PURPOSE:The impact of augmenting enteral protein delivery on nitrogen balance, urea generation, and kidney function in critically ill patients remains poorly defined. This study aimed to investigate these effects in a nested cohort within the TARGET Protein trial. METHODS:We conducted a single-center study nested within a cluster randomized crossover trial. Consecutive patients were enrolled during either the usual protein intake period (n = 52) or the augmented protein intake period (n = 55). Nitrogen balance, its components, plasma urea concentrations, and urea nitrogen accumulation were compared between groups. Multivariable analyses identified factors independently associated with nitrogen balance and incident acute kidney injury (AKI). A causal mediation analysis was performed to assess whether the effect of augmented protein delivery on urea concentrations was mediated through incident AKI. RESULTS:From day 1 to day 7, mean protein intake was 0.84 ± 0.73 g·kg-1·day-1 in the usual-protein group and 1.35 ± 0.94 g·kg-1·day-1 in the augmented-protein group. Patients receiving augmented protein achieved a less negative nitrogen balance than those receiving usual protein (mean difference, +5 g per day; 95% confidence interval [CI], 0.4 to 10; P = 0.033), driven by greater nitrogen intake (mean difference, +7 g per day; 95% CI, 5 to 10; P < 0.001). Independent predictors of nitrogen balance were ideal body weight (-0.18 g.kg-1; 95% CI, -0.35 to -0.01; P = 0.040), AKI at ICU admission (+4.7 g; 95% CI, 0.10 to 9.3; P = 0.046), and allocation to augmented protein therapy (+5.1 g; 95% CI, 0.43 to 9.7; P = 0.033). Compared with usual protein delivery, augmented protein delivery resulted in higher plasma urea concentrations (median, 14 vs. 11 mmol/L) and greater urea nitrogen accumulation (+3 g; 95% CI, 1.0 to 6.0; P = 0.035). Approximately 60% of the additional positive nitrogen balance was accounted for by urea generation. Among patients without AKI at ICU admission, augmented protein delivery was independently associated with incident AKI (odds ratio, 4.79; 95% CI, 1.14 to 26.4; P = 0.046). In mediation analyses, most of the increase in urea concentrations associated with augmented protein delivery was attributable to a direct effect rather than mediation through incident AKI. CONCLUSIONS:In critically ill patients, augmented protein delivery resulted in a less negative nitrogen balance but substantially increased urea generation and plasma urea concentrations. These findings suggest that a substantial proportion of additional protein intake may be directed toward nitrogen waste production rather than net anabolic utilization.

Abstract Background Abrupt cessation of alcohol consumption following hospital admission can induce alcohol withdrawal syndrome. This syndrome is challenging to manage and is associated with considerable morbidity and mortality. Current management of alcohol withdrawal syndrome in Australia is generally titrated benzodiazepine administration. In some regions, phenobarbital is preferred but evidence to support its superiority is weak. Methods We will conduct a single-center, three-arm, open-label, parallel-group, randomized clinical trial. Our primary objective is to determine the feasibility of embedding a randomized clinical trial within an electronic medical record to compare phenobarbital to single-agent benzodiazepine for patients with alcohol withdrawal. We will screen and randomize 45 patients using the Epic electronic medical record system. Patients will receive either low- or standard-dose intravenous phenobarbital (4 or 8 mg per kilogram), or usual care (benzodiazepine regimen). The primary outcomes to assess feasibility are usability, screening rates, enrollment rates, and compliance. Secondary outcomes are exploratory and include alcohol withdrawal scale scores, dose of benzodiazepine administered, health utilization, adjuvant drug treatments, and patient outcomes. Discussion There are limited high quality data evaluating the use of phenobarbital administration for alcohol withdrawal syndrome. Additionally, there is limited data evaluating the embedding of screening, randomization, and administration of a sedative drug within the electronic medical record. Our feasibility trial will establish whether this is possible within our health care system. In this protocol paper we detail how we will embed this trial within the electronic medical record Epic. Trial registration The study (RMH2024.320 v2 06/01/2025) is registered with Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12625000320459 . Registered on 17 April 2025. Trial Sponsor: The Royal Melbourne Hospital.

