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

BACKGROUND:Metabolic acidosis is common in critically ill patients and is associated with organ dysfunction and death. Sodium bicarbonate is used to correct acidemia, but its benefit in patients with metabolic acidosis who are receiving vasopressors remains uncertain. METHODS:In this pragmatic, adaptive, double-blind, randomized trial, we assigned adults with metabolic acidosis (pH, <7.30; base excess, no more than -4 mmol per liter; and partial pressure of arterial carbon dioxide, ≤45 mm Hg without intubation or ≤50 mm Hg with intubation) who were receiving vasopressors in the intensive care unit (ICU) to receive either sodium bicarbonate or placebo (5% dextrose). Sodium bicarbonate or placebo was infused for up to 5 hours, with the infusion rate adjusted for a target pH of at least 7.30 and base excess of at least 0 mmol per liter. The primary outcome was a major adverse kidney event, defined as death, use of renal-replacement therapy, or persistent renal dysfunction, within 30 days. RESULTS:A total of 500 patients were enrolled in 55 ICUs across seven countries; 245 patients were assigned to receive sodium bicarbonate and 255 to receive placebo. A major adverse kidney event within 30 days occurred in 98 of 244 patients (40.2%) in the sodium bicarbonate group and in 100 of 254 patients (39.4%) in the placebo group (adjusted difference, 1.2 percentage points; 95% confidence interval [CI], -7.1 to 9.4; P = 0.78). Renal-replacement therapy was used within 30 days in 16.8% of the patients in the sodium bicarbonate group and in 20.9% of those in the placebo group (adjusted difference, -3.9 percentage points; 95% CI, -10.6 to 2.7). In-hospital mortality by day 30 was 25.4% in the sodium bicarbonate group and 24.0% in the placebo group (adjusted difference, 1.8 percentage points; 95% CI, -5.6 to 9.2). Four patients (1.6%) in the sodium bicarbonate group had an adverse effect, as compared with none in the placebo group (P = 0.06). CONCLUSIONS:The use of sodium bicarbonate in critically ill patients with metabolic acidosis receiving vasopressors did not lead to a lower risk of major adverse kidney events within 30 days than placebo. (Funded by the National Health and Medical Research Council of Australia; SODa-BIC ClinicalTrials.gov number, NCT05697770.).

Background:Data on long-term survival after intensive care unit (ICU) admission for sepsis and septic shock are limited. This study aimed to evaluate survival over five years among critically ill sepsis or septic shock patients discharged alive from hospital. Methods:This retrospective cohort study of adults who survived to hospital discharge after non-elective ICU admission (2018-2024) used Australian and New Zealand Intensive Care Society Adult Patient Database. Sepsis, septic shock, or non-sepsis patients were classified using diagnostic codes and physiological/laboratory criteria during first 24-h of ICU admission. Mixed-effects Cox models with time-varying covariate effects were used, adjusting for demographics, comorbidities, frailty, illness severity, and ICU interventions. Findings:Of 557,538 hospital survivors, 7.3% had sepsis without shock, 11.5% septic shock, and 81.2% non-sepsis conditions. At five-years, unadjusted survival was lowest for septic shock (68.0%, 95% confidence interval/CI = 67.6-68.4%), sepsis without shock (74.2%, 73.7-74.6%), and non-sepsis (78.2%, 78.1-78.3%). After adjustment, hazards ratio/HR for sepsis without shock remained at or below the null relative to non-sepsis; 0-1 year: HR = 0.95, 0.92-0.98; 1-3 years: 0.96, 0.93-1.00; 3-5 years: 1.03, 0.97-1.08, while septic shock showed persistent independent excess mortality; 0-1 year: HR = 1.05,1.03-1.08; 1-3 years: 1.03, 1.00-1.06; and 3-5 years:1.09,1.05-1.14. Major predictors of mortality included age, frailty, comorbidities, and organ support. Interpretation:Septic shock was associated with persistent independent excess mortality over five years after hospital discharge, whereas in sepsis without shock, this was largely explained by pre-existing comorbidity and frailty. Funding:Medical Research Future Fund.

