The effect of high-dose selenium on mortality and postoperative organ dysfunction in post-cardiotomy cardiogenic shock patients supported with mechanical circulatory support - A post-hoc analysis of the SUSTAIN CSX trial.

PURPOSE: Cardiac surgery, post-cardiotomy cardiogenic shock (PCCS), and temporary mechanical circulatory support (tMCS) provoke substantial inflammation. We therefore investigated whether a selenium-based, anti-inflammatory strategy would benefit PCCS patients treated with tMCS in a post-hoc analysis of the sustain CSX trial. METHODS: Post-hoc analysis of patients receiving tMCS for PCCS in the Sustain CSX trial, which investigated the effects of high-dose selenium on postoperative organ dysfunction in cardiac surgery patients. PRIMARY OUTCOME: duration of tMCS therapy. SECONDARY OUTCOMES: postoperative organ dysfunction and 30-day mortality. RESULTS: Thirty-nine patients were treated with tMCS for PCCS. There was no difference in the median duration of tMCS between the selenium and the placebo group (3 days [IQR: 1-6] vs. 2 days [IQR: 1-7], p = 0.52). Median dialysis duration was longer in the selenium group (1.5 days [0-21.8] vs. 0 days [0-1.8], p = 0.048). There was no difference in 30-day mortality (53% vs. 41%, OR 1.44, 95% CI 0.32-6.47, p = 0.62). CONCLUSION: In this explorative study, a perioperative high-dose selenium-supplementation did not show beneficial effects on organ dysfunctions and mortality rates in patients with PCCS receiving tMCS.

Outcomes of extracorporeal blood purification with oXiris® membrane in critically ill patients: A systematic review and meta-analysis.

PURPOSE: To evaluate the efficacy of the novel oXiris® membrane in critically ill adult patients. METHODS: We systematically searched MEDLINE, EMBASE, and CENTRAL from inception to 01/06/2023 for relevant randomised controlled trials (RCTs) and non-randomised studies of intervention (NRSI). The primary outcome was overall mortality. Random effect meta-analyses were conducted in RevMan 5.4.1. Study quality was evaluated using Cochrane's risk of bias tool. (PROSPERO: CRD42023389198). RESULTS: Ten studies (2 RCTs and 8 NRSIs) with 481 patients were included. None had low risk of bias. Treatment using oXiris® was associated with reduced overall mortality (RR 0.78, 95%CI 0.62-0.98; p = 0.03; 6 NRSI). One RCT reported 28-day mortality, finding no significant difference between groups. Besides, pooled NRSIs results showed significant reductions in SOFA scores, norepinephrine dosage, and several inflammatory biomarkers (C-reactive protein [CRP], lactate, and interleukin-6 [IL-6]) post oXiris® treatment. However, other clinical outcomes (ICU and hospital length of stay, mechanical ventilation duration) were similar between groups. CONCLUSION: In critically ill patients, the use of oXiris® membrane was associated with reduced overall mortality, norepinephrine dosage, CRP, IL-6, lactate levels, along with improved organ function. However, the certainty of evidence was very low, necessitating high-quality RCTs to further evaluate its efficacy in this population.

Early experience of using regional citrate anticoagulation for continuous renal replacement therapy in critically ill patients in a resource-limited setting.

AIM: Despite the superiority of regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT), its application is limited in resource-limited settings. We aim to explore the cost and safety of RCA for CRRT in critically ill patients, compared to usual care. METHODS: This prospective observational study included patients requiring CRRT in a tertiary intensive care unit (ICU) from February 2022 to January 2023. They were classified to either the RCA or usual care groups based on the anticoagulation technique chosen by the treating physician, considering contraindications. The CRRT prescription follows the institutional protocol. All relevant data were obtained from the ICU CRRT-RCA charts and electronic medical records. A cost analysis was performed. RESULTS: A total of 54 patients (27 per group) were included, with no demographic differences. Sequential Organ Failure Assessment score and lactate levels were significantly higher in the usual care group. The number of filters used were comparable (p = .108). The median filter duration in the RCA group was numerically longer (35.00 [15.50-56.00] vs. 23.00 [17.00-29.00] h), but not statistically significant (p = .253). The duration of mechanical ventilation, vasopressor requirement, and mortality were similar, but the RCA group had a significantly longer ICU stay. The rate of adverse events was similar, with four severe metabolic alkalosis cases in the RCA group. The RCA group had higher total cost per patient per day (USD 611 vs. 408; p = .013). CONCLUSION: In this resource-limited setting, RCA for CRRT appeared safe and had clinically longer filter lifespan compared with usual care, albeit the increased cost.