Background and Aim Critically ill patients experience acute muscle wasting, associated with impaired clinical outcomes. It has been suggested that greater dietary protein delivery may attenuate muscle wasting and improve outcomes, but the optimal dose is unknown. The aim of this systematic review and meta-analysis was to evaluate the effect of enteral protein delivered to achieve doses recommended within international guidelines (1.2-2.0 g/kg bodyweight/day) compared to enteral protein delivered below international guidelines (<1.2 g/kg/day) on mortality and clinical, patient-centred, and muscle outcomes. Methods A systematic review of databases MEDLINE, EMBASE, CINAHL, and CENTRAL was performed from database inception through to 2 July 2025. Randomised controlled trials (RCTs) of adult critically ill patients comparing ‘greater protein’ delivery (1.2-2.0 g/kg/day) versus ‘lesser protein’ delivery (<1.2 g/kg/day) predominantly via enteral nutrition (EN), with similar energy delivery, were identified. Risk ratios were pooled for binary outcomes and mean differences or standardised mean differences for continuous outcomes using random-effects models. Subgroup analyses investigated the effect of exclusive EN; acute kidney injury (AKI) as defined within individual trials; and higher severity of illness (Sequential Organ Failure Assessment score ≥ 9) for the primary outcome (mortality). Results From a total of 10,414 citations, 14 RCTs were included, comprising n=6553 patients (n=3248 greater protein; n=3305 lesser protein) from 13 individual patient RCTs and one cluster randomised cross-over trial. Greater protein delivery did not affect mortality (pooled RR 1.01, 95% CI 0.92, 1.12, p=0.795; I2=0%; τ2=0.00; 12 RCTs: greater protein n=3197; lesser protein n=3243). Other clinical outcomes were not different; however, the point estimate suggested decreased quality of life for greater protein compared to lesser protein (pooled standardised mean difference -0.11, 95% CI -0.24, 0.01, p=0.081; I2=0%; τ2=0.00; 2 RCTs, n=921: greater protein n=456; lesser protein n=465). In patients with an AKI (as defined within individual trials), greater protein delivery was associated with increased mortality (pooled effect estimate 1.29, 95% CI 1.05, 1.58, p=0.015; I2=0%; τ2=0.00; 3 RCTs, n=755: greater protein n=390; lesser protein n=365), with ICEMAN evaluation suggesting that the evidence for effect modification was of moderate credibility. Conclusions Greater protein delivery does not reduce mortality or improve any clinical outcomes compared with lesser protein, and may be associated with increased mortality in patients with AKI, though subgroup definitions varied across trials. Systematic review registration CRD42025547923

RATIONALE:Variability in the outcomes of mobilization interventions is expected due to their complexity, and one of the post hoc hypotheses for the findings of the TEAM trial is the impact of "dosage" of mobilization on clinical outcomes. OBJECTIVES:The aim of the present study is to understand the impact of the "dose" of mobilization on 28-day mortality of patients included in the TEAM trial. METHODS:A target trial emulation estimating the per-protocol effect, which is the effect had all patients in the trial adhered to strategies with different "doses" and timing, was used. All patients included in the TEAM trial (adults in the intensive care unit [ICU] who were undergoing invasive mechanical ventilation) were included and the primary outcome was 28-day mortality. Simulated interventions combining different thresholds of duration of mobilization and different thresholds of highest ICU Mobility Scale (IMS) achieved in each day were assessed using g-formulas considering baseline and time-varying confounders. MEASUREMENTS AND MAIN RESULTS:Overall, 741 patients were included, with a median age of 62 (IQR, 51-71) years; 37% were female. Prolonged mobilization time carried worse outcomes when lower levels of mobility were achieved (risk ratio [RR], 1.33 [95% CI, 1.10-1.63] for mobilization time ≤20 minutes and mobility scale of 2). When an IMS >4 was achieved on a given day, prolonged duration of mobilization did not increase mortality compared to natural course (RR, 1.13 [95% CI, 0.96-1.46] for mobilization time ≤20 minutes and IMS of 4). CONCLUSIONS:Prolonged mobilization when only lower IMS levels could be achieved was associated with increased 28-day mortality.

