Letter to the Editor: Double-counting due to inadequate statistics leads to false-positive findings in "Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials".

Prokopidis et al have conducted a meta-analysis of randomized, placebo-controlled clinical trials to assess the effects of oral creatine supplementation on memory performance of healthy individuals. However, concerns were raised regarding the validity of their statistical analyses, which may have led to misleading conclusions. In this letter, we describe the statistical issue at hand and its potential implications.

Effect of tocilizumab, sarilumab, and baricitinib on mortality among patients hospitalized for COVID-19 treated with corticosteroids: a systematic review and meta-analysis.

BACKGROUND: Randomized controlled trials (RCT) established the mortality reduction by tocilizumab (Actemra), baricitinib (Olumiant), and sarilumab (Kevzara) in hospitalized COVID-19 patients. However, uncertainty remains about which treatment performs best in patients receiving corticosteroids. OBJECTIVES: To estimate probabilities of noninferiority between baricitinib and sarilumab compared to tocilizumab in patients treated with corticosteroids. DATA SOURCES: PubMed, Embase, Cochrane Library, and MedRxiv. STUDY ELIGIBILITY CRITERIA: Eligible RCTs assigning hospitalized adults with COVID-19 treated with corticosteroids to tocilizumab or baricitinib or sarilumab versus standard of care or placebo (control). METHODS: Reviewers independently abstracted published data and assessed study quality with the Risk of Bias 2 tool. Unpublished data, if required, were requested from authors of included studies. The outcome of interest was all-cause mortality at 28 days. PARTICIPANTS: Twenty-seven RCTs with 13 549 patients were included. Overall, the risk of bias was low. Bayesian pairwise meta-analyses were used to aggregate results of each treatment versus control. The average odds ratio for mortality was 0.78 (95% credible interval [CrI]: 0.65, 0.94) for tocilizumab; 0.78 (95% CrI: 0.56, 1.03) for baricitinib; and 0.91 (95% CrI: 0.60, 1.40) for sarilumab. The certainty of evidence (GRADE) ranged from moderate to low. Bayesian meta-regressions with multiple priors were used to estimate probabilities of noninferiority (margin of 13% greater effect by tocilizumab). Compared to tocilizumab, there were ≤94% and 90% probabilities of noninferiority with baricitinib and sarilumab, respectively. RESULTS: All but two studies included data with only indirect evidence for the comparison of interest. CONCLUSIONS: Among hospitalized COVID-19 treated with corticosteroids, there are high probabilities that both baricitinib and sarilumab are associated with similar mortality reductions in comparison to tocilizumab.

Quality appraisal of clinical nutrition practice guidelines for critically ill adult patients: a systematic review using the Advancing Guideline Development, Reporting and Evaluation in Health Care instrument II (AGREE-II) and AGREE-Recommendation Excellence (AGREE-REX).

Nutritional therapy should follow evidence-based practice, thus several societies regarding nutrition and critical care have developed specific Clinical Practice Guidelines (CPG). However, to be regarded as trustworthy, the quality of the CPG for critically ill patients and its recommendations need to be high. This systematic review aimed to appraise the methodology and recommendations of nutrition CPG for critically ill patients. We performed a systematic review (protocol number CRD42020184199) with literature search conducted on PubMed, Embase, Cochrane Library and other four specific databases of guidelines up to October 2021. Two reviewers, independently, assessed titles and abstracts and potentially eligible full-text reports to determine eligibility and subsequently four reviewers appraised the guidelines quality using the Advancing Guideline Development, Reporting and Evaluation in Health Care instrument II (AGREE-II) and AGREE-Recommendation Excellence (AGREE-REX). Ten CPG for nutrition in critically ill patients were identified. Only Academy of Nutrition and Dietetics and European Society of Intensive Care Medicine had a total acceptable quality and were recommended for daily practice according AGREE-II. None of the CPG recommendations had an overall quality score above 70 %, thus being classified as moderate quality according AGREE-REX. The methodological evaluation of the critically ill adult patient CPG revealed significant discrepancies and showed a need for improvement in its development and/or reporting. In addition, recommendations about nutrition care process presented a moderate quality.

Prognostic value of phase angle and bioelectrical impedance vector in critically ill patients: A systematic review and meta-analysis of observational studies.