BACKGROUND:In patients who are unresponsive after resuscitation from cardiac arrest, limiting oxygen exposure to that necessary to achieve acceptable oxygenation may increase the likelihood of survival with a favorable functional outcome. METHODS:We randomly assigned unresponsive adults receiving mechanical ventilation in the intensive care unit (ICU) after cardiac arrest to conservative or liberal oxygen therapy. In the two groups, the default lower limit of arterial oxygen saturation as measured by pulse oximetry (Spo2) was 90%. In the conservative-oxygen group, the alarm for the upper limit of the Spo2 was set at 95%, and the fraction of inspired oxygen (Fio2) was decreased to 0.21 provided that the Spo2 was above the lower limit. In the liberal-oxygen group, there were no measures limiting the upper Spo2, but the minimum Fio2 permitted during mechanical ventilation was 0.3. The primary outcome was survival with a favorable functional outcome at 180 days, assessed with the Extended Glasgow Outcome Scale (GOS-E). Levels on the GOS-E range from 1 (death) to 8 ("upper good recovery"). We defined survival with a favorable functional outcome as a GOS-E level of 5 ("lower moderate disability") or higher. RESULTS:A total of 1840 patients were recruited from 53 ICUs in Australia, New Zealand, and Ireland, with 882 assigned to conservative oxygen therapy and 958 assigned to liberal oxygen therapy. A favorable functional outcome at 180 days was observed for 313 of 819 patients (38.2%) in the conservative-oxygen group and 353 of 890 patients (39.7%) in the liberal-oxygen group (relative risk, 0.97; 95% confidence interval, 0.87 to 1.09; P = 0.65). No adverse events were reported. CONCLUSIONS:Among unresponsive adults undergoing mechanical ventilation in the ICU after a cardiac arrest, the percentage who survived with a favorable functional outcome was not higher with conservative oxygen therapy than with liberal oxygen therapy. (Funded by the Health Research Council of New Zealand and others; LOGICAL Australian New Zealand Clinical Trials Registry number, ACTRN12621000518864.).

Background and Aims: Energy and protein provision for critically ill patients who receive oral nutrition often falls below recommended targets. We compared characteristics and nutrition processes during hospital stay (within and post-intensive care unit [ICU] stay) of those who received oral nutrition as the sole nutrition source to those who first commenced enteral (EN) or parenteral nutrition (PN) within an Australian or New Zealand (ANZ) ICU. Methods: Multicentre, observational study of routine nutrition care in 44 hospitals across ANZ, including adult patients within ICU admitted for at least 48 h. Those receiving oral nutrition as the sole source of nutrition (with or without oral nutrition supplements) were included in the 'oral nutrition' group and those who first received EN and/or PN in the ICU as the 'EN/PN group'. The primary outcome was median daily energy delivery in ICU. Data are presented as number (%) or median [interquartile range]. Results: Of the 409 patients enroled, median [IQR] age was 64 [51-74] years and 257 patients (62%) were male. APACHE II score, use of invasive ventilation and hospital length of stay (LOS) were all lower in those receiving oral nutrition (n = 200) compared to those receiving EN/PN (n = 209). In ICU, 63 (31.5%) and 169 (81%) (p < 0.001), patients who were receiving oral nutrition and in the EN/PN group received a nutrition assessment, respectively. Oral nutrition supplements were provided for 40 (20%) patients in the oral nutrition group and 31 of 94 (33%) of those receiving oral nutrition in the EN/PN group (p = 0.019). Energy and protein intake in ICU for the oral nutrition group was 716 [597-1069] kcal/day and 37 [19-46] g/day versus 1158 [664-1583] kcal/day and 57 [31-77] g/day for those receiving EN/PN (p = 0.020 energy, p = 0.016 protein). Quantification of oral nutrition was attempted in 78/294 (27%) patients in ICU and completed on 27/78 (36%) occasions. On the ward, attempts were made for 120/273 (44%) patients, with 60/120 (50%) complete. Conclusion: Patients who received oral nutrition as the sole nutrition source in ICU had lower illness severity, rates of nutrition assessment and provision of oral supplements compared to those who first received EN/PN. Quantification of oral nutrition was often incomplete for all patients in ICU and on the ward.

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

OBJECTIVES:Sepsis trials likely include patients who vary in response to therapeutic interventions. The optimal approach to identify such differences in treatment response remains unclear. Estimating individualized absolute risk differences (iARDs) to model treatment response at an individual patient level using supervised effect models applied to randomized trial data may be informative. We explored the relationship between two subgrouping approaches and a recently published iARD model for the effect of early goal-directed therapy (EGDT) resuscitation in sepsis. DESIGN:Secondary analysis of the Protocolized Care for Early Septic Shock (ProCESS) and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials. We applied clinical subtypes (α, β, γ, δ) to 829 ProCESS and 1588 ARISE patients and biologic "hyperinflammatory" and "nonhyperinflammatory" subphenotypes to 363 ProCESS patients with biomarker data using established methods. We predicted iARDs with supervised learning using clinical variables as predictors and 90-day mortality as the primary outcome. We evaluated iARD variability within subgroups. SETTING:Eighty-one sites worldwide. PATIENTS/SUBJECTS:Adults with septic shock. INTERVENTIONS:EGDT or usual care. MEASUREMENTS AND MAIN RESULTS:The average treatment effect of EGDT appeared to vary within both clinical and biologic subphenotypes. EGDT appeared potentially beneficial in the β and nonhyperinflammatory subphenotypes but harmful in the γ and hyperinflammatory subphenotypes. However, the predicted iARDs within each subgroup ranged from considerable harm to considerable benefit. For example, for the β-subtype, the average mortality reduction from EGDT was 8.5% (95% CI, -0.4 to 17.5), but the iARDs ranged from a 29% increase to a 16% reduction in mortality, with 39% of patients predicted to be harmed. CONCLUSIONS:Although both clinical and biologic phenotyping may identify subgroups whose average treatment effect is beneficial or harmful, individual risks and benefits within subgroups still vary dramatically, raising concern that phenotyping may not reliably or safely personalize sepsis care.