PURPOSE OF REVIEW:The use of functional outcomes in critical care nutrition research is increasingly advocated; however, this inevitably gives rise to missing data. Consequently there is a need to adopt modern approaches to the foreseeable problem of missing functional and survival outcomes in research trials. RECENT FINDINGS:Analyses that ignore unobserved or missing data will often return biased effect estimates. An improved approach is to routinely anticipate the types and extent of missing data, and consider the likely mechanisms of that missingness. The researcher and their statistical advisor may then choose from a number of modern strategies to assess the sensitivity of the research conclusions to the patterns of missingness contained in these research data. Methods widely employed include multiple imputation of missing observations, mixed regression models, use of composite outcome variables with patients who die being attributed a value reflecting the lack of ability to function, and selected Bayesian methodology. SUMMARY:Conclusions from clinical research in critical care nutrition will become more clinically interpretable and generalizable with the adoption of modern methods for the statistical handling of missing data.

Guidelines recommend augmenting enteral protein during critical illness, but the impact on patient outcomes is uncertain. To determine whether augmenting enteral protein increases days alive and free from hospitalization. This cluster randomized, crossover, open-label trial recruited critically ill patients receiving enteral nutrition from 8 intensive care units (ICUs) in Australia and New Zealand from May 23, 2022, to August 23, 2023, with final follow-up on November 21, 2023. Two isocaloric enteral formulae were compared: augmented protein (100 g protein/L) vs usual protein (63 g protein/L). ICUs used formulae sequentially for 3 months over a 12-month period; 4 ICUs commenced with augmented protein and 4 commenced with usual protein. The primary outcome was the number of days free of admittance to the index hospital and alive at day 90. Secondary outcomes included days free of the index hospital at day 90 in survivors; alive at day 90; durations of invasive ventilation, ICU, and hospital admission; incidences of tracheostomy insertion and new kidney replacement therapy; and hospital discharge destination. A total of 3397 patients were included (median [IQR] age, 61 (48-71) years; 2157 [64%] male). The median (IQR) number of days free of the index hospital and alive at day 90 was 62 (0-77) days in the augmented protein group and 64 (0-77) days in the usual protein group, with an adjusted-for-period between-group median difference of −1.97 (95% CI, −7.24 to 3.30) days (P = .46). At day 90, a total of 1221 of 1681 patients (72.6%) were alive in the augmented protein group and 1269 of 1716 (74.0%) were alive in the usual protein group (risk ratio, 0.99 [95% CI, 0.95-1.03]). Between-group differences for secondary outcomes included the following: difference in median days free of hospital in survivors, 0.01 (95% CI, −1.94 to 1.96) days; difference in mean duration of invasive ventilation, 6.8 (95% CI, −3.0 to 16.5) hours; cause-specific hazard ratios for durations of ICU admission (time to live ICU discharge), 0.93 (95% CI, 0.88-1.00) and hospital admission (time to live hospital discharge), 0.96 (95% CI, 0.90-1.02); and risk ratio for tracheostomy, 1.15 (95% CI, 0.66-2.01) and new kidney replacement therapy, 0.97 (95% CI, 0.81-1.16). Discharge destinations were similar. Augmenting enteral protein during critical illness did not improve number of days free of the index hospital and alive at day 90. ANZCTR Identifier: ACTRN12621001484831

Objective: To compare the effects of fluid bolus therapy (FBT) with 20% albumin to crystalloid FBT on the incidence of cardiac surgery-associated acute kidney injury (CSA-AKI) and its severity and duration. Design: Secondary analysis of the multicenter, parallel-group, open-label, randomized HAS FLAIR-II trial. Setting: Six intensive care units. Participants: Patients who required clinician-determined FBT after cardiac surgery requiring cardiopulmonary bypass. Interventions: Patients were randomized to receive FBT with 20% albumin (up to 400 mL/day) or crystalloid fluid for all FBTs in the intensive care unit. Measurements and Main Results: A total of 452 patients were included in the modified intention-to-treat population (224 in the 20% albumin group and 228 in the crystalloid group). AKI occurred in 54 (24%) patients in the 20% albumin group and 50 (22%) in the crystalloid group (odds ratio: 1.13, 95% confidence interval [CI]: 0.73 to 1.76). However, in patients who developed stages 2 and 3 AKI, those allocated to 20% albumin had a significantly lower median time-weighted average (TWA) creatinine: 144 mu mol/L (interquartile range [IQR]: 109 to 162) versus 254 mu mol/L (IQR: 182 to 294) than the crystalloid group (difference -105 mu mol/L, [95% CI -170 to -41], p = 0.003) and a lower peak serum creatinine (-110 mu mol/L [-189 to -32], p = 0.01). The reduced TWA creatinine in the 20% albumin group was seen in patients with both a low (p = 0.04) and normal preoperative serum albumin concentration (p < 0.001). Conclusions: FBT with 20% albumin compared with crystalloid-based regimen did not reduce the occurrence of AKI in patients after cardiac surgery. However, it reduced the severity and duration of stages 2 and 3 AKI. (c) 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

