Publications by authors named "Arthur R H van Zanten"

88 Publications

Evaluation of the Initial General Ward Early Warning Score and ICU Admission, Hospital Length of Stay and Mortality.

West J Emerg Med 2021 Sep 2;22(5):1131-1138. Epub 2021 Sep 2.

Gelderse Vallei Hospital, Department of Intensive Care Medicine, Ede, The Netherlands.

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 increased ICU admission rate (3.1% vs 17.6%, P <0.001), and an extended hospital LOS (4.0 days vs 8.0 days, P <0.001).

Conclusion: Our findings suggest that an initial high-risk EWS in patients admitted to a general hospital ward was associated with an increased risk of in-hospital mortality, ICU admission, and prolonged hospital LOS. Close monitoring and precise documentation of the EWS in the EHR may facilitate predicting poor outcomes in individual hospitalized patients and help to identify patients for whom timely and adequate management may improve outcomes.
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http://dx.doi.org/10.5811/westjem.2021.6.50657DOI Listing
September 2021

Early high-dose vitamin C in post-cardiac arrest syndrome (VITaCCA): study protocol for a randomized, double-blind, multi-center, placebo-controlled trial.

Trials 2021 Aug 18;22(1):546. Epub 2021 Aug 18.

Department of Intensive Care Medicine, Research VUmc Intensive Care (REVIVE), Amsterdam Cardiovascular Science (ACS), Amsterdam Infection and Immunity Institute (AI&II), Amsterdam Medical Data Science (AMDS), Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Background: High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients.

Methods: This is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations.

Discussion: Vitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest.

Trial Registration: ClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662 European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL.
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http://dx.doi.org/10.1186/s13063-021-05483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371424PMC
August 2021

Case series of four secondary mucormycosis infections in COVID-19 patients, the Netherlands, December 2020 to May 2021.

Euro Surveill 2021 06;26(23)

Center for Infectious Disease Research, Diagnostics and Laboratory Surveillance National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

We describe four secondary fungal infections caused by Mucorales species in COVID-19 patients. Three COVID-19 associated mucormycosis (CAM) occurred in ICU, one outside ICU. All were men aged > 50 years, three died. Clinical presentations included pulmonary, rhino-orbital cerebral and disseminated infection. Infections occurred in patients with and without diabetes mellitus. CAM is an emerging disease and our observations underscore the need to be aware of invasive mucormycosis, including in COVID-19 patients without (poorly controlled) diabetes mellitus and outside ICU.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.23.2100510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193993PMC
June 2021

Development of a clinical prediction rule for sepsis in primary care: protocol for the TeSD-IT study.

Diagn Progn Res 2020 6;4:12. Epub 2020 Aug 6.

Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: Early recognition and treatment of sepsis is crucial to prevent detrimental outcomes. General practitioners (GPs) are often the first healthcare providers to encounter seriously ill patients. The aim of this study is to assess the value of clinical information and additional tests to develop a clinical prediction rule to support early diagnosis and management of sepsis by GPs.

Methods: We will perform a diagnostic study in the setting of out-of-hours home visits in four GP cooperatives in the Netherlands. Acutely ill adult patients suspected of a serious infection will be screened for eligibility by the GP. The following candidate predictors will be prospectively recorded: (1) age, (2) body temperature, (3) systolic blood pressure, (4) heart rate, (5) respiratory rate, (6) peripheral oxygen saturation, (7) mental status, (8) history of rigors, and (9) rate of progression. After clinical assessment by the GP, blood samples will be collected in all patients to measure C-reactive protein, lactate, and procalcitonin. All patients will receive care as usual. The primary outcome is the presence or absence of sepsis within 72 h after inclusion, according to an expert panel. The need for hospital treatment for any indication will be assessed by the expert panel as a secondary outcome. Multivariable logistic regression will be used to design an optimal prediction model first and subsequently derive a simplified clinical prediction rule that enhances feasibility of using the model in daily clinical practice. Bootstrapping will be performed for internal validation of both the optimal model and simplified prediction rule. Performance of both models will be compared to existing clinical prediction rules for sepsis.

Discussion: This study will enable us to develop a clinical prediction rule for the recognition of sepsis in a high-risk primary care setting to aid in the decision which patients have to be immediately referred to a hospital and who can be safely treated at home. As clinical signs and blood samples will be obtained prospectively, near-complete data will be available for analyses. External validation will be needed before implementation in routine care and to determine in which pre-hospital settings care can be improved using the prediction rule.

Trial Registration: The study is registered in the Netherlands Trial Registry (registration number NTR7026).
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http://dx.doi.org/10.1186/s41512-020-00080-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409626PMC
August 2020

Exposure Variability and Target Attainment of Vancomycin: A Systematic Review Comparing Intermittent and Continuous Infusion.

Ther Drug Monit 2020 06;42(3):381-391

Department of Intensive Care, Gelderse Vallei Hospital, Ede, the Netherlands.

