines how challenges affecting the design and conduct of paediatric pharmacological studies can be overcome using targeted pharmacometric strategies. Model-based approaches confer benefits at all stages of the drug life-cycle, from identifying the first dose to be used in children, to clinical trial design, and optimising the dosing regimens of older, off-patent medications. To benefit patients, strategies to ensure that new PK, PD and trial data are incorporated into evidence-based dosing recommendations are needed. This review summarises practical strategies to address current challenges, particularly the use of model-based (pharmacometric) approaches in study design and analysis. Recommendations for practice and directions for future paediatric pharmacological research are given, based on current literature and our joint international experience. Success of PK research in children requires a robust infrastructure, with sustainable funding mechanisms at its core, supported by political and regulatory initiatives, and international collaborations. There is a unique opportunity to advance paediatric medicines research at an unprecedented pace, bringing the age of evidence-based paediatric pharmacotherapy into sight. TI - Pharmacokinetic studies in children: recommendations for practice and research EP - 702 SN - 0003-9888 IS - iss. 7 SP - 695 JF - Archives of Disease in Childhood VL - vol. 103 DO - https://doi.org/10.1136/archdischild-2017-314506 ER - TY - JOUR AU - Monnier, A.A. AU - Schouten, J.A. AU - Marechal, M. Le AU - Tebano, G. AU - Pulcini, C. AU - Benic, M. Stanic AU - Vlahovic-Palcevski, V. AU - Milanic, R. AU - Adriaenssens, N. AU - Versporten, A. AU - Huttner, B. AU - Zanichelli, V. AU - Wertheim, H.F.L. AU - Hulscher, M.E. AU - Gyssens, I.C.J. PY - 2018 UR - https://hdl.handle.net/2066/193452 AB - Background: This study was conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project and aimed to develop generic quality indicators (QIs) for responsible antibiotic use in the inpatient setting. Methods: A RAND-modified Delphi method was applied. First, QIs were identified by a systematic review. A complementary search was performed on web sites of relevant organizations. Duplicates were removed and disease and patient-specific QIs were combined into generic indicators. The relevance of these QIs was appraised by a multidisciplinary international stakeholder panel through two questionnaires and an in-between consensus meeting. Results: The systematic review retrieved 70 potential generic QIs. The QIs were appraised by 25 international stakeholders with diverse backgrounds (medical community, public health, patients, antibiotic research and development, regulators, governments). Ultimately, 51 QIs were selected in consensus. QIs with the highest relevance score included: (i) an antibiotic plan should be documented in the medical record at the start of the antibiotic treatment; (ii) the results of bacteriological susceptibility testing should be documented in the medical record; (iii) the local guidelines should correspond to the national guidelines but should be adapted based on local resistance patterns; (iv) an antibiotic stewardship programme should be in place at the healthcare facility; and (v) allergy status should be taken into account when antibiotics are prescribed. Conclusions: This systematic and stepwise method combining evidence from literature and stakeholder opinion led to multidisciplinary international consensus on generic inpatient QIs that can be used globally to assess the quality of antibiotic use. TI - Quality indicators for responsible antibiotic use in the inpatient setting: a systematic review followed by an international multidisciplinary consensus procedure EP - vi39 SN - 0305-7453 IS - iss. suppl_6 SP - vi30 JF - Journal of Antimicrobial Chemotherapy VL - vol. 73 DO - https://doi.org/10.1093/jac/dky116 ER - TY - JOUR AU - Marechal, M. Le AU - Tebano, G. AU - Monnier, A.A. AU - Adriaenssens, N. AU - Gyssens, I.C.J. AU - Huttner, B. AU - Milanic, R. AU - Schouten, J.A. AU - Benic, M. Stanic AU - Versporten, A. AU - Vlahovic-Palcevski, V. AU - Zanichelli, V. AU - Wertheim, H.F.L. AU - Hulscher, M.E. AU - Pulcini, C. PY - 2018 UR - https://hdl.handle.net/2066/193451 AB - Objectives: Quality indicators (QIs) assessing the appropriateness of antibiotic use are essential to identify targets for improvement and guide antibiotic stewardship interventions. The aim of this study was to develop a set of QIs for the outpatient setting from a global perspective. Methods: A systematic literature review was performed by searching MEDLINE and relevant web sites in order to retrieve a list of QIs. These indicators were extracted from published trials, guidelines, literature reviews or consensus procedures. This evidence-based set of QIs was evaluated by a multidisciplinary, international group of stakeholders using a RAND-modified Delphi procedure, using two online questionnaires and a face-to-face meeting between them. Stakeholders appraised the QIs' relevance using a nine-point Likert scale. This work is part of the DRIVE-AB project. Results: The systematic literature review identified 43 unique QIs, from 54 studies and seven web sites. Twenty-five stakeholders from 14 countries participated in the consensus procedure. Ultimately, 32 QIs were retained, with a high level of agreement. The set of QIs included structure, process and outcome indicators, targeting both high- and middle- to low-income settings. Most indicators focused on general practice, addressing the common indications for antibiotic use in the community (particularly urinary and respiratory tract infections), and the organization of healthcare facilities. Twelve indicators specifically addressed outpatient parenteral antimicrobial therapy (OPAT). Conclusions: We identified a set of 32 outpatient QIs to measure the appropriateness of antibiotic use. These QIs can be used to identify targets for improvement and to evaluate the effects of antibiotic stewardship interventions. TI - Quality indicators assessing antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure EP - vi49 SN - 0305-7453 IS - iss. suppl_6 SP - vi40 JF - Journal of Antimicrobial Chemotherapy VL - vol. 73 DO - https://doi.org/10.1093/jac/dky117 ER - TY - JOUR AU - Hanskamp-Sebregts, M.E.C. AU - Robben, P.H.B. AU - Wollersheim, H.C. AU - Zegers, M. PY - 2018 UR - https://hdl.handle.net/2066/196354 AB - OBJECTIVE: To study to what extent internal audit results of hospitals can be shared with external supervisors and the necessary preconditions for this. DESIGN: Qualitative interview research. METHOD: In 2013-2015, we interviewed 36 individuals from six hospitals: 12 department heads (all medical specialists), 10 department managers; five members of the Board of Directors; five members of the Supervisory Board and the four account-holding hospital inspectors. We also performed a focus group interview with six other hospital inspectors of the Health and Youth Care Inspectorate. The interview data were analysed thematically. RESULTS: The interviewees pointed out that there is no coordination between internal and external supervision. They were in favour of sharing internal audit results with external supervisors to reduce the supervisory burden. They stated that internal audits give insight into quality improvements, how hospital directors govern quality and safety and the culture of improvement within healthcare provider teams. With this information, the Inspectorate can assess to what extent hospitals are learning organisations. The interviewees mentioned the following preconditions for sharing audit results: reliable and risk-based information about quality and safety, collected by expert, trained auditors and careful use of this information by the Inspectorate in order to maintain openness among audited healthcare providers. CONCLUSION: Internal audit results can be shared conditionally with external supervisors like the Health and Youth Care Inspectorate. When internal audit results show that hospitals are open, learning and self-cleansing organisations, the Inspectorate can supervise the hospitals remotely and supervisory burden will probably be reduced. TI - [Sharing internal audit results with the Inspectorate; interviews on the possibility and preconditions] SN - 0028-2162 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 162 ER - TY - JOUR AU - Zeldenrust, M.J.G. AU - Suylen, R.J. van AU - Ramakers, B.P.C. PY - 2018 UR - https://hdl.handle.net/2066/196355 AB - BACKGROUND: The Waterhouse-Friderichsen syndrome (WFS) is a serious illness associated with a high mortality rate and characterized by septic shock and signs of adrenocortical insufficiency. CASE DESCRIPTION: A 33-year-old male was seen in the emergency department with severe abdominal and back pain with diffuse mottled skin and rapidly progressive petechiae all over his body. Laboratory results showed severe lactate acidosis with renal dysfunction and indications of diffuse intravascular coagulation. Because he had signs of progressive septic shock, the patient was admitted to the ICU. There he subsequently developed hypoglycaemia (glucose < 0.1 mmol/l) and CPR had to be performed twice - the patient died shortly afterwards. Autopsy showed bilateral necrosis and haemorrhage of the adrenal glands, indicative of the diagnosis of WFS. Streptococcus pneumoniae was identified. CONCLUSION: In case of sepsis, with fever, rapidly expanding petechiae and purpura the Waterhouse-Friderichsen syndrome should be considered. Intensive therapy with antibiotics, fluids, vasopressors, and corticosteroids should be initiated immediately. TI - [The Waterhouse-Friderichsen syndrome] SN - 0028-2162 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 162 ER - TY - JOUR AU - Brule, J.M.D. van den AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2018 UR - https://hdl.handle.net/2066/196359 AB - Out of hospital cardiac arrest is the leading cause of death in industrialized countries. Recovery of hemodynamics does not necessarily lead to recovery of cerebral perfusion. The neurological injury induced by a circulatory arrest mainly determines the prognosis of patients after cardiac arrest and rates of survival with a favourable neurological outcome are low. This review focuses on the temporal course of cerebral perfusion and changes in cerebral autoregulation after out of hospital cardiac arrest. In the early phase after cardiac arrest, patients have a low cerebral blood flow that gradually restores towards normal values during the first 72 hours after cardiac arrest. Whether modification of the cerebral blood flow after return of spontaneous circulation impacts patient outcome remains to be determined. TI - Cerebral Perfusion and Cerebral Autoregulation after Cardiac Arrest SN - 2314-6133 JF - Biomed Research International VL - vol. 2018 DO - https://doi.org/10.1155/2018/4143636 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196359/196359.pdf?sequence=1 ER - TY - JOUR AU - Devlin, J.W. AU - Skrobik, Y. AU - Gelinas, C. AU - Needham, D.M. AU - Slooter, A.J. AU - Pandharipande, P.P. AU - Watson, P.L. AU - Weinhouse, G.L. AU - Nunnally, M.E. AU - Rochwerg, B. AU - Balas, M.C. AU - Boogaard, M.H.W.A. van den AU - Bosma, K.J. AU - Brummel, N.E. AU - Chanques, G. AU - Denehy, L. AU - Drouot, X. AU - Fraser, G.L. AU - Harris, J.E. AU - Joffe, A.M. AU - Kho, M.E. AU - Kress, J.P. AU - Lanphere, J.A. AU - McKinley, S. AU - Neufeld, K.J. AU - Pisani, M.A. AU - Payen, J.F. AU - Pun, B.T. AU - Puntillo, K.A. AU - Riker, R.R. AU - Robinson, B.R. AU - Shehabi, Y. AU - Szumita, P.M. AU - Winkelman, C. AU - Centofanti, J.E. AU - Price, C. AU - Nikayin, S. AU - Misak, C.J. AU - Flood, P.D. AU - Kiedrowski, K. AU - Alhazzani, W. PY - 2018 UR - https://hdl.handle.net/2066/196361 AB - OBJECTIVE: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. DESIGN: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017. METHODS: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. RESULTS: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. CONCLUSIONS: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population. TI - Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU EP - e873 SN - 0090-3493 IS - iss. 9 SP - e825 JF - Critical Care Medicine VL - vol. 46 DO - https://doi.org/10.1097/CCM.0000000000003299 ER - TY - JOUR AU - Rompaey, B. Van AU - Sabbe, K. AU - Dilles, T. AU - Boogaard, M. van den PY - 2018 UR - https://hdl.handle.net/2066/196370 TI - Delirium, introduction to a confused mind EP - 4 SN - 0964-3397 SP - 1 JF - Intensive and Critical Care Nursing VL - vol. 47 DO - https://doi.org/10.1016/j.iccn.2018.06.003 ER - TY - JOUR AU - Hofmeijer, J. AU - Kaam, C.R. van AU - Werff, B. van de AU - Vermeer, S.E. AU - Tjepkema-Cloostermans, M.C. AU - Putten, M.J.A.M. van PY - 2018 UR - https://hdl.handle.net/2066/196371 AB - Introduction: There is strong evidence suggesting detrimental effects of cortical spreading depolarization (CSD) in patients with acute ischemic stroke and severe traumatic brain injury. Previous studies implicated scalp electroencephalography (EEG) features to be correlates of CSD based on retrospective analysis of EEG epochs after having detected "CSD" in time aligned electrocorticography. We studied the feasibility of CSD detection in a prospective cohort study with continuous EEG in 18 patients with acute ischemic stroke and 18 with acute severe traumatic brain injury. Methods: Full band EEG with 21 silver/silver chloride electrodes was started within 48 h since symptom onset. Five additional electrodes were used above the infarct. We visually analyzed all raw EEG data in epochs of 1 h. Inspection was directed at detection of the typical combination of CSD characteristics, i.e., (i) a large slow potential change (SPC) accompanied by a simultaneous amplitude depression of >1Hz activity, (ii) focal presentation, and (iii) spread reflected as appearance on neighboring electrodes with a delay. Results: In 3,035 one-hour EEG epochs, infraslow activity (ISA) was present in half to three quarters of the registration time. Typically, activity was intermittent with amplitudes of 40-220 microV, approximately half was oscillatory. There was no specific spatial distribution. Relevant changes of ISA were always visible in multiple electrodes, and not focal, as expected in CSD. ISA appearing as "SPC" was mostly associated with an amplitude increase of faster activities, and never with suppression. In all patients, depressions of spontaneous brain activity occurred. However, these were not accompanied by simultaneous SPC, occurred simultaneously on all channels, and were not focal, let alone spread, as expected in CSD. Conclusion: With full band scalp EEG in patients with cortical ischemic stroke or traumatic brain injury, we observed various ISA, probably modulating cortical excitability. However, we were unable to identify unambiguous characteristics of CSD. TI - Detecting Cortical Spreading Depolarization with Full Band Scalp Electroencephalography: An Illusion? SN - 1664-2295 JF - Frontiers in Neurology VL - vol. 9 DO - https://doi.org/10.3389/fneur.2018.00017 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196371/196371.pdf?sequence=1 ER - TY - JOUR AU - Kamps, M. AU - Hoedemaekers, C.W. PY - 2018 UR - https://hdl.handle.net/2066/196374 TI - Early prognostication after cardiac arrest: Are we getting closer? EP - a4 SN - 0300-9572 SP - A3 JF - Resuscitation VL - vol. 129 DO - https://doi.org/10.1016/j.resuscitation.2018.05.017 ER - TY - JOUR AU - Simons, K.S. AU - Boeijen, E.R.K. AU - Mertens, M.C. AU - Rood, P. AU - Jager, C.P.C. de AU - Boogaard, M. van den PY - 2018 UR - https://hdl.handle.net/2066/196375 AB - BACKGROUND: Exposure to bright light has alerting effects. In nurses, alertness may be decreased because of shift work and high work pressure, potentially reducing work performance and increasing the risk for medical errors. OBJECTIVES: To determine whether high-intensity dynamic light improves cognitive performance, self-reported depressive signs and symptoms, fatigue, alertness, and well-being in intensive care unit nurses. METHODS: In a single-center crossover study in an intensive care unit of a teaching hospital in the Netherlands, 10 registered nurses were randomly divided into 2 groups. Each group worked alternately for 3 to 4 days in patients' rooms with dynamic light and 3 to 4 days in control lighting settings. High-intensity dynamic light was administered through ceiling-mounted fluorescent tubes that delivered bluish white light up to 1700 lux during the daytime, versus 300 lux in control settings. Cognitive performance, self-reported depressive signs and symptoms, fatigue, and well-being before and after each period were assessed by using validated cognitive tests and questionnaires. RESULTS: Cognitive performance, self-reported depressive signs and symptoms, and fatigue did not differ significantly between the 2 light settings. Scores of subjective well-being were significantly lower after a period of working in dynamic light. CONCLUSIONS: Daytime lighting conditions did not affect intensive care unit nurses' cognitive performance, perceived depressive signs and symptoms, or fatigue. Perceived quality of life, predominantly in the psychological and environmental domains, was lower for nurses working in dynamic light. TI - Effect of Dynamic Light Application on Cognitive Performance and Well-being of Intensive Care Nurses EP - 248 SN - 1062-3264 IS - iss. 3 SP - 245 JF - American Journal of Critical Care VL - vol. 27 DO - https://doi.org/10.4037/ajcc2018908 ER - TY - JOUR AU - Devlin, J.W. AU - Skrobik, Y. AU - Gelinas, C. AU - Needham, D.M. AU - Slooter, A.J. AU - Pandharipande, P.P. AU - Watson, P.L. AU - Weinhouse, G.L. AU - Nunnally, M.E. AU - Rochwerg, B. AU - Balas, M.C. AU - Boogaard, M. van den AU - Bosma, K.J. AU - Brummel, N.E. AU - Chanques, G. AU - Denehy, L. AU - Drouot, X. AU - Fraser, G.L. AU - Harris, J.E. AU - Joffe, A.M. AU - Kho, M.E. AU - Kress, J.P. AU - Lanphere, J.A. AU - McKinley, S. AU - Neufeld, K.J. AU - Pisani, M.A. AU - Payen, J.F. AU - Pun, B.T. AU - Puntillo, K.A. AU - Riker, R.R. AU - Robinson, B.R. AU - Shehabi, Y. AU - Szumita, P.M. AU - Winkelman, C. AU - Centofanti, J.E. AU - Price, C. AU - Nikayin, S. AU - Misak, C.J. AU - Flood, P.D. AU - Kiedrowski, K. AU - Alhazzani, W. PY - 2018 UR - https://hdl.handle.net/2066/196383 TI - Executive Summary: Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU EP - 1548 SN - 0090-3493 IS - iss. 9 SP - 1532 JF - Critical Care Medicine VL - vol. 46 DO - https://doi.org/10.1097/CCM.0000000000003259 ER - TY - JOUR AU - Peters, E. AU - Antonelli, M. AU - Wittebole, X. AU - Nanchal, R. AU - Francois, B. AU - Sakr, Y. AU - Vincent, J.L. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/194278 TI - A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from The Intensive Care Over Nations audit SN - 1466-609X JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2112-z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194278/194278.pdf?sequence=1 ER - TY - JOUR AU - Oerlemans, A.J.M. AU - Jonge, E. de AU - Hoeven, J.G. van der AU - Zegers, M. PY - 2018 UR - https://hdl.handle.net/2066/195155 TI - A systematic approach to develop a core set of parameters for boards of directors to govern quality of care in the ICU EP - 550 SN - 1353-4505 IS - iss. 7 SP - 545 JF - International Journal for Quality in Health Care VL - vol. 30 DO - https://doi.org/10.1093/intqhc/mzy048 ER - TY - JOUR AU - Geven, C.B.C.A.G. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/196331 TI - The mechanism of action of the adrenomedullin-binding antibody adrecizumab SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2074-1 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196331/196331.pdf?sequence=1 ER - TY - JOUR AU - Geven, C.B.C.A.G. AU - Bergmann, A. AU - Kox, M. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/196342 AB - Sepsis remains a major scientific and medical challenge, for which, apart from significant refinements in supportive therapy, treatment has barely changed over the last few decades. During sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock. The free circulating peptide adrenomedullin (ADM) is involved in the regulation of the endothelial barrier function and tone of blood vessels. Several animal studies have shown that ADM administration improves outcome of sepsis. However, in higher dosages, ADM administration may cause hypotension, limiting its clinical applicability. Moreover, ADM has a very short half-life and easily adheres to surfaces, further hampering its clinical use. The non-neutralizing anti-ADM antibody Adrecizumab (HAM8101) which causes a long-lasting increase of plasma ADM has shown promising results in animal models of systemic inflammation and sepsis; it reduced inflammation, attenuated vascular leakage, and improved hemodynamics, kidney function, and survival. Combined with an excellent safety profile derived from animal and phase I human studies, Adrecizumab represents a promising candidate drug for the adjunctive treatment of sepsis. In this review, we first provide a brief overview of the currently available data on the role of adrenomedullin in sepsis and describe its effects on endothelial barrier function and vasodilation. Furthermore, we provide a novel hypothesis concerning the mechanisms of action through which Adrecizumab may exert its beneficial effects in sepsis. TI - Vascular Effects of Adrenomedullin and the Anti-Adrenomedullin Antibody Adrecizumab in Sepsis EP - 140 SN - 1073-2322 IS - iss. 2 SP - 132 JF - Shock VL - vol. 50 DO - https://doi.org/10.1097/SHK.0000000000001103 ER - TY - JOUR AU - Geven, C.B.C.A.G. AU - Kox, M. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/196399 AB - Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted. TI - Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis SN - 1664-3224 JF - Frontiers in Immunology VL - vol. 9 DO - https://doi.org/10.3389/fimmu.2018.00292 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196399/196399.pdf?sequence=1 ER - TY - JOUR AU - Groenendael, R. van AU - Kox, M. AU - Eijk, L.T.G.J. van AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/196402 AB - The systemic inflammatory response following infectious or non-infectious insults is related to morbidity (including acute kidney injury) and mortality. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230, a linear tetrapeptide (Alanine-Glutamine-Glycine-Valine), derived from the beta-chain of the human chorionic gonadotropin hormone, has shown immunomodulatory and renoprotective properties in several pre-clinical animal models of systemic inflammation. Furthermore, an excellent safety profile of EA-230 was observed in phase 1 studies in humans, and the immunomodulatory effects of EA-230 were recently demonstrated in a phase IIa study during human experimental endotoxemia. A prospective double-blind placebo-controlled randomized trial in 180 patients undergoing elective CABG-surgery with or without valve surgery is currently conducted to investigate the immunomodulatory and renoprotective properties of EA-230. TI - Immunomodulatory and Kidney-Protective Effects of the Human Chorionic Gonadotropin Derivate EA-230 EP - 151 SN - 1660-8151 IS - iss. 2 SP - 148 JF - Nephron VL - vol. 140 DO - https://doi.org/10.1159/000490772 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196402/196402.pdf?sequence=1 ER - TY - JOUR AU - Brule, J.M.D. van den AU - Kaam, C.R. van AU - Hoeven, J.G. van der AU - Claassen, J.A.H.R. AU - Hoedemaekers, C.W.E. PY - 2018 UR - https://hdl.handle.net/2066/196407 AB - Objective: To determine if increasing variability of blood pressure influences determination of cerebral autoregulation. Methods: A prospective observational study was performed at the ICU of a university hospital in the Netherlands. 13 comatose patients after cardiac arrest underwent baseline and intervention (tilting of bed) measurements. Mean flow velocity (MFV) in the middle cerebral artery and mean arterial pressure (MAP) were measured. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, coherence, gain, and phase were calculated in the very low and low frequency bands. Results: The CV of MAP was significantly higher during intervention compared to baseline. On individual level, coherence in the VLF band changed in 5 of 21 measurements from unreliable to reliable and in 6 of 21 measurements from reliable to unreliable. In the LF band 1 of 21 measurements changed from unreliable to reliable and 3 of 21 measurements from reliable to unreliable. Gain in the VLF and LF band was lower during intervention compared to baseline. Conclusions: For the ICU setting, more attention should be paid to the exact experimental protocol, since changes in experimental settings strongly influence results of estimation of cerebral autoregulation. TI - Influence of Induced Blood Pressure Variability on the Assessment of Cerebral Autoregulation in Patients after Cardiac Arrest SN - 2314-6133 JF - Biomed Research International VL - vol. 2018 DO - https://doi.org/10.1155/2018/8153241 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196407/196407.pdf?sequence=1 ER - TY - JOUR AU - Peters van Ton, A.M. AU - Kox, M. AU - Abdo, W.F. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/196422 AB - Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis. TI - Precision Immunotherapy for Sepsis SN - 1664-3224 JF - Frontiers in Immunology VL - vol. 9 DO - https://doi.org/10.3389/fimmu.2018.01926 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196422/196422.pdf?sequence=1 ER - TY - JOUR AU - Boogaard, M. van den AU - Slooter, A.J. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/196425 TI - Prophylactic Haloperidol for Critically Ill Adults-Reply EP - 305 SN - 0098-7484 IS - iss. 3 SP - 304 JF - Jama : Journal of the American Medical Association VL - vol. 320 DO - https://doi.org/10.1001/jama.2018.6049 ER - TY - JOUR AU - Groen, B.D. AU - Steeg, E. Van de AU - Mooij, M.G. AU - Lipzig, M.M.H. van AU - Koning, B.A.E. de AU - Verdijk, R.M. AU - Wortelboer, H.M. AU - Gaedigk, R. AU - Bi, C. AU - Leeder, J.S. AU - Schaik, R.H. van AU - Rosmalen, J. van AU - Tibboel, D. AU - Vaes, W.H. AU - Wildt, S.N. de PY - 2018 UR - https://hdl.handle.net/2066/196426 AB - BACKGROUND: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples. METHODS: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age (gestational age [GA], postnatal age [PNA], and postmenstrual age); between protein and mRNA expression; and between protein expression and genotype. RESULTS: We analyzed 36 fetal (median GA 23.4weeks [range 15.3-41.3]), 12 premature newborn (GA 30.2weeks [24.9-36.7], PNA 1.0weeks [0.14-11.4]), 10 term newborn (GA 40.0weeks [39.7-41.3], PNA 3.9weeks [0.3-18.1]), 4 pediatric (PNA 4.1years [1.1-7.4]) and 8 adult liver samples. A relationship with age was found for BCRP, BSEP, GLUT1, MDR1, MRP1, MRP2, MRP3, NTCP, OATP1B1 and OCT1, with the strongest relationship for postmenstrual age. For most transporters mRNA and protein expression were not correlated. No genotype-protein expression relationship was detected. DISCUSSION AND CONCLUSION: Various developmental patterns of protein expression of hepatic transporters emerged in fetuses and newborns up to four months of age. Postmenstrual age was the most robust factor predicting transporter expression in this cohort. Our data fill an important gap in current pediatric transporter ontogeny knowledge. TI - Proteomics of human liver membrane transporters: a focus on fetuses and newborn infants EP - 227 SN - 0928-0987 SP - 217 JF - European Journal of Pharmaceutical Sciences VL - vol. 124 DO - https://doi.org/10.1016/j.ejps.2018.08.042 ER - TY - JOUR AU - Madotto, F. AU - Pham, T. AU - Bellani, G. AU - Bos, L.D. AU - Simonis, F.D. AU - Fan, E. AU - Artigas, A. AU - Brochard, L. AU - Schouten, J.A. AU - Schultz, M.J. AU - Laffey, J.G. PY - 2018 UR - https://hdl.handle.net/2066/196434 AB - PURPOSE: To evaluate patients with resolved versus confirmed ARDS, identify subgroups with substantial mortality risk, and to determine the utility of day 2 ARDS reclassification. METHODS: Our primary objective, in this secondary LUNG SAFE analysis, was to compare outcome in patients with resolved versus confirmed ARDS after 24 h. Secondary objectives included identifying factors associated with ARDS persistence and mortality, and the utility of day 2 ARDS reclassification. RESULTS: Of 2377 patients fulfilling the ARDS definition on the first day of ARDS (day 1) and receiving invasive mechanical ventilation, 503 (24%) no longer fulfilled the ARDS definition the next day, 52% of whom initially had moderate or severe ARDS. Higher tidal volume on day 1 of ARDS was associated with confirmed ARDS [OR 1.07 (CI 1.01-1.13), P = 0.035]. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both resolved and confirmed ARDS, age, non-respiratory SOFA score, lower PEEP and P/F ratio, higher peak pressure and respiratory rate were each associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated with mortality. The increase in area under the receiver operating curve for ARDS reclassification on day 2 was marginal. CONCLUSIONS: ARDS, whether resolved or confirmed at day 2, has a high mortality rate. ARDS reclassification at day 2 has limited predictive value for mortality. The substantial mortality risk in severe confirmed ARDS suggests that complex interventions might best be tested in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02010073. TI - Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study EP - 577 SN - 0342-4642 IS - iss. 5 SP - 564 JF - Intensive Care Medicine VL - vol. 44 DO - https://doi.org/10.1007/s00134-018-5152-6 ER - TY - JOUR AU - Jansen, D. AU - Jonkman, A.H. AU - Roesthuis, L.H. AU - Gadgil, S. AU - Hoeven, J.G. van der AU - Scheffer, G.J. AU - Girbes, A. AU - Doorduin, J. AU - Sinderby, C.S. AU - Heunks, L.M. PY - 2018 UR - https://hdl.handle.net/2066/196104 AB - BACKGROUND: Diaphragm dysfunction develops frequently in ventilated intensive care unit (ICU) patients. Both disuse atrophy (ventilator over-assist) and high respiratory muscle effort (ventilator under-assist) seem to be involved. A strong rationale exists to monitor diaphragm effort and titrate support to maintain respiratory muscle activity within physiological limits. Diaphragm electromyography is used to quantify breathing effort and has been correlated with transdiaphragmatic pressure and esophageal pressure. The neuromuscular efficiency index (NME) can be used to estimate inspiratory effort, however its repeatability has not been investigated yet. Our goal is to evaluate NME repeatability during an end-expiratory occlusion (NMEoccl) and its use to estimate the pressure generated by the inspiratory muscles (Pmus). METHODS: This is a prospective cohort study, performed in a medical-surgical ICU. A total of 31 adult patients were included, all ventilated in neurally adjusted ventilator assist (NAVA) mode with an electrical activity of the diaphragm (EAdi) catheter in situ. At four time points within 72 h five repeated end-expiratory occlusion maneuvers were performed. NMEoccl was calculated by delta airway pressure (DeltaPaw)/DeltaEAdi and was used to estimate Pmus. The repeatability coefficient (RC) was calculated to investigate the NMEoccl variability. RESULTS: A total number of 459 maneuvers were obtained. At time T = 0 mean NMEoccl was 1.22 +/- 0.86 cmH2O/muV with a RC of 82.6%. This implies that when NMEoccl is 1.22 cmH2O/muV, it is expected with a probability of 95% that the subsequent measured NMEoccl will be between 2.22 and 0.22 cmH2O/muV. Additional EAdi waveform analysis to correct for non-physiological appearing waveforms, did not improve NMEoccl variability. Selecting three out of five occlusions with the lowest variability reduced the RC to 29.8%. CONCLUSIONS: Repeated measurements of NMEoccl exhibit high variability, limiting the ability of a single NMEoccl maneuver to estimate neuromuscular efficiency and therefore the pressure generated by the inspiratory muscles based on EAdi. TI - Estimation of the diaphragm neuromuscular efficiency index in mechanically ventilated critically ill patients SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2172-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196104/196104.pdf?sequence=1 ER - TY - JOUR AU - Timmermans, K. AU - Slagt, C. AU - Kox, M. PY - 2018 UR - https://hdl.handle.net/2066/196113 TI - Hemorrhagic Shock EP - 1851 SN - 0028-4793 IS - iss. 19 SP - 1850 JF - The New England Journal of Medicine VL - vol. 378 DO - https://doi.org/10.1056/NEJMc1802361 ER - TY - JOUR AU - Schauwvlieghe, Alexander F.A.D. AU - Rijnders, Bart J.A. AU - Philips, Nele AU - Verwijs, Rosanne AU - Vanderbeke, Lore AU - Tienen, Carla Van AU - Verweij, P.E. AU - Veerdonk, F.L. van de AU - Hoedemaekers, A. AU - Boelens, Jerina AU - Wauters, J. PY - 2018 UR - https://hdl.handle.net/2066/196119 TI - Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study EP - 792 SN - 2213-2600 IS - iss. 10 SP - 782 JF - Lancet Respiratory Medicine VL - vol. 6 DO - https://doi.org/10.1016/S2213-2600(18)30274-1 ER - TY - JOUR AU - Eijk, L.T.G.J. van AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/196122 TI - Man flu: less inflammation but more consequences in men than women SN - 1756-1833 SP - k439 JF - Bmj. British Medical Journal (Online) VL - vol. 360 DO - https://doi.org/10.1136/bmj.k439 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196122/196122.pdf?sequence=1 ER - TY - JOUR AU - Mebazaa, Alexandre AU - Geven, C.B.C.A.G. AU - Hollinger, Alexa AU - Wittebole, X. AU - Chousterman, Benjamin Glen AU - Blet, A. AU - Pickkers, P. AU - Legrand, M. AU - Laterre, P.F. PY - 2018 UR - https://hdl.handle.net/2066/199454 TI - Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study SN - 1466-609X JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2243-2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/199454/199454.pdf?sequence=1 ER - TY - JOUR AU - Milton, A. AU - Schandl, A. AU - Soliman, I.W. AU - Meijers, K. AU - Boogaard, M. van den AU - Larsson, I.M. AU - Bottai, M. AU - Sackey, P.V. PY - 2018 UR - https://hdl.handle.net/2066/199463 TI - Development of an ICU discharge instrument predicting psychological morbidity: a multinational study EP - 2047 SN - 0342-4642 IS - iss. 12 SP - 2038 JF - Intensive Care Medicine VL - vol. 44 DO - https://doi.org/10.1007/s00134-018-5467-3 ER - TY - JOUR AU - Evers, R. AU - Piquette-Miller, M. AU - Polli, J.W. AU - Russel, F.G.M. AU - Sprowl, J.A. AU - Tohyama, K. AU - Ware, J.A. AU - Wildt, S.N. de AU - Xie, W AU - Brouwer, K.L.R. PY - 2018 UR - https://hdl.handle.net/2066/200052 AB - Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by inhibition, induction, genetic polymorphisms, or disease can have profound effects on overall physiology, drug pharmacokinetics, drug efficacy, and toxicity. This white paper provides a review of changes in transporter function associated with acute and chronic disease states, describes regulatory pathways affecting transporter expression, and identifies opportunities to advance the field. TI - Disease-Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper From the International Transporter Consortium EP - 915 SN - 0009-9236 IS - iss. 5 SP - 900 JF - Clinical Pharmacology and Therapeutics VL - vol. 104 DO - https://doi.org/10.1002/cpt.1115 ER - TY - JOUR AU - Geven, C.B.C.A.G. AU - Peters, E. AU - Schroedter, Mathias AU - Struck, Joachim AU - Bergmann, A. AU - McCook, Oscar AU - Kox, M. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/200063 TI - Effects of the humanized anti-adrenomedullin antibody adrecizumab (HAM8101) on vascular barrier function and survival in rodent models of systemic inflammation and sepsis EP - 654 SN - 1073-2322 IS - iss. 6 SP - 648 JF - Shock VL - vol. 50 DO - https://doi.org/10.1097/SHK.0000000000001102 ER - TY - JOUR AU - Albers, K.I. AU - Martini, C.H. AU - Scheffer, G.J. AU - Warle, M.C. PY - 2018 UR - https://hdl.handle.net/2066/200230 TI - Letter to the editor: considering the effects of deep neuromuscular blockade on endoscopic surgical conditions during transurethral resection of a bladder tumor (TURB) EP - 2094 SN - 0724-4983 IS - iss. 12 SP - 2093 JF - World Journal of Urology VL - vol. 36 DO - https://doi.org/10.1007/s00345-018-2417-1 ER - TY - JOUR AU - Leeuw, T.G. de AU - Wildt, S.N. de PY - 2018 UR - https://hdl.handle.net/2066/200365 TI - Reply to Stamer, Ulrike; Stuber, Frank, regarding their comment 'Analgesic efficacy of dipyrone children - Still an absence of evidence' SN - 1155-5645 IS - iss. 12 SP - 1156 JF - Paediatric Anaesthesia VL - vol. 28 DO - https://doi.org/10.1111/pan.13484 ER - TY - JOUR AU - Kleiber, N. AU - Rosmalen, J. van AU - Tibboel, D. AU - Wildt, S.N. de PY - 2018 UR - https://hdl.handle.net/2066/194729 TI - Hemodynamic Tolerance to IV Clonidine Infusion in the PICU* EP - E416 SN - 1529-7535 IS - iss. 8 SP - E409 JF - Pediatric Critical Care Medicine VL - vol. 19 DO - https://doi.org/10.1097/PCC.0000000000001602 ER - TY - JOUR AU - Brule, J.M.D. van den AU - Stolk, R.F. AU - Vinke, Elisabeth Janine AU - Loon, Lex Maxim van AU - Pickkers, P. AU - Hoeven, J.G. van der AU - Kox, M. AU - Hoedemaekers, C.W.E. PY - 2018 UR - https://hdl.handle.net/2066/194771 TI - Vasopressors Do Not Influence Cerebral Critical Closing Pressure During Systemic Inflammation Evoked by Experimental Endotoxemia and Sepsis in Humans EP - 535 SN - 1073-2322 IS - iss. 5 SP - 529 JF - Shock VL - vol. 49 DO - https://doi.org/10.1097/SHK.0000000000001003 ER - TY - JOUR AU - Doorduin, J. AU - Roesthuis, L.H. AU - Jansen, D. AU - Hoeven, J.G. van der AU - Hees, H.W.H. van AU - Heunks, L.M.A. PY - 2018 UR - https://hdl.handle.net/2066/194889 TI - Respiratory Muscle Effort during Expiration in Successful and Failed Weaning from Mechanical Ventilation EP - 501 SN - 0003-3022 IS - iss. 3 SP - 490 JF - Anesthesiology VL - vol. 129 DO - https://doi.org/10.1097/ALN.0000000000002256 ER - TY - JOUR AU - Geven, C.B.C.A.G. AU - Lier, D.P.T. van AU - Blet, A. AU - Peelen, R.V. AU - Elzen, Bas ten AU - Mebazaa, Alexandre AU - Kox, M. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/194891 TI - Safety, tolerability and pharmacokinetics/pharmacodynamics of the adrenomedullin antibody adrecizumab in a first-in-human study and during experimental human endotoxaemia in healthy subjects EP - 2141 SN - 0306-5251 IS - iss. 9 SP - 2129 JF - British Journal of Clinical Pharmacology VL - vol. 84 DO - https://doi.org/10.1111/bcp.13655 ER - TY - JOUR AU - Geense, W.W. AU - Gaal, B. van AU - Knoll, J.L. AU - Maas, N.M. AU - Kok, G. AU - Cornelissen, E.A.M. AU - Nijhuis-van der Sanden, M.W.G. PY - 2018 UR - https://hdl.handle.net/2066/195585 AB - BACKGROUND: Parents of children with chronic kidney disease (CKD) experience high levels of stress in the daily management of their child's illness. Parents need continuously available support and information, yet online support programs are lacking. e-Powered Parents was developed to fill this gap; it is an online program consisting of (1) medical information, (2) an interactive part, and (3) four training modules (stress management, setting limits, communication, and coping). Prior to a large-scale evaluation, we conducted a feasibility study that consisted of an effect study and a process evaluation. OBJECTIVE: The objectives of our study were to (1) identify the outcome measures that are most likely to capture the potential benefit, (2) evaluate the potential effectiveness and effect size, and (3) evaluate recruitment, reach, the dose received, and context. METHODS: We conducted a feasibility study with a two-armed, wait-list randomized controlled trial (RCT). Prior to baseline, parents (n=146) were randomly allocated to group 1 or group 2. After completing the baseline questionnaire, parents in group 1 were given access to e-Powered Parents, while those in group 2 received usual care. At the 6-month follow-up (T1), all parents received a questionnaire and parents in group 2 were given access to e-Powered Parents as well. After 1.5 years, through an extra measurement (T2), we evaluated the effect of long-term exposure. Outcomes were the child's quality of life (Child Vulnerability Scale), parental stress (Pediatric Inventory for Parents) and fatigue (Multidimensional Fatigue Inventory), self-efficacy in communication with health care professionals (Perceived Efficacy in Patient-Physician Interactions, PEPPI-5), and parental perceptions of family management (Family Management Measure). Floor and ceiling effects and percentage of parents showing no change in scores were calculated. We used linear mixed models to evaluate the potential effectiveness and effect sizes using the intention-to-treat and per-protocol analyses. In the process evaluation, we evaluated recruitment, reach, the dose received, and context using a questionnaire sent to the parents, log-in data, and a focus group interview with health care professionals. RESULTS: At T1 (n=86) and T2 (n=51), no significant effects were found on any of the five outcomes. The PEPPI-5 showed ceiling effects and high percentages of parents showing no change between the measurement times. The information and interactive part of the intervention were used by 84% (57/68) of the parents in group 1 and 49% (32/65) of the parents in group 2. The information pages were visited most often. Overall, 64% (85/133) of the parents logged in to the training platform and 31% (26/85) actually used the training modules. CONCLUSIONS: We did not observe any significant effect on any of the outcomes. This could possibly be explained by the minimal use of the intervention and by parents' heterogeneity. For continued participation, we recommend a tailored intervention and further studies to find out whether and how online programs could be used to support parents in the management of their child's CKD. TRIAL REGISTRATION: Netherlands Trial Registry NTR4808; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4808 (Archived by WebCite at http://www.webcitation.org/719rCicvW). TI - Effect and Process Evaluation of e-Powered Parents, a Web-Based Support Program for Parents of Children With a Chronic Kidney Disease: Feasibility Randomized Controlled Trial SN - 1438-8871 IS - iss. 8 JF - Journal of Medical Internet Research VL - vol. 20 DO - https://doi.org/10.2196/jmir.9547 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/195585/195585.pdf?sequence=1 ER - TY - JOUR AU - Boeschoten, S.A. AU - Buysse, C.M. AU - Merkus, P.J.F.M. AU - Wijngaarden, J.M.C. van AU - Heisterkamp, S.G.J. AU - Jongste, J.C. de AU - Rosmalen, J. van AU - Otter, S.C.M. AU - Lemson, J. AU - Boehmer, A.L.M. AU - Hoog, M. de PY - 2018 UR - https://hdl.handle.net/2066/193193 AB - The number of children requiring pediatric intensive care unit (PICU) admission for severe acute asthma (SAA) around the world has increased. OBJECTIVES: We investigated whether this trend in SAA PICU admissions is present in the Netherlands. METHODS: A multicenter retrospective cohort study across all tertiary care PICUs in the Netherlands. Inclusion criteria were children (2-18 years) hospitalized for SAA between 2003 and 2013. Data included demographic data, asthma diagnosis, treatment, and mortality. RESULTS: In the 11-year study period 590 children (660 admissions) were admitted to a PICU with a threefold increase in the number of admissions per year over time. The severity of SAA seemed unchanged, based on the first blood gas, length of stay and mortality rate (0.6%). More children received highflow nasal cannula (P < 0.001) and fewer children needed invasive ventilation (P < 0.001). In 58% of the patients the maximal intravenous (IV) salbutamol infusion rate during PICU admission was 1 mcg/kg/min. However, the number of patients treated with IV salbutamol in the referring hospitals increased significantly over time (P = 0.005). The proportion of steroid-naive patients increased from 35% to 54% (P = 0.004), with a significant increase in both age groups (2-4 years [P = 0.026] and 5-17 years [P = 0.036]). CONCLUSIONS: The number of children requiring PICU admission for SAA in the Netherlands has increased. We speculate that this threefold increase is explained by an increasing number of steroid-naive children, in conjunction with a lowered threshold for PICU admission, possibly caused by earlier use of salbutamol IV in the referring hospitals. TI - Children with severe acute asthma admitted to Dutch PICUs: A changing landscape EP - 865 SN - 8755-6863 IS - iss. 7 SP - 857 JF - Pediatric Pulmonology VL - vol. 53 DO - https://doi.org/10.1002/ppul.24009 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/193193/193193.pdf?sequence=1 ER - TY - JOUR AU - Rijssen, L.B. van AU - Zwart, M.J. AU - Dieren, S. van AU - Rooij, T. de AU - Bonsing, B.A. AU - Bosscha, K. AU - Dam, R.M. van AU - Eijck, C.H. van AU - Gerhards, M.F. AU - Gerritsen, J.J. AU - Harst, E AU - Hingh, I.H. de AU - Jong, K.P. de AU - Kazemier, G. AU - Klaase, J. AU - Kolk, B.M. van der AU - Laarhoven, C.J.H.M. van AU - Luyer, M.D. AU - Molenaar, I.Q. AU - Patijn, G.A. AU - Rupert, C.G. AU - Scheepers, J.J. AU - Schelling, G.P. van der AU - Vahrmeijer, A.L. AU - Busch, O.R. AU - Santvoort, H.C. van AU - Koerkamp, B. Groot AU - Besselink, M.G.H. PY - 2018 UR - https://hdl.handle.net/2066/195692 AB - BACKGROUND: In the mandatory nationwide Dutch Pancreatic Cancer Audit, rates of major complications and Failure to Rescue (FTR) after pancreatoduodenectomy between low- and high-mortality hospitals are compared, and independent predictors for FTR investigated. METHODS: Patients undergoing pancreatoduodenectomy in 2014 and 2015 in The Netherlands were included. Hospitals were divided into quartiles based on mortality rates. The rate of major complications (Clavien-Dindo >/=3) and death after a major complication (FTR) were compared between these quartiles. Independent predictors for FTR were identified by multivariable logistic regression analysis. RESULTS: Out of 1.342 patients, 391 (29%) developed a major complication and in-hospital mortality was 4.2%. FTR occurred in 56 (14.3%) patients. Mortality was 0.9% in the first hospital quartile (4 hospitals, 327 patients) and 8.1% in the fourth quartile (5 hospitals, 310 patients). The rate of major complications increased by 40% (25.7% vs 35.2%) between the first and fourth hospital quartile, whereas the FTR rate increased by 560% (3.6% vs 22.9%). Independent predictors of FTR were male sex (OR = 2.1, 95%CI 1.2-3.9), age >75 years (OR = 4.3, 1.8-10.2), BMI >/=30 (OR = 2.9, 1.3-6.6), histopathological diagnosis of periampullary cancer (OR = 2.0, 1.1-3.7), and hospital volume <30 (OR = 3.9, 1.6-9.6). CONCLUSIONS: Variations in mortality between hospitals after pancreatoduodenectomy were explained mainly by differences in FTR, rather than the incidence of major complications. TI - Variation in hospital mortality after pancreatoduodenectomy is related to failure to rescue rather than major complications: a nationwide audit EP - 767 SN - 1365-182X IS - iss. 8 SP - 759 JF - Hpb VL - vol. 20 DO - https://doi.org/10.1016/j.hpb.2018.02.640 ER - TY - JOUR AU - Jansen, D. AU - Vries, H. de AU - Heunks, L.M.A. PY - 2018 UR - https://hdl.handle.net/2066/194619 TI - Acetylcholine receptor antagonists in acute respiratory distress syndrome: much more than muscle relaxants SN - 1466-609X JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-1979-z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194619/194619.pdf?sequence=1 ER - TY - JOUR AU - Leliefeld, Pieter H.C. AU - Pillay, J. AU - Vrisekoop, Nienke AU - Heeres, Marjolein AU - Tak, Tamar AU - Kox, M. AU - Pickkers, P. AU - Leenen, Luke P.H. AU - Koenderman, L. PY - 2018 UR - https://hdl.handle.net/2066/193027 TI - Differential antibacterial control by neutrophil subsets EP - 1355 SN - 2473-9529 IS - iss. 11 SP - 1344 JF - Blood Advances VL - vol. 2 DO - https://doi.org/10.1182/bloodadvances.2017015578 ER - TY - JOUR AU - Wassenaar, A. AU - Schoonhoven, L. AU - Devlin, John W. AU - Haren, Frank M.P. van AU - Slooter, A.J. AU - Jorens, P.G. AU - Simons, Koen S. AU - Donders, A.R.T. AU - Pickkers, P. AU - Boogaard, M. van den PY - 2018 UR - https://hdl.handle.net/2066/191587 TI - Delirium prediction in the intensive care unit: comparison of two delirium prediction models SN - 1466-609X JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2037-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/191587/191587.pdf?sequence=1 ER - TY - THES AU - Wassenaar, A. PY - 2018 SN - 9789492896 UR - https://hdl.handle.net/2066/190667 PB - [S.l. : s.n.] TI - Prediction and non-pharmacological prevention of delirium in the intensive care unit N1 - Radboud University, 16 mei 2018 N1 - Promotores : Pickkers, P., Schoonhoven, L. Co-promotor : Boogaard, M. van den PS - 242 p. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190667/190667.pdf?sequence=1 ER - TY - JOUR AU - Vinke, E.J. AU - Eyding, J. AU - Korte, C.L. de AU - Slump, C.H. AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2018 UR - https://hdl.handle.net/2066/191340 AB - OBJECTIVE: The aim of this study was to investigate the feasibility of simultaneous visualization of the cerebral macrocirculation and microcirculation, using ultrasound perfusion imaging (UPI). In addition, we studied the sensitivity of this technique for detecting changes in cerebral blood flow (CBF). MATERIALS AND METHODS: We performed an observational study in ten healthy volunteers. Ultrasound contrast was used for UPI measurements during normoventilation and hyperventilation. For the data analysis of the UPI measurements, an in-house algorithm was used to visualize the DICOM files, calculate parameter images and select regions of interest (ROIs). Next, time intensity curves (TIC) were extracted and perfusion parameters calculated. RESULTS: Both volume- and velocity-related perfusion parameters were significantly different between the macrocirculation and the parenchymal areas. Hyperventilation-induced decreases in CBF were detectable by UPI in both the macrocirculation and microcirculation, most consistently by the volume-related parameters. The method was safe, with no adverse effects in our population. CONCLUSIONS: Bedside quantification of CBF seems feasible and the technique has a favourable safety profile. Adjustment of current method is required to improve its diagnostic accuracy. Validation studies using a 'gold standard' are needed to determine the added value of UPI in neurocritical care monitoring. TI - Quantification of Macrocirculation and Microcirculation in Brain Using Ultrasound Perfusion Imaging EP - 120 SN - 0065-1419 SP - 115 JF - Acta Neurochirurgica. Supplementum VL - vol. 126 DO - https://doi.org/10.1007/978-3-319-65798-1_25 ER - TY - JOUR AU - Boulkedid, R. AU - Abdou, A.Y. AU - Desselas, E. AU - Monegat, M. AU - Leeuw, T.G. de AU - Avez-Couturier, J. AU - Dugue, S. AU - Mareau, C. AU - Charron, B. AU - Alberti, C. AU - Kaguelidou, F. AU - Wildt, S.N. de AU - Pasqua, O.D. AU - Healy, P. PY - 2018 UR - https://hdl.handle.net/2066/191356 AB - BACKGROUND AND OBJECTIVE: Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain. METHODS: We performed a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. We included RCTs that involved children and adolescents (3 months-18 years) and evaluated the use of pharmacological or non-pharmacological intervention(s) in the context of pain persisting or re-occurring for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias (ROB) Tool. RESULTS: A total of 58 RCTs were identified and numbers steadily increased over time. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 47.5 participants (Q1,Q3: 32, 70). Forty-five percent of RCTs included both adults and children and the median of the mean ages at inclusion was 12.9 years (Q1,Q3: 11, 15). Testing of non-pharmacological interventions was predominant and only 5 RCTs evaluated analgesics or co-analgesics. Abdominal pain, headache/migraine and musculoskeletal pain were the most common types of chronic pain among participants. Methodological quality was poor with 90% of RCTs presenting a high or unclear ROB. CONCLUSIONS: Evaluation of analgesics targeting chronic pain relief in children and adolescents through RCTs is marginal. Infants and children with long-lasting painful conditions are insufficiently represented in RCTs. We discuss possible research constraints and challenges as well as methodologies to circumvent them. SIGNIFICANCE: There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non-pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long-lasting diseases. TI - The research gap in chronic paediatric pain: A systematic review of randomised controlled trials. EP - 271 SN - 1090-3801 IS - iss. 2 SP - 261 JF - European Journal of Pain VL - vol. 22 N1 - 1 februari 2018 DO - https://doi.org/10.1002/ejp.1137 ER - TY - JOUR AU - Slooff, V.D. AU - Dungen, D.K. van den AU - Beusekom, B.S. van AU - Jessurun, N. AU - Ista, E. AU - Tibboel, D. AU - Wildt, S.N. de PY - 2018 UR - https://hdl.handle.net/2066/191249 AB - OBJECTIVES: As delirium in critically ill children is increasingly recognized, more children are treated with the antipsychotic drug haloperidol, while current dosing guidelines are lacking solid evidence and appear to be associated with a high risk of adverse events. We aim to report on the safety and efficacy of a recently implemented clinical dose-titration protocol with active monitoring of adverse events. DESIGN: From July 2014 until June 2015, when a potential delirium was identified by regular delirium scores and confirmed by a child psychiatrist, haloperidol was prescribed according to the Dutch Pediatric Formulary. Daily, adverse events were systematically assessed, haloperidol plasma concentrations were measured, and delirium symptoms followed. Dependent on the clinical response, plasma concentration, and adverse event, the dose was adjusted. SETTING: A 28-bed tertiary PICU in the Netherlands. PATIENTS: All patients admitted to the PICU diagnosed with delirium. INTERVENTION: Treatment with haloperidol according to a dose-titration protocol MEASUREMENTS AND MAIN RESULTS:: Thirteen children (median age [range] 8.3 yr [0.4-13.8 yr]) received haloperidol, predominantly IV (median dose [range] 0.027 mg/kg/d [0.005-0.085 mg/kg/d]). In all patients, pediatric delirium resolved, but five of 13 patients developed possible adverse event. These were reversed after biperiden (n = 2), discontinuing (n = 3), and/or lowering the dose (n = 3). Plasma concentrations were all below the presumed therapeutic threshold of 3-12 microg/L. CONCLUSIONS: Prospective systematic monitoring of adverse event in critically ill children receiving haloperidol revealed a significant proportion of possible adverse events. Adverse event developed despite low plasma concentrations and recommended dose administration in the majority of the patients. Our data suggest that haloperidol can potentially improve pediatric delirium, but it might also put patients at risk for developing adverse events. TI - Monitoring Haloperidol Plasma Concentration and Associated Adverse Events in Critically Ill Children With Delirium: First Results of a Clinical Protocol Aimed to Monitor Efficacy and Safety. EP - e119 SN - 1529-7535 IS - iss. 2 SP - e112 JF - Pediatric Critical Care Medicine VL - vol. 19 N1 - 1 februari 2018 DO - https://doi.org/10.1097/PCC.0000000000001414 ER - TY - JOUR AU - Meulen, M. van der AU - Dalinghaus, M. AU - Burch, M. AU - Szatmari, A. AU - Castro Diez, C. AU - Khalil, F. AU - Swoboda, V. AU - Breur, J. AU - Bajcetic, M. AU - Jovanovic, I. AU - Lagler, F.B. AU - Klingmann, I. AU - Laeer, S. AU - Wildt, S.N. de PY - 2018 UR - https://hdl.handle.net/2066/191256 TI - Question 1: How safe are ACE inhibitors for heart failure in children? EP - 109 SN - 0003-9888 IS - iss. 1 SP - 106 JF - Archives of Disease in Childhood VL - vol. 103 N1 - 1 januari 2018 DO - https://doi.org/10.1136/archdischild-2017-312774 ER - TY - JOUR AU - Leeuw, T.G. de AU - Dirckx, M. AU - Wildt, S.N. de PY - 2018 UR - https://hdl.handle.net/2066/191257 TI - Reply to Ziesenitz, Victoria; Erb Thomas; Trachsel, Daniel; van den Anker Johannes, regarding their comment "Safety of dipryone (metamizole) in children-what's the risk of agranulocytosis?" EP - 306 SN - 1155-5645 IS - iss. 3 SP - 305 JF - Paediatric Anaesthesia VL - vol. 28 N1 - 1 maart 2018 DO - https://doi.org/10.1111/pan.13326 ER - TY - JOUR AU - Lewis, Roger J. AU - Angus, D.C. AU - Laterre, P.F. AU - Kjolbye, Anne Louise AU - Meulen, Egbert van der AU - Blemings, Allan AU - Pickkers, P. AU - Berry, Scott M. PY - 2018 UR - https://hdl.handle.net/2066/184039 TI - Rationale and Design of an Adaptive Phase 2b/3 Clinical Trial of Selepressin for Adults in Septic Shock Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial EP - 257 SN - 2325-6621 IS - iss. 2 SP - 250 JF - Annals of the American Thoracic Society VL - vol. 15 DO - https://doi.org/10.1513/AnnalsATS.201708-669SD ER - TY - JOUR AU - Boogaard, M.H.W.A. van den AU - Slooter, A.J. AU - Bruggemann, R.J.M. AU - Schoonhoven, L. AU - Beishuizen, Albertus AU - Hannink, G.J. AU - Vermeijden, J.Wytze AU - Simons, K.S. AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/189820 TI - Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium The REDUCE Randomized Clinical Trial EP - 690 SN - 0098-7484 IS - iss. 7 SP - 680 JF - Jama : Journal of the American Medical Association VL - vol. 319 DO - https://doi.org/10.1001/jama.2018.0160 ER - TY - JOUR AU - Wassenaar, A. AU - Reus, Jorn de AU - Donders, A.R.T. AU - Schoonhoven, L. AU - Cremer, O.L. AU - Lange, D.W. de AU - Pickkers, P. AU - Boogaard, M. van den PY - 2018 UR - https://hdl.handle.net/2066/189811 TI - Development and Validation of an Abbreviated Questionnaire to Easily Measure Cognitive Failure in ICU Survivors: A Multicenter Study EP - 84 SN - 0090-3493 IS - iss. 1 SP - 79 JF - Critical Care Medicine VL - vol. 46 DO - https://doi.org/10.1097/CCM.0000000000002806 ER - TY - JOUR AU - Draper, A. AU - Koch, R.M. AU - Meer, J.W.M. van der AU - Apps, M.A.J. AU - Pickkers, P. AU - Husain, M. AU - Schaaf, M.E. van der PY - 2018 UR - https://hdl.handle.net/2066/189848 AB - Sickness behavior in humans is characterized by low mood and fatigue, which have been suggested to reflect changes in motivation involving reorganization of priorities. However, it is unclear which specific processes underlying motivation are altered. We tested whether bacterial endotoxin E. coli lipopolysaccharide (LPS) affected two dissociable constructs of motivational behavior, ie, effort and reward sensitivity. After familiarization with 5 effort levels, participants made a series of accept/reject decisions on whether the stake offered (1, 4, 8, 12, or 15 apples) was 'worth the effort' (10%, 27.5%, 45%, 62.5%, and 80% of maximal voluntary contraction in a hand-held dynamometer). Effort and reward levels were parametrically modulated to dissociate their influence on choice. Overall, 29 healthy young males were administered LPS (2 ng/kg; n=14) or placebo (0.9% saline; n=15). The effort-stake task, and self-reported depression and fatigue were assessed prior to LPS/placebo injection, 2 and 5 h post injection. Cytokines and sickness symptoms were assessed hourly till 8 h after LPS injection. LPS transiently increased interleukin-6 and tumor necrosis factor-α, sickness symptoms, body temperature and self-reported fatigue, and depression post injection relative to baseline and placebo. These changes were accompanied by LPS-induced decreases in acceptance rates of high-effort options, without significantly affecting reward sensitivity 2 h post injection, which were partially recovered 5 h post injection. We suggest that LPS-induced changes in motivation may be due to alterations to mesolimbic dopamine. Our behavioral paradigm could be used to further investigate effects of inflammation on motivational behavior in psychiatric and chronic illnesses. TI - Effort but not reward sensitivity is altered by acute sickness induced by experimental endotoxemia in humans EP - 1118 SN - 0893-133X IS - iss. 5 SP - 1107 JF - Neuropsychopharmacology (New York) VL - vol. 43 PS - 12 p. DO - https://doi.org/10.1038/npp.2017.231 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/189848/189848.pdf?sequence=1 ER - TY - JOUR AU - Oppersma, E. AU - Doorduin, J. AU - Hoeven, J.G. van der AU - Veltink, P.H. AU - Hees, H.W.H. van AU - Heunks, L.M.A. PY - 2018 UR - https://hdl.handle.net/2066/184063 TI - The effect of metabolic alkalosis on the ventilatory response in healthy subjects EP - 53 SN - 1569-9048 SP - 47 JF - Respiratory Physiology & Neurobiology VL - vol. 249 DO - https://doi.org/10.1016/j.resp.2018.01.002 ER - TY - JOUR AU - Mutters, Nico T. AU - Angelis, Giulia De AU - Restuccia, Giovanni AU - Muzio, Francesca Di AU - Schouten, J.A. AU - Hulscher, M. AU - Antonelli, Massimo AU - Tacconelli, Evelina PY - 2018 UR - https://hdl.handle.net/2066/184131 TI - Use of evidence-based recommendations in an antibiotic care bundle for the intensive care unit EP - 70 SN - 0924-8579 IS - iss. 1 SP - 65 JF - International Journal of Antimicrobial Agents VL - vol. 51 DO - https://doi.org/10.1016/j.ijantimicag.2017.06.020 ER - TY - JOUR AU - Habes, Q.L.M. AU - Ede, L. van AU - Gerretsen, J. AU - Kox, M. AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/190898 TI - Norepinephrine contributes to enterocyte damage in septic shock patients : a prospective cohort study EP - 143 SN - 1073-2322 IS - iss. 2 SP - 137 JF - Shock VL - vol. 49 DO - https://doi.org/10.1097/SHK.0000000000000955 ER - TY - JOUR AU - Kotsopoulos, A. AU - Boing-Messing, F. AU - Jansen, N.E. AU - Vos, P AU - Abdo, W.F. PY - 2018 UR - https://hdl.handle.net/2066/190703 TI - External validation of prediction models for time to death in potential donors after circulatory death EP - 896 SN - 1600-6135 IS - iss. 4 SP - 890 JF - American Journal of Transplantation VL - vol. 18 DO - https://doi.org/10.1111/ajt.14529 ER - TY - JOUR AU - Leijte, G.P. AU - Custers, Hettie AU - Gerretsen, J. AU - Heijne, A. AU - Roth, Johannes AU - Vogl, Thomas AU - Scheffer, G.J. AU - Pickkers, P. AU - Kox, M. PY - 2018 UR - https://hdl.handle.net/2066/190715 TI - Increased Plasma Levels of Danger-Associated Molecular Patterns Are Associated With Immune Suppression and Postoperative Infections in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy SN - 1664-3224 JF - Frontiers in Immunology VL - vol. 9 DO - https://doi.org/10.3389/fimmu.2018.00663 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190715/190715.pdf?sequence=1 ER - TY - JOUR AU - Wiersinga, W.J. AU - Bonten, M.J.M. AU - Boersma, W.G. AU - Jonkers, R.E. AU - Aleva, R.M. AU - Kullberg, B.J. AU - Schouten, J.A. AU - Degener, J.E. AU - Garde, E.M. van de AU - Verheij, T.J. AU - Sachs, A.P. AU - Prins, J.M. PY - 2018 UR - https://hdl.handle.net/2066/196411 AB - The Dutch Working Party on Antibiotic Policy in collaboration with the Dutch Association of Chest Physicians, the Dutch Society for Intensive Care and the Dutch College of General Practitioners have updated their evidence-based guidelines on the diagnosis and treatment of community-acquired pneumonia (CAP) in adults who present to the hospital. This 2016 update focuses on new data on the aetiological and radiological diagnosis of CAP, severity classification methods, initial antibiotic treatment in patients with severe CAP and the role of adjunctive corticosteroids. Other parts overlap with the 2011 guideline. Apart from the Q fever outbreak in the Netherlands (2007-2010) no other shifts in the most common causative agents of CAP or in their resistance patterns were observed in the last five years. Low-dose CT scanning may ultimately replace the conventional chest X-ray; however, at present, there is insufficient evidence to advocate the use of CT scanning as the new standard in patients evaluated for CAP. A pneumococcal urine antigen test is now recommended for all patients presenting with severe CAP; a positive test result can help streamline therapy once clinical stability has been reached and no other pathogens have been detected. Coverage for atypical microorganisms is no longer recommended in empirical treatment of severe CAP in the non-intensive care setting. For these patients (with CURB-65 score >2 or Pneumonia Severity Index score of 5) empirical therapy with a 2nd/3rd generation cephalosporin is recommended, because of the relatively high incidence of Gram-negative bacteria, and to a lesser extent S. aureus. Corticosteroids are not recommended as adjunctive therapy for CAP. TI - Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT) EP - 13 SN - 0300-2977 IS - iss. 1 SP - 4 JF - Netherlands Journal of Medicine VL - vol. 76 ER - TY - JOUR AU - Vincent, J.L. AU - Lefrant, Jean-Yves AU - Kotfis, K. AU - Nanchal, R. AU - Martin-Loeches, I. AU - Wittebole, X. AU - Pickkers, P. AU - Moreno, R. AU - Sakr, Y. PY - 2018 UR - https://hdl.handle.net/2066/190107 TI - Comparison of European ICU patients in 2012 (ICON) versus 2002 (SOAP) EP - 344 SN - 0342-4642 IS - iss. 3 SP - 337 JF - Intensive Care Medicine VL - vol. 44 DO - https://doi.org/10.1007/s00134-017-5043-2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190107/190107.pdf?sequence=1 ER - TY - THES AU - Simons, K.S. PY - 2018 SN - 9789492896414 UR - https://hdl.handle.net/2066/194289 PB - [S.l. : s.n.] TI - The ICU environment. Impact of light and noise exposure on critically ill patients N1 - Radboud University, 14 september 2018 N1 - Promotores : Pickkers, P., Hoeven, J.G. van der Co-promotores : Boogaard, M. van den, Jager, C.P.C. de PS - 200 p. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194289/194289.pdf?sequence=1 ER - TY - JOUR AU - Nadim, Mitra K. AU - Forni, L. AU - Bihorac, Azra AU - Hobson, Charles AU - Koyner, Jay L. AU - Shaw, Andrew AU - Pickkers, P. AU - Ronco, C. AU - Kellum, J.A. PY - 2018 UR - https://hdl.handle.net/2066/192663 TI - Cardiac and Vascular Surgery-Associated Acute Kidney Injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group SN - 2047-9980 IS - iss. 11 JF - Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease VL - vol. 7 DO - https://doi.org/10.1161/JAHA.118.008834 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/192663/192663.pdf?sequence=1 ER - TY - JOUR AU - Pickkers, P. AU - Mehta, R.L. AU - Murray, P.T. AU - Joannidis, M. AU - Molitoris, B.A. AU - Kellum, J.A. AU - Berg, Erik van den AU - Arend, J. PY - 2018 UR - https://hdl.handle.net/2066/198279 TI - Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury : A Randomized Clinical Trial EP - 2009 SN - 0098-7484 IS - iss. 19 SP - 1998 JF - Jama : Journal of the American Medical Association VL - vol. 320 DO - https://doi.org/10.1001/jama.2018.14283 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/198279/198279.pdf?sequence=1 ER - TY - JOUR AU - Kallen, M.C. AU - Roos-Blom, M.J. AU - Dongelmans, Dave A. AU - Schouten, J.A. AU - Gude, Wouter T. AU - Jonge, E. de AU - Prins, J.M. AU - Keizer, N.F. de PY - 2018 UR - https://hdl.handle.net/2066/199462 TI - Development of actionable quality indicators and an action implementation toolbox for appropriate antibiotic use at intensive care units: A modified-RAND Delphi study SN - 1932-6203 IS - iss. 11 JF - PLoS One VL - vol. 13 DO - https://doi.org/10.1371/journal.pone.0207991 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/199462/199462.pdf?sequence=1 ER - TY - JOUR AU - Boyle, A.J. AU - Madotto, F. AU - Laffey, J.G. AU - Bellani, G. AU - Pham, T. AU - Pesenti, A. AU - Thompson, B.T. AU - O'Kane, C.M. AU - Schouten, J.A. AU - Deane, A.M. AU - McAuley, D.F. PY - 2018 UR - https://hdl.handle.net/2066/200164 AB - BACKGROUND: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). METHODS: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. RESULTS: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. CONCLUSIONS: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. TRIAL REGISTRATION: NCT02010073 . Registered on 12 December 2013. TI - Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database SN - 1466-609X IS - iss. 1 SP - 268 JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2158-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/200164/200164.pdf?sequence=1 ER - TY - JOUR AU - Hollinger, Alexa AU - Wittebole, X. AU - Francois, B. AU - Pickkers, P. AU - Antonelli, M. AU - Gayat, Etienne AU - Mebazaa, Alexandre AU - Legrand, M. PY - 2018 UR - https://hdl.handle.net/2066/197988 TI - Proenkephalin A 119-159 (Penkid) Is an Early Biomarker of Septic Acute Kidney Injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) Study EP - 1433 SN - 2468-0249 IS - iss. 6 SP - 1424 JF - Kidney International Reports VL - vol. 3 DO - https://doi.org/10.1016/j.ekir.2018.08.006 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/197988/197988.pdf?sequence=1 ER - TY - JOUR AU - Ista, Erwin AU - Beusekom, Babette van AU - Rosmalen, Joost van AU - Kneyber, Martin C.J. AU - Lemson, J. AU - Brouwers, Arno AU - Tibboel, Dick AU - Dijk, Monique van PY - 2018 UR - https://hdl.handle.net/2066/198246 TI - Validation of the SOS-PD scale for assessment of pediatric delirium: a multicenter study SN - 1466-609X JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2238-z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/198246/198246.pdf?sequence=1 ER - TY - JOUR AU - Simons, K.S. AU - Boogaard, M.H.W.A. van den AU - Hendriksen, Eva AU - Gerretsen, J. AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Jager, C.P. de PY - 2018 UR - https://hdl.handle.net/2066/191949 TI - Temporal biomarker profiles and their association with ICU acquired delirium: a cohort study SN - 1466-609X JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2054-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/191949/191949.pdf?sequence=1 ER - TY - JOUR AU - Vreugdenhil, Bas AU - Velden, W.J.F.M. van der AU - Feuth, T. AU - Kox, M. AU - Pickkers, P. AU - Veerdonk, F.L. van de AU - Blijlevens, N.M.A. AU - Bruggemann, R.J.M. PY - 2018 UR - https://hdl.handle.net/2066/194880 TI - Moderate correlation between systemic IL-6 responses and CRP with trough concentrations of voriconazole EP - 1988 SN - 0306-5251 IS - iss. 9 SP - 1980 JF - British Journal of Clinical Pharmacology VL - vol. 84 DO - https://doi.org/10.1111/bcp.13627 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194880/194880.pdf?sequence=1 ER - TY - THES AU - Kolk, B.M. van der PY - 2018 SN - 9789463751537 UR - https://hdl.handle.net/2066/196862 PB - [S.l. : s.n.] TI - Development, implementation and evaluation of high-risk surgery related clinical pathways in the intensive care: effects of a process intervention N1 - Radboud University, 15 november 2018 N1 - Promotores : Pickkers, P., Laarhoven, C.J.H.M. van Co-promotor : Boogaard, M. van den PS - 168 p. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196862/196862.pdf?sequence=1 ER - TY - JOUR AU - Loon, Lex M. van AU - Hoeven, J.G. van der AU - Veltink, Peter H. AU - Lemson, J. PY - 2018 UR - https://hdl.handle.net/2066/197410 TI - The influence of esmolol on right ventricular function in early experimental endotoxic shock SN - 2051-817X IS - iss. 19 JF - Physiological Reports VL - vol. 6 DO - https://doi.org/10.14814/phy2.13882 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/197410/197410.pdf?sequence=1 ER - TY - JOUR AU - Huijben, J.A. AU - Volovici, V. AU - Cnossen, M.C. AU - Haitsma, I.K. AU - Stocchetti, N. AU - Maas, A.I. AU - Menon, D.K. AU - Ercole, A. AU - Citerio, G. AU - Nelson, D. AU - Polinder, S. AU - Steyerberg, Ewout W. AU - Hoedemaekers, A. AU - Lingsma, H.F. AU - Jagt, M. van der PY - 2018 UR - https://hdl.handle.net/2066/196341 AB - BACKGROUND: General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. METHODS: We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. RESULTS: The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36-40 mmHg (4.8-5.3 kPa) in case of controlled intracranial pressure (ICP) < 20 mmHg (n = 45, 69%) and PaCO2 target of 30-35 mmHg (4-4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%). CONCLUSIONS: Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome. TI - Variation in general supportive and preventive intensive care management of traumatic brain injury: a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2000-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196341/196341.pdf?sequence=1 ER - TY - JOUR AU - Abe, T. AU - Madotto, F. AU - Pham, T. AU - Nagata, I. AU - Uchida, M. AU - Tamiya, N. AU - Schouten, J.A. AU - Kurahashi, K. AU - Bellani, G. AU - Laffey, J.G. PY - 2018 UR - https://hdl.handle.net/2066/196381 AB - BACKGROUND: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. METHODS: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. RESULTS: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. CONCLUSIONS: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02010073 . Registered on 12 December 2013. TI - Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2126-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196381/196381.pdf?sequence=1 ER - TY - JOUR AU - Cortegiani, A. AU - Madotto, F. AU - Gregoretti, C. AU - Bellani, G. AU - Laffey, J.G. AU - Pham, T. AU - Haren, F. van AU - Giarratano, A. AU - Antonelli, M. AU - Schouten, J.A. AU - Pesenti, A. AU - Grasselli, G. PY - 2018 UR - https://hdl.handle.net/2066/196401 AB - BACKGROUND: The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. METHODS: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. RESULTS: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. CONCLUSIONS: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02010073 . Registered on 12 December 2013. TI - Immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the LUNG SAFE database SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 22 DO - https://doi.org/10.1186/s13054-018-2079-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196401/196401.pdf?sequence=1 ER - TY - JOUR AU - Workum, J.D. AU - Jong, Suzanne W. de AU - Gresnigt, M.S. AU - Becker, K.L. AU - Pickkers, P. AU - Veerdonk, F.L. van de AU - Heijdra, Y.F. AU - Kolwijck, E. PY - 2018 UR - https://hdl.handle.net/2066/194434 TI - Microbiological and immunological characteristics of a lethal pulmonary Aspergillus niger infection in a non-neutropenic patient EP - 7 SN - 2211-7539 SP - 4 JF - Medical Mycology Case Reports VL - vol. 21 DO - https://doi.org/10.1016/j.mmcr.2018.03.002 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194434/194434.pdf?sequence=1 ER - TY - JOUR AU - Berrevoets, M.A.H. AU - Oerlemans, A.J.M. AU - Tromp, M.A. AU - Kullberg, B.J. AU - Oever, J. ten AU - Schouten, J.A. AU - Hulscher, M. PY - 2018 UR - https://hdl.handle.net/2066/200351 AB - OBJECTIVES: Current outpatient parenteral antimicrobial therapy (OPAT) guidelines recommend delivering patient-centred care. However, little is known about what patients define as good quality of OPAT care and what their needs and preferences are.The aim of this qualitative study is to explore the patients' perspective on high-quality care, and to explore what patient-centred care means to adult OPAT patients. DESIGN AND SETTING: This is an explorative, descriptive study using qualitative methods. We conducted focus group interviews with 16 adult patients (5 female, 11 male) from 3 different hospitals, who received OPAT and 2 individual semistructured interviews with their informal caregivers in the Netherlands. We used purposive sampling to ensure diversity of participants. We used the eight Picker principles of patient-centredness to guide data collection and analysis. RESULTS: Participants reported several elements considered as important for patient-centred OPAT care, like patient involvement in the decision-making process, a responsible OPAT lead, intensive collaboration between all disciplines involved, information provision and adherence to hygiene guidelines. Two central dimensions emerged as essential constituents of patient-centred OPAT care: freedom and safety. Both are heavily influenced by the behaviours of healthcare professionals and by organisational aspects beyond the direct influence of these professionals. CONCLUSION: This study provides insights into the needs and preferences of adult patients who receive OPAT care. Future interventions directed at the improvement of patient-centredness of OPAT care should focus on elements that enhance patients' feelings of freedom and safety. TI - Quality of outpatient parenteral antimicrobial therapy (OPAT) care from the patient's perspective: a qualitative study SN - 2044-6055 IS - iss. 11 SP - e024564 JF - BMJ Open VL - vol. 8 DO - https://doi.org/10.1136/bmjopen-2018-024564 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/200351/200351.pdf?sequence=1 ER - TY - JOUR AU - Kallen, M.C. AU - Oever, J. ten AU - Prins, J.M. AU - Kullberg, B.J. AU - Schouten, J.A. AU - Hulscher, M.E.J.L. PY - 2018 UR - https://hdl.handle.net/2066/199460 TI - A survey on antimicrobial stewardship prerequisites, objectives and improvement strategies: systematic development and nationwide assessment in Dutch acute care hospitals EP - 3504 SN - 0305-7453 IS - iss. 12 SP - 3496 JF - Journal of Antimicrobial Chemotherapy VL - vol. 73 DO - https://doi.org/10.1093/jac/dky367 ER - TY - JOUR AU - Oever, J. ten AU - Harmsen, M. AU - Schouten, J.A. AU - Ouwens, M.M. AU - Linden, P.D. van der AU - Verduin, C.M. AU - Kullberg, B.J. AU - Prins, J.M. AU - Hulscher, M.E.J.L. PY - 2018 UR - https://hdl.handle.net/2066/198464 TI - Human resources required for antimicrobial stewardship teams: a Dutch consensus report EP - 1279 SN - 1198-743X IS - iss. 12 SP - 1273 JF - Clinical Microbiology and Infection VL - vol. 24 DO - https://doi.org/10.1016/j.cmi.2018.07.005 ER - TY - JOUR AU - Smeets, X.J.N.M. AU - Costa, D.W. da AU - Fockens, P. AU - Mulder, C.J. AU - Timmer, R. AU - Kievit, W. AU - Zegers, M. AU - Bruno, M.J. AU - Besselink, M.G.H. AU - Vleggaar, F.P. AU - Hulst, R.W. van der AU - Poen, A.C. AU - Heine, G.D.N. AU - Venneman, N.G. AU - Kolkman, J.J. AU - Baak, L.C. AU - Romkens, T.E.H. AU - Dijk, S.M. van AU - Hallensleben, N.D. AU - Vrie, W. van de AU - Seerden, T.C. AU - Tan, A. AU - Voorburg, A. AU - Poley, J.W. AU - Witteman, B.J. AU - Bhalla, A. AU - Hadithi, M. AU - Thijs, W.J. AU - Schwartz, M.P. AU - Vrolijk, J.M. AU - Verdonk, R.C. AU - Delft, F. von AU - Keulemans, Y. AU - Goor, H. van AU - Drenth, J.P.H. AU - Geenen, E.J.M. van PY - 2018 UR - https://hdl.handle.net/2066/190882 AB - BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. METHODS: The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. DISCUSSION: The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. TRIAL REGISTRATION: EudraCT: 2015-000829-37 . Registered on 18 February 2015. ISRCTN: 13659155 . Registered on 18 May 2015. TI - Fluid hydration to prevent post-ERCP pancreatitis in average- to high-risk patients receiving prophylactic rectal NSAIDs (FLUYT trial): study protocol for a randomized controlled trial SN - 1745-6215 JF - Trials VL - vol. 19 DO - https://doi.org/10.1186/s13063-018-2583-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190882/190882.pdf?sequence=1 ER - TY - JOUR AU - Martinon-Torres, F. AU - Salas, A. AU - Rivero-Calle, Irene AU - Cebey-Lopez, Miriam AU - Pardo-Seco, Jacobo AU - Herberg, Jethro A. AU - Groot, R. de AU - Neeleman, C. AU - Deuren, M. van AU - Flier, M. van der AU - Levin, M. PY - 2018 UR - https://hdl.handle.net/2066/192621 TI - Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study EP - 414 SN - 2352-4642 IS - iss. 6 SP - 404 JF - The Lancet Child & Adolescent Health VL - vol. 2 DO - https://doi.org/10.1016/S2352-4642(18)30113-5 ER - TY - JOUR AU - Koch, R.M. AU - Kox, M. AU - Kieboom, C.H. van den AU - Ferwerda, G. AU - Gerretsen, J. AU - Bruggencate, Sandra ten AU - Hoeven, J.G. van der AU - Jonge, M.I. de AU - Pickkers, P. PY - 2018 UR - https://hdl.handle.net/2066/190080 TI - Short-term repeated HRV-16 exposure results in an attenuated immune response in vivo in humans SN - 1932-6203 IS - iss. 2 JF - PLoS One VL - vol. 13 DO - https://doi.org/10.1371/journal.pone.0191937 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190080/190080.pdf?sequence=1 ER - TY - JOUR AU - Koch, R.M. AU - Diavatopoulos, D.A. AU - Ferwerda, G. AU - Pickkers, P. AU - Jonge, M.I. de AU - Kox, M. PY - 2018 UR - https://hdl.handle.net/2066/196155 AB - BACKGROUND: Influenza infections are often complicated by secondary infections, which are associated with high morbidity and mortality, suggesting that influenza profoundly influences the immune response towards a subsequent pathogenic challenge. However, data on the immunological interplay between influenza and secondary infections are equivocal, with some studies reporting influenza-induced augmentation of the immune response, whereas others demonstrate that influenza suppresses the immune response towards a subsequent challenge. These contrasting results may be due to the use of various types of live bacteria as secondary challenges, which impedes clear interpretation of causal relations, and to differences in timing of the secondary challenge relative to influenza infection. Herein, we investigated whether influenza infection results in an enhanced or suppressed innate immune response upon a secondary challenge with bacterial lipopolysaccharide (LPS) in either the acute or the recovery phase of infection. METHODS: Male C57BL/6J mice were intranasally inoculated with 5 x 10(3) PFU influenza virus (pH1N1, strain A/Netherlands/602/2009) or mock treated. After 4 (acute phase) or 10 (recovery phase) days, 5 mg/kg LPS or saline was administered intravenously, and mice were sacrificed 90 min later. Cytokine levels in plasma and lung tissue, and lung myeloperoxidase (MPO) content were determined. RESULTS: LPS administration 4 days after influenza infection resulted in a synergistic increase in TNF-alpha, IL-1beta, and IL-6 concentrations in lung tissue, but not in plasma. This effect was also observed 10 days after influenza infection, albeit to a lesser extent. LPS-induced plasma levels of the anti-inflammatory cytokine IL-10 were enhanced 4 days after influenza infection, whereas a trend towards increased pulmonary IL-10 concentrations was found. LPS-induced increases in pulmonary MPO content tended to be enhanced as well, but only at 4 days post-infection. CONCLUSIONS: An LPS challenge in the acute phase of influenza infection results in an enhanced pulmonary pro-inflammatory innate immune response. These data increase our insight on influenza-bacterial interplay. Combing data of the present study with previous findings, it appears that this enhanced response is not beneficial in terms of protection against secondary infections, but rather damaging by increasing immunopathology. TI - The endotoxin-induced pulmonary inflammatory response is enhanced during the acute phase of influenza infection SN - 2197-425X IS - iss. 1 SP - 15 JF - Intensive Care Medicine Experimental VL - vol. 6 DO - https://doi.org/10.1186/s40635-018-0182-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196155/196155.pdf?sequence=1 ER - TY - JOUR AU - Rood, P.J.T. AU - Huisman, G.J. AU - Vermeulen, H. AU - Schoonhoven, L. AU - Pickkers, P. AU - Boogaard, M. van den PY - 2018 UR - https://hdl.handle.net/2066/193536 AB - BACKGROUND: Delirium occurs frequently in intensive care unit (ICU) patients and is associated with numerous deleterious outcomes. There is a large variation in reported delirium occurrence rates, ranging from 4% to 89%. Apart from patient and treatment-related factors, organisational factors could influence delirium incidence, but this is currently unknown. OBJECTIVE: To systematically review delirium incidence and determine whether or not organisational factors may contribute to the observed delirium incidence in adult ICU patients. METHODS: Systematic review of prospective cohort studies reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Included articles were independently assessed by two researchers. Quality of the articles was determined using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. Subsequently, apart from patient characteristics, a meta-regression analysis was performed on available organisational factors, including hospital type, screening method and screening frequency. DATA SOURCES: PubMed, Embase, CINAHL, and Cochrane Library databases were searched from inception to 27 January 2017, without language limitation. RESULTS: A total of 9357 articles were found, of which 19 articles met the inclusion criteria and were considered as true delirium incidence studies. The articles were of good methodological quality (median [interquartile range] 32/38 [30-35] points), published between 2005 and 2016, originated from 17 countries. A total of 9867 ICU patients were included. The incidence rate of delirium varied between 4% and 55%, with a mean +/- standard deviation of 29 +/- 14%. Data relating to three organisational factors were included in the studies, but they were not significantly associated with the reported delirium incidence: hospital type (p 0.48), assessment methods (p 0.41), and screening frequency (p 0.28). CONCLUSIONS: The mean incidence of delirium in the ICU was 29%. The organisational factors found including methods of delirium assessment, screening frequency, and hospital type were not related to the reported ICU delirium incidence. TI - Effect of organisational factors on the variation in incidence of delirium in intensive care unit patients: A systematic review and meta-regression analysis EP - 187 SN - 1036-7314 IS - iss. 3 SP - 180 JF - Australian Critical Care VL - vol. 31 DO - https://doi.org/10.1016/j.aucc.2018.02.002 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/193536/193536.pdf?sequence=1 ER - TY - JOUR AU - Verlaat, C.W.M. AU - Starre, C. van der AU - Hazelzet, J.A. AU - Tibboel, Dick AU - Hoeven, J.J. van der AU - Lemson, J. AU - Zegers, M. PY - 2018 UR - https://hdl.handle.net/2066/194768 TI - The occurrence of adverse events in low-risk non-survivors in pediatric intensive care patients: an exploratory study EP - 1358 SN - 0340-6199 IS - iss. 9 SP - 1351 JF - European Journal of Pediatrics VL - vol. 177 DO - https://doi.org/10.1007/s00431-018-3194-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194768/194768.pdf?sequence=1 ER - TY - JOUR AU - Howard, Philip AU - Huttner, Benedikt AU - Beovic, B. AU - Beraud, Guillaume AU - Kofteridis, Diamantis P. AU - Pardo, J. AU - Schouten, J.A. AU - Pulcini, Celine PY - 2017 UR - https://hdl.handle.net/2066/189891 TI - ESGAP inventory of target indicators assessing antibiotic prescriptions: a cross-sectional survey EP - 2914 SN - 0305-7453 IS - iss. 10 SP - 2910 JF - Journal of Antimicrobial Chemotherapy VL - vol. 72 DO - https://doi.org/10.1093/jac/dkx243 ER - TY - GEN AU - Wildt, S.N. de PY - 2017 UR - https://hdl.handle.net/2066/175173 PB - [S.l. : s.n.] TI - De hoogste tijd : van confectie naar couture N1 - Rede uitgesproken bij de aanvaarding van het ambt van hoogleraar Klinische Farmacologie aan de Radboud Universiteit/het Radboudumc op vrijdag 7 april 2017 PS - 23 p. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/175173/175173.pdf?sequence=1 ER - TY - JOUR AU - Azoulay, E. AU - Pickkers, P. AU - Soares, M. AU - Perner, A. AU - Rello, J. AU - Bauer, P.R. AU - Louw, A. van de AU - Hemelaar, P. AU - Lemiale, V. AU - Taccone, F.S. AU - Loeches, I.M. AU - Meyhoff, T.S. AU - Salluh, J. AU - Schellongowski, P. AU - Rusinova, K. AU - Terzi, N. AU - Mehta, S. AU - Antonelli, M. AU - Kouatchet, A. AU - Barratt-Due, A. AU - Valkonen, M. AU - Landburg, P.P. AU - Bruneel, F. AU - Bukan, R.B. AU - Pene, F. AU - Metaxa, V. AU - Moreau, A.S. AU - Souppart, V. AU - Burghi, G. AU - Girault, C. AU - Silva, U.V.A. AU - Montini, L. AU - Barbier, F. AU - Nielsen, L.B. AU - Gaborit, B. AU - Mokart, D. AU - Chevret, S. PY - 2017 UR - https://hdl.handle.net/2066/182567 AB - BACKGROUND: In immunocompromised patients with acute hypoxemic respiratory failure (ARF), initial management aims primarily to avoid invasive mechanical ventilation (IMV). METHODS: To assess the impact of initial management on IMV and mortality rates, we performed a multinational observational prospective cohort study in 16 countries (68 centers). RESULTS: A total of 1611 patients were enrolled (hematological malignancies 51.9%, solid tumors 35.2%, systemic diseases 17.3%, and solid organ transplantation 8.8%). The main ARF etiologies were bacterial (29.5%), viral (15.4%), and fungal infections (14.7%), or undetermined (13.2%). On admission, 915 (56.8%) patients were not intubated. They received standard oxygen (N = 496, 53.9%), high-flow oxygen (HFNC, N = 187, 20.3%), noninvasive ventilation (NIV, N = 153, 17.2%), and NIV + HFNC (N = 79, 8.6%). Factors associated with IMV included age (hazard ratio = 0.92/year, 95% CI 0.86-0.99), day-1 SOFA (1.09/point, 1.06-1.13), day-1 PaO2/FiO2 (1.47, 1.05-2.07), ARF etiology (Pneumocystis jirovecii pneumonia (2.11, 1.42-3.14), invasive pulmonary aspergillosis (1.85, 1.21-2.85), and undetermined cause (1.46, 1.09-1.98). After propensity score matching, HFNC, but not NIV, had an effect on IMV rate (HR = 0.77, 95% CI 0.59-1.00, p = 0.05). ICU, hospital, and day-90 mortality rates were 32.4, 44.1, and 56.4%, respectively. Factors independently associated with hospital mortality included age (odds ratio = 1.18/year, 1.09-1.27), direct admission to the ICU (0.69, 0.54-0.87), day-1 SOFA excluding respiratory score (1.12/point, 1.08-1.16), PaO2/FiO2 < 100 (1.60, 1.03-2.48), and undetermined ARF etiology (1.43, 1.04-1.97). Initial oxygenation strategy did not affect mortality; however, IMV was associated with mortality, the odds ratio depending on IMV conditions: NIV + HFNC failure (2.31, 1.09-4.91), first-line IMV (2.55, 1.94-3.29), NIV failure (3.65, 2.05-6.53), standard oxygen failure (4.16, 2.91-5.93), and HFNC failure (5.54, 3.27-9.38). CONCLUSION: HFNC has an effect on intubation but not on mortality rates. Failure to identify ARF etiology is associated with higher rates of both intubation and mortality. This suggests that in addition to selecting the appropriate oxygenation device, clinicians should strive to identify the etiology of ARF. TI - Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study EP - 1819 SN - 0342-4642 IS - iss. 12 SP - 1808 JF - Intensive Care Medicine VL - vol. 43 DO - https://doi.org/10.1007/s00134-017-4947-1 ER - TY - JOUR AU - Hoedemaekers, C.W.E. AU - Ainslie, P.N. AU - Hinssen, S. AU - Aries, M.J. AU - Bisschops, L.L. AU - Hofmeijer, J. AU - Hoeven, J.G. van der PY - 2017 UR - https://hdl.handle.net/2066/182574 AB - AIM OF THE STUDY: Estimation of cerebral anaerobic metabolism in survivors and non-survivors after cardiac arrest. METHODS: We performed an observational study in twenty comatose patients after cardiac arrest and 19 healthy control subjects. We measured mean flow velocity in the middle cerebral artery (MFVMCA) by transcranial Doppler. Arterial and jugular blood samples were used for calculation of the jugular venous-to-arterial CO2/arterial to-jugular venous O2 content difference ratio. RESULTS: After cardiac arrest, MFVMCA increased from 26.0[18.6-40.4]cm/sec on admission to 63.9[48.3-73.1]cm/sec after 72h (p<0.0001), with no significant differences between survivors and non-survivors (p=0.4853). The MFVMCA in controls was 59.1[52.8-69.0]cm/sec. The oxygen extraction fraction (O2EF) was 38.9[24.4-47.7]% on admission and decreased significantly to 17.3[12.1-26.2]% at 72h (p<0.0001). The decrease in O2EF was more pronounced in non-survivors (p=0.0173). O2EF in the control group was 35.4[32.4-38.7]%. The jugular bulb-arterial CO2 to arterial-jugular bulb O2 content difference ratio was >1 at all time points after cardiac arrest and did not change during admission, with no differences between survivors and non-survivors. Values in cardiac arrest patients were similar to those in normal subjects. CONCLUSIONS: In this study, low CBF after cardiac arrest is not associated with anaerobic metabolism. Hypoperfusion appears to be the consequence of a decrease of neuronal functioning and metabolic needs. Alternatively, hypoperfusion may decrease cerebral metabolism. Subsequently, metabolism increases in survivors, consistent with resumption of neuronal activity, whereas in non-survivors lasting low metabolism reflects irreversible neuronal damage. TI - Low cerebral blood flow after cardiac arrest is not associated with anaerobic cerebral metabolism EP - 50 SN - 0300-9572 SP - 45 JF - Resuscitation VL - vol. 120 DO - https://doi.org/10.1016/j.resuscitation.2017.08.218 ER - TY - JOUR AU - Azoulay, E. AU - Vincent, J.L. AU - Angus, D.C. AU - Arabi, Y.M. AU - Brochard, L. AU - Brett, S.J. AU - Citerio, G. AU - Cook, D.J. AU - Curtis, J.R. AU - Santos, C.C. Dos AU - Ely, E.W. AU - Hall, J. AU - Halpern, S.D. AU - Hart, N. t AU - Hopkins, R.O. AU - Iwashyna, T.J. AU - Jaber, S. AU - Latronico, N. AU - Mehta, S. AU - Needham, D.M. AU - Nelson, J. AU - Puntillo, K. AU - Quintel, M. AU - Rowan, K. AU - Rubenfeld, G. AU - Berghe, G. Van den AU - Hoeven, J.G. van der AU - Wunsch, H. AU - Herridge, M. PY - 2017 UR - https://hdl.handle.net/2066/182582 AB - In this review, we seek to highlight how critical illness and critical care affect longer-term outcomes, to underline the contribution of ICU delirium to cognitive dysfunction several months after ICU discharge, to give new insights into ICU acquired weakness, to emphasize the importance of value-based healthcare, and to delineate the elements of family-centered care. This consensus of 29 also provides a perspective and a research agenda about post-ICU recovery. TI - Recovery after critical illness: putting the puzzle together-a consensus of 29 SN - 1466-609X IS - iss. 1 JF - Critical Care VL - vol. 21 DO - https://doi.org/10.1186/s13054-017-1887-7 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182582/182582.pdf?sequence=1 ER - TY - JOUR AU - Azoulay, E. AU - Schellongowski, P. AU - Darmon, M. AU - Bauer, P.R. AU - Benoit, D. AU - Depuydt, P. AU - Divatia, J.V. AU - Lemiale, V. AU - Vliet, M. van AU - Meert, A.P. AU - Mokart, D. AU - Pastores, S.M. AU - Perner, A. AU - Pene, F. AU - Pickkers, P. AU - Puxty, K.A. AU - Vincent, F. AU - Salluh, J. AU - Soubani, A.O. AU - Antonelli, M. AU - Staudinger, T. AU - Bergwelt-Baildon, M. von AU - Soares, M. PY - 2017 UR - https://hdl.handle.net/2066/182587 AB - Over the coming years, accelerating progress against cancer will be associated with an increased number of patients who require life-sustaining therapies for infectious or toxic chemotherapy-related events. Major changes include increased number of cancer patients admitted to the ICU with full-code status or for time-limited trials, increased survival and quality of life in ICU survivors, changing prognostic factors, early ICU admission for optimal monitoring, and use of noninvasive diagnostic and therapeutic strategies. In this review, experts in the management of critically ill cancer patients highlight recent changes in the use and the results of intensive care in patients with malignancies. They seek to put forward a standard of care for the management of these patients and highlight important updates that are required to care for them. The research agenda they suggest includes important studies to be conducted in the next few years to increase our understanding of organ dysfunction in this population and to improve our ability to appropriately use life-saving therapies or select new therapeutic approaches that are likely to improve outcomes. This review aims to provide more guidance for the daily management of patients with cancer, in whom outcomes are constantly improving, as is our global ability to fight against what is becoming the leading cause of mortality in industrialized and non-industrialized countries. TI - The Intensive Care Medicine research agenda on critically ill oncology and hematology patients EP - 1382 SN - 0342-4642 IS - iss. 9 SP - 1366 JF - Intensive Care Medicine VL - vol. 43 DO - https://doi.org/10.1007/s00134-017-4884-z ER - TY - JOUR AU - Pickkers, P. AU - Ostermann, M. AU - Joannidis, M. AU - Zarbock, A. AU - Hoste, E. AU - Bellomo, R. AU - Prowle, J. AU - Darmon, M. AU - Bonventre, J.V. AU - Forni, L. AU - Bagshaw, S.M. AU - Schetz, M. PY - 2017 UR - https://hdl.handle.net/2066/182590 AB - Acute kidney injury (AKI) is a common complication in the critically ill. Current standard of care mainly relies on identification of patients at risk, haemodynamic optimization, avoidance of nephrotoxicity and the use of renal replacement therapy (RRT) in established AKI. The detection of early biomarkers of renal tissue damage is a recent development that allows amending the late and insensitive diagnosis with current AKI criteria. Increasing evidence suggests that the consequences of an episode of AKI extend long beyond the acute hospitalization. Citrate has been established as the anticoagulant of choice for continuous RRT. Conflicting results have been published on the optimal timing of RRT and on the renoprotective effect of remote ischaemic preconditioning. Recent research has contradicted that acute tubular necrosis is the common pathology in AKI, that septic AKI is due to global kidney hypoperfusion, that aggressive fluid therapy benefits the kidney, that vasopressor therapy harms the kidney and that high doses of RRT improve outcome. Remaining uncertainties include the impact of aetiology and clinical context on pathophysiology, therapy and prognosis, the clinical benefit of biomarker-driven interventions, the optimal mode of RRT to improve short- and long-term patient and kidney outcomes, the contribution of AKI to failure of other organs and the optimal approach for assessing and promoting renal recovery. Based on the established gaps in current knowledge the trials that must have priority in the coming 10 years are proposed together with the definition of appropriate clinical endpoints. TI - The intensive care medicine agenda on acute kidney injury EP - 1209 SN - 0342-4642 IS - iss. 9 SP - 1198 JF - Intensive Care Medicine VL - vol. 43 DO - https://doi.org/10.1007/s00134-017-4687-2 ER - TY - JOUR AU - Maas, A.I. AU - Menon, D.K. AU - Adelson, P.D. AU - Andelic, N. AU - Bell, M.J. AU - Belli, A. AU - Bragge, P. AU - Brazinova, A. AU - Buki, A. AU - Chesnut, R.M. AU - Citerio, G. AU - Coburn, M. AU - Cooper, D.J. AU - Crowder, A.T. AU - Czeiter, E. AU - Czosnyka, M. AU - Diaz-Arrastia, R. AU - Dreier, J.P. AU - Duhaime, A.C. AU - Ercole, A. AU - Essen, T.A. van AU - Feigin, V.L. AU - Gao, G. AU - Giacino, J. AU - Gonzalez-Lara, L.E. AU - Gruen, R.L. AU - Gupta, D. AU - Hartings, J.A. AU - Hill, S. AU - Jiang, J.Y. AU - Ketharanathan, N. AU - Kompanje, E.J.O. AU - Lanyon, L. AU - Laureys, S. AU - Lecky, F. AU - Levin, H. AU - Lingsma, H.F. AU - Maegele, M. AU - Majdan, M. AU - Manley, G. AU - Marsteller, J. AU - Mascia, L. AU - McFadyen, C. AU - Mondello, S. AU - Newcombe, V. AU - Palotie, A. AU - Parizel, P.M. AU - Peul, W. AU - Piercy, J. AU - Polinder, S. AU - Puybasset, L. AU - Rasmussen, T.E. AU - Rossaint, R. AU - Smielewski, P. AU - Soderberg, J. AU - Stanworth, S.J. AU - Stein, M.B. AU - Steinbuchel, N. von AU - Stewart, W. P. AU - Steyerberg, E.W. AU - Stocchetti, N. AU - Synnot, A. AU - Ao, B. Te AU - Tenovuo, O. AU - Theadom, A. AU - Tibboel, D. AU - Videtta, W. AU - Wang, K.K.W. AU - Williams, W.H. AU - Wilson, L. AU - Yaffe, K. AU - Bartels, R.H.M.A. AU - Boogert, H.F. den AU - Hoedemaekers, C.W. AU - Sir, O. AU - et al. PY - 2017 UR - https://hdl.handle.net/2066/182592 TI - Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research EP - 1048 SN - 1474-4422 IS - iss. 12 SP - 987 JF - Lancet Neurology VL - vol. 16 DO - https://doi.org/10.1016/S1474-4422(17)30371-X ER - TY - JOUR AU - Longhini, F. AU - Colombo, D. AU - Pisani, L. AU - Idone, F. AU - Chun, P. AU - Doorduin, J. AU - Ling, L. AU - Alemani, M. AU - Bruni, A. AU - Zhaochen, J. AU - Tao, Y. AU - Lu, W. AU - Garofalo, E. AU - Carenzo, L. AU - Maggiore, S.M. AU - Qiu, H. AU - Heunks, L. AU - Antonelli, M. AU - Nava, S. AU - Navalesi, P. PY - 2017 UR - https://hdl.handle.net/2066/182479 AB - The objective of this study was to assess ability to identify asynchronies during noninvasive ventilation (NIV) through ventilator waveforms according to experience and interface, and to ascertain the influence of breathing pattern and respiratory drive on sensitivity and prevalence of asynchronies. 35 expert and 35 nonexpert physicians evaluated 40 5-min NIV reports displaying flow-time and airway pressure-time tracings; identified asynchronies were compared with those ascertained by three examiners who evaluated the same reports displaying, additionally, tracings of diaphragm electrical activity. We determined: 1) sensitivity, specificity, and positive and negative predictive values; 2) the correlation between the double true index (DTI) of each report (i.e., the ratio between the sum of true positives and true negatives, and the overall breath count) and the corresponding asynchrony index (AI); and 3) the influence of breathing pattern and respiratory drive on both AI and sensitivity. Sensitivities to detect asynchronies were low either according to experience (0.20 (95% CI 0.14-0.29) for expert versus 0.21 (95% CI 0.12-0.30) for nonexpert, p=0.837) or interface (0.28 (95% CI 0.17-0.37) for mask versus 0.10 (95% CI 0.05-0.16) for helmet, p<0.0001). DTI inversely correlated with the AI (r(2)=0.67, p<0.0001). Breathing pattern and respiratory drive did not affect prevalence of asynchronies and sensitivity. Patient-ventilator asynchrony during NIV is difficult to recognise solely by visual inspection of ventilator waveforms. TI - Efficacy of ventilator waveform observation for detection of patient-ventilator asynchrony during NIV: a multicentre study SN - 2312-0541 IS - iss. 4 JF - ERJ Open Research VL - vol. 3 DO - https://doi.org/10.1183/23120541.00075-2017 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182479/182479.pdf?sequence=1 ER - TY - JOUR AU - Vinke, Elisabeth J. AU - Eyding, Jens AU - Korte, C.L. de AU - Slump, Cornelis H. AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2017 UR - https://hdl.handle.net/2066/179605 TI - REPEATABILITY OF BOLUS KINETICS ULTRASOUND PERFUSION IMAGING FOR THE QUANTIFICATION OF CEREBRAL BLOOD FLOW EP - 2764 SN - 0301-5629 IS - iss. 12 SP - 2758 JF - Ultrasound in Medicine and Biology VL - vol. 43 DO - https://doi.org/10.1016/j.ultrasmedbio.2017.08.1880 ER - TY - JOUR AU - Lebrun, L.J. AU - Lenaerts, K. AU - Kiers, D. AU - Barros, J.P. Pais de AU - Guern, N. Le AU - Plesnik, J. AU - Thomas, C. AU - Bourgeois, T. AU - Dejong, C.H. AU - Kox, M. AU - Hundscheid, I.H.R. AU - Khan, N.A. AU - Mandard, S. AU - Deckert, V. AU - Pickkers, P. AU - Drucker, D.J. AU - Lagrost, L. AU - Grober, J. PY - 2017 UR - https://hdl.handle.net/2066/182548 AB - Glucagon-like peptide 1 (GLP-1) is a hormone released from enteroendocrine L cells. Although first described as a glucoregulatory incretin hormone, GLP-1 also suppresses inflammation and promotes mucosal integrity. Here, we demonstrate that plasma GLP-1 levels are rapidly increased by lipopolysaccharide (LPS) administration in mice via a Toll-like receptor 4 (TLR4)-dependent mechanism. Experimental manipulation of gut barrier integrity after dextran sodium sulfate treatment, or via ischemia/reperfusion experiments in mice, triggered a rapid rise in circulating GLP-1. This phenomenon was detected prior to measurable changes in inflammatory status and plasma cytokine and LPS levels. In human subjects, LPS administration also induced GLP-1 secretion. Furthermore, GLP-1 levels were rapidly increased following the induction of ischemia in the human intestine. These findings expand traditional concepts of enteroendocrine L cell biology to encompass the sensing of inflammatory stimuli and compromised mucosal integrity, linking glucagon-like peptide secretion to gut inflammation. TI - Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion EP - 1168 SN - 2211-1247 IS - iss. 5 SP - 1160 JF - Cell Reports VL - vol. 21 DO - https://doi.org/10.1016/j.celrep.2017.10.008 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182548/182548.pdf?sequence=1 ER - TY - JOUR AU - Veerdonk, F.L. van de AU - Kolwijck, E. AU - Lestrade, P.P.A. AU - Hodiamont, C.J. AU - Rijnders, B.J. AU - Paassen, J. van AU - Haas, P.J. AU - Santos, C. dos AU - Kampinga, G.A. AU - Bergmans, D.C. AU - Dijk, K van AU - Haan, A.F.J. de AU - Dissel, J. van AU - Hoeven, H. van der AU - Verweij, P.E. PY - 2017 UR - https://hdl.handle.net/2066/182506 TI - Influenza-Associated Aspergillosis in Critically Ill Patients EP - 527 SN - 1073-449X IS - iss. 4 SP - 524 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 196 DO - https://doi.org/10.1164/rccm.201612-2540LE ER - TY - JOUR AU - Leeuw, T.G. de AU - Dirckx, M. AU - Candel, A.G. AU - Scoones, G.P. AU - Huygen, F. AU - Wildt, S.N. de PY - 2017 UR - https://hdl.handle.net/2066/182204 AB - Dipyrone has analgesic, spasmolytic, and antipyretic effects and is used to treat pain. Due to a possible risk of agranulocytosis with the use of dipyrone, it has been banned in a number of countries. The most commonly used data for the use of dipyrone are related to adults. Information relating to the use of dipyrone in children is scarce. Given the potential added value of dipyrone in the treatment of pain, a review of the literature was conducted to obtain more insight into the analgesic efficacy of dipyrone in children as well as the safety of dipyrone in terms of adverse events. A literature search was done for original articles (in English, German, or Spanish language) which met the following criteria: the use of dipyrone for pain and children up to the age of 17 years old. All titles and abstracts retrieved were reviewed, independently, by two of the authors, for their suitability for inclusion. The references of the selected articles were also checked for additional relevant papers. The publications were categorized into case reports, observational studies, or randomized controlled trials. To assess the methodological quality of the studies, the Jadad score was used. In the limited available data, the analgesic efficacy of intravenous dipyrone appears similar to that of intravenous paracetamol. Evidence is lacking to support the claim that dipyrone is equivalent or even superior to Non-Steroid-Anti-Inflammatory-Drugs in pediatric pain. While the absolute risk of agranulocytosis with dipyrone in children, based on available literature, cannot be determined, case reports suggest that this risk is not negligible. TI - The use of dipyrone (metamizol) as an analgesic in children: What is the evidence? A review EP - 1201 SN - 1155-5645 IS - iss. 12 SP - 1193 JF - Paediatric Anaesthesia VL - vol. 27 DO - https://doi.org/10.1111/pan.13257 ER - TY - JOUR AU - Geense, W.W. AU - Gaal, B. van AU - Knoll, J.L. AU - Cornelissen, E.A.M. AU - Achterberg, T. van PY - 2017 UR - https://hdl.handle.net/2066/182405 AB - BACKGROUND: Parents of children with a chronic kidney disease (CKD) have a crucial role in the management of their child's disease. The burden on parents is high: they are often exhausted, depressed and experience high levels of stress and a low quality of life, which could have a negative impact on their child's health outcomes. Support aiming at preventing and reducing parental stress is essential. Therefore, it is necessary to have insight in the problems and support needs among these parents. OBJECTIVE: Our aim is to describe parents' support needs regarding the problems they experience in having a child with CKD. METHODS: Five focus group interviews were conducted with parents of children: (i) with hereditary kidney disease, (ii) with nephrotic syndrome, (iii) with chronic kidney failure, (iv) using dialysis and (v) after renal transplantation. The children were treated at a paediatric nephrology unit in one university hospital in the Netherlands. The data were thematically analysed. RESULTS: Twenty-one parents participated in the focus groups. Parents need more information about their child's CKD and treatment options, and managing their own hobbies and work. Furthermore, parents need emotional support from their partner, family, friends, peers and healthcare professionals to help them cope with the disease of their child. Additionally, parents need practical support to hand over their care and support in transport, financial management and regarding their child at school. CONCLUSION: Needs regarding balancing their personal life are seldom prioritized by parents as the child's needs are considered more important. Therefore, it is important that healthcare professionals should not only attend to the abilities of parents concerning their child's disease management, but also focus on the parents' abilities in balancing their responsibilities as a caregiver with their own personal life. TI - The support needs of parents having a child with a chronic kidney disease: a focus group study EP - 838 SN - 0305-1862 IS - iss. 6 SP - 831 JF - Child: Care, Health and Development VL - vol. 43 DO - https://doi.org/10.1111/cch.12476 ER - TY - JOUR AU - Timmermans, K. AU - Leijte, G.P. AU - Kox, M. AU - Scheffer, G.J. AU - Blijlevens, N.M.A. AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/176918 AB - Chemotherapy may result in the release of danger-associated molecular patterns (DAMPs), which can cause immunoparalysis (deactivation of the immune system). We investigated DAMPs following chemotherapy and their relationship with markers of immunoparalysis in leukemia patients. In 6 patients with acute myeloid leukemia or myelodysplastic syndrome and 12 healthy subjects, DAMPs, cytokines, and markers of immunoparalysis were determined before and during the first week after chemotherapy initiation. In the patients, plasma levels of nuclear DNA (a marker of general DAMP release) were profoundly increased before chemotherapy and further increased 4-6 h afterwards, while the specific DAMP mitochondrial DNA showed only a trend towards increase. Circulating cytokine levels did not change following chemotherapy. Leukocyte cytokine production capacity and HLA-DR expression were similar in patients and healthy controls until day 4 when leukocytes were found to be virtually absent. In conclusion, in the early phase following chemotherapy in leukemia patients, increased DAMP release does not induce immunoparalysis. TI - Release of Danger-Associated Molecular Patterns following Chemotherapy Does Not Induce Immunoparalysis in Leukemia Patients EP - 43 SN - 0001-5792 IS - iss. 1 SP - 39 JF - Acta Haematologica VL - vol. 138 DO - https://doi.org/10.1159/000477530 ER - TY - JOUR AU - Kiers, D. AU - Timmers, H.J.L.M. AU - Gerretsen, J. AU - Pickkers, P. AU - Kox, M. PY - 2017 UR - https://hdl.handle.net/2066/177058 TI - LPS-Induced ex vivo Cytokine Production is Not Augmented in Patients with Von Hippel-Lindau Disease EP - 180 SN - 0300-9475 IS - iss. 3 SP - 179 JF - Scandinavian Journal of Immunology VL - vol. 86 DO - https://doi.org/10.1111/sji.12578 ER - TY - JOUR AU - Sluisveld, N. van AU - Oerlemans, A.J.M. AU - Westert, G.P. AU - Hoeven, J.G. van der AU - Wollersheim, H.C. AU - Zegers, M. PY - 2017 UR - https://hdl.handle.net/2066/174300 AB - BACKGROUND: Evidence indicates that suboptimal clinical handover from the intensive care unit (ICU) to general wards leads to unnecessary ICU readmissions and increased mortality. We aimed to gain insight into barriers and facilitators to implement and use ICU discharge practices. METHODS: A mixed methods approach was conducted, using 1) 23 individual and four focus group interviews, with post-ICU patients, ICU managers, and nurses and physicians working in the ICU or general ward of ten Dutch hospitals, and 2) a questionnaire survey, which contained 27 statements derived from the interviews, and was completed by 166 ICU physicians (21.8%) from 64 Dutch hospitals (71.1% of the total of 90 Dutch hospitals). RESULTS: The interviews resulted in 66 barriers and facilitators related to: the intervention (e.g., feasibility); the professional (e.g., attitude towards checklists); social factors (e.g., presence or absence of a culture of feedback); and the organisation (e.g., financial resources). A facilitator considered important by ICU physicians was a checklist to structure discharge communication (92.2%). Barriers deemed important were lack of a culture of feedback (55.4%), an absence of discharge criteria (23.5%), and an overestimation of the capabilities of general wards to care for complex patients by ICU physicians (74.7%). CONCLUSIONS: Based on the barriers and facilitators found in this study, improving handover communication, formulating specific discharge criteria, stimulating a culture of feedback, and preventing overestimation of the general ward are important to effectively improve the ICU discharge process. TI - Barriers and facilitators to improve safety and efficiency of the ICU discharge process: a mixed methods study EP - 251 SN - 1472-6963 IS - iss. 1 SP - 251 JF - BMC Health Services Research VL - vol. 17 DO - https://doi.org/10.1186/s12913-017-2139-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/174300/174300.pdf?sequence=1 ER - TY - JOUR AU - Sluisveld, N. van AU - Bakhshi-Raiez, F. AU - Keizer, N. de AU - Holman, R. AU - Westert, G.P. AU - Wollersheim, H.C. AU - Hoeven, J.G. van der AU - Zegers, M. PY - 2017 UR - https://hdl.handle.net/2066/174318 AB - BACKGROUND: Variation in intensive care unit (ICU) readmissions and in-hospital mortality after ICU discharge may indicate potential for improvement and could be explained by ICU discharge practices. Our objective was threefold: (1) describe variation in rates of ICU readmissions within 48 h and post-ICU in-hospital mortality, (2) describe ICU discharge practices in Dutch hospitals, and (3) study the association between rates of ICU readmissions within 48 h and post-ICU in-hospital mortality and ICU discharge practices. METHODS: We analysed data on 42,040 admissions to 82 (91.1%) Dutch ICUs in 2011 from the Dutch National Intensive Care Evaluation (NICE) registry to describe variation in standardized ICU readmission and post-ICU mortality rates using funnel-plots. We send a questionnaire to all Dutch ICUs. 75 ICUs responded and their questionnaire data could be linked to 38,498 admissions in the NICE registry. Generalized estimation equations analyses were used to study the association between ICU readmissions and post-ICU mortality rates and the identified discharge practices, i.e. (1) ICU discharge criteria; (2) bed managers; (3) early discharge planning; (4) step-down facilities; (5) medication reconciliation; (6) verbal and written handover; (7) monitoring of post-ICU patients; and (8) consulting ICU nurses. In all analyses, the outcomes were corrected for patient-related confounding factors. RESULTS: The standardized rate of ICU readmissions varied between 0.14 and 2.67 and 20.8% of the hospitals fell outside the 95% control limits and 3.6% outside the 99.8% control limits. The standardized rate of post-ICU mortality varied between 0.07 and 2.07 and 17.1% of the hospitals fell outside the 95% control limits and 4.9% outside the 99.8% control limits. We could not demonstrate an association between the eight ICU discharge practices and rates of ICU readmissions or post-ICU in-hospital mortality. Implementing a higher number of ICU discharge practices was also not associated with better patient outcomes. CONCLUSIONS: We found both variation in patient outcomes and variation in ICU discharge practices between ICUs. However, we found no association between discharge practices and rates of ICU readmissions or post-ICU mortality. Further research is necessary to find factors, which may influence these patient outcomes, in order to improve quality of care. TI - Variation in rates of ICU readmissions and post-ICU in-hospital mortality and their association with ICU discharge practices SN - 1472-6963 IS - iss. 1 SP - 281 JF - BMC Health Services Research VL - vol. 17 DO - https://doi.org/10.1186/s12913-017-2234-z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/174318/174318.pdf?sequence=1 ER - TY - JOUR AU - Muilwijk, E.W. AU - Dekkers, B.G.J. AU - Henriet, S.S.V. AU - Verweij, P.E. AU - Witjes, B. AU - Lashof, A. AU - Groeneveld, G.H. AU - Hoeven, J.G. van der AU - Alffenaar, J.W.C. AU - Russel, F.G. AU - Veerdonk, F.L. van de AU - Bruggemann, R.J.M. PY - 2017 UR - https://hdl.handle.net/2066/177025 AB - Combining voriconazole and flucloxacillin is indicated in patient cohorts experiencing both invasive aspergillosis and Gram-positive infections (e.g., patients with chronic granulomatous disease or postinfluenza pulmonary aspergillosis). We report a highly relevant interaction between voriconazole and flucloxacillin, resulting in subtherapeutic plasma voriconazole concentrations in more than 50% of patients, that poses a severe threat if not managed properly. TI - Flucloxacillin Results in Suboptimal Plasma Voriconazole Concentrations SN - 0066-4804 IS - iss. 9 JF - Antimicrobial Agents and Chemotherapy VL - vol. 61 DO - https://doi.org/10.1128/AAC.00915-17 ER - TY - JOUR AU - Matic, M. AU - Wildt, S.N. de AU - Tibboel, D. AU - Schaik, R.H. van PY - 2017 UR - https://hdl.handle.net/2066/174823 AB - BACKGROUND: The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT: We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY: The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context. TI - Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice EP - 1213 SN - 0009-9147 IS - iss. 7 SP - 1204 JF - Clinical Chemistry VL - vol. 63 DO - https://doi.org/10.1373/clinchem.2016.264986 ER - TY - JOUR AU - Darwich, A.S. AU - Ogungbenro, K. AU - Vinks, A.A. AU - Powell, J.R. AU - Reny, J.L. AU - Marsousi, N. AU - Daali, Y. AU - Fairman, D. AU - Cook, J. AU - Lesko, L.J. AU - McCune, J.S. AU - Knibbe, C. AU - Wildt, S.N. de AU - Leeder, J.S. AU - Neely, M. AU - Zuppa, A.F. AU - Vicini, P. AU - Aarons, L. AU - Johnson, T.N. AU - Boiani, J. AU - Rostami-Hodjegan, A. PY - 2017 UR - https://hdl.handle.net/2066/174855 AB - Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap. TI - Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future EP - 656 SN - 0009-9236 IS - iss. 5 SP - 646 JF - Clinical Pharmacology and Therapeutics VL - vol. 101 DO - https://doi.org/10.1002/cpt.659 ER - TY - JOUR AU - Kamps, M.J.A. AU - Kiers, D. AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/176841 AB - Steroids influence the immune response and blood pressure in patients with septic shock. Many trials have evaluated a putative positive effect of steroids as an adjuvant therapy in patients with sepsis and septic shock, with contradictory outcomes. As a consequence, the use of steroids in sepsis patients varies widely. A recently published randomized clinical trial has demonstrated that treatment with hydrocortisone does not delay or prevent progress to septic shock in patients with sepsis. Based on the current available data, the use of steroids in sepsis should be reserved for those patients who remain severely hemodynamic unstable after fluid resuscitation and vasopressor therapy, or those with a separate indication for steroid therapy. A corticotropin stimulation test to evaluate adrenal insufficiency is not useful. TI - [No glucocorticoids for treatment of sepsis; unless...] SN - 0028-2162 IS - iss. 0 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 161 ER - TY - JOUR AU - Habes, Q.L.M. AU - Linssen, V. AU - Nooijen, S. AU - Kiers, D. AU - Gerretsen, J. AU - Pickkers, P. AU - Scheffer, G.J. AU - Kox, M. PY - 2017 UR - https://hdl.handle.net/2066/175623 AB - OBJECTIVES: In patients undergoing cardiac surgery, both extracorporeal circulation (ECC) and intraoperative mesenterial hypoperfusion may account for increased cytokine levels and lead to postoperative gastrointestinal (GI) symptoms. METHODS: We investigated levels of the intestinal damage markers intestinal fatty acid binding protein (I-FABP in plasma [n = 72] and urine [n = 37]), citrulline (in plasma [n = 35]), and claudin-3 (in urine [n = 37]) in patients undergoing aortic or mitral valve surgery with or without coronary artery bypass grafting. Furthermore, the relationship between these markers and the surgery-induced cytokine response was explored by measuring serial plasma levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, and IL-10 (n = 35). Finally, the relationship between markers of intestinal damage and GI-symptoms (abdominal pain, ileus, vomiting, diarrhea, time to first defecation) was assessed. RESULTS: Plasma and urinary I-FABP levels, and urinary claudin-3 levels peaked at the end of surgery, while citrulline levels were not influenced by surgery. ECC duration correlated with plasma I-FABP levels (r = 0.31, P = 0.007). Plasma levels of all measured cytokines increased during surgery, with peak levels observed either at the end of surgery or on the first postoperative day. While ECC duration correlated with IL-6 and IL-8 release (r = 0.43, P = 0.01 and r = 0.36, P = 0.04 respectively), there was no direct relationship between I-FABP and claudin-3 levels and cytokine concentrations. No patients developed significant GI or non-GI complications, and I-FABP and claudin-3 release appeared not to be related to postoperative GI symptoms, although the incidence of these symptoms may have limited a reliable assessment. CONCLUSIONS: Longer duration of ECC is associated with a more pronounced release of intestinal injury markers and inflammatory cytokines, but intestinal injury markers are not directly related to the observed increase in cytokine levels or GI-symptoms. These findings indicate that ECC duration contributes to the cytokine response observed in cardiac surgery patients and that intestinal injury itself is not a causative factor for this response. TI - Markers of Intestinal Damage and their Relation to Cytokine Levels in Cardiac Surgery Patients EP - 714 SN - 1073-2322 IS - iss. 6 SP - 709 JF - Shock VL - vol. 47 DO - https://doi.org/10.1097/SHK.0000000000000803 ER - TY - JOUR AU - Timmermans, K. AU - Kox, M. AU - Vaneker, M. AU - Pickkers, P. AU - Scheffer, G.J. PY - 2017 UR - https://hdl.handle.net/2066/175626 AB - Exogenous administration of mitochondrial DNA (mtDNA) causes inflammatory lung injury in a toll-like receptor (TLR) 9-dependent manner. We investigated whether mechanical ventilation results in endogenous release of mtDNA and whether TLR9 plays a role in the pulmonary inflammatory response induced by mechanical ventilation.Wild-type and TLR9/ C57bl/6 mice were ventilated with low (8 mL/kg) and high (32 mL/kg) tidal volumes for 4 hours. Levels of nuclear DNA and mtDNA in bronchoalveolar lavage fluid, as well as pulmonary concentrations of keratinocyte-derived chemokine, interleukin-1beta, and interleukin-6, were determined.Cytokine and nuclear DNA, but not mtDNA, levels were increased after mechanical ventilation with both tidal volumes. Cytokine concentrations were similar between wild-type and TLR9/ mice. Mechanical ventilation does not result in the release of mtDNA, and TLR9 is not involved in mechanical ventilation-induced inflammation. TI - Mitochondrial DNA and TLR9 Signaling Is Not Involved in Mechanical Ventilation-Induced Inflammation EP - 534 SN - 0003-2999 IS - iss. 2 SP - 531 JF - Anesthesia and Analgesia VL - vol. 124 DO - https://doi.org/10.1213/ANE.0000000000001554 ER - TY - JOUR AU - Zanden, T.M. van der AU - Wildt, S.N. de AU - Liem, Y. AU - Offringa, M. AU - Hoog, M. de PY - 2017 UR - https://hdl.handle.net/2066/174803 AB - As many drugs in paediatrics are used off-label, prescribers face a lack of evidence-based dosing guidelines. A Dutch framework was developed to provide dosing guidelines based on best available evidence from registration data, investigator-initiated research, professional guidelines, clinical experience and consensus. This has clarified the scientific grounds of drug use for children and encouraged uniformity in prescribing habits in the Netherlands. The developed framework and the current content of the Dutch Paediatric Formulary could be used as basis for similar initiatives worldwide, preferably in a concerted effort to ultimately provide children with effective and safe drug therapy. TI - Developing a paediatric drug formulary for the Netherlands EP - 361 SN - 0003-9888 IS - iss. 4 SP - 357 JF - Archives of Disease in Childhood VL - vol. 102 DO - https://doi.org/10.1136/archdischild-2016-311674 ER - TY - JOUR AU - Wassenaar, A. AU - Boogaard, M.H.W.A. van den AU - Schoonhoven, L. AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/181521 TI - Determination of the feasibility of a multicomponent intervention program to prevent delirium in the Intensive Care Unit: A modified RAND Delphi study EP - 327 SN - 1036-7314 IS - iss. 6 SP - 321 JF - Australian Critical Care VL - vol. 30 DO - https://doi.org/10.1016/j.aucc.2016.12.004 ER - TY - JOUR AU - Kolk, B.M. van der AU - Boogaard, M.H.W.A. van den AU - Brugge-Speelman, Corine ter AU - Hol, Jeroen AU - Noyez, L. AU - Laarhoven, K. van AU - Hoeven, H. van der AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/181522 TI - Development and implementation of a clinical pathway for cardiac surgery in the intensive care unit: Effects on protocol adherence EP - 1298 SN - 1356-1294 IS - iss. 6 SP - 1289 JF - Journal of Evaluation in Clinical Practice VL - vol. 23 DO - https://doi.org/10.1111/jep.12778 ER - TY - JOUR AU - Martial, L.C. AU - Heine, R. ter AU - Schouten, J.A. AU - Hunfeld, N.G. AU - Leeuwen, H.J. van AU - Verweij, P.E. AU - Lange, D.W. de AU - Pickkers, P. AU - Bruggemann, R.J.M. PY - 2017 UR - https://hdl.handle.net/2066/181357 AB - OBJECTIVE: To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. METHODS: Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations. RESULTS: A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016. CONCLUSIONS: The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study. TI - Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients EP - 1206 SN - 0312-5963 IS - iss. 10 SP - 1197 JF - Clinical Pharmacokinetics VL - vol. 56 DO - https://doi.org/10.1007/s40262-017-0509-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/181357/181357.pdf?sequence=1 ER - TY - JOUR AU - Numan, T. AU - Boogaard, M.H.W.A. van den AU - Kampen, A.M. AU - Rood, P.J.T. AU - Peelen, L.M. AU - Slooter, A.J. PY - 2017 UR - https://hdl.handle.net/2066/181678 AB - OBJECTIVE: To determine the degree of agreement between delirium experts on the diagnosis of delirium based on exactly the same information, and to assess the sensitivity of delirium screening methods used by clinical nurses. DESIGN: Prospective observational longitudinal study. METHOD: Older patients (>/= 60 years) who underwent major surgery were included. During the first three days after surgery they had a standardised cognitive screening test which was recorded on video. Two delirium experts independently evaluated these videos and the information from the patient records. They classified the patients as having 'no delirium', 'possible delirium' or 'delirium'. If there was disagreement, a third expert was consulted. The final classification, based on consensus of two or three delirium experts, was compared with the result of the delirium screening carried out by the clinical nurses. RESULTS: A total of 167 patients were included and 424 postoperative classifications were obtained. The agreement between the experts was 0.61 (95% confidence interval (CI): 0.53-0.68), based on Cohen's kappa. In 89 (21.0%) of the postoperative classifications there was no agreement between the experts and a third expert was consulted. The nurses using the delirium screening tools recognised 32% of the cases that had been classified as delirium by the experts. CONCLUSION: There was considerable disagreement between the classifications of individual delirium experts, based on exactly the same information, indicating the difficulty of the diagnosis. Furthermore, the sensitivity of the delirium screening tools used by the clinical nurses was poor. Further research should focus on the development of objective methods for recognising delirium. TI - [Recognising postoperative delirium in the elderly] SN - 0028-2162 IS - iss. 0 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 161 ER - TY - JOUR AU - Tilanus, T.B.M. AU - Groothuis, J.T. AU - Broek-Pastoor, J.M.C. ten AU - Feuth, T. AU - Heijdra, Y.F. AU - Slenders, J.P.L. AU - Doorduin, J. AU - Engelen, B.G.M. van AU - Kampelmacher, M.J. AU - Raaphorst, J. PY - 2017 UR - https://hdl.handle.net/2066/176941 AB - BACKGROUND: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown which respiratory function test predicts an appropriate timing of the initiation of NIV. METHODS: We analysed, retrospectively, serial data of five respiratory function tests: forced vital capacity (FVC), peak cough flow (PCF), maximum inspiratory and expiratory pressure (MIP and MEP) and sniff nasal inspiratory pressure (SNIP) in patients with ALS. Patients who had had at least one assessment of respiratory function and one visit at the HVS, were included. Our aim was to detect the test with the highest predictive value for the need for elective NIV in the following 3 months. We analysed time curves, currently used cut-off values for referral, and respiratory function test results between 'NIV indication' and 'no-NIV indication' patients. RESULTS: One hundred ten patients with ALS were included of whom 87 received an NIV indication; 11.5% had one assessment before receiving an NIV indication, 88.5% had two or more assessments. The NIV indication was based on complaints of hypoventilation and/or proven (nocturnal) hypercapnia. The five respiratory function tests showed a descending trend during disease progression, where SNIP showed the greatest decline within the latest 3 months before NIV indication (mean = -22%). PCF at the time of referral to the HVS significantly discriminated between the groups 'NIV-indication' and 'no NIV-indication yet' patients at the first HVS visit: 259 (+/-92) vs. 348 (+/-137) L/min, p = 0.019. PCF and SNIP showed the best predictive characteristics in terms of sensitivity. CONCLUSION: SNIP showed the greatest decline prior to NIV indication and PCF significantly differentiated 'NIV-indication' from 'no NIV-indication yet' patients with ALS. Currently used cut-off values might be adjusted and other respiratory function tests such as SNIP and PCF may become part of routine care in patients with ALS in order to avoid non-timely initiation of (non-invasive) ventilation. TI - The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis SN - 1465-993X IS - iss. 1 JF - Respiratory Research VL - vol. 18 DO - https://doi.org/10.1186/s12931-017-0624-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/176941/176941.pdf?sequence=1 ER - TY - JOUR AU - Helmhout, P.H. AU - Witjes, M. AU - Nijhuis-van der Sanden, M.W.G. AU - Bron, C. AU - Aalst, M. Van der AU - Staal, J.B. PY - 2017 UR - https://hdl.handle.net/2066/170096 AB - BACKGROUND: It is assumed that low back pain patients who use pain-avoiding immobilizing strategies may benefit from specific back flexion and extension exercises aimed at reducing sagittal lumbar hypomobility. The aim of this study was to test this potential working mechanism in chronic low back pain patients undergoing lumbar extensor strengthening training. METHODS: A single-group prospective cohort design was used in this study. Patients with persistent low back complaints for at least 2 years were recruited at a specialized physical therapy clinics center. They participated in a progressive 11-week lumbar extensor strength training program, once a week. At baseline, sagittal lumbar mobility in flexion and extension was measured with a computer-assisted inclinometer. Self-rated pain intensity was measured using a visual analogue scale, back-specific functional status was assessed with the Quebec Back Pain Disability Scale and the Patient Specific Complains questionnaire. RESULTS: Statistically significant improvements were found in pain (28% decrease) and functional disability (23% to 36% decrease). Most progress was seen in the first 5 treatment weeks. Lumbar mobility in flexion showed non-significant increases over time (+12%). Pre-post treatment changes in flexion and extension mobility did not contribute significantly to the models. The retained factors together explained 15% to 48% of the variation in outcome. CONCLUSIONS: Specific lumbar strengthening showed clinically relevant improvements in pain and disability in patients with persistent chronic low back pain. These improvements did not necessarily relate to improvements in lumbar mobility. Parameters representing other domains of adaptations to exercise may be needed to evaluate the effects of back pain management. TI - The effects of lumbar extensor strength on disability and mobility in patients with persistent low back pain EP - 417 SN - 0022-4707 IS - iss. 4 SP - 411 JF - Journal of Sports Medicine and Physical Fitness VL - vol. 57 DO - https://doi.org/10.23736/S0022-4707.16.06270-8 ER - TY - JOUR AU - Vinke, E.J. AU - Kortenbout, A.J. AU - Eyding, J. AU - Slump, C.H. AU - Hoeven, J.G. van der AU - Korte, C.L. de AU - Hoedemaekers, C.W.E. PY - 2017 UR - https://hdl.handle.net/2066/181786 AB - Contrast-enhanced ultrasound (CEUS) has been suggested as a new method to measure cerebral perfusion in patients with acute brain injury. In this systematic review, the tolerability, repeatability, reproducibility and accuracy of different CEUS techniques for the quantification of cerebral perfusion were assessed. We selected studies published between January 1994 and March 2017 using CEUS to measure cerebral perfusion. We included 43 studies (bolus kinetics n = 31, refill kinetics n = 6, depletion kinetics n = 6) with a total of 861 patients. Tolerability was reported in 28 studies describing 12 patients with mild and transient side effects. Repeatability was assessed in 3 studies, reproducibility in 2 studies and accuracy in 19 studies. Repeatability was high for experienced sonographers and significantly lower for less experienced sonographers. Reproducibility of CEUS was not clear. The sensitivity and specificity of CEUS for the detection of cerebral ischemia ranged from 75% to 96% and from 60% to 100%. Limited data on repeatability, reproducibility and accuracy may suggest that this technique could be feasible for use in acute brain injury patients. TI - Potential of Contrast-Enhanced Ultrasound as a Bedside Monitoring Technique in Cerebral Perfusion: a Systematic Review EP - 2757 SN - 0301-5629 IS - iss. 12 SP - 2751 JF - Ultrasound in Medicine and Biology VL - vol. 43 DO - https://doi.org/10.1016/j.ultrasmedbio.2017.08.935 ER - TY - JOUR AU - Kleiber, N. AU - Mathot, R.A.A. AU - Ahsman, M.J. AU - Wildschut, E.D. AU - Tibboel, D. AU - Wildt, S.N. de PY - 2017 UR - https://hdl.handle.net/2066/174829 AB - AIMS: Clonidine is used for sedation in the paediatric intensive care unit. Extracorporeal membrane oxygenation (ECMO) provides temporary support if respiratory and cardiac function is threatened. ECMO influences the pharmacokinetics of drugs. Clonidine during paediatric ECMO cannot be effectively titrated as PK data are lacking. The aim of this study is to describe clonidine PK in a particular ECMO system and propose dosing guidelines for children on this particular ECMO circuit. METHODS: All children below the age of 18 years who received clonidine during ECMO were eligible. The pharmacokinetic analysis was conducted by nonlinear mixed effect modelling, which enables to establish the separate influences of determinants on drug blood level and to provide individualized dosing. RESULTS: Twenty-two patients, median age 1 month (IQR 6.4) and weight at inclusion 4 kg (IQR 3.1) were included of whom 90% in addition to ECMO received pre-emptive continuous venovenous hemofiltration to optimize fluid balance. The clonidine clearance rate was two-fold that measured in patients not on ECMO. Clearance increased steeply with postnatal age: at days 6, 8 and 10, respectively 30%, 50% and 70% of the adult clearance rate was reached. The use of diuretics was associated with a lower clearance. The volume of distribution increased by 55% during ECMO support. CONCLUSION: Our findings suggest that a higher dose of clonidine may be needed during ECMO. The PK parameters on ECMO and the dosing guidelines proposed hold the potential to improve sedation practices on ECMO but need to be repeated with different ECMO systems. TI - Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration EP - 1239 SN - 0306-5251 IS - iss. 6 SP - 1227 JF - British Journal of Clinical Pharmacology VL - vol. 83 DO - https://doi.org/10.1111/bcp.13235 ER - TY - JOUR AU - Cnossen, M.C. AU - Huijben, J.A. AU - Jagt, M. van der AU - Volovici, V. AU - Essen, T. van AU - Polinder, S. AU - Nelson, D. AU - Ercole, A. AU - Stocchetti, N. AU - Citerio, G. AU - Peul, W.C. AU - Maas, A.I. AU - Menon, D. AU - Steyerberg, E.W. AU - Lingsma, H.F. AU - Hoedemaekers, A. AU - Sir, O. AU - Naalt, J. van der PY - 2017 UR - https://hdl.handle.net/2066/178046 AB - BACKGROUND: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management strategies, resulting in practice variation. The aim of this study was to examine variation in monitoring and treatment policies for intracranial hypertension in patients with TBI. METHODS: A 29-item survey on ICP monitoring and treatment was developed on the basis of literature and expert opinion, and it was pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. RESULTS: The survey was completed by 66 centers (97% response rate). Centers were mainly academic hospitals (n = 60, 91%) and designated level I trauma centers (n = 44, 67%). The Brain Trauma Foundation guidelines were used in 49 (74%) centers. Approximately 90% of the participants (n = 58) indicated placing an ICP monitor in patients with severe TBI and computed tomographic abnormalities. There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first- and second-tier treatments for elevated ICP. Approximately half of the centers were classified as using a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas the others were considered more conservative (n = 34, 52%). CONCLUSIONS: Substantial variation was found regarding monitoring and treatment policies in patients with TBI and intracranial hypertension. The results of this survey indicate a lack of consensus between European neurotrauma centers and provide an opportunity and necessity for comparative effectiveness research. TI - Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: a survey in 66 neurotrauma centers participating in the CENTER-TBI study SN - 1466-609X IS - iss. 1 SP - 233 JF - Critical Care VL - vol. 21 DO - https://doi.org/10.1186/s13054-017-1816-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/178046/178046.pdf?sequence=1 ER - TY - JOUR AU - Matic, M. AU - Jongen, J.L. AU - Elens, L. AU - Wildt, S.N. de AU - Tibboel, D. AU - Smitt, P.A. Sillevis AU - Schaik, R.H. van PY - 2017 UR - https://hdl.handle.net/2066/177626 AB - AIM: To assess association between genetic variants and opioid requirement in cancer patients. MATERIALS & METHODS: A prospective observational trial of 243 advanced cancer patients with inadequate analgesia treated by the palliative care team was analyzed for ABCB1, ARRB2, COMT, GCH1, IL1RN, KCNJ6, OPRM1, RHBDF2, SCN9A and Stat6 polymorphisms. RESULTS: For patients carrying OPRM1 118AG/GG and COMT 472GG (Val158Val) or these genotypes alone, a significant higher median percentage dose increase was observed (95.2% [32.8-345]) compared with OPRM1 118AA and COMT 472GA/AA (158Met allele carriers; 48.5% [0-98.8]; p = 0.0016). No associations were found with morphine equivalent dose after consultation palliative care team or ketamine use. CONCLUSION: Patients with the combined OPRM1 118AG/GG and COMT 472GG genotype required 50% higher dose increase for sufficient analgesia. TI - Advanced cancer pain: the search for genetic factors correlated with interindividual variability in opioid requirement EP - 1142 SN - 1462-2416 IS - iss. 12 SP - 1133 JF - Pharmacogenomics VL - vol. 18 DO - https://doi.org/10.2217/pgs-2017-0060 ER - TY - JOUR AU - Brule, J.M.D. van den AU - Vinke, E.J. AU - Loon, L.M. van AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2017 UR - https://hdl.handle.net/2066/177627 AB - OBJECTIVE: To investigate spontaneous variability in the time and frequency domain in mean flow velocity (MFV) and mean arterial pressure (MAP) in comatose patients after cardiac arrest, and determine possible differences between survivors and non-survivors. METHODS: A prospective observational study was performed at the ICU of a tertiary care university hospital in the Netherlands. We studied 11 comatose patients and 10 controls. MFV in the middle cerebral artery was measured with simultaneously recording of MAP. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, the average spectral power of MAP and MFV were calculated in the very low, low and high frequency bands. RESULTS: In survivors CV of MFV increased from 4.66 [3.92-6.28] to 7.52 [5.52-15.23] % at T=72h. In non-survivors CV of MFV decreased from 9.02 [1.70-9.36] to 1.97 [1.97-1.97] %. CV of MAP was low immediately after admission (1.46 [1.09-2.25] %) and remained low at 72h (3.05 [1.87-3.63] %) (p=0.13). There were no differences in CV of MAP between survivors and non-survivors (p=0.30). We noticed significant differences between survivors and non-survivors in the VLF band for average spectral power of MAP (p=0.03) and MFV (p=0.003), whereby the power of both MAP and MFV increased in survivors during admission, while remaining low in non-survivors. CONCLUSIONS: Cerebral blood flow is altered after cardiac arrest, with decreased spontaneous fluctuations in non-survivors. Most likely, these changes are the consequence of impaired intrinsic myogenic vascular function and autonomic dysregulation. TI - Low spontaneous variability in cerebral blood flow velocity in non-survivors after cardiac arrest EP - 115 SN - 0300-9572 SP - 110 JF - Resuscitation VL - vol. 111 DO - https://doi.org/10.1016/j.resuscitation.2016.12.005 ER - TY - JOUR AU - Brule, J.M.D. van den AU - Vinke, E. AU - Loon, L.M. van AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2017 UR - https://hdl.handle.net/2066/177630 AB - AIM: This study estimated the critical closing pressure (CrCP) of the cerebrovascular circulation during the post-cardiac arrest syndrome and determined if CrCP differs between survivors and non-survivors. We also compared patients after cardiac arrest to normal controls. METHODS: A prospective observational study was performed at the ICU of a tertiary university hospital in Nijmegen, the Netherlands. We studied 11 comatose patients successfully resuscitated from a cardiac arrest and treated with mild therapeutic hypothermia and 10 normal control subjects. Mean flow velocity (MFV) in the middle cerebral artery was measured by transcranial Doppler at several time points after admission to the ICU. CrCP was determined by a cerebrovascular impedance model. RESULTS: MFV was similar in survivors and non-survivors upon admission to the ICU, but increased stronger in non-survivors compared to survivors throughout the observation period (P<0.001). MFV was significantly lower in survivors immediately after cardiac arrest compared to normal controls (P<0.001), with a gradual restoration toward normal values. CrCP decreased significantly from 61.4[51.0-77.1]mmHg to 41.7[39.9-51.0]mmHg in the first 48h, after which it remained stable (P<0.001). CrCP was significantly higher in survivors compared to non-survivors (P=0.002). CrCP immediately after cardiac arrest was significantly higher compared to the control group (P=0.02). CONCLUSIONS: CrCP is high after cardiac arrest with high cerebrovascular resistance and low MFV. This suggests that cerebral perfusion pressure should be maintained at a sufficient high level to avoid secondary brain injury. Failure to normalize the cerebrovascular profile may be a parameter of poor outcome. TI - Middle cerebral artery flow, the critical closing pressure, and the optimal mean arterial pressure in comatose cardiac arrest survivors-An observational study EP - 89 SN - 0300-9572 SP - 85 JF - Resuscitation VL - vol. 110 DO - https://doi.org/10.1016/j.resuscitation.2016.10.022 ER - TY - JOUR AU - Oppersma, Eline AU - Hatam, Nima AU - Doorduin, J. AU - Hoeven, J.G. van der AU - Marx, Gernot AU - Goetzenich, Andreas AU - Heunks, L.M.A. AU - Bruells, Christian S. PY - 2017 UR - https://hdl.handle.net/2066/180432 TI - Functional assessment of the diaphragm by speckle tracking ultrasound during inspiratory loading EP - 1070 SN - 8750-7587 IS - iss. 5 SP - 1063 JF - Journal of Applied Physiology VL - vol. 123 DO - https://doi.org/10.1152/japplphysiol.00095.2017 ER - TY - JOUR AU - Gelderen, S.C. van AU - Zegers, M. AU - Boeijen, W.M.J. AU - Westert, G.P. AU - Robben, P.B. AU - Wollersheim, H.C.H. PY - 2017 UR - https://hdl.handle.net/2066/177345 AB - OBJECTIVES: Hospital boards are legally responsible for safe healthcare. They need tools to assist them in their task of governing patient safety. Almost every Dutch hospital performs internal audits, but the effectiveness of these audits for hospital governance has never been evaluated. The aim of this study is to evaluate the organisation of internal audits and their effectiveness for hospitals boards to govern patient safety. DESIGN AND SETTING: A mixed-methods study consisting of a questionnaire regarding the organisation of internal audits among all Dutch hospitals (n=89) and interviews with stakeholders regarding the audit process and experienced effectiveness of audits within six hospitals. RESULTS: Response rate of the questionnaire was 76% and 43 interviews were held. In every responding hospital, the internal audits followed the plan-do-check-act cycle. Every hospital used interviews, document analysis and site visits as input for the internal audit. Boards stated that effective aspects of internal audits were their multidisciplinary scope, their structured and in-depth approach, the usability to monitor improvement activities and to change hospital policy and the fact that results were used in meetings with staff and boards of supervisors. The qualitative methods (interviews and site visits) used in internal audits enable the identification of soft signals such as unsafe culture or communication and collaboration problems. Reported disadvantages were the low frequency of internal audits and the absence of soft signals in the actual audit reports. CONCLUSION: This study shows that internal audits are regarded as effective for patient safety governance, as they help boards to identify patient safety problems, proactively steer patient safety and inform boards of supervisors on the status of patient safety. The description of the Dutch internal audits makes these audits replicable to other healthcare organisations in different settings, enabling hospital boards to complement their systems to govern patient safety. TI - Evaluation of the organisation and effectiveness of internal audits to govern patient safety in hospitals: a mixed-methods study SN - 2044-6055 IS - iss. 7 SP - e015506 JF - BMJ Open VL - vol. 7 DO - https://doi.org/10.1136/bmjopen-2016-015506 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177345/177345.pdf?sequence=1 ER - TY - JOUR AU - Verlaat, C.W.M. AU - Visser, I.H. AU - Wubben, N. AU - Hazelzet, J.A. AU - Lemson, J. AU - Waardenburg, D. van AU - Heide, D. van der AU - Dam, N.A. van AU - Jansen, N.J. AU - Heerde, M. van AU - Starre, C. van der AU - Asperen, R. van AU - Kneyber, M. AU - Woensel, J.B. van AU - Boogaard, M.H.W.A. van den AU - Hoeven, J.G. van der PY - 2017 UR - https://hdl.handle.net/2066/177587 AB - OBJECTIVE: To determine differences between survivors and nonsurvivors and factors associated with mortality in pediatric intensive care patients with low risk of mortality. DESIGN: Retrospective cohort study. SETTING: Patients were selected from a national database including all admissions to the PICUs in The Netherlands between 2006 and 2012. PATIENTS: Patients less than 18 years old admitted to the PICU with a predicted mortality risk lower than 1% according to either the recalibrated Pediatric Risk of Mortality or the Pediatric Index of Mortality 2 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 16,874 low-risk admissions were included of which 86 patients (0.5%) died. Nonsurvivors had more unplanned admissions (74.4% vs 38.5%; p < 0.001), had more complex chronic conditions (76.7% vs 58.8%; p = 0.001), were more often mechanically ventilated (88.1% vs 34.9%; p < 0.001), and had a longer length of stay (median, 11 [interquartile range, 5-32] d vs median, 3 [interquartile range, 2-5] d; p < 0.001) when compared with survivors. Factors significantly associated with mortality were complex chronic conditions (odds ratio, 3.29; 95% CI, 1.97-5.50), unplanned admissions (odds ratio, 5.78; 95% CI, 3.40-9.81), and admissions in spring/summer (odds ratio, 1.67; 95% CI, 1.08-2.58). CONCLUSIONS: Nonsurvivors in the PICU with a low predicted mortality risk have recognizable risk factors including complex chronic condition and unplanned admissions. TI - Factors Associated With Mortality in Low-Risk Pediatric Critical Care Patients in The Netherlands EP - e161 SN - 1529-7535 IS - iss. 4 SP - e155 JF - Pediatric Critical Care Medicine VL - vol. 18 DO - https://doi.org/10.1097/PCC.0000000000001086 ER - TY - JOUR AU - Sakr, Y. AU - Birri, P.N.R. AU - Kotfis, K. AU - Nanchal, R. AU - Shah, B. AU - Kluge, S. AU - Schroeder, M.E. AU - Marshall, J.C. AU - Vincent, J.L. AU - Pickkers, P. AU - Bray, B. AU - Brealey, D. PY - 2017 UR - https://hdl.handle.net/2066/177598 AB - OBJECTIVES: Excessive fluid therapy in patients with sepsis may be associated with risks that outweigh any benefit. We investigated the possible influence of early fluid balance on outcome in a large international database of ICU patients with sepsis. DESIGN: Observational cohort study. SETTING: Seven hundred and thirty ICUs in 84 countries. PATIENTS: All adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance. For this analysis, we included only the 1,808 patients with an admission diagnosis of sepsis. Patients were stratified according to quartiles of cumulative fluid balance 24 hours and 3 days after ICU admission. MEASUREMENTS AND MAIN RESULTS: ICU and hospital mortality rates were 27.6% and 37.3%, respectively. The cumulative fluid balance increased from 1,217 mL (-90 to 2,783 mL) in the first 24 hours after ICU admission to 1,794 mL (-951 to 5,108 mL) on day 3 and decreased thereafter. The cumulative fluid intake was similar in survivors and nonsurvivors, but fluid balance was less positive in survivors because of higher fluid output in these patients. Fluid balances became negative after the third ICU day in survivors but remained positive in nonsurvivors. After adjustment for possible confounders in multivariable analysis, the 24-hour cumulative fluid balance was not associated with an increased hazard of 28-day in-hospital death. However, there was a stepwise increase in the hazard of death with higher quartiles of 3-day cumulative fluid balance in the whole population and after stratification according to the presence of septic shock. CONCLUSIONS: In this large cohort of patients with sepsis, higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death. TI - Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit EP - 394 SN - 0090-3493 IS - iss. 3 SP - 386 JF - Critical Care Medicine VL - vol. 45 DO - https://doi.org/10.1097/CCM.0000000000002189 ER - TY - JOUR AU - Tak, T. AU - Wijten, P. AU - Heeres, M. AU - Pickkers, P. AU - Scholten, A. AU - Heck, A.J.R. van AU - Vrisekoop, N. AU - Leenen, L.P. AU - Borghans, J.A.M. AU - Tesselaar, K. AU - Koenderman, L. PY - 2017 UR - https://hdl.handle.net/2066/177600 AB - During acute inflammation, 3 neutrophil subsets are found in the blood: neutrophils with a conventional segmented nucleus, neutrophils with a banded nucleus, and T-cell-suppressing CD62Ldim neutrophils with a high number of nuclear lobes. In this study, we compared the in vivo kinetics and proteomes of banded, mature, and hypersegmented neutrophils to determine whether these cell types represent truly different neutrophil subsets or reflect changes induced by lipopolysaccharide (LPS) activation. Using in vivo pulse-chase labeling of neutrophil DNA with 6,6-2H2-glucose, we found that 2H-labeled banded neutrophils appeared much earlier in blood than labeled CD62Ldim and segmented neutrophils, which shared similar label kinetics. Comparison of the proteomes by cluster analysis revealed that CD62Ldim neutrophils were clearly separate from conventional segmented neutrophils despite having similar kinetics in peripheral blood. Interestingly, the conventional segmented cells were more related at a proteome level to banded cells despite a 2-day difference in maturation time. The differences between CD62Ldim and mature neutrophils are unlikely to have been a direct result of LPS-induced activation, because of the extremely low transcriptional capacity of CD62Ldim neutrophils and the fact that neutrophils do not directly respond to the low dose of LPS used in the study (2 ng/kg body weight). Therefore, we propose CD62Ldim neutrophils are a truly separate neutrophil subset that is recruited to the bloodstream in response to acute inflammation. This trial was registered at www.clinicaltrials.gov as #NCT01766414. TI - Human CD62Ldim neutrophils identified as a separate subset by proteome profiling and in vivo pulse-chase labeling EP - 3485 SN - 0006-4971 IS - iss. 26 SP - 3476 JF - Blood VL - vol. 129 DO - https://doi.org/10.1182/blood-2016-07-727669 ER - TY - JOUR AU - Kiers, D. AU - Heijden, W.A. van der AU - Ede, L. van AU - Gerretsen, J. AU - Mast, Q. de AU - Ven, A.J.A.M. van der AU - Messaoudi, S. El AU - Rongen, G.A.P.J.M. AU - Gomes, M.E.R. AU - Kox, M. AU - Pickkers, P. AU - Riksen, N.P. PY - 2017 UR - https://hdl.handle.net/2066/177777 AB - The use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y12 inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y12 antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFalpha by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y12 inhibition impaired platelet reactivity, there was no correlation with cytokine responses. TI - A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia EP - 1807 SN - 0340-6245 IS - iss. 9 SP - 1798 JF - Thrombosis and Haemostasis VL - vol. 117 DO - https://doi.org/10.1160/TH16-10-0799 ER - TY - JOUR AU - Netea, M.G. AU - Balkwill, F. AU - Chonchol, M. AU - Cominelli, F. AU - Donath, M.Y. AU - Giamarellos-Bourboulis, E.J. AU - Golenbock, D. AU - Gresnigt, M.S. AU - Heneka, M.T. AU - Hoffman, H.M. AU - Hotchkiss, R. AU - Joosten, L.A.B. AU - Kastner, D.L. AU - Korte, M. AU - Latz, E. AU - Libby, P. AU - Mandrup-Poulsen, T. AU - Mantovani, A. AU - Mills, K.H. AU - Nowak, K.L. AU - O'Neill, L.A. AU - Pickkers, P. AU - Poll, T. van der AU - Ridker, P.M. AU - Schalkwijk, J. AU - Schwartz, D.A. AU - Siegmund, B. AU - Steer, C.J. AU - Tilg, H. AU - Meer, J.W.M. van der AU - Veerdonk, F.L. van de AU - Dinarello, C.A. PY - 2017 UR - https://hdl.handle.net/2066/177132 AB - Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues. TI - A guiding map for inflammation EP - 831 SN - 1529-2908 IS - iss. 8 SP - 826 JF - Nature Immunology VL - vol. 18 DO - https://doi.org/10.1038/ni.3790 ER - TY - JOUR AU - Ahout, I.M.L. AU - Brand, K.H. AU - Zomer, A.L. AU - Hurk, W.H. van den AU - Schilders, G. AU - Brouwer, M.L. AU - Neeleman, C. AU - Groot, R. de AU - Ferwerda, G. PY - 2017 UR - https://hdl.handle.net/2066/177243 AB - INTRODUCTION: Respiratory viruses causing lower respiratory tract infections (LRTIs) are a major cause of hospital admissions in children. Since the course of these infections is unpredictable with potential fast deterioration into respiratory failure, infants are easily admitted to the hospital for observation. The aim of this study was to examine whether systemic inflammatory markers can be used to predict severity of disease in children with respiratory viral infections. METHODS: Blood and nasopharyngeal washings from children <3 years of age with viral LRTI attending a hospital were collected within 24 hours (acute) and after 4-6 weeks (recovery). Patients were assigned to a mild (observation only), moderate (supplemental oxygen and/or nasogastric feeding) or severe (mechanical ventilation) group. Linear regression analysis was used to design a prediction rule using plasma levels of C reactive protein (CRP), serum amyloid A (SAA), pentraxin 3 (PTX3), serum amyloid P component and properdin. This rule was tested in a validation cohort. RESULTS: One hundred and four children (52% male) were included. A combination of CRP, SAA, PTX3 and properdin was a better indicator of severe disease compared with any of the individual makers and age (69% sensitivity (95% CI 50 to 83), 90% specificity (95% CI 80 to 96)). Validation in 141 patients resulted in 71% sensitivity (95% CI 53 to 85), 87% specificity (95% CI 79 to 92), negative predictive value of 64% (95% CI 47 to 78) and positive predictive value of 90% (95% CI 82 to 95). The prediction rule was not able to identify patients with a mild course of disease. CONCLUSION: A combination of CRP, SAA, PTX3 and properdin was able to identify children with a severe course of viral LRTI disease, even in children under 2 months of age. To assess the true impact on clinical management, these results should be validated in a prospective randomised control study. TI - Prospective observational study in two Dutch hospitals to assess the performance of inflammatory plasma markers to determine disease severity of viral respiratory tract infections in children SN - 2044-6055 IS - iss. 6 SP - e014596 JF - BMJ Open VL - vol. 7 DO - https://doi.org/10.1136/bmjopen-2016-014596 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177243/177243.pdf?sequence=1 ER - TY - JOUR AU - Douw, G. AU - Huisman-de Waal, G.J. AU - Zanten, A.R. van AU - Hoeven, J.G. van der AU - Schoonhoven, L. PY - 2017 UR - https://hdl.handle.net/2066/177311 AB - AIMS AND OBJECTIVES: To determine the predictive value of individual and combined dutch-early-nurse-worry-indicator-score indicators at various Early Warning Score levels, differentiating between Early Warning Scores reaching the trigger threshold to call a rapid response team and Early Warning Score levels not reaching this point. BACKGROUND: Dutch-early-nurse-worry-indicator-score comprises nine indicators underlying nurses' 'worry' about a patient's condition. All indicators independently show significant association with unplanned intensive care/high dependency unit admission or unexpected mortality. Prediction of this outcome improved by adding the dutch-early-nurse-worry-indicator-score indicators to an Early Warning Score based on vital signs. DESIGN: An observational cohort study was conducted on three surgical wards in a tertiary university-affiliated teaching hospital. METHODS: Included were surgical, native-speaking, adult patients. Nurses scored presence of 'worry' and/or dutch-early-nurse-worry-indicator-score indicators every shift or when worried. Vital signs were measured according to the prevailing protocol. Unplanned intensive care/high dependency unit admission or unexpected mortality was the composite endpoint. Percentages of 'worry' and dutch-early-nurse-worry-indicator-score indicators were calculated at various Early Warning Score levels in control and event groups. Entering all dutch-early-nurse-worry-indicator-score indicators in a multiple logistic regression analysis, we calculated a weighted score and calculated sensitivity, specificity, positive predicted value and negative predicted value for each possible total score. RESULTS: In 3522 patients, 102 (2.9%) had an unplanned intensive care/high dependency unit admissions (n = 97) or unexpected mortality (n = 5). Patients with such events and only slightly changed vital signs had significantly higher percentages of 'worry' and dutch-early-nurse-worry-indicator-score indicators expressed than patients in the control group. Increasing number of dutch-early-nurse-worry-indicator-score indicators showed higher positive predictive values. CONCLUSIONS: Dutch-early-nurse-worry-indicator-score indicators alert in an early stage of deterioration, before reaching the trigger threshold to call a rapid response team and can improve interdisciplinary communication on surgical wards during regular rounds, and when calling for assistance. RELEVANCE TO CLINICAL PRACTICE: Dutch-early-nurse-worry-indicator-score structures communication and recording of signs known to be associated with a decline in a patient's condition and can empower nurses to call assistance on the 'worry' criterion in an early stage of deterioration. TI - Capturing early signs of deterioration: the dutch-early-nurse-worry-indicator-score and its value in the Rapid Response System EP - 2613 SN - 0962-1067 IS - iss. 17-18 SP - 2605 JF - Journal of Clinical Nursing VL - vol. 26 DO - https://doi.org/10.1111/jocn.13648 ER - TY - JOUR AU - Lin, J.C. AU - Spinella, P.C. AU - Fitzgerald, J.C. AU - Tucci, M. AU - Bush, J.L. AU - Nadkarni, V.M. AU - Thomas, N.J. AU - Weiss, S.L. AU - Lemson, J. AU - Sherring, C. AU - Bushell, T. PY - 2017 UR - https://hdl.handle.net/2066/177441 AB - OBJECTIVES: To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. DESIGN: Secondary analysis of a prospective, cross-sectional, point prevalence study. SETTING: International, multicenter PICUs. PATIENTS: Pediatric patients with severe sepsis identified on five separate days over a 1-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001). CONCLUSIONS: Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts are needed to validate whether reducing new or progressive multiple organ dysfunction syndrome leads to improvements in more definitive morbidity and mortality endpoints. TI - New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality EP - 16 SN - 1529-7535 IS - iss. 1 SP - 8 JF - Pediatric Critical Care Medicine VL - vol. 18 DO - https://doi.org/10.1097/PCC.0000000000000978 ER - TY - JOUR AU - Jonkman, A.H. AU - Jansen, D. AU - Heunks, L.M. PY - 2017 UR - https://hdl.handle.net/2066/177443 AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 . TI - Novel insights in ICU-acquired respiratory muscle dysfunction: implications for clinical care SN - 1466-609X IS - iss. 1 SP - 64 JF - Critical Care VL - vol. 21 DO - https://doi.org/10.1186/s13054-017-1642-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177443/177443.pdf?sequence=1 ER - TY - JOUR AU - Numan, T. AU - Boogaard, M.H.W.A. van den AU - Kamper, A.M. AU - Rood, P.J.T. AU - Peelen, L.M. AU - Slooter, A.J. PY - 2017 UR - https://hdl.handle.net/2066/177457 AB - OBJECTIVES: To evaluate to what extent delirium experts agree on the diagnosis of delirium when independently assessing exactly the same information and to evaluate the sensitivity of delirium screening tools in routine daily practice of clinical nurses. DESIGN: Prospective observational longitudinal study. SETTING: Three medical centers in the Netherlands. PARTICIPANTS: Elderly postoperative adults (n = 167). MEASUREMENTS: A researcher examined participants daily (Postoperative Day 1-3) for delirium using a standardized cognitive assessment and interview including the Delirium Rating Scale Revised-98 as global impression without any cut-off values that was recorded on video. Two delirium experts independently evaluated the videos and clinical information from the last 24 hours in the participants' record and classified each assessment as delirious, possibly delirious, or not delirious. Interrater agreement between the delirium experts was determined using weighted Cohen's kappa. When there was no consensus, a third expert was consulted. Final classification was based on median score and compared with the results of the Confusion Assessment Method for Intensive Care Unit and Delirium Observation Scale that clinical nurses administered. RESULTS: Four hundred twenty-four postoperative assessments of 167 participants were included. The overall kappa was 0.61 (95% confidence interval = 0.53-0.68). There was no agreement between the experts for 89 (21.0%) assessments and a third delirium expert was needed for the final classification. Delirium screening that nurses performed detected 32% of the assessments that the experts diagnosed as (possibly) delirious. CONCLUSION: There was considerable disagreement in classification of delirium by experts who independently assessed exactly the same information, showing the difficulty of delirium diagnosis. Furthermore, the sensitivity of daily delirium screening by clinical nurses was poor. Future research should focus on development of objective instruments to diagnose delirium. TI - Recognition of Delirium in Postoperative Elderly Patients: A Multicenter Study EP - 1938 SN - 0002-8614 IS - iss. 9 SP - 1932 JF - Journal of the American Geriatrics Society VL - vol. 65 DO - https://doi.org/10.1111/jgs.14933 ER - TY - JOUR AU - Peters van Ton, A.M. AU - Kox, M. AU - Pickkers, P. AU - Abdo, W.F. PY - 2017 UR - https://hdl.handle.net/2066/177458 TI - Reduced glial activity after surgery: A sign of immunoparalysis of the brain? SN - 0364-5134 IS - iss. 1 SP - 152 JF - Annals of Neurology VL - vol. 82 DO - https://doi.org/10.1002/ana.24966 ER - TY - JOUR AU - Matic, M. AU - Bosch, G.E. van den AU - Wildt, S.N. de AU - Tibboel, D. AU - Schaik, R.H. van PY - 2017 UR - https://hdl.handle.net/2066/177463 TI - Reply - Pain versus analgesia: TAOK3 as a pharmacogene EP - 1623 SN - 0304-3959 IS - iss. 8 SP - 1623 JF - Pain VL - vol. 158 DO - https://doi.org/10.1097/j.pain.0000000000000945 ER - TY - JOUR AU - Schellekens, W.J.M. AU - Jansen, D. AU - Dorresteijn, M.J. AU - Heunks, L.M. PY - 2017 UR - https://hdl.handle.net/2066/177464 TI - Respiratory Muscles and Ventilator-induced Lung Injury Critical Care EP - 260 SN - 1073-449X IS - iss. 2 SP - 258 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 195 DO - https://doi.org/10.1164/rccm.201608-1627RR ER - TY - JOUR AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/177469 TI - Simultaneously Mounted Pro- and Anti-inflammatory Host Response Relates to the Development of Secondary Infections in Patients with Sepsis EP - 407 SN - 1073-449X IS - iss. 4 SP - 406 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 196 DO - https://doi.org/10.1164/rccm.201701-0253ED ER - TY - JOUR AU - Witjes, M. AU - Kotsopoulos, A. AU - Herold, I.H.F. AU - Otterspoor, L. AU - Simons, K.S. AU - Vliet, J. van AU - Blauw, M. de AU - Festen, B. AU - Eijkenboom, J.J. AU - Jansen, N.E. AU - Hoeven, J.G. van der AU - Abdo, W.F. PY - 2017 UR - https://hdl.handle.net/2066/177480 AB - Many patients with acute devastating brain injury die outside intensive care units and could go unrecognized as potential organ donors. We conducted a prospective observational study in seven hospitals in the Netherlands to define the number of unrecognized potential organ donors outside intensive care units, and to identify the effect that end-of-life care has on organ donor potential. Records of all patients who died between January 2013 and March 2014 were reviewed. Patients were included if they died within 72 h after hospital admission outside the intensive care unit due to devastating brain injury, and fulfilled the criteria for organ donation. Physicians of included patients were interviewed using a standardized questionnaire regarding logistics and medical decisions related to end-of-life care. Of the 5170 patients screened, we found 72 additional potential organ donors outside intensive care units. Initiation of end-of-life care in acute settings and lack of knowledge and experience in organ donation practices outside intensive care units can result in under-recognition of potential donors equivalent to 11-34% of the total pool of organ donors. Collaboration with the intensive care unit and adjusting the end-of-life path in these patients is required to increase the likelihood of organ donation. TI - The Influence of End-of-Life Care on Organ Donor Potential EP - 1927 SN - 1600-6135 IS - iss. 7 SP - 1922 JF - American Journal of Transplantation VL - vol. 17 DO - https://doi.org/10.1111/ajt.14286 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177480/177480.pdf?sequence=1 ER - TY - JOUR AU - Yipp, B.G. AU - Kim, J.H. AU - Lima, R. AU - Zbytnuik, L.D. AU - Petri, B. AU - Swanlund, N. AU - Ho, M. AU - Szeto, V.G. AU - Tak, T. AU - Koenderman, L. AU - Pickkers, P. AU - Tool, A.T. AU - Kuijpers, T.W. AU - Berg, T.K. van den AU - Looney, M.R. AU - Krummel, M.F. AU - Kubes, P. PY - 2017 UR - https://hdl.handle.net/2066/177482 AB - Bloodstream infection is a hallmark of sepsis, a medically emergent condition requiring rapid treatment. However, upregulation of host defense proteins through toll-like receptors and NFkappaB requires hours after endotoxin detection. Using confocal pulmonary intravital microscopy, we identified that the lung provides a TLR4-Myd88-and abl tyrosine kinase-dependent niche for immediate CD11b-dependent neutrophil responses to endotoxin and Gram-negative bloodstream pathogens. In an in vivo model of bacteremia, neutrophils crawled to and rapidly phagocytosed Escherichia coli sequestered to the lung endothelium. Therefore, the lung capillaries provide a vascular defensive niche whereby endothelium and neutrophils cooperate for immediate detection and capture of disseminating pathogens. TI - The Lung is a Host Defense Niche for Immediate Neutrophil-Mediated Vascular Protection SN - 2470-9468 IS - iss. 10 JF - Science Immunology VL - vol. 2 DO - https://doi.org/10.1126/sciimmunol.aam8929 ER - TY - JOUR AU - Fikkers, B.G. AU - Delwig, H. PY - 2017 UR - https://hdl.handle.net/2066/177500 AB - Tracheotomy is one of the oldest interventions in medical sciences. It is a procedure that is frequently used in patients who have been admitted to the intensive care unit. Over the last twenty years, the use of the dilation technique has increased in frequency. We believe that the timing of a tracheostoma placement should be evaluated individually for every patient and should always be weighed against the potential risks of an operative intervention. This is illustrated with case reports of four patients with respiratory problems; in the case of one of these patients, the decision was made not to perform tracheotomy, which nonetheless resulted in a favourable clinical outcome. TI - [Tracheotomy in the intensive care unit is a tailor-made decision] SN - 0028-2162 IS - iss. 0 SP - D1248 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 161 ER - TY - JOUR AU - Steen, M. van der AU - Dieperink, P. AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/177501 AB - The first official definition of sepsis was published in 1992. Last year, in 2016, the third version was published. In this article we discuss the various definitions, the evolving insights into pathophysiology and several of the treatments that have been implemented over the last 25 years. TI - [Treatment of sepsis in perspective: what have 25 years of sepsis definition brought us?] SN - 0028-2162 IS - iss. 0 SP - D1841 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 161 ER - TY - JOUR AU - Osinski, A. AU - Vreugdenhil, G. AU - Koning, J. de AU - Hoeven, J.G. van der PY - 2017 UR - https://hdl.handle.net/2066/177573 AB - Discussing do-not-resuscitate (DNR) orders is part of daily hospital practice in oncology departments. Several medical factors and patient characteristics are associated with issuing DNR orders in cancer patients. DNR orders are often placed late in the disease process. This may be a cause for disagreements between doctors and between doctors and patients and may cause for unnecessary treatments and admissions. In addition, DNR orders on itself may influence the rest of the medical treatment for patients. We present recommendations for discussing DNR orders and medical futility in practice through shared decision-making. Prospective studies are needed to investigate in which a patient's cardiopulmonary resuscitation (CPR) is futile and whether or not DNR orders influence the medical care of patients. TI - Do-not-resuscitate orders in cancer patients: a review of literature EP - 685 SN - 0941-4355 IS - iss. 2 SP - 677 JF - Supportive Care in Cancer VL - vol. 25 DO - https://doi.org/10.1007/s00520-016-3459-9 ER - TY - JOUR AU - Schouten, J.A. AU - Berrevoets, M.A.H. AU - Hulscher, M.E.J.L. PY - 2017 UR - https://hdl.handle.net/2066/174292 TI - Quality Indicators to Measure Appropriate Antibiotic Use: Some Thoughts on the Black Box EP - 1295 SN - 1058-4838 IS - iss. 9 SP - 1295 JF - Clinical Infectious Diseases VL - vol. 64 DO - https://doi.org/10.1093/cid/cix172 ER - TY - JOUR AU - Luijten, J. AU - Voet, M AU - Gier, R.P.E. de AU - Nusmeier, A. AU - Scharbatke, H.E. AU - Vliet, J.A. van der AU - Cornelissen, E.A.M. PY - 2017 UR - https://hdl.handle.net/2066/174076 TI - Transplantation of adult living donor kidneys in small children, a single-centre initial experience EP - 642 SN - 0934-0874 IS - iss. 6 SP - 640 JF - Transplant International VL - vol. 30 DO - https://doi.org/10.1111/tri.12947 ER - TY - JOUR AU - Witteveen, E. AU - Sommers, J. AU - Wieske, L. AU - Doorduin, J. AU - Alfen, N. van AU - Schultz, M.J. AU - Schaik, I.N. van AU - Horn, J. AU - Verhamme, C. PY - 2017 UR - https://hdl.handle.net/2066/175961 AB - BACKGROUND: Neuromuscular ultrasound is a noninvasive investigation, which can be easily performed at the bedside on the ICU. A reduction in muscle thickness and increase in echo intensity over time have been described in ICU patients, but the relation to ICU-acquired weakness (ICU-AW) is unknown. We hypothesized that quantitative assessment of muscle and nerve parameters with ultrasound can differentiate between patients with and without ICU-AW. The aim of this cross-sectional study was to investigate the diagnostic accuracy of neuromuscular ultrasound for diagnosing ICU-AW. METHODS: Newly admitted ICU patients, mechanically ventilated for at least 48 h, were included. As soon as patients were awake and attentive, an ultrasound was made of four muscles and two nerves (index test) and ICU-AW was evaluated using muscle strength testing (reference standard; ICU-AW defined as mean Medical Research Council score <4). Diagnostic accuracy of muscle thickness, echo intensity and homogeneity (echo intensity standard deviation) as well as nerve cross-sectional area, thickness and vascularization were evaluated with the area under the curve of the receiver operating characteristic curve (ROC-AUC). We also evaluated diagnostic accuracy of z-scores of muscle thickness, echo intensity and echo intensity standard deviation. RESULTS: Seventy-one patients were evaluated of whom 41 had ICU-AW. Ultrasound was done at a median of 7 days after admission in patients without ICU-AW and 9 days in patients with ICU-AW. Diagnostic accuracy of all muscle and nerve parameters was low. ROC-AUC ranged from 51.3 to 68.0% for muscle parameters and from 51.0 to 66.7% for nerve parameters. CONCLUSION: Neuromuscular ultrasound does not discriminate between patients with and without ICU-AW at the time the patient awakens and is therefore not able to reliably diagnose ICU-AW in ICU patients relatively early in the disease course. TI - Diagnostic accuracy of quantitative neuromuscular ultrasound for the diagnosis of intensive care unit-acquired weakness: a cross-sectional observational study SN - 2110-5820 IS - iss. 1 SP - 40 JF - Annals of Intensive Care VL - vol. 7 DO - https://doi.org/10.1186/s13613-017-0263-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/175961/175961.pdf?sequence=1 ER - TY - JOUR AU - Doorduin, J. AU - Nollet, J.L. AU - Roesthuis, L.H. AU - Hees, H.W.H. van AU - Brochard, L.J. AU - Sinderby, C.A. AU - Hoeven, J.G. van der AU - Heunks, L.M.A. PY - 2017 UR - https://hdl.handle.net/2066/176006 AB - RATIONALE: Controlled mechanical ventilation is used to deliver lung-protective ventilation in patients with acute respiratory distress syndrome. Despite recognized benefits, such as preserved diaphragm activity, partial support ventilation modes may be incompatible with lung-protective ventilation due to high Vt and high transpulmonary pressure. As an alternative to high-dose sedatives and controlled mechanical ventilation, pharmacologically induced neuromechanical uncoupling of the diaphragm should facilitate lung-protective ventilation under partial support modes. OBJECTIVES: To investigate whether partial neuromuscular blockade can facilitate lung-protective ventilation while maintaining diaphragm activity under partial ventilatory support. METHODS: In a proof-of-concept study, we enrolled 10 patients with lung injury and a Vt greater than 8 ml/kg under pressure support ventilation (PSV) and under sedation. After baseline measurements, rocuronium administration was titrated to a target Vt of 6 ml/kg during neurally adjusted ventilatory assist (NAVA). Thereafter, patients were ventilated in PSV and NAVA under continuous rocuronium infusion for 2 hours. Respiratory parameters, hemodynamic parameters, and blood gas values were measured. MEASUREMENTS AND MAIN RESULTS: Rocuronium titration resulted in significant declines of Vt (mean +/- SEM, 9.3 +/- 0.6 to 5.6 +/- 0.2 ml/kg; P < 0.0001), transpulmonary pressure (26.7 +/- 2.5 to 10.7 +/- 1.2 cm H2O; P < 0.0001), and diaphragm electrical activity (17.4 +/- 2.3 to 4.5 +/- 0.7 muV; P < 0.0001), and could be maintained under continuous rocuronium infusion. During titration, pH decreased (7.42 +/- 0.02 to 7.35 +/- 0.02; P < 0.0001), and mean arterial blood pressure increased (84 +/- 6 to 99 +/- 6 mm Hg; P = 0.0004), as did heart rate (83 +/- 7 to 93 +/- 8 beats/min; P = 0.0004). CONCLUSIONS: Partial neuromuscular blockade facilitates lung-protective ventilation during partial ventilatory support, while maintaining diaphragm activity, in sedated patients with lung injury. TI - Partial Neuromuscular Blockade during Partial Ventilatory Support in Sedated Patients with High Tidal Volumes EP - 1042 SN - 1073-449X IS - iss. 8 SP - 1033 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 195 DO - https://doi.org/10.1164/rccm.201605-1016OC ER - TY - JOUR AU - Kiers, D. AU - Koch, R.M. AU - Hamers, L. AU - Gerretsen, J. AU - Thijs, E.J. AU - Ede, L. van AU - Riksen, N.P. AU - Kox, M. AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/169916 AB - Investigating the systemic inflammatory response in patients with critical illness such as sepsis, trauma and burns is complicated due to uncertainties about the onset, duration and severity of the insult. Therefore, in vivo models of inflammation are essential to study the pathophysiology and to evaluate immunomodulatory therapies. Intravenous bolus administration of endotoxin to healthy volunteers is a well-established model of a short-lived systemic inflammatory response, characterized by increased plasma cytokine levels, flu-like symptoms and fever. In contrast, patients suffering from systemic inflammation are often exposed to inflammatory stimuli for an extended period of time. Therefore, continuous infusion of endotoxin may better reflect the kinetics of the inflammatory response encountered in these patients. Herein, we characterize a novel model of systemic inflammation elicited by a bolus infusion of 1 ng/kg, followed by a 3hr continuous infusion of 1 ng/kg/h of endotoxin in healthy volunteers, and compared it with models of bolus administrations of 1 and 2 ng/kg of endotoxin. The novel model was well-tolerated and resulted in a more pronounced increase in plasma cytokine levels with different kinetics and more prolonged symptoms and fever compared with the bolus-only models. Therefore, the continuous endotoxin infusion model provides novel insights into kinetics of the inflammatory response during continuous inflammatory stimuli and accommodates a larger time window to evaluate immunomodulating therapies. TI - Characterization of a model of systemic inflammation in humans in vivo elicited by continuous infusion of endotoxin SN - 2045-2322 JF - Scientific Reports VL - vol. 7 DO - https://doi.org/10.1038/srep40149 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169916/169916.pdf?sequence=1 ER - TY - JOUR AU - Hanskamp-Sebregts, M. AU - Zegers, M. AU - Gurp, P.J.M. van AU - Vet, H.C. de AU - Wollersheim, H.C. PY - 2017 UR - https://hdl.handle.net/2066/170046 AB - OBJECTIVES: Record review is the most used method to quantify patient safety. We systematically reviewed the reliability and validity of adverse event detection with record review. DESIGN: A systematic review of the literature. METHODS: We searched PubMed, EMBASE, CINAHL, PsycINFO and the Cochrane Library and from their inception through February 2015. We included all studies that aimed to describe the reliability and/or validity of record review. Two reviewers conducted data extraction. We pooled kappa values (kappa) and analysed the differences in subgroups according to number of reviewers, reviewer experience and training level, adjusted for the prevalence of adverse events. RESULTS: In 25 studies, the psychometric data of the Global Trigger Tool (GTT) and the Harvard Medical Practice Study (HMPS) were reported and 24 studies were included for statistical pooling. The inter-raterreliability of the GTT and HMPS showed a pooled kappa of 0.65 and 0.55, respectively. The inter-rater agreement was statistically significantly higher when the group of reviewers within a study consisted of a maximum five reviewers. We found no studies reporting on the validity of the GTT and HMPS. CONCLUSIONS: The reliability of record review is moderate to substantial and improved when a small group of reviewers carried out record review. The validity of the record review method has never been evaluated, while clinical data registries, autopsy or direct observations of patient care are methods that can be used to test concurrent validity. TI - [Measurement of patient safety: a systematic review of the reliability and validity of adverse event detection with record review] SN - 0028-2162 IS - iss. 0 SP - D1167 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 161 ER - TY - THES AU - Peters, E. PY - 2017 SN - 9789492380333 UR - https://hdl.handle.net/2066/169251 PB - [S.l.] : s.l. ; s.n. TI - Alkaline phosphatase to treat septic acute kidney injury N1 - Radboud University, 19 mei 2017 N1 - Promotores : Pickkers, P., Masereeuw (UU), R. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169251/169251.pdf?sequence=1 ER - TY - JOUR AU - Paardekooper, L.M. AU - Bogaart, G. van den AU - Kox, M. AU - Dingjan, I. AU - Neerincx, A.H. AU - Bendix, M.B. AU - Beest, M.T. AU - Harren, F.J.M AU - Risby, T. AU - Pickkers, P. AU - Marczin, N. AU - Cristescu, S.M. PY - 2017 UR - https://hdl.handle.net/2066/177581 AB - Ethylene is a major plant hormone mediating developmental processes and stress responses to stimuli such as infection. We show here that ethylene is also produced during systemic inflammation in humans and is released in exhaled breath. Traces of ethylene were detected by laser spectroscopy both in vitro in isolated blood leukocytes exposed to bacterial lipopolysaccharide (LPS) as well as in vivo following LPS administration in healthy volunteers. Exposure to LPS triggers formation of ethylene as a product of lipid peroxidation induced by the respiratory burst. In humans, ethylene was detected prior to the increase of blood levels of inflammatory cytokines and stress-related hormones. Our results highlight that ethylene release is an early and integral component of in vivo lipid peroxidation with important clinical implications as a breath biomarker of bacterial infection. TI - Ethylene, an early marker of systemic inflammation in humans SN - 2045-2322 JF - Scientific Reports VL - vol. 7 DO - https://doi.org/10.1038/s41598-017-05930-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177581/177581.pdf?sequence=1 ER - TY - JOUR AU - Bellomo, R. AU - Ronco, C. AU - Mehta, R.L. AU - Asfar, P. AU - Boisrame-Helms, J. AU - Darmon, M. AU - Diehl, J.L. AU - Duranteau, J. AU - Hoste, E.A.J. AU - Olivier, J.B. AU - Legrand, M. AU - Lerolle, N. AU - Malbrain, M. AU - Martensson, J. AU - Oudemans-van Straaten, H.M. AU - Parienti, J.J. AU - Payen, D. AU - Perinel, S. AU - Peters, E. AU - Pickkers, P. AU - Rondeau, E. AU - Schetz, M. AU - Vinsonneau, C. AU - Wendon, J. AU - Zhang, L. AU - Laterre, P.F. PY - 2017 UR - https://hdl.handle.net/2066/174812 AB - The French Intensive Care Society organized its yearly Paris International Conference in intensive care on June 18-19, 2015. The main purpose of this meeting is to gather the best experts in the field in order to provide the highest quality update on a chosen topic. In 2015, the selected theme was: "Acute Renal Failure in the ICU: from injury to recovery." The conference program covered multiple aspects of renal failure, including epidemiology, diagnosis, treatment and kidney support system, prognosis and recovery together with acute renal failure in specific settings. The present report provides a summary of every presentation including the key message and references and is structured in eight sections: (a) diagnosis and evaluation, (b) old and new diagnosis tools TI - Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference SN - 2110-5820 IS - iss. 1 SP - 49 JF - Annals of Intensive Care VL - vol. 7 DO - https://doi.org/10.1186/s13613-017-0260-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/174812/174812.pdf?sequence=1 ER - TY - JOUR AU - Hopman, J. AU - Tostmann, A. AU - Wertheim, H.F.L. AU - Bos, M. AU - Kolwijck, E. AU - Akkermans, R.P. AU - Sturm, P.D.J. AU - Voss, A. AU - Pickkers, P. AU - Hoeven, H. van der PY - 2017 UR - https://hdl.handle.net/2066/174295 AB - BACKGROUND: Sinks in patient rooms are associated with hospital-acquired infections. The aim of this study was to evaluate the effect of removal of sinks from the Intensive Care Unit (ICU) patient rooms and the introduction of 'water-free' patient care on gram-negative bacilli colonization rates. METHODS: We conducted a 2-year pre/post quasi-experimental study that compared monthly gram-negative bacilli colonization rates pre- and post-intervention using segmented regression analysis of interrupted time series data. Five ICUs of a tertiary care medical center were included. Participants were all patients of 18 years and older admitted to our ICUs for at least 48 h who also received selective digestive tract decontamination during the twelve month pre-intervention or the twelve month post-intervention period. The effect of sink removal and the introduction of 'water-free' patient care on colonization rates with gram-negative bacilli was evaluated. The main outcome of this study was the monthly colonization rate with gram-negative bacilli (GNB). Yeast colonization rates were used as a 'negative control'. In addition, colonization rates were calculated for first positive culture results from cultures taken >/=3, >/=5, >/=7, >/=10 and >/=14 days after ICU-admission, rate ratios (RR) were calculated and differences tested with chi-squared tests. RESULTS: In the pre-intervention period, 1496 patients (9153 admission days) and in the post-intervention period 1444 patients (9044 admission days) were included. Segmented regression analysis showed that the intervention was followed by a statistically significant immediate reduction in GNB colonization in absence of a pre or post intervention trend in GNB colonization. The overall GNB colonization rate dropped from 26.3 to 21.6 GNB/1000 ICU admission days (colonization rate ratio 0.82; 95%CI 0.67-0.99; P = 0.02). The reduction in GNB colonization rate became more pronounced in patients with a longer ICU-Length of Stay (LOS): from a 1.22-fold reduction (>/=2 days), to a 1.6-fold (>/=5 days; P = 0.002), 2.5-fold (for >/=10 days; P < 0.001) to a 3.6-fold (>/=14 days; P < 0.001) reduction. CONCLUSIONS: Removal of sinks from patient rooms and introduction of a method of 'water-free' patient care is associated with a significant reduction of patient colonization with GNB, especially in patients with a longer ICU length of stay. TI - Reduced rate of intensive care unit acquired gram-negative bacilli after removal of sinks and introduction of 'water-free' patient care SN - 2047-2994 JF - Antimicrobial Resistance and Infection Control VL - vol. 6 DO - https://doi.org/10.1186/s13756-017-0213-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/174295/174295.pdf?sequence=1 ER - TY - JOUR AU - Mooij, M.G. AU - Duijn, E. van AU - Knibbe, C.A. AU - Allegaert, K. AU - Windhorst, A.D. AU - Rosmalen, J. van AU - Hendrikse, N.H. AU - Tibboel, D. AU - Vaes, W.H. AU - Wildt, S.N. de PY - 2017 UR - https://hdl.handle.net/2066/182183 AB - BACKGROUND: We previously showed the practical and ethical feasibility of using [(14)C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [(14)C]paracetamol (AAP). METHODS: Infants admitted to the intensive care unit received a single oral [(14)C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [(14)C]AAP pharmacokinetic parameters were estimated. [(14)C]AAP and metabolites were measured with accelerator mass spectrometry. The plasma area under the concentration-time curve from time zero to infinity and urinary recovery ratios were related to age as surrogate markers of metabolism. RESULTS: Fifty children [median age 6 months (range 3 days-6.9 years)] received a microdose (3.3 [2.0-3.5] ng/kg; 64 [41-71] Bq/kg). Plasma [(14)C]AAP apparent total clearance was 0.4 (0.1-2.6) L/h/kg, apparent volume of distribution was 1.7 (0.9-8.2) L/kg, and the half-life was 2.8 (1-7) h. With increasing age, plasma and urinary AAP-glu/AAP and AAP-glu/AAP-sul ratios significantly increased by four fold, while the AAP-sul/AAP ratio significantly decreased. CONCLUSION: Using [(14)C]labeled microdosing, the effect of age on orally administered AAP metabolism was successfully elucidated in both plasma and urine. With minimal burden and risk, microdosing is attractive to study developmental changes in drug disposition in children. TI - Successful Use of [(14)C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism EP - 1195 SN - 0312-5963 IS - iss. 10 SP - 1185 JF - Clinical Pharmacokinetics VL - vol. 56 DO - https://doi.org/10.1007/s40262-017-0508-6 ER - TY - JOUR AU - Bruggemann, R.J.M. AU - Middel-Baars, V. AU - Lange, D.W. de AU - Colbers, A. AU - Girbes, A.R. AU - Pickkers, P. AU - Swart, E.L. PY - 2017 UR - https://hdl.handle.net/2066/169781 AB - Echinocandins, such as anidulafungin, are the first-line treatment for candidemia or invasive candidiasis in critically ill patients. There are conflicting data on the pharmacokinetic properties of anidulafungin in intensive care unit (ICU) patients. Adult ICU patients (from 3 hospitals) receiving anidulafungin for suspected or proven fungal infections were included in the present study. Patients were considered evaluable if a pharmacokinetic curve for day 3 could be completed. Twenty-three of 36 patients (7 female and 16 male) were evaluable. The median (range) age and body weight were 66 (28 to 88) years and 76 (50 to 115) kg, respectively. Pharmacokinetic sampling on day 3 (n = 23) resulted in a median anidulafungin area under the concentration-time curve from 0 to 24 h (AUC0-24) of 72.1 (interquartile range [IQR], 61.3 to 94.0) mg . h . liter-1, a median daily trough concentration (C24) of 2.2 (IQR, 1.9 to 2.9) mg/liter, a median maximum concentration of drug in serum (Cmax) of 5.3 (IQR, 4.1 to 6.0) mg/liter, a median volume of distribution (V) of 46.0 (IQR, 32.2 to 60.2) liters, and a median clearance (CL) of 1.4 (IQR, 1.1 to 1.6) liters . h-1 Pharmacokinetic sampling on day 7 (n = 13) resulted in a median AUC0-24 of 82.7 (IQR, 73.0 to 129.5) mg . h . liter-1, a median minimum concentration of drug in serum (Cmin) of 2.8 (IQR, 2.2 to 4.2) mg/liter, a median Cmax of 5.9 (IQR, 4.6 to 8.0) mg/liter, a median V of 39.7 (IQR, 32.2 to 54.4) liters, and a median CL of 1.2 (IQR, 0.8 to 1.4) liters . h-1 The geometric mean ratio for the AUCday7/AUCday3 term was 1.13 (90% confidence interval [CI], 1.03 to 1.25). The exposure in the ICU patient population was in accordance with previous reports on anidulafungin pharmacokinetics in ICU patients but was lower than that for healthy volunteers or other patient populations. Larger cohorts of patients or pooled data analyses are necessary to retrieve relevant covariates. (This study has been registered at ClinicalTrials.gov under identifier NCT01438216.). TI - Pharmacokinetics of Anidulafungin in Critically Ill Intensive Care Unit Patients with Suspected or Proven Invasive Fungal Infections SN - 0066-4804 IS - iss. 2 JF - Antimicrobial Agents and Chemotherapy VL - vol. 61 DO - https://doi.org/10.1128/AAC.01894-16 ER - TY - JOUR AU - Berrevoets, M.A.H. AU - Pot, J. AU - Houterman, A.E. AU - Dofferhoff, A. AU - Nabuurs-Franssen, M.H. AU - Fleuren, H. AU - Kullberg, B.J. AU - Schouten, J.A. AU - Sprong, T. PY - 2017 UR - https://hdl.handle.net/2066/177437 AB - BACKGROUND: Timely switch from intravenous (iv) antibiotics to oral therapy is a key component of antimicrobial stewardship programs in order to improve patient safety, promote early discharge and reduce costs. We have introduced a time-efficient and easily implementable intervention that relies on a computerized trigger tool, which identifies patients who are candidates for an iv to oral antibiotic switch. METHODS: The intervention was introduced on all internal medicine wards in a teaching hospital. Patients were automatically identified by an electronic trigger tool when parenteral antibiotics were used for >48 h and clinical or pharmacological data did not preclude switch therapy. A weekly educational session was introduced to alert the physicians on the intervention wards. The intervention wards were compared with control wards, which included all other hospital wards. An interrupted time-series analysis was performed to compare the pre-intervention period with the post-intervention period using '% of i.v. prescriptions >72 h' and 'median duration of iv therapy per prescription' as outcomes. We performed a detailed prospective evaluation on a subset of 244 prescriptions to evaluate the efficacy and appropriateness of the intervention. RESULTS: The number of intravenous prescriptions longer than 72 h was reduced by 19% in the intervention group (n = 1519) (p < 0.01) and the median duration of iv antibiotics was reduced with 0.8 days (p = <0.05). Compared to the control group (n = 4366) the intervention was responsible for an additional decrease of 13% (p < 0.05) in prolonged prescriptions. The detailed prospective evaluation of a subgroup of patients showed that adherence to the electronic reminder was 72%. CONCLUSIONS: An electronic trigger tool combined with a weekly educational session was effective in reducing the duration of intravenous antimicrobial therapy. TI - An electronic trigger tool to optimise intravenous to oral antibiotic switch: a controlled, interrupted time series study SN - 2047-2994 SP - 81 JF - Antimicrobial Resistance and Infection Control VL - vol. 6 DO - https://doi.org/10.1186/s13756-017-0239-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177437/177437.pdf?sequence=1 ER - TY - JOUR AU - Peters, E. AU - Schirris, T.J. AU - Asbeck, A.H. van AU - Gerretsen, J. AU - Eymael, J. AU - Ashikov, A.M. AU - Adjobo-Hermans, M.J.W. AU - Russel, F.G. AU - Pickkers, P. AU - Masereeuw, R. PY - 2017 UR - https://hdl.handle.net/2066/169651 AB - Sepsis-associated acute kidney injury is a multifactorial syndrome in which inflammation and renal microcirculatory dysfunction play a profound role. Subsequently, renal tubule mitochondria reprioritize cellular functions to prevent further damage. Here, we investigated the putative protective effects of human recombinant alkaline phosphatase (recAP) during inhibition of mitochondrial respiration in conditionally immortalized human proximal tubule epithelial cells (ciPTEC). Full inhibition of mitochondrial oxygen consumption was obtained after 24h antimycin A treatment, which did not affect cell viability. While recAP did not affect the antimycin A-induced decreased oxygen consumption and increased hypoxia-inducible factor-1alpha or adrenomedullin gene expression levels, the antimycin A-induced increase of pro-inflammatory cytokines IL-6 and IL-8 was attenuated. Antimycin A tended to induce the release of detrimental purines ATP and ADP, which reached statistical significance when antimycin A was co-incubated with lipopolysaccharide, and were completely converted into cytoprotective adenosine by recAP. As the adenosine A2A receptor was up-regulated after antimycin A exposure, an adenosine A2A receptor knockout ciPTEC cell line was generated in which recAP still provided protection. Together, recAP did not affect oxygen consumption but attenuated the inflammatory response during impaired mitochondrial function, an effect suggested to be mediated by dephosphorylating ATP and ADP into adenosine. TI - Effects of a human recombinant alkaline phosphatase during impaired mitochondrial function in human renal proximal tubule epithelial cells EP - 157 SN - 0014-2999 SP - 149 JF - European Journal of Pharmacology VL - vol. 796 DO - https://doi.org/10.1016/j.ejphar.2016.12.034 ER - TY - JOUR AU - Turner, M.A. AU - Attar, S. AU - Wildt, S.N. de AU - Vassal, G. AU - Mangiarini, L. AU - Giaquinto, C. PY - 2017 UR - https://hdl.handle.net/2066/182173 AB - The evaluation of drugs that are used in children has been neglected historically but is now well established as an essential part of clinical drug development. The increase in pediatric activity among industry, and other sectors, has highlighted the importance of joint working. All participants in pediatric drug development need to be aware of the "big picture." An increasingly important part of this big picture in pediatrics, as in other populations, is the design and conduct of clinical trials in networks. This narrative review provides an overview of the roles of clinical research networks in pediatric drug development. Networks take many forms as specialty networks and geographic networks but work toward common principles, including sharing resources between trials, and using experience with trial conduct to improve trial design. Networks develop standardized processes for trial conduct (including performance management) that increase the speed and predictability of trial conduct while reducing burdens on sites, sponsors, and intermediaries. Networks can provide validated, real-world information about natural history, participant distribution, and standards of care to inform planning of development programs, including extrapolation and clinical trial simulation. Networks can work across geographic and jurisdictional barriers to promote global interoperability of drug development. Networks support participant centrality. Networks offer an opportunity to develop relationships with investigators, sites, and methodological experts that span pre-competitive foundations for drug development and specific products. Sustainable networks benefit all stakeholders by providing a multifunctional platform that promotes the quality and timeliness of clinical drug development. TI - Roles of Clinical Research Networks in Pediatric Drug Development EP - 1948 SN - 0149-2918 IS - iss. 10 SP - 1939 JF - Clinical Therapeutics VL - vol. 39 DO - https://doi.org/10.1016/j.clinthera.2017.09.001 ER - TY - THES AU - Doorduin, J. PY - 2017 SN - 9789082678420 UR - https://hdl.handle.net/2066/173271 PB - [S.l. : s.n.] TI - Diaphragm dysfunction in critically ill patients. From monitoring to interventions N1 - Radboud University, 22 juni 2017 N1 - Promotores : Hoeven, J.G. van der, Heunks, L.M.A. Co-promotor : Hees, H.W.H. van L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/173271/173271.pdf?sequence=1 ER - TY - JOUR AU - Wassenaar, A. AU - Rood, P.J.T. AU - Schoonhoven, L. AU - Teerenstra, S. AU - Zegers, M. AU - Pickkers, P. AU - Boogaard, M.H.W.A. van den PY - 2017 UR - https://hdl.handle.net/2066/169856 AB - BACKGROUND: Delirium is a common disorder in Intensive Care Unit (ICU) patients and is associated with serious short- and long-term consequences, including re-intubations, ICU readmissions, prolonged ICU and hospital stay, persistent cognitive problems, and higher mortality rates. Considering the high incidence of delirium and its consequences, prevention of delirium is imperative. This study focuses on a program of standardized nursing and physical therapy interventions to prevent delirium in the ICU, called UNDERPIN-ICU (nUrsiNg DEliRium Preventive INterventions in the ICU). OBJECTIVE: To determine the effect of the UNDERPIN-ICU program on the number of delirium-coma-free days in 28days and several secondary outcomes, such as delirium incidence, the number of days of survival in 28 and 90days and delirium-related outcomes. DESIGN AND SETTING: A multicenter stepped wedge cluster randomized controlled trial. METHODS: Eight to ten Dutch ICUs will implement the UNDERPIN-ICU program in a randomized order. Every two months the UNDERPIN-ICU program will be implemented in an additional ICU following a two months period of staff training. UNDERPIN-ICU consists of standardized protocols focusing on several modifiable risk factors for delirium, including cognitive impairment, sleep deprivation, immobility and visual and hearing impairment. PARTICIPANTS: ICU patients aged >/=18years (surgical, medical, or trauma) and at high risk for delirium, E-PRE-DELIRIC >/=35%, will be included, unless delirium was detected prior ICU admission, expected length of ICU stay is less then one day or when delirium assessment is not possible. DISCUSSION: For every intervention the balance between putative benefit and potential unwanted side effects needs to be considered. In non-ICU patients, it has been shown that a similar program resulted in a significant reduction of delirium incidence and duration. Recent small studies using multi component interventions to prevent delirium in ICU patients have also shown beneficial effect, without unwanted side effects. We therefore feel that the proportionality of potential positive effects of the UNDERPIN-ICU program, weighed against potential unwanted side effects is favourable. Since this has not been rigorously proven in ICU patients, we will study the effects of this program in ICU patients using a stepped wedge design. TRIAL REGISTRATION: The study is registered in the clinical trials registry: https://clinicaltrials.gov/. REPORTING METHOD: Standard Protocol Items: Recommendations for Interventional Trails (SPIRIT). TI - The impact of nUrsiNg DEliRium Preventive INnterventions in the Intensive Care Unit (UNDERPIN-ICU): A study protocol for a multi-centre, stepped wedge randomized controlled trial EP - 8 SN - 0020-7489 SP - 1 JF - International Journal of Nursing Studies VL - vol. 68 DO - https://doi.org/10.1016/j.ijnurstu.2016.11.018 ER - TY - JOUR AU - Pickkers, P. AU - Kox, M. PY - 2017 UR - https://hdl.handle.net/2066/177489 TI - Towards precision medicine for sepsis patients SN - 1466-609X IS - iss. 1 SP - 11 JF - Critical Care VL - vol. 21 DO - https://doi.org/10.1186/s13054-016-1583-z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177489/177489.pdf?sequence=1 ER - TY - JOUR AU - Pickkers, P. AU - Payen, D. PY - 2017 UR - https://hdl.handle.net/2066/182596 TI - What's new in the extracorporeal treatment of sepsis? EP - 1500 SN - 0342-4642 IS - iss. 10 SP - 1498 JF - Intensive Care Medicine VL - vol. 43 DO - https://doi.org/10.1007/s00134-017-4738-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182596/182596.pdf?sequence=1 ER - TY - JOUR AU - Kolk, M. van der AU - Boogaard, M.H.W.A. van den AU - Becking-Verhaar, F. AU - Custers, H. AU - Hoeven, H. van der AU - Pickkers, P. AU - Laarhoven, K. van PY - 2017 UR - https://hdl.handle.net/2066/181924 AB - INTRODUCTION: Medical and nursing protocols in perioperative care for pancreaticoduodenectomy are mainly mono-disciplinary, limiting their integration and transparency in a continuous health care system. The aims of this study were to evaluate adherence to a multidisciplinary clinical pathway for all pancreaticoduodenectomy patients during their entire hospital stay and to determine if the use of this clinical pathway is associated with beneficial effects on clinical end points. MATERIALS AND METHODS: A prospective cohort study was conducted in 95 pancreaticoduodenectomy patients treated according to a clinical pathway, including a variance report, compared to a historical control group (n = 52) with a traditional treatment regime. RESULTS: Process evaluation of the clinical pathway group revealed that protocol adherence throughout all units was above 80%. Major complications according to Clavien-Dindo classification grade >/=3 decreased from 27 to 13%; p = 0.02. Hospital length of stay was significantly shorter in the clinical pathway group, median 10 days [IQR 8-15], compared with the control group, median 13 days [IQR 10-18]; p = 0.02. CONCLUSION: The use of a clinical pathway in pancreaticoduodenectomy patients was associated with high protocol adherence, improved outcome and shorter hospital length of stay. Variance report analysis and protocol adherence with a Prepare-Act-Reflect Cycle are essential in surveillance of outcome. TI - Implementation and Evaluation of a Clinical Pathway for Pancreaticoduodenectomy Procedures: a Prospective Cohort Study EP - 1441 SN - 1091-255X IS - iss. 9 SP - 1428 JF - Journal of Gastrointestinal Surgery VL - vol. 21 DO - https://doi.org/10.1007/s11605-017-3459-1 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/181924/181924.pdf?sequence=1 ER - TY - JOUR AU - Tak, T. AU - Groenendael, R. van AU - Pickkers, P. AU - Koenderman, L. PY - 2017 UR - https://hdl.handle.net/2066/177635 AB - Three human monocyte subsets are recognized with different functions in the immune system: CD14++/CD16- classical monocytes (CM), CD14++/CD16+ intermediate monocytes (IM) and CD14+/CD16++ non-classical monocytes (NCM). Increased IM and NCM percentages have been reported under inflammatory conditions, yet little is known about monocyte subsets at the onset of inflammation. The human endotoxemia model is uniquely capable of studying the first phases of acute inflammation induced by intravenous injection of 2 ng/kg bodyweight lipopolysaccharide (LPS) into healthy volunteers. After that, monocyte subset counts, activation/differentiation status and chemokine levels were studied over 24 h. The numbers of all subsets were decreased by >95% after LPS injection. CM numbers recovered first (3- 6 h), followed by IM (6-8 h) and NCM numbers (8-24 h). Similarly, increased monocyte counts were observed first in CM (8 h), followed by IM and NCM (24 h). Monocytes did not display a clear activated phenotype (minor increase in CD11b and CD38 expression). Plasma levels of CCL2, CCL4 and CX3CL1 closely resembled the cell numbers of CM, IM and NCM, respectively. Our study provides critical insights into the earliest stages of acute inflammation and emphasizes the necessity to stain for different monocyte subsets when studying the role of monocytes in disease, as neither function nor kinetics of the subsets overlap. TI - Monocyte Subsets Are Differentially Lost from the Circulation during Acute Inflammation Induced by Human Experimental Endotoxemia EP - 474 SN - 1662-811X IS - iss. 5 SP - 464 JF - Journal of Innate Immunity VL - vol. 9 DO - https://doi.org/10.1159/000475665 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177635/177635.pdf?sequence=1 ER - TY - THES AU - Haerkens, M.H.T.M. PY - 2017 SN - 9789077245668 UR - https://hdl.handle.net/2066/162528 AB - Despite modern equipment, increasing emphasis on patient safety, and excellent training facilities medical care frequently results in unintentional harm to patients. Human Factors (HF) appear to play an important role in adverse events, especially in high risk clinical departments. A sound safety climate is considered essential, as it is positively related to safety outcomes. This thesis focused on HF and critical team performance in clinical medicine. First, an overview of existing literature, our healthcare CRM training curriculum, and a three-phase implementation structure were described. An open source safety climate assessment tool (Safety Attitudes Questionnaire-NL) was validated and an aviation-derived HF awareness / team concept (Crew Resource Management - CRM) was adapted to the clinical setting. Additionally, CRM was implemented in multiple hospital departments and its impact on patient safety assessed. A study into the impact of a CRM-intervention in a large ICU yielded an association of CRM with a reduction in serious complications, and lower mortality, in critically ill patients. Also, safety climate improved. CRM implementation in the Trauma Room of a level 1 Emergency Department (ED) was associated with an improved safety climate, although the time spent by trauma patients in the ED increased. CRM implementation in 17 high-risk clinical departments was associated with an improved safety climate. The results were related to perceived implementation success factors as well as threats to success. Also, points for improvement formulated by healthcare providers and potential barriers to transfer of CRM training to the work floor were provided. Finally all research findings, current issues and future perspectives for healthcare CRM are discussed. The challenge of adapting the medical organizational context to fully integrate HF principles into daily health operations was described and operational, educational, standardization and inspectorate/judicial aspects of this challenge identified. PB - [S.l. : s.n.] TI - Human factors and team performance N1 - Radboud University, 19 januari 2017 N1 - Promotores : Hoeven, J.G. van der, Pickkers, P. Co-promotor : Kox, M. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/162528/162528.pdf?sequence=1 ER - TY - JOUR AU - Lelubre, C. AU - Medfai, H. AU - Akl, I. AU - Leentjens, J. AU - Kox, M. AU - Pickkers, P. AU - Rousseau, A. AU - Biston, P. AU - Piagnerelli, M. AU - Vanhaeverbeek, M. AU - Uzureau, P. AU - Vincent, J.L. AU - Vanhamme, L. AU - Boudjeltia, K.Z. PY - 2017 UR - https://hdl.handle.net/2066/177623 AB - Phosphodiesterases (PDEs) may modulate inflammatory pathways, but PDE expression is poorly documented in humans with sepsis. Using quantitative PCR on whole blood leukocytes, we characterized PDE mRNA expression in healthy volunteers (n = 20), healthy volunteers given lipopolysaccharide (LPS; n = 18), and critically ill patients with (n = 20) and without (n = 20) sepsis. PDE4B protein expression was also studied in magnetic-activated cell sorting (MACS)-isolated CD15+ neutrophils (from 7 healthy volunteers, 5 patients without and 5 with sepsis). We studied relationships between PDE expression, HLA-DR (mRNA and expression on CD14+ monocytes), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 levels. LPS administration in volunteers was associated with increases in PDE4B and PDE4D and decreases in PDE4A and PDE7A mRNAs. The observed global down-regulation of the HLA-DR complex was correlated with PDE7A. Critically ill patients had lower TNF-alpha/IL-10 mRNA ratios than the volunteers had and global down-regulation of the HLA-DR complex. Septic patients had persistently lower mRNA levels of PDE7A, PDE4A, and 4B (also at a protein level) and decreasing levels of PDE4D over time. Low PDE4D mRNA levels correlated negatively with HLA-DMA and HLA-DMB. LPS administration and sepsis are, therefore, associated with different PDE mRNA expression patterns. The effect of PDE changes on immune dysfunction and HLA-DR expression requires further investigation. TI - Leukocyte phosphodiesterase expression after lipopolysaccharide and during sepsis and its relationship with HLA-DR expression EP - 1426 SN - 0741-5400 IS - iss. 6 SP - 1419 JF - Journal of Leukocyte Biology VL - vol. 101 DO - https://doi.org/10.1189/jlb.5A0516-240R ER - TY - JOUR AU - Leentjens, J. AU - Gresnigt, M.S. AU - Veerdonk, F.L. van de AU - Kox, M. AU - Kullberg, B.J. AU - Pickkers, P. AU - Brouwer, A.E. AU - Netea, M.G. PY - 2017 UR - https://hdl.handle.net/2066/174790 AB - Despite advances in medical care, mortality due to cerebral Nocardia abscesses remains unacceptably high. The case of a typical immunocompromised patient, who deteriorated clinically despite optimal antimicrobial treatment, is reported here. Adjuvant immunotherapy with interferon-gamma resulted in partial restoration of the immune response and a corresponding clinical and radiographic recovery. TI - Adjuvant interferon-gamma immunotherapy in a patient with progressive cerebral Nocardia abscesses EP - 28 SN - 1201-9712 SP - 25 JF - International Journal of Infectious Diseases VL - vol. 59 DO - https://doi.org/10.1016/j.ijid.2017.03.013 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/174790/174790.pdf?sequence=1 ER - TY - JOUR AU - Berrevoets, M.A.H. AU - Oever, J. ten AU - Sprong, T. AU - Hest, R.M. van AU - Groothuis, I. AU - Heijl, I. van AU - Schouten, J.A. AU - Hulscher, M.E.J.L. AU - Kullberg, B.J. PY - 2017 UR - https://hdl.handle.net/2066/177222 AB - BACKGROUND: The Dutch Working Party on Antibiotic Policy is developing a national antimicrobial stewardship registry. This registry will report both the quality of antibiotic use in hospitals in the Netherlands and the stewardship activities employed. It is currently unclear which aspects of the quality of antibiotic use are monitored by antimicrobial stewardship teams (A-teams) and can be used as indicators for the stewardship registry. In this pilot study we aimed to determine which stewardship objectives are eligible for the envisioned registry. METHODS: We performed an observational pilot study among five Dutch hospitals. We assessed which of the 14 validated stewardship objectives (11 process of care recommendations and 3 structure of care recommendations) the A-teams monitored and documented in individual patients. They provided, where possible, data to compute quality indicator (QI) performance scores in line with recently developed QIs to measure appropriate antibiotic use in hospitalized adults for the period of January 2015 through December 2015 RESULTS: All hospitals had a local antibiotic guideline describing recommended antimicrobial use. All A-teams monitored the performance of bedside consultations in Staphylococcus aureus bacteremia and the prescription of restricted antimicrobials. Documentation and reporting were the best for the use of restricted antimicrobials: 80% of the A-teams could report data. Lack of time and the absence of an electronic medical record system enabling documentation during the daily work flow were the main barriers hindering documentation and reporting. CONCLUSIONS: Five out of 11 stewardship objectives were actively monitored by A-teams. Without extra effort, 4 A-teams could report on the quality of use of restricted antibiotics. Therefore, this aspect of antibiotic use should be the starting point of the national antimicrobial stewardship registry. Our registry is expected to become a powerful tool to evaluate progress and impact of antimicrobial stewardship programs in hospitals. TI - Monitoring, documenting and reporting the quality of antibiotic use in the Netherlands: a pilot study to establish a national antimicrobial stewardship registry SN - 1471-2334 IS - iss. 1 JF - BMC Infectious Diseases VL - vol. 17 DO - https://doi.org/10.1186/s12879-017-2673-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177222/177222.pdf?sequence=1 ER - TY - JOUR AU - Koch, R.M. AU - Kox, M. AU - Jonge, M.I. de AU - Hoeven, J.G. van der AU - Ferwerda, G. AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/170576 AB - Immunosuppression renders the host increased susceptible for secondary infections. It is becoming increasingly clear that not only bacterial sepsis, but also respiratory viruses with both severe and mild disease courses such as influenza, respiratory syncytial virus, and the human rhinovirus may induce immunosuppression. In this review, the current knowledge on (mechanisms of) bacterial- and virus-induced immunosuppression and the accompanying susceptibility toward various secondary infections is described. In addition, the frequently encountered secondary pathogens and their preferred localizations are presented. Finally, future perspectives in the context of the development of diagnostic markers and possibilities for personalized therapy to improve the diagnosis and treatment of immunocompromised patients are discussed. TI - Patterns in Bacterial- and Viral-Induced Immunosuppression and Secondary Infections in the ICU EP - 12 SN - 1073-2322 IS - iss. 1 SP - 5 JF - Shock VL - vol. 47 DO - https://doi.org/10.1097/SHK.0000000000000731 ER - TY - JOUR AU - Langereis, J.D. AU - Pickkers, P. AU - Kleijn, S. de AU - Gerretsen, J. AU - Jonge, M.I. de AU - Kox, M. PY - 2017 UR - https://hdl.handle.net/2066/182392 TI - Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia EP - 1409 SN - 0741-5400 IS - iss. 6 SP - 1401 JF - Journal of Leukocyte Biology VL - vol. 102 DO - https://doi.org/10.1189/jlb.3A0217-051RR ER - TY - JOUR AU - Koch, R.M. AU - Kox, M. AU - Thijs, E.J.M. AU - Rahamat-Langendoen, J.C. AU - Veerdonk, F.L. van de AU - Gerretsen, J. AU - Diavatopoulos, D.A. AU - Netea, M.G. AU - Jonge, M.I. de AU - Pickkers, P. PY - 2017 UR - https://hdl.handle.net/2066/181612 TI - Development of Endotoxin Tolerance Does Not Influence the Response to a Challenge with the Mucosal Live-Attenuated Influenza Vaccine in Humans In Vivo SN - 1664-3224 JF - Frontiers in Immunology VL - vol. 8 DO - https://doi.org/10.3389/fimmu.2017.01600 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/181612/181612.pdf?sequence=1 ER - TY - JOUR AU - Geense, W.W. AU - Zegers, M. AU - Vermeulen, H. AU - Boogaard, M.H.W.A. van den AU - Hoeven, J.G. van der PY - 2017 UR - https://hdl.handle.net/2066/182346 AB - INTRODUCTION: Due to advances in critical care medicine, more patients survive their critical illness. However, intensive care unit (ICU) survivors often experience long-term physical, cognitive and mental problems, summarised as post-intensive care syndrome (PICS), impacting their health-related quality of life (HRQoL). In what frequency PICS occurs, and to what extent this influences ICU survivors' HRQoL, is mostly unknown. The aims of this study are therefore to study the: (1) 5-year patient outcomes, (2) predictors for PICS, (3) ratio between HRQoL of ICU survivors and healthcare-related costs, and (4) care and support needs. METHODS: The MONITOR-IC study is a multicentre prospective controlled cohort study, carried out in ICUs in four Dutch hospitals. Patients will be included between July 2016 and July 2021 and followed for 5 years. We estimated to include 12000 ICU patients. Outcomes are the HRQoL, physical, cognitive and mental symptoms, ICU survivors' care and support needs, healthcare use and related costs. A control cohort of otherwise seriously ill patients will be assembled to compare long-term patient-reported outcomes. We will use a mixed methods design, including questionnaires, medical data from patient records, cost data from health insurance companies and interviews with patients and family members. ETHICS AND DISSEMINATION: Insights from this study will be used to inform ICU patients and their family members about long-term consequences of ICU care, and to develop prediction and screening instruments to detect patients at risk for PICS. Subsequently, tailored interventions can be developed and implemented to prevent and mitigate long-term consequences. Additionally, insights into the ratio between HRQoL of ICU patients and related healthcare costs during 5 years after ICU admission can be used to discuss the added value of ICU care from a community perspective. The study has been approved by the research ethics committee of the Radboud University Medical Center (2016-2724). CLINICAL TRIAL REGISTRATION: NCT03246334. TI - MONITOR-IC study, a mixed methods prospective multicentre controlled cohort study assessing 5-year outcomes of ICU survivors and related healthcare costs: a study protocol SN - 2044-6055 IS - iss. 11 JF - BMJ Open VL - vol. 7 DO - https://doi.org/10.1136/bmjopen-2017-018006 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182346/182346.pdf?sequence=1 ER - TY - THES AU - Dorresteijn, M.J. PY - 2016 SN - 9789462334250 UR - https://hdl.handle.net/2066/161236 PB - [S.l. : s.n.] TI - Heme oxygenase and inflammation N1 - Radboud University, 16 december 2016 N1 - Promotores : Pickkers, P., Hoeven, J.G. van der Co-promotor : Wagener, F.A.D.T.G. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/161236/161236.pdf?sequence=1 ER - TY - JOUR AU - Bucx, M.J.L. AU - Krijtenburg, P. AU - Kox, M. PY - 2016 UR - https://hdl.handle.net/2066/171250 AB - STUDY OBJECTIVE: Although anxiolytic-sedative agents are used preoperatively since the advent of anesthesia, many aspects of this treatment, including the intended effects among which anxiolysis, effectiveness, and optimal agents, remain unclear. The objective of this study was to provide insight into the preoperative use of anxiolytic-sedative agents in the Netherlands and to relate the administration of these agents to the anxiolytic-sedative state of patients. DESIGN: Questionnaire study. SETTING: University, general, and specialized hospitals in the Netherlands. PATIENTS: One anesthesiologist in each hospital was asked for details about premedication in all elective procedures, except cardiothoracic surgery, in normal weighted adults in good to fair clinical condition. INTERVENTIONS: None. MEASUREMENTS: Estimated percentage of patients receiving anxiolytic-sedative premedication, type, dose, route of administration and timing of these agents, and anxiolytic state of patients when arriving at the holding area. MAIN RESULTS: All 8 university hospitals, 69 of 82 general hospitals and 2 of 3 specialized hospitals participated in this study (response rate, 84.9%). The estimated percentage of patients that received anxiolytic-sedative agents was 46.8% for in-patients and 30.4% for day care patients (P<.0001), with large between-hospital variation. Midazolam (62.7%), oxazepam (20.2%), and temazepam (7.8%) were most frequently used and were virtually always orally administered 1 hour preoperatively. There was no relationship between use of anxiolytic-sedative agents and reduction of perceived anxiety (r=-0.09, P=.46 and r=-0.01, P=.91 for clinical and day care patients, respectively). CONCLUSIONS: Anxiolytic-sedative agents are used preoperatively in a substantial number of patients in the Netherlands, and the pharmacokinetic characteristics of many agents are not optimal of their intended use. In addition, we found no relationship with reduced anxiety. This study stresses the need for clear guidelines on preoperative use of anxiolytic-sedative agents. TI - Preoperative use of anxiolytic-sedative agents; are we on the right track? EP - 140 SN - 0952-8180 SP - 135 JF - Journal of Clinical Anesthesia VL - vol. 33 DO - http://dx.doi.org/10.1016/j.jclinane.2016.03.025 ER - TY - JOUR AU - Postma, N. AU - Kiers, D. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171396 TI - Reply to: Re: The challenge of Clostridium difficile infection: overview of clinical manifestations, diagnostic tools and therapeutic options SN - 0924-8579 IS - iss. 3 SP - 243 JF - International Journal of Antimicrobial Agents VL - vol. 47 DO - http://dx.doi.org/10.1016/j.ijantimicag.2015.12.013 ER - TY - JOUR AU - Rots, M.L. AU - Putten, M.J. van AU - Hoedemaekers, C.W. AU - Horn, J. PY - 2016 UR - https://hdl.handle.net/2066/172208 AB - INTRODUCTION: Early identification of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is a major challenge. The aim of this study was to investigate whether quantitative EEG (qEEG) features can detect DCI prior to clinical or radiographic findings. METHODS: A prospective cohort study was performed in aSAH patients in whom continuous EEG (cEEG) was recorded. We studied 12 qEEG features. We compared the time point at which qEEG changed with the time point that clinical deterioration occurred or new ischemia was noted on CT scan. Results : Twenty aSAH patients were included of whom 11 developed DCI. The alpha/delta ratio (ADR) was the most promising feature that showed a significant difference in change over time in the DCI group (median -62 % with IQR -87 to -39 %) compared to the control group (median +27 % with IQR -32 to +104 %, p = 0.013). Based on the ROC curve, a threshold was chosen for a combined measure of ADR and alpha variability (AUC: 91.7, 95 % CI 74.2-100). The median time that elapsed between change of qEEG and clinical DCI diagnosis was seven hours (IQR -11-25). Delay between qEEG and CT scan changes was 44 h (median, IQR 14-117). CONCLUSION: In this study, ADR and alpha variability could detect DCI development before ischemic changes on CT scan was apparent and before clinical deterioration was noted. Implementation of cEEG in aSAH patients can probably improve early detection of DCI. TI - Continuous EEG Monitoring for Early Detection of Delayed Cerebral Ischemia in Subarachnoid Hemorrhage: A Pilot Study EP - 216 SN - 1541-6933 IS - iss. 2 SP - 207 JF - Neurocritical Care VL - vol. 24 DO - http://dx.doi.org/10.1007/s12028-015-0205-y ER - TY - JOUR AU - Sivakumar, S. AU - Taccone, F.S. AU - Desai, K.S. AU - Rood, P.J.T. AU - Schoor, F. van de AU - Tertholen, K. van AU - Pickkers, P. AU - Boogaard, M.H.W.A. van den AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/172382 TI - ESICM LIVES 2016: part two : Milan, Italy. 1-5 October 2016 EP - 30 SN - 2197-425X IS - iss. 1 SP - 30 JF - Intensive Care Medicine Experimental VL - vol. 4 DO - http://dx.doi.org/10.1186/s40635-016-0099-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172382/172382.pdf?sequence=1 ER - TY - JOUR AU - Farmakis, D. AU - Alvarez, J. AU - Gal, T.B. AU - Brito, D. AU - Fedele, F. AU - Fonseca, C. AU - Gordon, A.C. AU - Gotsman, I. AU - Grossini, E. AU - Guarracino, F. AU - Harjola, V.P. AU - Hellman, Y. AU - Heunks, L.M. AU - Ivancan, V. AU - Karavidas, A. AU - Kivikko, M. AU - Lomivorotov, V. AU - Longrois, D. AU - Masip, J. AU - Metra, M. AU - Morelli, A. AU - Nikolaou, M. AU - Papp, Z. AU - Parkhomenko, A. AU - Poelzl, G. AU - Pollesello, P. AU - Ravn, H.B. AU - Rex, S. AU - Riha, H. AU - Ricksten, S.E. AU - Schwinger, R.H. AU - Vrtovec, B. AU - Yilmaz, M.B. AU - Zielinska, M. AU - Parissis, J. PY - 2016 UR - https://hdl.handle.net/2066/167320 AB - Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps. TI - Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper EP - 312 SN - 0167-5273 SP - 303 JF - International Journal of Cardiology VL - vol. 222 DO - https://doi.org/10.1016/j.ijcard.2016.07.202 ER - TY - JOUR AU - Lemson, J. AU - Tibby, S.M. PY - 2016 UR - https://hdl.handle.net/2066/171378 TI - Reliability of the Ultrasound Cardiac Output Monitor for Pediatric Patients EP - 618 SN - 0172-0643 IS - iss. 3 SP - 618 JF - Pediatric Cardiology VL - vol. 37 DO - https://doi.org/10.1007/s00246-016-1353-3 ER - TY - JOUR AU - Palmers, I. AU - Ydens, E. AU - Put, E. AU - Depreitere, B. AU - Bongers-Janssen, H. AU - Pickkers, P. AU - Hendrix, S. AU - Somers, V. PY - 2016 UR - https://hdl.handle.net/2066/171493 AB - BACKGROUND: Recent evidence implicates antibody responses as pivotal damaging factors in spinal cord injury (SCI)-induced neuroinflammation. To date, only a limited number of the antibody targets have been uncovered, and the discovery of novel targets with pathologic and clinical relevance still represents a major challenge. METHODS: In this study, we, therefore, applied an unbiased, innovative and powerful strategy, called serological antigen selection (SAS), to fully identify the complex information present within the antibody repertoire of SCI patients. RESULTS: We constructed a high-quality cDNA phage display library derived from human spinal cord tissue to screen for antibody reactivity in pooled plasma samples from traumatic SCI patients (n = 10, identification cohort). By performing SAS, we identified a panel of 19 antigenic targets to which the individual samples of the plasma pool showed antibody reactivity. Sequence analysis to identify the selected antigenic targets uncovered 5 known proteins, to which antibody reactivity has not been associated with SCI before, as well as linear peptides. Immunoreactivity against 9 of the 19 novel identified targets was validated in 41 additional SCI patients and an equal number of age- and gender-matched healthy subjects. Overall, we found elevated antibody levels to at least 1 of the 9 targets in 51 % of our total SCI patient cohort (n = 51) with a specificity of 73 %. By combining 6 of these 9 targets into a panel, an overall reactivity of approximately half of the SCI patients could be maintained while increasing the specificity to 82 %. CONCLUSIONS: In conclusion, our innovative high-throughput approach resulted in the identification of previously unexplored antigenic targets with elevated immunoreactivity in more than 50 % of the SCI patients. Characterization of the validated antibody responses and their targets will not only provide new insight into the underlying disease processes of SCI pathology but also significantly contribute to uncovering potential antibody biomarkers for SCI patients. TI - Antibody profiling identifies novel antigenic targets in spinal cord injury patients SN - 1742-2094 IS - iss. 1 SP - 243 JF - Journal of Neuroinflammation VL - vol. 13 DO - https://doi.org/10.1186/s12974-016-0713-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171493/171493.pdf?sequence=1 ER - TY - JOUR AU - Nobile, L. AU - Taccone, F.S. AU - Szakmany, T. AU - Sakr, Y. AU - Jakob, S.M. AU - Pellis, T. AU - Antonelli, M. AU - Leone, M. AU - Wittebole, X. AU - Pickkers, P. AU - Vincent, J.L. PY - 2016 UR - https://hdl.handle.net/2066/171739 AB - BACKGROUND: We used data from a large international database to assess the incidence and impact of extracerebral organ dysfunction on prognosis of patients admitted after cardiac arrest (CA). METHODS: This was a sub-analysis of the Intensive Care Over Nations (ICON) database, which contains data from all adult patients admitted to one of 730 participating intensive care units (ICUs) in 84 countries from 8-18 May 2012, except admissions for routine postoperative surveillance. For this analysis, patients admitted after CA (defined as those with "post-anoxic coma" or "cardiac arrest" as the reason for ICU admission) were included. Data were collected daily in the ICU for a maximum of 28 days; patients were followed up for outcome data until death, hospital discharge, or a maximum of 60 days in-hospital. Favorable neurological outcome was defined as alive at hospital discharge with a last available neurological Sequential Organ Failure Assessment (SOFA) subscore of 0-2. RESULTS: Among the 469 patients admitted after CA, 250 (53 %) had had out-of-hospital CA; 210 (45 %) patients died in the ICU and 357 (76 %) had an unfavorable neurological outcome. Non-survivors had a higher incidence of renal (43 vs. 16 %), cardiovascular (56 vs. 45 %), and respiratory (62 vs. 48 %) failure on admission and during the ICU stay than survivors (all p < 0.05). Similar results were found for patients with unfavorable vs. favorable neurological outcomes. In multivariable analysis, independent predictors of ICU mortality were renal failure on admission, high admission Simplified Acute Physiology Score (SAPS) II, high maximum serum lactate levels within the first 24 h after ICU admission, and development of sepsis. Independent predictors of unfavorable neurological outcome were mechanical ventilation on admission, high admission SAPS II score, and neurological dysfunction on admission. CONCLUSIONS: In this multicenter cohort, extracerebral organ dysfunction was common in CA patients. Renal failure on admission was the only extracerebral organ dysfunction independently associated with higher ICU mortality. TI - The impact of extracerebral organ failure on outcome of patients after cardiac arrest: an observational study from the ICON database SN - 1466-609X IS - iss. 1 SP - 368 JF - Critical Care VL - vol. 20 DO - https://doi.org/10.1186/s13054-016-1528-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171739/171739.pdf?sequence=1 ER - TY - JOUR AU - Bellani, G. AU - Laffey, J.G. AU - Pham, T. AU - Fan, E. AU - Brochard, L. AU - Esteban, A. AU - Gattinoni, L. AU - Haren, F. van AU - Larsson, A. AU - McAuley, D.F. AU - Ranieri, M. AU - Rubenfeld, G. AU - Thompson, B.T. AU - Wrigge, H. AU - Slutsky, A.S. AU - Pesenti, A. AU - Heunks, L.M.A. AU - Wezel, H.M.P. van AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/172480 AB - IMPORTANCE: Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES: To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS: The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES: Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES: The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS: Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE: Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02010073. TI - Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries EP - 800 SN - 0098-7484 IS - iss. 8 SP - 788 JF - Jama : Journal of the American Medical Association VL - vol. 315 DO - https://doi.org/10.1001/jama.2016.0291 ER - TY - JOUR AU - Laffey, J.G. AU - Bellani, G. AU - Pham, T. AU - Fan, E. AU - Madotto, F. AU - Bajwa, E.K. AU - Brochard, L. AU - Clarkson, K. AU - Esteban, A. AU - Gattinoni, L. AU - Haren, F. van AU - Heunks, L.M.A. AU - Kurahashi, K. AU - Laake, J.H. AU - Larsson, A. AU - McAuley, D.F. AU - McNamee, L. AU - Nin, N. AU - Qiu, H. AU - Ranieri, M. AU - Rubenfeld, G.D. AU - Thompson, B.T. AU - Wrigge, H. AU - Slutsky, A.S. AU - Pesenti, A. PY - 2016 UR - https://hdl.handle.net/2066/171220 AB - PURPOSE: To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. METHODS: The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1-2 who received invasive mechanical ventilation. RESULTS: 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO2/FiO2 ratio, and higher non-pulmonary SOFA score were associated with poorer outcome. Of the 578 (24.3 %) patients with a limitation of life-sustaining therapies or measures decision, 498 (86.0 %) died in hospital. Factors associated with increased likelihood of limitation of life-sustaining therapies or measures decision included older age, immunosuppression, neoplasia, lower pH and increased non-pulmonary SOFA scores. CONCLUSIONS: Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02010073. TI - Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study EP - 1876 SN - 0342-4642 IS - iss. 12 SP - 1865 JF - Intensive Care Medicine VL - vol. 42 DO - https://doi.org/10.1007/s00134-016-4571-5 ER - TY - JOUR AU - Schellekens, W.J. AU - Heunks, L.M. PY - 2016 UR - https://hdl.handle.net/2066/171593 TI - Appropriate positioning of the NAVA catheter EP - 634 SN - 0342-4642 IS - iss. 4 SP - 633 JF - Intensive Care Medicine VL - vol. 42 DO - https://doi.org/10.1007/s00134-016-4213-y ER - TY - JOUR AU - Carteaux, G. AU - Cordoba-Izquierdo, A. AU - Lyazidi, A. AU - Heunks, L.M.A. AU - Thille, A.W. AU - Brochard, L. PY - 2016 UR - https://hdl.handle.net/2066/172172 AB - OBJECTIVES: To understand the potential equivalence between neurally adjusted ventilatory assist and pressure support ventilation levels in terms of respiratory muscle unloading. To compare the respiratory pattern, variability, synchronization, and neuromuscular coupling within comparable ranges of assistance. DESIGN: Prospective single-center physiologic study. SETTING: A 13-bed university medical ICU. PATIENTS: Eleven patients recovering from respiratory failure. INTERVENTIONS: The following levels of assistance were consecutively applied in a random order: neurally adjusted ventilatory assist levels: 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 7 cm H2O/muvolt; pressure support levels: 7, 10, 15, 20, and 25 cm H2O. MEASUREMENTS AND MAIN RESULTS: Flow, airway pressure, esophageal pressures, and peak electrical activity of the diaphragm were continuously recorded. Breathing effort was calculated. To express the percentage of assist assumed by the ventilator, the total pressure including muscular and ventilator pressure was calculated. The median percentage of assist ranged from 33% (24-47%) to 82% (72-90%) between pressure support 7 and 25 cm H2O. Similar levels of unloading were observed for neurally adjusted ventilatory assist levels from 0.5 cm H2O/muvolt (46% [40-51%]) to 2.5 cm H2O/muvolt (80% [74-84%]). Tidal variability was higher during neurally adjusted ventilatory assist and ineffective efforts appeared only in pressure support. In neurally adjusted ventilatory assist, double triggering occurred sometimes when electrical activity of the diaphragm signal depicted a biphasic aspect, and an abnormal oscillatory pattern was frequently observed from 4 cm H2O/muvolt. For both modes, the relationship between peak electrical activity of the diaphragm and muscle pressure depicted a curvilinear profile. CONCLUSIONS: In patients recovering from acute respiratory failure, levels of neurally adjusted ventilatory assist between 0.5 and 2.5 cm H2O/muvolt are comparable to pressure support levels ranging from 7 to 25 cm H2O in terms of respiratory muscle unloading. Neurally adjusted ventilatory assist provides better patient-ventilator interactions but can be sometimes excessively sensitive to electrical activity of the diaphragm in terms of triggering. TI - Comparison Between Neurally Adjusted Ventilatory Assist and Pressure Support Ventilation Levels in Terms of Respiratory Effort EP - 511 SN - 0090-3493 IS - iss. 3 SP - 503 JF - Critical Care Medicine VL - vol. 44 DO - https://doi.org/10.1097/CCM.0000000000001418 ER - TY - JOUR AU - Haerkens, M.H.T.M. AU - Leeuwen, W. van AU - Sexton, J.B. AU - Pickkers, P. AU - Hoeven, J.G. van der PY - 2016 UR - https://hdl.handle.net/2066/171911 AB - BACKGROUND: As the first objective of caring for patients is to do no harm, patient safety is a priority in delivering clinical care. An essential component of safe care in a clinical department is its safety climate. Safety climate correlates with safety-specific behaviour, injury rates, and accidents. Safety climate in healthcare can be assessed by the Safety Attitudes Questionnaire (SAQ), which provides insight by scoring six dimensions: Teamwork Climate, Job Satisfaction, Safety Climate, Stress Recognition, Working Conditions and Perceptions of Management. The objective of this study was to assess the psychometric properties of the Dutch language version of the SAQ in a variety of clinical departments in Dutch hospitals. METHODS: The Dutch version (SAQ-NL) of the SAQ was back translated, and analyzed for semantic characteristics and content. From October 2010 to November 2015 SAQ-NL surveys were carried out in 17 departments in two university and seven large non-university teaching hospitals in the Netherlands, prior to a Crew Resource Management human factors intervention. Statistical analyses were used to examine response patterns, mean scores, correlations, internal consistency reliability and model fit. Cronbach's alpha's and inter-item correlations were calculated to examine internal consistency reliability. RESULTS: One thousand three hundred fourteen completed questionnaires were returned from 2113 administered to health care workers, resulting in a response rate of 62 %. Confirmatory Factor Analysis revealed the 6-factor structure fit the data adequately. Response patterns were similar for professional positions, departments, physicians and nurses, and university and non-university teaching hospitals. The SAQ-NL showed strong internal consistency (alpha = .87). Exploratory analysis revealed differences in scores on the SAQ dimensions when comparing different professional positions, when comparing physicians to nurses and when comparing university to non-university hospitals. CONCLUSIONS: The SAQ-NL demonstrated good psychometric properties and is therefore a useful instrument to measure patient safety climate in Dutch clinical work settings. As removal of one item resulted in an increased reliability of the Working Conditions dimension, revision or deletion of this item should be considered. The results from this study provide researchers and practitioners with insight into safety climate in a variety of departments and functional positions in Dutch hospitals. TI - Validation of the Dutch language version of the Safety Attitudes Questionnaire (SAQ-NL) SN - 1472-6963 IS - iss. a SP - 385 JF - BMC Health Services Research VL - vol. 16 DO - https://doi.org/10.1186/s12913-016-1648-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171911/171911.pdf?sequence=1 ER - TY - JOUR AU - Dekker, D. AU - Dorresteijn, M.J. AU - Peters, W.H.M. AU - Bilos, A. AU - Pennings, S.W.C. AU - Wagener, F.A.D.T.G. AU - Smits, P. PY - 2016 UR - https://hdl.handle.net/2066/171925 AB - This translational randomized and vehicle-controlled cross-over study was performed to assess the impact of haem arginate treatment on haem oxygenase-1 induction, endothelial function and insulin sensitivity in subjects with the metabolic syndrome (n = 14). Both treatment periods consisted of 5 days. Haem arginate or vehicle (l-arginine) was administered intravenously on Days 1 and 3. Forearm blood flow in response to acetylcholine and nitroglycerine was measured by venous occlusion plethysmography (Day 3), insulin sensitivity by a hyperinsulinaemic clamp procedure (Day 5). Haem arginate did not improve endothelial function or insulin sensitivity but significantly reduced the vasodilator response to nitroglycerine (p < 0.01). These negative findings are in contrast to the preclinical data, which may be due to short duration of therapy and limited haem oxygenase-1 induction as well as interference by markedly elevated plasma haem levels observed after haem arginate treatment (p < 0.01). Future studies should pay attention to the delicate balance between sufficient dosing and timely normalization of plasma haem levels. TI - Vascular and metabolic effects of the haem oxygenase-1 inducer haem arginate in subjects with the metabolic syndrome: A translational cross-over study. EP - 48 SN - 1479-1641 IS - iss. 1 SP - 41 JF - Diabetes & Vascular Disease Research VL - vol. 13 N1 - 1 januari 2016 DO - https://doi.org/10.1177/1479164115605047 ER - TY - JOUR AU - Timmermans, K. AU - Kox, M. AU - Scheffer, G.J. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171197 AB - BACKGROUND: Plasma levels of the danger-associated molecular patterns (DAMPs) nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) have been shown to be related to sepsis mortality. However, the intermediate factors and/or mechanisms contributing to this relation are largely unknown. Our aim was to determine whether plasma levels of nDNA and mtDNA are related to the markers of inflammation, severity of shock, and organ damage in septic shock patients. Moreover, we investigated the relationship between plasma levels of nDNA/mtDNA and inflammatory cytokines during experimental human endotoxemia, a model of systemic inflammation in humans in vivo mimicking some of the hallmarks of early sepsis. METHODS: Blood was sampled from the onset of septic shock until day 28 in 121 septic shock patients and from 1 h before endotoxin administration until 8 h afterward in 12 healthy volunteers. Plasma concentrations of five cytokines and circulating levels of nDNA and mtDNA were measured, and correlations with shock-related parameters and markers of organ damage were investigated. RESULTS: In septic shock patients plasma cytokine concentrations, as well as nDNA and mtDNA levels, were increased at the onset of septic shock and remained elevated. During the first 5 days of septic shock, nDNA levels consistently correlated with plasma cytokine concentrations as well as with the shock-related parameter norepinephrine infusion rate and markers of organ damage (total bilirubin and creatinine). Experimental human endotoxemia also resulted in increased levels of plasma nDNA and mtDNA, but to a lesser extent than in septic shock patients. Furthermore, nDNA levels correlated with pro-inflammatory cytokines during endotoxemia. CONCLUSIONS: Our findings indicate a relationship between plasma nDNA levels and the inflammatory response. Furthermore, nDNA levels are associated with markers of shock and organ damage in septic shock patients. Nevertheless, the correlations found are relatively weak and it remains to be determined whether nDNA is merely a marker or directly involved in the pathophysiology of septic shock. TI - Plasma Nuclear and Mitochondrial DNA Levels, and Markers of Inflammation, Shock, and Organ Damage in Patients with Septic Shock EP - 612 SN - 1073-2322 IS - iss. 6 SP - 607 JF - Shock VL - vol. 45 DO - http://dx.doi.org/10.1097/SHK.0000000000000549 ER - TY - JOUR AU - Basile, D.P. AU - Bonventre, J.V. AU - Mehta, R. AU - Nangaku, M. AU - Unwin, R. AU - Rosner, M.H. AU - Kellum, J.A. AU - Ronco, C. AU - Pickkers, P. AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/171281 AB - Recent clinical studies indicate a strong link between AKI and progression of CKD. The increasing prevalence of AKI must compel the nephrology community to consider the long-term ramifications of this syndrome. Considerable gaps in knowledge exist regarding the connection between AKI and CKD. The 13th Acute Dialysis Quality Initiative meeting entitled "Therapeutic Targets of Human Acute Kidney Injury: Harmonizing Human and Experimental Animal Acute Kidney Injury" convened in April of 2014 and assigned a working group to focus on issues related to progression after AKI. This article provides a summary of the key conclusions and recommendations of the group, including an emphasis on terminology related to injury and repair processes for both clinical and preclinical studies, elucidation of pathophysiologic alterations of AKI, identification of potential treatment strategies, identification of patients predisposed to progression, and potential management strategies. TI - Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments EP - 697 SN - 1046-6673 IS - iss. 3 SP - 687 JF - Journal of the American Society of Nephrology VL - vol. 27 DO - http://dx.doi.org/10.1681/ASN.2015030309 ER - TY - JOUR AU - Matejovic, M. AU - Ince, C. AU - Chawla, L.S. AU - Blantz, R. AU - Molitoris, B.A. AU - Rosner, M.H. AU - Okusa, M.D. AU - Kellum, J.A. AU - Ronco, C. AU - Pickkers, P. AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/171381 AB - Novel therapeutic interventions are required to prevent or treat AKI. To expedite progress in this regard, a consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 to develop recommendations for research priorities and future directions. Here, we highlight the concepts related to renal hemodynamics in AKI that are likely to reveal new treatment targets on investigation. Overall, we must better understand the interactions between systemic, total renal, and glomerular hemodynamics, including the role of tubuloglomerular feedback. Furthermore, the net consequences of therapeutic maneuvers aimed at restoring glomerular filtration need to be examined in relation to the nature, magnitude, and duration of the insult. Additionally, microvascular blood flow heterogeneity in AKI is now recognized as a common occurrence; timely interventions to preserve the renal microcirculatory flow may interrupt the downward spiral of injury toward progressive kidney failure and should, therefore, be investigated. Finally, development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies. TI - Renal Hemodynamics in AKI: In Search of New Treatment Targets EP - 58 SN - 1046-6673 IS - iss. 1 SP - 49 JF - Journal of the American Society of Nephrology VL - vol. 27 DO - http://dx.doi.org/10.1681/ASN.2015030234 ER - TY - JOUR AU - Humphreys, B.D. AU - Cantaluppi, V. AU - Portilla, D. AU - Singbartl, K. AU - Yang, L. AU - Rosner, M.H. AU - Kellum, J.A. AU - Ronco, C. AU - Pickkers, P. AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/171621 AB - AKI remains a highly prevalent disease associated with poor short- and long-term outcomes and high costs. Although significant advances in our understanding of repair after AKI have been made over the last 5 years, this knowledge has not yet been translated into new AKI therapies. A consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 and reviewed new evidence on successful kidney repair to identify the most promising pathways that could be translated into new treatments. In this paper, we provide a summary of current knowledge regarding successful kidney repair and offer a framework for conceptualizing the therapeutic targeting that may facilitate this process. We outline gaps in knowledge and suggest a research agenda to more efficiently bring new discoveries regarding repair after AKI to the clinic. TI - Targeting Endogenous Repair Pathways after AKI EP - 998 SN - 1046-6673 IS - iss. 4 SP - 990 JF - Journal of the American Society of Nephrology VL - vol. 27 DO - http://dx.doi.org/10.1681/ASN.2015030286 ER - TY - JOUR AU - Okusa, M.D. AU - Rosner, M.H. AU - Kellum, J.A. AU - Ronco, C. AU - Pickkers, P. AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/171789 AB - The opportunity to make advances in the prevention and treatment of AKI has never been greater than it is today. Major advances have been made in the understanding of the biology of AKI, the design of clinical trials, and the use of diagnostic and prognostic biomarkers. These advances have been supplemented by the coordinated effort of societies, federal agencies, and industry, such that we are poised in the ensuing years to positively address the unrelenting harm that this disorder has created. Over the past decade, major advances have been made in understanding the pathophysiology of AKI, mainly through the study of small animal models. However, translating these findings to human AKI remains a barrier, which is typified by the absence of effective therapeutic agents. The purpose of the Acute Dialysis Quality Initiative (ADQI) XIII was to harmonize human and animal studies and determine what is known about potential therapeutic targets and what gaps in knowledge remain. A series of invited reviews will distill key concepts from this initiative that focus on different pathogenic features of AKI, including hemodynamics, immunity and inflammation, cellular and molecular pathways, progression, and regeneration and repair. This series will convey the status of our knowledge of the pathophysiology of human AKI and propose therapeutic targets for further investigation. TI - Therapeutic Targets of Human AKI: Harmonizing Human and Animal AKI EP - 48 SN - 1046-6673 IS - iss. 1 SP - 44 JF - Journal of the American Society of Nephrology VL - vol. 27 DO - http://dx.doi.org/10.1681/ASN.2015030233 ER - TY - JOUR AU - Timmermans, K. AU - Kox, M. AU - Scheffer, G.J. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/172257 AB - Danger-associated molecular patterns (DAMPs) that are released by injured, threatened, or dead cells, or that originate from the extracellular matrix, influence the immune system. This is of great relevance in critically ill patients, in whom trauma or surgery-related cell damage, hypoxia, ischemia, and infections can result in extensive release of DAMPs. As many patients at the intensive care unit suffer from immune system-related complications, DAMPs could serve as markers for the prognosis of these patients and represent possible therapeutic targets. In the present review, we provide an overview of several well known DAMPs (high-mobility group box 1, heat-shock proteins, s100 proteins, nucleic acids, and hyaluronan) and their effects on the immune system. Furthermore, we discuss the role of DAMPs as markers or therapeutic targets in several conditions frequently encountered in critically ill patients, such as sepsis, trauma, ventilator-induced lung injury, and cardiac arrest. TI - Danger in the Intensive Care Unit: DAMPs in critically ill patients EP - 116 SN - 1073-2322 IS - iss. 2 SP - 108 JF - Shock VL - vol. 45 DO - https://doi.org/10.1097/SHK.0000000000000506 ER - TY - JOUR AU - Simons, K.S. AU - Laheij, R.J. AU - Boogaard, M. van den AU - Moviat, M.A. AU - Paling, A.J. AU - Polderman, F.N. AU - Rozendaal, F.W. AU - Salet, G.A. AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Jager, C.P. de PY - 2016 UR - https://hdl.handle.net/2066/172369 AB - BACKGROUND: Disturbed circadian rhythm is a potentially modifiable cause of delirium among patients in intensive-care units (ICUs). Bright-light therapy in the daytime can realign circadian rhythm and reduce the incidence of delirium. We investigated whether a high-intensity dynamic light application (DLA) would reduce ICU-acquired delirium. METHODS: This was a randomised, controlled, single-centre trial of medical and surgical patients admitted to the ICU of a teaching hospital in the Netherlands. Patients older than 18 years, expected to stay in the ICU longer than 24 h and who could be assessed for delirium were randomised to DLA or normal lighting (control), according to a computer-generated schedule. The DLA was administered through ceiling-mounted fluorescent tubes that delivered bluish-white light up to 1700 lux between 0900 h and 1600 h, except for 1130-1330 h, when the light was dimmed to 300 lux. The light could only be turned off centrally by investigators. Control light levels were 300 lux and lights could be turned on and off from inside the room. The primary endpoint was the cumulative incidence of ICU-acquired delirium. Analyses were by intention to treat and per protocol. The study was terminated prematurely after an interim analysis for futility. This study is registered with Clinicaltrials.gov, number NCT01274819. FINDINGS: Between July 1, 2011, and Sept 9, 2013, 734 patients were enrolled, 361 in the DLA group and 373 in the control group. Delirium occurred in 137 (38%) of 361 DLA patients and 123 (33%) of 373 control patients (odds ratio 1.24, 95% CI 0.92-1.68, p=0.16). No adverse events were noted in patients or staff. INTERPRETATION: DLA as a single intervention does not reduce the cumulative incidence of delirium. Bright-light therapy should be assessed as part of a multicomponent strategy. FUNDING: None. TI - Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial EP - 202 SN - 2213-2600 IS - iss. 3 SP - 194 JF - Lancet Respiratory Medicine VL - vol. 4 DO - https://doi.org/10.1016/S2213-2600(16)00025-4 ER - TY - JOUR AU - Rabb, H. AU - Griffin, M.D. AU - McKay, D.B. AU - Swaminathan, S. AU - Pickkers, P. AU - Rosner, M.H. AU - Kellum, J.A. AU - Ronco, C. PY - 2016 UR - https://hdl.handle.net/2066/172809 AB - Inflammation is a complex biologic response that is essential for eliminating microbial pathogens and repairing tissue after injury. AKI associates with intrarenal and systemic inflammation; thus, improved understanding of the cellular and molecular mechanisms underlying the inflammatory response has high potential for identifying effective therapies to prevent or ameliorate AKI. In the past decade, much knowledge has been generated about the fundamental mechanisms of inflammation. Experimental work in small animal models has revealed many details of the inflammatory response that occurs within the kidney after typical causes of AKI, including insights into the molecular signals released by dying cells, the role of pattern recognition receptors, the diverse subtypes of resident and recruited immune cells, and the phased transition from destructive to reparative inflammation. Although this expansion of the basic knowledge base has increased the number of mechanistically relevant targets of intervention, progress in developing therapies that improve AKI outcomes by modulation of inflammation remains slow. In this article, we summarize the most important recent developments in understanding the inflammatory mechanisms of AKI, highlight key limitations of the commonly used animal models and clinical trial designs that may prevent successful clinical application, and suggest priority approaches for research toward clinical translation in this area. TI - Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps EP - 379 SN - 1046-6673 IS - iss. 2 SP - 371 JF - Journal of the American Society of Nephrology VL - vol. 27 DO - http://dx.doi.org/10.1681/ASN.2015030261 ER - TY - JOUR AU - Pene, F. AU - Pickkers, P. AU - Hotchkiss, R.S. PY - 2016 UR - https://hdl.handle.net/2066/172870 TI - Is this critically ill patient immunocompromised? EP - 1054 SN - 0342-4642 IS - iss. 6 SP - 1051 JF - Intensive Care Medicine VL - vol. 42 DO - http://dx.doi.org/10.1007/s00134-015-4161-y ER - TY - JOUR AU - Heijden, H.H. van der AU - Truin, G.J. AU - Verhaeg, J. AU - Pol, P. van der AU - Lemson, J. PY - 2016 UR - https://hdl.handle.net/2066/171914 AB - INTRODUCTION: Capnography is used to monitor the endtidal carbon dioxide tension (EtCO 2 ) in exhaled gas. Sidestream capnography has great potential to monitor mechanically ventilated pediatric patients, given the continuous sampling from the endotracheal tube into a gas sensor. However, hemodynamic and respiratory impairments may reduce reliability and validity of sidestream capnography to monitor arterial carbon dioxide tension (PaCO 2) in critically ill, mechanically ventilated children. METHODS: In 47 mechanically ventilated pediatric patients (aged 0-14 years, median age 17.2 months), a total of 341 consecutive measurements of PaCO 2, EtCO 2 , respiratory and hemodynamic parameters were performed, and capnogram shape was determined. Validity was assessed with the Bland-Altman limit of agreement (loa), mixed models were used to adjust for variation between patients, and potential confounders were considered with multivariable analyses. RESULTS: EtCO 2 (mean 4.50 +/- 0.96 kPa) underestimated PaCO 2 (mean 5.37 +/- 0.87) considerably, resulting in a loa of 0.87 kPa [95% confidence interval (95% CI) -1.03;2.77] and 42.2% percentage error. The association improved significantly b = 0.54 [95 %CI = 0.45;0.64, P < 0.001] when corrected for individual differences. The association between EtCO 2 and PaCO 2 was not influenced by any of the potential confounders. CONCLUSIONS: Sidestream capnography in mechanically ventilated infants and children seems moderately reliable and valid when corrected for individual differences. Therefore, it could only be used with caution for trend estimation in the individual patient. TI - Validity of sidestream endtidal carbon dioxide measurement in critically ill, mechanically ventilated children. EP - 299 SN - 1155-5645 IS - iss. 3 SP - 294 JF - Paediatric Anaesthesia VL - vol. 26 N1 - 1 maart 2016 DO - https://doi.org/10.1111/pan.12827 ER - TY - JOUR AU - Haerkens, M.H.T.M. AU - Tan, E.C.T.H. AU - Bleeker, C.P. AU - Hoeven, J.G. van der PY - 2016 UR - https://hdl.handle.net/2066/165859 AB - The recent terror attacks in Paris and Brussels have made the subject of injuries caused by explosives, also known as 'blast injuries', a very current one. The Netherlands has limited experience with terrorist attacks. This means that Dutch medical care providers possibly do not have sufficient knowledge about dealing with blast injuries. After explaining the mechanisms of explosions and the effects that these have on the human body, we go on to provide 15 tips on the main principles of treating blast injuries. These tips will help healthcare providers to deal with the complex requirements of victims of terror. TI - [How to deal with blast injuries. 15 tips for healthcare providers] J2 - Wat te doen bij een bomaanslag? 15 tips SN - 0028-2162 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 160 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/165859/165859.pdf?sequence=1 ER - TY - JOUR AU - Middendorp, H. van AU - Kox, M. AU - Pickkers, P. AU - Evers, A.W. PY - 2016 UR - https://hdl.handle.net/2066/171774 AB - Expectancies play a major role for the treatment outcome of a broad variety of immune-mediated conditions and may strengthen or mimic the effects of regular long-term therapies. This study adds to a recently published study of Kox et al. (PNAS 111:7379-7384, 2014) on the ability to voluntarily influence the physiological stress response in healthy men after a training program consisting of meditation, breathing techniques, and exposure to cold, which found highly promising results on the clinical, autonomic, and immune response to experimentally induced inflammation (using the experimental human endotoxemia model). Within this project, a number of variables were included to assess the role of generalized (optimism, neuroticism) and specific outcome expectancies (related to the effects of the training on health) on the response to endotoxin administration after training. Indications were found that especially the generalized outcome expectancy optimism is a potential determinant of the autonomic (epinephrine: rho = 0.76, p < .01) and immune response (interleukin-10: rho = 0.60, p < .05) to induced inflammation after training, whereas more specific expectations with regard to the effects of the training could be especially relevant for the clinical symptom report (flu-like symptoms: rho = -0.71, p < .01). This proof-of-principle study provides first indications for potential innovative treatments to change immune-modulating responses by means of psychological mechanisms. If replicated, these findings may be used for predicting training responses and potentiate their effects by means of optimism-inducing interventions in patients with immune-mediated rheumatic conditions. TI - The role of outcome expectancies for a training program consisting of meditation, breathing exercises, and cold exposure on the response to endotoxin administration: a proof-of-principle study EP - 1085 SN - 0770-3198 IS - iss. 4 SP - 1081 JF - Clinical Rheumatology VL - vol. 35 DO - https://doi.org/10.1007/s10067-015-3009-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171774/171774.pdf?sequence=1 ER - TY - JOUR AU - Dinkla, S. AU - Eijk, L.T.G.J. van AU - Fuchs, B. AU - Schiller, J. AU - Joosten, I. AU - Brock, R.E. AU - Pickkers, P. AU - Bosman, G.J.C.G.M. PY - 2016 UR - https://hdl.handle.net/2066/172811 AB - BACKGROUND: Reduced erythrocyte survival and deformability may contribute to the so-called anemia of inflammation observed in septic patients. Erythrocyte structure and function are affected by both the membrane lipid composition and the organization. We therefore aimed to determine whether these parameters are affected during systemic inflammation. METHODS: A sensitive matrix-assisted laser desorption and ionization time-of-flight mass spectrometric method was used to investigate the effect of plasma components of 10 patients with septic shock and of 10 healthy volunteers subjected to experimental endotoxemia on erythrocyte membrane lipid composition. RESULTS: Incubation of erythrocytes from healthy control donors with plasma from patients with septic shock resulted in membrane phosphatidylcholine hydrolysis into lysophosphatidylcholine (LPC). Plasma from volunteers undergoing experimental human endotoxemia did not induce LPC formation. The secretory phospholipase A2 IIA concentration was enhanced up to 200-fold in plasma of septic patients and plasma from endotoxin-treated subjects, but did not correlate with the ability of these plasmas to generate LPC. Erythrocyte phosphatidylserine exposure increased up to two-fold during experimental endotoxemia. CONCLUSIONS: Erythrocyte membrane lipid remodeling as reflected by LPC formation and/or PS exposure occurs during systemic inflammation in a secretory phospholipase A2 IIA-independent manner. GENERAL SIGNIFICANCE: Sepsis-associated inflammation induces a lipid remodeling of the erythrocyte membrane that is likely to affect erythrocyte function and survival, and that is not fully mimicked by experimental endotoxemia. TI - Inflammation-associated changes in lipid composition and the organization of the erythrocyte membrane EP - 192 SN - 2214-6474 SP - 186 JF - Bba Clinical VL - vol. 5 DO - https://doi.org/10.1016/j.bbacli.2016.03.007 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172811/172811.pdf?sequence=1 ER - TY - THES AU - Eijk, L.T.G.J. van PY - 2016 SN - 9789463320658 UR - https://hdl.handle.net/2066/160309 PB - [S.l. : s.n.] TI - Iron and innate immunity N1 - RU Radboud Universiteit, 17 oktober 2016 N1 - Promotores : Pickkers, P., Swinkels, D.W. Co-promotor : Kox, M. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/160309/160309.pdf?sequence=1 ER - TY - JOUR AU - Vrancken, S.L.A.G. AU - Heijst, A.F.J. van AU - Hopman, J.C. AU - Liem, K.D. AU - Hoeven, J.G. van der AU - Boode, W.P. de PY - 2016 UR - https://hdl.handle.net/2066/168744 AB - OBJECTIVES: We investigated the accuracy of left-to-right shunt detection using transpulmonary ultrasound dilution (TPUD) and compared the agreement between pulmonary over systemic blood flow (Qp/Qs) ratio measured by TPUD [Qp/Qs(tpud)] and ultrasonic flow probes [Qp/Qs(ufp)]. METHODS: Seven newborn lambs under general anesthesia were connected to the TPUD monitor (COstatus) after insertion of arterial and central venous catheters. A Gore-Tex(R) shunt, inserted between the descending aorta and left pulmonary artery, was intermittently opened and closed while cardiac output was varied by blood withdrawals. Flow probes were placed around the main pulmonary artery (Qufp) and the descending aorta proximal (Qpre) and distal (Qpost) to the shunt insertion. Qp/Qs(ufp) was calculated as (Qufp+Qpre-Qpost)/Qufp. RESULTS: Seventy-two paired measurement sessions were analyzed. Shunts were detected by TPUD with a positive predictive value of 86%, a negative predictive value of 100%, a sensitivity of 100% and a specificity of 83%. The Bland-Altman analysis comparing Qp/Qs(tpud) and Qp/Qs(ufp) showed an overall mean bias (SD) of 0.1 (0.3), limits of agreement (LOA) of +/-0.6 and a percentage error of 34.8%. CONCLUSIONS: The qualitative diagnostic accuracy of TPUD for shunt detection is high. Modification of the algorithm seems required as shunt quantification by TPUD is accurate, but not yet very precise. TI - Detection and quantification of left-to-right shunting using transpulmonary ultrasound dilution (TPUD): a validation study in neonatal lambs EP - 932 SN - 0300-5577 IS - iss. 8 SP - 925 JF - Journal of Perinatal Medicine VL - vol. 44 DO - https://doi.org/10.1515/jpm-2015-0310 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/168744/168744.pdf?sequence=1 ER - TY - JOUR AU - Habes, Q.L.M. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171987 AB - - Overfeeding of critically ill patients is associated with a higher incidence of infections and an increased length of ventilation. However, trophic nutrition or permissive underfeeding appears to have no negative effect on the patient and may even provide a survival benefit.- Initiation of enteral nutrition within 24-48 hours after Intensive Care Unit (ICU) admission may reduce the number of complications and increase the chance of survival.- Total parenteral nutrition is associated with a higher risk of infections than enteral nutrition. This seems to be related to the higher calorie intake with parenteral nutrition rather than the route of administration.- In previously well-nourished patients, in whom enteral nutrition is only partially successful, it is safe to wait for up to 8 days before initiating supplemental parenteral nutrition.- In critically ill children, it is also safe to start supplemental parenteral nutrition at a late (on the 8th day after admission) rather than an early stage (within 24 hours of admission). Late supplemental parenteral nutrition may even result in fewer infectious complications and shorter hospitalisation. TI - [When enteral nutrition is not possible in intensive care patients: whether to wait or use parenteral nutrition?] SN - 0028-2162 IS - iss. 0 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 160 ER - TY - JOUR AU - Kiers, H.D. AU - Scheffer, G.J. AU - Hoeven, J.G. van der AU - Eltzschig, H.K. AU - Pickkers, P. AU - Kox, M. PY - 2016 UR - https://hdl.handle.net/2066/172742 AB - Hypoxia and immunity are highly intertwined at clinical, cellular, and molecular levels. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the intensive care unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts antiinflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacologic modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacologic modulation of hypoxia-signaling pathways in critically ill patients. TI - Immunologic Consequences of Hypoxia during Critical Illness EP - 249 SN - 0003-3022 IS - iss. 1 SP - 237 JF - Anesthesiology VL - vol. 125 DO - https://doi.org/10.1097/ALN.0000000000001163 ER - TY - JOUR AU - Messaoudi, S. El AU - Wouters, C.W. AU - Swieten, H.A. van AU - Pickkers, P. AU - Noyez, L. AU - Kievit, P.C. AU - Abbink, E.J. AU - Rasing-Hoogveld, J.H. AU - Bouw, T. AU - Peters, J.G. AU - Coenen, M.J.H. AU - Donders, A.R.T. AU - Riksen, N.P. AU - Rongen, G.A. PY - 2016 UR - https://hdl.handle.net/2066/169180 AB - Dipyridamole reduces reperfusion-injury in preclinical trials and may be beneficial in patients undergoing coronary angioplasty, but its effect on patients undergoing coronary artery bypass grafting (CABG) is unknown. We hypothesized that dipyridamole limits myocardial reperfusion-injury in patients undergoing CABG. The trial design was a double-blind trial randomizing between pretreatment with dipyridamole or placebo. In all, 94 patients undergoing elective on-pump CABG were recruited between February 2010 and June 2012. The primary endpoint was plasma high-sensitive (hs-) troponin-I at 6, 12, and 24 hours after reperfusion. Secondary endpoints were the occurrence of bleeding, arrhythmias, need for inotropic support, and intensive care unit length of stay. Finally, 79 patients (33 dipyridamole) were included in the per-protocol analysis. Dipyridamole did not significantly affect postoperative hs-troponin-I (change in plasma hs-troponin I -3% [95% confidence interval -23% to 36%]; P > 0.1). Secondary endpoints did not differ between groups. Dipyridamole prior to CABG does not significantly reduce postoperative hs-troponin release. TI - Effect of dipyridamole on myocardial reperfusion injury: A double-blind randomized controlled trial in patients undergoing elective coronary artery bypass surgery EP - 389 SN - 0009-9236 IS - iss. 4 SP - 381 JF - Clinical Pharmacology and Therapeutics VL - vol. 99 DO - https://doi.org/10.1002/cpt.106 ER - TY - JOUR AU - Stolk, R.F. AU - Poll, T. van der AU - Angus, D.C. AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Kox, M. PY - 2016 UR - https://hdl.handle.net/2066/171219 AB - Septic shock is a major cause of death worldwide and a considerable healthcare burden in the twenty-first century. Attention has shifted from damaging effects of the proinflammatory response to the detrimental role of antiinflammation, a phenomenon known as sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis may render patients vulnerable to secondary infections and is associated with impaired outcome. The immunoparalysis hypothesis compels us to reevaluate the current management of septic shock and to assess whether we are inadvertently compromising or altering the host immune response. In this perspective, we discuss the potential detrimental role of norepinephrine, the cornerstone treatment for septic shock, in sepsis-induced immunoparalysis. We provide a short overview of the current understanding of the immunologic pathophysiology of sepsis, followed by a detailed description of the immunomodulatory effects of norepinephrine and alternative vasopressors. We conclude that although the development of novel therapies aimed at reversing immunoparalysis is underway, the use of norepinephrine may aggravate the development, extent, and duration of sepsis-induced immunoparalysis. Current in vitro and animal data indicate that norepinephrine treatment exerts immunosuppressive and bacterial growth-promoting effects and may increase susceptibility toward infections. However, evidence in humans is circumstantial, as immunologic effects of norepinephrine have not been investigated properly in experimental or clinical studies. Alternatives such as vasopressin/selepressin, angiotensin II, and phenylephrine could have a fundamental advantage over norepinephrine with respect to their immunologic properties. However, also for these agents, in vivo immunologic data in humans are largely lacking. As such, human studies on the immunomodulatory properties of norepinephrine and viable alternatives are highly warranted. TI - Potentially Inadvertent Immunomodulation: Norepinephrine Use in Sepsis EP - 558 SN - 1073-449X IS - iss. 5 SP - 550 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 194 DO - https://doi.org/10.1164/rccm.201604-0862CP ER - TY - JOUR AU - Mooij, M.G. AU - Steeg, E. Van de AU - Rosmalen, J. van AU - Windster, J.D. AU - Koning, B.A.E. de AU - Vaes, W.H. AU - Groen, B.D. AU - Tibboel, D. AU - Wortelboer, H.M. AU - Wildt, S.N. de PY - 2016 UR - https://hdl.handle.net/2066/171296 AB - Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little is known on maturation of transporter protein expression levels, especially during early life. We aimed to study the protein expression of 10 transporters in liver tissue from fetuses, infants, and adults. Transporter protein expression levels [ATP-binding cassette transporter (ABC)B1, ABCG2, ABCC2, ABCC3, bile salt efflux pump, glucose transporter 1, monocarboxylate transporter 1, organic anion transporter polypeptide (OATP)1B1, OATP2B1, and organic cation/carnitine transporter 2) were quantified using ultraperformance liquid chromatography tandem mass spectrometry in snap-frozen postmortem fetal, infant, and adult liver samples. Protein expression was quantified in isolated crude membrane fractions. The possible association between postnatal and postmenstrual age versus protein expression was studied. We studied 25 liver samples, as follows: 10 fetal [median gestational age 23.2 wk (range 16.4-37.9)], 12 infantile [gestational age at birth 35.1 wk (27.1-41.0), postnatal age 1 wk (0-11.4)], and 3 adult. The relationship of protein expression with age was explored by comparing age groups. Correlating age within the fetal/infant age group suggested four specific protein expression patterns, as follows: stable, low to high, high to low, and low-high-low. The impact of growth and development on human membrane transporter protein expression is transporter-dependent. The suggested age-related differences in transporter protein expression may aid our understanding of normal growth and development, and also may impact the disposition of substrate drugs in neonates and young infants. TI - Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life EP - 1013 SN - 0090-9556 IS - iss. 7 SP - 1005 JF - Drug Metabolism and Disposition VL - vol. 44 DO - https://doi.org/10.1124/dmd.115.068577 ER - TY - JOUR AU - Oerlemans, A.J.M. AU - Wollersheim, H.C.H. AU - Sluisveld, N. van AU - Hoeven, J.G. van der AU - Dekkers, W.J.M. AU - Zegers, M. PY - 2016 UR - https://hdl.handle.net/2066/171342 AB - BACKGROUND: Internationally, there is no consensus on how to best deal with admission requests in cases of full ICU bed occupancy. Knowledge about the degree of dissension and insight into the reasons for this dissension is lacking. Information about the opinion of ICU physicians can be used to improve decision-making regarding allocation of ICU resources. The aim of this study was to: Assess which factors play a role in the decision-making process regarding the admission of ICU patients; Assess the adherence to a Dutch guideline pertaining to rationing of ICU resources; Investigate factors influencing the adherence to this guideline. METHODS: In March 2013, an online questionnaire was sent to all ICU physician members (n = 761, in 90 hospitals) of the Dutch Society for Intensive Care. RESULTS: 166 physicians (21.8 %) working in 64 different Dutch hospitals (71.1 %) completed the questionnaire. Factors associated with a patient's physical condition and quality of life were generally considered most important in admission decisions. Scenario-based adherence to the Dutch guideline "Admission request in case of full ICU bed occupancy" was found to be low (adherence rate 50.0 %). There were two main reasons for this poor compliance: unfamiliarity with the guideline and disagreement with the fundamental approach underlying the guideline. CONCLUSIONS: Dutch ICU physicians disagree about how to deal with admission requests in cases of full ICU bed occupancy. The results of this study contribute to the discussion about the fundamental principles regarding admission of ICU patients in case of full bed occupancy. TI - Rationing in the intensive care unit in case of full bed occupancy: a survey among intensive care unit physicians SN - 1471-2253 JF - BMC Anesthesiology VL - vol. 16 DO - https://doi.org/10.1186/s12871-016-0190-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171342/171342.pdf?sequence=1 ER - TY - JOUR AU - Matic, M. AU - Wildt, S.N. de AU - Elens, L. AU - Hoon, J.N. de AU - Annaert, P. AU - Tibboel, D. AU - Schaik, R.H. van AU - Allegaert, K. PY - 2016 UR - https://hdl.handle.net/2066/171443 AB - BACKGROUND: This study determined whether the SLC22A1 [encoding the organic cation transporter 1 (OCT1)] genotype could explain, in addition to the postmenstrual age (referring to gestational plus postnatal age) and CYP2D6 genotype, the tramadol (M) pharmacokinetic variability in early infancy. METHODS: Fifty infants, median postmenstrual age 39.5 (interquartile range: 36.8-41.3) weeks, received an i.v. M loading dose (2 mg/kg) followed by a continuous infusion (5-8 mg.kg.24 h). Blood was sampled from 4 to 24 hours after start of the M treatment, which generated 230 observations. M and O-desmethyltramadol (M1) concentrations were measured by high-performance liquid chromatography. RESULTS: Linear mixed-model analysis illustrated that the SLC22A1/OCT1 genotype was independently associated with a log-transformed M1/M ratio (P = 0.013), with carriers of <2 SLC22A1/OCT1 functional gene copies having a higher M1/M ratio (2.25; 95% CI, 2.01-2.48) than infants with 2 functional gene copies (1.86; 95% CI, 1.66-2.06). The CYP2D6/SLC22A1 combined genotype was associated with 57.8% higher M1/M ratio in carriers of >/=2 CYP2D6 functional gene copies and <2 SLC22A1/OCT1 functional gene copies compared with infants with <2 active CYP2D6 functional gene copies and SLC22A1/OCT1 normal activity (P < 0.001). CONCLUSIONS: These findings highlight the additional role of SLC22A1/OCT1 genetics in M1 exposure in neonates. They also suggest that OCT1 is already active early after birth, which may have impact on the disposition of other OCT1 substrates in this population. TI - SLC22A1/OCT1 Genotype Affects O-desmethyltramadol Exposure in Newborn Infants EP - 492 SN - 0163-4356 IS - iss. 4 SP - 487 JF - Therapeutic Drug Monitoring VL - vol. 38 DO - https://doi.org/10.1097/FTD.0000000000000307 ER - TY - JOUR AU - Vet, N.J. AU - Kleiber, N. AU - Ista, E. AU - Hoog, M. de AU - Wildt, S.N. de PY - 2016 UR - https://hdl.handle.net/2066/171472 AB - This article discusses the rationale of sedation in respiratory failure, sedation goals, how to assess the need for sedation as well as effectiveness of interventions in critically ill children, with validated observational sedation scales. The drugs and non-pharmacological approaches used for optimal sedation in ventilated children are reviewed, and specifically the rationale for drug selection, including short- and long-term efficacy and safety aspects of the selected drugs. The specific pharmacokinetic and pharmacodynamic aspects of sedative drugs in the critically ill child and consequences for dosing are presented. Furthermore, we discuss different sedation strategies and their adverse events, such as iatrogenic withdrawal syndrome and delirium. These principles can guide clinicians in the choice of sedative drugs in pediatric respiratory failure. TI - Sedation in Critically Ill Children with Respiratory Failure SN - 2296-2360 JF - Frontiers in Pediatrics VL - vol. 4 DO - https://doi.org/10.3389/fped.2016.00089 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171472/171472.pdf?sequence=1 ER - TY - JOUR AU - Vet, N.J. AU - Wildt, S.N. de AU - Verlaat, C.W.M. AU - Mooij, M.G. AU - Tibboel, D. AU - Hoog, M. de AU - Buysse, C.M. PY - 2016 UR - https://hdl.handle.net/2066/171502 AB - OBJECTIVE: Our earlier pediatric daily sedation interruption trial showed that daily sedation interruption in addition to protocolized sedation in critically ill children does not reduce duration of mechanical ventilation, length of stay, or amounts of sedative drugs administered when compared with protocolized sedation only, but undersedation was more frequent in the daily sedation interruption + protocolized sedation group. We now report the preplanned analysis comparing short-term health-related quality of life and posttraumatic stress symptoms between the two groups. DESIGN: Preplanned prospective part of a randomized controlled trial. SETTING: Two tertiary medical-surgical PICUs in the Netherlands. PATIENTS: Critically ill children requiring mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eight weeks after a child's discharge from the PICU, health-related quality of life was assessed with the validated Child Health Questionnaire and, only for children above 4 years old, posttraumatic stress was assessed with the Dutch Children's Responses to Trauma Inventory. Additionally, health-related quality of life of all study patients was compared with Dutch normative data. Of the 113 patients from two participating centers in the original study, 96 patients were eligible for follow-up and 64 patients were included (response rate, 67%). No difference was found with respect to health-related quality of life between the two study groups. None of the eight children more than 4 years old showed posttraumatic stress symptoms. CONCLUSIONS: Daily sedation interruption in addition to protocolized sedation for critically ill children did not seem to have an effect on short-term health-related quality of life. Also in view of the earlier found absence of effect on clinical outcome, we cannot recommend the use of daily sedation interruption + protocolized sedation. TI - Short-Term Health-Related Quality of Life of Critically Ill Children Following Daily Sedation Interruption EP - e520 SN - 1529-7535 IS - iss. 11 SP - e513 JF - Pediatric Critical Care Medicine VL - vol. 17 DO - https://doi.org/10.1097/PCC.0000000000000956 ER - TY - JOUR AU - Vet, N.J. AU - Wildt, S.N. de AU - Tibboel, D. AU - Hoog, M. de PY - 2016 UR - https://hdl.handle.net/2066/171552 TI - Striving for an effective but parsimonious use of sedation in pediatric intensive care EP - 1104 SN - 0342-4642 IS - iss. 6 SP - 1103 JF - Intensive Care Medicine VL - vol. 42 DO - https://doi.org/10.1007/s00134-016-4334-3 ER - TY - JOUR AU - Kleiber, N. AU - Wildt, S.N. de AU - Cortina, G. AU - Clifford, M. AU - Rosmalen, J. van AU - Dijk, M. van AU - Tibboel, D. AU - Millar, J. PY - 2016 UR - https://hdl.handle.net/2066/171626 AB - OBJECTIVE: To compare the effect of two sedation practices on cardiovascular stability during the early postoperative period in young infants following cardiac surgery: the routine early use of midazolam infusion (preemptive sedation) and the discretionary use of sedatives tailored to the patient's clinical condition (targeted sedation). DESIGN: Retrospective cohort study with matched controls. SETTING: A 15-bedded pediatric cardiac ICU. PATIENTS: Sedation strategies were compared by matching patients before and after the introduction of a targeted sedation guideline, replacing the existing practice of preemptive sedation. Inclusion criteria were age less than 6 months and cardiopulmonary bypass time greater than 150 minutes. Matching criteria were surgical procedure, age, and duration of cardiopulmonary bypass and cross-clamp. The main outcome was cardiovascular instability, defined by the presence of one of the following criteria in the first 12 hours after PICU admission: 1) simultaneous administration of greater than or equal to two inotropic or vasopressor drugs; 2) administration of greater than 60 mL/kg fluid boluses. Secondary outcomes were: 1) markers of cardiac output adequacy (heart rate, blood pressure, vasoactive inotropic score, urine output, volume of fluid boluses, central venous oxygen saturation, lactate); 2) occurrence of adverse events (cardiac arrest, extracorporeal membrane oxygenation, death); 3) sedatives administered and depth of sedation. INTERVENTIONS: Introduction of a guideline of targeted sedation. MEASUREMENTS AND MAIN RESULTS: Thirty-three patients with preemptive sedation were matched to 33 patients with targeted sedation. Targeted sedation resulted in less frequent oversedation, without compromising cardiovascular stability, as indicated by similar occurrence of cardiovascular instability (68.8% with preemptive sedation vs 62.5% with targeted sedation; p = 0.53) and adverse events, and similar markers of cardiac output adequacy. Although all preemptively sedated patients received an infusion of midazolam in the first 12 hours after surgery, only 19.4% of patients in the targeted sedation group received a sedative infusion (p < 0.001). CONCLUSIONS: Our data suggest that after high-risk cardiac surgery in young infants, routine sedation with midazolam may not prevent low cardiac output syndrome. When accompanied by a careful assessment of level of sedation, routine sedation of infants after high-risk cardiac surgery can be avoided without compromising hemodynamic stability or patient safety. The potential benefit of this approach is reduced exposure to sedative. TI - A Comparative Analysis of Preemptive Versus Targeted Sedation on Cardiovascular Stability After High-Risk Cardiac Surgery in Infants EP - 331 SN - 1529-7535 IS - iss. 4 SP - 321 JF - Pediatric Critical Care Medicine VL - vol. 17 DO - https://doi.org/10.1097/PCC.0000000000000663 ER - TY - JOUR AU - Kleiber, N. AU - Tromp, K. AU - Tibboel, D. AU - Wildt, S.N. de PY - 2016 UR - https://hdl.handle.net/2066/171861 TI - Trial Recruitment in the Pediatric Intensive Care: Ask Consent Before You Start?! EP - 10 SN - 0090-3493 IS - iss. 5 SP - e309 JF - Critical Care Medicine VL - vol. 44 DO - https://doi.org/10.1097/CCM.0000000000001551 ER - TY - JOUR AU - Mooij, M.G. AU - Nies, A.T. AU - Knibbe, C.A. AU - Schaeffeler, E. AU - Tibboel, D. AU - Schwab, M. AU - Wildt, S.N. de PY - 2016 UR - https://hdl.handle.net/2066/172297 AB - Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug-drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children. TI - Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics EP - 524 SN - 0312-5963 IS - iss. 5 SP - 507 JF - Clinical Pharmacokinetics VL - vol. 55 DO - https://doi.org/10.1007/s40262-015-0328-5 ER - TY - JOUR AU - Oostenbrink, R. AU - Wildt, S.N. de PY - 2016 UR - https://hdl.handle.net/2066/172362 TI - Drug trials: Kids are no little adults and not all kids are the same EP - 112 SN - 0895-4356 SP - 111 JF - Journal of Clinical Epidemiology VL - vol. 71 DO - https://doi.org/10.1016/j.jclinepi.2015.06.020 ER - TY - JOUR AU - Prytula, A.A. AU - Cransberg, K. AU - Bouts, A.H. AU - Schaik, R.H. van AU - Jong, H. de AU - Wildt, S.N. de AU - Mathot, R.A.A. PY - 2016 UR - https://hdl.handle.net/2066/171654 AB - BACKGROUND: The aim of this study was to develop a population pharmacokinetic model of tacrolimus in paediatric patients at least 1 year after renal transplantation and simulate individualised dosage regimens. PATIENTS AND METHODS: We included 54 children with median age of 11.1 years (range 3.8-18.4 years) with 120 pharmacokinetic profiles performed over 2 to 4 h. The pharmacokinetic analysis was performed using the non-linear mixed-effects modelling software (NONMEM((R))). The impact of covariates including concomitant medications, age, the cytochrome P450 (CYP) CYP3A5*3 gene and the adenosine triphosphate binding cassette protein B1 (ABCB1) 3435 C-->T gene polymorphism on tacrolimus pharmacokinetics was analysed. The final model was externally validated on an independent dataset and dosing regimens were simulated. RESULTS: A two-compartment model adequately described tacrolimus pharmacokinetics. Apparent oral clearance (CL/F) was associated with weight (allometric scaling) but not age. Children with lower weight and CYP3A5 expressers required higher weight-normalised tacrolimus doses. CL/F was inversely associated with haematocrit (P < 0.05) and gamma-glutamyl transpeptidase (gammaGT) (P < 0.001) and was increased by 45 % in carriers of the CYP3A5*1 allele (P < 0.001). CL/F was not associated with concomitant medications. Dose simulations show that a daily tacrolimus dose of 0.2 mg/kg generates a pre-dose concentration (C 0) ranging from 5 to 10 microg/L depending on the weight and CYP3A5 polymorphism. The median area under the plasma concentration-time curve (AUC) corresponding with a tacrolimus C 0 of 4-8 microg/L was 97 h.microg/L (interquartile range 80-120). CONCLUSIONS: In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A5*1 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A5*1 allele have higher weight-normalised tacrolimus dose requirements. TI - The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients EP - 1143 SN - 0312-5963 IS - iss. 9 SP - 1129 JF - Clinical Pharmacokinetics VL - vol. 55 DO - https://doi.org/10.1007/s40262-016-0390-7 ER - TY - JOUR AU - Vet, N.J. AU - Wildt, S.N. de AU - Verlaat, C.W. AU - Knibbe, C.A. AU - Mooij, M.G. AU - Woensel, J.B. van AU - Rosmalen, J. van AU - Tibboel, D. AU - Hoog, M. de PY - 2016 UR - https://hdl.handle.net/2066/172433 AB - PURPOSE: To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children. METHODS: In this multicenter randomized controlled trial in three pediatric intensive care units in the Netherlands, mechanically ventilated critically ill children with need for sedative drugs were included. They were randomly assigned to either DSI + PS or PS only. Children in both study arms received sedation adjusted on the basis of validated sedation scores. Provided a safety screen was passed, children in the DSI + PS group received daily blinded infusions of saline; children in the PS group received blinded infusions of the previous sedatives/analgesics. If a patient's sedation score indicated distress, the blinded infusions were discontinued, a bolus dose of midazolam was given and the 'open' infusions were resumed: DSI + PS at half of infusion rate, PS at previous infusion rate. The primary endpoint was the number of ventilator-free days at day 28. Data were analyzed by intention to treat. RESULTS: From October 2009 to August 2014, 129 children were randomly assigned to DSI + PS (n = 66) or PS (n = 63). The study was terminated prematurely due to slow recruitment rates. Median number of ventilator-free days did not differ: DSI + PS 24.0 days (IQR 21.6-25.8) versus PS 24.0 days (IQR 20.6-26.0); median difference 0.02 days (95 % CI -0.91 to 1.09), p = 0.90. Median ICU and hospital length of stay were similar in both groups: DSI + PS 6.9 days (IQR 5.2-11.0) versus PS 7.4 days (IQR 5.3-12.8), p = 0.47, and DSI + PS 13.3 days (IQR 8.6-26.7) versus PS 15.7 days (IQR 9.3-33.2), p = 0.19, respectively. Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 versus 0/63, p = 0.03), though no causal relationship to the intervention could be established. Median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6-22.6) versus PS 17.0 mg/kg (IQR 8.2-39.8), p = 0.11. CONCLUSION: In critically ill children, daily sedation interruption in addition to protocolized sedation did not improve clinical outcome and was associated with increased mortality compared with protocolized sedation only. TI - A randomized controlled trial of daily sedation interruption in critically ill children EP - 244 SN - 0342-4642 IS - iss. 2 SP - 233 JF - Intensive Care Medicine VL - vol. 42 DO - https://doi.org/10.1007/s00134-015-4136-z ER - TY - JOUR AU - Vet, N.J. AU - Brussee, J.M. AU - Hoog, M. de AU - Mooij, M.G. AU - Verlaat, C.W.M. AU - Jerchel, I.S. AU - Schaik, R.H. van AU - Koch, B.C. AU - Tibboel, D. AU - Knibbe, C.A. AU - Wildt, S.N. de PY - 2016 UR - https://hdl.handle.net/2066/165109 AB - RATIONALE: Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES: To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children. METHODS: From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-alpha), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MEASUREMENTS AND MAIN RESULTS: In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ. CONCLUSIONS: Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity. TI - Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children EP - 66 SN - 1073-449X IS - iss. 1 SP - 58 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 194 DO - https://doi.org/10.1164/rccm.201510-2114OC ER - TY - JOUR AU - Kleiber, N. AU - Wildt, S.N. de AU - Cortina, G. AU - Clifford, M. AU - Ducruet, T. AU - Tibboel, D. AU - Millar, J. PY - 2016 UR - https://hdl.handle.net/2066/167192 AB - OBJECTIVES: To determine the cardiovascular tolerance of clonidine used as a first-line sedative after cardiac surgery in small infants. DESIGN: Retrospective chart review. SETTING: A tertiary and quaternary referral cardiac PICU. PATIENTS: All infants younger than 2 months who received a clonidine infusion for sedation after cardiac surgery from October 2011 to July 2013. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Heart rate, blood pressure, central venous and left atrial pressure, vasoactive inotropic score, volume of fluid bolus, and lactate and central mixed venous saturation were assessed. Preinfusion values were compared with postinfusion values. Of 224 potentially eligible patients, only 23 infants met inclusion criteria, as most patients only received high doses of morphine and some received midazolam instead of clonidine. Clonidine administration was started at a median of 12 hours after surgery (Q1-Q3, 5-23), and infusion rate was 0.5-2 mug/kg/hr for a median duration of 30 hours (Q1-Q3, 12-54). Heart rate decreased (maximal mean decrease: 12% [149 beats/min (SD, 17) to 131 beats/min (SD, 17)]; p < 0.0001). Apart from a transient and limited drop in diastolic blood pressure of 13% (maximal mean decrease: from 42.8 mm Hg [SD, 5.9] to 37.1 mm Hg [SD, 4.0]; p = 0.018), all other cardiovascular variables were stable or improved. A contemporaneous cohort of patients who received midazolam, did so sooner after surgery, stayed longer in the PICU and showed less favorable hemodynamics. CONCLUSIONS: IV clonidine as sedative added to morphine in selected patients seems hemodynamically safe. The observed decrease in heart rate and diastolic blood pressure seems of minimal clinical importance as all other hemodynamic variables remained stable or improved. The safety of clonidine given early after cardiac surgery as alternative to midazolam merits further study. TI - Clonidine as a First-Line Sedative Agent After Neonatal Cardiac Surgery: Retrospective Cohort Study EP - 341 SN - 1529-7535 IS - iss. 4 SP - 332 JF - Pediatric Critical Care Medicine VL - vol. 17 DO - https://doi.org/10.1097/PCC.0000000000000672 ER - TY - JOUR AU - Matic, M. AU - Bosch, G.E. van den AU - Wildt, S.N. de AU - Tibboel, D. AU - Schaik, R.H. van PY - 2016 UR - https://hdl.handle.net/2066/172622 AB - Pain sensitivity is an inherited factor that varies strongly between individuals. We investigated whether genetic polymorphisms in the candidate genes COMT, OPRM1, OPRD1, TAOK3, TRPA1, TRPV1, and SCN9A are contributing to experimental pain variability between children. Our study included 136 children and adolescents (8-18 years). Cold and heat pain thresholds were determined with a Thermal Sensory Analyzer. Women and young children were significantly more sensitive to pain (P < 0.05). After correction for age, gender, reaction time, and correction for multiple testing, OPRM1 118A>G G-allele carriers (AG and GG) rated the hot stimulus as significantly less painful than did OPRM1 118A>G AA genotyped individuals (2[1-5] vs 7 [3-9], respectively; P = 0.00005). Additionally, OPRM1 118G allele carriers reached more frequently the minimum temperature limit (44% vs 17%, respectively; P = 0.003) and maximum temperature limit (52% vs 24%, respectively; P = 0.0052), indicative for lower pain sensitivity. The combined genotype, based on expected pain sensitivity, OPRM1 118AA/COMT 472 GA or AA genotyped children, was associated with lower pain thresholds (ie, higher pain sensitivity) than were the OPRM1 118GA or GG/COMT 472GG genotyped children. This is the first study reporting on genetic variants and experimental thermal pain in children and adolescents. OPRM1 rs1799971 and the combined OPRM1/COMT genotype could serve as biomarkers for pain sensitivity. TI - Genetic variants associated with thermal pain sensitivity in a paediatric population EP - 2482 SN - 0304-3959 IS - iss. 11 SP - 2476 JF - Pain VL - vol. 157 DO - https://doi.org/10.1097/j.pain.0000000000000664 ER - TY - JOUR AU - Mooij, M.G. AU - Koning, B.E. de AU - Lindenbergh-Kortleve, D.J. AU - Simons-Oosterhuis, Y. AU - Groen, B.D. AU - Tibboel, D. AU - Samsom, J.N. AU - Wildt, S.N. de PY - 2016 UR - https://hdl.handle.net/2066/172709 AB - The intestinal influx oligopeptide transporter peptide transporter 1 (PEPT1) (SLC15A1) is best known for nutrient-derived di- and tripeptide transport. Its role in drug absorption is increasingly recognized. To better understand the disposition of PEPT1 substrate drugs in young infants, we studied intestinal PEPT1 mRNA expression and tissue localization across the pediatric age range. PEPT1 mRNA expression was determined using real-time reverse-transcription polymerase chain reaction in small intestinal tissues collected from surgical procedures (neonates and infants) or biopsies (older children and adolescents). PEPT1 mRNA relative to villin mRNA expression was compared between neonates/infants and older children/adolescents. PEPT1 was visualized in infant tissue using immunohistochemical staining. Other transporters [multidrug resistance protein 1 (MDR1), multidrug resistance-like protein 2 (MRP2), and organic anion transporter polypeptide 2B1 (OATP2B1)] were also stained to describe the localization in relation to PEPT1. Twenty-six intestinal samples (n = 20 neonates/infants, n = 2 pediatric, n = 4 adolescents) were analyzed. The young infant samples were collected at a median (range) gestational age at birth of 29.2 weeks (24.7-40) and postnatal age of 2.4 weeks (0-16.6). The PEPT1 mRNA expression of the neonates/infants was only marginally lower (0.8-fold) than the older children (P < 0.05). Similar and clear apical PEPT1 and MRP2 staining, apical and lateral MDR1 staining, and intraepithelial OATP2B1 staining at the basolateral membrane of the enterocyte were detected in 12 infant and 2 adolescent samples. Although small intestinal PEPT1 expression tended to be lower in neonates than in older children, this difference is small and tissue distribution is similar. This finding suggests similar oral absorption of PEPT1 substrates across the pediatric age range. TI - Human Intestinal PEPT1 Transporter Expression and Localization in Preterm and Term Infants EP - 1019 SN - 0090-9556 IS - iss. 7 SP - 1014 JF - Drug Metabolism and Disposition VL - vol. 44 DO - https://doi.org/10.1124/dmd.115.068809 ER - TY - JOUR AU - Franken, L.G. AU - Andrews, L.M. AU - Slooff, V.D. AU - Wildt, S.N. de AU - Koch, B.C. PY - 2016 UR - https://hdl.handle.net/2066/172851 AB - The authors discuss the case of a 14-year-old girl who was transferred to the ICU of our hospital with ethanol intoxication (3.3 g/L), loss of consciousness (E5M3V1), and severe amnesia on recovery that was suspected of gamma-hydroxybutyric acid (GHB) intoxication. STAT toxicology screening may be necessary, when sexual assault under GHB intoxication is suspected. Therefore, the initial analysis of a urine sample was performed with a new enzymatic assay analysis for GHB. The enzymatic assay reported a GHB concentration of 26 mg/L, which is above the cut-off value of 10 mg/L. This cut-off value is to differentiate endogenous and exogenous levels because low levels of GHB occur naturally in the body. However, confirmation of these results by gas chromatography, which is common practice to confirm a positive GHB, gave a negative result. This discrepancy is probably contributed to interference of ethanol with the assay. This is a substantial downside of the GHB rapid screening, since the combination of GHB and ethanol is common. It is therefore advised to confirm that the positive GHB results are lower than 50 mg/L by gas chromatography, when using the rapid screening. This way the false-positive results and consequent inappropriate social and legal actions may be avoided. TI - Intoxication of a Young Girl Reveals the Pitfalls of GHB Rapid Screening EP - 3 SN - 0163-4356 IS - iss. 1 SP - 1 JF - Therapeutic Drug Monitoring VL - vol. 38 DO - https://doi.org/10.1097/FTD.0000000000000244 ER - TY - JOUR AU - Lock, J. AU - Bekker-Grob, E.W. de AU - Urhan, G. AU - Peters, M. AU - Meijer, K. AU - Brons, P.P. AU - Meer, F.J. van der AU - Driessens, M.H. AU - Collins, P.W. AU - Fijnvandraat, K. AU - Leebeek, F.W. AU - Cnossen, M.H. AU - Laros-van Gorkom, B.A.P. AU - Wildt, S.N. de AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/165633 AB - INTRODUCTION: Patients', parents' and providers' preferences with regard to medical innovations may have a major impact on their implementation. AIM: To evaluate barriers and facilitators for individualized pharmacokinetic (PK)-guided dosing of prophylaxis in haemophilia patients, parents of young patients, and treating professionals by discrete choice experiment (DCE) questionnaire. PATIENTS/METHODS: The study population consisted of patients with haemophilia currently or previously on prophylactic treatment with factor concentrate (n = 114), parents of patients aged 12-18 years (n = 19) and haemophilia professionals (n = 91). DCE data analysis was performed, taking preference heterogeneity into account. RESULTS: Overall, patients and parents, and especially professionals were inclined to opt for PK-guided dosing of prophylaxis. In addition, if bleeding was consequently reduced, more frequent infusions were acceptable. However, daily dosing remained an important barrier for all involved. 'Reduction of costs for society' was a facilitator for implementation in all groups. CONCLUSIONS: To achieve implementation of individualized PK-guided dosing of prophylaxis in haemophilia, reduction of bleeding risk and reduction of costs for society should be actively discussed as they are motivating for implementation; daily dosing is still reported to be a barrier for all groups. The knowledge of these preferences will enlarge support for this innovation, and aid in the drafting of implementable guidelines and information brochures for patients, parents and professionals. TI - Facilitating the implementation of pharmacokinetic-guided dosing of prophylaxis in haemophilia care by discrete choice experiment EP - e10 SN - 1351-8216 IS - iss. 1 SP - e1 JF - Haemophilia VL - vol. 22 DO - https://doi.org/10.1111/hae.12851 ER - TY - JOUR AU - Groenendael, R. van AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/172342 TI - Does high-dose perioperative use of statins ameliorate acute kidney injury following cardiac surgery? EP - e1237 SN - 2072-1439 IS - iss. 10 SP - E1235 JF - Journal of Thoracic Disease VL - vol. 8 DO - https://doi.org/10.21037/jtd.2016.10.22 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172342/172342.pdf?sequence=1 ER - TY - JOUR AU - Velasquez, T. AU - Mackey, G. AU - Lusk, J. AU - Kyle, U.G. AU - Rood, P.J.T. AU - Frenzel, T. AU - Verhage, R. AU - Bonn, M. AU - Pickkers, P. AU - Hoeven, J.G. van der AU - Boogaard, M.H.W.A. van den AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/172381 TI - ESICM LIVES 2016: part three : Milan, Italy. 1-5 October 2016. EP - 28 SN - 2197-425X IS - iss. 1 SP - 28 JF - Intensive Care Medicine Experimental VL - vol. 4 DO - https://doi.org/10.1186/s40635-016-0100-7 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172381/172381.pdf?sequence=1 ER - TY - JOUR AU - Burt, T. AU - Yoshida, K. AU - Lappin, G. AU - Vuong, L. AU - John, C. AU - Wildt, S.N. de AU - Sugiyama, Y. AU - Rowland, M. PY - 2016 UR - https://hdl.handle.net/2066/170970 TI - Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development EP - 88 SN - 1752-8054 IS - iss. 2 SP - 74 JF - Cts-Clinical and Translational Science VL - vol. 9 DO - https://doi.org/10.1111/cts.12390 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/170970/170970.pdf?sequence=1 ER - TY - JOUR AU - Zegers, H.W. AU - Hesselink, G. AU - Geense, W. AU - Vincent, C. AU - Wollersheim, H. PY - 2016 UR - https://hdl.handle.net/2066/172502 AB - OBJECTIVE: To provide an overview of effective interventions aimed at reducing rates of adverse events in hospitals. DESIGN: Systematic review of systematic reviews. DATA SOURCES: PubMed, CINAHL, PsycINFO, the Cochrane Library and EMBASE were searched for systematic reviews published until October 2015. STUDY SELECTION: English-language systematic reviews of interventions aimed at reducing adverse events in hospitals, including studies with an experimental design and reporting adverse event rates, were included. Two reviewers independently assessed each study's quality and extracted data on the study population, study design, intervention characteristics and adverse patient outcomes. RESULTS: Sixty systematic reviews with moderate to high quality were included. Statistically significant pooled effect sizes were found for 14 types of interventions, including: (1) multicomponent interventions to prevent delirium; (2) rapid response teams to reduce cardiopulmonary arrest and mortality rates; (3) pharmacist interventions to reduce adverse drug events; (4) exercises and multicomponent interventions to prevent falls; and (5) care bundle interventions, checklists and reminders to reduce infections. Most (82%) of the significant effect sizes were based on 5 or fewer primary studies with an experimental study design. CONCLUSIONS: The evidence for patient-safety interventions implemented in hospitals worldwide is weak. The findings address the need to invest in high-quality research standards in order to identify interventions that have a real impact on patient safety. Interventions to prevent delirium, cardiopulmonary arrest and mortality, adverse drug events, infections and falls are most effective and should therefore be prioritised by clinicians. TI - Evidence-based interventions to reduce adverse events in hospitals: a systematic review of systematic reviews SN - 2044-6055 IS - iss. 9 SP - e012555 JF - BMJ Open VL - vol. 6 DO - https://doi.org/10.1136/bmjopen-2016-012555 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172502/172502.pdf?sequence=1 ER - TY - JOUR AU - Novakovic, B. AU - Habibi, E. AU - Wang, S.Y. AU - Arts, R.J. AU - Davar, R. AU - Megchelenbrink, W. AU - Kim, B. AU - Kuznetsova, T. AU - Kox, M. AU - Zwaag, J. AU - Matarese, F. AU - Heeringen, S.J. van AU - Janssen-Megens, E.M. AU - Sharifi, N. AU - Wang, C. AU - Keramati, F. AU - Schoonenberg, V. AU - Flicek, P. AU - Clarke, L. AU - Pickkers, P. AU - Heath, S. AU - Gut, I. AU - Netea, M.G. AU - Martens, J.H. AU - Logie, C. AU - Stunnenberg, H.G. PY - 2016 UR - https://hdl.handle.net/2066/165879 AB - Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, beta-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo beta-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. VIDEO ABSTRACT. TI - beta-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance EP - 1368 SN - 0092-8674 IS - iss. 5 SP - 1354 JF - Cell VL - vol. 167 DO - https://doi.org/10.1016/j.cell.2016.09.034 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/165879/165879.pdf?sequence=1 ER - TY - JOUR AU - Kiers, H.D. AU - Kox, M. AU - Heijden, W.A. van der AU - Riksen, N.P. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/169179 TI - Aspirin may improve outcome in sepsis by augmentation of the inflammatory response SN - 0342-4642 IS - iss. 6 SP - 1096 JF - Intensive Care Medicine VL - vol. 42 DO - https://doi.org/10.1007/s00134-016-4264-0 ER - TY - JOUR AU - Douw, G. AU - Huisman-de Waal, G.J. AU - Zanten, A.R. van AU - Hoeven, J.G. van der AU - Schoonhoven, L. PY - 2016 UR - https://hdl.handle.net/2066/171075 AB - BACKGROUND: Nurses' 'worry' is used as a calling criterion in many Rapid Response Systems, however it is valued inconsistently. Furthermore, barriers to call the Rapid Response Team can cause delay in escalating care. The literature identifies nine indicators which trigger nurses to worry about a patient's condition. OBJECTIVES: The objective of this study is to determine the significance of nurses' 'worry' and/or indicators underlying 'worry' to predict unplanned Intensive-Care/High-Dependency-Unit admission or unexpected mortality among surgical ward patients. DESIGN: A prospective cohort study. SETTINGS: A 500-bed tertiary University affiliated teaching hospital. PARTICIPANTS: Adult, native speaking surgical patients, admitted to three surgical wards (traumatology, vascular- and abdominal/oncological surgery). We excluded patients with a non-ICU policy or with no curative treatment. Mentally incapacitated patients were also excluded. METHODS: We developed a new clinical assessment tool, the Dutch-Early-Nurse-Worry-Indicator-Score (DENWIS) based on signs underlying 'worry'. Nurses systematically scored their 'worry' and the DENWIS once per shift or at any moment of 'worry'. DENWIS measurements were linked to routinely measured vital signs. The composite endpoint was unplanned Intensive-Care/High-Dependency-Unit admission or unexpected mortality. The DENWIS-indicators were included in a univariate and multivariate logistic regression analysis, subsequently inserting 'worry' and the Early Warning Score into the model. We calculated the area under the receiver-operating characteristics curve. RESULTS: In 3522 patients there were 102 (2.9%) patients with unplanned Intensive Care Unit/High Dependency Unit-admissions or unexpected mortality. 'Worry' (0.81) and the DENWIS-model (0.85) had a lower area under the receiver-operating characteristics curve than the Early Warning Score (0.86). Adding 'worry' and the Early Warning Score to the DENWIS-model resulted in higher areas under the receiver operating characteristics curves (0.87 and 0.91, respectively) compared with the Early Warning Score only based on vital signs. CONCLUSIONS: In this single-center study we showed that adding the Early Warning Score based on vital signs to the DENWIS-indicators improves prediction of unplanned Intensive-Care/High-Dependency-Unit admission or unexpected mortality. TI - Nurses' 'worry' as predictor of deteriorating surgical ward patients: A prospective cohort study of the Dutch-Early-Nurse-Worry-Indicator-Score EP - 140 SN - 0020-7489 SP - 134 JF - International Journal of Nursing Studies VL - vol. 59 DO - https://doi.org/10.1016/j.ijnurstu.2016.04.006 ER - TY - JOUR AU - Timmermans, K. AU - Kox, M. AU - Vaneker, M. AU - Berg, M. van den AU - John, A. AU - Laarhoven, A. van AU - Hoeven, H. van der AU - Scheffer, G.J. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171199 AB - PURPOSE: Danger-associated molecular patterns (DAMPs) released of trauma could contribute to an immune suppressed state that renders patients vulnerable towards nosocomial infections. We investigated DAMP release in trauma patients, starting in the prehospital phase, and assessed its relationship with immune suppression and nosocomial infections. METHODS: Blood was obtained from 166 adult trauma patients at the trauma scene, emergency room (ER), and serially afterwards. Circulating levels of DAMPs and cytokines were determined. Immune suppression was investigated by determination of HLA-DRA gene expression and ex vivo lipopolysaccharide-stimulated cytokine production. RESULTS: Compared with healthy controls, plasma levels of nuclear DNA (nDNA) and heat shock protein-70 (HSP70) but not mitochondrial DNA were profoundly increased immediately following trauma and remained elevated for 10 days. Plasma cytokines were increased at the ER, and levels of anti-inflammatory IL-10 but not of pro-inflammatory cytokines peaked at this early time-point. HLA-DRA expression was attenuated directly after trauma and did not recover during the follow-up period. Plasma nDNA (r = -0.24, p = 0.006) and HSP70 (r = -0.38, p < 0.0001) levels correlated negatively with HLA-DRA expression. Ex vivo cytokine production revealed an anti-inflammatory phenotype already at the trauma scene which persisted in the following days, characterized by attenuated TNF-alpha and IL-6, and increased IL-10 production. Finally, higher concentrations of nDNA and a further decrease of HLA-DRA expression were associated with infections. CONCLUSIONS: Plasma levels of DAMPs are associated with immune suppression, which is apparent within minutes/hours following trauma. Furthermore, aggravated immune suppression during the initial phase following trauma is associated with increased susceptibility towards infections. TI - Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients EP - 561 SN - 0342-4642 IS - iss. 4 SP - 551 JF - Intensive Care Medicine VL - vol. 42 DO - https://doi.org/10.1007/s00134-015-4205-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171199/171199.pdf?sequence=1 ER - TY - JOUR AU - Tak, R.O. AU - Semmekrot, B.A. AU - Warris, A. AU - Yntema, J.L. AU - Stelma, F.F. AU - Neeleman, C. PY - 2016 UR - https://hdl.handle.net/2066/172009 TI - Bacterial Tracheitis and Septic Shock EP - 227 SN - 0891-3668 IS - iss. 2 SP - 226 JF - Pediatric Infectious Disease Journal VL - vol. 35 DO - https://doi.org/10.1097/INF.0000000000000981 ER - TY - JOUR AU - Koch, R.M. AU - Kox, M. AU - Rahamat-Langendoen, J.C. AU - Timmermans, K. AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/172800 TI - Increased risk for secondary infections in trauma patients with viral reactivation. EP - 1829 SN - 0342-4642 IS - iss. 11 SP - 1828 JF - Intensive Care Medicine VL - vol. 42 DO - https://doi.org/10.1007/s00134-016-4474-5 ER - TY - JOUR AU - Pizzaballa, M.L. AU - Doronzio, A. AU - Balicco, B. AU - Kiers, H.D. AU - Heijden, W.A. van der AU - Gerretsen, J. AU - Mast, Q. de AU - El Messaoudi, S. AU - Rongen, G.A. AU - Gomes, M.E.R. AU - Kox, M. AU - Pickkers, P. AU - Riksen, N.P. AU - Kashiwagi, Y. AU - Okada, M. AU - Hayashi, K. AU - Inagaki, Y. AU - Fujita, S. AU - Nakamae, M.N. AU - Kang, Y.R. AU - Souza, R.B. AU - Liberatore, A.M. AU - Koh, I.H. AU - Blet, A. AU - Sadoune, M. AU - et al. PY - 2016 UR - https://hdl.handle.net/2066/172380 TI - ESICM LIVES 2016: part one : Milan, Italy. 1-5 October 2016 EP - 27 SN - 2197-425X IS - iss. 1 SP - 27 JF - Intensive Care Medicine Experimental VL - vol. 4 DO - https://doi.org/10.1186/s40635-016-0098-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172380/172380.pdf?sequence=1 ER - TY - JOUR AU - Mourad, S.M. AU - Mies, R. AU - Frenzel, T. AU - Willems, S. AU - Heijden, E. van der AU - Schultze Kool, L.J. PY - 2016 UR - https://hdl.handle.net/2066/165849 AB - BACKGROUND: The incidence of hereditary haemorrhagic telangiectasia (HHT - Osler-Weber-Rendu disease) in the Netherlands is 1:5000 but approximately 1:1300 in people from the Antilles. The disease is characterised by the development of telangiectasia and arteriovenous malformations (AVMs) that may result in serious morbidity and mortality. CASE DESCRIPTION: A 31-year-old primigravid patient consulted her general practitioner at 31 1/7 weeks gestational age with dyspnoea. She was referred for further diagnostics because of suspected pulmonary embolism. A CT scan showed haemothorax and a bleeding arteriovenous malformation (AVM) in the left lung. Family history suggested the possibility of HHT. After multidisciplinary consideration, a primary caesarean section was performed, followed by embolisation of the AVM during the same surgical session. The patient had a gene mutation consistent with HHT type 2. CONCLUSION: Pregnant patients with HHT are at risk of serious morbidity, especially if they are not screened for AVMs. A multidisciplinary approach for such patients, with consideration of various scenarios, is highly recommended. TI - [A pregnant patient with spontaneous haemothorax: hereditary haemorrhagic telangiectasia in pregnancy] SN - 0028-2162 IS - iss. 0 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 160 ER - TY - JOUR AU - Vrancken, S.L.A.G. AU - Nusmeier, A. AU - Hopman, J.C. AU - Liem, K.D. AU - Hoeven, J.G. van der AU - Lemson, J. AU - Heijst, A.F.J. van AU - Boode, W.P. de PY - 2016 UR - https://hdl.handle.net/2066/168747 AB - Increased extravascular lung water (EVLW) may contribute to respiratory failure in neonates. Accurate measurement of EVLW in these patients is limited due to the lack of bedside methods. The aim of this pilot study was to investigate the reliability of the transpulmonary ultrasound dilution (TPUD) technique as a possible method for estimating EVLW in a neonatal animal model. Pulmonary edema was induced in 11 lambs by repeated surfactant lavages. In between the lavages, EVLW indexed by bodyweight was estimated by TPUD (EVLWItpud) and transpulmonary dye dilution (EVLWItpdd) (n = 22). Final EVLWItpud measurements were also compared with EVLWI estimations by gold standard post mortem gravimetry (EVLWIgrav) (n = 6). EVLWI was also measured in two additional lambs without pulmonary edema. Bland-Altman plots showed a mean bias between EVLWItpud and EVLWItpdd of -3.4 mL/kg (LOA +/- 25.8 mL/kg) and between EVLWItpud and EVLWIgrav of 1.7 mL/kg (LOA +/- 8.3 mL/kg). The percentage errors were 109 and 43 % respectively. The correlation between changes in EVLW measured by TPUD and TPDD was r2 = 0.22. Agreement between EVLWI measurements by TPUD and TPDD was low. Trending ability to detect changes between these two methods in EVLWI was questionable. The accuracy of EVLWItpud was good compared to the gold standard gravimetric method but the TPUD lacked precision in its current prototype. Based on these limited data, we believe that TPUD has potential for future use to estimate EVLW after adaptation of the algorithm. Larger studies are needed to support our findings. TI - Estimation of extravascular lung water using the transpulmonary ultrasound dilution (TPUD) method: a validation study in neonatal lambs EP - 994 SN - 1387-1307 IS - iss. 6 SP - 985 JF - Journal of Clinical Monitoring and Computing VL - vol. 30 DO - https://doi.org/10.1007/s10877-015-9803-7 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/168747/168747.pdf?sequence=1 ER - TY - JOUR AU - Heskamp, L. AU - Lansdorp, B. AU - Hopman, J. AU - Lemson, J. AU - Boode, W.P. de PY - 2016 UR - https://hdl.handle.net/2066/171928 AB - During positive pressure ventilation, arterial pressure variations, like the pulse pressure variation (PPV), are observed in neonates. However, the frequency of the PPV does not always correspond with the respiratory rate. It is hypothesized that PPV is caused by cardiopulmonary interaction, but that this mismatch is related to the low respiratory rate/heart rate ratio. Therefore, the goal of this study is to investigate the relation between PPV and ventilation in neonates. A prospective observational cross-sectional study was carried out in a third-level neonatal intensive care unit in a university hospital. Neonates on synchronized intermittent mandatory ventilation (SIMV) or high-frequency ventilation (HFV) participated in the study. The arterial blood pressure was continuously monitored in 20 neonates on SIMV and 10 neonates on HFV. In neonates on SIMV the CO2 waveform and neonates on HFV the thorax impedance waveform were continuously monitored and defined as the respiratory signal. Correlation and coherence between the respiratory signal and pulse pressure were determined. The correlation between the respiratory signal and pulse pressure was -0.64 +/- 0.18 and 0.55 +/- 0.16 and coherence at the respiratory frequency was 0.95 +/- 0.11 and 0.76 +/- 0.4 for SIMV and HFV, respectively. The arterial pressure variations observed in neonates on SIMV or HFV are related to cardiopulmonary interaction. Despite this relation, it is not likely that PPV will reliably predict fluid responsiveness in neonates due to physiological aliasing. TI - Ventilator-induced pulse pressure variation in neonates SN - 2051-817X IS - iss. 4 JF - Physiological Reports VL - vol. 4 DO - https://doi.org/10.14814/phy2.12716 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171928/171928.pdf?sequence=1 ER - TY - JOUR AU - Hanskamp-Sebregts, M.E.C. AU - Zegers, M. AU - Vincent, C. AU - Gurp, P.J.M. van AU - Vet, H.C. de AU - Wollersheim, H.C. PY - 2016 UR - https://hdl.handle.net/2066/170948 AB - OBJECTIVES: Record review is the most used method to quantify patient safety. We systematically reviewed the reliability and validity of adverse event detection with record review. DESIGN: A systematic review of the literature. METHODS: We searched PubMed, EMBASE, CINAHL, PsycINFO and the Cochrane Library and from their inception through February 2015. We included all studies that aimed to describe the reliability and/or validity of record review. Two reviewers conducted data extraction. We pooled kappa values (kappa) and analysed the differences in subgroups according to number of reviewers, reviewer experience and training level, adjusted for the prevalence of adverse events. RESULTS: In 25 studies, the psychometric data of the Global Trigger Tool (GTT) and the Harvard Medical Practice Study (HMPS) were reported and 24 studies were included for statistical pooling. The inter-rater reliability of the GTT and HMPS showed a pooled kappa of 0.65 and 0.55, respectively. The inter-rater agreement was statistically significantly higher when the group of reviewers within a study consisted of a maximum five reviewers. We found no studies reporting on the validity of the GTT and HMPS. CONCLUSIONS: The reliability of record review is moderate to substantial and improved when a small group of reviewers carried out record review. The validity of the record review method has never been evaluated, while clinical data registries, autopsy or direct observations of patient care are potential reference methods that can be used to test concurrent validity. TI - Measurement of patient safety: a systematic review of the reliability and validity of adverse event detection with record review SN - 2044-6055 IS - iss. 8 SP - e011078 JF - BMJ Open VL - vol. 6 DO - https://doi.org/10.1136/bmjopen-2016-011078 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/170948/170948.pdf?sequence=1 ER - TY - JOUR AU - Peters, E. AU - Ergin, B. AU - Kandil, A. AU - Gurel-Gurevin, E. AU - Elsas, A. van AU - Masereeuw, R. AU - Pickkers, P. AU - Ince, C. PY - 2016 UR - https://hdl.handle.net/2066/172437 AB - Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n=18) were subjected to renal ischemia (30min) and reperfusion (I/R), or sham-operated. In a second model, rats (n=18) received a 30min infusion of lipopolysaccharide (LPS; 2.5mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000U/kg) was administered intravenously (15min before reperfusion, or 90min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS-induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial. TI - Effects of a human recombinant alkaline phosphatase on renal hemodynamics, oxygenation and inflammation in two models of acute kidney injury EP - 96 SN - 0041-008X SP - 88 JF - Toxicology and Applied Pharmacology VL - vol. 313 DO - https://doi.org/10.1016/j.taap.2016.10.015 ER - TY - JOUR AU - Tunjungputri, R.N. AU - Peters, E. AU - Ven, A. van der AU - Groot, P.G. de AU - Mast, Q. de AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/172714 AB - Sepsis-associated acute kidney injury (AKI) is associated with high morbidity and mortality. Excessive platelet activation contributes to AKI through the formation of microthrombi and amplification of systemic inflammation. Two phase II trials demonstrated that bovine-intestinal alkaline phosphatase (AP) improved renal function in critically ill patients with sepsis-associated AKI. In this study, we characterised the platelet-inhibiting effects of a human recombinant AP. Whole blood and platelet-rich plasma (PRP) of healthy volunteers (n=6) was pre-treated ex vivo with recAP, whereafter platelet reactivity to ADP, collagen-related peptide (CRP-XL) and Pam3CSK4 was determined by flow cytometry. RecAP (40 U/ml) reduced the platelet reactivity to ADP (inhibition with a median of 47 %, interquartile range 43-49 %; p<0.001) and tended to reduce platelet reactivity to CRP-XL (9 %, 2-25 %; p=0.08) in whole blood. The platelet-inhibiting effects of recAP were more pronounced in PRP both for ADP- (64 %, 54-68 %; p=0.002) and CRP-XL-stimulated samples (60 %, 46-71 %; p=0.002). RecAP rapidly converted ADP into adenosine, whereas antagonism of the A2A adenosine receptor partially reversed the platelet inhibitory effects of recAP. Platelets of septic shock patients (n=5) showed a 31% (22-34%; p=0.03) more pronounced reactivity compared to healthy volunteers, and this was completely reversed by recAP treatment. In conclusion, we demonstrate that recAP inhibits ex vivo human platelet activation through dephosphorylation of ADP and formation of adenosine as its turnover product. RecAP is able to reverse the platelet hyperreactivity present in septic shock patients. These effects may contribute to the beneficial effects of recAP as a new therapeutic candidate for sepsis-associated AKI. TI - Human recombinant alkaline phosphatase inhibits ex vivo platelet activation in humans EP - 1121 SN - 0340-6245 IS - iss. 6 SP - 1111 JF - Thrombosis and Haemostasis VL - vol. 116 DO - https://doi.org/10.1160/TH16-03-0206 ER - TY - JOUR AU - Peters, E. AU - Stevens, J. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171406 TI - Response to letter to editor EP - 281 SN - 0378-5173 IS - iss. 1-2 SP - 279 JF - International Journal of Pharmaceutics VL - vol. 503 DO - https://doi.org/10.1016/j.ijpharm.2016.01.078 ER - TY - JOUR AU - Jansen, J.J. AU - Hilvering, B. AU - Doel, A. van den AU - Pickkers, P. AU - Koenderman, L. AU - Buydens, L.M.C. AU - Brink, O.F. van den PY - 2016 UR - https://hdl.handle.net/2066/157351 TI - FLOOD: FLow cytometric Orthogonal Orientation for Diagnosis EP - 135 SN - 0169-7439 SP - 126 JF - Chemometrics and Intelligent Laboratory Systems VL - vol. 151 DO - https://doi.org/10.1016/j.chemolab.2015.12.001 ER - TY - JOUR AU - Jansen, D. AU - Peters, E. AU - Heemskerk, S. AU - Koster-Kamphuis, L. AU - Bouw, M.P.W.J.M. AU - Roelofs, H.M.J. AU - Oeveren, W. van AU - Heyst, A.F.J. van AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171867 AB - Objective We evaluated whether urinary excretion of tubular injury markers could be useful for early detection of gentamicin (GM)-induced renal damage in neonates. Study Design We conducted a prospective, observational trial in neonates admitted to the neonatal intensive care unit (26 GM treated, 20 control). Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG), and pi- and alpha-glutathione-S-transferase (GSTP1-1 and GSTA1-1) were measured every 2 hours during admission and compared with serum creatinine (sCr) and urine output. Results Nine neonates developed AKI during the course of the study. The peak in excretion of urinary biomarkers preceded the peak in sCr (p < 0.0001). GM administration resulted in a more pronounced increase of sCr compared with control (13 [12-28] vs. 10 micromol/L [8.5-17]; p < 0.05). The urinary excretion of NAG (178 [104-698] vs. 32 ng/mol Cr [9-82]; p < 0.001) and NGAL (569 [168-1,681] vs. 222 ng/mol Cr [90-497]; p < 0.05) was higher in the GM group compared with control and preceded the peak of sCr and urine output decrease. Conclusion GM administration to neonates is associated with renal damage reflected by a more pronounced increase in sCr preceded by urinary excretion of biomarkers. Urinary biomarkers may be useful for earlier identification of renal injury in neonates. TI - Tubular Injury Biomarkers to Detect Gentamicin-Induced Acute Kidney Injury in the Neonatal Intensive Care Unit EP - 187 SN - 0735-1631 IS - iss. 2 SP - 180 JF - American Journal of Perinatology VL - vol. 33 DO - https://doi.org/10.1055/s-0035-1563714 ER - TY - JOUR AU - Novakovic, B. AU - Habibi, E. AU - Wang, S. AU - Arts, R.J. AU - Davar, R. AU - Megchelenbrink, W. AU - Kim, B. AU - Kuznetsova, T. AU - Kox, M. AU - Zwaag, J. AU - Matarese, F. AU - van Heeringen, S.J. AU - Janssen-Megens, E.M. AU - Sharifi, N. AU - Wang, C. AU - Keramati, F. AU - Schoonenberg, V. AU - Flicek, P. AU - Clarke, L. AU - Pickkers, P. AU - Heath, S. AU - Gut, I. AU - Netea, M.G. AU - Martens, J.H.A. AU - Logie, C. AU - Stunnenberg, H.G. PY - 2016 UR - https://hdl.handle.net/2066/163356 TI - beta-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance EP - 1368.e14 SN - 0092-8674 IS - iss. 5 SP - 1354 JF - Cell VL - vol. 167 DO - https://doi.org/10.1016/j.cell.2016.09.034 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/163356/163356.pdf?sequence=1 ER - TY - JOUR AU - Mooij, C.F. AU - Hermsen, Rick AU - Hoppenreijs, E.P.A.H. AU - Bleeker-Rovers, C.P. AU - IJland, M.M. AU - Geus-Oei, L.F. de PY - 2016 UR - https://hdl.handle.net/2066/169249 AB - BACKGROUND: Henoch-Schonlein vasculitis is the most common systemic vasculitis in children. Arthritis or arthralgia occurs in 80 % of patients. We believe this to be the first case report to describe the finding of polyarthritis in a fludeoxyglucose positron emission tomography-computed tomography scan in a patient with Henoch-Schonlein vasculitis without clinical signs of arthritis. CASE PRESENTATION: A 4.5-year-old Caucasian boy presented with fever of 4 days' duration followed by debilitating migratory arthralgia and inflammation. He underwent a fludeoxyglucose positron emission tomography-computed tomography scan to exclude a possible malignant cause or to detect any infectious or autoimmune focus of his symptoms. Fludeoxyglucose uptake was observed in multiple large joints and in multiple tendons. These findings suggested active polyarthritis and polytendinitis. However, physical and ultrasound evaluations did not show any signs of arthritis in our patient, despite his evident arthralgia. CONCLUSIONS: Fludeoxyglucose positron emission tomography-computed tomography might be able to detect inflammatory activity in painful joints that cannot yet be detected clinically or with ultrasound evaluation in a patient with Henoch-Schonlein vasculitis. Therefore, fludeoxyglucose positron emission tomography-computed tomography can be of additional value in the diagnostic workup of patients with an unresolved diagnosis of suspected autoimmune disease, especially in patients with unresolved arthralgia and fever of unknown cause. TI - Fludeoxyglucose positron emission tomography-computed tomography scan showing polyarthritis in a patient with an atypical presentation of Henoch-Schonlein vasculitis without clinical signs of arthritis: a case report SN - 1752-1947 IS - iss. 1 SP - 159 JF - Journal of Medical Case Reports VL - vol. 10 DO - https://doi.org/10.1186/s13256-016-0913-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169249/169249.pdf?sequence=1 ER - TY - JOUR AU - Peters, E. AU - Mehta, R.L. AU - Murray, P.T. AU - Hummel, J. AU - Joannidis, M. AU - Kellum, J.A. AU - Arend, J. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171555 AB - INTRODUCTION: Acute kidney injury (AKI) occurs in 55-60% of critically ill patients, and sepsis is the most common underlying cause. No pharmacological treatment options are licensed to treat sepsis-associated AKI (SA-AKI); only supportive renal replacement therapy (RRT) is available. One of the limited number of candidate compounds in clinical development to treat SA-AKI is alkaline phosphatase (AP). The renal protective effect of purified bovine intestinal AP has been demonstrated in critically ill sepsis patients. To build on these observations, a human recombinant AP (recAP) was developed, of which safety and efficacy in patients with SA-AKI will be investigated in this trial. METHODS: This is a randomised, double-blind, placebo-controlled, 4-arm, proof-of-concept, dose-finding adaptive phase IIa/IIb study, conducted in critically ill patients with SA-AKI. A minimum of 290 patients will be enrolled at approximately 50 sites in the European Union and North America. The study involves 2 parts. Patients enrolled during Part 1 will be randomly assigned to receive either placebo (n=30) or 1 of 3 different doses of recAP (n=30 per group) once daily for 3 days (0.4, 0.8 or 1.6 mg/kg). In Part 2, patients will be randomly assigned to receive the most efficacious dose of recAP (n=85), selected during an interim analysis, or placebo (n=85). Treatment must be administered within 24 hours after SA-AKI is first diagnosed and within 96 hours from first diagnosis of sepsis. The primary end point is the area under the time-corrected endogenous creatinine clearance curve from days 1 to 7. The key secondary end point is RRT incidence during days 1-28. ETHICS AND DISSEMINATION: This study is approved by the relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will reveal the efficacy of recAP for the improvement of renal function in critically ill patients with SA-AKI and will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT02182440; Pre-results. TI - Study protocol for a multicentre randomised controlled trial: Safety, Tolerability, efficacy and quality of life Of a human recombinant alkaline Phosphatase in patients with sepsis-associated Acute Kidney Injury (STOP-AKI) SN - 2044-6055 IS - iss. 9 SP - e012371 JF - BMJ Open VL - vol. 6 DO - https://doi.org/10.1136/bmjopen-2016-012371 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171555/171555.pdf?sequence=1 ER - TY - JOUR AU - Groot, J.J.A.M. de AU - Hoek, M. van AU - Hoedemaekers, C.W.E. AU - Hoitsma, A.J. AU - Schilderman, J.B.A.M. AU - Smeets, W. AU - Vernooij-Dassen, M.J.F.J. AU - Leeuwen, E. van PY - 2016 UR - https://hdl.handle.net/2066/167536 AB - BACKGROUND: In the Netherlands, consent from relatives is obligatory for post mortal donation. This study explored the perspectives of relatives regarding the request for consent for donation in cases without donor registration. METHODS: A content analysis of narratives of 24 bereaved relatives (14 in-depth interviews and one letter) of unregistered, eligible, brain-dead donors was performed. RESULTS: Relatives of unregistered, brain-dead patients usually refuse consent for donation, even if they harbour pro-donation attitudes themselves, or knew that the deceased favoured organ donation. Half of those who refused consent for donation mentioned afterwards that it could have been an option. The decision not to consent to donation is attributed to contextual factors, such as feeling overwhelmed by the notification of death immediately followed by the request; not being accustomed to speaking about death; inadequate support from other relatives or healthcare professionals, and lengthy procedures. CONCLUSION: Healthcare professionals could provide better support to relatives prior to donation requests, address their informational needs and adapt their message to individual circumstances. It is anticipated that the number of consenting families could be enlarged by examining the experience of decoupling and offering the possibility of consent for donation after circulatory death if families refuse consent for donation after brain-death. TI - Request for organ donation without donor registration: a qualitative study of the perspectives of bereaved relatives SN - 1472-6939 JF - BMC Medical Ethics VL - vol. 17 N1 - 11 juli 2016 PS - 14 p. DO - https://doi.org/10.1186/s12910-016-0120-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/167536/167536.pdf?sequence=1 ER - TY - JOUR AU - Peters, E. AU - Heuberger, J.A. AU - Tiessen, R. AU - Elsas, A. van AU - Masereeuw, R. AU - Arend, J. AU - Stevens, J. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/171174 AB - BACKGROUND AND OBJECTIVE: Previous clinical trials have suggested that bovine intestinal alkaline phosphatase has renal protective effects in patients with sepsis-associated acute kidney injury. We conducted a first-in-human study to investigate the pharmacokinetics, safety and tolerability of a novel human recombinant alkaline phosphatase (recAP), and we developed a population pharmacokinetic model to support dose selection for future patient studies. METHODS: In a randomized, double-blind, placebo-controlled, phase I trial, healthy volunteers received a single dose of recAP (200, 500, 1000 or 2000 U/kg; n = 33; 3:1 ratio) or multiple doses of recAP (500 or 1000 U/kg; n = 18; 2:1 ratio) via a 1-h intravenous infusion on three consecutive days. Serum recAP concentrations, alkaline phosphatase (AP) activity levels and anti-drug antibodies were measured, and safety parameters were monitored. A population pharmacokinetic model was developed, and simulations were performed to guide dose selection for a phase IIa/b trial. RESULTS: Peak concentrations of recAP and peak AP activity were reached at the end of the 1-h infusion and showed a rapid decline, with about 10 % of the maximum concentration remaining at 4 h and less than 5 % remaining 24 h post-start. RecAP treatment was generally well tolerated, and anti-drug antibodies could not be detected in the serum up to 2 weeks post-injection after a single dose, or up to 3 weeks post-injection after multiple doses. A four-compartment model best described the pharmacokinetics of recAP administration, with moderate inter-individual variability on the central volume of distribution and elimination rate constant. Simulations showed that 1-h intravenous infusions of 250, 500 and 1000 U/kg recAP once every 24 h for three consecutive days constituted the dosing regimen that best met the criteria for dose selection in patient studies. CONCLUSION: RecAP did not raise any safety concerns when administered to healthy volunteers. A population pharmacokinetic model was developed to support dose selection for patient studies. TRIAL REGISTRATION: 2013-002694-21 (EudraCT). TI - Pharmacokinetic Modeling and Dose Selection in a Randomized, Double-Blind, Placebo-Controlled Trial of a Human Recombinant Alkaline Phosphatase in Healthy Volunteers EP - 1237 SN - 0312-5963 IS - iss. 10 SP - 1227 JF - Clinical Pharmacokinetics VL - vol. 55 DO - https://doi.org/10.1007/s40262-016-0399-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171174/171174.pdf?sequence=1 ER - TY - JOUR AU - Cheheili Sobbi, S. AU - Boogaard, M.H.W.A. van den AU - Slooter, A.J. AU - Swieten, H.A. van AU - Ceelen, L. AU - Pop, G.A. AU - Abdo, W.F. AU - Pickkers, P. PY - 2016 UR - https://hdl.handle.net/2066/172643 AB - BACKGROUND: Delirium after cardiothoracic surgery is common and associated with impaired outcomes. Although several mechanisms have been proposed (including changes in cerebral perfusion), the pathophysiology of postoperative delirium remains unclear. Blood viscosity is related to cerebral perfusion and thereby might contribute to the development of delirium after cardiothoracic surgery. The aim of this study was to investigate whether whole blood viscosity differs between cardiothoracic surgery patients with and without delirium. METHODS: In this observational study postoperative whole blood viscosity of patients that developed delirium (cases) were compared with non-delirious cardiothoracic surgery patients (controls). Cases were matched with the controls, yielding a 1:4 case-control study. Serial hematocrit, fibrinogen, and whole blood viscosity were determined pre-operatively and at each postoperative day. Delirium was assessed using the validated Confusion Assessment Method for the Intensive Care Unit or Delirium Screening Observation scale. RESULTS: In total 80 cardiothoracic surgery patients were screened of whom 12 delirious and 48 matched non-delirious patients were included. No significant difference was found between both groups in fibrinogen (p = 0.36), hematocrit (p = 0.23) and the area under curve of the whole blood viscosity between shear rates 0.02 and 50 s(-1) (p = 0.80) or between shear rates 0.02 and 5 s(-1) (p = 0.78). CONCLUSION: In this case control study in cardiothoracic surgery patients changes in whole blood viscosity were not associated with the development of delirium. TI - Absence of association between whole blood viscosity and delirium after cardiac surgery: a case-controlled study SN - 1749-8090 IS - iss. 1 SP - 132 JF - Journal of Cardiothoracic Surgery VL - vol. 11 DO - https://doi.org/10.1186/s13019-016-0517-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172643/172643.pdf?sequence=1 ER - TY - JOUR AU - Ingelse, S.A. AU - Wösten-van Asperen, R.M. AU - Lemson, J. AU - Daams, J.G. AU - Bem, R.A. AU - Woensel, J.B. van PY - 2016 UR - https://hdl.handle.net/2066/171146 AB - The administration of an appropriate volume of intravenous fluids, while avoiding fluid overload, is a major challenge in the pediatric intensive care unit. Despite our efforts, fluid overload is a very common clinical observation in critically ill children, in particular in those with pediatric acute respiratory distress syndrome (PARDS). Patients with ARDS have widespread damage of the alveolar-capillary barrier, potentially making them vulnerable to fluid overload with the development of pulmonary edema leading to prolonged course of disease. Indeed, studies in adults with ARDS have shown that an increased cumulative fluid balance is associated with adverse outcome. However, age-related differences in the development and consequences of fluid overload in ARDS may exist due to disparities in immunologic response and body water distribution. This systematic review summarizes the current literature on fluid imbalance and management in PARDS, with special emphasis on potential differences with adult patients. It discusses the adverse effects associated with fluid overload and the corresponding possible pathophysiological mechanisms of its development. Our intent is to provide an incentive to develop age-specific fluid management protocols to improve PARDS outcomes. TI - Pediatric Acute Respiratory Distress Syndrome: Fluid Management in the PICU SN - 2296-2360 JF - Frontiers in Pediatrics VL - vol. 4 DO - https://doi.org/10.3389/fped.2016.00021 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/171146/171146.pdf?sequence=1 ER - TY - JOUR AU - Podnar, S. AU - Doorduin, J. PY - 2016 UR - https://hdl.handle.net/2066/167427 AB - INTRODUCTION: Controversy persists as to whether the lung interposes on the needle electrode insertion path during diaphragm electromyography (EMG). METHODS: Using high-resolution ultrasonography, we measured the distances between the medial recess of the intercostal spaces (ICSs) around the mid-clavicular line (MCL) and the lung margin. We performed measurements bilaterally during quiet breathing in the seated and supine positions. RESULTS: We studied 10 young healthy men and found that, in the first ICS with the medial recess clearly (i.e., several cm) lateral to MCL (usually the eighth ICS), the distance between the recommended insertion site and the lung margin varied from 7.5 to 17 cm. The distance was slightly larger on the right side and in the supine position. CONCLUSIONS: This study confirms that properly conducted "trans-intercostal" needle EMG of the diaphragm is generally safe in healthy subjects. Muscle Nerve 54: 54-57, 2016. TI - Safety of needle electromyography of the diaphragm: Anterior lung margins in quietly breathing healthy subjects EP - 57 SN - 0148-639X IS - iss. 1 SP - 54 JF - Muscle and Nerve VL - vol. 54 DO - https://doi.org/10.1002/mus.24992 ER - TY - JOUR AU - Schellekens, W.J. AU - Hees, H.W.H. van AU - Doorduin, J. AU - Roesthuis, L.H. AU - Scheffer, G.J. AU - Hoeven, J.G. van der AU - Heunks, L.M. PY - 2016 UR - https://hdl.handle.net/2066/168156 AB - Respiratory muscle dysfunction may develop rapidly in critically ill ventilated patients and is associated with increased morbidity, length of intensive care unit stay, costs, and mortality. This review briefly discusses the pathophysiology of respiratory muscle dysfunction in intensive care unit patients and then focuses on strategies that prevent the development of muscle weakness or, if weakness has developed, how respiratory muscle function may be improved. We propose a simple strategy for how these can be implemented in clinical care. TI - Strategies to optimize respiratory muscle function in ICU patients SN - 1466-609X IS - iss. 1 SP - 103 JF - Critical Care VL - vol. 20 DO - https://doi.org/10.1186/s13054-016-1280-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/168156/168156.pdf?sequence=1 ER - TY - JOUR AU - Doorduin, J. AU - Nollet, J.L. AU - Vugts, M.P. AU - Roesthuis, L.H. AU - Akankan, F. AU - Hoeven, J.G. van der AU - Hees, H.W.H. van AU - Heunks, L.M. PY - 2016 UR - https://hdl.handle.net/2066/168195 AB - BACKGROUND: Physiological dead space (VD/VT) represents the fraction of ventilation not participating in gas exchange. In patients with acute respiratory distress syndrome (ARDS), VD/VT has prognostic value and can be used to guide ventilator settings. However, VD/VT is rarely calculated in clinical practice, because its measurement is perceived as challenging. Recently, a novel technique to calculate partial pressure of carbon dioxide in alveolar air (PACO2) using volumetric capnography (VCap) was validated. The purpose of the present study was to evaluate how VCap and other available techniques to measure PACO2 and partial pressure of carbon dioxide in mixed expired air (PeCO2) affect calculated VD/VT. METHODS: In a prospective, observational study, 15 post-cardiac surgery patients and 15 patients with ARDS were included. PACO2 was measured using VCap to calculate Bohr dead space or substituted with partial pressure of carbon dioxide in arterial blood (PaCO2) to calculate the Enghoff modification. PeCO2 was measured in expired air using three techniques: Douglas bag (DBag), indirect calorimetry (InCal), and VCap. Subsequently, VD/VT was calculated using four methods: Enghoff-DBag, Enghoff-InCal, Enghoff-VCap, and Bohr-VCap. RESULTS: PaCO2 was higher than PACO2, particularly in patients with ARDS (post-cardiac surgery PACO2 = 4.3 +/- 0.6 kPa vs. PaCO2 = 5.2 +/- 0.5 kPa, P < 0.05; ARDS PACO2 = 3.9 +/- 0.8 kPa vs. PaCO2 = 6.9 +/- 1.7 kPa, P < 0.05). There was good agreement in PeCO2 calculated with DBag vs. VCap (post-cardiac surgery bias = 0.04 +/- 0.19 kPa; ARDS bias = 0.03 +/- 0.27 kPa) and relatively low agreement with DBag vs. InCal (post-cardiac surgery bias = -1.17 +/- 0.50 kPa; ARDS mean bias = -0.15 +/- 0.53 kPa). These differences strongly affected calculated VD/VT. For example, in patients with ARDS, VD/VTcalculated with Enghoff-InCal was much higher than Bohr-VCap (VD/VT Enghoff-InCal = 66 +/- 10 % vs. VD/VT Bohr-VCap = 45 +/- 7 %; P < 0.05). CONCLUSIONS: Different techniques to measure PACO2 and PeCO2 result in clinically relevant mean and individual differences in calculated VD/VT, particularly in patients with ARDS. Volumetric capnography is a promising technique to calculate true Bohr dead space. Our results demonstrate the challenges clinicians face in interpreting an apparently simple measurement such as VD/VT. TI - Assessment of dead-space ventilation in patients with acute respiratory distress syndrome: a prospective observational study SN - 1466-609X IS - iss. 1 SP - 121 JF - Critical Care VL - vol. 20 DO - https://doi.org/10.1186/s13054-016-1311-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/168195/168195.pdf?sequence=1 ER - TY - JOUR AU - Doorduin, J. AU - Hoeven, J.G. van der AU - Heunks, L.M. PY - 2016 UR - https://hdl.handle.net/2066/171711 AB - PURPOSE OF REVIEW: In this review, we discuss the causes for a failed weaning trial and specific diagnostic tests that could be conducted to identify the cause for weaning failure. We briefly highlight treatment strategies that may enhance the chance of weaning success. RECENT FINDINGS: Impaired respiratory mechanics, respiratory muscle dysfunction, cardiac dysfunction, cognitive dysfunction, and metabolic disorders are recognized causes for weaning failure. In addition, iatrogenic factors may be at play. Most studies have focused on respiratory muscle dysfunction and cardiac dysfunction. Recent studies demonstrate that both ultrasound and electromyography are valuable tools to evaluate respiratory muscle function in ventilated patients. Sophisticated ultrasound techniques and biomarkers such as B-type natriuretic peptide, are valuable tools to identify cardiac dysfunction as a cause for weaning failure. Once a cause for weaning failure has been identified specific treatment should be instituted. Concerning treatment, both strength training and endurance training should be considered for patients with respiratory muscle weakness. Inotropes and vasodilators should be considered in case of heart failure. SUMMARY: Understanding the complex pathophysiology of weaning failure in combination with a systematic diagnostic approach allows identification of the primary cause of weaning failure. This will help the clinician to choose a specific treatment strategy and therefore may fasten liberation from mechanical ventilation. TI - The differential diagnosis for failure to wean from mechanical ventilation EP - 157 SN - 0952-7907 IS - iss. 2 SP - 150 JF - Current Opinion in Anesthesiology VL - vol. 29 DO - https://doi.org/10.1097/ACO.0000000000000297 ER - TY - JOUR AU - Martial, L.C. AU - Bruggemann, R.J.M. AU - Schouten, J.A. AU - Leeuwen, H.J. van AU - Zanten, A.R. van AU - Lange, D.W. de AU - Muilwijk, E.W. AU - Verweij, P.E. AU - Burger, D.M. AU - Aarnoutse, R.E. AU - Pickkers, P. AU - Dorlo, T.P. PY - 2016 UR - https://hdl.handle.net/2066/172349 AB - BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies. METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg.h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 microg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 microg/mL. CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 microg/mL. TI - Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure EP - 733 SN - 0312-5963 IS - iss. 6 SP - 723 JF - Clinical Pharmacokinetics VL - vol. 55 DO - https://doi.org/10.1007/s40262-015-0347-2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172349/172349.pdf?sequence=1 ER - TY - JOUR AU - Kolwijck, E. AU - Hoeven, H. van der AU - Sevaux, R.G.L. de AU - Oever, J. ten AU - Rijstenberg, L.L. AU - Lee, H.A.L. van der AU - Zoll, J. AU - Melchers, W.J.G. AU - Verweij, P.E. PY - 2016 UR - https://hdl.handle.net/2066/166535 TI - Voriconazole-Susceptible and Voriconazole-Resistant Aspergillus fumigatus Coinfection EP - 929 SN - 1073-449X IS - iss. 8 SP - 927 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 193 DO - https://doi.org/10.1164/rccm.201510-2104LE ER - TY - THES AU - Leentjens, J. PY - 2016 SN - 9789462599758 UR - https://hdl.handle.net/2066/150171 PB - [S.l. : s.n.] TI - Immunomodulation in severe infections N1 - Radboud Universiteit Nijmegen, 8 januari 2016 N1 - Promotores : Pickkers, P., Netea, M.G. Co-promotor : Kox, M. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/150171/150171.pdf?sequence=1 ER - TY - JOUR AU - Cheng, S.C. AU - Scicluna, B.P. AU - Arts, R.J.W. AU - Gresnigt, M.S. AU - Lachmandas, E.L. AU - Giamarellos-Bourboulis, E.J. AU - Kox, M. AU - Manjeri, G.R. AU - Wagenaars, J.A. AU - Cremer, O.L. AU - Leentjens, J. AU - Meer, A.J. van der AU - Veerdonk, F.L. van de AU - Bonten, M.J. AU - Schultz, M.J. AU - Willems, P.H. AU - Pickkers, P. AU - Joosten, L.A. AU - Poll, T. van der AU - Netea, M.G. PY - 2016 UR - https://hdl.handle.net/2066/172049 AB - The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-gamma, which suggested that metabolic processes might represent a therapeutic target in sepsis. TI - Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis EP - 413 SN - 1529-2908 IS - iss. 4 SP - 406 JF - Nature Immunology VL - vol. 17 DO - https://doi.org/10.1038/ni.3398 ER - TY - JOUR AU - Koch, R.M. AU - Kox, M. AU - Pickkers, P. AU - Jonge, M.I. de PY - 2016 UR - https://hdl.handle.net/2066/172441 AB - The "experimental cold model" is widely used to investigate effects of HRV infection. However, effects of serostatus and gender on the HRV-induced immune response have not been clarified. 40 healthy seropositive and seronegative (1:1) male and female (1:1) subjects were inoculated with HRV-16. HRV infection increased viral load in nasal wash, which tended to be more pronounced in seronegative subjects. Furthermore, HRV infection increased levels of IP-10, IL-6, and IL-10 and leukocyte numbers in nasal wash of seronegative, but not of seropositive subjects. No differences in any of the parameters were found between both sexes. The HRV-induced local immune response is diminished in seropositive subjects compared with seronegative subjects, while gender does not influence this response. These results have important implications for the design of future experimental cold studies: seronegative subjects, from both sexes can be included. TI - Effects of serostatus and gender on the HRV-16-induced local immune response EP - 4091 SN - 0264-410X IS - iss. 35 SP - 4087 JF - Vaccine VL - vol. 34 DO - https://doi.org/10.1016/j.vaccine.2016.06.076 ER - TY - THES AU - Bisschops, L.L.A. PY - 2015 SN - 9789462596207 UR - https://hdl.handle.net/2066/139518 PB - [S.l. : s.n.] TI - Hypothermia and rewarming after cardiac arrest. Dynamics in cerebral blood flow, cerebral metabolism and inflammation N1 - Radboud Universiteit Nijmegen, 21 april 2015 N1 - Promotor : Hoeven, J.G. van der Co-promotor : Hoedemaekers, C.W.E. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/139518/139518.pdf?sequence=1 ER - TY - THES AU - Santen, S. van PY - 2015 UR - https://hdl.handle.net/2066/141369 PB - [S.l. : s.n.] TI - Iron homeostasis in inflammation, malaria and pregnancy N1 - Radboud Universiteit Nijmegen, 16 juni 2015 N1 - Promotores : Ven, A.J.A.M. van der, Swinkels, D.W. Co-promotor : Mast, Q. de L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/141369/MMUBN000001_107296662X.pdf?sequence=1 ER - TY - JOUR AU - Haerkens, M.H. AU - Kox, M. AU - Lemson, J. AU - Houterman, S. AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/154903 AB - BACKGROUND: Human factors account for the majority of adverse events in both aviation and medicine. Human factors awareness training entitled "Crew Resource Management (CRM)" is associated with improved aviation safety. We determined whether implementation of CRM impacts outcome in critically ill patients. METHODS: We performed a prospective 3-year cohort study in a 32-bed ICU, admitting 2500-3000 patients yearly. At the end of the baseline year, all personnel received CRM training, followed by 1 year of implementation. The third year was defined as the clinical effect year. All 7271 patients admitted to the ICU in the study period were included. The primary outcome measure was ICU complication rate. Secondary outcome measures were ICU and hospital length of stay, and standardized mortality ratio. RESULTS: Occurrence of serious complications was 67.1/1000 patients and 66.4/1000 patients during the baseline and implementation year respectively, decreasing to 50.9/1000 patients in the post-implementation year (P = 0.03). Adjusted odds ratios for occurrence of complications were 0.92 (95% CI 0.71-1.19, P = 0.52) and 0.66 (95% CI 0.51-0.87, P = 0.003) in the implementation and post-implementation year. The incidence of cardiac arrests was 9.2/1000 patients and 8.3/1000 patients during the baseline and implementation year, decreasing to 3.5/1000 patients (P = 0.04) in the post-implementation year, while cardiopulmonary resuscitation success rate increased from 19% to 55% and 67% (P = 0.02). Standardized mortality ratio decreased from 0.72 (95% CI 0.63-0.81) in the baseline year to 0.60 (95% CI 0.53-0.67) in the post-implementation year (P = 0.04). CONCLUSION: Our data indicate an association between CRM implementation and reduction in serious complications and lower mortality in critically ill patients. TI - Crew Resource Management in the Intensive Care Unit: a prospective 3-year cohort study EP - 1329 SN - 0001-5172 IS - iss. 10 SP - 1319 JF - Acta Anaesthesiologica Scandinavica VL - vol. 59 DO - http://dx.doi.org/10.1111/aas.12573 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/154903/154903.pdf?sequence=1 ER - TY - JOUR AU - Groot, J.J.A.M. de AU - Hoek, M. AU - Hoedemaekers, C.W.E. AU - Hoitsma, A.J. AU - Smeets, W. AU - Vernooij-Dassen, M.J.F.J. AU - Leeuwen, E. van PY - 2015 UR - https://hdl.handle.net/2066/154942 AB - BACKGROUND: This article is part of a study to gain insight into the decision-making process by looking at the views of the relatives of potential brain dead donors. Alongside a literature review, focus interviews were held with healthcare professionals about their role in the request and decision-making process when post-mortal donation is at stake. This article describes the perspectives of the relatives. METHODS: A content-analysis of 22 semi-structured in-depth interviews with relatives involved in an organ donation decision. RESULTS: Three themes were identified: 'conditions', 'ethical considerations' and 'look back'. Conditions were: 'sense of urgency', 'incompetence to decide' and 'agreement between relatives'. Ethical considerations result in a dilemma for non-donor families: aiding people or protecting the deceased's body, especially when they do not know his/her preference. Donor families respect the deceased's last will, generally confirmed in the National Donor Register. Looking back, the majority of non-donor families resolved their dilemma by justifying their decision with external arguments (lack of time, information etc.). Some non-donor families would like to be supported during decision-making. DISCUSSION: The discrepancy between general willingness to donate and the actual refusal of a donation request can be explained by multiple factors, with a cumulative effect. Firstly, half of the participants (most non-donor families) stated that they felt that they were not competent to decide in such a crisis and they seem to struggle with utilitarian considerations against their wish to protect the body. Secondly, non-donor families refused telling that they did not know the deceased's wishes or contesting posthumous autonomy of the eligible. Thirdly, the findings emphasise the importance of Donor Registration, because it seems to prevent dilemmas in decision-making, at least for donor families. CONCLUSION: Discrepancies between willingness to consent to donate and refusal at the bedside can be attributed to an unresolved dilemma: aiding people or protect the body of the deceased. Non-donor families felt incompetent to decide. They refused consent for donation, since their deceased had not given any directive. When ethical considerations do not lead to an unambiguous answer, situational factors were pivotal. Relatives of unregistered eligible donors are more prone to unstable decisions. To overcome ambivalence, coaching during decision-making is worth investigation. TI - Decision making on organ donation: the dilemmas of relatives of potential brain dead donors SN - 1472-6939 IS - iss. 1 SP - 64 JF - BMC Medical Ethics VL - vol. 16 DO - http://dx.doi.org/10.1186/s12910-015-0057-1 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/154942/154942.pdf?sequence=1 ER - TY - JOUR AU - Hamers, L.A.C. AU - Kox, M. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/153942 AB - Sepsis remains the leading cause of death in the ICU. Considering the key role of the immune system in sepsis, immunomodulation represents an attractive target for adjunctive therapy. Until recently, clinical trials focused on suppression of the immune system, but this approach failed to improve sepsis outcome. Recent advances in the understanding of sepsis have led to the view that not the initial hyperinflammatory state, but rather a profoundly suppressed state of the immune system, called sepsis-induced immunoparalysis, accounts for the majority of sepsis-related deaths. Immunoparalysis results in ineffective clearance of septic foci, and renders the septic patient more vulnerable to secondary infections, as well as reactivation of latent infections. Several mechanisms behind immunoparalysis have been recognised. Furthermore, due to recognition of the importance of immunoparalysis, immunostimulatory treatment is emerging as a possible adjunctive treatment for sepsis. As such, identification of patients suffering from immunoparalysis using biomarkers is of utmost importance to guide immunostimulatory treatment. In this review, an short overview of the concept of immunoparalysis is presented, while the main focus is on potential biological markers of immunoparalysis and promising immunostimulatory therapeutic agents. The challenging heterogeneity of septic patients in respect to immunomodulatory advances will be discussed, and recommendations for future research are provided. TI - Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options EP - 439 SN - 0375-9393 IS - iss. 4 SP - 426 JF - Minerva Anestesiologica VL - vol. 81 ER - TY - JOUR AU - Abdo, W.F. AU - Hoeven, J.G. van der PY - 2015 UR - https://hdl.handle.net/2066/154100 TI - An unusual journey of a pulmonary artery catheter through the heart EP - 917 SN - 0342-4642 IS - iss. 5 SP - 916 JF - Intensive Care Medicine VL - vol. 41 DO - http://dx.doi.org/10.1007/s00134-014-3587-y ER - TY - JOUR AU - Kluge, G.H. AU - Brinkman, S. AU - Berkel, G. van AU - Hoeven, J.G. van der AU - Jacobs, C AU - Snel, Y.E. AU - Vogelaar, J.P. AU - Keizer, N.F. de AU - Boon, E.S. PY - 2015 UR - https://hdl.handle.net/2066/154146 AB - PURPOSE: The relationship between the number of patients admitted to an intensive care unit (ICU) volume and mortality is currently the subject of debate. After implementation of a national guideline in 2006, all Dutch ICUs have been classified into three levels based on ICU size, patient volume, ventilation days, and staffing. The goal of this study is to investigate the association between ICU level and mortality of ICU patients in the Netherlands. METHODS: We analyzed data from 132,159 patients admitted to 87 ICUs between January 1, 2009 and October 1, 2011. Logistic GEE analyses were performed to assess the influence of ICU level on in-hospital mortality and 90-day mortality in the total ICU population and in different ICU subgroups while adjusting for severity of illness by APACHE IV. Results : No significant differences were found in the adjusted in-hospital mortality of the total ICU population and in different subgroups admitted to level 1, 2 and 3 ICUs. In-hospital mortality in level 2 and 3 ICUs as opposed to level 1 ICUs was 1.06 (0.93-1.22) and 1.10 (0.94-1.29), respectively, and 90-day mortality was 0.92 (0.80-1.06) and 1.01 (0.88-1.17). CONCLUSION: We demonstrated that ICU level was not associated with significant differences in the case-mix adjusted in-hospital and long-term mortality of ICU patients. This finding is in contrast with some earlier studies suggesting a volume-outcome relationship. Our results may be explained by the successful implementation of nationwide mandatory quality requirements and adequate staffing in all three levels of ICUs over the last years. TI - The association between ICU level of care and mortality in the Netherlands EP - 311 SN - 0342-4642 IS - iss. 2 SP - 304 JF - Intensive Care Medicine VL - vol. 41 DO - http://dx.doi.org/10.1007/s00134-014-3620-1 ER - TY - JOUR AU - Weiss, S.L. AU - Fitzgerald, J.C. AU - Maffei, F.A. AU - Kane, J.M. AU - Rodriguez-Nunez, A. AU - Hsing, D.D. AU - Franzon, D. AU - Kee, S.Y. AU - Bush, J.L. AU - Roy, J.A. AU - Thomas, N.J. AU - Nadkarni, V.M. AU - Pickkers, P. AU - et al. PY - 2015 UR - https://hdl.handle.net/2066/155036 AB - INTRODUCTION: Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). METHODS: We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients <18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen's kappa. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria. Results : Of the 706 patients, 301 (42.6%) met both definitions. The inter-rater agreement (kappa +/- SE) between physician diagnosis and consensus criteria was 0.57 +/- 0.02. Of the 438 patients with a physician's diagnosis of severe sepsis, only 69% (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria. CONCLUSIONS: Physician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis. TI - Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study SN - 1466-609X SP - 325 JF - Critical Care VL - vol. 19 DO - http://dx.doi.org/10.1186/s13054-015-1055-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/155036/155036.pdf?sequence=1 ER - TY - JOUR AU - Hooijman, P.E. AU - Beishuizen, A. AU - Witt, C.C. AU - Waard, M.C. de AU - Girbes, A.R. AU - Spoelstra-de Man, A.M. AU - Niessen, H.W. AU - Manders, E. AU - Hees, H.W.H. van AU - Brom, C.E. van den AU - Silderhuis, V. AU - Lawlor, M.W. AU - Labeit, S. AU - Stienen, G.J. AU - Hartemink, K.J. AU - Paul, M.A. AU - Heunks, L.M.A. AU - Ottenheijm, C.A. PY - 2015 UR - https://hdl.handle.net/2066/155008 AB - RATIONALE: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood. OBJECTIVES: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm. METHODS: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation. CONCLUSIONS: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning. TI - Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients EP - 1138 SN - 1073-449X IS - iss. 10 SP - 1126 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 191 DO - https://doi.org/10.1164/rccm.201412-2214OC ER - TY - JOUR AU - Zaane, B. van AU - Klei, W.A. van AU - Buhre, W.F. AU - Bauer, P. AU - Boerma, E.C. AU - Hoeft, A. AU - Metnitz, P. AU - Moreno, R.P. AU - Pearse, R. AU - Pelosi, P. AU - Sander, M. AU - Vallet, B. AU - Pettila, V. AU - Vincent, J.L. AU - Rhodes, A. AU - Bouw, M.P. AU - Pickkers, P. AU - et al. PY - 2015 UR - https://hdl.handle.net/2066/152541 AB - BACKGROUND: Evidence suggests that sleep deprivation associated with night-time working may adversely affect performance resulting in a reduction in the safety of surgery and anaesthesia. OBJECTIVE: Our primary objective was to evaluate an association between nonelective night-time surgery and in-hospital mortality. We hypothesised that urgent surgery performed during the night was associated with higher in-hospital mortality and also an increase in the duration of hospital stay and the number of admissions to critical care. DESIGN: A prospective cohort study. This is a secondary analysis of a large database related to perioperative care and outcome (European Surgical Outcome Study). SETTING: Four hundred and ninety-eight hospitals in 28 European countries. PATIENTS: Men and women older than 16 years who underwent nonelective, noncardiac surgery were included according to time of the procedure. INTERVENTION: None. MAIN OUTCOME MEASURES: Primary outcome was in-hospital mortality; the secondary outcome was the duration of hospital stay and critical care admission. RESULTS: Eleven thousand two hundred and ninety patients undergoing urgent surgery were included in the analysis with 636 in-hospital deaths (5.6%). Crude mortality odds ratios (ORs) increased sequentially from daytime [426 deaths (5.3%)] to evening [150 deaths (6.0%), OR 1.14; 95% confidence interval 0.94 to 1.38] to night-time [60 deaths (8.3%), OR 1.62; 95% confidence interval 1.22 to 2.14]. Following adjustment for confounding factors, surgery during the evening (OR 1.09; 95% confidence interval 0.91 to 1.31) and night (OR 1.20; 95% confidence interval 0.9 to 1.6) was not associated with an increased risk of postoperative death. Admittance rate to an ICU increased sequentially from daytime [891 (11.1%)], to evening [347 (13.8%)] to night time [149 (20.6%)]. CONCLUSION: In patients undergoing nonelective urgent noncardiac surgery, in-hospital mortality was associated with well known risk factors related to patients and surgery, but we did not identify any relationship with the time of day at which the procedure was performed. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01203605. TI - Nonelective surgery at night and in-hospital mortality: Prospective observational data from the European Surgical Outcomes Study EP - 485 SN - 0265-0215 IS - iss. 7 SP - 477 JF - European Journal of Anaesthesiology VL - vol. 32 DO - https://doi.org/10.1097/EJA.0000000000000256 ER - TY - JOUR AU - Ludikhuize, J. AU - Brunsveld-Reinders, A.H. AU - Dijkgraaf, M.G. AU - Smorenburg, S.M. AU - Rooij, S.E. De AU - Adams, R. AU - Maaijer, P.F. de AU - Fikkers, B.G. AU - Tangkau, P. AU - Jonge, E. de PY - 2015 UR - https://hdl.handle.net/2066/152559 AB - OBJECTIVE: To describe the effect of implementation of a rapid response system on the composite endpoint of cardiopulmonary arrest, unplanned ICU admission, or death. DESIGN: Pragmatic prospective Dutch multicenter before-after trial, Cost and Outcomes analysis of Medical Emergency Teams trial. SETTING: Twelve hospitals participated, each including two surgical and two nonsurgical wards between April 2009 and November 2011. The Modified Early Warning Score and Situation-Background-Assessment-Recommendation instruments were implemented over 7 months. The rapid response team was then implemented during the following 17 months. The effects of implementing the rapid response team were measured in the last 5 months of this period. PATIENTS: All patients 18 years old and older admitted to the study wards were included. MEASUREMENTS AND MAIN RESULTS: In total, 166,569 patients were included in the study representing 1,031,172 hospital admission days. No differences were observed in patient demographics between periods. The composite endpoint of cardiopulmonary arrest, unplanned ICU admission, or death per 1,000 admissions was significantly reduced in the rapid response team versus the before phase (adjusted odds ratio, 0.847; 95% CI, 0.725-0.989; p = 0.036). Cardiopulmonary arrests and in-hospital mortality were also significantly reduced (odds ratio, 0.607; 95% CI, 0.393-0.937; p = 0.018 and odds ratio, 0.802; 95% CI, 0.644-1.0; p = 0.05, respectively). Unplanned ICU admissions showed a declining trend (odds ratio, 0.878; 95% CI, 0.755-1.021; p = 0.092), whereas severity of illness at the moment of ICU admission was not different between periods. CONCLUSIONS: In this study, introduction of nationwide implementation of rapid response systems was associated with a decrease in the composite endpoint of cardiopulmonary arrests, unplanned ICU admissions, and mortality in patients in general hospital wards. These findings support the implementation of rapid response systems in hospitals to reduce severe adverse events. TI - Outcomes Associated With the Nationwide Introduction of Rapid Response Systems in The Netherlands EP - 2551 SN - 0090-3493 IS - iss. 12 SP - 2544 JF - Critical Care Medicine VL - vol. 43 DO - https://doi.org/10.1097/CCM.0000000000001272 ER - TY - JOUR AU - Kooi, A.W. van der AU - Peelen, L.M. AU - Raijmakers, R.J. AU - Vroegop, R.L. AU - Bakker, D.F. AU - Tekatli, H. AU - Boogaard, M.H.W.A. van den AU - Slooter, A.J. PY - 2015 UR - https://hdl.handle.net/2066/152907 AB - BACKGROUND: Increasing evidence indicates that harmful effects are associated with the use of physical restraint. OBJECTIVES: To characterize the use of physical restraint in intensive care units. Prevalence, adherence to protocols, and correlates of the use of physical restraint were determined. For comparisons between ICUs, adjustments were made for differences in patients' characteristics. METHODS: A prospective, cross-sectional, observational multicenter study with a representative sample (n = 25) of all Dutch intensive care units, ranging from local hospitals to academic centers. Each unit was visited twice, and all 379 patients admitted during these visits were included and were examined for use of physical restraint. RESULTS: Physical restraint was used in 23% of all patients (range, 0%-56% for different units). Of all 346 nurses interviewed, 31% reported using a protocol when applying physical restraint. When corrections were made for clustering within units, the risk for use of physical restraint was increased in patients with delirium or coma, in patients who could not communicate verbally, and in patients receiving psychoactive or sedative medications. Sex, severity of illness, and nurse to patient ratio were not independently related to use of physical restraint. In 11 units (44%), use of physical restraint was more frequent than expected on the basis of patients' characteristics, although this finding was not significant. CONCLUSIONS: Physical restraint is frequently used in Dutch intensive care units. The differences in frequency between units suggest that opportunities exist to limit the use of physical restraint. TI - Use of Physical Restraints in Dutch Intensive Care Units: A Prospective Multicenter Study EP - 495 SN - 1062-3264 IS - iss. 6 SP - 488 JF - American Journal of Critical Care VL - vol. 24 DO - https://doi.org/10.4037/ajcc2015348 ER - TY - JOUR AU - Ronco, C. AU - Ricci, Z. AU - Backer, D. De AU - Kellum, J.A. AU - Taccone, F.S. AU - Joannidis, M. AU - Pickkers, P. AU - Cantaluppi, V. AU - Turani, F. AU - Saudan, P. AU - Bellomo, R. AU - Joannes-Boyau, O. AU - Antonelli, M. AU - Payen, D. AU - Prowle, J.R. AU - Vincent, J.L. PY - 2015 UR - https://hdl.handle.net/2066/153854 AB - Renal replacement therapies (RRTs) represent a cornerstone in the management of severe acute kidney injury. This area of intensive care and nephrology has undergone significant improvement and evolution in recent years. Continuous RRTs have been a major focus of new technological and treatment strategies. RRT is being used increasingly in the intensive care unit, not only for renal indications but also for other organ-supportive strategies. Several aspects related to RRT are now well established, but others remain controversial. In this review, we review the available RRT modalities, covering technical and clinical aspects. We discuss several controversial issues, provide some practical recommendations, and where possible suggest a research agenda for the future. TI - Renal replacement therapy in acute kidney injury: controversy and consensus SN - 1466-609X JF - Critical Care VL - vol. 19 DO - https://doi.org/10.1186/s13054-015-0850-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153854/153854.pdf?sequence=1 ER - TY - JOUR AU - Aman, J. AU - Koppenhagen, L. van AU - Snoek, A.M. AU - Hoeven, J.G. van der AU - Lely, A.J. van der PY - 2015 UR - https://hdl.handle.net/2066/154732 TI - Cerebral fat embolism after bone fractures SN - 0140-6736 IS - iss. 10001 SP - e16 JF - The Lancet (London) VL - vol. 386 DO - https://doi.org/10.1016/S0140-6736(15)60064-2 ER - TY - JOUR AU - Strang, S.G. AU - Waes, O.J. van AU - Hoven, B. van der AU - Ali, S. AU - Verhofstad, M.H.J. AU - Pickkers, P. AU - Lieshout, E.M. van PY - 2015 UR - https://hdl.handle.net/2066/153210 AB - BACKGROUND: Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) have detrimental effects on all organ systems and are associated with increased morbidity and mortality in critically ill patients admitted to an intensive care unit. Intra-bladder measurement of the intra-abdominal pressure (IAP) is currently the gold standard. However, IAH is not always indicative of intestinal ischemia, which is an early and rapidly developing complication. Sensitive biomarkers for intestinal ischemia are needed to be able to intervene before damage becomes irreversible. Gut wall integrity loss, including epithelial cell disruption and tight junctions breakdown, is an early event in intestinal damage. Intestinal Fatty Acid Binding Protein (I-FABP) is excreted in urine and blood specifically from damaged intestinal epithelial cells. Claudin-3 is a specific protein which is excreted in urine following disruption of intercellular tight junctions. This study aims to investigate if I-FABP and Claudin-3 can be used as a diagnostic tool for identifying patients at risk for IAP-related complications. METHODS/DESIGN: In a multicenter, prospective cohort study 200 adult patients admitted to the intensive care unit with at least two risk factors for IAH as defined by the World Society of the Abdominal Compartment Syndrome (WSACS) will be included. Patients in whom an intra-bladder IAP measurement is contra-indicated or impossible and patients with inflammatory bowel diseases that may affect I-FABP levels will be excluded. The IAP will be measured using an intra-bladder technique. During the subsequent 72 hours, the IAP measurement will be repeated every six hours. At these time points, a urine and serum sample will be collected for measurement of I-FABP and Claudin-3 levels. Clinical outcome of patients during their stay at the intensive care unit will be monitored using the Sequential Organ Failure Assessment (SOFA) score. DISCUSSION: Successful completion of this trial will provide evidence on the eventual role of the biomarkers I-FABP and Claudin-3 in predicting the risk of IAP-associated adverse outcome. This may aid early (surgical) intervention. TRIAL REGISTRATION: The trial is registered at the Netherlands Trial Register (NTR4638). TI - Intestinal fatty acid binding protein as a marker for intra-abdominal pressure-related complications in patients admitted to the intensive care unit; study protocol for a prospective cohort study (I-Fabulous study) SN - 1757-7241 SP - 6 JF - Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine VL - vol. 23 DO - https://doi.org/10.1186/s13049-015-0088-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153210/153210.pdf?sequence=1 ER - TY - JOUR AU - Schellekens, W.J.M. AU - Hees, H.W.H. van AU - Heunks, L.M.A. PY - 2015 UR - https://hdl.handle.net/2066/153271 TI - Letter to the Editor SN - 0022-3751 IS - iss. 15 SP - 3389 JF - Journal of Physiology VL - vol. 593 DO - https://doi.org/10.1113/JP270385 ER - TY - JOUR AU - Schellekens, W.J.M. AU - Hees, H.W.H. van AU - Linkels, M. AU - Dekhuijzen, P.N.R. AU - Scheffer, G.J. AU - Hoeven, J.G. van der AU - Heunks, L.M.A. PY - 2015 UR - https://hdl.handle.net/2066/153276 AB - INTRODUCTION: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to possess anti-oxidative and anti-inflammatory properties. The aim of the present study was to investigate the effects of levosimendan on markers for diaphragm nitrosative and oxidative stress, inflammation and proteolysis in a mouse model of endotoxemia and mechanical ventilation. METHODS: Three groups were studied: (1) unventilated mice (CON, n =8), (2) mechanically ventilated endotoxemic mice (MV LPS, n =17) and (3) mechanically ventilated endotoxemic mice treated with levosimendan (MV LPS + L, n =17). Immediately after anesthesia (CON) or after 8 hours of mechanical ventilation, blood and diaphragm muscle were harvested for biochemical analysis. RESULTS: Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1beta, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations. Levosimendan decreased nitrosylated proteins by 10% (P <0.05) and 4-hydroxy-2-nonenal protein concentrations by 13% (P <0.05), but it augmented the rise of iNOS mRNA by 47% (P <0.05). Levosimendan did not affect the inflammatory response in the diaphragm induced by mechanical ventilation and endotoxemia. CONCLUSIONS: Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation. Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response. TI - Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice SN - 1466-609X IS - iss. 1 SP - 69 JF - Critical Care VL - vol. 19 DO - https://doi.org/10.1186/s13054-015-0798-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153276/153276.pdf?sequence=1 ER - TY - JOUR AU - Felten-Barentsz, K.M. AU - Haans, A.J.C. AU - Slutsky, A.S. AU - Heunks, L.M.A. AU - Hoeven, J.G. van der PY - 2015 UR - https://hdl.handle.net/2066/155272 TI - Feasibility and safety of hydrotherapy in critically ill ventilated patients EP - 477 SN - 1073-449X IS - iss. 4 SP - 476 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 191 DO - https://doi.org/10.1164/rccm.201408-1559LE ER - TY - JOUR AU - Kox, M. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/152489 AB - The innate immune system is a defense mechanism that is of vital importance to our survival. However, excessive or unwanted activation of the innate immune system, which can occur in major surgery, sepsis, trauma, ischemia-reperfusion injury and autoimmune diseases, can lead to damage of the kidneys and other organs. Therefore, therapeutic approaches aimed at attenuating the innate immune response could have beneficial effects in these conditions. The vagus nerve exerts anti-inflammatory effects through the so-called cholinergic anti-inflammatory pathway. Since its discovery, numerous animal studies have shown beneficial effects of stimulation of this pathway in models of inflammatory diseases, either through (electrical) stimulation of the vagus nerve or pharmacological approaches. However, human data are very scarce. In this review, we present an overview of the molecular and anatomical bases of the cholinergic anti-inflammatory pathway, but mainly focus on human studies. We discuss the difficulties and drawbacks associated with investigating this pathway in humans, and finally, we provide future perspectives. TI - Modulation of the Innate Immune Response through the Vagus Nerve EP - 84 SN - 1660-8151 IS - iss. 2 SP - 79 JF - Nephron VL - vol. 131 DO - http://dx.doi.org/10.1159/000435843 ER - TY - JOUR AU - Timmermans, K. AU - Sir, O. AU - Kox, M. AU - Vaneker, M. AU - Jong, C. de AU - Gerretsen, J. AU - Edwards, M.J. AU - Scheffer, G.J. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/154766 AB - Both the initial trauma and the subsequent hemodynamic instability may contribute to intestinal damage, which is of great importance in (immunological) posttrauma complications. This study assesses intestinal damage using the biomarker intestinal Fatty Acid Binding Protein (iFABP) in trauma patients during the first days of their hospital admission and the risk factors involved. Plasma iFABP levels were measured in blood samples obtained from adult multiple trauma patients (n = 93) at the trauma scene by the Helicopter Emergency Medical Services, at arrival at the emergency department (ED), and at days 1, 3, 5, 7, 10, and 14 after trauma and related to injury severity and hemodynamic parameters. Plasma iFABP concentrations showed highest levels immediately after trauma at time points Helicopter Emergency Medical Services and ED. Nonsurvivors demonstrated higher iFABP levels at the ED compared with survivors. Furthermore, iFABP values at the ED correlated with Injury Severity Scores, and patients suffering from abdominal trauma demonstrated significantly higher iFABP concentrations in comparison with patients with other types of trauma or healthy controls. Also, patients presenting with a mean arterial pressure (MAP) less than 70 mmHg at the ED demonstrated significantly higher plasma iFABP concentrations in comparison with patients with a normal (70-99 mmHg) or high (>100 mmHg) MAP or healthy controls. Finally, patients with a low hemoglobin (Hb) (<80% of reference value) displayed significantly higher iFABP concentrations in comparison with patients with a normal Hb or healthy controls. Plasma iFABP levels, indicative of intestinal injury, are increased immediately after trauma in patients with abdominal trauma, low MAP, or low Hb and are related to the severity of the trauma. As intestinal injury is suggested to be related to late complications, such as multiorgan dysfunction syndrome or sepsis in trauma patients, strategies to prevent intestinal damage after trauma could be of benefit to these patients. TI - Circulating iFABP Levels as a marker of intestinal damage in trauma patients EP - 120 SN - 1073-2322 IS - iss. 2 SP - 117 JF - Shock VL - vol. 43 DO - http://dx.doi.org/10.1097/SHK.0000000000000284 ER - TY - JOUR AU - Weiss, S.L. AU - Fitzgerald, J.C. AU - Pappachan, J. AU - Wheeler, D. AU - Jaramillo-Bustamante, J.C. AU - Salloo, A. AU - Singhi, S.C. AU - Erickson, S. AU - Roy, J.A. AU - Bush, J.L. AU - Nadkarni, V.M. AU - Thomas, N.J. AU - Pickkers, P. AU - et al. PY - 2015 UR - https://hdl.handle.net/2066/155373 AB - RATIONALE: Limited data exist about the international burden of severe sepsis in critically ill children. OBJECTIVES: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. METHODS: A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. MEASUREMENTS AND MAIN Results : Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,437 patients per group. CONCLUSIONS: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted. TI - Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study EP - 1157 SN - 1073-449X IS - iss. 10 SP - 1147 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 191 DO - http://dx.doi.org/10.1164/rccm.201412-2323OC ER - TY - JOUR AU - Sakr, Y. AU - Alhussami, I. AU - Nanchal, R. AU - Wunderink, R.G. AU - Pellis, T. AU - Wittebole, X. AU - Martin-Loeches, I. AU - Francois, B. AU - Leone, M. AU - Vincent, J.L. AU - Pickkers, P. AU - et al. PY - 2015 UR - https://hdl.handle.net/2066/151975 AB - OBJECTIVE: To assess the effect of body mass index on ICU outcome and on the development of ICU-acquired infection. DESIGN: A substudy of the Intensive Care Over Nations audit. SETTING: Seven hundred thirty ICUs in 84 countries. PATIENTS: All adult ICU patients admitted between May 8 and 18, 2012, except those admitted for less than 24 hours for routine postoperative monitoring (n = 10,069). In this subanalysis, only patients with complete data on height and weight (measured or estimated) on ICU admission in order to calculate the body mass index were included (n = 8,829). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Underweight was defined as body mass index less than 18.5 kg/m, normal weight as body mass index 18.5-24.9 kg/m, overweight as body mass index 25-29.9 kg/m, obese as body mass index 30-39.9 kg/m, and morbidly obese as body mass index greater than or equal to 40 kg/m. The mean body mass index was 26.4 +/- 6.5 kg/m. The ICU length of stay was similar among categories, but overweight and obese patients had longer hospital lengths of stay than patients with normal body mass index (10 [interquartile range, 5-21] and 11 [5-21] vs 9 [4-19] d; p < 0.01 pairwise). ICU mortality was lower in morbidly obese than in normal body mass index patients (11.2% vs 16.6%; p = 0.015). In-hospital mortality was lower in morbidly obese and overweight patients and higher in underweight patients than in those with normal body mass index. In a multilevel Cox proportional hazard analysis, underweight was independently associated with a higher hazard of 60-day in-hospital death (hazard ratio, 1.32; 95% CI, 1.05-1.65; p = 0.018), whereas overweight was associated with a lower hazard (hazard ratio, 0.79; 95% CI, 0.71-0.89; p < 0.001). No body mass index category was associated with an increased hazard of ICU-acquired infection. CONCLUSIONS: In this large cohort of critically ill patients, underweight was independently associated with a higher hazard of 60-day in-hospital death and overweight with a lower hazard. None of the body mass index categories as independently associated with an increased hazard of infection during the ICU stay. TI - Being Overweight Is Associated With Greater Survival in ICU Patients: Results From the Intensive Care Over Nations Audit EP - 2632 SN - 0090-3493 IS - iss. 12 SP - 2623 JF - Critical Care Medicine VL - vol. 43 DO - https://doi.org/10.1097/CCM.0000000000001310 ER - TY - JOUR AU - Timmermans, K. AU - Vaneker, M. AU - Scheffer, G.J. AU - Maassen, P. AU - Janssen, S. AU - Kox, M. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/152733 AB - INTRODUCTION: Soluble urokinase-type plasminogen activator (suPAR) represents a marker for immune activation and has predictive value in critically ill patients. The kinetics of suPAR and its correlation with the immune response and outcome in trauma patients are unknown. METHODS: Plasma concentrations of inflammatory cytokines and suPAR were determined in adult trauma patient (n = 69) samples obtained by the Helicopter Emergency Medical Services at arrival at the emergency department (ED) and at days 1, 3, 5, 7, 10, and 14. Results : Initial suPAR levels were unrelated to injury severity score and higher in nonsurvivors compared with survivors, although no difference was observed between early and late mortality. The area under the receiver operating characteristic curve to predict mortality was 0.6 (95% confidence interval, 0.48-0.72). Soluble urokinase-type plasminogen activator levels increased over time in 94% of patients, although suPAR increase did not precede death. Tumor necrosis factor alpha at the ED correlated with suPAR at that time point, whereas concentrations of other proinflammatory cytokines at the ED correlated with suPAR levels at days 1 and 5. CONCLUSIONS: After trauma, initial suPAR plasma concentrations are higher in nonsurvivors compared with survivors, but its predictive value is low. Soluble urokinase-type plasminogen activator levels increase over time after trauma, and concentrations at later time points are related to cytokine levels at the ED. TI - Soluble urokinase-type plasminogen activator levels are related to plasma cytokine levels but have low predictive value for mortality in trauma patients EP - 480 SN - 0883-9441 IS - iss. 3 SP - 476 JF - Journal of Critical Care VL - vol. 30 DO - http://dx.doi.org/10.1016/j.jcrc.2015.01.006 ER - TY - JOUR AU - Postma, N. AU - Kiers, D. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/152821 AB - The most important infectious cause of antibiotic-associated diarrhoea and colitis is Clostridium difficile, which is a Gram-positive, anaerobic, spore-forming, toxin-producing bacillus. In this overview we will discuss the diagnostic and therapeutic management of patients presenting with suspected or proven C. difficile infection (CDI). The clinical spectrum varies from asymptomatic C. difficile carriers to fulminant colitis with multi-organ failure. The onset of symptoms is usually within 2 weeks after initiation of antibiotic treatment. Diagnosis is based on the combination of clinical symptoms and either a positive stool test for C. difficile toxins or endoscopic or histological findings of pseudomembranous colitis. There is no indication for treatment of asymptomatic carriers, but patients with proven CDI should be treated. Treatment consists of cessation of the provoking antibiotic treatment, secondary prevention by infection control strategies, and treatment with metronidazole or vancomycin. Treatment of recurring CDI, severe infection, the need for surgery, and novel alternative potential treatment strategies will be discussed. The concurrent increase in multiresistant colonisation and increasing numbers of asymptomatic carriers of C. difficile will lead to an increase of the situation in which patients with severe infections, treated with broad-spectrum antibiotics, will develop concurrent severe CDI. We will discuss possible therapy strategies for these patients. TI - The challenge of Clostridium difficile infection: Overview of clinical manifestations, diagnostic tools and therapeutic options EP - 50 SN - 0924-8579 SP - S47 JF - International Journal of Antimicrobial Agents VL - vol. 46 Suppl 1 DO - http://dx.doi.org/10.1016/j.ijantimicag.2015.11.001 ER - TY - JOUR AU - Pickkers, P. AU - Ven, A. van der AU - Netea, M.G. PY - 2015 UR - https://hdl.handle.net/2066/153071 TI - Immunomodulatory adjunctive treatment options for Ebola virus disease patients SN - 0342-4642 IS - iss. 5 SP - 965 JF - Intensive Care Medicine VL - vol. 41 DO - http://dx.doi.org/10.1007/s00134-015-3773-6 ER - TY - JOUR AU - Vincent, J.L. AU - Marshall, J.C. AU - Dellinger, R.P. AU - Simonson, S.G. AU - Guntupalli, K. AU - Levy, M.M. AU - Singer, M. AU - Malik, R. AU - Pickkers, P. AU - et al. PY - 2015 UR - https://hdl.handle.net/2066/154081 AB - OBJECTIVE: Talactoferrin alfa is a recombinant form of the human glycoprotein, lactoferrin, which has been shown to have a wide range of effects on the immune system. This phase II/III clinical trial compared talactoferrin with placebo, in addition to standard of care, in patients with severe sepsis. DESIGN: Multicenter, randomized, placebo-controlled, phase II/III clinical study. SETTING: Seventy-seven centers in 10 countries. PATIENTS: Adult (> 18 yr) patients admitted to one of the participating centers with severe sepsis who were receiving antimicrobial therapy and able to take liquid medication by mouth or feeding tube. INTERVENTIONS: Patients were randomized to receive either talactoferrin (1.5 g, 15 mL) or placebo three times a day orally or by another enteral route for 28 days or until ICU discharge. MEASUREMENTS AND MAIN RESULTS: The study was terminated after 305 patients had been enrolled (153 talactoferrin and 152 placebo) because of futility and safety concerns identified by the Data Safety Monitoring Board. There were no significant differences between groups in baseline characteristics including age, sex, site of infection, and severity scores. Twenty-eight-day mortality was higher in talactoferrin-treated patients although this difference was not statistically significant (24.8% vs 17.8% placebo; p = 0.117). The difference was largely the result of differences in patients with shock (talactoferrin, 33/105 [31.4%] vs placebo, 21/104 [20.2%]; p = 0.064); no mortality difference was seen in patients without shock (talactoferrin, 5/48 [10.4%] vs placebo, 6/48 [12.5%]; p = 0.806). In-hospital (43/153 [28.1%] vs 27/152 [17.8%]; p = 0.037) and 3-month (46/153 [30.1%] vs 31/152 [20.4%]; p = 0.036) mortality rates were significantly higher in talactoferrin-treated patients than in patients in the placebo group. The occurrence of treatment-related adverse or serious adverse events was similar between groups. CONCLUSIONS: Administration of oral talactoferrin was not associated with reduced 28-day mortality in patients with severe sepsis and may even be harmful. TI - Talactoferrin in Severe Sepsis: Results From the Phase II/III Oral tAlactoferrin in Severe sepsIS Trial EP - 1838 SN - 0090-3493 IS - iss. 9 SP - 1832 JF - Critical Care Medicine VL - vol. 43 DO - https://doi.org/10.1097/CCM.0000000000001090 ER - TY - JOUR AU - Sakr, Y. AU - Moreira, C.L. AU - Rhodes, A. AU - Ferguson, N.D. AU - Kleinpell, R. AU - Pickkers, P. AU - Kuiper, M.A. AU - Lipman, J. AU - Vincent, J.L. PY - 2015 UR - https://hdl.handle.net/2066/154195 AB - OBJECTIVE: To investigate the impact of various facets of ICU organization on outcome in a large cohort of ICU patients from different geographic regions. DESIGN: International, multicenter, observational study. SETTING: All 1,265 ICUs in 75 countries that contributed to the 1-day point prevalence Extended Prevalence of Infection in Intensive Care study. PATIENTS: All adult patients present on a participating ICU on the study day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The Extended Prevalence of Infection in Intensive Care study included data on 13,796 adult patients. Organizational characteristics of the participating hospitals and units varied across geographic areas. Participating North American hospitals had greater availability of microbiologic examination and more 24-hour emergency departments than did the participating European and Latin American units. Of the participating ICUs, 82.9% were closed format, with the lowest prevalence among North American units (62.7%) and the highest in ICUs in Oceania (92.6%). The proportion of participating ICUs with 24-hour intensivist coverage was lower in North America than in Latin America (86.8% vs 98.1%, p = 0.002). ICU volume was significantly lower in participating ICUs from Western Europe, Latin America, and Asia compared with North America. In multivariable logistic regression analysis, medical and mixed ICUs were independently associated with a greater risk of in-hospital death. A nurse:patient ratio of more than 1:1.5 on the study day was independently associated with a lower risk of in-hospital death. CONCLUSIONS: In this international large cohort of ICU patients, hospital and ICU characteristics varied worldwide. A high nurse:patient ratio was independently associated with a lower risk of in-hospital death. These exploratory data need to be confirmed in large prospective studies that consider additional country-specific ICU practice variations. TI - The impact of hospital and ICU organizational factors on outcome in critically ill patients: results from the extended prevalence of infection in intensive care study* EP - 526 SN - 0090-3493 IS - iss. 3 SP - 519 JF - Critical Care Medicine VL - vol. 43 DO - https://doi.org/10.1097/CCM.0000000000000754 ER - TY - JOUR AU - Eijk, L.T.G.J. van AU - Kox, M. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/152965 TI - Hepcidin as a target of therapy in the treatment of anemia after trauma EP - e37 SN - 0090-3493 IS - iss. 1 SP - e36 JF - Critical Care Medicine VL - vol. 43 DO - https://doi.org/10.1097/CCM.0000000000000689 ER - TY - JOUR AU - Dorresteijn, M.J. AU - Paine, A. AU - Zilian, E. AU - Fenten, M.G.E. AU - Frenzel, E. AU - Janciauskiene, S. AU - Figueiredo, C. AU - Eiz-Vesper, B. AU - Blasczyk, R. AU - Dekker, D. AU - Pennings, B. AU - Scharstuhl, A. AU - Smits, P. AU - Larmann, J. AU - Theilmeier, G. AU - Hoeven, J.G. van der AU - Wagener, F.A.D.T.G. AU - Pickkers, P. AU - Immenschuh, S. PY - 2015 UR - https://hdl.handle.net/2066/154724 AB - Heme oxygenase (HO)-1 is the inducible isoform of the heme-degrading enzyme HO, which is upregulated by multiple stress stimuli. HO-1 has major immunomodulatory and anti-inflammatory effects via its cell-type-specific functions in mononuclear cells. Contradictory findings have been reported on HO-1 regulation by the Toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) in these cells. Therefore, we reinvestigated the effects of LPS on HO-1 gene expression in human and murine mononuclear cells in vitro and in vivo. Remarkably, LPS downregulated HO-1 in primary human peripheral blood mononuclear cells (PBMCs), CD14(+) monocytes, macrophages, dendritic cells, and granulocytes, but upregulated this enzyme in primary murine macrophages and human monocytic leukemia cell lines. Furthermore, experiments with human CD14(+) monocytes revealed that activation of other TLRs including TLR1, -2, -5, -6, -8, and -9 decreased HO-1 mRNA expression. LPS-dependent downregulation of HO-1 was specific, because expression of cyclooxygenase-2, NADP(H)-quinone oxidoreductase-1, and peroxiredoxin-1 was increased under the same experimental conditions. Notably, LPS upregulated expression of Bach1, a critical transcriptional repressor of HO-1. Moreover, knockdown of this nuclear factor enhanced basal and LPS-dependent HO-1 expression in mononuclear cells. Finally, downregulation of HO-1 in response to LPS was confirmed in PBMCs from human individuals subjected to experimental endotoxemia. In conclusion, LPS downregulates HO-1 expression in primary human mononuclear cells via a Bach1-mediated pathway. As LPS-dependent HO-1 regulation is cell-type- and species-specific, experimental findings in cell lines and animal models need careful interpretation. TI - Cell-type-specific downregulation of heme oxygenase-1 by lipopolysaccharide via Bach1 in primary human mononuclear cells EP - 232 SN - 0891-5849 SP - 224 JF - Free Radical Biology and Medicine VL - vol. 78 DO - https://doi.org/10.1016/j.freeradbiomed.2014.10.579 ER - TY - JOUR AU - Kiers, H.D. AU - Gerretsen, J. AU - Janssen, E. AU - John, A. AU - Groeneveld, R. AU - Hoeven, J.G. van der AU - Scheffer, G.J. AU - Pickkers, P. AU - Kox, M. PY - 2015 UR - https://hdl.handle.net/2066/152722 AB - Oxygen therapy to maintain tissue oxygenation is one of the cornerstones of critical care. Therefore, hyperoxia is often encountered in critically ill patients. Epidemiologic studies have demonstrated that hyperoxia may affect outcome, although mechanisms are unclear. Immunologic effects might be involved, as hyperoxia was shown to attenuate inflammation and organ damage in preclinical models. However, it remains unclear whether these observations can be ascribed to direct immunosuppressive effects of hyperoxia or to preserved tissue oxygenation. In contrast to these putative anti-inflammatory effects, hyperoxia may elicit an inflammatory response and organ damage in itself, known as oxygen toxicity. Here, we demonstrate that, in the absence of systemic inflammation, short-term hyperoxia (100% O2 for 2.5 hours in mice and 3.5 hours in humans) does not result in increased levels of inflammatory cytokines in both mice and healthy volunteers. Furthermore, we show that, compared with room air, hyperoxia does not affect the systemic inflammatory response elicited by administration of bacterial endotoxin in mice and man. Finally, neutrophil phagocytosis and ROS generation are unaffected by short-term hyperoxia. Our results indicate that hyperoxia does not exert direct anti-inflammatory effects and temper expectations of using it as an immunomodulatory treatment strategy. TI - Short-term hyperoxia does not exert immunologic effects during experimental murine and human endotoxemia SN - 2045-2322 JF - Scientific Reports VL - vol. 5 DO - https://doi.org/10.1038/srep17441 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/152722/152722.pdf?sequence=1 ER - TY - JOUR AU - El Messaoudi, S. AU - Nederlof, R. AU - Zuurbier, C.J. AU - Swieten, H.A. van AU - Pickkers, P. AU - Noyez, L. AU - Dieker, H.J. AU - Coenen, M.J.H. AU - Donders, A.R.T. AU - Vos, A. AU - Rongen, G.A.P.J.M. AU - Riksen, N.P. PY - 2015 UR - https://hdl.handle.net/2066/155124 AB - BACKGROUND: During coronary artery bypass graft (CABG) surgery, ischaemia and reperfusion damage myocardial tissue, and increased postoperative plasma troponin concentration is associated with a worse outcome. We investigated whether metformin pretreatment limits cardiac injury, assessed by troponin concentrations, during CABG surgery in patients without diabetes. METHODS: We did a placebo-controlled, double-blind, single-centre study in an academic hospital in Nijmegen (Netherlands) in adult patients without diabetes undergoing an elective on-pump CABG procedure. We randomly assigned patients (1:1) in blocks of ten via a computer-generated randomisation sequence to either metformin hydrochloride (500 mg three times per day) or placebo (three times per day) for 3 days before surgery. The last dose was given roughly 3 h before surgery. Patients, investigators, trial staff, and the statistician were all masked to treatment allocation. The primary endpoint was the plasma concentration of high-sensitive troponin I at 6, 12, and 24 h postreperfusion after surgery, analysed in the per-protocol population with a mixed-model analysis using all these timepoints. Secondary endpoints included the occurrence of clinically relevant arrhythmias within 24 hours after reperfusion, the need for inotropic support, time to detubation, duration of stay in the intensive-care unit, and postoperative use of insulin. This study is registered with ClinicalTrials.gov, number NCT01438723. FINDINGS: Between Nov 8, 2011, and Nov 22, 2013, we randomly assigned 111 patients to treatment (57 to metformin and 54 to placebo). Five patients dropped out from the metformin group, and six from the placebo group. 52 patients in the metformin group and 48 patients in the placebo group were included in the per-protocol analysis. Geometric mean high-sensitivity troponin I increased from 0 mug/L to 3.67 mug/L (95% CI 3.06-4.41) with metformin and to 3.32 mug/L (2.75-4.01) with placebo at 6 h after reperfusion; 2.84 mug/L (2.37-3.41) and 2.45 mug/L (2.02-2.96), respectively, at 12 h; and to 1.77 mug/L (1.47-2.12) and 1.60 mug/L (1.32-1.94) at 24 h. The concentrations did not differ significantly between the groups (difference 12.3% for all timepoints [95% CI -12.4 to 44.1] p=0.35). Occurrence of arrhythmias did not differ between groups (three [5.8%] of 52 patients who received metformin vs three [6.3%] of 48 patients who received placebo; p=1.00). There was no difference between groups in the need for inotropic support, time to detubation, duration of stay in the intensive-care unit, or postoperative use of insulin. No patients died within 30 days after surgery. Occurrence of gastrointestinal discomfort (mostly diarrhoea) was significantly higher with metformin than with placebo (11 [21.2%] of 52 vs two [4.2%] of 48 patients; p=0.01). INTERPRETATION: Short-term metformin pretreatment, although safe, does not seem to be an effective strategy to reduce periprocedural myocardial injury in patients without diabetes undergoing CABG surgery. FUNDING: Netherlands Organisation for Health Research and Development and Netherlands Heart Foundation. TI - Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomised controlled trial EP - 623 SN - 2213-8587 IS - iss. 8 SP - 615 JF - Lancet Diabetes & Endocrinology VL - vol. 3 DO - https://doi.org/10.1016/S2213-8587(15)00121-7 ER - TY - JOUR AU - Kolwijck, E. AU - Scheper, H. AU - Beuving, J. AU - Kuijper, E.J. AU - Hoeven, J.G. van der AU - Verweij, P.E. PY - 2015 UR - https://hdl.handle.net/2066/154528 AB - BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a life-threatening infection that occurs predominantly in severely immunocompromised patients. Recently, IPA is also increasingly seen in less severely immunocompromised patients, such as patients with COPD receiving glucocorticoids and patients on ventilation in an IC unit. CASE DESCRIPTION: Here we present the case of a 59-year-old male who died of influenza complicated by a superinfection with Aspergillus fumigatus. This patient had no known previous medical history, except schizophrenia. CONCLUSION: Since the 2009 influenza pandemic, IPA has been increasingly reported as a superinfection in patients with a severe influenza virus infection. This combined Aspergillus and influenza infection often has a fatal outcome. An Aspergillus sputum culture should be taken seriously in patients with severe influenza pneumonia, and treatment should be considered early in the disease course. TI - [Invasive pulmonary aspergillosis in influenza] SN - 0028-2162 IS - iss. 0 SP - A7431 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 159 ER - TY - JOUR AU - Ramakers, B.P.C. AU - Giamarellos-Bourboulis, E.J. AU - Tasioudis, C. AU - Coenen, M.J. AU - Kox, M. AU - Vermeulen, H.H. AU - Groothuismink, J.M. AU - Hoeven, J.G. van der AU - Routsi, C. AU - Savva, A. AU - Prekates, A. AU - Diamantea, F. AU - Sinapidis, D. AU - Smits, P. AU - Toutouzas, K. AU - Riksen, N.P. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/152177 AB - INTRODUCTION: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. METHODS: The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. RESULTS: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-alpha by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. CONCLUSIONS: Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation. TI - Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients EP - 547 SN - 1073-2322 IS - iss. 6 SP - 542 JF - Shock VL - vol. 44 DO - https://doi.org/10.1097/SHK.0000000000000456 ER - TY - JOUR AU - Zwaag, J. AU - Pickkers, P. AU - Kox, M. PY - 2015 UR - https://hdl.handle.net/2066/153002 TI - Hormone and Cytokine Responses to Repeated Endotoxin Exposures-No Evidence of Endotoxin Tolerance After 5 Weeks in Humans EP - 385 SN - 1073-2322 IS - iss. 4 SP - 384 JF - Shock VL - vol. 44 DO - https://doi.org/10.1097/SHK.0000000000000432 ER - TY - JOUR AU - Sluisveld, P.H.J. van AU - Hesselink, G.J. AU - Hoeven, J.G. van der AU - Westert, G.P. AU - Wollersheim, H.C. AU - Zegers, M. PY - 2015 UR - https://hdl.handle.net/2066/153116 AB - PURPOSE: To systematically review and evaluate the effectiveness of interventions in order to improve the safety and efficiency of patient handover between intensive care unit (ICU) and general ward healthcare professionals at ICU discharge. METHODS: PubMed, CINAHL, PsycINFO, EMBASE, Web of Science, and the Cochrane Library were searched for intervention studies with the aim to improve clinical handover between ICU and general ward healthcare professionals that had been published up to and including June 2013. The methods for article inclusion and data analysis were pre-specified and aligned with recommendations outlined in the PRISMA guideline. Two reviewers independently extracted data (study purpose, setting, population, method of sampling, sample size, intervention characteristics, outcome, and implementation activities) and assessed the quality of the included studies. RESULTS: From the 6,591 citations initially extracted from the six databases, we included 11 studies in this review. Of these, six (55 %) reported statistically significant effects. Effective interventions included liaison nurses to improve communication and coordination of care and forms to facilitate timely, complete and accurate handover information. Effective interventions resulted in improved continuity of care (e.g., reduced discharge delay) and in reduced adverse events. Inconsistent effects were observed for use of care, namely, reduction of length of stay versus increase of readmissions to higher care. No statistically significant effects were found in the reduction of mortality. The overall methodological quality of the 11 studies reviewed was relatively low, with an average score of 4.5 out of 11 points. CONCLUSIONS: This review shows that liaison nurses and handover forms are promising interventions to improve the quality of patient handover between the ICU and general ward. More robust evidence is needed on the effectiveness of interventions aiming to improve ICU handover and supportive implementation strategies. TI - Improving clinical handover between intensive care unit and general ward professionals at intensive care unit discharge EP - 604 SN - 0342-4642 IS - iss. 4 SP - 589 JF - Intensive Care Medicine VL - vol. 41 DO - https://doi.org/10.1007/s00134-015-3666-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153116/153116.pdf?sequence=1 ER - TY - JOUR AU - Cox, L.A.E. AU - Eijk, L.T.G.J. van AU - Ramakers, B.P.C. AU - Dorresteijn, M.J. AU - Gerretsen, J. AU - Kox, M. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/153168 AB - Although endothelial dysfunction is central to the pathogenesis of sepsis, no specific and clinically applicable marker for endothelial dysfunction is currently available. Endocan, a proteoglycan excreted by endothelial cells in response to inflammatory cytokines, may serve as such a marker. Our objective was to investigate the kinetics of endocan and its relationship with inflammation-induced endothelial dysfunction during experimental human endotoxemia. Endothelial function was assessed in 17 healthy male volunteers before and 4 h after the administration of 2 ng/kg lipopolysaccharide (LPS) by determination of the vasodilatory response of forearm blood vessels to intra-arterial infusion of endothelium-dependent (acetylcholine) or endothelium-independent (nitroglycerin/sodium nitroprusside) vasodilators using venous occlusion plethysmography. Plasma levels of endocan, inflammatory cytokines, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) were measured, and correlations with endothelial dysfunction were explored. Plasma levels of all measured cytokines, endocan, ICAM, and VCAM concentrations significantly increased after LPS administration. Furthermore, LPS administration resulted in a significantly blunted response to acetylcholine (mean +/- SD increase in forearm blood flow [FBF] of 383% +/- 320% before LPS vs. 173% +/- 134% after LPS, P = 0.03), whereas the response to nitroglycerin/sodium nitroprusside was not affected (mean +/- SD increase in FBF of 174% +/- 120% before LPS vs. 110% +/- 82% after LPS, P = 0.11). Furthermore, there was a significant correlation between the increase in plasma endocan levels and the attenuation of vasodilatory responses to acetylcholine (r = -0.48, P < 0.05). No correlation existed between plasma levels of ICAM or VCAM and the attenuation of the acetylcholine-induced vasodilatory response. Endocan levels are related to endothelial dysfunction in humans in vivo during systemic inflammation evoked by experimental endotoxemia. Therefore, this study suggests that endocan could be a novel marker of endothelial dysfunction in inflammatory conditions. TI - Inflammation-Induced Increases in Plasma Endocan Levels are Associated With Endothelial Dysfunction in Humans in vivo EP - 326 SN - 1073-2322 IS - iss. 4 SP - 322 JF - Shock VL - vol. 43 DO - https://doi.org/10.1097/SHK.0000000000000320 ER - TY - JOUR AU - Kox, M. AU - Eijk, L.T.G.J. van AU - Verhaak, T. AU - Frenzel, T. AU - Kiers, H.D. AU - Gerretsen, J. AU - Hoeven, J.G. van der AU - Kornet, L. AU - Scheiner, A. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/154339 AB - INTRODUCTION: Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia. METHODS: We performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5-C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0-10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg(-1) Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation. RESULTS: No serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS. CONCLUSIONS: tVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT01944228 . Registered 12 September 2013. TI - Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study SN - 1478-6354 SP - 150 JF - Arthritis Research & Therapy VL - vol. 17 DO - https://doi.org/10.1186/s13075-015-0667-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/154339/154339.pdf?sequence=1 ER - TY - JOUR AU - Weyer, R.W. van der AU - Ramakers, B.P.C. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/154529 AB - Leptospirosis is a zoonosis caused by pathogenic Leptospira species. Leptospira infection can range from subclinical to life-threatening disease. Renal failure and severe respiratory symptoms may occur and are associated with a high mortality rate. It is important to realise that renal failure and other symptoms can occur in the absence of icterus. Leptospiraemia occurs mostly during the first week of acute illness, so blood cultures should be taken as soon as possible. Most cases of leptospirosis are diagnosed by serology. Antibodies are detectable in the blood approximately 5 to 7 days after onset of symptoms. Early recognition and treatment with either cephalosporins or penicillin may shorten the duration and severity of multi-organ failure and is therefore mandatory. TI - [Leptospirosis] SN - 0028-2162 IS - iss. 0 SP - A7797 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 159 ER - TY - JOUR AU - Kubbenga, I.E. AU - Postma, N. AU - Ramakers, B.P.C. PY - 2015 UR - https://hdl.handle.net/2066/154539 AB - BACKGROUND: Over the past few years there has been an increase in the use of ecstasy among the Dutch population. A number of complications are associated with this drug, hyperthermia being the most well-known. A less commonly-occurring complication is pneumomediastinum. CASE DESCRIPTION: A 20-year-old man presented at the emergency department with extensive subcutaneous emphysema, pneumomediastinum, pneumopericardium and pneumorachis (air within the spinal canal), which had developed after visiting a festival. After excluding the most likely causes, it was concluded that it was due to a combination of ecstasy use and intensive activity (dancing). He was managed conservatively and after two days of observation in the ICU the patient fully recovered. CONCLUSION: This case illustrates a rare complication that seems - indirectly - related to using ecstasy. In most cases conservative treatment is adequate but the presence of pneumopericardium means that given the risk of cardiovascular complications, cardiopulmonary monitoring is essential to trace them. TI - [Pneumorachis and pneumopericardium after ecstasy use: an uncommon complication] SN - 0028-2162 SP - A8592 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 159 ER - TY - JOUR AU - Nusmeier, A. AU - Cecchetti, C. AU - Blohm, M. AU - Lehman, R. AU - Hoeven, J.G. van der AU - Lemson, J. PY - 2015 UR - https://hdl.handle.net/2066/153476 AB - OBJECTIVES: To define near-normal values of extravascular lung water indexed to body weight in children. DESIGN: Prospective multicenter observational study. SETTING: Medical/surgical PICUs of 5 multinational hospitals. PATIENTS: Fifty-eight children with a median age of 4 years (range 1 month to 17 year) with heterogeneous PICU admission diagnoses were included. Extravascular lung water measurements from these children were collected after resolution of their illness. Obtained values were indexed to actual body weight and height and subsequently related to age. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Extravascular lung water indexed to body weight correlated with age (r2 = 0.7) and could be categorized in three-age groups consisting of significantly different median extravascular lung water indexed to body weight values (5th-95th percentile): less than 1 year, 9-29 mL/kg; 1-5 years, 7-25 mL/kg; and 5-17 years, 5-13 mL/kg. Extravascular lung water indexed to height did not correlate to age and resulted in an age-independent near-normal value of less than 315 mL/m. CONCLUSIONS: Younger children have higher values of extravascular lung water indexed to actual body weight. Age categorized near-normal values of extravascular lung water indexed to body weight are presented for possible clinical use. Furthermore, we suggest to index extravascular lung water to height, which seems to be age independent. TI - Near-normal values of extravascular lung water in children EP - 33 SN - 1529-7535 IS - iss. 2 SP - e28 JF - Pediatric Critical Care Medicine VL - vol. 16 DO - https://doi.org/10.1097/PCC.0000000000000312 ER - TY - JOUR AU - Wassenaar, A. AU - Boogaard, M.H.W.A. van den AU - Hooft, T. van der AU - Pickkers, P. AU - Schoonhoven, L. PY - 2015 UR - https://hdl.handle.net/2066/155178 AB - AIMS AND OBJECTIVES: To describe and understand intensive care unit (ICU) nurses' views regarding their role in ICU patients' perception of safety. BACKGROUND: Feeling safe is an important issue for ICU patients. Not feeling safe may result in adverse effects including traumatic experiences, having nightmares and feeling depressed. Nursing care plays a major role in patients' perception of safety. However, it is unknown whether ICU nurses are aware of this role. DESIGN: A grounded theory approach following Corbin and Strauss. METHODS: A total of 13 participants were included in the study following maximum variation sampling, by selecting ICU nurses who differed in gender, age, work experience as registered ICU nurse, and were employed in different IC units. In-depth interviews were performed using open-ended questions guided by a topic list with broad question areas. Data collection and analysis were executed during an iterative process. RESULTS: The core category, building a bond of trust to provide good and comfortable care, arose from four main categories: explaining and informing ICU patients, using patients' family bond, ICU nurses' attitudes and expertise, and creating physical safety. CONCLUSION: The ICU nurses stated that they were not explicitly aware of ICU patients' perception of safety, but that they strived to provide good and comfortable care, through building a bond of trust with their patients. According to the nurses, a bond of trust is essential for patients to feel safe in the ICU. RELEVANCE TO CLINICAL PRACTICE: The importance of feeling safe in ICU patients should be addressed within the education and clinical practice of ICU nurses, to ensure that they become aware of ICU patients' perception of safety. TI - 'Providing good and comfortable care by building a bond of trust': nurses views regarding their role in patients' perception of safety in the Intensive Care Unit EP - 3244 SN - 0962-1067 IS - iss. 21-22 SP - 3233 JF - Journal of Clinical Nursing VL - vol. 24 DO - https://doi.org/10.1111/jocn.12995 ER - TY - JOUR AU - Tilburgs, B. AU - Nijkamp, M.D. AU - Bakker, E.C. AU - Hoeven, H. van der PY - 2015 UR - https://hdl.handle.net/2066/152845 AB - OBJECTIVES: To determine the influence of instrumental, emotional and informative support on the quality of life of former intensive care unit (ICU) patients and to establish their preferred sources of social support. RESEARCH METHODOLOGY: In a cross-sectional survey, former intensive care patients (n=88) completed the "social support interactions/discrepancies list", the "RAND-36 Health Survey" and reported their preferred sources of the different types of social support. SETTING: A 35 bed intensive care unit in the Radboudumc university hospital in the Netherlands. MAIN OUTCOME MEASURES: Psychological, physical and social domains of quality of life and patient preferences regarding sources of social support. RESULTS: Instrumental and emotional support show a buffering effect on the physical dimension of the quality of life. The discrepancies between the expected and the received instrumental, informative and emotional support have a negative influence on psychological quality of life. Former ICU patients prefer receiving social support from family members rather than friends, professional caregivers or fellow former ICU patients. CONCLUSION: This study emphasises the buffering effect of social support on diminished quality of life in former intensive care patients. It is suggested that hospitals provide an intensive care after-care programme including both patients and relatives to help fulfilling this need for social support. TI - The influence of social support on patients' quality of life after an intensive care unit discharge: A cross-sectional survey EP - 342 SN - 0964-3397 IS - iss. 6 SP - 336 JF - Intensive and Critical Care Nursing VL - vol. 31 DO - https://doi.org/10.1016/j.iccn.2015.07.002 ER - TY - JOUR AU - Wassenaar, A. AU - Boogaard, M.H.W.A. van den AU - Achterberg, T. van AU - Slooter, A.J. AU - Kuiper, M.A. AU - Hoogendoorn, M.E. AU - Simons, K.S. AU - Maseda, E. AU - Pinto, N. AU - Jones, C. AU - Luetz, A. AU - Schandl, A. AU - Verbrugghe, W. AU - Aitken, L.M. AU - Haren, F.M. van AU - Donders, A.R.T. AU - Schoonhoven, L. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/153446 AB - RATIONALE: Delirium incidence in intensive care unit (ICU) patients is high and associated with poor outcome. Identification of high-risk patients may facilitate its prevention. PURPOSE: To develop and validate a model based on data available at ICU admission to predict delirium development during a patient's complete ICU stay and to determine the predictive value of this model in relation to the time of delirium development. METHODS: Prospective cohort study in 13 ICUs from seven countries. Multiple logistic regression analysis was used to develop the early prediction (E-PRE-DELIRIC) model on data of the first two-thirds and validated on data of the last one-third of the patients from every participating ICU. RESULTS: In total, 2914 patients were included. Delirium incidence was 23.6 %. The E-PRE-DELIRIC model consists of nine predictors assessed at ICU admission: age, history of cognitive impairment, history of alcohol abuse, blood urea nitrogen, admission category, urgent admission, mean arterial blood pressure, use of corticosteroids, and respiratory failure. The area under the receiver operating characteristic curve (AUROC) was 0.76 [95 % confidence interval (CI) 0.73-0.77] in the development dataset and 0.75 (95 % CI 0.71-0.79) in the validation dataset. The model was well calibrated. AUROC increased from 0.70 (95 % CI 0.67-0.74), for delirium that developed <2 days, to 0.81 (95 % CI 0.78-0.84), for delirium that developed >6 days. CONCLUSION: Patients' delirium risk for the complete ICU length of stay can be predicted at admission using the E-PRE-DELIRIC model, allowing early preventive interventions aimed to reduce incidence and severity of ICU delirium. TI - Multinational development and validation of an early prediction model for delirium in ICU patients EP - 1056 SN - 0342-4642 IS - iss. 6 SP - 1048 JF - Intensive Care Medicine VL - vol. 41 DO - https://doi.org/10.1007/s00134-015-3777-2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153446/153446.pdf?sequence=1 ER - TY - JOUR AU - Douw, G. AU - Schoonhoven, L. AU - Holwerda, T. AU - Huisman-de Waal, G.J. AU - Zanten, A.R. van AU - Achterberg, T. van AU - Hoeven, J.G. van der PY - 2015 UR - https://hdl.handle.net/2066/153532 AB - INTRODUCTION: Nurses often recognize deterioration in patients through intuition rather than through routine measurement of vital signs. Adding the 'worry or concern' sign to the Rapid Response System provides opportunities for nurses to act upon their intuitive feelings. Identifying what triggers nurses to be worried or concerned might help to put intuition into words, and potentially empower nurses to act upon their intuitive feelings and obtain medical assistance in an early stage of deterioration. The aim of this systematic review is to identify the signs and symptoms that trigger nurses' worry or concern about a patient's condition. METHODS: We searched the databases PubMed, CINAHL, Psychinfo and Cochrane Library (Clinical Trials) using synonyms related to the three concepts: 'nurses', 'worry/concern' and 'deterioration'. We included studies concerning adult patients on general wards in acute care hospitals. The search was performed from the start of the databases until 14 February 2014. RESULTS: The search resulted in 4,006 records, and 18 studies (five quantitative, nine qualitative and four mixed-methods designs) were included in the review. A total of 37 signs and symptoms reflecting the nature of the criterion worry or concern emerged from the data and were summarized in 10 general indicators. The results showed that worry or concern can be present with or without change in vital signs. CONCLUSIONS: The signs and symptoms we found in the literature reflect the nature of nurses' worry or concern, and nurses may incorporate these signs in their assessment of the patient and their decision to call for assistance. The fact that it is present before changes in vital signs suggests potential for improving care in an early stage of deterioration. TI - Nurses' worry or concern and early recognition of deteriorating patients on general wards in acute care hospitals: a systematic review SN - 1466-609X SP - 230 JF - Critical Care VL - vol. 19 DO - https://doi.org/10.1186/s13054-015-0950-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153532/153532.pdf?sequence=1 ER - TY - JOUR AU - Fuijkschot, J. AU - Vernhout, B. AU - Lemson, J. AU - Draaisma, J.M.T. AU - Loeffen, J.L.C.M. PY - 2015 UR - https://hdl.handle.net/2066/154398 AB - Timely recognition of deterioration of hospitalised children is important to improve mortality. We developed a modified Paediatric Early Warning Score (PEWS) and studied the effects by performing three different cohort studies using different end points. Taking unplanned Paediatric Intensive Care Unit admission as end point and only using data until 2 h prior to end point, we found a sensitivity of 0.67 and specificity of 0.88 to timely recognise patients. This proves that earlier identification is possible without a loss of sensitivity compared to other PEWS systems. When determining the corresponding clinical condition in patients with an elevated PEWS dichotomously as 'sick' or 'well', this resulted in a total of 27 % false-positive scores. This can cause motivational problems for caregivers to use the system but is a consequence of PEWS design to minimise false-negative rates because of high mortality associated with paediatric resuscitation. Using the need for emergency medical interventions as end point, sensitivity of PEWS is high and it seems, therefore, that it is also fit to alert health-care professionals that urgent interventions may be needed. CONCLUSION: These data show the effectiveness of a modified PEWS in identifying critically ill patients in an early phase making early interventions possible and hopefully reduce mortality. TI - Validation of a Paediatric Early Warning Score: first results and implications of usage EP - 21 SN - 0340-6199 IS - iss. 1 SP - 15 JF - European Journal of Pediatrics VL - vol. 174 DO - https://doi.org/10.1007/s00431-014-2357-8 ER - TY - JOUR AU - Lansdorp, B. AU - Lemson, J. AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/154147 TI - The authors reply SN - 0090-3493 IS - iss. 2 SP - e53 JF - Critical Care Medicine VL - vol. 43 DO - https://doi.org/10.1097/CCM.0000000000000808 ER - TY - JOUR AU - Vrancken, S.L.A.G. AU - Heijst, A.F.J. van AU - Hopman, J.C.W. AU - Liem, K.D. AU - Hoeven, J.G. van der AU - Boode, W.P. de PY - 2015 UR - https://hdl.handle.net/2066/152964 AB - To analyze changes in cardiac output and hemodynamic volumes using transpulmonary ultrasound dilution (TPUD) in a neonatal animal model under different hemodynamic conditions. 7 lambs (3.5-8.3 kg) under general anesthesia received arterial and central venous catheters. A Gore-Tex((R)) shunt was surgically inserted between the descending aorta and the left pulmonary artery to mimic a patent ductus arteriosus. After shunt opening and closure, induced hemorrhagic hypotension (by repetitive blood withdrawals) and repetitive volume challenges, the following parameters were assessed using TPUD: cardiac output, active circulating volume index (ACVI), central blood volume index (CBVI) and total end-diastolic volume index (TEDVI). 27 measurement sessions were analyzed. After shunt opening, there was a significant increase in TEDVI and a significant decrease in cardiac output with minimal change in CBVI and ACVI. With shunt closure, these results reversed. After progressive hemorrhage, cardiac output and all volumes decreased significantly, except for ACVI. Following repetitive volume resuscitation, cardiac output increased and all hemodynamic volumes increased significantly. Correlations between changes in COufp and changes in hemodynamic volumes (ACVI 0.83; CBVI 0.84 and TEDVI 0.78 respectively) were (slightly) better than between changes in COufp and changes in heart rate (0.44) and central venous pressure (0.7). Changes in hemodynamic volumes using TPUD were as expected under different conditions. Hemodynamic volumetry using TPUD might be a promising technique that has the potential to improve the assessment and interpretation of the hemodynamic status in critically ill newborns and children. TI - Hemodynamic volumetry using transpulmonary ultrasound dilution (TPUD) technology in a neonatal animal model EP - 652 SN - 1387-1307 IS - iss. 5 SP - 643 JF - Journal of Clinical Monitoring and Computing VL - vol. 29 DO - https://doi.org/10.1007/s10877-014-9647-6 ER - TY - JOUR AU - Bartels, R.H.M.A. AU - Meijer, F.J.A. AU - Hoeven, H. van der AU - Edwards, M.J. AU - Prokop, M. PY - 2015 UR - https://hdl.handle.net/2066/152480 AB - BACKGROUND: Traumatic acute subdural hematoma has a high mortality despite intensive treatment. Despite the existence of several prediction models, it is very hard to predict an outcome. We investigated whether a specific combination of initial head CT-scan findings is a factor in predicting outcome, especially non-survival. METHODS: We retrospectively studied admission head CT scans of all adult patients referred for a traumatic acute subdural hematoma between April 2009 and April 2013. Chart review was performed for every included patient. Midline shift and thickness of the hematoma were measured by two independent observers. The difference between midline shift and thickness of the hematoma was calculated. These differences were correlated with outcome. IRB has approved the study. RESULTS: A total of 59 patients were included, of whom 29 died. We found a strong correlation between a midline shift exceeding the thickness of the hematoma by 3 mm or more, and subsequent mortality. For each evaluation, specificity was 1.0 (95 % CI: 0.85-1 for all evaluations), positive predictive value 1.0 (95 % CI between 0.31-1 and 0.56-1), while sensitivity ranged from 0.1 to 0.23 (95 % CI between 0.08-0.39 and 0.17-0.43), and negative predictive value varied from 0.52 to 0.56 (95 % CI between 0.38-0.65 and 0.41-0.69). CONCLUSIONS: In case of a traumatic acute subdural hematoma, a difference between the midline shift and the thickness of the hematoma >/= 3 mm at the initial CT predicted mortality in all cases. This is the first time that such a strong correlation was reported. Especially for the future development of prediction models, the relation between midline shift and thickness of the hematoma could be included as a separate factor. TI - Midline shift in relation to thickness of traumatic acute subdural hematoma predicts mortality SN - 1471-2377 SP - 220 JF - BMC Neurology VL - vol. 15 DO - https://doi.org/10.1186/s12883-015-0479-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/152480/152480.pdf?sequence=1 ER - TY - JOUR AU - Peters, E. AU - Stevens, J. AU - Arend, J. AU - Guan, Z. AU - Raaben, W. AU - Laverman, P. AU - Elsas, A. van AU - Masereeuw, R. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/154642 AB - Clinical trials showed renal protective effects of bovine intestinal alkaline phosphatase (AP) in patients with sepsis-associated acute kidney injury (AKI). Subsequently, a human recombinant chimeric AP (recAP) was developed as a pharmaceutically acceptable alternative. Here, we investigated the biodistribution and pharmacokinetics (PK) of recAP and developed a translational population PK model. Biodistribution was studied during LPS-induced AKI in rats. Iodine-125-labeled recAP was primarily taken up by liver, spleen, adrenals, heart, lungs and kidneys followed by the gastro-intestinal tract and thyroid. Tissue distribution was not critically affected by endotoxemia. PK parameters were determined in rats and minipigs during IV bolus injections of recAP, administered once, or once daily during seven consecutive days. Plasma concentrations of recAP increased with increasing dose and disappeared in a biphasic manner. Exposure to recAP, estimated by AUC and Cmax, was similar on days 1 and 7. Subsequently, population approach nonlinear mixed effects modeling was performed with recAP rat and minipig and biAP phase I PK data. Concentration versus time data was accurately described in all species by a two-compartmental model with allometric scaling based on body weight. This model provides a solid foundation for determining the optimal dose and duration of first-in-man recAP studies. TI - Biodistribution and translational pharmacokinetic modeling of a human recombinant alkaline phosphatase EP - 131 SN - 0378-5173 IS - iss. 1 SP - 122 JF - International Journal of Pharmaceutics VL - vol. 495 DO - https://doi.org/10.1016/j.ijpharm.2015.08.090 ER - TY - JOUR AU - Lempers, V.J.C. AU - Schouten, J.A. AU - Hunfeld, N.G. AU - Colbers, A. AU - Leeuwen, H.J. van AU - Burger, D.M. AU - Verweij, P.E. AU - Pickkers, P. AU - Brüggemann, R.J.M. PY - 2015 UR - https://hdl.handle.net/2066/153821 TI - Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients. EP - 4409 SN - 0066-4804 IS - iss. 8 SP - 4403 JF - Antimicrobial Agents and Chemotherapy VL - vol. 59 DO - https://doi.org/10.1128/AAC.00623-15 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153821/153821.pdf?sequence=1 ER - TY - JOUR AU - Timmermans, K. AU - Kox, M. AU - Gerretsen, J. AU - Peters, E. AU - Scheffer, G.J. AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Hoedemaekers, C.W.E. PY - 2015 UR - https://hdl.handle.net/2066/154124 AB - OBJECTIVES: After cardiac arrest, patients are highly vulnerable toward infections, possibly due to a suppressed state of the immune system called "immunoparalysis." We investigated if immunoparalysis develops following cardiac arrest and whether the release of danger-associated molecular patterns could be involved. DESIGN: Observational study. SETTING: ICU of a university medical center. PATIENTS: Fourteen post-cardiac arrest patients treated with mild therapeutic hypothermia for 24 hours and 11 control subjects. MEASUREMENTS AND MAIN RESULTS: Plasma cytokines showed highest levels within 24 hours after cardiac arrest and decreased during the next 2 days. By contrast, ex vivo production of cytokines interleukin-6, tumor necrosis factor-alpha, and interleukin-10 by lipopolysaccharide-stimulated leukocytes was severely impaired compared with control subjects, with most profound effects observed at day 0, and only partially recovering afterward. Compared with incubation at 37 degrees C, incubation at 32 degrees C resulted in higher interleukin-6 and lower interleukin-10 production by lipopolysaccharide-stimulated leukocytes of control subjects, but not of patients. Plasma nuclear DNA, used as a marker for general danger-associated molecular pattern release, and the specific danger-associated molecular patterns (EN-RAGE and heat shock protein 70) were substantially higher in patients at days 0 and 1 compared with control subjects. Furthermore, plasma heat shock protein 70 levels were negatively correlated with ex vivo production of inflammatory mediators interleukin-6, tumor necrosis factor-alpha, and interleukin-10. Extracellular newly identified receptor for advanced glycation end products-binding protein levels only showed a significant negative correlation with ex vivo production of interleukin-6 and tumor necrosis factor-alpha and a borderline significant inverse correlation with interleukin-10. No significant correlations were observed between plasma nuclear DNA levels and ex vivo cytokine production. INTERVENTIONS: None. CONCLUSIONS: Release of danger-associated molecular patterns during the first days after cardiac arrest is associated with the development of immunoparalysis. This could explain the increased susceptibility toward infections in cardiac arrest patients. TI - The Involvement of Danger-Associated Molecular Patterns in the Development of Immunoparalysis in Cardiac Arrest Patients EP - 2338 SN - 0090-3493 IS - iss. 11 SP - 2332 JF - Critical Care Medicine VL - vol. 43 DO - https://doi.org/10.1097/CCM.0000000000001204 ER - TY - JOUR AU - Aerts, M.B. AU - Esselink, R.A.J. AU - Abdo, W.F. AU - Meijer, F.J.A. AU - Drost, G. AU - Norgren, N. AU - Janssen, M.J.R. AU - Borm, G.F. AU - Bloem, B.R. AU - Verbeek, M.M. PY - 2015 UR - https://hdl.handle.net/2066/154200 AB - Various ancillary investigations can assist clinicians in the differential diagnosis of patients with parkinsonism. It is unknown which test offers greatest diagnostic value in clinical practice. We included 156 consecutive patients with parkinsonism, but with an initially uncertain diagnosis. At baseline, all patients underwent extensive clinical testing and the following ancillary investigations: brain magnetic resonance imaging (MRI); (123)I-iodobenzamide single photon-emission computed tomography (IBZM-SPECT); analysis of cerebrospinal fluid (CSF); and anal sphincter electromyography (EMG). The final diagnosis was established after 3-year follow-up by two movement disorder specialists, according to international consensus criteria. We determined the diagnostic value by comparing the baseline clinical parameters and ancillary studies with the final diagnosis. Out of a potential 138 parameters, univariate analysis identified 35 parameters that discriminated Parkinson's disease (PD, n = 62) and atypical parkinsonism (AP, n = 94), with AUC of 0.55-0.81. Stepwise logistic regression showed that the combination of tandem gait, axial UPDRS subscore, slow saccadic eye movements and dysphagia yielded an AUC of 0.93, adjusted for optimism. The combination of tandem gait and axial UDPRS subscore yielded an AUC of 0.90. None of the ancillary investigations alone or in combination with clinical testing improved this clinically based diagnostic accuracy, not even in a subgroup of patients with the greatest diagnostic uncertainty at baseline. Our study demonstrates that a comprehensive set of clinical tests provides good accuracy to differentiate PD from AP. Our results also suggest that routine MRI, IBZM-SPECT, CSF analysis and anal sphincter EMG do not improve this diagnostic accuracy. Future work should evaluate the possible diagnostic value of more advanced diagnostic tests. TI - Ancillary investigations to diagnose parkinsonism: a prospective clinical study EP - 356 SN - 0340-5354 IS - iss. 2 SP - 346 JF - Journal of Neurology VL - vol. 262 DO - https://doi.org/10.1007/s00415-014-7568-4 ER - TY - JOUR AU - Peters, E. AU - Geraci, S. AU - Heemskerk, S. AU - Wilmer, M.J. AU - Bilos, A. AU - Kraenzlin, B. AU - Gretz, N. AU - Pickkers, P. AU - Masereeuw, R. PY - 2015 UR - https://hdl.handle.net/2066/152594 AB - BACKGROUND AND PURPOSE: Recently, two phase-II trials demonstrated improved renal function in critically ill patients with sepsis-associated acute kidney injury treated with the enzyme alkaline phosphatase. Here, we elucidated the dual active effect on renal protection of alkaline phosphatase. EXPERIMENTAL APPROACH: The effect of human recombinant alkaline phosphatase (recAP) on LPS-induced renal injury was studied in Sprague-Dawley rats. Renal function was assessed by transcutaneous measurement of FITC-sinistrin elimination in freely moving, awake rats. The mechanism of action of recAP was further investigated in vitro using conditionally immortalized human proximal tubular epithelial cells (ciPTEC). KEY RESULTS: In vivo, LPS administration significantly prolonged FITC-sinistrin half-life and increased fractional urea excretion, which was prevented by recAP co-administration. Moreover, recAP prevented LPS-induced increase in proximal tubule injury marker, kidney injury molecule-1 expression and excretion. In vitro, LPS-induced production of TNF-alpha, IL-6 and IL-8 was significantly attenuated by recAP. This effect was linked to dephosphorylation, as enzymatically inactive recAP had no effect on LPS-induced cytokine production. RecAP-mediated protection resulted in increased adenosine levels through dephosphorylation of LPS-induced extracellular ADP and ATP. Also, recAP attenuated LPS-induced increased expression of adenosine A2A receptor. However, the A2A receptor antagonist ZM-241385 did not diminish the effects of recAP. CONCLUSIONS AND IMPLICATIONS: These results indicate that the ability of recAP to reduce renal inflammation may account for the beneficial effect observed in septic acute kidney injury patients, and that dephosphorylation of ATP and LPS are responsible for this protective effect. TI - Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate EP - 4945 SN - 0007-1188 IS - iss. 20 SP - 4932 JF - British Journal of Pharmacology VL - vol. 172 DO - https://doi.org/10.1111/bph.13261 ER - TY - JOUR AU - Bucx, M.J.L. AU - Landman, J.J. AU - Onzenoort, H.A.W. van AU - Kox, M. AU - Scheffer, G.J. PY - 2015 UR - https://hdl.handle.net/2066/153078 AB - STUDY OBJECTIVE: The study objective is to investigate the effects of a simple price list sticker placed on vaporizers on anesthetic use and costs. The price list only showed the cost per hour of the annually most expensive drugs, which had a low-cost alternative. DESIGN: The design is a prospective database study with historical controls. SETTING: The setting is at operating rooms. PATIENTS: All patients are undergoing a surgical procedure under anesthesia in both study periods, except cardiothoracic and day care patients. INTERVENTIONS: The intervention is application of a price list sticker on the vaporizers. MEASUREMENTS: Monthly cost and amount of anesthetic agents used during the 9 months before and after the intervention. MAIN RESULTS: After application of the price stickers, the use of both the annually most expensive agents and the anesthetic budget decreased substantially. Most notable was a decrease of 28% in the use of sevoflurane. CONCLUSIONS: Price sticker on vaporizers may be an effective, simple, and cheap method to reduce anesthetic costs. TI - A simple intervention to reduce the anesthetic pharmacy budget; the effect of price list stickers placed on vaporizers EP - 310 SN - 0952-8180 IS - iss. 4 SP - 307 JF - Journal of Clinical Anesthesia VL - vol. 27 DO - https://doi.org/10.1016/j.jclinane.2015.03.001 ER - TY - JOUR AU - Heunks, L.M.A. AU - Doorduin, J. AU - Hoeven, J.G. van der PY - 2015 UR - https://hdl.handle.net/2066/153420 AB - PURPOSE OF REVIEW: The present review summarizes developments in the field of respiratory muscle monitoring, in particular in critically ill patients. RECENT FINDINGS: Patients admitted to the ICU may develop severe respiratory muscle dysfunction in a very short time span. Among other factors, disuse and sepsis have been associated with respiratory muscle dysfunction in these patients. Because weakness is associated with adverse outcome, including prolonged mechanical ventilation and mortality, it is surprising that respiratory muscle dysfunction largely develops without being noticed by the clinician. Respiratory muscle monitoring is not standard of care in most ICUs. Improvements in technology have opened windows for monitoring the respiratory muscles in critically ill patients. Diaphragm electromyography and esophageal pressure measurement are feasible techniques for respiratory muscle monitoring, although the effect on outcome remains to be investigated. SUMMARY: Respiratory muscle dysfunction develops rapidly in selected critically ill patients and is associated with adverse outcome. Recent technological advances allow real-time monitoring of respiratory muscle activity in these patients. Although this field is in its infancy, from a physiological perspective, it is reasonable to assume that monitoring respiratory muscle activity improves outcome in these patients. TI - Monitoring and preventing diaphragm injury EP - 41 SN - 1070-5295 IS - iss. 1 SP - 34 JF - Current Opinion in Critical Care VL - vol. 21 DO - https://doi.org/10.1097/MCC.0000000000000168 ER - TY - JOUR AU - Doorduin, J. AU - Sinderby, C.A. AU - Beck, J. AU - Hoeven, J.G. van der AU - Heunks, L.M. PY - 2015 UR - https://hdl.handle.net/2066/151946 AB - BACKGROUND: In patients with acute respiratory distress syndrome (ARDS), the use of assisted mechanical ventilation is a subject of debate. Assisted ventilation has benefits over controlled ventilation, such as preserved diaphragm function and improved oxygenation. Therefore, higher level of "patient control" of ventilator assist may be preferable in ARDS. However, assisted modes may also increase the risk of high tidal volumes and lung-distending pressures. The current study aims to quantify how differences in freedom to control the ventilator affect lung-protective ventilation, breathing pattern variability, and patient-ventilator interaction. METHODS: Twelve patients with ARDS were ventilated in a randomized order with assist pressure control ventilation (PCV), pressure support ventilation (PSV), and neurally adjusted ventilatory assist (NAVA). Transpulmonary pressure, tidal volume, diaphragm electrical activity, and patient-ventilator interaction were measured. Respiratory variability was assessed using the coefficient of variation of tidal volume. RESULTS: During inspiration, transpulmonary pressure was slightly lower with NAVA (10.3 +/- 0.7, 11.2 +/- 0.7, and 9.4 +/- 0.7 cm H2O for PCV, PSV, and NAVA, respectively; P < 0.01). Tidal volume was similar between modes (6.6 [5.7 to 7.0], 6.4 [5.8 to 7.0], and 6.0 [5.6 to 7.3] ml/kg for PCV, PSV, and NAVA, respectively), but respiratory variability was higher with NAVA (8.0 [6.4 to 10.0], 7.1 [5.9 to 9.0], and 17.0 [12.0 to 36.1] % for PCV, PSV, and NAVA, respectively; P < 0.001). Patient-ventilator interaction improved with NAVA (6 [5 to 8] % error) compared with PCV (29 [14 to 52] % error) and PSV (12 [9 to 27] % error); P < 0.0001. CONCLUSION: In patients with mild-to-moderate ARDS, increasing freedom to control the ventilator maintains lung-protective ventilation in terms of tidal volume and lung-distending pressure, but it improves patient-ventilator interaction and preserves respiratory variability. TI - Assisted Ventilation in Patients with Acute Respiratory Distress Syndrome: Lung-distending Pressure and Patient-Ventilator Interaction EP - 190 SN - 0003-3022 IS - iss. 1 SP - 181 JF - Anesthesiology VL - vol. 123 DO - https://doi.org/10.1097/ALN.0000000000000694 ER - TY - JOUR AU - Muilwijk, E.W. AU - Lempers, V.J.C. AU - Burger, D.M. AU - Warris, A. AU - Pickkers, P. AU - Aarnoutse, R.E. AU - Bruggemann, R.J.M. PY - 2015 UR - https://hdl.handle.net/2066/153098 AB - Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases. TI - Impact of special patient populations on the pharmacokinetics of echinocandins EP - 815 SN - 1478-7210 IS - iss. 6 SP - 799 JF - Expert Review of Anti-Infective Therapy VL - vol. 13 DO - https://doi.org/10.1586/14787210.2015.1028366 ER - TY - JOUR AU - Doorduin, J. AU - Leentjens, J. AU - Kox, M. AU - Hees, H.W.H. van AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Heunks, L.M.A. PY - 2015 UR - https://hdl.handle.net/2066/155091 AB - INTRODUCTION: Systemic inflammation is a well-known risk factor for respiratory muscle weakness. Studies using animal models of inflammation have shown that endotoxin administration induces diaphragm dysfunction. However, the effects of in vivo endotoxin administration on diaphragm function in humans have not been studied. Our aim was to evaluate diaphragm function in a model of systemic inflammation in healthy subjects. METHODS: Two groups of 12 male volunteers received an intravenous bolus of 2 ng/kg of Escherichia coli lipopolysaccharide (LPS) and were monitored until 8 h after LPS administration. In the first group, the twitch transdiaphragmatic pressure (Pditw) and compound muscle action potential of the diaphragm (CMAPdi) were measured. In addition, plasma levels of cytokines, heart rate, and arterial blood pressure were measured. In the second group, catecholamines as well as respiratory rate and blood gas values were measured. Diaphragm ultrasonography was performed in four subjects with severe shivering. RESULTS: Lipopolysaccharide administration resulted in flulike symptoms, hemodynamic alterations, and increased plasma levels of cytokines. The Pditw increased after LPS administration from 31.2 +/- 2.0 cmH2O (baseline) to 38.8 +/- 2.0 cmH2O (t = 1 h) and 35.4 +/- 2.0 cmH2O (t = 1.5 h). There was no correlation between cytokine plasma levels and the Pditw. We found a trend toward a gradual decrease in the CMAPdi from 0.78 +/- 0.07 mV (baseline) to 0.58 +/- 0.05 mV (t = 2 h). Respiratory rate increased after LPS administration from 16.8 +/- 0.5 breaths/min (baseline) to 20.3 +/- 0.6 breaths/min (t = 4 h), with a resulting decrease in PaCO2 of 0.5 +/- 0.1 kPa. Plasma levels of epinephrine peaked at t = 1.5 h, with an increase of 1.3 +/- 0.3 nmol/L from baseline. Rapid diaphragm contractions consistent with shivering were observed. CONCLUSIONS: This study shows that, in contrast to diaphragm dysfunction observed in animal models of inflammation, in vivo diaphragm contractility is augmented in the early phase after low-dose endotoxin administration in humans. TI - Effects of experimental human endotoxemia on diaphragm function EP - 322 SN - 1073-2322 IS - iss. 4 SP - 316 JF - Shock VL - vol. 44 DO - https://doi.org/10.1097/SHK.0000000000000435 ER - TY - JOUR AU - Buddingh, E.P. AU - Leentjens, J. AU - Lugt, J. van der AU - Dik, W.A. AU - Gresnigt, M.S. AU - Netea, M.G. AU - Pickkers, P. AU - Driessen, G.J. PY - 2015 UR - https://hdl.handle.net/2066/152382 AB - Despite advances in supportive care and novel antifungal agents, mortality due to invasive Candida infection is high. Athree-year-old boy with disseminatedC.dubliniensis infection during induction chemotherapy for acute lymphoblastic leukemiadeteriorated despite resolution of neutropenia and appropriate antifungal treatment. Monocyte HLA-DR-expression was extremely low, suggesting immunoparalysis. Adjuvant immunotherapy with IFN-gamma restored the immune response, which was accompanied by clinical and radiographic recovery. TI - Interferon-gamma immunotherapy in a patient with refractory disseminated candidiasis EP - 1394 SN - 0891-3668 IS - iss. 12 SP - 1391 JF - Pediatric Infectious Disease Journal VL - vol. 34 DO - https://doi.org/10.1097/INF.0000000000000909 ER - TY - JOUR AU - Leentjens, J. AU - Kox, M. AU - Stokman, R. AU - Gerretsen, J. AU - Diavatopoulos, D.A. AU - Crevel, R. van AU - Rimmelzwaan, G.F. AU - Pickkers, P. AU - Netea, M.G. PY - 2015 UR - https://hdl.handle.net/2066/151964 AB - BACKGROUND: Influenza-related morbidity and mortality remain high. Seasonal vaccination is the backbone of influenza management but does not always result in protective antibody titers. Nonspecific effects of BCG vaccination related to enhanced function of myeloid antigen-presenting cells have been reported. We hypothesized that BCG vaccination could also enhance immune responses to influenza vaccination. METHODS: Healthy volunteers received either live attenuated BCG vaccine (n = 20) or placebo (n = 20) in a randomized fashion, followed by intramuscular injection of trivalent influenza vaccine 14 days later. Hemagglutination-inhibiting (HI) antibodies and cellular immunity measured by ex vivo leukocyte responses were assessed. RESULTS: In BCG-vaccinated subjects, HI antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain were significantly enhanced, compared with the placebo group, and there was a trend toward more-rapid seroconversion. Additionally, apart from enhanced proinflammatory leukocyte responses following BCG vaccination, nonspecific effects of influenza vaccination were also observed, with modulation of cytokine responses against unrelated pathogens. CONCLUSIONS: BCG vaccination prior to influenza vaccination results in a more pronounced increase and accelerated induction of functional antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain. These results may have implications for the design of vaccination strategies and could lead to improvement of vaccination efficacy. TI - BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study EP - 1938 SN - 0022-1899 IS - iss. 12 SP - 1930 JF - The Journal of Infectious Diseases VL - vol. 212 DO - https://doi.org/10.1093/infdis/jiv332 ER - TY - JOUR AU - Hamers, L.A.C. AU - Kox, M. AU - Arts, R.J.W. AU - Blok, B. AU - Leentjens, J. AU - Netea, M.G. AU - Pickkers, P. PY - 2015 UR - https://hdl.handle.net/2066/155336 AB - Bacille Calmette-Guerin (BCG) vaccine exerts nonspecific immunostimulatory effects and may therefore represent a novel therapeutic option to treat sepsis-induced immunoparalysis. We investigated whether BCG vaccination modulates the systemic innate immune response in humans in vivo during experimental endotoxemia. We used inactivated gamma-irradiated BCG vaccine because of the potential risk of disseminated disease with the live vaccine in immunoparalyzed patients. In a randomized double-blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG (n = 10) or placebo (n = 10) and received 1 ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess the in vivo immune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assess ex vivo immune responses. BCG vaccination resulted in a scar in 90% of vaccinated subjects. LPS administration elicited a profound systemic immune response, characterized by increased levels of pro- and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG modulated neither this in vivo immune response, nor ex vivo leukocyte responses at any time point. In conclusion, gamma-irradiated BCG is unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis. This trial is registered with NCT02085590. TI - Gamma-irradiated bacille Calmette-Guerin vaccination does not modulate the innate immune response during experimental human endotoxemia in adult males SN - 2314-8861 SP - 261864 JF - Journal of Immunology Research VL - vol. 2015 DO - https://doi.org/10.1155/2015/261864 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/155336/155336.pdf?sequence=1 ER - TY - JOUR AU - Wal, S.E.I. van der AU - Vaneker, M. AU - Steegers, M.A.H. AU - Berkum, B. van AU - Kox, M. AU - Laak, J.A. van der AU - Hoeven, J.G. van der AU - Vissers, K. AU - Scheffer, G.J. PY - 2015 UR - https://hdl.handle.net/2066/153279 AB - BACKGROUND: Mechanical ventilation (MV) induces an inflammatory response that may result in (acute) lung injury. Lidocaine, an amide local anesthetic, has anti-inflammatory properties in vitro and in vivo, possibly due to an attenuation of pro-inflammatory cytokines, intracellular adhesion molecule-1 (ICAM-1), and reduction of neutrophils influx. We hypothesized an attenuation of MV-induced inflammatory response with intravenously administered lidocaine. METHODS: Lidocaine (Lido) (2, 4, and 8 mg/kg/h) was intravenously administered during 4 h of MV with a tidal volume of 8 ml/kg, positive end expiratory pressure 1,5 cmH2O and FiO2 0.4. We used one ventilated control (CON) group receiving vehicle. After MV, mice were euthanized, and lungs and blood were immediately harvested, and cytokine levels and ICAM-1 levels were measured in plasma and lung homogenates. Pulmonary neutrophils influx was determined in LEDER-stained slices of lungs. Anesthetic need was determined by painful hind paw stimulation. RESULTS: Lidocaine-treated animals (Lido 2, 4 and 8 mg/kg/h) showed higher interleukin (IL)-10 plasma levels compared to control animals. Lidocaine treatment with 8 mg/kg/h (Lido 8) resulted in higher IL-10 in lung homogenates. No differences were observed in pro-inflammatory cytokines, ICAM-1, and pulmonary influx between the different ventilated groups. CONCLUSIONS: Intravenously administered lidocaine increases levels of plasma IL-10 with infusion from 2, 4, and 8 mg/kg/h and pulmonary levels of IL-10 with 8 mg/kg/h in a murine mechanical ventilation model. Intravenously administered lidocaine appears to reduce anesthetic need in mice. TI - Lidocaine increases the anti-inflammatory cytokine IL-10 following mechanical ventilation in healthy mice EP - 55 SN - 0001-5172 IS - iss. 1 SP - 47 JF - Acta Anaesthesiologica Scandinavica VL - vol. 59 DO - https://doi.org/10.1111/aas.12417 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153279/153279.pdf?sequence=1 ER - TY - JOUR AU - Abdo, W.F. PY - 2014 UR - https://hdl.handle.net/2066/137265 AB - Recently, organ donation after euthanasia has been a topic of discussion in the Dutch media and scientific literature. Unfortunately, both the articles in question and the media interviews contained several unsubstantiated statements. This article describes the background of organ donation after euthanasia and refutes some of the recent statements. It discusses why it is expected that organ donation after euthanasia will result in a far fewer additional organ donors that originally stated. In conclusion, euthanasia is a topic that should be handled with great care. TI - [Organ donation after euthanasia. Handle with great care] SN - 0028-2162 IS - iss. 0 SP - A8617 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 158 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/137265/137265.pdf?sequence=1 ER - TY - JOUR AU - Bisschops, L.L.A. AU - Pop, G.A.M. AU - Teerenstra, S. AU - Struijk, P.C. AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2014 UR - https://hdl.handle.net/2066/136280 AB - OBJECTIVES: To determine blood viscosity in adult comatose patients treated with mild therapeutic hypothermia after cardiac arrest and to assess the relation between blood viscosity, cerebral blood flow, and cerebral oxygen extraction. DESIGN: Observational study. SETTING: Tertiary care university hospital. PATIENTS: Ten comatose patients with return of spontaneous circulation after out-of-hospital cardiac arrest. INTERVENTION: Treatment with mild therapeutic hypothermia for 24 hours followed by passive rewarming to normothermia. MEASUREMENTS AND MAIN RESULTS: Median viscosity at shear rate 50/s was 5.27 mPa . s (4.29-5.91 mPa . s) at admission; it remained relatively stable during the first 12 hours and decreased significantly to 3.00 mPa . s (2.72-3.58 mPa . s) at 72 hours (p < 0.001). Median mean flow velocity in the middle cerebral artery was low (27.0 cm/s [23.8-30.5 cm/s]) at admission and significantly increased to 63.0 cm/s (51.0-80.0 cm/s) at 72 hours. Median jugular bulb saturation at the start of the study was 61.5% (55.5-75.3%) and significantly increased to 73.0% (69.0-81.0%) at 72 hours. Median hematocrit was 0.41 L/L (0.36-0.44 L/L) at admission and subsequently decreased significantly to 0.32 L/L (0.27-0.35 L/L) at 72 hours. Median C-reactive protein concentration was low at admission (2.5 mg/L [2.5-6.5 mg/L]) and increased to 101 mg/L (65-113.3 mg/L) in the following hours. Median fibrinogen concentration was increased at admission 2,795 mg/L (2,503-3,565 mg/L) and subsequently further increased to 6,195 mg/L (5,843-7,368 mg/L) at 72 hours. There was a significant negative association between blood viscosity and the mean flow velocity in the middle cerebral artery (p = 0.0008). CONCLUSIONS: Changes in blood viscosity in vivo are associated with changes in flow velocity in the middle cerebral artery. High viscosity early after cardiac arrest may reduce cerebral blood flow and may contribute to secondary brain injury. Further studies are needed to determine the optimal viscosity during the different stages of the postcardiac arrest syndrome. TI - Effects of viscosity on cerebral blood flow after cardiac arrest EP - 637 SN - 0090-3493 IS - iss. 3 SP - 632 JF - Critical Care Medicine VL - vol. 42 DO - http://dx.doi.org/10.1097/CCM.0000000000000027 ER - TY - JOUR AU - Bles, C. AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2014 UR - https://hdl.handle.net/2066/138809 TI - Acetozolamide induced hyperammonaemia: a case report and review of the literature EP - 27 SN - 1569-3511 IS - iss. 1 SP - 25 JF - Netherlands Journal of Critical Care VL - vol. 18 ER - TY - JOUR AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/138920 TI - Minder sterfte bij IC-patienten door arteriele lijn? SN - 0028-2162 SP - A8439 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 158 ER - TY - JOUR AU - Marik, P.E. AU - Lemson, J. PY - 2014 UR - https://hdl.handle.net/2066/138048 TI - Fluid responsiveness: an evolution of our understanding EP - 620 SN - 0007-0912 IS - iss. 4 SP - 617 JF - British Journal of Anaesthesia VL - vol. 112 DO - http://dx.doi.org/10.1093/bja/aet590 ER - TY - JOUR AU - Santen, S. van AU - Mast, Q. de AU - Oosting, J.D. AU - Ede, A.E. van AU - Swinkels, D.W. AU - Ven, A.J. van der PY - 2014 UR - https://hdl.handle.net/2066/138156 TI - Hematologic parameters predicting a response to oral iron therapy in chronic inflammation EP - 3 SN - 0390-6078 IS - iss. 9 SP - e171 JF - Haematologica VL - vol. 99 DO - http://dx.doi.org/10.3324/haematol.2014.106799 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138156/138156.pdf?sequence=1 ER - TY - JOUR AU - Sobbi, S.C. AU - Boogaard, M.H.W.A. van den PY - 2014 UR - https://hdl.handle.net/2066/138302 AB - The pathophysiological mechanism of the serious and frequently occurring disorder delirium is poorly understood. Inflammation and sepsis are known risk factors for ICU delirium and therefore these patients are highly susceptible to delirium. Several studies have been performed to determine which cytokines are most associated with delirium but the results are inconclusive. Also, new biomarkers associated with brain dysfunction and cognitive impairment are still recognized and need to be studied to determine their relation with delirium. In this commentary we address some limitations concerning an interesting new study that warrants directions for future studies. TI - Inflammation biomarkers and delirium in critically ill patients: new insights? SN - 1466-609X IS - iss. 3 SP - 153 JF - Critical Care VL - vol. 18 DO - http://dx.doi.org/10.1186/cc13930 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138302/138302.pdf?sequence=1 ER - TY - JOUR AU - Hoedemaekers, C.W. AU - Hoeven, J.G. van der PY - 2014 UR - https://hdl.handle.net/2066/138359 TI - Is alpha-stat or pH-stat the best strategy during hypothermia after cardiac arrest?* EP - 1951 SN - 0090-3493 IS - iss. 8 SP - 1950 JF - Critical Care Medicine VL - vol. 42 DO - http://dx.doi.org/10.1097/CCM.0000000000000377 ER - TY - JOUR AU - Lemson, J. AU - Haerkens, M. PY - 2014 UR - https://hdl.handle.net/2066/136378 TI - Never waste an opportunity to debrief* EP - 1741 SN - 0090-3493 IS - iss. 7 SP - 1740 JF - Critical Care Medicine VL - vol. 42 DO - http://dx.doi.org/10.1097/CCM.0000000000000370 ER - TY - JOUR AU - Hoedemaekers, C.W.E. AU - Abdo, W.F. PY - 2014 UR - https://hdl.handle.net/2066/137092 TI - Bispectral index for prognostication after cardiac arrest: the holy grail at last? EP - 1313 SN - 0090-3493 IS - iss. 5 SP - 1312 JF - Critical Care Medicine VL - vol. 42 DO - http://dx.doi.org/10.1097/CCM.0000000000000187 ER - TY - JOUR AU - Lemson, J. PY - 2014 UR - https://hdl.handle.net/2066/137621 TI - Chest compressions for cardiac arrest: easier said than done EP - 406 SN - 0375-9393 IS - iss. 4 SP - 404 JF - Minerva Anestesiologica VL - vol. 80 ER - TY - JOUR AU - Dieperink, P. AU - Hoeven, J.G. van der AU - Niesten, E.D. PY - 2014 UR - https://hdl.handle.net/2066/137785 TI - A misdiagnosed case of symptomatic hyponatraemia EP - 421 SN - 0310-057X IS - iss. 3 SP - 420 JF - Anaesthesia and Intensive Care VL - vol. 42 ER - TY - JOUR AU - Kox, M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/133822 TI - Management of critically ill patients-reply EP - 478 SN - 2168-6106 IS - iss. 3 SP - 477 JF - Jama Internal Medicine VL - vol. 174 DO - http://dx.doi.org/10.1001/jamainternmed.2013.13682 ER - TY - JOUR AU - Kox, M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/133878 TI - Reply: Mesenchymal stromal (stem) cell therapy: an emerging immunomodulatory strategy for the adjunctive treatment of sepsis EP - 365 SN - 1073-449X IS - iss. 3 SP - 364 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 189 DO - http://dx.doi.org/10.1164/rccm.201307-1386LE ER - TY - JOUR AU - Kox, M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/134026 TI - Adrenomedullin: its double-edged sword during sepsis slices yet again SN - 2197-425X SP - 1 JF - Intensive Care Medicine Experimental VL - vol. 2 DO - http://dx.doi.org/10.1186/2197-425X-2-1 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/134026/134026.pdf?sequence=1 ER - TY - JOUR AU - Pickkers, P. AU - Peek, N.B. AU - Keizer, N.F. de PY - 2014 UR - https://hdl.handle.net/2066/136974 TI - The authors reply SN - 0090-3493 IS - iss. 3 SP - e253 JF - Critical Care Medicine VL - vol. 42 DO - http://dx.doi.org/10.1097/CCM.0000000000000182 ER - TY - JOUR AU - Verlaat, C.W.M. AU - Heesen, G.P. AU - Vet, N.J. AU - Hoog, M. de AU - Hoeven, J.G. van der AU - Kox, M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/133867 AB - AIM: To study the feasibility of daily interruption of sedatives in critically ill children. METHODS: Prospective randomized controlled open-label trial, performed in a pediatric intensive care unit of a tertiary care teaching and referring hospital. 30 children (0-12 years) receiving mechanically ventilation for >24 h were included. In the intervention group, all sedatives were stopped daily and restarted when COMFORT-behavior score >/=17. The control group received standard care. Primary end points were amounts of sedatives and number of bolus medications in the first 3 days after enrollment and number of (near) incidents. Secondary end points were duration of mechanical ventilation, length of stay in pediatric intensive care, and changes in COMFORT-behavior score. Results : Midazolam and morphine use were lower in the intervention group compared with the control group (P = 0.007 and P = 0.02, respectively), whereas the number of bolus medications did not differ between groups. Two complications were recorded: one patient (intervention group) lost his intravenous line, and one patient (control group) had an unplanned extubation. Duration of mechanical ventilation was significantly shorter in the intervention group compared with the control group (median [interquartile range] of 4 [3-8] and 9 [4-10] days, respectively, P = 0.03). Length of stay in the PICU in the intervention group was significantly shorter than in the control group (median [interquartile range] of 6 [4-9] and 10 [7-15] days, respectively, P = 0.01). CONCLUSIONS: Daily interruption of sedatives in critically ill children is feasible, results in decreased use of sedation, earlier extubation, and shorter length of stay. TI - Randomized controlled trial of daily interruption of sedatives in critically ill children EP - 156 SN - 1155-5645 IS - iss. 2 SP - 151 JF - Paediatric Anaesthesia VL - vol. 24 DO - http://dx.doi.org/10.1111/pan.12245 ER - TY - JOUR AU - Ewalds, E. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/138736 TI - The use of statins for sepsis-associated ARDS EP - 3 SN - 1569-3511 IS - iss. 5 SP - 2 JF - Netherlands Journal of Critical Care VL - vol. 18 ER - TY - JOUR AU - Sandroni, C. AU - Cariou, A. AU - Cavallaro, F. AU - Cronberg, T. AU - Friberg, H. AU - Hoedemaekers, C.W. AU - Horn, J. AU - Nolan, J.P. AU - Rossetti, A.O. AU - Soar, J. PY - 2014 UR - https://hdl.handle.net/2066/138933 AB - OBJECTIVES: To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy. METHODS: GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included. RESULTS AND CONCLUSIONS: Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at >/=72 h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron-specific enolase at 48-72 h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients. TI - Prognostication in comatose survivors of cardiac arrest: An advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine EP - 1831 SN - 0342-4642 IS - iss. 12 SP - 1816 JF - Intensive Care Medicine VL - vol. 40 DO - http://dx.doi.org/10.1007/s00134-014-3470-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138933/138933.pdf?sequence=1 ER - TY - JOUR AU - Pickkers, P. AU - Peek, N. AU - Keizer, N. de PY - 2014 UR - https://hdl.handle.net/2066/136975 TI - The authors reply EP - 5 SN - 0090-3493 IS - iss. 3 SP - e254 JF - Critical Care Medicine VL - vol. 42 DO - https://doi.org/10.1097/CCM.0000000000000196 ER - TY - JOUR AU - Pickkers, P. AU - Peek, N. AU - Keizer, N. de PY - 2014 UR - https://hdl.handle.net/2066/136976 TI - The authors reply EP - 2 SN - 0090-3493 IS - iss. 1 SP - e81 JF - Critical Care Medicine VL - vol. 42 DO - https://doi.org/10.1097/CCM.0000000000000078 ER - TY - JOUR AU - Waele, J. De AU - Lipman, J. AU - Sakr, Y. AU - Marshall, J.C. AU - Vanhems, P. AU - Barrera Groba, C. AU - Leone, M. AU - Vincent, J.L. AU - Pickkers, P. AU - et al. PY - 2014 UR - https://hdl.handle.net/2066/138263 AB - BACKGROUND: Abdominal infections are frequent causes of sepsis and septic shock in the intensive care unit (ICU) and are associated with adverse outcomes. We analyzed the characteristics, treatments and outcome of ICU patients with abdominal infections using data extracted from a one-day point prevalence study, the Extended Prevalence of Infection in the ICU (EPIC) II. METHODS: EPIC II included 13,796 adult patients from 1,265 ICUs in 75 countries. Infection was defined using the International Sepsis Forum criteria. Microbiological analyses were performed locally. Participating ICUs provided patient follow-up until hospital discharge or for 60 days. RESULTS: Of the 7,087 infected patients, 1,392 (19.6%) had an abdominal infection on the study day (60% male, mean age 62 +/- 16 years, SAPS II score 39 +/- 16, SOFA score 7.6 +/- 4.6). Microbiological cultures were positive in 931 (67%) patients, most commonly Gram-negative bacteria (48.0%). Antibiotics were administered to 1366 (98.1%) patients. Patients who had been in the ICU for /= 25% (highABR: Greece, Israel, Italy, Malta, Portugal, Spain, and Turkey) and countries with MRSA rates of < 5% (lowABR: Denmark, Finland, Netherlands, Norway, and Sweden). RESULTS: On the study day, 1187/2204 (53.9%) patients in the HighABR ICUs were infected and 255/558 (45.7%) in the LowABR ICUs (P < 0.01). Patients in the HighABR ICUs were more severely ill than those in the LowABR ICUs, as reflected by a higher SAPS II score (35.6 vs 32.7, P < 0.05) and had longer median ICU (12 days vs 5 days) and hospital (24 days vs 16 days) lengths of stay. They also had higher crude ICU (20.0% vs 15.4%) and hospital (27.0% vs 21.5%) mortality rates (both P < 0.05). However, after multivariable adjustment and matched pair analysis there were no differences in ICU or hospital mortality rates between High or LowABR ICU patients overall or among those with infections. CONCLUSIONS: Being hospitalized in an ICU in a region with high levels of antimicrobial resistance is not associated per se with a worse outcome. TI - Infections, antibiotic treatment and mortality in patients admitted to ICUs in countries considered to have high levels of antibiotic resistance compared to those with low levels SN - 1471-2334 SP - 513 JF - BMC Infectious Diseases VL - vol. 14 DO - https://doi.org/10.1186/1471-2334-14-513 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138301/138301.pdf?sequence=1 ER - TY - JOUR AU - Gustot, T. AU - Felleiter, P. AU - Pickkers, P. AU - Sakr, Y. AU - Rello, J. AU - Velissaris, D. AU - Pierrakos, C. AU - Taccone, F.S. AU - Sevcik, P. AU - Moreno, C. AU - Vincent, J.L. AU - Investigators, E.I. PY - 2014 UR - https://hdl.handle.net/2066/138898 AB - BACKGROUND: Infections are a leading cause of death in patients with advanced cirrhosis, but there are relatively few data on the epidemiology of infection in intensive care unit (ICU) patients with cirrhosis. AIMS: We used data from the Extended Prevalence of Infection in Intensive Care (EPIC) II 1-day point-prevalence study to better define the characteristics of infection in these patients. METHODS: We compared characteristics, including occurrence and types of infections in non-cirrhotic and cirrhotic patients who had not undergone liver transplantation. RESULTS: The EPIC II database includes 13,796 adult patients from 1265 ICUs: 410 of the patients had cirrhosis. The prevalence of infection was higher in cirrhotic than in non-cirrhotic patients (59 vs. 51%, P < 0.01). The lungs were the most common site of infection in all patients, but abdominal infections were more common in cirrhotic than in non-cirrhotic patients (30 vs. 19%, P < 0.01). Infected cirrhotic patients more often had Gram-positive (56 vs. 47%, P < 0.05) isolates than did infected non-cirrhotic patients. Methicillin-resistant Staphylococcus aureus (MRSA) was more frequent in cirrhotic patients. The hospital mortality rate of cirrhotic patients was 42%, compared to 24% in the non-cirrhotic population (P < 0.001). Severe sepsis and septic shock were associated with higher in-hospital mortality rates in cirrhotic than in non-cirrhotic patients (41% and 71% vs. 30% and 49%, respectively, P < 0.05). CONCLUSIONS: Infection is more common in cirrhotic than in non-cirrhotic ICU patients and more commonly caused by Gram-positive organisms, including MRSA. Infection in patients with cirrhosis was associated with higher mortality rates than in non-cirrhotic patients. TI - Impact of infection on the prognosis of critically ill cirrhotic patients: results from a large worldwide study EP - 1503 SN - 1478-3223 IS - iss. 10 SP - 1496 JF - Liver International VL - vol. 34 DO - https://doi.org/10.1111/liv.12520 ER - TY - JOUR AU - Vincent, J.L. AU - Marshall, J.C. AU - Namendys-Silva, S.A. AU - Francois, B. AU - Martin-Loeches, I. AU - Lipman, J. AU - Reinhart, K. AU - Antonelli, M. AU - Pickkers, P. AU - Njimi, H. AU - Jimenez, E. AU - Sakr, Y. AU - investigators, I. PY - 2014 UR - https://hdl.handle.net/2066/136693 AB - BACKGROUND: Global epidemiological data regarding outcomes for patients in intensive care units (ICUs) are scarce, but are important in understanding the worldwide burden of critical illness. We, therefore, did an international audit of ICU patients worldwide and assessed variations between hospitals and countries in terms of ICU mortality. METHODS: 730 participating centres in 84 countries prospectively collected data on all adult (>16 years) patients admitted to their ICU between May 8 and May 18, 2012, except those admitted for fewer than 24 h for routine postoperative monitoring. Participation was voluntary. Data were collected daily for a maximum of 28 days in the ICU and patients were followed up for outcome data until death or hospital discharge. In-hospital death was analysed using multilevel logistic regression with three levels: patient, hospital, and country. FINDINGS: 10,069 patients were included from ICUs in Europe (5445 patients; 54.1%), Asia (1928; 19.2%), the Americas (1723; 17.1%), Oceania (439; 4.4%), the Middle East (393; 3.9%), and Africa (141; 1.4%). Overall, 2973 patients (29.5%) had sepsis on admission or during the ICU stay. ICU mortality rates were 16.2% (95% CI 15.5-16.9) across the whole population and 25.8% (24.2-27.4) in patients with sepsis. Hospital mortality rates were 22.4% (21.6-23.2) in the whole population and 35.3% (33.5-37.1) in patients with sepsis. Using a multilevel analysis, the unconditional model suggested significant between-country variations (var=0.19, p=0.002) and between-hospital variations (var=0.43, p<0.0001) in the individual risk of in-hospital death. There was a stepwise increase in the adjusted risk of in-hospital death according to decrease in global national income. INTERPRETATION: This large database highlights that sepsis remains a major health problem worldwide, associated with high mortality rates in all countries. Our findings also show a significant association between the risk of death and the global national income and suggest that ICU organisation has an important effect on risk of death. FUNDING: None. TI - Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit EP - 386 SN - 2213-2600 IS - iss. 5 SP - 380 JF - Lancet Respiratory Medicine VL - vol. 2 DO - https://doi.org/10.1016/S2213-2600(14)70061-X ER - TY - JOUR AU - Kamps, M.J. AU - Horn, J. AU - Oddo, M. AU - Fugate, J.E. AU - Storm, C. AU - Cronberg, T. AU - Wu, O. AU - Binnekade, J.M. AU - Hoedemaekers, C.W.E. PY - 2014 UR - https://hdl.handle.net/2066/136719 TI - Response to De Jonghe et al.: Prognostication of neurological outcome after cardiac arrest: standardization of neurological examination conditions is needed SN - 0342-4642 IS - iss. 2 SP - 295 JF - Intensive Care Medicine VL - vol. 40 DO - https://doi.org/10.1007/s00134-013-3178-3 ER - TY - JOUR AU - Voort, P.H. van der AU - Boerma, E.C. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/137012 TI - The furosemide stress test to predict renal function after continuous renal replacement therapy SN - 1466-609X IS - iss. 3 SP - 429 JF - Critical Care VL - vol. 18 DO - https://doi.org/10.1186/cc13871 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/137012/137012.pdf?sequence=1 ER - TY - JOUR AU - Bosch, C.M.A. van den AU - Hulscher, M. AU - Natsch, S.S. AU - Gyssens, I.C. AU - Prins, J.M. AU - Geerlings, S.E. AU - Pickkers, P. AU - Hoedemaekers, C.W. AU - et al. PY - 2014 UR - https://hdl.handle.net/2066/136247 AB - BACKGROUND: Outcomes in patients with sepsis are better if initial empirical antimicrobial use is appropriate. Several studies have shown that adherence to guidelines dictating appropriate antimicrobial use positively influences clinical outcome, shortens length of hospital stay and contributes to the containment of antibiotic resistance.Quality indicators (QIs) can be systematically developed from these guidelines to define and measure appropriate antimicrobial use. We describe the development of a concise set of QIs to assess the appropriateness of antimicrobial use in adult patients with sepsis on a general medical ward or Intensive Care Unit (ICU). METHODS: A RAND-modified, five step Delphi procedure was used. A multidisciplinary panel of 14 experts appraised and prioritized 40 key recommendations from within the Dutch national guideline on antimicrobial use for adult hospitalized patients with sepsis (http://www.swab.nl/guidelines). A procedure to select QIs relevant to clinical outcome, antimicrobial resistance and costs was performed using two rounds of questionnaires with a face-to-face consensus meeting between the rounds over a period of three months. RESULTS: The procedure resulted in the selection of a final set of five QIs, namely: obtain cultures; prescribe empirical antimicrobial therapy according to the national guideline; start intravenous drug therapy; start antimicrobial treatment within one hour; and streamline antimicrobial therapy. CONCLUSION: This systematic, stepwise method, which combined evidence and expert opinion, led to a concise and therefore feasible set of QIs for optimal antimicrobial use in hospitalized adult patients with sepsis. The next step will entail subjecting these quality indicators to an applicability test for their clinimetric properties and ultimately, using these QIs in quality-improvement projects. This information is crucial for antimicrobial stewardship teams to help set priorities and to focus improvement. TI - Development of quality indicators for antimicrobial treatment in adults with sepsis SN - 1471-2334 SP - 345 JF - BMC Infectious Diseases VL - vol. 14 DO - https://doi.org/10.1186/1471-2334-14-345 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/136247/136247.pdf?sequence=1 ER - TY - JOUR AU - Schellekens, W.J.M. AU - Hees, H.W.H. van AU - Kox, M. AU - Linkels, M. AU - Acuna, G.L. AU - Dekhuijzen, P.N.R. AU - Scheffer, G.J. AU - Hoeven, J.G. van der AU - Heunks, L.M.A. PY - 2014 UR - https://hdl.handle.net/2066/134064 AB - INTRODUCTION: Diaphragm weakness induced by prolonged mechanical ventilation may contribute to difficult weaning from the ventilator. Hypercapnia is an accepted side effect of low tidal volume mechanical ventilation, but the effects of hypercapnia on respiratory muscle function are largely unknown. The present study investigated the effect of hypercapnia on ventilator-induced diaphragm inflammation, atrophy and function. METHODS: Male Wistar rats (n = 10 per group) were unventilated (CON), mechanically ventilated for 18 hours without (MV) or with hypercapnia (MV + H, Fico2 = 0.05). Diaphragm muscle was excised for structural, biochemical and functional analyses. RESULTS: Myosin concentration in the diaphragm was decreased in MV versus CON, but not in MV + H versus CON. MV reduced diaphragm force by approximately 22% compared with CON. The force-generating capacity of diaphragm fibers from MV + H rats was approximately 14% lower compared with CON. Inflammatory cytokines were elevated in the diaphragm of MV rats, but not in the MV + H group. Diaphragm proteasome activity did not significantly differ between MV and CON. However, proteasome activity in the diaphragm of MV + H was significantly lower compared with CON. LC3B-II a marker of lysosomal autophagy was increased in both MV and MV + H. Incubation of MV + H diaphragm muscle fibers with the antioxidant dithiothreitol restored force generation of diaphragm fibers. CONCLUSIONS: Hypercapnia partly protects the diaphragm against adverse effects of mechanical ventilation. TI - Hypercapnia attenuates ventilator-induced diaphragm atrophy and modulates dysfunction SN - 1466-609X IS - iss. 1 SP - R28 JF - Critical Care VL - vol. 18 DO - https://doi.org/10.1186/cc13719 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/134064/134064.pdf?sequence=1 ER - TY - JOUR AU - Hees, H.W.H. van AU - Schellekens, W.J. AU - Dekhuijzen, P.N.R. AU - Heunks, L.M.A. PY - 2014 UR - https://hdl.handle.net/2066/138681 TI - Diaphragm dysfunction in mechanically ventilated patients results from several factors EP - 2 SN - 0022-3751 SP - 1 JF - Journal of Physiology ER - TY - JOUR AU - Boogaard, M.H.W.A. van den AU - Schoonhoven, L. AU - Maseda, E. AU - Plowright, C. AU - Jones, C. AU - Luetz, A. AU - Sackey, P.V. AU - Jorens, P.G. AU - Aitken, L.M. AU - Haren, F.M.P. van AU - Donders, R. AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/136662 AB - PURPOSE: Recalibration and determining discriminative power, internationally, of the existing delirium prediction model (PRE-DELIRIC) for intensive care patients. METHODS: A prospective multicenter cohort study was performed in eight intensive care units (ICUs) in six countries. The ten predictors (age, APACHE-II, urgent and admission category, infection, coma, sedation, morphine use, urea level, metabolic acidosis) were collected within 24 h after ICU admission. The confusion assessment method for the intensive care unit (CAM-ICU) was used to identify ICU delirium. CAM-ICU screening compliance and inter-rater reliability measurements were used to secure the quality of the data. RESULTS: A total of 2,852 adult ICU patients were screened of which 1,824 (64 %) were eligible for the study. Main reasons for exclusion were length of stay <1 day (19.1 %) and sustained coma (4.1 %). CAM-ICU compliance was mean (SD) 82 +/- 16 % and inter-rater reliability 0.87 +/- 0.17. The median delirium incidence was 22.5 % (IQR 12.8-36.6 %). Although the incidence of all ten predictors differed significantly between centers, the area under the receiver operating characteristic (AUROC) curve of the eight participating centers remained good: 0.77 (95 % CI 0.74-0.79). The linear predictor and intercept of the prediction rule were adjusted and resulted in improved re-calibration of the PRE-DELIRIC model. CONCLUSIONS: In this multinational study, we recalibrated the PRE-DELIRIC model. Despite differences in the incidence of predictors between the centers in the different countries, the performance of the PRE-DELIRIC-model remained good. Following validation of the PRE-DELIRIC model, it may facilitate implementation of strategies to prevent delirium and aid improvements in delirium management of ICU patients. TI - Recalibration of the delirium prediction model for ICU patients (PRE-DELIRIC): a multinational observational study EP - 369 SN - 0342-4642 IS - iss. 3 SP - 361 JF - Intensive Care Medicine VL - vol. 40 DO - https://doi.org/10.1007/s00134-013-3202-7 ER - TY - JOUR AU - Boogaard, M.H.W.A. van den AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/137152 TI - Untangling ICU delirium: is establishing its prevention in high-risk patients the final frontier? Reply to van der Jagt et al SN - 0342-4642 IS - iss. 8 SP - 1183 JF - Intensive Care Medicine VL - vol. 40 DO - http://dx.doi.org/10.1007/s00134-014-3393-6 ER - TY - JOUR AU - Gomez, H. AU - Ince, C. AU - Backer, D. de AU - Pickkers, P. AU - Payen, D. AU - Hotchkiss, J. AU - Kellum, J.A. PY - 2014 UR - https://hdl.handle.net/2066/138018 AB - Given that the leading clinical conditions associated with acute kidney injury (AKI), namely, sepsis, major surgery, heart failure, and hypovolemia, are all associated with shock, it is tempting to attribute all AKI to ischemia on the basis of macrohemodynamic changes. However, an increasing body of evidence has suggested that in many patients, AKI can occur in the absence of overt signs of global renal hypoperfusion. Indeed, sepsis-induced AKI can occur in the setting of normal or even increased renal blood flow. Accordingly, renal injury may not be entirely explained solely on the basis of the classic paradigm of hypoperfusion, and thus other mechanisms must come into play. Herein, we put forward a "unifying theory" to explain the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult. We propose that this response is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI. TI - A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury EP - 11 SN - 1073-2322 IS - iss. 1 SP - 3 JF - Shock VL - vol. 41 DO - https://doi.org/10.1097/SHK.0000000000000052 ER - TY - JOUR AU - Groot, J.J.A.M. de AU - Vernooij-Dassen, M.J.F.J. AU - Vries, A. de AU - Hoedemaekers, C.W. AU - Hoitsma, A.J. AU - Smeets, W. AU - Leeuwen, E. van PY - 2014 UR - https://hdl.handle.net/2066/138323 AB - BACKGROUND: Effectiveness of the donation request is generally measured by consent rates, rather than by relatives' satisfaction with their decision. Our aim was to elicit Dutch ICU staffs' views and experiences with the donation request, to investigate their awareness of (dis)satisfaction with donation decisions by relatives, specifically in the case of refusal, and to collect advice that may leave more relatives satisfied with their decision. METHODS: Five focus groups with a total of 32 participants (IC physicians, IC nurses and transplant coordinators) from five university hospitals in the Netherlands. Transcripts were examined using standard qualitative methods. RESULTS: Four themes (donation request perceived by ICU staff from the perspective of relatives; donation request perceived by ICU staff from their own perspective; aftercare; donation in society) divided into 14 categories were identified. According to ICU staff, relatives mentioned their own values more frequently than values of the potential donor as important for the decision. ICU staff observed this imbalance, but reacted empathically to the relatives' point of view. ICU staff rarely suggested reconsideration of refusal and did not ask relatives for arguments. ICU staff did not always feel comfortable with a request in the delicate context of brain death. Sometimes the interests of patient, relatives and those on the waiting list were irreconcilable. ICU staff were mostly unaware of relatives' regret following their decisions. Aftercare did not provide this type of information. Donation request by IC physicians was influenced by the way organ donation has been regulated in society (law, donor register, education, media). CONCLUSIONS: Our findings lead to the hypothesis that giving relatives more time and inviting them to reconsider their initial refusal will lead to a more stable decision and possibly more consent. TI - Intensive care staff, the donation request and relatives' satisfaction with the decision: a focus group study SN - 1471-2253 JF - BMC Anesthesiology VL - vol. 14 DO - https://doi.org/10.1186/1471-2253-14-52 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138323/138323.pdf?sequence=1 ER - TY - JOUR AU - Eijk, L.T.G.J. van AU - Pluijm, R.W. van der AU - Ramakers, B.P.C. AU - Dorresteijn, M.J. AU - Hoeven, J.G. van der AU - Kox, M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/133915 AB - A higher body mass index (BMI) appears to be associated with lower mortality in critically ill patients, possibly explained by an altered innate immune response. However, the precise relationship between BMI and the innate immune response in humans in vivo is unknown. We investigated the relationship between BMI and the systemic cytokine response during experimental human endotoxemia. Endotoxemia was induced in 112 healthy male volunteers by intravenous administration of 2 ng/kg Escherichia coli endotoxin. Plasma concentrations of TNF-alpha, IL-6, IL-10 and IL-1RA were serially determined. The relationship between BMI and the cytokine response, as well as body temperature, was investigated. The BMIs of the participants ranged from 18.3 to 33.6 kg/m(2), (median: 22.7 kg/m(2)). All participants showed a marked increase in plasma cytokine levels [median (interquartile range)] peak levels: TNF-alpha 509 (353-673) pg/ml; IL-6 757 (522-1098) pg/ml; IL-10 271 (159-401) pg/ml; IL-1RA 4882 (3927-6025) pg/ml; and an increase in body temperature [1.8(1.4-2.2)] during endotoxemia. No significant correlations were found between BMI and levels of any of the cytokines or body temperature. No relationship between BMI and the cytokine response was found in healthy volunteers subjected to experimental endotoxemia. These data question the relationship between BMI and cytokine responses in critical illness. TI - Body mass index is not associated with cytokine induction during experimental human endotoxemia EP - 67 SN - 1753-4259 IS - iss. 1 SP - 61 JF - Innate Immunity VL - vol. 20 DO - https://doi.org/10.1177/1753425913481821 ER - TY - JOUR AU - Eijk, L.T.G.J. van AU - John, A.S. AU - Schwoebel, F. AU - Summo, L. AU - Vauleon, S. AU - Zollner, S. AU - Laarakkers, C.M. AU - Kox, M. AU - Hoeven, J.G. van der AU - Swinkels, D.W. AU - Riecke, K. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/136275 AB - Increased hepcidin production is key to the development of anemia of inflammation. We investigated whether lexaptepid, an antihepcidin l-oligoribonucleotide, prevents the decrease in serum iron during experimental human endotoxemia. This randomized, double-blind, placebo-controlled trial was carried out in 24 healthy males. At T = 0 hours, 2 ng/kg Escherichia coli lipopolysaccharide was intravenously administered, followed by an intravenous injection of 1.2 mg/kg lexaptepid or placebo at T = 0.5 hours. The lipopolysaccharide-induced inflammatory response was similar in subjects treated with lexaptepid or placebo regarding clinical and biochemical parameters. At T = 9 hours, serum iron had increased by 15.9 +/- 9.8 micromol/L from baseline in lexaptepid-treated subjects compared with a decrease of 8.3 +/- 9.0 micromol/L in controls (P < .0001). This study delivers proof of concept that lexaptepid achieves clinically relevant hepcidin inhibition enabling investigations in the treatment of anemia of inflammation. This trial was registered at www.clinicaltrial.gov as #NCT01522794. TI - Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans EP - 2646 SN - 0006-4971 IS - iss. 17 SP - 2643 JF - Blood VL - vol. 124 DO - https://doi.org/10.1182/blood-2014-03-559484 ER - TY - JOUR AU - Eijk, L.T.G.J. van AU - Heemskerk, S. AU - Pluijm, R.W. van der AU - Wijk, S.M. van AU - Peters, W.H.M. AU - Hoeven, J.G. van der AU - Kox, M. AU - Swinkels, D.W. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/136110 AB - In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433+/-37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6+/-9.7% of baseline at T=8 h in the placebo group versus 84+/-15% and 60.4+/-8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-alpha, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699). TI - The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial EP - 587 SN - 0390-6078 IS - iss. 3 SP - 579 JF - Haematologica VL - vol. 99 DO - https://doi.org/10.3324/haematol.2013.088047 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/136110/136110.pdf?sequence=1 ER - TY - JOUR AU - Eijk, L.T. AU - Kox, M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/134051 TI - Gender-specific differences in outcome after trauma may be explained by differences in immunity SN - 1466-609X IS - iss. 2 SP - 418 JF - Critical Care VL - vol. 18 DO - https://doi.org/10.1186/cc13768 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/134051/134051.pdf?sequence=1 ER - TY - JOUR AU - Habes, Q.L.M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/134057 TI - Has the prognosis of septic patients improved over time? EP - 3 SN - 1569-3511 IS - iss. 4 SP - 2 JF - Netherlands Journal of Critical Care VL - vol. Augustus 2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/134057/134057.pdf?sequence=1 ER - TY - JOUR AU - Messaoudi, S. El AU - Wouters, C.W. AU - Swieten, H.A. van AU - Pickkers, P. AU - Noyez, L. AU - Kievit, P.C. AU - Abbink-Zandbergen, E.J. AU - Rading-Hoogveld, A. AU - Bouw, M.P.W.J.M. AU - Peters, M.J.W. AU - Donders, A.R.T. AU - Riksen, N.P. AU - Rongen, G.A.P.J.M. PY - 2014 UR - https://hdl.handle.net/2066/136253 TI - Dipyridamole Does not Limit Myocardial Ischemia-Reperfusion Injury. A Double-Blind Randomized Placebo-Controlled Trial in Patients Undergoing Elective Coronary Artery Bypass Surgery SN - 0149-2918 IS - iss. 8 SP - 13 JF - Clinical Therapeutics VL - vol. 36 ER - TY - JOUR AU - Muilwijk, E.W. AU - Schouten, J.A. AU - Leeuwen, H.J. van AU - Zanten, A.R. van AU - Lange, D.W. de AU - Colbers, A. AU - Verweij, P.E. AU - Burger, D.M. AU - Pickkers, P. AU - Bruggemann, R.J.M. PY - 2014 UR - https://hdl.handle.net/2066/136011 AB - OBJECTIVES: Caspofungin is used for treatment of invasive fungal infections. As the pharmacokinetics (PK) of antimicrobial agents in critically ill patients can be highly variable, we set out to explore caspofungin PK in ICU patients. METHODS: ICU patients receiving caspofungin were eligible. Patients received a loading dose of 70 mg followed by 50 mg daily (70 mg if body weight >80 kg); they were evaluable upon completion of the first PK curve at day 3. Additionally, daily trough samples were taken and a second PK curve was recorded at day 7. PK analysis was performed using a standard two-stage approach. RESULTS: Twenty-one patients were evaluable. Median (range) age and body weight were 71 (45-80) years and 75 (50-99) kg. PK sampling on day 3 (n = 21) resulted in the following median (IQR) parameters: AUC0-24 88.7 (72.2-97.5) mg.h/L; Cmin 2.15 (1.40-2.48) mg/L; Cmax 7.51 (6.05-8.17) mg/L; V 7.72 (6.12-9.01) L; and CL 0.57 (0.54-0.77) L/h. PK sampling on day 7 (n = 13) resulted in AUC0-24 107.2 (90.4-125.3) mg.h/L, Cmin 2.55 (1.82-3.08) mg/L, Cmax 8.65 (7.16-9.34) mg/L, V 7.03 (5.51-7.73) L and CL 0.54 (0.44-0.60) L/h. We did not identify any covariates significantly affecting caspofungin PK in ICU patients (e.g. body weight, albumin, liver function). Caspofungin was well tolerated and no unexpected side effects were observed. CONCLUSIONS: Caspofungin PK in ICU patients showed limited intraindividual and moderate interindividual variability, and caspofungin was well tolerated. A standard two-stage approach did not reveal significant covariates. Our study showed similar caspofungin PK parameters in ICU patients compared with non-critically ill patients. TI - Pharmacokinetics of caspofungin in ICU patients EP - 3299 SN - 0305-7453 IS - iss. 12 SP - 3294 JF - Journal of Antimicrobial Chemotherapy VL - vol. 69 DO - https://doi.org/10.1093/jac/dku313 ER - TY - JOUR AU - Kox, M. AU - Eijk, L.T.G.J. van AU - Zwaag, J. AU - Wildenberg, J. van den AU - Sweep, C.G.J. AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/133920 AB - Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti-inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-alpha, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases. TI - Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans EP - 7384 SN - 0027-8424 IS - iss. 20 SP - 7379 JF - Proceedings of the National Academy of Sciences USA VL - vol. 111 DO - https://doi.org/10.1073/pnas.1322174111 ER - TY - JOUR AU - Vet, N.J. AU - Wildt, S.N. de AU - Verlaat, C.W.M. AU - Knibbe, C.A. AU - Mooij, M.G. AU - Hop, W.C.J. AU - Rosmalen, J. van AU - Tibboel, D. AU - Hoog, M. de PY - 2014 UR - https://hdl.handle.net/2066/137736 AB - BACKGROUND: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and efficacy of daily sedation interruption in critically ill children. METHODS/DESIGN: Children between 0 and 18 years of age who require mechanical ventilation, with an expected duration of at least 48 h and need for sedative infusion, will be included. After enrollment patients will be randomly assigned to DSI in combination with protocolized sedation (intervention group) or protocolized continuous sedation (control group). A sedation protocol that contains an algorithm for increasing and weaning of sedatives and analgesics will be used. The sedative infusion will be restarted if the patient becomes uncomfortable or agitated according to the sedation protocol. The primary endpoint is the number of ventilator-free days at 28 days. TRIAL REGISTRATION: NTR2030. TI - Daily interruption of sedation in critically ill children: study protocol for a randomized controlled trial SN - 1745-6215 JF - Trials VL - vol. 15 DO - https://doi.org/10.1186/1745-6215-15-55 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/137736/137736.pdf?sequence=1 ER - TY - JOUR AU - Ramakers, B.P.C. AU - Riksen, N.P. