The effects of higher versus lower protein delivery in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: A recent large multicentre trial found no difference in clinical outcomes but identified a possibility of increased mortality rates in patients with acute kidney injury (AKI) receiving higher protein. These alarming findings highlighted the urgent need to conduct an updated systematic review and meta-analysis to inform clinical practice. METHODS: From personal files, citation searching, and three databases searched up to 29-5-2023, we included randomized controlled trials (RCTs) of adult critically ill patients that compared higher vs lower protein delivery with similar energy delivery between groups and reported clinical and/or patient-centred outcomes. We conducted random-effect meta-analyses and subsequently trial sequential analyses (TSA) to control for type-1 and type-2 errors. The main subgroup analysis investigated studies with and without combined early physical rehabilitation intervention. A subgroup analysis of AKI vs no/not known AKI was also conducted. RESULTS: Twenty-three RCTs (n = 3303) with protein delivery of 1.49 ± 0.48 vs 0.92 ± 0.30 g/kg/d were included. Higher protein delivery was not associated with overall mortality (risk ratio [RR]: 0.99, 95% confidence interval [CI] 0.88-1.11; I2 = 0%; 21 studies; low certainty) and other clinical outcomes. In 2 small studies, higher protein combined with early physical rehabilitation showed a trend towards improved self-reported quality-of-life physical function measurements at day-90 (standardized mean difference 0.40, 95% CI - 0.04 to 0.84; I2 = 30%). In the AKI subgroup, higher protein delivery significantly increased mortality (RR 1.42, 95% CI 1.11-1.82; I2 = 0%; 3 studies; confirmed by TSA with high certainty, and the number needed to harm is 7). Higher protein delivery also significantly increased serum urea (mean difference 2.31 mmol/L, 95% CI 1.64-2.97; I2 = 0%; 7 studies). CONCLUSION: Higher, compared with lower protein delivery, does not appear to affect clinical outcomes in general critically ill patients but may increase mortality rates in patients with AKI. Further investigation of the combined early physical rehabilitation intervention in non-AKI patients is warranted. PROSPERO ID: CRD42023441059.

The Efficacy of Glutamine Supplementation in Severe Adult Burn Patients: A Systematic Review With Trial Sequential Meta-Analysis.

OBJECTIVES: Evidence supporting glutamine supplementation in severe adult burn patients has created a state of uncertainty due to the variability in the treatment effect reported across small and large randomized controlled trials (RCTs). We aimed to systematically review the effect of glutamine supplementation on mortality in severe adult burn patients. DATA SOURCES: MEDLINE, Embase, CINAHL, and Cochrane Central were searched from inception to February 10, 2023. STUDY SELECTION: RCTs evaluating the effect of enteral or IV glutamine supplementation alone in severe adult burn patients were included. DATA EXTRACTION: Two reviewers independently extracted data on study characteristics, burn injury characteristics, description of the intervention between groups, adverse events, and clinical outcomes. DATA SYNTHESIS: Random effects meta-analyses were performed to estimate the pooled risk ratio (RR). Trial sequential analyses (TSA) for mortality and infectious complications were performed. Ten RCTs (1,577 patients) were included. We observed no significant effect of glutamine supplementation on overall mortality (RR, 0.65, 95% CI, 0.33-1.28; p = 0.21), infectious complications (RR, 0.83; 95% CI, 0.63-1.09; p = 0.18), or other secondary outcomes. In subgroup analyses, we observed no significant effects based on administration route or burn severity. We did observe a significant subgroup effect between single and multicenter RCTs in which glutamine significantly reduced mortality and infectious complications in singe-center RCTs but not in multicenter RCTs. However, TSA showed that the pooled results of single-center RCTs were type 1 errors and further trials would be futile. CONCLUSIONS: Glutamine supplementation, regardless of administration, does not appear to improve clinical outcomes in severely adult burned patients.

Critical Appraisal of a Systematic Review: A Concise Review.