Background: Studies comparing the clinical outcomes between vancomycin intermittent infusion (InI) and continuous infusion (CoI) treated patients are generally underpowered. Moreover, due to large differences in the design and efficacy end points in these studies, a meta-analysis of the currently available data is not feasible. Therefore, this systematic review aimed to compare the exposure variability and target attainment with vancomycin during InI and CoI.

Patients And Methods: A literature search was performed, and clinical studies reporting on vancomycin-treated populations were selected. After exclusion of reviews, case reports, and articles not published in the English language, 505 articles were screened for reported data on vancomycin serum concentrations. A total of 34 studies were included in the review. Relative standard deviations reported in the included studies were assessed, and vancomycin serum concentration variability and target attainment were compared between vancomycin InI and CoI.

Results: The variability in serum concentrations was significantly larger for InI than for CoI (relative standard deviations 46.5% and 32.1%, respectively; P = 0.001). Notably, variability appeared to be independent of the study population or design. Studies directly comparing target attainment between both modes of administration denoted higher and faster target attainment with CoI in all instances.

Conclusions: In conclusion, CoI was associated with lower variabilities in the serum concentration and favorable target attainment rates compared with InI. These findings are important because vancomycin exposure is considered a major predictor of the patients' clinical outcomes. However, the role of lower serum concentration variability and higher target attainment rates in achieving better clinical outcomes needs to be evaluated in patients treated with vancomycin CoI compared with InI.
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http://dx.doi.org/10.1097/FTD.0000000000000755DOI Listing
June 2020

Mitochondrial Dysfunction in Critical Illness: Implications for Nutritional Therapy.

Curr Nutr Rep 2019 12;8(4):363-373

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede, The Netherlands.

Purpose Of The Review: This paper will review the evidence for mitochondrial dysfunction in critical illness, describe the mechanisms which lead to multiple organ failure, and detail the implications of this pathophysiologic process on nutritional therapy.

Recent Findings: Mitochondria are particularly sensitive to increased oxidative stress in critical illness. The functional and structural abnormalities which occur in this organelle contribute further to the excessive production of reactive oxygen species and the reduction in generation of adenosine triphosphate (ATP). To reduce metabolic demand, mitochondrial dysfunction develops (a process likened to hibernation), which helps sustain the life of the cell at a cost of organ system failure. Aggressive feeding in the early phases of critical illness might inappropriately increase demand at a time when ATP production is limited, further jeopardizing cell survival and potentiating the processes leading to multiple organ failure. Several potential therapies exist which would promote mitochondrial function in the intensive care setting through support of autophagy, antioxidant defense systems, and the biogenesis and recovery of the organelle itself. Nutritional therapy should supplement micronutrients required in the mitochondrial metabolic pathways and provide reduced delivery of macronutrients through slower advancement of feeding in the early phases of critical illness. A better understanding of mitochondrial dysfunction in the critically ill patient should lead to more innovative therapies in the future.
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http://dx.doi.org/10.1007/s13668-019-00296-yDOI Listing
December 2019

Metabolic support in the critically ill: a consensus of 19.

Crit Care 2019 09 18;23(1):318. Epub 2019 Sep 18.

Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, 1070, Brussels, Belgium.

Metabolic alterations in the critically ill have been studied for more than a century, but the heterogeneity of the critically ill patient population, the varying duration and severity of the acute phase of illness, and the many confounding factors have hindered progress in the field. These factors may explain why management of metabolic alterations and related conditions in critically ill patients has for many years been guided by recommendations based essentially on expert opinion. Over the last decade, a number of randomized controlled trials have been conducted, providing us with important population-level evidence that refutes several longstanding paradigms. However, between-patient variation means there is still substantial uncertainty when translating population-level evidence to individuals. A cornerstone of metabolic care is nutrition, for which there is a multifold of published guidelines that agree on many issues but disagree on others. Using a series of nine questions, we provide a review of the latest data in this field and a background to promote efforts to address the need for international consistency in recommendations related to the metabolic care of the critically ill patient. Our purpose is not to replace existing guidelines, but to comment on differences and add perspective.
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http://dx.doi.org/10.1186/s13054-019-2597-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751850PMC
September 2019

Mid-arm circumference method is invalid to estimate the body weight of elderly Emergency Department patients in the Netherlands.

Medicine (Baltimore) 2019 Aug;98(32):e16722

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede.

In the Emergency Department (ED) actual body weight (ABW) is essential for accurate drug dosing. Frequently, the ABW is unknown and direct measurement troublesome. A method using the mid-arm circumference (MAC) to estimate ABW has been developed and validated in the United States of America (USA). This study aimed to validate the MAC-formula for estimating ABW in the Dutch population and compare its performance within the American population.Data were obtained from the Dutch National Institute for Public Health and the Environment (RIVM) and extracted from the American National Health and Nutrition Examination Survey (NHANES) datasets. We included all subjects' ≥70 years whose MAC and weight were recorded and obtained additional anthropometric data. We used the equation: kg = 4 × MAC-50 to estimate the ABW of all subjects and compared results.We retrieved 723 and 972 subjects from the Dutch and American dataset, respectively. The MAC is better correlated with ABW in the American dataset when compared with the Dutch dataset (Pearson r = 0.84 and 0.68, respectively). Bland-Altman bias was -7.49 kg (Limits-of-Agreement [LOA] -27.5 to 12.27 kg) and -0.50 kg (LOA -20.99 to 19.99 kg) in the Dutch and American datasets, respectively.The MAC based formula to estimate ABW is a promising tool for the elderly American population. However it is not accurate within the Dutch elderly ED population. Consequently, it is not applicable to Dutch EDs. This study highlights that the results of anthropometric studies performed within the USA are not per se generalizable to the European population.
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http://dx.doi.org/10.1097/MD.0000000000016722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709104PMC
August 2019

