Highlights in the clinical nutrition literature: A critical appraisal of current research.

Within the American Society for Parenteral and Enteral Nutrition (ASPEN), the Physician Engagement Committee (PEC) was created in 2017 by the ASPEN Board of Directors with the goal of growing the physician community both nationally and internationally. The PEC meets each month throughout the year to develop educational and research initiatives. In 2022, the PEC began an initiative to systematically review and evaluate practice-changing literature annually with the overall aim to highlight these studies at the annual ASPEN conferences and to critically discuss the potential clinical implications. The objective of the held meeting session was to present identified key papers in the fields of critical care medicine, gastroenterology and hepatology, and adult internal medicine that were published in 2022, which would complement the knowledge of the pathogenesis, diagnosis, and management of nutrition topics as well as to identify areas of future research. Overall, several large-scale randomized controlled studies were identified in each of these sections, with practice-changing major results. This manuscript summarizes the information that was presented and the discussions that followed.

Relevance of Protein Intake for Weaning in the Mechanically Ventilated Critically Ill: Analysis of a Large International Database.

OBJECTIVES: The association between protein intake and the need for mechanical ventilation (MV) is controversial. We aimed to investigate the associations between protein intake and outcomes in ventilated critically ill patients. DESIGN: Analysis of a subset of a large international point prevalence survey of nutritional practice in ICUs. SETTING: A total of 785 international ICUs. PATIENTS: A total of 12,930 patients had been in the ICU for at least 96 hours and required MV by the fourth day after ICU admission at the latest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We modeled associations between the adjusted hazard rate (aHR) of death in patients requiring MV and successful weaning (competing risks), and three categories of protein intake (low: < 0.8 g/kg/d, standard: 0.8-1.2 g/kg/d, high: > 1.2 g/kg/d). We compared five different hypothetical protein diets (an exclusively low protein intake, a standard protein intake given early (days 1-4) or late (days 5-11) after ICU admission, and an early or late high protein intake). There was no evidence that the level of protein intake was associated with time to weaning. However, compared with an exclusively low protein intake, a standard protein intake was associated with a lower hazard of death in MV: minimum aHR 0.60 (95% CI, 0.45-0.80). With an early high intake, there was a trend to a higher risk of death in patients requiring MV: maximum aHR 1.35 (95% CI, 0.99-1.85) compared with a standard diet. CONCLUSIONS: The duration of MV does not appear to depend on protein intake, whereas mortality in patients requiring MV may be improved by a standard protein intake. Adverse effects of a high protein intake cannot be excluded.

Identifying a target group for selenium supplementation in high-risk cardiac surgery: a secondary analysis of the SUSTAIN CSX trial.

BACKGROUND: Recent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment. METHODS: Patients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity. RESULTS: Two hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes. CONCLUSIONS: The identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients.

Vitamin C in critical illness: end of the story or still a place?

PURPOSE OF REVIEW: Critical illness is associated with decreased micronutrient levels, including vitamin C, an essential antioxidant for systemic inflammation. This review discusses the most recent evidence of high-dose vitamin C monotherapy in critically ill adults. RECENT FINDINGS: Three randomized-controlled trials (RCTs) were published in 2022. A pilot study including 40 patients with septic shock could not detect significant differences in outcome parameters after administering vitamin C. A multicenter study with 124 septic patients showed no significant difference in 28-day mortality, while vitamin C was associated with an increased risk of acute kidney dysfunction. The LOVIT trial, an international prospective RCT in 872 septic patients, revealed an increased risk of the composite endpoint persistent organ dysfunction plus death at day 28 in the high-dose vitamin C group. Six systematic reviews and meta-analyses (SRMA), including up to 4740 patients published before and 2 SRMA publications including these RCTs showed divergent results on clinical endpoints including mortality. SUMMARY: The use of high-dose intravenous vitamin C cannot be recommended for the septic critically ill in clinical practice since the LOVIT trial. Further research is needed to evaluate its potential role in other critically ill patients.

