Papers by Arthur Van Zanten
JAMA
IMPORTANCE The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncer... more IMPORTANCE The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from −1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, −1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, −0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days.
Excluded studies of enteral versus parenteral nutrition. (PDF 109 kb)
Subgroup analysis comparing the effect of enteral versus parenteral nutrition on infectious compl... more Subgroup analysis comparing the effect of enteral versus parenteral nutrition on infectious complications in newer versus older trials (with the publication date 1995 as cutoff). CI confidence interval, EN enteral nutrition, M-H Mantel-Haenszel test, PN parenteral nutrition. (PDF 88 kb)
Subgroup analysis comparing the effect of enteral versus parenteral nutrition according to the ca... more Subgroup analysis comparing the effect of enteral versus parenteral nutrition according to the caloric intake on length of intensive care unit stay (N = 4 studies). Panel A shows the subgroup of aggregated trials in which the caloric intake in the PN group was significantly higher than in the EN group, Panel B shows the subgroup of aggregated trials in which the PN and EN groups received similar caloric intake and Panel C including one trial where caloric intake was not reported. CI confidence interval, EN enteral nutrition, M-H Mantel-Haenszel test, PN parenteral nutrition. Figure A2. Subgroup analysis comparing the effect of enteral versus parenteral nutrition on length of hospital stay according to the caloric intake (N = 7 studies). Panel A shows the subgroup of aggregated trials in which the caloric intake in the PN group was significantly higher than in the EN group, Panel B shows the subgroup of aggregated trials in which the PN and EN groups received similar caloric intake a...
British Journal of General Practice, 2022
Background: Recognising patients who need immediate hospital treatment for sepsis while simultane... more Background: Recognising patients who need immediate hospital treatment for sepsis while simultaneously limiting unnecessary referrals is challenging for GPs. Aim: Develop and validate a sepsis prediction model for adult patients in primary care. Design and setting: Prospective cohort study in four out-of-hours primary care services in the Netherlands, between June 2018 and March 2020. Method: Acutely ill adult patients who received home visits were included. Nine clinical variables were candidate predictors, next to the biomarkers C-reactive protein, procalcitonin, and lactate. The primary endpoint was sepsis within 72 hours of inclusion, as established by an expert panel. Multivariable logistic regression with backwards selection was used to design an optimal model with continuous clinical variables. The added value of the biomarkers was evaluated. Subsequently, a simple model using single cutoff points of continuous variables was developed and externally validated in two emergency...
Full list of inclusion and exclusion criteria, product composition of control (SHPF) and test (VH... more Full list of inclusion and exclusion criteria, product composition of control (SHPF) and test (VHPF) products, descriptive statistics on protein intake at day 5, intake from parenteral nutrition, gastrointestinal parameters per day, number (k) and incidence (n) of (S)AEs per body system. (DOCX 45 kb)
Clinical pharmacokinetics, Jun 9, 2015
Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of i... more 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. 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). A two-compartment model best fitted the data. Clearance was 0...
Cahiers de Nutrition et de Diététique, 2013
Journal of Parenteral and Enteral Nutrition, 2012
European Journal of Anaesthesiology, 2010
To study the characteristics of patients dying in the ICU, dying after ICU treatment during the s... more To study the characteristics of patients dying in the ICU, dying after ICU treatment during the same hospitalization period in general wards and post-ICU hospital survivors. In addition, causes of death and post-ICU mortality (PICUM) predictors were addressed. The present study is a retrospective single centre cohort study in a mixed medical-surgical 12-bed ICU. Patients were divided into three groups: ICU deaths, post-ICU deaths and hospital survivors. Causes of death were determined by an independent review panel of three intensive care physicians. Daly&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s mortality prediction model was applied in retrospect to evaluate risk of PICUM. Other predictors were also tested for predictive value. In total, 405 patients were included: 146 ICU deaths, 92 post-ICU deaths and 167 survivors (random computerized sample from 680 survivors). ICU mortality was 16.3% and PICUM 10.3%. Sepsis was the most common cause of death in both ICU deaths (48.3%) and post-ICU deaths (30.1%). Multivariate analysis identified age, comorbidities, length of stay in ICU, Acute Physiology and Chronic Health Evaluation II score and a do-not-resuscitate code as independent predictors of PICUM. Based on Daly&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s mortality prediction model, 63% of patients were discharged with a high risk of PICUM. Of these, 51% actually died. Specificity was low. Causes of deaths were equally distributed among study groups, except for sepsis. Sepsis was more frequently encountered among ICU deaths. Five PICUM predictors were found: age, Acute Physiology and Chronic Health Evaluation II score, length of ICU stay, do-not-resuscitate code and comorbidities. A do-not-resuscitate code during the first 24 h after admission was the most important predictor of PICUM. Prospective research is warranted to evaluate the applicability of PICUM prediction models in individual ICU patients.