The effect of a selenium-based anti-inflammatory strategy on postoperative functional recovery in high-risk cardiac surgery patients - A nested sub-study of the sustain CSX trial.

AIM: The cardiac surgery-related ischemia-reperfusion-related oxidative stress triggers the release of cytotoxic reactive oxygen and nitrogen species, contributing to organ failure and ultimately influencing patients' short- and long-term outcomes. Selenium is an essential co-factor for various antioxidant enzymes, thereby contributing to the patients' endogenous antioxidant and anti-inflammatory defense mechanisms. Given these selenium's pleiotropic functions, we investigated the effect of a high-dose selenium-based anti-inflammatory perioperative strategy on functional recovery after cardiac surgery. MATERIALS AND METHODS: This prospective study constituted a nested sub-study of the SUSTAIN CSX trial, a double-blinded, randomized, placebo-controlled multicenter trial to investigate the impact of high-dose selenium supplementation on high-risk cardiac surgery patients' postoperative recovery. Functional recovery was assessed by 6-min walk distance, Short Form-36 (SF-36) and Barthel Index questionnaires. KEY FINDINGS: 174 patients were included in this sub-study. The mean age (SD) was 67.3 (8.9) years, and 78.7 % of the patients were male. The mean (SD) predicted 30-day mortality by the European System for Cardiac Operative Risk Evaluation II score was 12.6 % (9.4 %). There was no difference at hospital discharge and after three months in the 6-min walk distance between the selenium and placebo groups (131 m [IQR: not performed - 269] vs. 160 m [IQR: not performed - 252], p = 0.80 and 400 m [IQR: 299-461] vs. 375 m [IQR: 65-441], p = 0.48). The SF-36 and Barthel Index assessments also revealed no clinically meaningful differences between the selenium and placebo groups. SIGNIFICANCE: A perioperative anti-inflammatory strategy with high-dose selenium supplementation did not improve functional recovery in high-risk cardiac surgery patients.

The Association Between Malnutrition and High Protein Treatment on Outcomes in Critically Ill Patients: A Post Hoc Analysis of the EFFORT Protein Randomized Trial.

BACKGROUND: Preexisting malnutrition in critically ill patients is associated with adverse clinical outcomes. Malnutrition can be diagnosed with the Global Leadership Initiative on Malnutrition using parameters such as weight loss, muscle wasting, and BMI. International critical care nutrition guidelines recommend high protein treatment to improve clinical outcomes in critically ill patients diagnosed with preexisting malnutrition. However, this recommendation is based on expert opinion. RESEARCH QUESTION: In critically ill patients, what is the association between preexisting malnutrition and time to discharge alive (TTDA), and does high protein treatment modify this association? STUDY DESIGN AND METHODS: This multicenter randomized controlled trial involving 16 countries was designed to investigate the effects of high vs usual protein treatment in 1,301 critically ill patients. The primary outcome was TTDA. Multivariable regression was used to identify if preexisting malnutrition was associated with TTDA and if protein delivery modified their association. RESULTS: The prevalence of preexisting malnutrition was 43.8%, and the cumulative incidence of live hospital discharge by day 60 was 41.2% vs 52.9% in the groups with and without preexisting malnutrition, respectively. The average protein delivery in the high vs usual treatment groups was 1.6 g/kg per day vs 0.9 g/kg per day. Preexisting malnutrition was independently associated with slower TTDA (adjusted hazard ratio, 0.81; 95% CI, 0.67-0.98). However, high protein treatment in patients with and without preexisting malnutrition was not associated with TTDA (adjusted hazard ratios of 0.84 [95% CI, 0.63-1.11] and 0.97 [95% CI, 0.77-1.21]). Furthermore, no effect modification was observed (ratio of adjusted hazard ratio, 0.84; 95% CI, 0.58-1.20). INTERPRETATION: Malnutrition was associated with slower TTDA, but high protein treatment did not modify the association. These findings challenge current international critical care nutrition guidelines. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03160547; URL: www. CLINICALTRIALS: gov.

The impact of high versus standard enteral protein provision on functional recovery following intensive care admission: Protocol for a pre-planned secondary Bayesian analysis of the PRECISe trial.