German Patient Blood Management Network: effectiveness and safety analysis in 1.2 million patients.

BACKGROUND: Patient Blood Management (PBM) is a patient-centred, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood whilst promoting patient safety and empowerment. The effectiveness and safety of PBM over a longer period have not yet been investigated. METHODS: We performed a prospectively designed, multicentre follow-up study with non-inferiority design. Data were retrospectively extracted case-based from electronic hospital information systems. All in-hospital patients (≥18 yr) undergoing surgery and discharged between January 1, 2010 and December 31, 2019 were included in the analysis. The PBM programme focused on three domains: preoperative optimisation of haemoglobin concentrations, blood-sparing techniques, and guideline adherence/standardisation of allogeneic blood product transfusions. The outcomes were utilisation of blood products, composite endpoint of in-hospital mortality and postoperative complications (myocardial infarction/ischaemic stroke/acute renal failure with renal replacement therapy/sepsis/pneumonia), anaemia rate at admission and discharge, and hospital length of stay. RESULTS: A total of 1 201 817 (pre-PBM: n=441 082 vs PBM: n=760 735) patients from 14 (five university/nine non-university) hospitals were analysed. Implementation of PBM resulted in a substantial reduction of red blood cell utilisation. The mean number of red blood cell units transfused per 1000 patients was 547 in the PBM cohort vs 635 in the pre-PBM cohort (relative reduction of 13.9%). The red blood cell transfusion rate was significantly lower (P<0.001) with odds ratio 0.86 (0.85-0.87). The composite endpoint was 5.8% in the PBM vs 5.6% in the pre-PBM cohort. The non-inferiority aim (safety of PBM) was achieved (P<0.001). CONCLUSIONS: Analysis of >1 million surgical patients showed that the non-inferiority condition (safety of Patient Blood Management) was fulfilled, and PBM was superior with respect to red blood cell transfusion. CLINICAL TRIAL REGISTRATION: NCT02147795.

[Laboratory and calorimetric monitoring of medical nutrition therapy in intensive and intermediate care units : Second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI)]. / Laborchemisches und kalorimetrisches Monitoring der medizinischen Ernährungstherapie auf der Intensiv- und Intermediate Care Station : Zweites Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI).

This second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) provides recommendations on the laboratory monitoring of macro- and micronutrient intake as well as the use of indirect calorimetry in the context of medical nutrition therapy of critically ill adult patients. In addition, recommendations are given for disease-related or individual (level determination) substitution and (high-dose) pharmacotherapy of vitamins and trace elements.

The role of PEEP for cannulation of the subclavian vein: A prospective observational study.

PURPOSE: The role of positive endexpiratory pressure (PEEP) for successful cannulation of the subclavian vein (SCV) remains inconclusive. The aim of our study was to assess the effect of different levels of PEEP on distance from SCV to parietal pleura (DVP) and on the cross-sectional area (CSA) of the SCV. METHODS: Invasive mechanically ventilated adult patients with a clinical indication for a stepwise PEEP-trial (0, 5, 10, and 15 cm H2O) were included in this prospective observational single-center study. Ultrasound examinations of SCV were performed with a linear ultrasound probe using the infraclavicular view. DVP and CSA were measured on the right and left bodyside. Examinations were repeated at each PEEP step. RESULTS: 27 patients were enrolled (12 female; 60±21 years; BMI 24.6±4.9 kg/m2; 20 patients on controlled, 7 on assisted ventilation). A statistically significant increase of DVP in the in-plane view was found on the left side which was not clinically relevant. No significant differences of DVP were observed in all other views. PEEP induced changes in CSAs were statistically significant but clinically not relevant on both sides. The largest change in CSA (2mm2) was observed when comparing PEEP 10 with PEEP 0 cm H2O. CONCLUSION: A stepwise PEEP increase was not associated with clinically relevant changes of the DVP and CSA. Thus, a PEEP-optimization for the cannulation of the subclavian vein is not indicated.