BACKGROUND AND AIMS: Assessment of the raw parameters derived from bioelectrical impedance analysis (BIA) has gained emphasis in critically ill patients. The phase angle (PhA) reflects the integrity of the cell membrane, and bioelectrical impedance vector analysis (BIVA) is indicative of patients' hydration status. The aim of this study was to investigate whether these parameters are associated with clinical outcomes in the intensive care unit (ICU) setting. METHODS: We conducted a systematic review with meta-analysis. We searched PubMed, Embase, Scopus and Web of Science for all published observational studies without language restrictions up to April 2022. Two reviewers independently performed study selection and data extraction. We judged the risk of bias by the Newcastle-Ottawa Scale and the certainty of evidence by the GRADE approach. Mortality was the primary outcome. Secondary outcomes included ICU length of stay, hospital length of stay, duration of mechanical ventilation, nutritional risk, and malnutrition. A meta-analysis with a random-effect model was performed to combine data on R version 3.6.2. RESULTS: Twenty-seven studies were included in the systematic review (4872 participants). Pooled analysis revealed that patients with low PhA had a higher risk of death (14 studies; RR = 1.82, 95% CI 1.46 to 2.26; I2 = 42%) and spent more days in ICU (6 studies; MD = 1.79, 95% CI 0.33 to 3.24, I2 = 69%) in comparison to patients with normal PhA. The pooled analysis also showed higher PhA values in survivors compared to non-survivor patients (12 studies; MD = 0.75°, 95% CI 0.60° to 0.91°, I2 = 31%). Overhydration defined by BIVA was not a predictor of mortality (4 studies; RR = 1.01, 95% CI 0.70 to 1.46; I2 = 0%). More than 40% of primary studies were classified with a high risk of bias, and the quality of evidence ranged from low to very low. CONCLUSIONS: This meta-analysis revealed, with limited evidence, that low PhA was associated with higher mortality and ICU length of stay, while overhydration identified by BIVA was not a predictor of death in critically ill patients.

Markers of respiratory function response to high-carbohydrate and high-fat intake in patients with lung diseases: a systematic review with meta-analysis of randomized clinical trials.

BACKGROUND: Macronutrients can differently affect respiratory function markers such as VO2 , VCO2 , PaO2 , PaCO2 , and respiratory quotients (RQs), but systematic appraisal of the evidence on randomized clinical trials (RCTs) is lacking. OBJECTIVE: The objective of this work is to compare the response of respiratory function markers with high-carbohydrate and high-fat intake in patients with lung diseases. METHODS: Systematic review conducted according to Cochrane Collaboration recommendations, reported following Preferred Reporting Items for Systematic Reviews and Meta-Analysis for pairwise systematic reviews of interventions 2020. PubMed, EMBASE, Scopus, and Cochrane CENTRAL were searched up to July 2021. Two reviewers selected the RCTs and extracted the data. Risk of bias and the certainty of evidence were assessed by RoB 2 and Grading of Recommendations Assessment, Development, and Evaluation System criteria, respectively. Statistical and graphical data guided the publication bias investigation. Meta-analyses were conducted. RESULTS: We included 14 RCTs (362 participants), four of which were parallel. Most studies included patients with chronic obstructive pulmonary disease. High-fat intake decreased VCO2 (mean difference [MD] = -35.89 ml/min [95% confidence interval (CI), -45.24 to -26.21]); I² = 0%), VO2 (MD = -29.30 ml/min [95% CI, -40.94 to -17.66]; I² = 0%), PaCO2 mm Hg (MD = -4.62 [95% CI, -7.67 to -1.58]; I² = 84%), and RQ (MD = -0.08 [95% CI, -0.09 to -0.06]; I² = 0%) in the subset of parallel RCTs. In crossover RCTs, there was generally no evidence of effect except for a greater decrease in RQ (MD = -0.09 [95% CI, -0.12 to -0.02]; I² = 96%) in favor of high-fat intake. CONCLUSION: High-fat intake resulted in greater reductions of VCO2 , VO2 , PaCO2 , and RQ in adult patients with lung diseases. The certainty of the evidence is very low/low, and it precludes a specific recommendation on macronutrients contribution to energy intake of these patients.

Increased energy and/or protein intake improves anthropometry and muscle strength in chronic obstructive pulmonary disease patients: a systematic review with meta-analysis on randomised controlled clinical trials.

Compromised nutritional status is associated with a poor prognosis in chronic obstructive pulmonary disease (COPD) patients. However, the impact of nutritional support in this group of patients is controversial. The present study systematically reviewed the effect of energy and or protein supplements or food fortification on anthropometry and muscle strength of COPD patients. We searched MEDLINE (PubMed), EMBASE, Cochrane Library and Scopus for all published randomised clinical trials without language restriction up to May 2021. Three reviewers performed study selection and data extraction independently. We judged the risk of bias by RoB 2 and the certainty of evidence by the GRADE approach. We included thirty-two randomised controlled trials and compiled thirty-one of them (1414 participants) in the random-effects model meta-analyses. Interventions were energy and/or protein oral nutritional supplements or food fortification added to the diet for at least one week. Pooled analysis revealed that nutritional interventions increased body weight (muscle circumference (MD) = 1·44 kg, 95 % CI 0·81, 2·08, I2 = 73 %), lean body mass (standardised mean difference (SMD) = 0·37; 95 % CI 0·15, 0·59, I2 = 46 %), midarm muscle circumference (MD = 0·29 mm2, 95 % CI 0·02, 0·57, I2 = 0 %), triceps skinfold (MD = 1·09 mm, 95 % CI 0·01, 2·16, I2 = 0 %) and handgrip strength (SMD = 0·39, 95 % CI 0·07, 0·71, I2 = 62 %) compared with control diets. Certainty of evidence ranged from very low to low, and most studies were judged with some concerns or at high risk of bias. This meta-analysis revealed, with limited evidence, that increased protein and/or energy intake positively impacts anthropometric measures and handgrip strength of COPD patients.