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/138728 TI - The immunomodulatory actions of adenosine during systemic inflammation EP - 10 SN - 1569-3511 IS - iss. 5 SP - 4 JF - Netherlands Journal of Critical Care VL - vol. 18 ER - TY - JOUR AU - Nusmeier, A. AU - Vrancken, S.L. AU - Boode, W.P. de AU - Hoeven, J.G. van der AU - Lemson, J. PY - 2014 UR - https://hdl.handle.net/2066/137171 AB - OBJECTIVE: The measurement of extravascular lung water using the transpulmonary thermodilution technique enables the bedside quantification of the amount of pulmonary edema. Children have higher indexed to body weight values of extravascular lung water compared with adults. Transpulmonary thermodilution measurements of extravascular lung water in children have not yet been validated. The purpose of this study was to validate the extravascular lung water measurements with the transpulmonary thermodilution method over a wide range of lung water values in a pediatric animal model. DESIGN: Experimental animal intervention study. SETTING: Animal laboratory at the Radboud University Nijmegen, The Netherlands. SUBJECTS: Eleven lambs. INTERVENTION: Pulmonary edema was induced using a surfactant washout model. MEASUREMENTS AND MAIN RESULTS: Between the lavages, extravascular lung water index was estimated using transpulmonary single and double indicator dilution. Two additional lambs were used to estimate extravascular lung water index in lungs without pulmonary edema. The final extravascular lung water index results were compared with the extravascular lung water index estimations by postmortem gravimetry (EVLWIG). The results were analyzed using both correlation and Bland-Altman statistics. Extravascular lung water index by transpulmonary thermodilution (EVLWITPTD) correlated significantly with either EVLWIG (r = 0.88) or with extravascular lung water index by transpulmonary double indicator dilution (EVLWITPDD) (r = 0.98). The mean bias with EVLWIG was 12.2 mL/kg (limits of agreement +/- 10.9 mL/kg) and with EVLWITPDD 2.4 mL/kg (limits of agreement +/- 3.8 mL/kg). The percentage errors were 41% and 14%, respectively. The bias became more positive when the mean of EVLWITPTD and EVLWIG increased (r = 0.72; p = 0.003). CONCLUSIONS: EVLWITPTD was significantly correlated to the postmortem gravimetric gold standard, although a significant overestimation was demonstrated with increasing pulmonary edema. TI - Validation of extravascular lung water measurement by transpulmonary thermodilution in a pediatric animal model EP - 33 SN - 1529-7535 IS - iss. 5 SP - e226 JF - Pediatric Critical Care Medicine VL - vol. 15 DO - https://doi.org/10.1097/PCC.0000000000000104 ER - TY - JOUR AU - Wassenaar, A. AU - Schouten, J.A. AU - Schoonhoven, L. PY - 2014 UR - https://hdl.handle.net/2066/138019 AB - BACKGROUND: Feeling safe in the intensive care unit is of great importance while recovering from critical illness. Moreover, feeling unsafe can result in distress. In order to meet the safety needs of intensive care patients as well as to stimulate their recovery and prevent distress, nurses must be aware of factors promoting patients' perception of feeling safe during an intensive care admission. To our knowledge, there is no synthesis of these factors available as yet. OBJECTIVE: To systematically describe the factors that promote patients' perception of feeling safe in an intensive care unit. DESIGN: A systematic review of qualitative and quantitative studies. DATA SOURCES: PubMed, Embase, CINAHL, and PsycINFO were searched up to March 2012. REVIEW METHODS: Methodological quality was assessed by two authors using the QualSyst tool. Data from the included studies were extracted into a customised data extraction form. RESULTS: The initial search resulted in 1326 records. Ultimately, eleven studies were relevant to the research question and included in the review. No studies needed to be excluded because of low quality scores. Analysis of the factors in these studies resulted in four overarching themes that promote intensive care patients' perception of feeling safe. These themes were: nursing care, patients' issues, relatives, and technological support. Nursing care was described most frequently as an important factor promoting patients' feeling of safety in an intensive care unit. Relatives were the link between intensive care patients and staff. CONCLUSIONS: Nurses can increase the perception of feeling safe in critically ill patients by taking into account the promoting factors described in this review. By being aware of these factors nurses can improve quality of care in their intensive care unit. TI - Factors promoting intensive care patients' perception of feeling safe: A systematic review EP - 273 SN - 0020-7489 IS - iss. 2 SP - 261 JF - International Journal of Nursing Studies VL - vol. 51 DO - https://doi.org/10.1016/j.ijnurstu.2013.07.003 ER - TY - JOUR AU - Hofhuizen, C.M. AU - Lansdorp, B. AU - Hoeven, J.G. van der AU - Scheffer, G.J. AU - Lemson, J. PY - 2014 UR - https://hdl.handle.net/2066/133916 AB - INTRODUCTION: Nexfin (Edwards Lifesciences, Irvine, CA) allows for noninvasive continuous monitoring of blood pressure (ABPNI) and cardiac output (CONI) by measuring finger arterial pressure (FAP). To evaluate the accuracy of FAP in measuring ABPNI and CONI as well as the adequacy of detecting changes in ABP and CO, we compared FAP to intra-arterially measured blood pressure (ABPIA) and transpulmonary thermodilution(COTD) in post cardiac surgery patients during a fluid challenge (FC). METHODS: Twenty sedated patients post cardiac surgery were included, and 28 FCs were performed. Measurements of ABP and CO were simultaneously collected before and after an FC, and we compared CO and blood pressure. RESULTS: Finger arterial pressure was obtainable in all patients.When comparing ABPNI with ABPIA, bias was2.7 mm Hg (limits of agreement [LOA], +/- 22.2), 4.9 mm Hg (LOA, +/- 13.6), and 4.2 mm Hg (LOA, +/-13.7) for systolic,diastolic, and mean arterial pressure, respectively. Concordance between changes in ABPNI and ABPIA was 100%.Mean bias between CONI and COTD was -0.26 (LOA, +/- 2.2), with a percentage error of 38.9%. Concordance between changes in CONI vs COTD and was 100%. CONCLUSION: Finger arterial pressure reliably measures ABP and adequately tracks changes in ABP. Although CONI is not interchangeable with COTD, it follows changes in CO closely. TI - Validation of noninvasive pulse contour cardiac output using finger arterial pressure in cardiac surgery patients requiring fluid therapy EP - 165 SN - 0883-9441 IS - iss. 1 SP - 161 JF - Journal of Critical Care VL - vol. 29 DO - https://doi.org/10.1016/j.jcrc.2013.09.005 ER - TY - JOUR AU - Lavieren, M. van AU - Veelenturf, J. AU - Hofhuizen, C.M. AU - Kolk, M. van der AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Lemson, J. AU - Lansdorp, B. PY - 2014 UR - https://hdl.handle.net/2066/136266 AB - BACKGROUND: Optimizing cardiac stroke volume during major surgery is of interest to many as a therapeutic target to decrease the incidence of postoperative complications. Because dynamic preload indicators are strongly correlated with stroke volume, it is suggested that these indices can be used for goal directed fluid therapy. However, threshold values of these indicators depend on many factors that are influenced by surgery, including opening of the abdomen. The aim of this study was therefore to assess the effect of opening the abdomen on arterial pressure variations in patients undergoing abdominal surgery. METHODS: Blood pressure and bladder pressure were continuously recorded just before and after opening of the abdomen in patients undergoing elective laparotomy. Based on waveform analysis of the non-invasively derived blood pressure, the stroke volume index, pulse pressure variation (PPV) and stroke volume variation (SVV) were calculated off-line. RESULTS: Thirteen patients were included. After opening the abdomen, PPV and SVV decreased from 11.5 +/- 5.8% to 6.4 +/- 2.9% (p < 0.005, a relative decrease of 40 +/- 19%) and 12.7 +/- 6.1% to 4.8 +/- 1.6% (p < 0.05, a relative decrease of 53 +/- 26%), respectively. Although mean arterial pressure and stroke volume index tended to increase (41 +/- 6 versus 45 +/- 4 ml/min/m2, p = 0.14 and 41 +/- 6 versus 45 +/- 4 ml/min/m2, p = 0.05), and heart rate tended to decrease (73 +/- 15 versus 68 +/- 11 1/min, p = 0.05), no significant change was found. No significant change was found in respiratory parameter (tidal volume, respiratory rate or inspiratory pressure; p = 0.36, 0.34 and 0.17, respectively) or bladder pressure (6.0 +/- 3.7 versus 5.6 +/- 2.7 mmHg, p = 0.6) either. CONCLUSIONS: Opening of the abdomen decreases PPV and SVV. During goal directed therapy, current thresholds for fluid responsiveness should be changed accordingly. TI - Dynamic preload indicators decrease when the abdomen is opened SN - 1471-2253 JF - BMC Anesthesiology VL - vol. 14 DO - https://doi.org/10.1186/1471-2253-14-90 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/136266/136266.pdf?sequence=1 ER - TY - JOUR AU - Lansdorp, B. AU - Hofhuizen, C.M. AU - Lavieren, M. van AU - Swieten, H.A. van AU - Lemson, J. AU - Putten, M.J.A.M. van AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/133826 AB - OBJECTIVE: Mechanical ventilation causes cyclic changes in the heart's preload and afterload, thereby influencing the circulation. However, our understanding of the exact physiology of this cardiopulmonary interaction is limited. We aimed to thoroughly determine airway pressure distribution, how this is influenced by tidal volume and chest compliance, and its interaction with the circulation in humans during mechanical ventilation. DESIGN: Intervention study. SETTING: ICU of a university hospital. PATIENTS: Twenty mechanically ventilated patients following coronary artery bypass grafting surgery. INTERVENTION: Patients were monitored during controlled mechanical ventilation at tidal volumes of 4, 6, 8, and 10 mL/kg with normal and decreased chest compliance (by elastic binding of the thorax). MEASUREMENTS AND MAIN RESULTS: Central venous pressure, airway pressure, pericardial pressure, and pleural pressure; pulse pressure variations, systolic pressure variations, and stroke volume variations; and cardiac output were obtained during controlled mechanical ventilation at tidal volume of 4, 6, 8, and 10 mL/kg with normal and decreased chest compliance. With increasing tidal volume (4, 6, 8, and 10 mL/kg), the change in intrathoracic pressures increased linearly with 0.9 +/- 0.2, 0.5 +/- 0.3, 0.3 +/- 0.1, and 0.3 +/- 0.1 mm Hg/mL/kg for airway pressure, pleural pressure, pericardial pressure, and central venous pressure, respectively. At 8 mL/kg, a decrease in chest compliance (from 0.12 +/- 0.07 to 0.09 +/- 0.03 L/cm H2O) resulted in an increase in change in airway pressure, change in pleural pressure, change in pericardial pressure, and change in central venous pressure of 1.1 +/- 0.7, 1.1 +/- 0.8, 0.7 +/- 0.4, and 0.8 +/- 0.4 mm Hg, respectively. Furthermore, increased tidal volume and decreased chest compliance decreased stroke volume and increased arterial pressure variations. Transmural pressure of the superior vena cava decreased during inspiration, whereas the transmural pressure of the right atrium did not change. CONCLUSIONS: Increased tidal volume and decreased chest wall compliance both increase the change in intrathoracic pressures and the value of the dynamic indices during mechanical ventilation. Additionally, the transmural pressure of the vena cava is decreased, whereas the transmural pressure of the right atrium is not changed. TI - Mechanical ventilation-induced intrathoracic pressure distribution and heart-lung interactions* EP - 1990 SN - 0090-3493 IS - iss. 9 SP - 1983 JF - Critical Care Medicine VL - vol. 42 DO - https://doi.org/10.1097/CCM.0000000000000345 ER - TY - JOUR AU - Ruijter, B.J. AU - Putten, M.J.A.M. van AU - Horn, J. AU - Blans, M.J. AU - Beishuizen, A. AU - Rootselaar, A.F. van AU - Hofmeijer, J. AU - Pickkers, P. AU - Hoedemaekers, C.W. AU - et al. PY - 2014 UR - https://hdl.handle.net/2066/138739 AB - BACKGROUND: Electroencephalographic (EEG) status epilepticus is described in 10 to 35% of patients with postanoxic encephalopathy after successful cardiopulmonary resuscitation and is associated with case fatality rates of 90 to 100%. It is unclear whether these EEG patterns represent a condition to be treated with anticonvulsants to improve outcome, or an expression of severe ischemic damage, in which treatment is futile. METHODS/DESIGN: TELSTAR is a multicenter clinical trial with two parallel groups, randomized treatment allocation, open label treatment, and blinded endpoint evaluation (PROBE design). We aim to enroll 172 adult patients with postanoxic encephalopathy and electroencephalographic status epilepticus after successful cardiopulmonary resuscitation, admitted to the ICU, in whom continuous EEG monitoring is started within 24 hours after admission. Patients are randomly assigned to either medical treatment to suppress all electrographic seizure activity, or no treatment of electroencephalographic status epilepticus. Antiepileptic treatment is based on guidelines for treatment of overt status epilepticus and is started within 3 hours after the diagnosis. If status epilepticus returns during tapering of sedative medication after suppression of all epileptiform activity for 2 x 24 hours, it will be considered refractory. The primary outcome measure is neurological outcome defined as the Cerebral Performance Category (CPC) score at 3 months, dichotomized into 'good' (CPC 1 to 2 = no or moderate neurological disability) and 'poor' (CPC 3 to 5 = severe disability, coma, or death). Secondary outcome measures include mortality and, for patients surviving up to 12 months, cognitive functioning, health related quality of life, and depression. TRIAL REGISTRATION: Clinicaltrials.gov; NCT02056236. Date of registration: 4 February 2014. TI - Treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation (TELSTAR): study protocol for a randomized controlled trial SN - 1745-6215 JF - Trials VL - vol. 15 DO - https://doi.org/10.1186/1745-6215-15-433 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138739/138739.pdf?sequence=1 ER - TY - JOUR AU - Bucx, M.J.L. AU - Landman, J.J. AU - Onzenoort, H.A.W. van AU - Kox, M. AU - Scheffer, G.J. PY - 2014 UR - https://hdl.handle.net/2066/133870 TI - Reducing the cost of anaesthesia EP - 526 SN - 0003-2409 IS - iss. 5 SP - 525 JF - Anaesthesia VL - vol. 69 DO - https://doi.org/10.1111/anae.12687 ER - TY - JOUR AU - Nonnekes, J.H. AU - Aerts, M.B. AU - Abdo, W.F. AU - Bloem, B.R. PY - 2014 UR - https://hdl.handle.net/2066/138918 TI - Medio-Lateral Balance Impairment Differentiates between Parkinson's Disease and Atypical Parkinsonism EP - 569 SN - 1877-7171 SP - 567 JF - Journal of Parkinson's Disease VL - vol. 4 DO - https://doi.org/10.3233/JPD-140436 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138918/138918.pdf?sequence=1 ER - TY - JOUR AU - Hooijman, P.E. AU - Beishuizen, A. AU - Waard, M.C. de AU - Man, F.S. de AU - Vermeijden, J.W. AU - Steenvoorde, P. AU - Bouwman, R.A. AU - Lommen, W. AU - Hees, H.W.H. van AU - Heunks, L.M.A. AU - Dickhoff, C. AU - Peet, D.L. van der AU - Girbes, A.R.J. AU - Jasper, J.R. AU - Malik, F.I. AU - Stienen, G.J. AU - Hartemink, K.J. AU - Paul, M.A. AU - Ottenheijm, C.A.C. PY - 2014 UR - http://repository.ubn.ru.nl/handle/2066/127753 TI - Diaphragm fiber strength is reduced in critically ill patients and restored by a troponin activator EP - 865 SN - 1073-449X IS - iss. 7 SP - 863 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 189 DO - https://doi.org/10.1164/rccm.201312-2260LE ER - TY - JOUR AU - Vliet, M. van AU - Boogaard, M.W. van den AU - Donnelly, J.P. AU - Evers, A.W.M. AU - Blijlevens, N.M.A. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/138558 AB - OBJECTIVE: Long-term health-related quality of life (HRQoL) was determined for patients admitted to the haematology ward who needed intensive care treatment (H-IC+) and compared with those who did not (H-IC-) as well as with that for patients admitted to the general ICU (nH-IC+). METHODS: A cross-sectional study was carried out median 18 months after admission by employing the short form-36, checklist for individual strength, cognitive failure questionnaire and hospital anxiety and depression scale. RESULTS: 27 (79%) of the 34 H-IC+ patients approached, and 93 (85%) of the 109 H-IC- patients approached replied. Data were adjusted for relevant covariates and matched with those of 149 patients in the general ICU. Apart from the lower role-physical functioning score for H-IC+ (P = 0.04) no other differences were found between H-IC+ and H-IC-. Groups H-IC+ and nH-IC+ evaluated their HRQoL on SF-36 similarly, except for the lower aggregated physical component summary (PCS) for H-IC+ (P<0.0001). After adjusting for PCS, no significant differences in CIS, CFQ and HADS were observed between the groups. CONCLUSIONS: Eighteen months after admission, patients treated for haematological malignancies reported similar HRQoL, whether or not they had received intensive care treatment, but reported a lower PCS than those of patients in the general ICU. Hence, there is no reason to assume that admission to the ICU has a negative impact on long-term HRQoL, so this should not affect the decision whether or not to transfer patients with haematological malignancies to the ICU. TI - Long-term health related quality of life following intensive care during treatment for haematological malignancies SN - 1932-6203 IS - iss. 1 JF - PLoS One VL - vol. 9 DO - https://doi.org/10.1371/journal.pone.0087779 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138558/138558.pdf?sequence=1 ER - TY - JOUR AU - Vliet, M. van AU - Verburg, I.W. AU - Boogaard, M.H.W.A. van den AU - Keizer, N.F. de AU - Peek, N. AU - Blijlevens, N.M.A. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/137126 AB - PURPOSE: To explore trends over time in admission prevalence and (risk-adjusted) mortality of critically ill haematological patients and compare these trends to those of several subgroups of patients admitted to the medical intensive care unit (medical ICU patients). METHODS: A total of 1,741 haematological and 60,954 non-haematological patients admitted to the medical ICU were analysed. Trends over time and differences between two subgroups of haematological medical ICU patients and four subgroups of non-haematological medical ICU patients were assessed, as well as the influence of leukocytopenia. RESULTS: The proportion of haematological patients among all medical ICU patients increased over time [odds ratio (OR) 1.06; 95 % confidence interval (CI) 1.03-1.10 per year; p < 0.001]. Risk-adjusted mortality was significantly higher for haematological patients admitted to the ICU with white blood cell (WBC) counts of <1.0 x 10(9)/L (47 %; 95 % CI 41-54 %) and >/=1.0 x 10(9)/L (45 %; 95 % CI 42-49 %), respectively, than for patients admitted with chronic heart failure (27 %; 95 % CI 26-28 %) and with chronic liver cirrhosis (38 %; 95 % CI 35-42 %), but was not significantly different from patients admitted with solid tumours (40 %; 95 % CI 36-45 %). Over the years, the risk-adjusted hospital mortality rate significantly decreased in both the haematological and non-haematological group with an OR of 0.93 (95 % CI 0.92-0.95) per year. After correction for case-mix using the APACHE-II score (with WBC omitted), a WBC <1.0 x 10(9)/L was not a predictor of mortality in haematological patients (OR 0.86; 95 % CI 0.46-1.64; p = 0.65). We found no case-volume effect on mortality for haematological ICU patients. CONCLUSIONS: An increasing number of haematological patients are being admitted to Dutch ICUs. While mortality is significantly higher in this group of medical ICU patients than in subgroups of non-haematological ones, the former show a similar decrease in raw and risk-adjusted mortality rate over time, while leukocytopenia is not a predictor of mortality. These results suggest that haematological ICU patients have benefitted from improved intensive care support during the last decade. TI - Trends in admission prevalence, illness severity and survival of haematological patients treated in Dutch intensive care units EP - 1284 SN - 0342-4642 IS - iss. 9 SP - 1275 JF - Intensive Care Medicine VL - vol. 40 DO - https://doi.org/10.1007/s00134-014-3373-x ER - TY - JOUR AU - Peters, E. AU - Masereeuw, R. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/136963 TI - The Potential of Alkaline Phosphatase as a Treatment for Sepsis-Associated Acute Kidney Injury EP - 148 SN - 1660-2110 IS - iss. 1-4 SP - 144 JF - Nephron. Clinical Practice VL - vol. 127 DO - https://doi.org/10.1159/000363256 ER - TY - JOUR AU - Peters, E. AU - Heemskerk, S. AU - Masereeuw, R. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/137419 AB - Acute kidney injury (AKI) is a common disease in the intensive care unit and accounts for high morbidity and mortality. Sepsis, the predominant cause of AKI in this setting, involves a complex pathogenesis in which renal inflammation and hypoxia are believed to play an important role. A new therapy should be aimed at targeting both these processes, and the enzyme alkaline phosphatase, with its dual mode of action, might be a promising candidate. First, alkaline phosphatase is able to reduce inflammation through dephosphorylation and thereby detoxification of endotoxin (lipopolysaccharide), which is an important mediator of sepsis. Second, adenosine triphosphate, released during cellular stress caused by inflammation and hypoxia, has detrimental effects but can be converted by alkaline phosphatase into adenosine with anti-inflammatory and tissue-protective effects. These postulated beneficial effects of alkaline phosphatase have been confirmed in animal experiments and two phase 2a clinical trials showing that kidney function improved in critically ill patients with sepsis-associated AKI. Because renal inflammation and hypoxia also are observed commonly in AKI induced by other causes, it would be of interest to investigate the therapeutic effect of alkaline phosphatase in these nephropathies as well. TI - Alkaline phosphatase: a possible treatment for sepsis-associated acute kidney injury in critically ill patients EP - 1048 SN - 0272-6386 IS - iss. 6 SP - 1038 JF - American Journal of Kidney Diseases VL - vol. 63 DO - https://doi.org/10.1053/j.ajkd.2013.11.027 ER - TY - JOUR AU - Simmes, F. AU - Schoonhoven, L. AU - Mintjes-de Groot, A.J. AU - Adang, E.M. AU - Hoeven, J.G. van der PY - 2014 UR - https://hdl.handle.net/2066/138038 AB - RATIONALE, AIMS AND OBJECTIVES: Rapid response systems (RRSs) are recommended by the Institute for Healthcare Improvement and implemented worldwide. Our study on the effects of an RRS showed a non-significant decrease in cardiac arrest and/or unexpected death from 0.5% to 0.25%. Unplanned intensive care unit (ICU) admissions increased significantly from 2.5% to 4.2% without a decrease in APACHE II scores. In this study, we estimated the mean costs of an RRS per patient day and tested the hypothesis that admitting less severely ill patients to the ICU reduces costs. METHODS: A cost analysis of an RRS on a surgical ward, including costs for implementation, a 1-day training programme for nurses, nursing time for extra vital signs observation, medical emergency team (MET) consults and differences in unplanned ICU days before and after RRS implementation. To test the hypothesis, we performed a scenario analysis with a mean APACHE II score of 14 points instead of the empirical 17.6 points for the unplanned ICU admissions, including 33% extra MET consults and 22% extra unplanned ICU admissions. RESULTS: Mean RRS costs were euro26.87 per patient-day: implementation euro0.33 (1%), training euro0.90 (3%), nursing time spent on extended observation of vital signs euro2.20 (8%), MET consults euro0.57 (2%) and increased number of unplanned ICU days after RRS implementation euro22.87 (85%). In the scenario analysis mean costs per patient-day were euro10.18. CONCLUSIONS: The costs for extra unplanned ICU days were relatively high but the remaining RRS costs were relatively low. The 'APACHE II 14' scenario confirmed the hypothesis that costs for the number of unplanned ICU days can be reduced if less severely ill patients are referred to the ICU. Based upon these findings, our hospital stimulates earlier referral to the ICU, although further implementation strategies are needed to achieve these aims. TI - Financial consequences of the implementation of a rapid response system on a surgical ward EP - 347 SN - 1356-1294 IS - iss. 4 SP - 342 JF - Journal of Evaluation in Clinical Practice VL - vol. 20 DO - https://doi.org/10.1111/jep.12134 ER - TY - THES AU - Simmes, W.M.C. PY - 2014 SN - 9789462592568 UR - https://hdl.handle.net/2066/129681 PB - [S.l. : s.n.] TI - Critically ill, well assessed. Evaluation of the rapid response system in a university medical center N1 - Radboud Universiteit Nijmegen, 26 september 2014 N1 - Promotor : Hoeven, J.G. van der Co-promotores : Schoonhoven, L., Mintjes-de Groot, A.J. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/129681/129681.pdf?sequence=1 ER - TY - JOUR AU - Simons, K.S. AU - Workum, J.D. AU - Slooter, A.J. AU - Boogaard, M.H.W.A. van den AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/137886 AB - PURPOSE: It is assumed that there is a relation between light exposure and delirium incidence. The aim of our study was to determine the effect of prehospital light exposure on the incidence of intensive care unit (ICU)-acquired delirium. MATERIALS AND METHODS: Data from 3 ICUs in the Netherlands were analyzed retrospectively. Delirium was assessed with the Confusion Assessment Method for the ICU. Daily light intensity data were obtained from meteorological stations in the vicinity of the 3 hospitals. The association between light intensity and delirium incidence was analyzed using logistic regression analysis adjusting for known covariates for delirium. RESULTS: Data of 3198 patients, aged (mean +/- SD) 61.9 +/- 15.3 years with Acute Physiology and Chronic Health Evaluation II score 16.4 +/- 6.6 were analyzed. Delirium incidence was 31.2% and did not vary significantly throughout the year. Twenty-eight-day preadmission photoperiod was highest in spring and lowest in winter; however, no association between light exposure and delirium incidence was found (odds ratio, 1.00; 95% confidence interval, 0.99-1.00; P = 0.72). Furthermore, delirium was significantly associated with age, infection, use of sedatives, Acute Physiology and Chronic Health Evaluation II score, and diagnosis of neurological disease or trauma. CONCLUSIONS: The incidence of delirium does not differ per season and prior sunlight exposure does not play a role of importance in the development of ICU-acquired delirium. TI - Effect of preadmission sunlight exposure on intensive care unit-acquired delirium: a multicenter study EP - 286 SN - 0883-9441 IS - iss. 2 SP - 283 JF - Journal of Critical Care VL - vol. 29 DO - https://doi.org/10.1016/j.jcrc.2013.10.027 ER - TY - JOUR AU - Vliet, M. van AU - Burgt, M.P.E.M. van der AU - Velden, W.J.F.M. van der AU - Hoeven, J.G. van der AU - Haan, A.F.J. de AU - Donnelly, J.P. AU - Pickkers, P. AU - Blijlevens, N.M.A. PY - 2014 UR - https://hdl.handle.net/2066/137127 AB - BACKGROUND: Because of the assumed dismal prognosis there is still reluctance to admit haematological patients to the intensive care unit (ICU). This study was conducted to determine trends in outcome of allogeneic haematopoietic stem cell transplant (HSCT) recipients transferred to the intensive care unit in a Dutch tertiary care hospital. METHODS: All patients who received allogeneic HSCT between 2004-2010 were included in the analyses. Baseline and outcome characteristics were compared and risk factors for ICU admission and survival were identified. Changes in outcome over time of three cohorts of HSCT recipients were investigated. RESULTS: Of 319 consecutive HSCT recipients, 49 (15%) were transferred to the ICU for a median (IQR) of 10 (6-45) days following their transplantation, of whom 43% were severely neutropenic and 90% had received systemic immunosuppressive therapy for graft-versus-host disease prophylaxis. Univariate logistic regression showed that transplantation from an unrelated donor and myeloablative conditioning were significant risk factors for ICU admission. Prolonged use of vasopressors, invasive mechanical ventilation and male gender were significant predictors for ICU mortality, while neutropenia and graft-versus-host disease were not. Over the years, APACHE-II severity of illness scores remained unchanged (21.0+/-7.1, 20.1+/-5.6, 21.2+/-6.6), while 100-day post-transplant mortality of patients who had been transferred to the ICU decreased significantly from 78% (2004/2005) to 57% (2006/2007), and 35% (2008/2009). CONCLUSIONS: While for allogeneic HSCT patients the severity of illness on admission to the ICU did not change, the 100-day post-transplant survival improved. These data indicate that reluctance to submit haematological patients to the ICU is not warranted. TI - Trends in the outcomes of Dutch haematological patients receiving intensive care support EP - 112 SN - 0300-2977 IS - iss. 2 SP - 107 JF - Netherlands Journal of Medicine VL - vol. 72 ER - TY - JOUR AU - Oever, J. ten AU - Kox, M. AU - Veerdonk, F.L. van de AU - Mothapo, K.M. AU - Slavcovici, A. AU - Jansen, T.L.Th.A. AU - Tweehuysen, L. AU - Giamarellos-Bourboulis, E.J. AU - Schneeberger, P.M. AU - Wever, P.C. AU - Stoffels, M. AU - Simon, A. AU - Meer, J.W.M. van der AU - Johnson, M.D. AU - Kullberg, B.J. AU - Pickkers, P. AU - Pachot, A. AU - Joosten, L.A. AU - Netea, M.G. PY - 2014 UR - https://hdl.handle.net/2066/138726 AB - BackgroundThe extracellular domains of cytokine receptors are released during inflammation, but little is known about the shedding of Toll-like receptors (TLR) and whether they can be used as diagnostic biomarkers.MethodsThe release of sTLR2 and sTLR4 was studied in in-vitro stimulations, as well as in-vivo during experimental human endotoxemia (n inverted question mark= inverted question mark11, 2 ng/kg LPS), and in plasma of 394 patients with infections (infectious mononucleosis, measles, respiratory tract infections, bacterial sepsis and candidemia) or non-infectious inflammation (Crohn inverted question marks disease, gout, rheumatoid arthritis, autoinflammatory syndromes and pancreatitis). Using C-statistics, the value of sTLR2 and sTLR4 levels for discrimination between infections and non-infectious inflammatory diseases, as well as between viral and bacterial infections was analyzed.ResultsIn-vitro, peripheral blood mononuclear cells released sTLR2 and sTLR4 by exposure to microbial ligands. During experimental human endotoxemia, plasma concentrations peaked after 2 hours (sTLR4) and 4 hours (sTLR2). sTLR4 did not correlate with cytokines, but sTLR2 correlated positively with TNF inverted question mark (rs inverted question mark= inverted question mark0.80, P inverted question mark< inverted question mark0.05), IL-6 (rs inverted question mark= inverted question mark0.65, P inverted question mark< inverted question mark0.05), and IL-1Ra (rs inverted question mark= inverted question mark0.57, P inverted question mark= inverted question mark0.06), and negatively with IL-10 (rs inverted question mark= inverted question mark-0.58, P inverted question mark= inverted question mark0.06), respectively. sTLR4 had a similar area under the ROC curve [AUC] for differentiating infectious and non-infectious inflammation compared to CRP: 0.72 (95% CI 0.66-0.79) versus 0.74 (95% CI 0.69-0.80) [P inverted question mark= inverted question mark0.80], while sTLR2 had a lower AUC: 0.60 (95% CI 0.54-0.66) [P inverted question mark= inverted question mark0.0004]. CRP differentiated bacterial infections better from viral infections than sTLR2 and sTLR4: AUC 0.94 (95% CI 0.90-0.96) versus 0.58 (95% CI 0.51-0.64) and 0.75 (95% CI 0.70-0.80), respectively [P inverted question mark< inverted question mark0.0001 for both].ConclusionssTLRs are released into the circulation, and suggest the possibility to use sTLRs as diagnostic tool in inflammatory conditions. TI - The discriminative capacity of soluble Toll-like receptor (sTLR)2 and sTLR4 in inflammatory diseases SN - 1471-2172 IS - iss. 1 SP - 55 JF - BMC Immunology VL - vol. 15 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138726/138726.pdf?sequence=1 ER - TY - JOUR AU - Delsing, C. AU - Gresnigt, M.S. AU - Leentjens, J. AU - Preijers, F.W. AU - Frager, F.A. AU - Kox, M. AU - Monneret, G. AU - Venet, F. AU - Bleeker-Rovers, C.P. AU - Veerdonk, F.L. van de AU - Pickkers, P. AU - Pachot, A. AU - Kullberg, B.J. AU - Netea, M.G. PY - 2014 UR - https://hdl.handle.net/2066/138333 TI - Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series SN - 1471-2334 SP - 166 JF - BMC Infectious Diseases VL - vol. 14 DO - https://doi.org/10.1186/1471-2334-14-166 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/138333/138333.pdf?sequence=1 ER - TY - JOUR AU - Leentjens, J. AU - Kox, M. AU - Pickkers, P. PY - 2014 UR - https://hdl.handle.net/2066/137250 AB - Sepsis is a major cause of death worldwide. In recent years it has become clear that most septic patients do not die from an overwhelming initial pro-inflammatory immune response, but die in the subsequent immunosuppressive phase, called 'immunoparalysis', which is characterized by increased susceptibility to secondary and opportunistic infections. Although infection control and supportive therapies, especially in the early phase of sepsis, will remain the cornerstone of treatment, the discovery of immunoparalysis and its detrimental effects currently causes a profound shift in the sepsis research field. Hitherto, whereas research into sepsis therapies predominantly focused on suppression of the immune system (for example with anti-cytokine therapies or glucocorticoids), recent studies increasingly concentrate on immunostimulatory treatment. Promising immunostimulatory compounds such as interferon-gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF) have already shown promising results in experimental settings, and are currently studied in clinical trials. TI - [Immunomodulation for sepsis: a change of tack?] SN - 0028-2162 SP - A6859 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 158 ER - TY - JOUR AU - Leentjens, J. AU - Quintin, J. AU - Gerretsen, J. AU - Kox, M. AU - Pickkers, P. AU - Netea, M.G. PY - 2014 UR - https://hdl.handle.net/2066/133902 AB - RATIONALE: To prevent or combat infection, increasing the effectiveness of the immune response is highly desirable, especially in case of compromised immune system function. However, immunostimulatory therapies are scarce, expensive, and often have unwanted side-effects. beta-glucans have been shown to exert immunostimulatory effects in vitro and in vivo in experimental animal models. Oral beta-glucan is inexpensive and well-tolerated, and therefore may represent a promising immunostimulatory compound for human use. METHODS: We performed a randomized open-label intervention pilot-study in 15 healthy male volunteers. Subjects were randomized to either the beta -glucan (n = 10) or the control group (n = 5). Subjects in the beta-glucan group ingested beta-glucan 1000 mg once daily for 7 days. Blood was sampled at various time-points to determine beta-glucan serum levels, perform ex vivo stimulation of leukocytes, and analyze microbicidal activity. RESULTS: beta-glucan was barely detectable in serum of volunteers at all time-points. Furthermore, neither cytokine production nor microbicidal activity of leukocytes were affected by orally administered beta-glucan. CONCLUSION: The present study does not support the use of oral beta-glucan to enhance innate immune responses in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01727895. TI - The effects of orally administered Beta-glucan on innate immune responses in humans, a randomized open-label intervention pilot-study SN - 1932-6203 IS - iss. 9 JF - PLoS One VL - vol. 9 DO - https://doi.org/10.1371/journal.pone.0108794 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/133902/133902.pdf?sequence=1 ER - TY - JOUR AU - Wal, S.E.I. van der AU - Vaneker, M. AU - Kox, M. AU - Braak, G. AU - Hees, H.W.H. van AU - Brink, I. van den AU - Pol, F.M. van de AU - Heunks, L.M.A. AU - Hoeven, J.G. van der AU - Joosten, L.A.B. AU - Vissers, K.C.P. AU - Scheffer, G.J. PY - 2014 UR - https://hdl.handle.net/2066/136061 AB - BACKGROUND: Mechanical ventilation (MV) can result in inflammation and subsequent lung injury. Toll-like receptor (TLR)4 and NF-kappaB are proposed to play a crucial role in the MV-induced inflammatory response. Resveratrol (RVT) exhibits anti-inflammatory effects in vitro and in vivo supposedly by interfering with TLR4 signaling and NF-kappaB. In the present study, we investigated the role of RVT in MV-induced inflammation in mice. METHODS: RVT (10 mg/kg, 20 mg/kg and 40 mg/kg) or vehicle was intraperitoneally administered 1 h before start of MV (4 h, tidal volume 8 ml/kg, positive end-expiratory pressure 1,5 cmH2 O and FiO2 0.4). Blood and lungs were harvested for cytokine analysis. DNA binding activity of transcription factor NF-kappaB was measured in lung homogenates. RESULTS: MV resulted in elevated pulmonary concentrations of IL-1beta, IL-6, keratinocyte-derived chemokine (KC) and NF-kappaB DNA-binding activity. RVT at 10, 20 and 40 mg/kg reduced NF-kappaB's DNA-binding activity following MV compared with ventilated controls. However, no differences in cytokine release were found between RVT-treated and control ventilated mice. Similarly, in plasma, MV resulted in elevated concentrations of TNF-alpha, KC and IL-6, but RVT did not affect cytokine levels. CONCLUSIONS: RVT abrogates the MV-induced increase in pulmonary NF-kappaB activity but does not attenuate cytokine levels. This implies a less prominent role for NF-kappaB in MV-induced inflammation than previously assumed. TI - Resveratrol attenuates NF-kappaB-binding activity but not cytokine production in mechanically ventilated mice EP - 494 SN - 0001-5172 IS - iss. 4 SP - 487 JF - Acta Anaesthesiologica Scandinavica VL - vol. 58 DO - https://doi.org/10.1111/aas.12276 ER - TY - JOUR AU - Brink, I. van den AU - Pol, F. van de AU - Vaneker, M. AU - Kox, M. AU - Schellekens, W.J.M. AU - Ritskes-Hoitinga, M. AU - Scheffer, G.J. PY - 2013 UR - https://hdl.handle.net/2066/118790 AB - Mechanical ventilation is frequently used in patients under general anesthesia during invasive procedures. Invasive animal experiments similarly require the maintenance of normal hemodynamic and pulmonary parameters during long-term general anesthesia. The authors describe a method for mechanical ventilation of mice. Mice were ventilated and monitored for up to 8 h of general anesthesia during surgery. Hemodynamic and pulmonary parameters remained within the normal ranges. The authors believe that this ventilation technique can be of great value for experimental procedures in mice that require general anesthesia. TI - Mechanical ventilation of mice under general anesthesia during experimental procedures EP - 257 SN - 0023-6772 IS - iss. 7 SP - 253 JF - Laboratory Animals VL - vol. 42 ER - TY - JOUR AU - Riksen, N.P. AU - Rongen, G.A. AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/125655 TI - Metformin improves survival in intensive care unit patients, but why? SN - 1466-609X IS - iss. 6 SP - 471 JF - Critical Care VL - vol. 17 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/125655/125655.pdf?sequence=1 ER - TY - JOUR AU - Boogaard, M. van den AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/125694 TI - Hope for haloperidol in delirium SN - 2213-2600 SP - e27 JF - Lancet Respiratory Medicine VL - vol. 1 ER - TY - JOUR AU - Pickkers, P. AU - Hoeven, J.G. van der PY - 2013 UR - https://hdl.handle.net/2066/119053 AB - If an intensive care unit (ICU) is managed by intensivists, the prognosis of critically ill patients improves. Some retrospective analyses of patient databases suggest that critically ill patients admitted to the ICU during off-hours suffer a higher mortality rate compared to patients admitted during office hours. While this suggests that this difference might be related to the presence/absence of experienced intensivists at night, differences in case mix of patients admitted during the day/night may play an important role. Recently, the first prospective randomized controlled trial was published on this issue. Alternating every 7 nights an intensivist was present in the hospital or was available for consultation by telephone. No effect on ICU-length of stay, mortality or any of the secondary end points was found. Despite the compelling face value of nighttime intensivist staffing this practice should not be recommended in the absence of experimental evidence of its effectiveness. TI - [Is nighttime intensivist staffing beneficial?] SN - 0028-2162 IS - iss. 33 SP - A6596 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 157 ER - TY - JOUR AU - Pretorius, D. AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/126270 TI - Statins for Sepsis? SN - 1569-3511 IS - iss. 3 SP - 22 JF - Netherlands Journal of Critical Care VL - vol. 17 ER - TY - JOUR AU - Kox, M. AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/117399 AB - The current view in intensive care medicine is that very sick patients need very intensive treatment. However, in this group of highly vulnerable patients, more intensive treatment may promote the chances of unwanted adverse effects and hence, iatrogenic damage. Therefore, we state that critically ill patients probably benefit from a more cautious approach. Using data from large clinical trials of previous years, we exemplify that less intensive treatment is associated with a better outcome in intensive care patients and suggest that we reappraise patient management as well as trial design in intensive care medicine while bearing in mind the "less is more" paradigm. We illustrate our case by describing the intensity of the most relevant treatment options for patients with septic shock, including mechanical ventilation, fluid management, blood pressure-targeted therapy, corticosteroids, patient monitoring, sedation, and nutrition. We conclude that treatment of critically ill patients while keeping in mind the "less is more" paradigm might not only benefit the patient but could also have a notable impact on the ever-increasing intensive care-related health care costs. TI - "Less is more" in critically ill patients: not too intensive EP - 1372 SN - 2168-6106 IS - iss. 14 SP - 1369 JF - Jama Internal Medicine VL - vol. 173 DO - http://dx.doi.org/10.1001/jamainternmed.2013.6702 ER - TY - JOUR AU - Timmermans, K. AU - Plantinga, T.S. AU - Kox, M. AU - Vaneker, M. AU - Scheffer, G.J. AU - Adema, G.J. AU - Joosten, L.A.B. AU - Netea, M.G. PY - 2013 UR - https://hdl.handle.net/2066/118068 AB - Innate immunity activation largely depends on recognition of microorganism structures by Pattern Recognition Receptors (PRRs). PRR downstream signaling results in production of pro- and anti-inflammatory cytokines and other mediators. Moreover, PRR engagement in antigen-presenting cells initiates the activation of adaptive immunity. Recent reports suggest that for the activation of innate immune responses and initiation of adaptive immunity, synergistic effects between two or more PRRs are necessary. No systematic analysis of the interaction between the major PRR pathways were performed to date. In this study, a systematical analysis of the interactions between PRR signaling pathways was performed. PBMCs derived from 10 healthy volunteers were stimulated with either a single PRR ligand or a combination of two PRR ligands. Known ligands for the major PRR families were used: Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), and RigI-helicases. After 24 h of incubation, production of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta), IL-6, and IL-10 was measured in supernatants by enzyme-linked immunosorbent assay (ELISA). The consistency of the PRR interactions (both inhibitory and synergistic) between the various individuals was assessed. A number of PRR-dependent signaling interactions were found to be consistent, both between individuals and with regard to multiple cytokines. The combinations of TLR2 and NOD2, TLR5 and NOD2, TLR5 and TLR3, and TLR5 and TLR9 acted as synergistic combinations. Surprisingly, inhibitory interactions between TLR4 and TLR2, TLR4 and Dectin-1, and TLR2 and TLR9 as well as TLR3 and TLR2 were observed. These consistent signaling interactions between PRR combinations may represent promising targets for immunomodulation and vaccine adjuvant development. TI - Blueprints of signaling interactions between pattern recognition receptors: implications for the design of vaccine adjuvants EP - 432 SN - 1556-6811 IS - iss. 3 SP - 427 JF - Clinical and Vaccine Immunology VL - vol. 20 DO - http://dx.doi.org/10.1128/CVI.00703-12 ER - TY - JOUR AU - Pop, G.A.M. AU - Bisschops, L.L.A. AU - Iliev, B. AU - Struijk, P.C. AU - Hoeven, J.G. van der AU - Hoedemaekers, C.W.E. PY - 2013 UR - https://hdl.handle.net/2066/118896 AB - Blood viscosity is an important determinant of microvascular hemodynamics and also reflects systemic inflammation. Viscosity of blood strongly depends on the shear rate and can be characterized by a two parameter power-law model. Other major determinants of blood viscosity are hematocrit, level of inflammatory proteins and temperature. In-vitro studies have shown that these major parameters are related to the electrical impedance of blood. A special central venous catheter was developed to measure electrical impedance of blood in-vivo in the right atrium. Considering that blood viscosity plays an important role in cerebral blood flow, we investigated the feasibility to monitor blood viscosity by electrical bioimpedance in 10 patients during the first 3 days after successful resuscitation from a cardiac arrest. The blood viscosity-shear rate relationship was obtained from arterial blood samples analyzed using a standard viscosity meter. Non-linear regression analysis resulted in the following equation to estimate in-vivo blood viscosity (Viscosity(imp)) from plasma resistance (R(p)), intracellular resistance (R(i)) and blood temperature (T) as obtained from right atrium impedance measurements: Viscosity(imp)=(-15.574+15.576R(p)T)SR ((-.138RpT-.290Ri)). This model explains 89.2% (R(2)=.892) of the blood viscosity-shear rate relationship. The explained variance was similar for the non-linear regression model estimating blood viscosity from its major determinants hematocrit and the level of fibrinogen and C-reactive protein (R(2)=.884). Bland-Altman analysis showed a bias between the in-vitro viscosity measurement and the in-vivo impedance model of .04 mPa s at a shear rate of 5.5s(-1) with limits of agreement between -1.69 mPa s and 1.78 mPa s. In conclusion, this study demonstrates the proof of principle to monitor blood viscosity continuously in the human right atrium by a dedicated central venous catheter equipped with an impedance measuring device. No safety problems occurred and there was good agreement with in-vitro measurements of blood viscosity. TI - On-line blood viscosity monitoring in vivo with a central venous catheter, using electrical impedance technique EP - 601 SN - 0956-5663 SP - 595 JF - Biosensors and Bioelectronics VL - vol. 41 DO - http://dx.doi.org/10.1016/j.bios.2012.09.033 ER - TY - JOUR AU - Schutte, D. AU - Zwitserloot, A.M. AU - Houmes, R. AU - Hoog, M. de AU - Draaisma, J.M.T. AU - Lemson, J. PY - 2013 UR - https://hdl.handle.net/2066/126246 AB - BACKGROUND: /st> Asthma is a common disease in children and often develops early in life. This multicentre retrospective case series describe the use and effectiveness of sevoflurane inhalation therapy in a series of children with severe asthma in the paediatric intensive care unit (PICU). METHODS: /st> Seven children ranging from 4 to 13 yr of age admitted to the PICU of two tertiary care hospitals in the Netherlands were included. They all were admitted with the diag-nosis of severe asthma requiring invasive mechanical ventilation and were treated with sevoflurane inhalation therapy. RESULTS: /st> The median (range) Pco2 level at the start, after 2 h, and at the end of sevoflurane treatment were 14 (5.1-24.8), 9.8 (5.4-17.0), and 6.2 (4.5-11.4) kPa (P=0.05) while the median (range) pH was 7.02 (6.97-7.36), 7.18 (7.04-7.35), and 7.43 (7.15-7.47) kPa (P=0.01), respectively. The median (range) peak pressure values declined from 30 (23-56) to 20.4 (14-33) cm H2O (P=0.03). No severe adverse effects besides hypotension, with sufficient response to norepinephrine treatment, were seen. CONCLUSIONS: /st> Sevoflurane inhalation corrects high levels of Pco2 and provides clinical improvement in mechanically ventilated children with life-threatening asthma who fail to respond to conventional treatment. TI - Sevoflurane therapy for life-threatening asthma in children. EP - 970 SN - 0007-0912 IS - iss. 6 SP - 967 JF - British Journal of Anaesthesia VL - vol. 111 N1 - 1 december 2013 DO - http://dx.doi.org/10.1093/bja/aet257 ER - TY - JOUR AU - Eckert, J.K. AU - Kim, Y. J. AU - Kim, J.I. AU - Gurtler, K. AU - Oh, D.Y. AU - Sur, S. AU - Lundvall, L. AU - Hamann, L. AU - Ploeg, A. van der AU - Pickkers, P. AU - Giamarellos-Bourboulis, E. AU - Kubarenko, A.V. AU - Weber, A.N. AU - Kabesch, M. AU - Kumpf, O. AU - An, H.J. AU - Lee, J.O. AU - Schumann, R.R. PY - 2013 UR - https://hdl.handle.net/2066/126091 AB - Lipopolysaccharide (LPS) binding protein (LBP) is an acute-phase protein that initiates an immune response after recognition of bacterial LPS. Here, we report the crystal structure of murine LBP at 2.9 A resolution. Several structural differences were observed between LBP and the related bactericidal/permeability-increasing protein (BPI), and the LBP C-terminal domain contained a negatively charged groove and a hydrophobic "phenylalanine core." A frequent human LBP SNP (allelic frequency 0.08) affected this region, potentially generating a proteinase cleavage site. The mutant protein had a reduced binding capacity for LPS and lipopeptides. SNP carriers displayed a reduced cytokine response after in vivo LPS exposure and lower cytokine concentrations in pneumonia. In a retrospective trial, the LBP SNP was associated with increased mortality rates during sepsis and pneumonia. Thus, the structural integrity of LBP may be crucial for fighting infections efficiently, and future patient stratification might help to develop better therapeutic strategies. TI - The Crystal Structure of Lipopolysaccharide Binding Protein Reveals the Location of a Frequent Mutation that Impairs Innate Immunity EP - 660 SN - 1074-7613 IS - iss. 4 SP - 647 JF - Immunity VL - vol. 39 DO - https://doi.org/10.1016/j.immuni.2013.09.005 ER - TY - JOUR AU - Kolk, A. van der AU - Yang, K.G. AU - Tamminga, R. AU - Hoeven, H. van der PY - 2013 UR - https://hdl.handle.net/2066/125830 AB - The aim of this study was to determine the effect of radial extracorporeal shock-wave therapy (rESWT) on patients with chronic tendinitis of the rotator cuff. This was a randomised controlled trial in which 82 patients (mean age 47 years (24 to 67)) with chronic tendinitis diagnosed clinically were randomly allocated to a treatment group who received low-dose rESWT (three sessions at an interval 10 to 14 days, 2000 pulses, 0.11 mJ/mm(2), 8 Hz) or to a placebo group, with a follow-up of six months. The patients and the treating orthopaedic surgeon, who were both blinded to the treatment, evaluated the results. A total of 44 patients were allocated to the rESWT group and 38 patients to the placebo group. A visual analogue scale (VAS) score for pain, a Constant-Murley (CMS) score and a simple shoulder test (SST) score significantly improved in both groups at three and six months compared with baseline (all p 48 h that received SDD (n=2045), SOD (n=1904) or SC (n=1990). INTERVENTIONS: SDD or SOD. PRIMARY AND SECONDARY OUTCOME MEASURES: Effects were based on hospital survival, expressed as crude Life Years Gained (cLYG). The incremental cost-effectiveness ratio (ICER) was calculated, with corresponding cost acceptability curves. Sensitivity analyses were performed for discount rates, costs of SDD, SOD and mechanical ventilation. RESULTS: Total costs per patient were euro41 941 for SC (95% CI euro40 184 to euro43 698), euro40 433 for SOD (95% CI euro38 838 to euro42 029) and euro41 183 for SOD (95% CI euro39 408 to euro42 958). SOD and SDD resulted in crude LYG of +0.04 and +0.25, respectively, as compared with SC, implying that both SDD and SOD are dominant (ie, cheaper and more beneficial) over SC. In cost-effectiveness acceptability curves probabilities for cost-effectiveness, compared with standard care, ranged from 89% to 93% for SOD and from 63% to 72% for SDD, for acceptable costs for 1 LYG ranging from euro0 to euro20 000. Sensitivity analysis for mechanical ventilation and discount rates did not change interpretation. Yet, if costs of the topical component of SDD and SOD would increase 40-fold to euro400/day and euro40/day (maximum values based on free market prices in 2012), the estimated ICER as compared with SC for SDD would be euro21 590 per LYG. SOD would remain cost-saving. CONCLUSIONS: SDD and SOD were both effective and cost-saving in Dutch ICUs. TI - Selective decontamination of the digestive tract and selective oropharyngeal decontamination in intensive care unit patients: a cost-effectiveness analysis SN - 2044-6055 IS - iss. 3 JF - BMJ Open VL - vol. 3 DO - https://doi.org/10.1136/bmjopen-2012-002529 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/117631/117631.pdf?sequence=1 ER - TY - JOUR AU - Thomas, D AU - Maes, K. AU - Agten, A. AU - Heunks, L.M. AU - Dekhuijzen, R. AU - Decramer, M. AU - Hees, H.W. van AU - Gayan-Ramirez, G. PY - 2013 UR - https://hdl.handle.net/2066/178107 AB - Controlled mechanical ventilation (CMV) is known to result in rapid and severe diaphragmatic dysfunction, but the recovery response of the diaphragm to normal function after CMV is unknown. Therefore, we examined the time course of diaphragm function recovery in an animal model of CMV. Healthy rats were submitted to CMV for 24-27 h (n = 16), or to 24-h CMV followed by either 1 h (CMV + 1 h SB, n = 9), 2 h (CMV + 2 h SB, n = 9), 3 h (CMV + 3 h SB, n = 9), or 4-7 h (CMV + 4-7 h SB, n = 9) of spontaneous breathing (SB). At the end of the experiment, the diaphragm muscle was excised for functional and biochemical analysis. The in vitro diaphragm force was significantly improved in the CMV + 3 h SB and CMV + 4-7 h SB groups compared with CMV (maximal tetanic force: +27%, P < 0.05, and +59%, P < 0.001, respectively). This was associated with an increase in the type IIx/b fiber dimensions (P < 0.05). Neutrophil influx was increased in the CMV + 4-7 h SB group (P < 0.05), while macrophage numbers remained unchanged. Markers of protein synthesis (phosphorylated Akt and eukaryotic initiation factor 4E binding protein 1) were significantly increased (+/-40%, P < 0.001, and +/-52%, P < 0.01, respectively) in the CMV + 3 h SB and CMV + 4-7 h SB groups and were positively correlated with diaphragm force (P < 0.05). Finally, also the maximal specific force generation of skinned single diaphragm fibers was increased in the CMV + 4-7 h SB group compared with CMV (+45%, P < 0.05). In rats, reloading the diaphragm for 3 h after CMV is sufficient to improve diaphragm function, while complete recovery occurs after longer periods of reloading. Enhanced muscle fiber dimensions, increased protein synthesis, and improved intrinsic contractile properties of diaphragm muscle fibers may have contributed to diaphragm function recovery. TI - Time course of diaphragm function recovery after controlled mechanical ventilation in rats EP - 784 SN - 8750-7587 IS - iss. 6 SP - 775 JF - Journal of Applied Physiology VL - vol. 115 DO - https://doi.org/10.1152/japplphysiol.00302.2012 ER - TY - JOUR AU - Nieminen, M.S. AU - Fruhwald, S. AU - Heunks, L.M.A. AU - Suominen, P.K. AU - Gordon, A.C. AU - Kivikko, M. AU - Pollesello, P. PY - 2013 UR - https://hdl.handle.net/2066/125611 AB - Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy. TI - Levosimendan: current data, clinical use and future development EP - 245 SN - 2282-8419 IS - iss. 4 SP - 227 JF - Heart, Lung and Vessels VL - vol. 5 ER - TY - JOUR AU - Boogaard, M. van den AU - Schoonhoven, L. AU - Achterberg, T. van AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/125507 AB - ABSTRACT: INTRODUCTION: Delirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures. METHODS: This study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of >/= 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase. RESULTS: In 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 +/- 19% and 73 +/- 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group. CONCLUSIONS: Our evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial. TRIAL REGISTRATION: clinicaltrial.gov Identifier: NCT01187667. TI - Haloperidol prophylaxis in critically ill patients with a high risk for delirium SN - 1466-609X IS - iss. 1 SP - R9 JF - Critical Care VL - vol. 17 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/125507/125507.pdf?sequence=1 ER - TY - JOUR AU - Jacobs, B. AU - Beems, T. AU - Vliet, T.M. van der AU - Vugt, A.B. van AU - Hoedemaekers, C.W. AU - Horn, J. AU - Franschman, G. AU - Haitsma, I. AU - Naalt, J. van der AU - Andriessen, T.M.J.C. AU - Borm, G.F. AU - Vos, P.E. PY - 2013 UR - http://repository.ubn.ru.nl/handle/2066/127318 AB - BACKGROUND: With this study we aimed to design validated outcome prediction models in moderate and severe traumatic brain injury (TBI) using demographic, clinical, and radiological parameters. METHODS: Seven hundred consecutive moderate or severe TBI patients were included in this observational prospective cohort study. After inclusion, clinical data were collected, initial head computed tomography (CT) scans were rated, and at 6 months outcome was determined using the extended Glasgow Outcome Scale. Multivariate binary logistic regression analysis was applied to evaluate the association between potential predictors and three different outcome endpoints. The prognostic models that resulted were externally validated in a national Dutch TBI cohort. RESULTS: In line with previous literature we identified age, pupil responses, Glasgow Coma Scale score and the occurrence of a hypotensive episode post-injury as predictors. Furthermore, several CT characteristics were associated with outcome; the aspect of the ambient cisterns being the most powerful. After external validation using Receiver Operating Characteristic (ROC) analysis our prediction models demonstrated adequate discriminative values, quantified by the area under the ROC curve, of 0.86 for death versus survival and 0.83 for unfavorable versus favorable outcome. Discriminative power was less for unfavorable outcome in survivors: 0.69. CONCLUSIONS: Outcome prediction in moderate and severe TBI might be improved using the models that were designed in this study. However, conventional demographic, clinical and CT variables proved insufficient to predict disability in surviving patients. The information that can be derived from our prediction rules is important for the selection and stratification of patients recruited into clinical TBI trials. TI - Outcome prediction in moderate and severe traumatic brain injury: a focus on computed tomography variables EP - 89 SN - 1541-6933 IS - iss. 1 SP - 79 JF - Neurocritical Care VL - vol. 19 DO - https://doi.org/10.1007/s12028-012-9795-9 ER - TY - JOUR AU - Oostdijk, E.A. AU - Smet, A.M. de AU - Bonten, M.J. AU - Kalkman, C.J. AU - Joore, C. AU - Hall, M.A. AU - Blok, H.E. AU - Kluytmans, J.A. AU - Meer, J.W.M. van der AU - Mascini, E.M. AU - Kaasjager, K. AU - Bosch, F.H. AU - Benus, R.F. AU - Werf, T.S. van der AU - Arends, J.P. AU - Hoeven, J.G. van der AU - Pickkers, P. AU - Sturm, P.D. AU - Voss, A. AU - Bernards, A.T. AU - Kuijper, E.J. AU - Harinck, H.I. AU - Bindels, A.J. AU - Jansz, A.R. AU - Wesseling, R.M. AU - Jongh, B.M. de AU - Dennesen, P.J. AU - Asselt, G.J. van AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/142734 TI - Effects of decontamination of the digestive tract and oropharynx in intensive care unit patients on 1-year survival EP - 120 SN - 1073-449X IS - iss. 1 SP - 117 JF - American Journal of Respiratory and Critical Care Medicine VL - vol. 188 ER - TY - JOUR AU - Boogaard, M. van den AU - Slooter, A.J. AU - Bruggemann, R.J.M. AU - Schoonhoven, L. AU - Kuiper, M.A. AU - Voort, P.H. van der AU - Hoogendoorn, M.E. AU - Beishuizen, A. AU - Schouten, J.A. AU - Spronk, P.E. AU - Houterman, S. AU - Hoeven, J.G. van der AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/125795 AB - BACKGROUND: Delirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences. Therefore, preventive treatment for delirium may be beneficial. Worldwide, haloperidol is the first choice for pharmacological treatment of delirious patients. In daily clinical practice, a lower dose is sometimes used as prophylaxis. Some studies have shown the beneficial effects of prophylactic haloperidol on delirium incidence as well as on mortality, but evidence for effectiveness in ICU patients is limited. The primary objective of our study is to determine the effect of haloperidol prophylaxis on 28-day survival. Secondary objectives include the incidence of delirium and delirium-related outcome and the side effects of haloperidol prophylaxis. METHODS: This will be a multicenter three-armed randomized, double-blind, placebo-controlled, prophylactic intervention study in critically ill patients. We will include consecutive non-neurological ICU patients, aged >/=18 years with an expected ICU length of stay >1 day. To be able to demonstrate a 15% increase in 28-day survival time with a power of 80% and alpha of 0.05 in both intervention groups, a total of 2,145 patients will be randomized; 715 in each group. The anticipated mortality rate in the placebo group is 12%. The intervention groups will receive prophylactic treatment with intravenous haloperidol 1 mg/q8h or 2 mg/q8h, and patients in the control group will receive placebo (sodium chloride 0.9%), both for a maximum period of 28-days. In patients who develop delirium, study medication will be stopped and patients will subsequently receive open label treatment with a higher (therapeutic) dose of haloperidol. We will use descriptive summary statistics as well as Cox proportional hazard regression analyses, adjusted for covariates. DISCUSSION: This will be the first large-scale multicenter randomized controlled prevention study with haloperidol in ICU patients with a high risk of delirium, adequately powered to demonstrate an effect on 28-day survival. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01785290.EudraCT number: 2012-004012-66. TI - Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial SN - 1745-6215 JF - Trials VL - vol. 14 DO - https://doi.org/10.1186/1745-6215-14-400 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/125795/125795.pdf?sequence=1 ER - TY - JOUR AU - Goeij, M. de AU - Eijk, L.T.G.J. van AU - Vanelderen, P. AU - Wilder-Smith, O.H.G. AU - Vissers, K.C.P. AU - Hoeven, J.G. van der AU - Kox, M. AU - Scheffer, G.J. AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/126296 AB - BACKGROUND: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods. METHODS AND RESULTS: Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-alpha, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20+/-4 % and 13+/-3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7+/-3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques. CONCLUSIONS AND SIGNIFICANCE: In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception. TI - Systemic inflammation decreases pain threshold in humans in vivo SN - 1932-6203 IS - iss. 12 JF - PLoS One VL - vol. 8 DO - https://doi.org/10.1371/journal.pone.0084159 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/126296/126271.pdf?sequence=1 ER - TY - JOUR AU - Kiers, H.D. AU - Boogaard, M.H.W.A. van den AU - Schoenmakers, M.C.J. AU - Hoeven, J.G. van der AU - Swieten, H.A. van AU - Heemskerk, S. AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/118182 AB - BACKGROUND: Cardiac surgery-related acute kidney injury (CS-AKI) results in increased morbidity and mortality. Different models have been developed to identify patients at risk of CS-AKI. While models that predict dialysis and CS-AKI defined by the RIFLE criteria are available, their predictive power and clinical applicability have not been compared head to head. METHODS: Of 1388 consecutive adult cardiac surgery patients operated with cardiopulmonary bypass, risk scores of eight prediction models were calculated. Four models were only applicable to a subgroup of patients. The area under the receiver operating curve (AUROC) was calculated for all levels of CS-AKI and for need for dialysis (AKI-D) for each risk model and compared for the models applicable to the largest subgroup (n = 1243). RESULTS: The incidence of AKI-D was 1.9% and for CS-AKI 9.3%. The models of Rahmanian, Palomba and Aronson could not be used for preoperative risk assessment as postoperative data are necessary. The three best AUROCs for AKI-D were of the model of Thakar: 0.93 [95% confidence interval (CI) 0.91-0.94], Fortescue: 0.88 (95% CI 0.87-0.90) and Wijeysundera: 0.87 (95% CI 0.85-0.89). The three best AUROCs for CS-AKI-risk were 0.75 (95% CI 0.73-0.78), 0.74 (95% CI 0.71-0.76) and 0.70 (95% CI 0.73-0.78), for Thakar, Mehta and both Fortescue and Wijeysundera, respectively. The model of Thakar performed significantly better compared with the models of Mehta, Rahmanian, Fortescue and Wijeysundera (all P-values <0.01) at different levels of severity of CS-AKI. CONCLUSIONS: The Thakar model offers the best discriminative value to predict CS-AKI and is applicable in a preoperative setting and for all patients undergoing cardiac surgery. TI - Comparison and clinical suitability of eight prediction models for cardiac surgery-related acute kidney injury EP - 351 SN - 0931-0509 IS - iss. 2 SP - 345 JF - Nephrology, Dialysis, Transplantation VL - vol. 28 ER - TY - JOUR AU - Lubbers, T. AU - Kox, M. AU - Haan, J.J. de AU - Greve, J.W. AU - Pompe, J.C. AU - Ramakers, B.P.C. AU - Pickkers, P. AU - Buurman, W.A. PY - 2013 UR - https://hdl.handle.net/2066/118213 AB - OBJECTIVE: : An overzealous inflammatory response is an important cause of morbidity and mortality in surgical, trauma, and critically ill patients. Enteral administration of lipid-rich nutrition was previously shown to attenuate inflammation and reduce organ damage via a cholecystokinin-1 receptor-mediated vagovagal reflex in animal studies. The current preclinical study investigates the immunomodulatory potential of a custom-made enteral nutrition during systemic inflammation in man. DESIGN: : Double-blind, randomized controlled trial. SETTING: : Intensive care research unit. SUBJECTS: : Male volunteers. INTERVENTIONS: : After an overnight fast, 18 healthy male subjects received an IV bolus of Escherichia coli lipopolysaccharide (2 ng/kg). Subjects in the fasted group (n = 6) were deprived of food throughout the study, while subjects in the intervention groups were fed either custom-made lipid- and protein-rich nutrition (n = 6) or isocaloric control nutrition (n = 6) via nasojejunal tube, starting 1 hour prior to lipopolysaccharide administration until 6 hours afterward. MEASUREMENTS AND MAIN RESULTS: : Bolus lipopolysaccharide administration resulted in a marked inflammatory response. Continuous postpyloric administration of nutrition significantly increased plasma cholecystokinin levels throughout the lipopolysaccharide-induced inflammatory response. Lipid- and protein-rich nutrition attenuated circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 and the interleukin-1 receptor antagonist compared with control nutrition (all p < 0.05) and fasted subjects (all p < 0.05). In additional, lipid- and protein-rich nutrition augmented the anti-inflammatory response, reflected by increased plasma levels of interleukin-10 compared with fasted subjects (p < 0.0001). CONCLUSIONS: : The current preclinical study expands the immunomodulating effects of enteral nutrition as previously observed in rodents to man. Continuous administration of enteral nutrition resulted in a rapid anti-inflammatory effect. Furthermore, enrichment of the nutritional composition with lipid and protein was shown to enhance the anti-inflammatory potential. Therefore, continuous enteral administration of lipid- and protein-rich nutrition is a promising intervention to modulate the immune response in the early course of systemic inflammation in man. TI - Continuous administration of enteral lipid- and protein-rich nutrition limits inflammation in a human endotoxemia model EP - 1265 SN - 0090-3493 IS - iss. 5 SP - 1258 JF - Critical Care Medicine VL - vol. 41 DO - https://doi.org/10.1097/CCM.0b013e31827c0a17 ER - TY - JOUR AU - Nusmeier, A. AU - Vrancken, S.L. AU - Boode, W.P. de AU - Hoeven, J.G. van der AU - Lemson, J. PY - 2013 UR - https://hdl.handle.net/2066/117883 AB - BACKGROUND: /st> The transpulmonary thermodilution (TPTD) technique is widely used in clinical practice for measuring cardiac output (CO). This study was designed to investigate the influence of various levels of pulmonary oedema on the reliability of CO measurements by the TPTD method. METHODS: /st> In 11 newborn lambs pulmonary oedema was induced using a surfactant washout technique. Serial CO measurements using TPTD (COTPTD) were performed at various amounts of lung water. Simultaneously, CO was measured by an ultrasound flow probe around the main pulmonary artery (COMPA) and used as the standard reference. CO was divided by the body surface area to calculate cardiac index (CI). Data were analysed using correlational statistics and Bland-Altman analysis. RESULTS: /st> One lamb died prematurely. A total of 56 measurements in 10 lambs were analysed with a median CIMPA of 2.95 (IQR 1.04) litre min(-1) m(-2). Mean percentage increase in extravascular lung water (EVLW) between the start and the end of the study was 126.4% (sd 40.4). Comparison of the two CO methods showed a mean bias CI of -0.16 litre min(-1) m(-2) (limits of agreement +/-0.73 litre min(-1) m(-2)) and a percentage error of 23.8%. Intraclass correlation coefficients were 0.91 (95% CI 0.81-0.95) for absolute agreement and 0.92 (95% CI 0.87-0.95) for consistency. Acceptable agreement was confirmed by a tolerability-agreement ratio of 0.39. The within-subject correlation between the amount of EVLWI and the bias between the two methods was not significant (-0.02; P=0.91). CONCLUSIONS: /st> CO measurements by the transpulmonary thermodilution technique over a wide range of CI values are not affected by the presence of high EVLWI. The slight underestimation of the CO is independent of the amount of pulmonary oedema. TI - Transpulmonary thermodilution cardiac output measurement is not affected by severe pulmonary oedema: a newborn animal study EP - 292 SN - 0007-0912 IS - iss. 2 SP - 286 JF - British Journal of Anaesthesia VL - vol. 111 DO - https://doi.org/10.1093/bja/aet021 ER - TY - JOUR AU - Boode, W.P. de AU - Vrancken, S.L.A.G. AU - Lemson, J. AU - Nusmeier, A. AU - Tibby, S.M. PY - 2013 UR - https://hdl.handle.net/2066/119288 TI - Gold standard must be solid gold. EP - 1331 SN - 0342-4642 IS - iss. 7 SP - 1330 JF - Intensive Care Medicine VL - vol. 39 N1 - 1 juli 2013 DO - https://doi.org/10.1007/s00134-013-2924-x ER - TY - JOUR AU - Ulden-Bleumink, W.M. van AU - Dom, P.G. AU - Ramakers, B.P.C. AU - Adrichem, N.P. van PY - 2013 UR - https://hdl.handle.net/2066/186322 AB - A pure leiomyoma of the prostate is a rare benign tumor. An 82-year-old man was referred to our urology department with gross hematuria and complete urinary retention. Examination revealed a benign prostatic hyperplasia. Transrectal ultrasound showed a prostate of 125 mL. Serum PSA was 1.9 microg/L. A simple retropubic prostatectomy was performed. Histopathological examination showed a pure leiomyoma of the prostate, without the presence of glandular prostate tissue. The diagnosis, characteristics, and treatment of this tumor are described. TI - A rare prostatic diagnosis of an old man: a pure prostatic leiomyoma SN - 2090-696X SP - 741235 JF - Case Reports in Urology VL - vol. 2013 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/186322/186322.pdf?sequence=1 ER - TY - JOUR AU - Sluisveld, P.H. van AU - Zegers, M. AU - Westert, G.P. AU - Hoeven, J.G. van der AU - Wollersheim, H.C. PY - 2013 UR - https://hdl.handle.net/2066/118558 AB - BACKGROUND: To use intensive care unit (ICU) facilities efficiently and ensure high quality of care, an optimal patient flow is necessary. Discharging patients relieves the pressure on ICU beds but the risk of premature discharge must be managed carefully. Suboptimal patient discharge may result in ICU readmissions and in patients' death.The aim of this study is to obtain insight into the safety and efficiency of current ICU discharge practices and into barriers and facilitators to the implementation of effective ICU discharge interventions, and to develop an implementation strategy tailored to the barriers and facilitators identified. METHODS/DESIGN: This study exists of five phases. Phase A: analysis of routinely registered data on variation in ICU readmissions and hospital mortality after ICU discharge of all ICUs participating in the Dutch National Intensive Care Evaluation registry (n=83). Phase B: systematic review of effective interventions aiming to improve the efficiency and safety of the ICU discharge process. Phase C: assessing the intervention adherence with a questionnaire survey among all Dutch ICUs (n=90). Phase D: assessing barriers and facilitators to the implementation of effective ICU discharge interventions with a questionnaire survey among all Dutch intensivists (n=700). The questionnaire will be based on barriers and facilitators identified by focus groups (n=4) and individual interviews with professionals of ICUs and general wards and adult discharged ICU patients (n=25 to 30). Phase E: systematic development of an implementation strategy based on the sampled data in phase A to D, and effective implementation strategies from the literature using the intervention mapping method. DISCUSSION: Using theory and empirical data, an implementation strategy will be developed to improve the safety and efficiency of the ICU discharge process. The developed strategy will be evaluated in a subsequent study. The knowledge obtained in this study should be used for further implementation of ICU discharge interventions, and can be used for implementation of handover interventions in other healthcare transition settings. TI - A strategy to enhance the safety and efficiency of handovers of ICU patients: study protocol of the pICUp study EP - 67 SN - 1748-5908 SP - 67 JF - Implementation Science VL - vol. 8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/118558/118558.pdf?sequence=1 ER - TY - THES AU - Nusmeier, A. PY - 2013 SN - 9789057501135 UR - https://hdl.handle.net/2066/117512 PB - [S.l. : s.n.] TI - Advanced hemodynamic monitoring in children N1 - Radboud Universiteit Nijmegen, 28 november 2013 N1 - Promotor : Hoeven, J.G. van der Co-promotores : Lemson, J., Boode, W.P. de L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/117512/117512.pdf?sequence=1 ER - TY - JOUR AU - Lansdorp, B. AU - Putten, M. van der AU - Keijzer, A. de AU - Pickkers, P. AU - Oostrom, J. van PY - 2013 UR - https://hdl.handle.net/2066/128626 TI - A Mathematical Model for the Prediction of Fluid Responsiveness EP - 62 SN - 1869-408X IS - iss. 1 SP - 53 JF - Cardiovascular Engineering and Technology VL - vol. 4 ER - TY - JOUR AU - Moviat, M. AU - Boogaard, M. van den AU - Intven, F. AU - Voort, P. van der AU - Hoeven, H. van der AU - Pickkers, P. PY - 2013 UR - https://hdl.handle.net/2066/126275 AB - PURPOSE: This study aimed to describe Stewart parameters in critically ill patients with an apparently normal acid-base state and to determine the incidence of mixed metabolic acid-base disorders in these patients. MATERIALS AND METHODS: We conducted a prospective, observational multicenter study of 312 consecutive Dutch intensive care unit patients with normal pH (7.35