What the clinician needs to know about medical nutrition therapy in critically ill patients in 2023: A narrative review.

Medical nutrition therapy (MNT) represents an essential element in the medical care of critically ill patients admitted to an intensive care unit (ICU). Increasing awareness exists that energy and nutrients not only preserve body structures such as lean body/muscle mass but also represent promising therapeutic elements to target the profound metabolic, inflammatory, endocrinologic, and immunologic alterations occurring during critical illness. However, despite intense research activities for years, diverse aspects of MNT such as the optimal timing, dosing, and composition of energy and macronutrient supply, as well as the role of micronutrients, are still an issue of debate resulting from strong heterogeneity in methods and findings of respective studies. These discrepancies are also reflected in diverging recommendations of international clinical nutrition guidelines for specific topics. In addition, implementing targeted, personalized MNT strategies in routine clinical practice underlies difficulties and challenges resulting from disease-specific issues and/or organizational, structural, and educational aspects. This narrative review aims to summarize the most recent evidence relevant to clinical practice on selected aspects of MNT in adult patients in the ICU and to provide guidance for implementing evidence-based approaches for adequate energy and nutrient supply in the ICU setting.

Current practices in nutrition therapy in cardiac surgery patients: An international multicenter observational study.

BACKGROUND: Cardiac surgery patients with a prolonged stay in the intensive care unit (ICU) are at high risk for acquired malnutrition. Medical nutrition therapy practices for cardiac surgery patients are unknown. The objective of this study is to describe the current nutrition practices in critically ill cardiac surgery patients worldwide. METHODS: We conducted a prospective observational study in 13 international ICUs involving mechanically ventilated cardiac surgery patients with an ICU stay of at least 72 h. Collected data included the energy and protein prescription, type of and time to the initiation of nutrition, and actual quantity of energy and protein delivered (maximum: 12 days). RESULTS: Among 237 enrolled patients, enteral nutrition (EN) was started, on average, 45 h after ICU admission (range, 0-277 h; site average, 53 [range, 10-79 h]). EN was prescribed for 187 (79%) patients and combined EN and parenteral nutrition in 33 (14%). Overall, patients received 44.2% (0.0%-117.2%) of the prescribed energy and 39.7% (0.0%-122.8%) of the prescribed protein. At a site level, the average nutrition adequacy was 47.5% (30.5%-78.6%) for energy and 43.6% (21.7%-76.6%) for protein received from all nutrition sources. CONCLUSION: Critically ill cardiac surgery patients with prolonged ICU stay experience significant delays in starting EN and receive low levels of energy and protein. There exists tremendous variability in site performance, whereas achieving optimal nutrition performance is doable.

Current practice of gastric residual volume measurements and related outcomes of critically ill patients: A secondary analysis of the intestinal-specific organ function assessment study.

BACKGROUND: Gastric residual volume (GRV) measurement to detect gastrointestinal (GI) dysfunction is a common diagnostic procedures in critical care, albeit still not well standardized being operator-, patient-, and tube-dependent. Our aim was to describe current practice of GRV measurements and its association with clinical outcomes in critically ill patients. METHODS: This was a secondary analysis of an international prospective observational cohort study (intestinal-specific organ function assessment). Eligibility criteria were defined as ≥1 GRV measurement during the 7-day study period. Data collection included GRV measurement practices, tube diameters and volumes, symptoms of GI dysfunction, and clinical outcomes. The primary aim was to describe current practices of GRV measurements, and the secondary aim was to test the association of high (>200 ml) vs. low GRV with symptoms of GI dysfunction and clinical outcomes using generalized linear regression and survival models. RESULTS: Two hundred fifty-eight patients with 2422 GRV measurements on 875 study days were analyzed. GRV was mainly measured via passive drainage twice daily using large diameter tubes. There was no significant association between tube size or measurement technique and high GRV. High GRV occurred in 34% of patients and was associated with other GI symptoms and with increased disease severity but not with 28-day or 90-day mortality, intensive care unit-free and ventilator-free days. CONCLUSION: There was substantial variability of GRV measurement techniques, but this had no impact on the amount of GRV. High GRV was not associated with mortality or ventilator-free days but may serve as a marker of GI dysfunction and disease severity.