BACKGROUND: The PRECISe trial is a pragmatic, multicenter randomized controlled trial that evaluates the effect of high versus standard enteral protein provision on functional recovery in adult, mechanically ventilated critically ill patients. The current protocol presents the rationale and analysis plan for an evaluation of the primary and secondary outcomes under the Bayesian framework, with an emphasis on clinically important effect sizes. METHODS: This protocol was drafted in agreement with the ROBUST-statement, and is submitted for publication before database lock and primary data analysis. The primary outcome is health-related quality of life as measured by the EQ-5D-5L health utility score and is longitudinally assessed. Secondary outcomes comprise the 6-min walking test and handgrip strength over the entire follow-up period (longitudinal analyses), and 60-day mortality, duration of mechanical ventilation, and EQ-5D-5L health utility scores at 30, 90 and 180 days (cross-sectional). All analyses will primarily be performed under weakly informative priors. When available, informative priors elicited from contemporary literature will also be incorporated under alternative scenarios. In all other cases, objectively formulated skeptical and enthusiastic priors will be defined to assess the robustness of our results. Relevant identified subgroups were: patients with acute kidney injury, severe multi-organ failure and patients with or without sepsis. Results will be presented as absolute risk differences, mean differences, and odds ratios, with accompanying 95% credible intervals. Posterior probabilities will be estimated for clinically important benefit and harm. DISCUSSION: The proposed secondary, pre-planned Bayesian analysis of the PRECISe trial will provide additional information on the effects of high protein on functional and clinical outcomes in critically ill patients, such as probabilistic interpretation, probabilities of clinically important effect sizes, and the integration of prior evidence. As such, it will complement the interpretation of the primary outcome as well as several secondary and subgroup analyses.

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.

Enhanced exclusive enteral nutrition delivery during the first 7 days is associated with decreased 28-day mortality in critically ill patients with normal lactate level: a post hoc analysis of a multicenter randomized trial.

BACKGROUND AND AIMS: Exclusive enteral nutrition (EN) is often observed during the first week of ICU admission because of the extra costs and safety considerations for early parenteral nutrition. This study aimed to assess the association between nutrition intake and 28-day mortality in critically ill patients receiving exclusive EN. METHODS: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion. RESULTS: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L. CONCLUSIONS: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L. TRIAL REGISTRATION: ISRCTN12233792, registered on November 24, 2017.

A Comparison of High and Usual Protein Dosing in Critically Ill Patients With Obesity: A Post Hoc Analysis of an International, Pragmatic, Single-Blinded, Randomized Clinical Trial.

OBJECTIVES: Across guidelines, protein dosing for critically ill patients with obesity varies considerably. The objective of this analysis was to evaluate whether this population would benefit from higher doses of protein. DESIGN: A post hoc subgroup analysis of the effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicenter, pragmatic, registry-based randomized trial. SETTING: Eighty-five adult ICUs across 16 countries. PATIENTS: Patients with obesity defined as a body mass index (BMI) greater than or equal to 30 kg/m 2 ( n = 425). INTERVENTIONS: In the primary study, patients were randomized into a high-dose (≥ 2.2 g/kg/d) or usual-dose protein group (≤ 1.2 g/kg/d). MEASUREMENTS AND MAIN RESULTS: Protein intake was monitored for up to 28 days, and outcomes (time to discharge alive [TTDA], 60-d mortality, days of mechanical ventilation [MV], hospital, and ICU length of stay [LOS]) were recorded until 60 days post-randomization. Of the 1301 patients in the primary study, 425 had a BMI greater than or equal to 30 kg/m 2 . After adjusting for sites and covariates, we observed a nonsignificant slower rate of TTDA with higher protein that ruled out a clinically important benefit (hazard ratio, 0.78; 95% CI, 0.58-1.05; p = 0.10). We found no evidence of difference in TTDA between protein groups when subgroups with different classes of obesity or patients with and without various nutritional and frailty risk variables were examined, even after the removal of patients with baseline acute kidney injury. Overall, 60-day mortality rates were 31.5% and 28.2% in the high protein and usual protein groups, respectively (risk difference, 3.3%; 95% CI, -5.4 to 12.1; p = 0.46). Duration of MV and LOS in hospital and ICU were not significantly different between groups. CONCLUSIONS: In critically ill patients with obesity, higher protein doses did not improve clinical outcomes, including those with higher nutritional and frailty risk.