A multicenter, randomized, double-blind study of ulimorelin and metoclopramide in the treatment of critically ill patients with enteral feeding intolerance: PROMOTE trial.

Intensive Care Med 2019 05 6;45(5):647-656. Epub 2019 May 6.

Lyric Pharmaceuticals, San Francisco, CA, USA.

Purpose: Enteral feeding intolerance (EFI) is a frequent problem in the intensive care unit (ICU), but current prokinetic agents have uncertain efficacy and safety profiles. The current study compared the efficacy and safety of ulimorelin, a ghrelin agonist, with metoclopramide in the treatment of EFI.

Methods: One hundred twenty ICU patients were randomized 1:1 to ulimorelin or metoclopramide for 5 days. EFI was diagnosed by a gastric residual volume (GRV) ≥ 500 ml. A volume-based feeding protocol was employed, and enteral formulas were standardized. The primary end point was the percentage daily protein prescription (%DPP) received by patients over 5 days of treatment. Secondary end points included feeding success, defined as 80% DPP; gastric emptying, assessed by paracetamol absorption; incidences of recurrent intolerance (GRV ≥ 500 ml); vomiting or regurgitation; aspiration, defined by positive tracheal aspirates for pepsin; and pulmonary infection.

Results: One hundred twenty patients were randomized and received the study drug (ulimorelin 62, metoclopramide 58). Mean APACHE II and SOFA scores were 21.6 and 8.6, and 63.3% of patients had medical reasons for ICU admission. Ulimorelin and metoclopramide resulted in comparable %DPPs over 5 days of treatment (median [Q1, Q3]: 82.9% [38.4%, 100.2%] and 82.3% [65.6%, 100.2%], respectively, p = 0.49). Five-day rates of feeding success were 67.7% and 70.6% when terminations unrelated to feeding were excluded, and there were no differences in any secondary outcomes or adverse events between the two groups.

Conclusions: Both prokinetic agents achieved similar rates of feeding success, and no safety differences between the two treatment groups were observed.
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http://dx.doi.org/10.1007/s00134-019-05593-2DOI Listing
May 2019

Metabolic effects of beta-blockers in critically ill patients: A retrospective cohort study.

Heart Lung 2019 Jul - Aug;48(4):278-286. Epub 2019 Mar 26.

Department of Intensive Care Medicine, Head of ICU, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, the Netherlands. Electronic address:

Background: Beta-blockers have potential protective features during critical illness. Heart rate reduction, with limited effect on blood pressure and beneficial effects on metabolism, organ function and inflammation have been reported. We examined metabolic effects of beta-blockers among ICU patients, to address the effect on the estimated energy expenditure, measured by carbon dioxide production (VCO). Furthermore, we investigated effects on organ function and inflammation.

Methods: A retrospective study in adult patients admitted to our 17-beds mixed medical-surgical ICU from January 2013 to March 2016. Mechanically ventilated patients who commenced beta-blockers were eligible for inclusion. Exclusion criteria were: beta-blocker therapy in the 7 previous days, treatment duration <48 h, therapeutic hypothermia, and no VCO measurements. Outcome parameters were obtained at 6 different time points from 24 h before until 48 h after beta-blocker commencement. Linear mixed models were used to evaluate trends.

Results: In total 58 patients were included. Various types of beta-blockers were administered, with a median equivalent daily dose to metoprolol of 50.0 mg (IQR 25.0-62.5). The mean heart rate decreased from 103 ± 20 to 91 ± 19 beats per minute after 48 h (p < 0.001), with unaltered blood pressures. Metabolic and other parameters did not show significant differences over time, or parameter changes were due to trends that had already started before beta-blocker commencement.

Conclusions: No changes in VCO after beta-blocker commencement were demonstrated suggesting no alterations in energy expenditure. Heart rates significantly decreased with unaltered blood pressures. Other parameters did not show trends that could be attributed to beta-blockers effects.
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http://dx.doi.org/10.1016/j.hrtlng.2019.02.004DOI Listing
March 2020

ESPEN guideline on clinical nutrition in the intensive care unit.

Clin Nutr 2019 02 29;38(1):48-79. Epub 2018 Sep 29.

Department of Nutritional Medicine/Prevention, University of Hohenheim, Stuttgart, Germany.