Effects of different sources of dietary protein on markers of kidney function in individuals with diabetes: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: The type of dietary protein may modulate markers of diabetic kidney disease; however, no attempt to summarize the evidence from randomized controlled trials (RCTs) has been performed to date. OBJECTIVE: To assess the effects of different types of dietary protein on urinary albumin excretion and glomerular filtration rate in individuals with diabetes. DATA SOURCES: MEDLINE, EMBASE, and Scopus were searched for all published RCTs, with no language restriction, up to July 2020. DATA EXTRACTION: Study selection and data extraction were performed independently by 3 authors. Risk of bias was assessed independently by 2 authors, and the GRADE approach was used to assess the quality of the evidence. RESULTS: Twelve RCTs were included, of which 11 (involving 228 participants) were compiled in meta-analyses of random-effects models. Interventions consisted of diets emphasizing plant or white meat protein, with reduced intake of animal or red meat protein. Pooled data from crossover trials (n = 8) favored intervention diets for urinary albumin excretion (ratio of means, 0.86; 95% confidence interval 0.80 to 0.94; I2 = 4%) and glomerular filtration rate (ratio of means, 0.90; 95% confidence interval 0.87 to 0.94; I2 = 45%), compared with control diets. Results from parallel-design studies (n = 3), however, were not statistically significant for any outcome. The quality of the evidence ranged from very low to moderate, and most studies were judged with at least some concerns in terms of risk of bias. CONCLUSION: This meta-analysis found weak evidence for small to moderate improvements in markers of kidney function in favor of interventions with lower animal protein (or red meat protein) compared with usual diets in short-term crossover trials. These findings require confirmation in well-designed randomized controlled trials.

Association of specialized enteral nutrition with glycemic control and clinical outcomes in critically ill patients: A meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the association of glycemic-control formulae (GCF) with measurements of glycemic control and clinical outcomes compared to standard enteral formulae (SF) in critically ill patients. DATA SOURCES: MEDLINE, EMBASE, Scopus and the Cochrane Central Register of Controlled Trials were searched from inception up to January, 2021. STUDY SELECTION: RCTs that assessed the effects of GCF relative to SF in adult critically ill patients. DATA EXTRACTION: Measurements of glycemic control were the primary outcomes. Secondary outcomes included insulin requirements, mechanical ventilation (MV), length of intensive care unit (ICU) stay and mortality. Two authors independently extracted data and assessed risk of bias using the Cochrane's RoB 2 tool and the GRADE approach was used to assess the quality of evidence. DATA SYNTHESIS: Ten studies (12 reports, 685 patients) were included. The use of GCFs was associated with lower blood glucose (WMD, -16.06 mg/dL; 95% CI -23.48 to -8.63; I2 = 47%) and lower daily administered insulin (WMD, -7.20 IU; 95% CI -13.92 to -0.48; I2 = 53%). Glycemic variability, measured by the coefficient of variation, was also associated with the use of GCFs (WMD, -6.84%; 95% CI, -13.57 to -0.11; I2 = 95%). In contrast, analyses for length of ICU stay (WMD, -0.12, 95% CI -1.77 to 1.52; I2 = 0%), duration of MV (WMD, -0.34 days; 95% CI, -1.72 to 1.04; I2 = 0%) and mortality (RR, 1.13; 95% CI 0.82 to 1.56; I2 = 0%) were not statistically significant. Quality of evidence ranged from low to very low, and only one study was judged as at low risk of bias. CONCLUSIONS: In this meta-analysis, GCFs were significantly associated with lower insulin requirements and improved glycemic control. Although results for clinical outcomes were not statistically significant, there is insufficient evidence to confirm or exclude important differences due to serious imprecision in the effect estimates and overall low quality of evidence. The effects of GCFs on clinical outcomes require confirmation in larger randomized trials.

Accuracy of three tools for malnutrition diagnosis in hospitalised patients: Comparison to subjective global assessment.