OBJECTIVES: Concise definitive review of how to read and critically appraise a systematic review. DATA SOURCES: None. STUDY SELECTION: Current literature describing the conduct, reporting, and appraisal of systematic reviews and meta-analyses. DATA EXTRACTION: Best practices for conducting, reporting, and appraising systematic review were summarized. DATA SYNTHESIS: A systematic review is a review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant original research, and to collect and analyze data from the studies that are included in the review. Critical appraisal methods address both the credibility (quality of conduct) and rate the confidence in the quality of summarized evidence from a systematic review. The A Measurement Tool to Assess Systematic Reviews-2 tool is a widely used practical tool to appraise the conduct of a systematic review. Confidence in estimates of effect is determined by assessing for risk of bias, inconsistency of results, imprecision, indirectness of evidence, and publication bias. CONCLUSIONS: Systematic reviews are transparent and reproducible summaries of research and conclusions drawn from them are only as credible and reliable as their development process and the studies which form the systematic review. Applying evidence from a systematic review to patient care considers whether the results can be directly applied, whether all important outcomes have been considered, and if the benefits are worth potential harms and costs.

IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: To conduct a systematic review and meta-analysis to evaluate the impact of IV vitamin C on outcomes in critically ill patients. DATA SOURCES: Systematic search of MEDLINE, EMBASE, CINAHL, and the Cochrane Register of Controlled Trials. STUDY SELECTION: Randomized controlled trials testing IV vitamin C in critically ill patients. DATA ABSTRACTION: Two independent reviewers abstracted patient characteristics, treatment details, and clinical outcomes. DATA SYNTHESIS: Fifteen studies involving 2,490 patients were identified. Compared with placebo, IV vitamin C administration is associated with a trend toward reduced overall mortality (relative risk, 0.87; 95% CI, 0.75-1.00; p = 0.06; test for heterogeneity I2 = 6%). High-dose IV vitamin C was associated with a significant reduction in overall mortality (relative risk, 0.70; 95% CI, 0.52-0.96; p = 0.03), whereas low-dose IV vitamin C had no effect (relative risk, 0.94; 95% CI, 0.79-1.07; p = 0.46; test for subgroup differences, p = 0.14). IV vitamin C monotherapy was associated with a significant reduction in overall mortality (relative risk, 0.64; 95% CI, 0.49-0.83; p = 0.006), whereas there was no effect with IV vitamin C combined therapy. No trial reported an increase in adverse events related to IV vitamin C. CONCLUSIONS: IV vitamin C administration appears safe and may be associated with a trend toward reduction in overall mortality. High-dose IV vitamin C monotherapy may be associated with improved overall mortality, and further randomized controlled trials are warranted.

Omega-6 sparing effects of parenteral lipid emulsions-an updated systematic review and meta-analysis on clinical outcomes in critically ill patients.

BACKGROUND: Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients. METHODS: A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed. RESULTS: 1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] - 6.88; 95% CI - 11.27, - 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD - 3.53; 95% CI - 6.16, - 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care. CONCLUSION: Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact. Trial registration PROSPERO international prospective database of systematic reviews (CRD42021259238).

Meeting nutritional targets of critically ill patients by combined enteral and parenteral nutrition: review and rationale for the EFFORTcombo trial.

While medical nutrition therapy is an essential part of the care for critically ill patients, uncertainty exists about the right form, dosage, timing and route in relation to the phases of critical illness. As enteral nutrition (EN) is often withheld or interrupted during the intensive care unit (ICU) stay, combined EN and parenteral nutrition (PN) may represent an effective and safe option to achieve energy and protein goals as recommended by international guidelines. We hypothesise that critically ill patients at high nutritional risk may benefit from such a combined approach during their stay on the ICU. Therefore, we aim to test if an early combination of EN and high-protein PN (EN+PN) is effective in reaching energy and protein goals in patients at high nutritional risk, while avoiding overfeeding. This approach will be tested in the here-presented EFFORTcombo trial. Nutritionally high-risk ICU patients will be randomised to either high (≥2·2 g/kg per d) or low protein (≤1·2 g/kg per d). In the high protein group, the patients will receive EN+PN; in the low protein group, patients will be given EN alone. EN will be started in accordance with international guidelines in both groups. Efforts will be made to reach nutrition goals within 48-96 h. The efficacy of the proposed nutritional strategy will be tested as an innovative approach by functional outcomes at ICU and hospital discharge, as well as at a 6-month follow-up.