OBJECTIVES:Early mobilization is recommended by the Society of Critical Care Medicine ICU Liberation Bundle. The Treatment of Mechanically Ventilated Adults With Early Activity and Mobilization (TEAM) randomized controlled trial (RCT) compared early active mobilization to usual care mobilization and found no difference in the primary outcome of days alive and out of hospital to day 180; however, it did find an increase in adverse events in the intervention group. To date, no RCT of early mobilization has reported costs or cost-effectiveness. We aimed to determine the cost-effectiveness of early active mobilization from the perspective of the healthcare sector. DESIGN:We conducted a prospective, within-trial cost-effectiveness analysis alongside the TEAM study. SETTING:Forty-nine ICUs in six countries (Australia, New Zealand, United Kingdom, Ireland, Germany, and Brazil). PATIENTS:The cost-effectiveness analysis included 733 adult ICU patients who were undergoing invasive mechanical ventilation and enrolled in the TEAM study. INTERVENTIONS:Early active mobilization or usual care mobilization. MEASUREMENTS AND MAIN RESULTS:A significantly higher number of hours were spent by staff in delivering high-dose early active mobilization vs. usual care mobilization; however, incremental costs were not significantly different between the groups ($1,823; 95% CI, -$10,552 to $12,027). EuroQoL-5D 5-level utility scores at 6 months were not significantly different between the groups (0.532 [ se , 0.021] vs. 0.548 [ se , 0.021]; p = 0.585). The probability of early active mobilization being cost-effective is less than 50%, even at a willingness-to-pay threshold of $200,000/quality-adjusted life year (QALY). Sensitivity analyses incorporating meta-analysis data indicated that early active mobilization may be cost-saving; however, this involves the occurrence of lower QALY gains when compared with usual care mobilization. CONCLUSIONS:Our trial-based analysis found no evidence that higher-dose early active mobilization is a cost-effective intervention compared with usual care mobilization for mechanically ventilated adult ICU patients; however, results from sensitivity analyses provided some evidence that it may be cost saving if one is willing to accept poorer outcomes. Further research is necessary to determine whether there are scenarios in which early active mobilization provides value for money.

Importance:Guidelines recommend augmenting enteral protein during critical illness, but the impact on patient outcomes is uncertain. Objective:To determine whether augmenting enteral protein increases days alive and free from hospitalization. Design, Setting, and Participants:This cluster randomized, crossover, open-label trial recruited critically ill patients receiving enteral nutrition from 8 intensive care units (ICUs) in Australia and New Zealand from May 23, 2022, to August 23, 2023, with final follow-up on November 21, 2023. Intervention:Two isocaloric enteral formulae were compared: augmented protein (100 g protein/L) vs usual protein (63 g protein/L). ICUs used formulae sequentially for 3 months over a 12-month period; 4 ICUs commenced with augmented protein and 4 commenced with usual protein. Main Outcomes and Measures:The primary outcome was the number of days free of admittance to the index hospital and alive at day 90. Secondary outcomes included days free of the index hospital at day 90 in survivors; alive at day 90; durations of invasive ventilation, ICU, and hospital admission; incidences of tracheostomy insertion and new kidney replacement therapy; and hospital discharge destination. Results:A total of 3397 patients were included (median [IQR] age, 61 (48-71) years; 2157 [64%] male). The median (IQR) number of days free of the index hospital and alive at day 90 was 62 (0-77) days in the augmented protein group and 64 (0-77) days in the usual protein group, with an adjusted-for-period between-group median difference of -1.97 (95% CI, -7.24 to 3.30) days (P = .46). At day 90, a total of 1221 of 1681 patients (72.6%) were alive in the augmented protein group and 1269 of 1716 (74.0%) were alive in the usual protein group (risk ratio, 0.99 [95% CI, 0.95-1.03]). Between-group differences for secondary outcomes included the following: difference in median days free of hospital in survivors, 0.01 (95% CI, -1.94 to 1.96) days; difference in mean duration of invasive ventilation, 6.8 (95% CI, -3.0 to 16.5) hours; cause-specific hazard ratios for durations of ICU admission (time to live ICU discharge), 0.93 (95% CI, 0.88-1.00) and hospital admission (time to live hospital discharge), 0.96 (95% CI, 0.90-1.02); and risk ratio for tracheostomy, 1.15 (95% CI, 0.66-2.01) and new kidney replacement therapy, 0.97 (95% CI, 0.81-1.16). Discharge destinations were similar. Conclusions and Relevance:Augmenting enteral protein during critical illness did not improve number of days free of the index hospital and alive at day 90. Trial Registration:ANZCTR Identifier: ACTRN12621001484831.