[Bacterial gut microbiota-key player in sepsis]. / Das bakterielle intestinale Mikrobiom ­ Key Player in der Sepsis.

The gut microbiota is comprised of over 1200 different bacteria and forms a symbiotic community with the human organism, the holobiont. It plays an important role in the maintenance of homeostasis, e.g., of the immune system and essential metabolic processes. Disturbances in the balance of this reciprocal relationship are called dysbiosis and, in the field of sepsis, are associated with incidence of disease, extent of the systemic inflammatory response, severity of organ dysfunction, and mortality. In addition to providing guiding principles in the fascinating relationship between "human and microbe," this article summarizes recent findings regarding the role of the bacterial gut microbiota in sepsis, which is one a very relevant in intensive care medicine.

The prevalence of sepsis-induced coagulopathy in patients with sepsis - a secondary analysis of two German multicenter randomized controlled trials.

BACKGROUND: Sepsis and septic shock are frequently accompanied by coagulopathy. Since the sepsis-induced coagulopathy (SIC) score was first described, subsequent studies from Asia revealed a SIC prevalence of 40-60%. In Europe, however, SIC prevalence in patients fulfilling sepsis criteria according to the third international consensus definition (SEPSIS-3) has not yet been evaluated. METHODS: The Critical Care Trials Group of the German Sepsis Competence Network (SepNet) conducted a secondary analysis of two randomized controlled trials. Only patients fulfilling sepsis criteria according SEPSIS-3 were included in this secondary analysis. In a two step approach, SIC prevalence was determined in 267 patients with sepsis but not septic shock (at the time of inclusion) from the "Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis" (HYPRESS) trial. Then, we estimated SIC prevalence in 1,018 patients from the "Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock" (SISPCT) trial using a simplified SIC score based on the platelet-SIC-subscore (PSSC). Study aims were to assess (i) the prevalence of SIC in patients with SEPSIS-3, (ii) the association of SIC with 90-day mortality and morbidity, (iii) the time when patients become SIC positive during the course of sepsis, and (iv) the value of the PSSC for predicting SIC. RESULTS: In the HYPRESS trial, SIC prevalence was 22.1% (95% confidence interval [CI] 17.5-27.5%). The estimated SIC prevalence in the SISPCT trial was 24.2% (95% CI 21.6-26.9%). In the HYPRESS trial, SIC was associated with significantly higher 90-day mortality (13.9% vs. 26.8%, p = 0.027) and morbidity. Logistic regression analysis adjusted for age, sex, treatment arm, and (SIC-adapted) SOFA score confirmed the negative association of SIC with survival (p = 0.011). In the SISPCT trial, increased PSSCs were associated with higher 90-day mortality (PSSC 0: 34.4%, PSSC 1: 40.5%, PSSC 2: 53.3%; p < 0.001). In both trials, SIC was already present at sepsis diagnosis or occurred during the following 4 days. CONCLUSIONS: SIC is a clinically relevant complication of sepsis. Although it might be less frequent than previously reported, its occurrence is associated with higher morbidity and mortality and should be interpreted as an early warning sign.

Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients: The SUSTAIN CSX Randomized Clinical Trial.