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.

The impact of higher protein dosing on outcomes in critically ill patients with acute kidney injury: a post hoc analysis of the EFFORT protein trial.

BACKGROUND: Based on low-quality evidence, current nutrition guidelines recommend the delivery of high-dose protein in critically ill patients. The EFFORT Protein trial showed that higher protein dose is not associated with improved outcomes, whereas the effects in critically ill patients who developed acute kidney injury (AKI) need further evaluation. The overall aim is to evaluate the effects of high-dose protein in critically ill patients who developed different stages of AKI. METHODS: In this post hoc analysis of the EFFORT Protein trial, we investigated the effect of high versus usual protein dose (≥ 2.2 vs. ≤ 1.2 g/kg body weight/day) on time-to-discharge alive from the hospital (TTDA) and 60-day mortality and in different subgroups in critically ill patients with AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria within 7 days of ICU admission. The associations of protein dose with incidence and duration of kidney replacement therapy (KRT) were also investigated. RESULTS: Of the 1329 randomized patients, 312 developed AKI and were included in this analysis (163 in the high and 149 in the usual protein dose group). High protein was associated with a slower time-to-discharge alive from the hospital (TTDA) (hazard ratio 0.5, 95% CI 0.4-0.8) and higher 60-day mortality (relative risk 1.4 (95% CI 1.1-1.8). Effect modification was not statistically significant for any subgroup, and no subgroups suggested a beneficial effect of higher protein, although the harmful effect of higher protein target appeared to disappear in patients who received kidney replacement therapy (KRT). Protein dose was not significantly associated with the incidence of AKI and KRT or duration of KRT. CONCLUSIONS: In critically ill patients with AKI, high protein may be associated with worse outcomes in all AKI stages. Recommendation of higher protein dosing in AKI patients should be carefully re-evaluated to avoid potential harmful effects especially in patients who were not treated with KRT. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT03160547) on May 17th 2017.

Association between intraoperative remifentanil use and postoperative hyperalgesia in adolescent idiopathic scoliosis surgery: a retrospective study.

BACKGROUND: The liberal use of remifentanil in spine surgery has been associated with an increased incidence of postoperative hyperalgesia. Nevertheless, controversies remain as the existing evidence is inconclusive to determine the relationship between remifentanil use and the development of opioid-induced hyperalgesia. We hypothesized that intraoperative infusion of higher dose remifentanil during scoliosis surgery is associated with postoperative hyperalgesia, manifesting clinically as greater postoperative morphine consumption and pain scores. METHODS: Ninety-seven patients with adolescent idiopathic scoliosis (AIS) who underwent posterior spinal fusion surgery at a single tertiary institution from March 2019 until June 2020 were enrolled in this retrospective study. Anesthesia was maintained using a target-controlled infusion of remifentanil combined with volatile anesthetic desflurane in 92 patients, while five patients received it as part of total intravenous anesthesia. Intravenous ketamine, paracetamol, and fentanyl were administered as multimodal analgesia. All patients received patient-controlled analgesia (PCA) morphine postoperatively. Pain scores at rest and on movement, assessed using the numerical rating scale, and the cumulative PCA morphine consumption were collected at a six-hourly interval for up to 48 h. According to the median intraoperative remifentanil dose usage of 0.215 µg/kg/min, patients were divided into two groups: low dose and high dose group. RESULTS: There were no significant differences in the pain score and cumulative PCA morphine consumption between the low and high dose remifentanil group. The mean duration of remifentanil infusion was 134.9 ± 22.0 and 123.4 ± 23.7 min, respectively. CONCLUSION: Intraoperative use of remifentanil as an adjuvant in AIS patients undergoing posterior spinal fusion surgery was not associated with postoperative hyperalgesia.

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.