[Nutrition in Critically Ill Patients - Challenges in Special Patient Groups]. / Ernährung des Intensivpatienten: Herausforderung bei besonderen Patientengruppen.

Medical nutrition therapy in daily intensive care often is challenging for the clinician. The severity of disease with possible compromises of conscience, hemodynamics, respiration, renal and gastrointestinal systems requires an individual adaptation of the nutrient-supply adjusted to the disease phase and secondary metabolic tolerance. For these adjustments, clinicians should consider the nature of the acute disease leading to critical illness and also the preceding nutrition state, comorbidities and demographics, as well as the prognosis of the patient. Close monitoring is necessary for a rapid response in case the medical condition changes or new medical or nutritional problems arise.This pragmatic educational article describes recommended nutrition therapies for different patient cohorts in intensive care medicine based on currently valid (inter)national guidelines.

[Role of Nutrition Support in Cardiac Surgery Patients - an Overview]. / Die Rolle der Ernährung beim herzchirurgischen Patienten ­ eine Übersicht.

Cardiac surgery patients regularly experience a systemic inflammation response to the surgery and a postoperative stay in the intensive care unit. Nutritional support is one strategy to improve the outcome of cardiosurgical patients. A preoperatively diagnosed malnutrition contributes to a higher morbidity and mortality in this patient group. Preoperative fasting, glucose-free infusions during long and invasive operations and delayed postoperative nutrition therapy aggravate the nutrition situation. However, conclusive evidence for this population, consisting of well-conducted clinical trials is lacking.This article outlines the main causes for malnutrition in cardiosurgical patients and summarizes possibilities to identify patients at high nutritional risk, who are most likely to profit from aggressive nutritional therapy. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy based on current recommendations of ASPEN, ESPEN and an international multidisciplinary consensus group is presented. The amount and kind of nutrition, as well as the best time to initiate nutrition support, ways to monitor nutrition therapy and the potential use of pharmaconutrition to modulate the inflammatory response to cardiopulmonary bypass are presented to benefit patients undergoing cardiac surgery.

[Position paper on working in the intensive care unit during pregnancy : DIVI recommendations for improving the situation of pregnant employees in the ICU]. / Positionspapier zum Arbeiten in der Schwangerschaft auf der Intensivstation : DIVI-Empfehlungen zur Verbesserung der Lage von schwangeren Mitarbeiterinnen auf einer Intensivstation.

The Maternity Protection Act is intended to protect the mother and the child from hazards, excessive demands and damage to health in the workplace, and from financial disadvantages and loss of employment. However, the objectives defined by the Maternity Protection Act-the safety and health of the pregnant employee on the one hand and the prevention of disadvantages in working life on the other-are not yet adequately achieved in the intensive care unit (ICU). Implementation of the Maternity Protection Act to the benefit of all involved parties should also be promoted in the specialist areas represented by the DIVI, in particular the work of pregnant physicians and nursing staff and other working specialists (respiratory therapists, physiotherapists, speech therapists, psychotherapists, and social workers) in the ICU. The aim of this paper is to raise awareness of the need to consider each pregnant and breastfeeding staff member individually and to work together to find a personal solution for continuing to work in the ICU. Possible ways and solutions to achieve this goal are outlined and practical examples are given for implementation in everyday clinical routine. These are also based on comprehensive presentation of activities according to a traffic light color-code system for all occupational groups. Arguments against pregnant employees working in the ICU are discussed and possible solutions are presented.