Following the new ESPEN Standard Operating Procedures, the previous guidelines to provide best medical nutritional therapy to critically ill patients have been updated. These guidelines define who are the patients at risk, how to assess nutritional status of an ICU patient, how to define the amount of energy to provide, the route to choose and how to adapt according to various clinical conditions. When to start and how to progress in the administration of adequate provision of nutrients is also described. The best determination of amount and nature of carbohydrates, fat and protein are suggested. Special attention is given to glutamine and omega-3 fatty acids. Particular conditions frequently observed in intensive care such as patients with dysphagia, frail patients, multiple trauma patients, abdominal surgery, sepsis, and obesity are discussed to guide the practitioner toward the best evidence based therapy. Monitoring of this nutritional therapy is discussed in a separate document.
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http://dx.doi.org/10.1016/j.clnu.2018.08.037DOI Listing
February 2019

Management of sepsis in out-of-hours primary care: a retrospective study of patients admitted to the intensive care unit.

BMJ Open 2018 09 17;8(9):e022832. Epub 2018 Sep 17.

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede, The Netherlands.

Objectives: Timely recognition and treatment of sepsis is essential to reduce mortality and morbidity. Acutely ill patients often consult a general practitioner (GP) as the first healthcare provider. During out-of-hours, GP cooperatives deliver this care in the Netherlands. The aim of this study is to explore the role of these GP cooperatives in the care for patients with sepsis.

Design: Retrospective study of patient records from both the hospital and the GP cooperative.

Setting: An intensive care unit (ICU) of a general hospital in the Netherlands, and the colocated GP cooperative serving 260 000 inhabitants.

Participants: We used data from 263 patients who were admitted to the ICU due to community-acquired sepsis between January 2011 and December 2015.

Main Outcome Measures: Contact with the GP cooperative within 72 hours prior to hospital admission, type of contact, delay from the contact until hospital arrival, GP diagnosis, initial vital signs and laboratory values, and hospital mortality.

Results: Of 263 patients admitted to the ICU, 127 (48.3%) had prior GP cooperative contacts. These contacts concerned home visits (59.1%), clinic consultations (18.1%), direct ambulance deployment (12.6%) or telephone advice (10.2%). Patients assessed by a GP were referred in 64% after the first contact. The median delay to hospital arrival was 1.7 hours. The GP had not suspected an infection in 43% of the patients. In this group, the in-hospital mortality rate was significantly higher compared with patients with suspected infections (41.9% vs 17.6%). Mortality difference remained significant after correction for confounders.

Conclusion: GP cooperatives play an important role in prehospital management of sepsis and recognition of sepsis in this setting proved difficult. Efforts to improve management of sepsis in out-of-hours primary care should not be limited to patients with a suspected infection, but also include severely ill patients without clear signs of infection.
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http://dx.doi.org/10.1136/bmjopen-2018-022832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144400PMC
September 2018

Monitoring nutrition in the ICU.

Clin Nutr 2019 04 20;38(2):584-593. Epub 2018 Jul 20.

Department of General Intensive Care, Institute for Nutrition Research, Rabin Medical Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Israel. Electronic address:

Background & Aims: This position paper summarizes theoretical and practical aspects of the monitoring of artificial nutrition and metabolism in critically ill patients, thereby completing ESPEN guidelines on intensive care unit (ICU) nutrition.

Methods: Available literature and personal clinical experience on monitoring of nutrition and metabolism was systematically reviewed by the ESPEN group for ICU nutrition guidelines.

Results: We did not identify any studies comparing outcomes with monitoring versus not monitoring nutrition therapy. The potential for abnormal values to be associated with harm was clearly recognized. The necessity to create locally adapted standard operating procedures (SOPs) for follow up of enteral and parenteral nutrition is emphasised. Clinical observations, laboratory parameters (including blood glucose, electrolytes, triglycerides, liver tests), and monitoring of energy expenditure and body composition are addressed, focusing on prevention, and early detection of nutrition-related complications.

Conclusion: Understanding and defining risks and developing local SOPs are critical to reduce specific risks.
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http://dx.doi.org/10.1016/j.clnu.2018.07.009DOI Listing
April 2019

Optimal timing, dose and route of early nutrition therapy in critical illness and shock: the quest for the Holy Grail.

Intensive Care Med 2018 09 27;44(9):1558-1560. Epub 2018 Jul 27.

King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS) and King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1007/s00134-018-5302-xDOI Listing
September 2018

[Early recognition of sepsis; a diagnostic challenge for the general practitioner].

Ned Tijdschr Geneeskd 2018 May 14;162. Epub 2018 May 14.

Ziekenhuis Gelderse Vallei, afd. Intensive Care, Ede.

Early recognition and treatment of sepsis is essential to prevent morbidity and mortality. Many sepsis patients are initially assessed by a general practitioner (GP). Delay can be prevented if patients are referred to the hospital as soon as possible. However, signs and symptoms of sepsis can be subtle or aspecific, complicating the distinction between patients who need urgent care and patients who can be safely treated at home. We describe three patients who were admitted to the intensive care after repeated assessment by GPs in an out-of-hours setting: a 76-year-old man who was diagnosed with urosepsis, an 86-year-old man who was diagnosed with pneumosepsis and a 49-year-old man who was admitted after cardiopulmonary resuscitation due to sepsis. In all cases risk factors and signs of sepsis were present, but the sepsis had not been recognized until presentation to the hospital.
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May 2018

Reply-Letter to the Editor - Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation: The PROTINVENT retrospective study.