BACKGROUND:The Treatment of Mechanically Ventilated Adults with Early Activity and Mobilisation (TEAM) trial reported a higher occurrence of adverse events with greater mobilisation. However, their timing and nature remained unexplored. We conducted an in-depth exploration of such events. OBJECTIVE:The purpose of this paper is to thoroughly examine the timing and characteristics of adverse events reported within the TEAM trial. METHODS:Adverse event data were collected daily in real time. Categorical data were compared using the Fisher's exact test. The relationship between adverse events and patient survival was analysed using a Cox-regression frailty model. RESULTS:Overall, 37 out of 371 patients (10.0%) in the early mobilisation group and 16 out of 370 patients (4.3%) in the usual care group experienced adverse events, with 71 events in the early mobilisation group compared to 24 events in the usual care group. The most common adverse events were altered blood pressure in 21 out of 53 patients (39.6%), arrhythmia in 17 out of 53 patients (32.1%), and oxygen desaturation in nine of 53 patients (17.0%). Patients with an adverse event were more likely to have congestive heart failure (absolute percentage difference: 16.1, 95% confidence interval [CI]: 6.1 to 26.1), peripheral vascular disease (absolute percentage difference: 6.4, 95% CI: 1.3 to 11.5), heart attack (absolute percentage difference: 13.5, 95% CI: 5.9 to 21.1), or stroke (absolute percentage difference: 9.3, 95% CI: 3.5 to 15.1). Adverse events occurred at a median of 4 days with early mobilisation and 7 days with usual care. There was no significant difference in survival for patients who experienced an adverse event compared to those without an adverse event. CONCLUSION:Adverse events were more common in patients randomised to early active mobilisation, were cardiovascular and respiratory in nature, tended to occur earlier with active mobilisation, and cardiovascular comorbidities were more common in such patients. This information can help guide future studies in this field. TRIAL REGISTRATION:TEAM ClinicalTrials.gov number, NCT03133377, registered 28 April 2017.

BackgroundThe TARGET Protein trial will evaluate the effect of greater enteral protein delivery (augmented protein) on clinical outcomes of critically ill adult patients when compared to usual care.ObjectiveTo describe the statistical analysis plan for the TARGET Protein trial.MethodsTARGET Protein is a cluster randomized, cross-sectional, double cross-over, open-label, registry-embedded, pragmatic clinical trial conducted across Australia and New Zealand. The trial randomized eight intensive care units (ICU) to receive enteral formula containing either higher dose enteral protein (augmented protein) or usual dose protein in a 1:1 ratio. Each ICU received one trial formula for a 3-month period and then switched to the alternate formulae. This sequence was repeated, for a total trial length of 12 months. The primary outcome is the number of days free of the index hospital and alive at day 90. Secondary outcomes include proportion of patients alive at day 90, survivor-only analysis of days free of the index hospital at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. The statistical methods and models which will be used to estimate the effects for the primary and secondary outcomes are described. All statistical models will account for the cluster-randomized cross-over design to ensure correct estimation of the 95% confidence intervals. Trial enrolment is complete with 3412 patients enrolled. Data linkage is ongoing.ConclusionThis statistical analysis plan enables transparent reporting of the TARGET Protein trial. It will reduce the risk of potential selective reporting biases.Trial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12621001484831). Registered on November 1, 2021.