BACKGROUND: Malnutrition is prevalent in hospital, and the Subjective Global Assessment (SGA) has been widely used for its identification. However, in the last decade, new tools were proposed by the Academy of Nutrition and Dietetics-American Society for Parenteral and Enteral Nutrition (AND-ASPEN), European Society for Clinical Nutrition and Metabolism (ESPEN) and Global Leadership Initiative on Malnutrition (GLIM). The diagnostic test accuracy of these tools has been scarcely investigated. Thus, we aimed to compare the accuracy of AND-ASPEN, ESPEN and GLIM for malnutrition diagnosis in hospitalised patients. METHODS: A cross-sectional study was conducted with hospitalised patients aged ≥ 18 years from a five-unit complex hospital. Malnutrition was diagnosed within 48 h of admission using SGA, AND-ASPEN, ESPEN and GLIM. The accuracy of these tools was evaluated by the area under the receiver operating characteristic (AUROC) curve, considering SGA as reference, which was compared by the DeLong test. RESULTS: Six hundred patients (55.7 ± 14.8 years, 51.3% male) were evaluated. AND-ASPEN [AUROC 0.846; 95% confidence interval (CI) = 0.810-0.883] and GLIM presented a satisfactory accuracy (AUROC 0.842; 95% CI, 0.807-0.877), whereas ESPEN had a substantially lower accuracy (AUROC, 0.572; 95% CI, 0.522-0.622). The AUROC of AND-ASPEN and GLIM were not different from each other (p = 0.785) and both had significantly higher accuracy than ESPEN (p < 0.001). AND-ASPEN and GLIM presented sensitivity, specificity and negative predictive value > 80%, whereas ESPEN sensitivity was < 20%. CONCLUSIONS: AND-ASPEN and GLIM were accurate methods for diagnosing malnutrition and could be applied in hospitalised patients. By contrast, the ESPEN criteria had unsatisfactory accuracy.

Decline of nutritional status in the first week of hospitalisation predicts longer length of stay and hospital readmission during 6-month follow-up.

Nutritional status (NS) monitoring is an essential step of the nutrition care process. To assess changes in NS throughout hospitalisation and its ability to predict clinical outcomes, a prospective cohort study with patients over 18 years of age was conducted. The Subjective Global Assessment (SGA) was performed within 48 h of admission and 7 d later. For each patient, decline in NS was assessed by two different methods: changes in SGA category and severe weight loss alone (≥2 % during the first week of hospitalisation). Patients were followed up until discharge to assess length of hospital stay (LOS) and in-hospital mortality and contacted 6 months post-discharge to assess hospital readmission and death. Out of the 601 patients assessed at admission, 299 remained hospitalised for at least 7 d; of those, 16·1 % had a decline in SGA category and 22·8 % had severe weight loss alone. In multivariable analysis, decline in SGA category was associated with 2-fold (95 % CI 1·06, 4·21) increased odds of prolonged LOS and 3·6 (95 % CI 1·05, 12·26) increased odds of hospital readmission at 6 months. Severe weight loss alone was associated with 2·5-increased odds (95 % CI 1·40, 4·64) of prolonged LOS. In conclusion, deterioration of NS was more often identified by severe weight loss than by decline in SGA category. While both methods were associated with prolonged LOS, only changes in the SGA predicted hospital readmission. These findings reinforce the importance of nutritional monitoring and provide guidance for further research to prevent short-term NS deterioration from being left undetected.

Nutritional risk in critically ill patients: how it is assessed, its prevalence and prognostic value: a systematic review.

CONTEXT: Nutritional risk (NR) screening is the first step of nutrition care process. Few data are available in literature about its prevalence, nor, to our knowledge, is a universally accepted reference method for the intensive care unit (ICU). OBJECTIVE: The aim for this systematic review was to summarize evidence regarding the prevalence of NR and the predictive validity of different tools applied for NR screening of critically ill patients. DATA SOURCES: The PubMed, Embase, and Scopus databases were searched up to December 2019 using the subject headings related to critically ill patients and NR screening. The current systematic review is registered with PROSPERO (identifier: CRD42019129668). DATA EXTRACTION: Data on NR prevalence, predictive validity of nutritional screening tools, and interaction between caloric-protein balance and NR in outcome prediction were collected. DATA ANALYSIS: Results were summarized qualitatively in text and tables, considering the outcomes of interest. RESULTS: From 15 669 articles initially identified, 36 fulfilled the inclusion criteria, providing data from 8 nutritional screening tools: modified Nutrition Risk in the Critically Ill (mNUTRIC; n = 26 studies) and Nutritional Risk Screening-2002 (NRS-2002; n = 7 studies) were the most frequent; the NR prevalence was 55.9% (range, 16.0% to 99.5%). Nutritional risk was a predictor of 28-day and ICU mortality in 8 studies. Interactions between caloric-protein balance and NR on outcome prediction presented were scarcely tested and presented heterogeneous results (n = 8). CONCLUSIONS: Prevalence of NR in patients in the ICU varies widely; a satisfactory predictive validity was observed, especially when mNUTRIC or NRS-2002 were applied.