Clin Nutr 2018 10 7;37(5):1772-1773. Epub 2018 Jul 7.

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.clnu.2018.06.977DOI Listing
October 2018

Changing paradigms in metabolic support and nutrition therapy during critical illness.

Curr Opin Crit Care 2018 08;24(4):223-227

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede, The Netherlands.

Purpose Of Review: To summarize the most recent advances in acute metabolic care and critical care nutrition.

Recent Findings: Recent research has demonstrated unknown consequences of high protein and amino acid administration in the early phase of ICU stay associated with dysregulated glucagon release leading to hepatic amino acid breakdown and suggested adverse effects on autophagy and long-term outcome. Progress has been made to measure body composition in the ICU. Refeeding hypophosphatemia and refeeding syndrome are common during critical illness, phosphate monitoring is essential after the start of nutrition therapy, and caloric restriction is recommendable in these patients.In recent studies, enteral nutrition is no longer superior to parenteral nutrition and signals of harm using the enteral route in shock have been suggested. However, during extracorporeal life support, enteral nutrition seems well tolerated. Intermittent or bolus enteral feeding seems an exciting concept concerning its potential anabolic effects. Studies on vitamin C, thiamine, and corticosteroid combinations suggest potential to improve outcome.

Summary: These new findings will probably change the practice of metabolic and nutrition therapy in critical illness and challenge paradigms advocated for long.
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http://dx.doi.org/10.1097/MCC.0000000000000519DOI Listing
August 2018

Refeeding syndrome: relevance for the critically ill patient.

Curr Opin Crit Care 2018 08;24(4):235-240

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede, The Netherlands.

Purpose Of Review: To provide an overview of recent findings concerning refeeding syndrome (RFS) among critically ill patients and recommendations for daily practice.

Recent Findings: Recent literature shows that RFS is common among critically ill ventilated patients. Usual risk factors for non-ICU patients addressed on ICU admission do not identify patients developing RFS. A marked drop of phosphate levels (>0.16 mmol/l) from normal levels within 72 h of commencement of feeding, selects patients that benefit from hypocaloric or restricted caloric intake for at least 48 h resulting in lower long-term mortality.

Summary: RFS is a potentially life-threatening condition induced by initiation of feeding after a period of starvation. Although a uniform definition is lacking, most definitions comprise a complex constellation of laboratory markers (i.e. hypophosphatemia, hypokalemia, hypomagnesemia) or clinical symptoms, including cardiac and pulmonary failure. Recent studies show that low caloric intake results in lower mortality rates in critically ill RFS patients compared with RFS patients on full nutritional support. Therefore, standard monitoring of RFS-markers (especially serum phosphate) and caloric restriction when RFS is diagnosed should be considered. Furthermore, standard therapy with thiamin and electrolyte supplementation is essential.
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http://dx.doi.org/10.1097/MCC.0000000000000514DOI Listing
August 2018

Very high intact-protein formula successfully provides protein intake according to nutritional recommendations in overweight critically ill patients: a double-blind randomized trial.

Crit Care 2018 06 12;22(1):156. Epub 2018 Jun 12.

Nutricia Research, Utrecht, The Netherlands.

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) 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 2 February 2016.
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http://dx.doi.org/10.1186/s13054-018-2070-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998555PMC
June 2018

The safety and efficacy of nicotine replacement therapy in the intensive care unit: a randomised controlled pilot study.

Ann Intensive Care 2018 Jun 7;8(1):70. Epub 2018 Jun 7.

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands.

Background: Studies evaluating nicotine replacement therapy (NRT) to prevent nicotine withdrawal symptoms in ICU patients have yielded conflicting results. We performed a randomised controlled double-blind pilot study to assess the safety and efficacy of NRT in critically ill patients. Mechanically ventilated patients admitted to two medical-surgical intensive care units and smoking more than 10 cigarettes per day before ICU admission were enrolled in this study. Participants were randomised to transdermal NRT (14 or 21 mg per day) or placebo until ICU discharge or day 30. Smoking status was confirmed by the biomarkers serum cotinine and urinary NNAL. The primary endpoint was 30-day mortality. Among secondary endpoints and post hoc endpoints, 90-day mortality, safety, time spent without delirium, sedation and coma, and patient destination at day 30 were addressed.

Results: We enrolled 47 patients. No differences were found between NRT and control group patients concerning 30-day mortality (9.5 vs. 7.7%, p = 0.84) and 90-day mortality (14.3 vs. 19.2%, p = 0.67). The number of serious adverse events was comparable between groups (NRT: 4, control: 11, p = 0.13). At day 20, average time alive without delirium, sedation and coma was 16.6 days among NRT patients versus 12.6 days among control patients (p = 0.03). At day 30, more NRT group patients were discharged from the ICU or hospital compared with controls (p = 0.03).