Importance: Selenium contributes to antioxidative, anti-inflammatory, and immunomodulatory pathways, which may improve outcomes in patients at high risk of organ dysfunctions after cardiac surgery. Objective: To assess the ability of high-dose intravenous sodium selenite treatment to reduce postoperative organ dysfunction and mortality in cardiac surgery patients. Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled trial took place at 23 sites in Germany and Canada from January 2015 to January 2021. Adult cardiac surgery patients with a European System for Cardiac Operative Risk Evaluation II score-predicted mortality of 5% or more or planned combined surgical procedures were randomized. Interventions: Patients were randomly assigned (1:1) by a web-based system to receive either perioperative intravenous high-dose selenium supplementation of 2000 µg/L of sodium selenite prior to cardiopulmonary bypass, 2000 µg/L immediately postoperatively, and 1000 µg/L each day in intensive care for a maximum of 10 days or placebo. Main Outcomes and Measures: The primary end point was a composite of the numbers of days alive and free from organ dysfunction during the first 30 days following cardiac surgery. Results: A total of 1416 adult cardiac surgery patients were analyzed (mean [SD] age, 68.2 [10.4] years; 1043 [74.8%] male). The median (IQR) predicted 30-day mortality by European System for Cardiac Operative Risk Evaluation II score was 8.7% (5.6%-14.9%), and most patients had combined coronary revascularization and valvular procedures. Selenium did not increase the number of persistent organ dysfunction-free and alive days over the first 30 postoperative days (median [IQR], 29 [28-30] vs 29 [28-30]; P = .45). The 30-day mortality rates were 4.2% in the selenium and 5.0% in the placebo group (odds ratio, 0.82; 95% CI, 0.50-1.36; P = .44). Safety outcomes did not differ between the groups. Conclusions and Relevance: In high-risk cardiac surgery patients, perioperative administration of high-dose intravenous sodium selenite did not reduce morbidity or mortality. The present data do not support the routine perioperative use of selenium for patients undergoing cardiac surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT02002247.

Resting Energy Expenditure in the Critically Ill and Healthy Elderly-A Retrospective Matched Cohort Study.

The use of indirect calorimetry to measure resting energy expenditure (mREE) is widely recommended as opposed to calculating REE (cREE) by predictive equations (PE). The aim of this study was to compare mREE with cREE in critically ill, mechanically ventilated patients aged ≥ 75 years and a healthy control group matched by age, gender and body mass index. The primary outcome was the PE accuracy rate of mREE/cREE, derived using Bland Altman plots. Secondary analyses included linear regression analyses for determinants of intraindividual mREE/cREE differences in the critically ill and interindividual mREE differences in the matched healthy cohort. In this retrospective study, 90 critically ill patients (median age 80 years) and 58 matched healthy persons were included. Median mREE was significantly higher in the critically ill (1457 kcal/d) versus the healthy cohort (1351 kcal/d), with low PE accuracy rates (21% to 49%). Independent predictors of mREE/cREE differences in the critically ill were body temperature, heart rate, FiO2, hematocrit, serum sodium and urea. Body temperature, respiratory rate, and FiO2 were independent predictors of interindividual mREE differences (critically ill versus healthy control). In conclusion, the commonly used PE in the elderly critically ill are inaccurate. Respiratory, metabolic and energy homeostasis variables may explain intraindividual mREE/cREE as well as interindividual mREE differences.

Medical nutrition therapy in patients receiving ECMO: Evidence-based guidance for clinical practice.

Patients receiving extracorporeal membrane oxygenation (ECMO) inherit substantial disease-associated metabolic, endocrinologic, and immunologic modifications. Along with the technical components of ECMO, the aforementioned alterations may affect patients' needs and feasibility of adequate macronutrient and micronutrient supply and intake. Thus, patients receiving ECMO are at increased risk for iatrogenic malnutrition and require targeted individual medical nutrition therapy (MNT). However, specific recommendations for MNT in patients receiving ECMO are limited and, with some exceptions, based on an evidence base encompassing general patients who are critically ill. Consequently, clinician decision-making for MNT in patients receiving ECMO is unguided, which may further increase nutrition risk, culminating in iatrogenic malnutrition and ultimately affecting patient outcomes. The purpose of this article is to provide educational background and highlight specific points for MNT in adult patients receiving ECMO, which might serve as evidence-based guidance to develop institutional standard operating procedures and nutrition protocols for daily clinical practice.