[Position paper on working in the intensive care unit during pregnancy : DIVI recommendations for improving the situation of pregnant employees in the ICU]. / Positionspapier zum Arbeiten in der Schwangerschaft auf der Intensivstation : DIVI-Empfehlungen zur Verbesserung der Lage von schwangeren Mitarbeiterinnen auf einer Intensivstation.

The Maternity Protection Act is intended to protect the mother and the child from hazards, excessive demands and damage to health in the workplace, and from financial disadvantages and loss of employment. However, the objectives defined by the Maternity Protection Act-the safety and health of the pregnant employee on the one hand and the prevention of disadvantages in working life on the other-are not yet adequately achieved in the intensive care unit (ICU). Implementation of the Maternity Protection Act to the benefit of all involved parties should also be promoted in the specialist areas represented by the DIVI, in particular the work of pregnant physicians and nursing staff and other working specialists (respiratory therapists, physiotherapists, speech therapists, psychotherapists, and social workers) in the ICU. The aim of this paper is to raise awareness of the need to consider each pregnant and breastfeeding staff member individually and to work together to find a personal solution for continuing to work in the ICU. Possible ways and solutions to achieve this goal are outlined and practical examples are given for implementation in everyday clinical routine. These are also based on comprehensive presentation of activities according to a traffic light color-code system for all occupational groups. Arguments against pregnant employees working in the ICU are discussed and possible solutions are presented.

[Vitamin C and D supplementation in critically ill patients]. / Supplementierung von Vitamin C und D bei kritisch Kranken.

Micronutrient supplementation as part of the medical nutrition therapy for critically ill patients has received much attention in the past few years. Nevertheless, in clinical practice uncertainty remains about the optimal supplementation strategy, including which substance at which dosage should be administered at what time to specific groups of patients. Thus, the aim of this narrative review is to summarize the current evidence and recommendations for the micronutrients vitamin C and vitamin D. The physiological and pathophysiological roles of both vitamins are presented, recently published clinical trials are discussed, and the recommendations of the current guidelines are summarized. In addition, pragmatic tips for use in everyday clinical practice in the intensive care unit are given.

History of scurvy and use of vitamin C in critical illness: A narrative review.

In 1747, an important milestone in the history of clinical research was set, as the Scottish surgeon James Lind conducted the first randomized controlled trial. Lind was interested in scurvy, a severe vitamin C deficiency which caused the death of thousands of British seamen. He found that a dietary intervention with oranges and lemons, which are rich in vitamin C by nature, was effective to recover from scurvy. Because of its antioxidative properties and involvement in many biochemical processes, the essential micronutrient vitamin C plays a key role in the human biology. Moreover, the use of vitamin C in critical illness-a condition also resulting in death of thousands in the 21st century-has gained increasing interest, as it may restore vascular responsiveness to vasoactive agents, ameliorate microcirculatory blood flow, preserve endothelial barriers, augment bacterial defense, and prevent apoptosis. Because of its redox potential and powerful antioxidant capacity, vitamin C represents an inexpensive and safe antioxidant, with the potential to modify the inflammatory cascade and improve clinical outcomes of critically ill patients. This narrative review aims to update and provide an overview on the role of vitamin C in the human biology and in critically ill patients, and to summarize current evidence on the use of vitamin C in diverse populations of critically ill patients, in specific focusing on patients with sepsis and coronavirus disease 2019.

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.

[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.

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.

An update of the effects of vitamins D and C in critical illness.

Many critically ill patients are vitamin D and vitamin C deficient and the current international guidelines state that hypovitaminoses should be compensated. However, uncertainty about optimal dosage, timing and indication exists in clinical routine, mainly due to the conflicting evidence. This narrative review discusses both micronutrients with regards to pathophysiology, clinical evidence of benefits, potential risks, and guideline recommendations. Evidence generated from the most recent clinical trials are summarized and discussed. In addition, pragmatic tips for the application of these vitamins in the clinical routine are given. The supplementations of vitamin D and C represent cost-effective and simple interventions with excellent safety profiles. Regarding vitamin D, critically ill individuals require a loading dose to improve 25(OH)D levels within a few days, followed by a daily or weekly maintenance dose, usually higher doses than healthy individuals are needed. For vitamin C, dosages of 100-200 mg/d are recommended for patients receiving parenteral nutrition, but needs may be as high as 2-3 g/d in acutely ill patients.