Conclusions: NRT did not affect mortality or the number of (serious) adverse events compared with placebo. Time alive without delirium, sedation and coma at day 20 in NRT patients was longer than in control patients. An adequately powered randomised controlled trial to further study safety and efficacy of NRT in ICU patients seems feasible and is warranted. Trial registration ClinicalTrials.gov, number NCT01362959, registered 1 June 2011.
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http://dx.doi.org/10.1186/s13613-018-0399-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991106PMC
June 2018

Surgical ward nurses' responses to worry: An observational descriptive study.

Int J Nurs Stud 2018 Sep 21;85:90-95. Epub 2018 May 21.

Radboud University Medical Centre, Radboud Institute for Health Sciences, Scientific Center for Quality of Healthcare (IQ healthcare), Geert Grooteplein 21 (route 114), 6525 EZ Nijmegen, The Netherlands; Faculty of Health Sciences, University of Southampton, Level A (MP11) South Academic Block, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, United Kingdom; National Institute for Health Research Collaboration for Applied Health Research and Care (CLAHRC) Wessex, Southampton, United Kingdom. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ijnurstu.2018.05.009DOI Listing
September 2018

Associations of hyperosmolar medications administered via nasogastric or nasoduodenal tubes and feeding adequacy, food intolerance and gastrointestinal complications amongst critically ill patients: A retrospective study.

Clin Nutr ESPEN 2018 06 17;25:78-86. Epub 2018 Apr 17.

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716, Ede, The Netherlands. Electronic address:

Background: Adequate nutrition is essential during critical illness. However, providing adequate nutrition is often hindered by gastro-intestinal complications, including feeding intolerance. It is suggested that hyperosmolar medications could be causally involved in the development of gastro-intestinal complications. The aims of the present study were 1) to determine the osmolality of common enterally administered dissolved medications and 2) to study the associations between nasogastric and nasoduodenal administered hyperosmolar medications and nutritional adequacy as well as food intolerance and gastro-intestinal symptoms.

Methods: This retrospective observational cohort study was performed in a medical-surgical ICU in the Netherlands. Adult critically ill patients receiving enteral nutrition and admitted for a minimum ICU duration of 7 days were eligible. The osmolalities of commonly used enterally administrated medications were measured using an osmometer. Patients were divided in two groups: Use of hyperosmolar medications (>500 mOsm/kg) on at least one day during the first week versus none. The associations between the use of hyperosmolar medications and nutritional adequacy were assessed using multiple logistic regression analysis. The associations between hyperosmolar medication and food intolerance as well as gastrointestinal symptoms were assessed using ordinal logistic regression.

Results: In total 443 patients met the inclusion criteria. Of the assessed medications, only three medications were found hyperosmolar. We observed no associations between the use of hyperosmolar medications and nutritional adequacy in the first week of ICU admission (caloric intake β -0.27 95%CI -1.38; 0.83, protein intake β 0.32 95%CI -0.90; 1.53). In addition, no associations were found for enteral feeding intolerance, diarrhea, obstipation, gastric residual volume, nausea and vomiting in ICU patients receiving hyperosmolar medications via a nasogastric tube. A subgroup analysis of patients on duodenal feeding showed that postpyloric administration of hyperosmolar medications was associated with increased risk of diarrhea (OR 138.7 95%CI 2.33; 8245).

Conclusions: Our results suggest that nasogastric administration of hyperosmolar medication via a nasogastric tube does not affect nutritional adequacy, development of enteral feeding intolerance and other gastro-intestinal complications during the first week after ICU admission. During nasoduodenal administration an increased diarrhea incidence may be encountered.
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http://dx.doi.org/10.1016/j.clnesp.2018.04.001DOI Listing
June 2018

Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation: The PROTINVENT retrospective study.

Clin Nutr 2019 04 17;38(2):883-890. Epub 2018 Feb 17.

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands. Electronic address:

Background & Aims: Optimal protein intake during critical illness is unknown. Conflicting results on nutritional support during the first week of ICU stay have been published. We addressed timing of protein intake and outcomes in ICU patients requiring prolonged mechanical ventilation.

Methods: We retrospectively collected nutritional and clinical data on the first 7 days of ICU admission of adult critically ill patients, who were mechanically ventilated in our ICU for at least 7 days and admitted between January 1st 2011 and December 31st 2015. Based on recent literature, patients were divided into 3 protein intake categories, <0.8 g/kg/day, 0.8-1.2 g/kg/day and >1.2 g/kg/day. Our primary aim was to identify the optimum protein dose and timing related to the lowest 6 month mortality. Secondary endpoints were ventilation duration, need for renal replacement therapy (RRT), ICU length of stay (LOS) and mortality and hospital LOS and mortality.