Mid- and Long-Term Surgical Outcomes Due to Infective Endocarditis in Elderly Patients: A Retrospective Cohort Study.

BACKGROUND: Infective endocarditis (IE) is one of the true remaining dreaded situations in cardiovascular medicine. Current international guidelines do not include specific recommendations for treatment options of infective endocarditis (conventional vs. surgical) based on the patient's age, functional status or comorbidities. Elderly patients have less invasive and often delayed surgeries compared to younger patients due to their shorter long-term survival probabilities. In the setting of IE, this might not be the right treatment, as surgery is the only curative option in up to 50% of all endocarditis patients. The aim of our study was to evaluate the mid- and long-term surgical outcomes due to infective endocarditis of patients aged ≥70 years. METHODS: Between 2002 and 2020, a retrospective study with 137 patients aged 70 years and older and 276 patients aged below 70 years was conducted. Altogether, 413 consecutive patients who received surgery due to infective native or prosthetic valve endocarditis were assigned to either the elderly (E)-Group or the control (C)-Group. Primary endpoints were short- and long-term MACCEs (Major Adverse Cardiac and Cerebrovascular Events) as a composite of death or major adverse events, and secondary endpoints were intraoperative variables and postoperative course. RESULTS: Preoperative risk factors differed significantly. Elderly patients had more arterial hypertension, atrial fibrillation, diabetes, chronic renal insufficiency and coronary heart disease. Fewer of them were in a state of emergency. Time from diagnosis to OR, antibiotic pretreatment, length of surgery and cardiopulmonary bypass time were significantly longer in the E-Group. Furthermore, 44.5% of patients in the E-Group had prosthesis endocarditis as opposed to 29.7% in the C-group. During postoperative follow-up, new onset of hemodialysis, duration of ventilation, delirium, reintubation and tracheotomy rates were significantly higher in the E-Group. There were significant differences in 7- and 30-day mortality. One- year survival was 62% for the E-Group and 79% for the C-Group. Five-year survival was 47% for the E-Group and 67% for the C-Group. CONCLUSIONS: This study demonstrates that surgery for infective endocarditis is a high-risk procedure, especially for elderly people. Nevertheless, as it is more or less the only concept to increase long-term survival, it should be offered generously to all patients who are still able to take care of themselves.

Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials.

BACKGROUND: The clinical significance of vitamin D administration in critically ill patients remains inconclusive. The purpose of this systematic review with meta-analysis was to investigate the effect of vitamin D and its metabolites on major clinical outcomes in critically ill patients, including a subgroup analysis based on vitamin D status and route of vitamin D administration. METHODS: Major databases were searched through February 9, 2022. Randomized controlled trials of adult critically ill patients with an intervention group receiving vitamin D or its metabolites were included. Random-effect meta-analyses were performed to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Risk of bias assessment included the Cochrane tool for assessing risk of bias in randomized trials. RESULTS: Sixteen randomized clinical trials with 2449 patients were included. Vitamin D administration was associated with lower overall mortality (16 studies: risk ratio 0.78, 95% confidence interval 0.62-0.97, p = 0.03; I2 = 30%), reduced intensive care unit length of stay (12 studies: mean difference - 3.13 days, 95% CI - 5.36 to - 0.89, n = 1250, p = 0.006; I2 = 70%), and shorter duration of mechanical ventilation (9 studies: mean difference - 5.07 days, 95% CI - 7.42 to - 2.73, n = 572, p < 0.0001; I2 = 54%). Parenteral administration was associated with a greater effect on overall mortality than enteral administration (test of subgroup differences, p = 0.04), whereas studies of parenteral subgroups had lower quality. There were no subgroup differences based on baseline vitamin D levels. CONCLUSIONS: Vitamin D supplementation in critically ill patients may reduce mortality. Parenteral administration might be associated with a greater impact on mortality. Heterogeneity and assessed certainty among the studies limits the generalizability of the results. TRIAL REGISTRATION: PROSPERO international prospective database of systematic reviews (CRD42021256939-05 July 2021).