Benefit or harm from early mobilisation (EM) in mechanically ventilated patients may vary by individual patient characteristics. We used machine learning to predict individualised treatment effects (ITEs) in the “Early Active Mobilization during Mechanical Ventilation in the ICU” (TEAM) trial. This was a secondary analysis of the TEAM trial using a causal inference approach to estimate ITEs, which compared enhanced EM to usual care EM. Baseline variables in the original publication were used as predictor variables. The primary outcome was death by day 180. The dataset was randomly split into two halves (train and test) by site. In the training data, fivefold cross-validation was used to compare six candidate machine learning algorithms. The best-performing model was evaluated in the test dataset. Patients were stratified into tertiles based on predicted ITEs, reflecting estimated benefit, no effect or harm. We included 687 patients from 40 sites, and 141 (20.5

BACKGROUND:Critically ill patients with a traumatic brain injury (TBI) may require prolonged intensive care unit (ICU) admission and hence receive greater exposure to hospital enteral nutrition. It is unknown if augmented energy delivery with enteral nutrition during ICU admission impacts quality of life in survivors or gastrointestinal tolerance during nutrition delivery in the ICU. OBJECTIVES:The objective of this study was to compare health-related quality of life, using the EuroQol five-dimensions five-level visual analogue scale at 6 months, in survivors who presented with a TBI and received augmented energy (1.5 kcal/ml) to those who received routine energy (1.0 kcal/ml). Secondary objectives were to explore differences in total energy and protein delivery, gastrointestinal tolerance, and mortality between groups. METHODS:Secondary analysis of participants admitted with a TBI in the Augmented versus Routine Approach to Giving Energy Trial (TARGET) randomised controlled trial. Data are represented as n (%) or median (interquartile range). RESULTS:Of the 3957 patients in TARGET, 231 (5.8%) were admitted after a TBI (augmented = 124; routine = 107). Patients within TARGET who were admitted with a TBI were relatively young (42 [27, 61] years) and received TARGET enteral nutrition for an extended period (9 [5, 15] days). At 6 months, EuroQol five-dimensions five-level quality-of-life scores were available for 166 TBI survivors (72% of TBI cohort randomised, augmented = 97, routine = 69). There was no evidence of a difference in quality of life (augmented = 70 [52, 90]; routine = 70 [55, 85]; median difference augmented vs routine = 0 [95% confidence interval: -5, 10]). TBI participants assigned to augmented energy received more energy with a similar protein than the routine group. Gastrointestinal tolerance was similar between groups. CONCLUSION:While patients admitted after a TBI received enteral nutrition for an extended period, an increased exposure to augmented energy did not affect survivors' quality-of-life scores.

Background Patients in the intensive care unit (ICU) frequently develop hyperactive delirium, which may be accompanied by behaviour that increases clinical risks to themselves as well as other patients and staff. There is a paucity of evidence to inform the urgent enteral administration of antipsychotic drugs to treat such hyperactive delirium and behavioural disturbances. Objective The aim of this study is to test the efficacy and safety of administering enteral olanzapine when compared to quetiapine in critically ill patients with hyperactive delirium. Design, setting, participants, and interventions This is a cluster-randomised, double-crossover, clinical trial. Critically ill adult patients admitted to three tertiary Australian intensive care units over a 12-month period will be eligible. Randomisation will occur at the site level, with allocation to open-label olanzapine or quetiapine use over four treatment periods of 3-month duration. Main outcome measure The primary outcome and days alive and delirium-/coma-free (censored at 14 days post enrolment) will be analysed using median quantile regression accounting for clustering at sites' level and time period and treatment order. Results and conclusion This trial will compare the effect of enteral olanzapine to quetiapine in critically ill adults with hyperactive delirium on an important indicator of patient outcome.