Results: In total 455 patients met the inclusion criteria. We found a time-dependent association of protein intake and mortality; low protein intake (<0.8 g/kg/day) before day 3 and high protein intake (>0.8 g/kg/day) after day 3 was associated with lower 6-month mortality, adjusted HR 0.609; 95% CI 0.480-0.772, p < 0.001) compared to patients with overall high protein intake. Lowest 6-month mortality was found when increasing protein intake from <0.8 g/kg/day on day 1-2 to 0.8-1.2 g/kg/day on day 3-5 and >1.2 g/kg/day after day 5. Moreover, overall low protein intake was associated with the highest ICU, in-hospital and 6-month mortality. No differences in ICU LOS, need for RRT or ventilation duration were found.

Conclusions: Our data suggest that although overall low protein intake is associated with the highest mortality risk, high protein intake during the first 3-5 days of ICU stay is also associated with increased long-term mortality. Therefore, timing of high protein intake may be relevant for optimizing ICU, in-hospital and long-term mortality outcomes.
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http://dx.doi.org/10.1016/j.clnu.2018.02.012DOI Listing
April 2019

Nutrition in the ICU: new trends versus old-fashioned standard enteral feeding?

Curr Opin Anaesthesiol 2018 Apr;31(2):136-143

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede, The Netherlands.

Purpose Of Review: The narrative review aims to summarize the relevant studies from the last 2 years and provide contextual information to understand findings.

Recent Findings: Recent ICU studies have provided insight in the pathophysiology and time course of catabolism, anabolic resistance, and metabolic and endocrine derangements interacting with the provision of calories and proteins.Early provision of high protein intake and caloric overfeeding may confer harm. Refeeding syndrome warrants caloric restriction and to identify patients at risk phosphate monitoring is mandatory.Infectious complications of parenteral nutrition are associated with overfeeding. In recent studies enteral nutrition is no longer superior over parenteral nutrition.Previously reported benefits of glutamine, selenium, and fish oil seem to have vanished in recent studies; however, studies on vitamin C, thiamine, and corticosteroid combinations show promising results.

Summary: Studies from the last 2 years will have marked impact on future nutritional support strategies and practice guidelines for critical care nutrition as they challenge several old-fashioned concepts.
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http://dx.doi.org/10.1097/ACO.0000000000000571DOI Listing
April 2018

Is refeeding syndrome relevant for critically ill patients?

Curr Opin Clin Nutr Metab Care 2018 03;21(2):130-137

Department of Intensive Care, Gelderse Vallei Hospital, Ede, The Netherlands.

Purpose Of Review: To summarize recent relevant studies regarding refeeding syndrome (RFS) in critically ill patients and provide recommendations for clinical practice.

Recent Findings: Recent knowledge regarding epidemiology of refeeding syndrome among critically ill patients, how to identify ICU patients at risk, and strategies to reduce the potential negative impact on outcome are discussed.

Summary: RFS is a potentially fatal acute metabolic derangement that ultimately can result in marked morbidity and even mortality. These metabolic derangements in ICU patients differ from otherwise healthy patients with RFS, as there is lack of anabolism. This is because of external stressors inducing a hypercatabolic response among other reasons also reflected by persistent high glucagon despite initiation of feeding. Lack of a proper uniform definition complicates diagnosis and research of RFS. However, refeeding hypophosphatemia is commonly encountered during critical illness. The correlations between risk factors proposed by international guidelines and the occurrence of RFS in ICU patients remains unclear. Therefore, regular phosphate monitoring is recommended. Based on recent trials among critically ill patients, only treatment with supplementation of electrolytes and vitamins seems not sufficient. In addition, caloric restriction for several days and gradual increase of caloric intake over days is recommendable.
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http://dx.doi.org/10.1097/MCO.0000000000000449DOI Listing
March 2018

Hydrolysed protein enteral nutrition is not superior to polymeric whole protein feeding with regard to gastrointestinal feeding tolerance and feeding adequacy.

Crit Care 2017 09 5;21(1):232. Epub 2017 Sep 5.

Department of Anaesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 Haus 12, D-24105, Kiel, Germany.

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http://dx.doi.org/10.1186/s13054-017-1817-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585887PMC
September 2017

Impact of caloric intake in critically ill patients with, and without, refeeding syndrome: A retrospective study.

Clin Nutr 2018 10 10;37(5):1609-1617. Epub 2017 Aug 10.

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands. Electronic address:

Background & Aims: Refeeding syndrome comprises metabolic disturbances that occur after the reintroduction of feeding after prolonged fasting. Standard care consists of correcting fluid and electrolytes imbalances. Energy intake during refeeding syndrome is heavily debated. This study addresses the effect of caloric intake on outcome during the management of refeeding syndrome.

Methods: A retrospective study among critically ill invasive mechanically ventilated patients admitted for >7 days to a medical-surgical ICU. Refeeding syndrome was diagnosed by the occurrence of new onset hypophosphatemia (<0.65 mmol/l) within 72 h of the start of nutritional support. Primary outcome was 6-month mortality. Secondary outcomes were 3-month mortality, ICU and hospital length of stay and duration of mechanical ventilation. Outcomes of patients with and without refeeding syndrome were compared and subgroup analysis on energy intake within the refeeding population was performed for the duration of survival.