Intravenous vitamin C monotherapy in critically ill patients: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: A recent landmark randomized controlled trial (RCT) in septic patients demonstrated an increased risk of death and persistent organ dysfunction with intravenous Vitamin C (IVVC) monotherapy, which represents a disparate result from previous systematic reviews and meta-analyses (SRMA). We performed an updated SRMA of IVVC monotherapy to summarize and explore heterogeneity across current trials and conduct trial sequential analysis (TSA) to guard against type-I or type-II statistical errors. METHODS: RCTs evaluating IVVC in adult critically ill patients were included. Four databases were searched from inception to 22 June 2022 without language restrictions. The primary outcome was overall mortality. Random effect meta-analysis was performed to estimate the pooled risk ratio. TSA for mortality was performed using the DerSimonian-Laird random effect model, alpha 5%, beta 10%, and relative risk reduction (RRR) of 30%, 25%, and 20%. RESULTS: We included 16 RCTs (n = 2130). IVVC monotherapy is associated with significant reduction in overall mortality [risk ratio (RR) 0.73, 95% confidence interval (CI) 0.60-0.89; p = 0.002; I2 = 42%]. This finding is supported by TSA using RRR of 30% and 25%, and sensitivity analysis using fixed-effect meta-analysis. However, the certainty of our mortality finding was rated low using GRADE due to the serious risk of bias and inconsistency. In a priori subgroup analyses, we found no differences between single vs multicenter, higher (≥ 10,000 mg/day) vs lower dose and sepsis vs non-sepsis trials. Post-hoc, we found no differences in subgroup analysis of earlier (< 24 h) vs delayed treatment, longer (> 4 days) vs shorter treatment duration, and low vs other risk of bias studies. IVVC may have the greatest benefit in trials that enrolled patients above (i.e., > 37.5%; RR 0.65, 95% CI 0.54-0.79) vs below (i.e., ≤ 37.5%; RR 0.89, 95% CI 0.68-1.16) median control group mortality (test for subgroup differences: p = 0.06), and TSA supported this. CONCLUSIONS: IVVC monotherapy may be associated with mortality benefits in critically ill patients, particularly in patients with a high risk of dying. Given the low certainty of evidence, this potentially life-saving therapy warrants further studies to identify the optimal timing, dosage, treatment duration, and patient population that will benefit most from IVVC monotherapy. PROSPERO Registration ID: CRD42022323880. Registered 7th May 2022.

Benefits and harm of probiotics and synbiotics in adult critically ill patients. A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND & AIMS: Several systematic reviews and meta-analyses of randomized controlled trials concluded that probiotics administration in critically ill patients was safe and associated with reduced rates of ventilator-associated pneumonia and diarrhea. However, a recent large multicenter trial found probiotics administration, compared to placebo, was not efficacious and increased adverse events. An updated meta-analysis that controls for type-1 and -2 errors using trial sequential analysis, with a detailed account of adverse events associated with probiotic administration, is warranted to confirm the safety and efficacy of probiotic use in critically ill patients. METHODS: RCTs that compared probiotics or synbiotics to usual care or placebo and reported clinical and diarrheal outcomes were searched in 4 electronic databases from inception to March 8, 2022 without language restriction. Four reviewers independently extracted data and assessed the study qualities using the Critical Care Nutrition (CCN) Methodological Quality Scoring System. Random-effect meta-analysis and trial sequential analysis (TSA) were used to synthesize the results. The primary outcome was ventilator-associated pneumonia (VAP). The main subgroup analysis compared the effects of higher versus lower quality studies (based on median CCN score). RESULTS: Seventy-five studies with 71 unique trials (n = 8551) were included. In the overall analysis, probiotics significantly reduced VAP incidence (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.56-0.88; I2 = 65%; 16 studies). However, such benefits were demonstrated only in lower (RR 0.47, 95% CI 0.32, 0.69; I2 = 44%; 7 studies) but not higher quality studies (RR 0.89, 95% CI 0.73, 1.08; I2 = 43%; 9 studies), with significant test for subgroup differences (p = 0.004). Additionally, TSA showed that the VAP benefits of probiotics in the overall and subgroup analyses were type-1 errors. In higher quality trials, TSA found that future trials are unlikely to demonstrate any benefits of probiotics on infectious complications and diarrhea. Probiotics had higher adverse events than control (pooled risk difference: 0.01, 95% CI 0.01, 0.02; I2 = 0%; 22 studies). CONCLUSION: High-quality RCTs did not support a beneficial effect of probiotics on clinical or diarrheal outcomes in critically ill patients. Given the lack of benefits and the increased incidence of adverse events, probiotics should not be routinely administered to critically ill patients. PROSPERO REGISTRATION: CRD42022302278.

The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial.

BACKGROUND: On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes. METHODS: This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547. FINDINGS: Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline. INTERPRETATION: Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores. FUNDING: None.

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.