Rationale: Patients with diabetes represent almost 20% of all ICU admissions and might respond differently to high-dose early active mobilization. Objectives: To assess whether diabetes modified the relationship between the dose of early mobilization on clinical outcomes in the TEAM trial. Methods: All TEAM trial patients were included. The primary outcome was days alive and out of the hospital at Day 180. Secondary outcomes included 180-day mortality and long-term functional outcomes at Day 180. Logistic and median regression models were used to explore the effect of high-dose early mobilization on outcomes by diabetes status. Measurements and Main Results: All 741 patients from the original trial were included. Of these, 159 patients (21.4%) had diabetes. Patients with diabetes had fewer days alive and out of the hospital at Day 180 (124 [0-153] vs. 147 [82-164]; P = 0.013) and higher 180-day mortality (30% vs. 18%; P = 0.044). In patients receiving high-dose early mobilization, the number of days alive and out of the hospital at Day 180 was 73.0 (0.0-144.5) in patients with diabetes and 146.5 (95.8-163.0) in patients without diabetes (P value for interaction = 0.108). However, in patients with diabetes, high-dose early mobilization increased the odds of mortality at 180 days (adjusted odds ratio, 3.47; 95% confidence interval, 1.67-7.61; P value for interaction = 0.001). Conclusions: In this secondary analysis of the TEAM trial, in patients with diabetes, a high-dose early mobilization strategy did not significantly decrease the number of days alive and out of the hospital at Day 180, but it increased 180-day mortality.

After cardiac surgery, fluid bolus therapy (FBT) with 20

Introduction: Continuous Renal Replacement Therapy (CRRT) is common in the Intensive Care Unit (ICU) but a high Net ultrafiltration rate (UFNET) calculated with daily data may increase mortality. We aimed to study early UFNET practice using minute-by-minute CRRT machine recordings and to assess its association with admission diagnosis and mortality. Methods: We studied CRRT treatments in three adult ICUs over 7-years. We calculated early UFNET rates minute-by-minute and categorised UFNET into tertiles of mean UFNET in the first 72 hours and admission diagnosis. We applied Cox-proportional hazards modelling with censoring of patients who died within 72 hours. Results: We studied 1218 patients; 154,712 hours and 9,282,729 minutes of CRRT (5,702 circuits). Mean early UFNET was 1.52 (1.46 to 1.57) mL/kg/hr. Early UFNET tertiles were similar to previously reported values at 0.00-1.20 mL/kg/hr, 1.21 to 1.93mL/kg/hr and >1.93mL/kg/hr. UFNET values were similar whether evaluated at 24 or 72 hours or for the entire duration of CRRT. There was, however, significant variation in UFNET practice by admission diagnosis: higher in respiratory diseases (pneumonia P=0.01, other P<0.0001), and cardiovascular disease (P=0.005) but lower in cardiothoracic surgery (P=0.04), renal (P=0.0003) and toxicology-associated diagnoses (P=0.01). Higher UFNET was associated with an increased hazard of death, HR 1.24 (1.13 to 1.37), independent of admission diagnosis, weight, age, sex, presence of ESKD and severity of illness. Conclusion: Early UFNET practice reflects known tertiles but varies significantly by admission diagnosis. Higher early UFNET is independently associated with mortality. Impacts of UFNET on mortality may vary by admission diagnosis. Further work is required to elucidate the nature and mechanisms responsible for this association.

Purpose: Neuromuscular blockers (NMBs) are often used during prone positioning to facilitate mechanical ventilation in COVID-19 related ARDS. However, their impact on oxygenation is uncertain.Methods: Multi-centre observational study of invasively ventilated COVID-19 ARDS adults treated with prone positioning. We collected data on baseline characteristics, prone positioning, NMB use and patient outcome. We assessed arterial blood gas data during supine and prone positioning and after return to the supine position.Results: We studied 548 prone episodes in 220 patients (mean age 54 years, 61% male) of whom 164 (75%) received NMBs. Mean PaO2:FiO(2) (P/F ratio) during the first prone episode with NMBs reached 208 +/- 63 mmHg compared with 161 +/- 66 mmHg without NMBs (Delta(mean) = 47 +/- 5 mmHg) for an absolute increase from baseline of 76 +/- 56 mmHg versus 55 +/- 56 mmHg (p(adj) < 0.001). The mean P/F ratio on return to the supine position was 190 +/- 63 mmHg in the NMB group versus 141 +/- 64 mmHg in the non-NMB group for an absolute increase from baseline of 59 +/- 58 mmHg versus 34 +/- 56 mmHg (p(adj) < 0.001).Conclusion: During prone positioning, NMB is associated with increased oxygenation compared to non-NMB therapy, with a sustained effect on return to the supine position. These findings may help guide the use of NMB during prone positioning in COVID-19 ARDS.