Results: Of 337 enrolled patients, 124 (36.8%) developed refeeding syndrome and 213 patients (63.2%) maintained normal serum phosphate levels. Between the two groups, no statistical significant differences in clinical outcomes were observed. Within the refeeding syndrome group, a reduced 6-month mortality risk for low caloric intake (<50% of target) was seen compared with normal intake, adjusted Hazard Ratio 0.39, (95% CI 0.16-0.95, p = 0.037). In this group, low caloric intake was associated with an increased overall survival time at day 180 (153.0 (SE 10.1) vs 119.1 (SE 8.0) days, log-rank p = 0.018).

Conclusions: Refeeding syndrome is common among prolonged mechanically ventilated critically ill patients, however not predictable by baseline characteristics. Among patients that develop refeeding syndrome low caloric intake was associated with a reduction in 6-month mortality risk. This effect was not seen in patients without refeeding syndrome. Findings support caloric restriction in refeeding syndrome during critical illness.
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http://dx.doi.org/10.1016/j.clnu.2017.08.001DOI Listing
October 2018

Diagnostic accuracy of novel serological biomarkers to detect acute mesenteric ischemia: a systematic review and meta-analysis.

Intern Emerg Med 2017 Sep 6;12(6):821-836. Epub 2017 May 6.

Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands.

Laparotomy remains the gold standard for diagnosis of acute mesenteric ischemia (AMI), but is often unhelpful or too late due to non-specific clinical and radiological signs. This systematic review and meta-analysis aims to evaluate the diagnostic accuracy of the novel serological biomarkers intestinal fatty acid-binding protein (I-FABP), α-glutathione S-transferase (α-GST), D-lactate, ischemia modified albumin (IMA), and citrulline to detect AMI. A systematic search of electronic databases was performed to identify all published diagnostic accuracy studies on I-FABP, α-GST, D-lactate, IMA, and citrulline. Articles were selected based on pre-defined inclusion and exclusion criteria. Risk of bias and applicability were assessed. Two-by-two contingency tables were constructed to calculate accuracy standards. Summary estimates were computed using random-effects models. The search yielded 1925 papers, 21 were included in the final analysis. Pooled sensitivity and specificity for investigated biomarkers were: I-FABP (Uden); 79.0 (95% CI 66.5-88.5) and 91.3 (87.0-94.6), I-FABP (Osaka); 75.0 (67.9-81.2) and 79.2 (76.2-82.0), D-lactate; 71.7 (58.6-82.5) and 74.2 (69.0-79.0), α-GST; 67.8 (54.2-79.5) and 84.2 (75.3-90.9), IMA; 94.7 (74.0-99.9) and 86.4 (65.1-97.1), respectively. One study investigated accuracy standards for citrulline: sensitivity 39% and specificity 100%. The novel serological biomarkers I-FABP, α-GST, IMA, and citrulline may offer improved diagnostic accuracy of acute mesenteric ischemia; however, further research is required to specify threshold values and accuracy standards for different aetiological forms.
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http://dx.doi.org/10.1007/s11739-017-1668-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559578PMC
September 2017

Parenteral glutamine should not be routinely used in adult critically ill patients.

Clin Nutr 2017 08 7;36(4):1184-1185. Epub 2017 Apr 7.

Department of Anaesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 Haus 12, 24105, Kiel, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clnu.2017.03.030DOI Listing
August 2017

The intensive care medicine research agenda in nutrition and metabolism.

Intensive Care Med 2017 Sep 3;43(9):1239-1256. Epub 2017 Apr 3.

Nutrition and Dietetics, Department of Internal Medicine, and Department of Intensive Care Medicine, VU University Medical Center, Amsterdam, The Netherlands.

Purpose: The objectives of this review are to summarize the current practices and major recent advances in critical care nutrition and metabolism, review common beliefs that have been contradicted by recent trials, highlight key remaining areas of uncertainty, and suggest recommendations for the top 10 studies/trials to be done in the next 10 years.

Methods: Recent literature was reviewed and developments and knowledge gaps were summarized. The panel identified candidate topics for future trials in critical care nutrition and metabolism. Then, members of the panel rated each one of the topics using a grading system (0-4). Potential studies were ranked on the basis of average score.

Results: Recent randomized controlled trials (RCTs) have challenged several concepts, including the notion that energy expenditure must be met universally in all critically ill patients during the acute phase of critical illness, the routine monitoring of gastric residual volume, and the value of immune-modulating nutrition. The optimal protein dose combined with standardized active and passive mobilization during the acute phase and post-acute phase of critical illness were the top ranked studies for the next 10 years. Nutritional assessment, nutritional strategies in critically obese patients, and the effects of continuous versus intermittent enteral nutrition were also among the highest-ranking studies.

Conclusions: Priorities for clinical research in the field of nutritional management of critically ill patients were suggested, with the prospect that different nutritional interventions targeted to the appropriate patient population will be examined for their effect on facilitating recovery and improving survival in adequately powered and properly designed studies, probably in conjunction with physical activity.
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http://dx.doi.org/10.1007/s00134-017-4711-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569654PMC
September 2017
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