Combination of enteral and parenteral nutrition in the acute phase of critical illness: An updated systematic review and meta-analysis.

BACKGROUND: Uncertainty remains about the best route and timing of medical nutrition therapy in the acute phase of critical illness. Early combined enteral nutrition (EN) and parenteral nutrition (PN) may represent an attractive option to achieve recommended energy and protein goals in select patient groups. This meta-analysis aims to update and summarize the current evidence. METHODS: This systematic review and meta-analysis includes randomized controlled trials (RCTs) targeting the effect of EN alone vs a combination of EN with PN in the acute phase of critical illness in adult patients. Assessed outcomes include mortality, intensive care unit (ICU) and hospital length of stay (LOS), ventilation days, infectious complications, physical recovery, and quality-of-life outcomes. RESULTS: Twelve RCTs with 5543 patients were included. Treatment with a combination of EN with PN led to increased delivery of macronutrients. No statistically significant effect of a combination of EN with PN vs EN alone on any of the parameters was observed: mortality (risk ratio = 1.0; 95% CI, 0.79-1.28; P = .99), hospital LOS (mean difference, -1.44; CI, -5.59 to 2.71; P = .50), ICU LOS, and ventilation days. Trends toward improved physical outcomes were observed in two of four trials. CONCLUSION: A combination of EN with PN improved nutrition intake in the acute phase of critical illness in adults and was not inferior regarding the patients' outcomes. Large, adequately designed trials in select patient groups are needed to answer the question of whether this nutrition strategy has a clinically relevant treatment effect.

Proenkephalin A and bioactive adrenomedullin are useful for risk prognostication in cardiac surgery.

Introduction: Various clinical scores have been developed to predict organ dysfunction and mortality in patients undergoing cardiac surgery, but outcome prediction may be inaccurate for some patient groups. Proenkephalin A (penKid) and bioactive adrenomedullin (bio-ADM) have emerged as promising biomarkers correlating with shock and organ dysfunction. This imposes the question of whether they can be used as prognostic biomarkers for risk stratification in the perioperative setting of cardiac surgery. Methods: Patients undergoing cardiac surgery were prospectively enrolled in this observational study. PenKid and bio-ADM plasma levels, as well as markers evaluating inflammation and organ dysfunction, were measured at five perioperative time points from before the induction of anesthesia to up to 48 h postoperatively. Clinical data regarding organ dysfunction and patient outcomes were recorded during the intensive care unit (ICU)-stay with a special focus on acute kidney injury (AKI). Results: In 136 patients undergoing cardiac surgery, the bio-ADM levels increased and the penKid levels decreased significantly over time. PenKid was associated with chronic kidney disease (CKD), the incidence of AKI, and renal replacement therapy (RRT). Bio-ADM was associated with lactate and the need for vasopressors. PenKid was useful to predict an ICU-length of stay (LOS)>1 day and added prognostic value to the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE) II when measured after the end of cardiopulmonary bypass and 24 h after cardiac surgery. For bio-ADM, the same was true when measured 24 h after surgery. PenKid also added prognostic value to the EuroSCORE II for the combined outcome "ICU length of stay >1 day and in-hospital mortality." Conclusion: The combination of preoperative EuroSCORE II and intraoperative measurement of penKid may be more useful to predict a prolonged ICU LOS and increased mortality than EuroSCORE II alone. Bio-ADM correlates with markers of shock. More research is encouraged for early risk stratification and validation of penKid and bio-ADM as a tool involved in clinical decisions, which may enable the early initiation of organ protective strategies.