Critical Care Medicine, 2009
Critical Care Medicine, 2012
American Journal of Critical Care, 2010
Nutrition (ASPEN) Clinical Guidelines for Critical Care in collaboration with SCCM. www.nutrition... more Nutrition (ASPEN) Clinical Guidelines for Critical Care in collaboration with SCCM. www.nutritioncare .org (requires set up of free account for access). • AACN Procedure Manual for Critical Care, 5th ed. Procedure 142, Enteral Nutrition: 1142-1149. Available at www.aacn.org (product #128150). T here is evidence to support the early initiation of enteral feedings in critically ill patients to improve outcomes. However, concern about possible ischemia of the gut and fear that the oxygen demand related to feeding could cause stress on oxygen delivery have supported hemodynamic instability as a relative contraindication to early feeding.
JAMA, 2014
IMPORTANCE Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty ac... more IMPORTANCE Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients. DESIGN, SETTING, AND PARTICIPANTS The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations. INTERVENTIONS High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions. RESULTS There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups. CONCLUSIONS AND RELEVANCE Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients. TRIAL REGISTRATION trialregister.nl Identifier: NTR2181.
Critical Care
Background: Optimal energy and protein provision through enteral nutrition is essential for criti... more Background: Optimal energy and protein provision through enteral nutrition is essential for critically ill patients. However, in clinical practice, the intake achieved is often far below the recommended targets. Because no polymeric formula with sufficient protein content is available, adequate protein intake can be achieved only by supplemental amino acids or semi-elemental formula administration. In the present study, we investigated whether protein intake can be increased with a new, very high intact-protein formula (VHPF) for enteral feeding. Methods: In this randomized, controlled, double-blind, multicenter trial, 44 overweight (body mass index ≥ 25 kg/m 2) intensive care unit patients received either a VHPF (8 g/100 kcal) or a commercially available standard high protein formula (SHPF) (5 g/100 kcal). Protein and energy intake, gastrointestinal tolerance (gastric residual volume, vomiting, diarrhea, and constipation), adverse events, and serious adverse events were recorded. Total serum amino acid levels were measured at baseline and day 5. Results: The primary outcome, protein intake at day 5, was 1.49 g/kg body weight (95% CI 1.21-1.78) and 0.76 g/kg body weight (95% CI 0.49-1.03, P < 0.001) for VHPF and SHPF, respectively. Daily protein intake was statistically significantly higher in the VHPF group compared with the SHPF group from day 2 to day 10. Protein intake in the VHPF group as a percentage of target (1.5 g/kg ideal body weight) was 74.7% (IQR 53.2-87.6%) and 111.6% (IQR 51.7-130.7%) during days 1-3 and days 4-10, respectively. Serum amino acid concentrations were higher at day 5 in the VHPF group than in the SHPF group (P = 0.031). No differences were found in energy intake, measures of gastrointestinal tolerance, and safety. Conclusions: Enteral feeding with VHPF (8 g/100 kcal) resulted in higher protein intake and plasma amino acid concentrations than an isocaloric SHPF (5 g/100 kcal), without an increase in energy intake. This VHPF facilitates feeding according to nutritional guidelines and is suitable as a first-line nutritional treatment for critically ill overweight patients. Trial registration: Netherlands Trial Register, NTR5643. Registered on
New Zealand medical journal (Print), Oct 27, 2006
Coma can be a challenging diagnosis for the critical care doctor, especially in alcoholic patient... more Coma can be a challenging diagnosis for the critical care doctor, especially in alcoholic patients. We report a case of a 55-year-old male patient in whom the diagnosis of the coma was initially unclear and only discovered with magnetic resonance imaging (MRI).
Critical Care
The preferential use of the oral/enteral route in critically ill patients over gut rest is unifor... more The preferential use of the oral/enteral route in critically ill patients over gut rest is uniformly recommended and applied. This article provides practical guidance on enteral nutrition in compliance with recent American and European guidelines. Low-dose enteral nutrition can be safely started within 48 h after admission, even during treatment with small or moderate doses of vasopressor agents. A percutaneous access should be used when enteral nutrition is anticipated for ≥ 4 weeks. Energy delivery should not be calculated to match energy expenditure before day 4–7, and the use of energy-dense formulas can be restricted to cases of inability to tolerate full-volume isocaloric enteral nutrition or to patients who require fluid restriction. Low-dose protein (max 0.8 g/kg/day) can be provided during the early phase of critical illness, while a protein target of > 1.2 g/kg/day could be considered during the rehabilitation phase. The occurrence of refeeding syndrome should be assess...
Western Journal of Emergency Medicine
Introduction: Despite widespread implementation of the Early Warning Score (EWS) in hospitals, it... more Introduction: Despite widespread implementation of the Early Warning Score (EWS) in hospitals, its effect on patient outcomes remains mostly unknown. We aimed to evaluate associations between the initial EWS and in-hospital mortality, intensive care unit (ICU) admission, and hospital length of stay (LOS). Methods: We performed a retrospective cohort study of adult patients admitted to a general hospital ward between July 1, 2014–December 31, 2017. Data were obtained from electronic health records (EHR). The primary outcome was in-hospital mortality. Secondary outcomes were ICU admission and hospital LOS. We categorized patients into three risk groups (low, medium or high risk of clinical deterioration) based on EWS. Descriptive analyses were used. Results: After applying inclusion and exclusion criteria, we included 53,180 patients for analysis. We found that the initial (low- vs high-risk) EWS was associated with an increased in-hospital mortality (1.5% vs 25.3%, P <0.001), an i...
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Papers by Arthur Van Zanten