Background: The Augmented versus Routine Approach to Giving Energy Trial (TARGET) was a 4000 patient trial in which augmented enteral calorie dose did not influence outcomes. Aim: We aimed to quantify practice change following TARGET. Methods: Three single-day, prospective, multicentre, point-prevalence audits of adult patients receiving enteral nutrition (EN) in participating Australian and New Zealand intensive care units at 10:00 AM were conducted: (i) 2010 (before conducting TARGET); (ii) 2018 (immediately before publishing TARGET results); and (iii) 2020 (2 years after TARGET publication). Data included baseline characteristics, clinical outcomes, and nutrition data. Data are n (%), mean +/- standard deviation, or median [interquartile range]. Differences in enteral calorie prescription between 2018 and 2020 were compared using the Mann-Whitney test. Results: The percentage of patients receiving EN (2010 42%, 2018 38%, 2020 33%; P = 0.012) and the prescription of calorie-dense EN formula (>= 1.5 kcal/ml) (2010 33%, 2018 24%, 2020 23%; P = 0.038) decreased over time. However, when comparing prepublication and postpublication (2018-2020), calorie dose and calorie density were similar: 22.9 +/- 8.6 versus 23.4 +/- 12.8 kcal/kg/day (P = 0.816) and <1.5 kcal/ml: 76 versus 77% (P = 0.650), respectively. Conclusion: In Australian and New Zealand intensive care units, enteral calorie dose and calorie density of prescribed EN were similar before TARGET publication and 2 years later. (c) 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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.

Rationale: Engaging patients and families in critical care research is recognized as best practice. The extent of engagement in critical care trials in Australia and New Zealand is unknown after introduction of national guidelines in 2016. Objectives: To assess the extent of patient and family engagement in adult critical care research studies endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). Methods: Prospective studies endorsed between January 2017 and December 2023 or previously endorsed and still recruiting during this period were included. The study design included a two-stage process: 1) retrospective independent assessment of patient and family engagement in study protocols, progress reports, and manuscripts and 2) prospective self-reported survey of study principal investigators and project managers to understand priority of engagement, types of activities, barriers, and facilitators. Both stages assessed engagement using a modified version of an existing tool developed by the Canadian Critical Care Trials Group (CCCTG) Patient and Family Partnership Committee. The Guidance for Reporting Involvement of Patients and Public 2 tool was also used in stage 1. Results: Stage 1 was a retrospective analysis using the CCCTG and Guidance for Reporting Involvement of Patients and Public 2 tools. Of the 35 studies reviewed in stage 1, patient and family engagement was infrequently reported (reported in eight protocols submitted to ANZICS CTG for endorsement [8 of 35; 23%], reported in one trial progress report [1 of 34; 3%] and in one protocol publication [1 of 17; 6%], and not reported in the 10 primary trial publications [0 of 10; 0%]). Stage 2 involved survey responses using the CCCTG tool. Twenty-eight (80%) of 35 studies had at least one survey response. Respondents for 20 of these studies (20 of 28; 71%) reported undertaking some form of patient and family engagement. The most common facilitator of engagement was staff engagement experience (12 of 28; 43%), and lack of resources (12 of 28; 43%) was identified as a key barrier. Conclusions: This study identified low rates of reported patient and family engagement in clinical trial protocols and manuscripts via independent appraisal compared with a high self-reported rate of engagement activities among studies endorsed via the ANZICS CTG. This study highlighted the importance of adequate resourcing for engagement activities, including experienced personnel and funding.

Background:The optimal choice of fluid therapy for patients with diabetic ketoacidosis (DKA) is uncertain, though preliminary data suggest that buffered crystalloid solutions (Plasma-Lyte® 148) may offer some advantages over 0.9% saline. Objective:To describe the study protocol for the 'Balanced Electrolyte Solution versus Saline Trial for Diabetic Ketoacidosis' (BEST-DKA) trial. Design setting and participants:BEST-DKA is a Phase 3 cluster-crossover, blinded, pragmatic, randomised, controlled trial comparing the effects of saline or buffered crystalloid solution in patients with moderate to severe DKA treated in the emergency department and/or intensive care unit at twenty hospitals in Australia. Each hospital will be randomised to use either saline or buffered crystalloid solution for a period of 12 months before crossing over to the alternate fluid for the next 12 months. The blinded study fluid will be used for all resuscitation and maintenance purposes for included patients. Main outcome measures:This cluster-randomised, crossover randomised controlled trial (RCT) has been designed with the aim of enrolling a minimum of 400 patients, which will provide >91.4% power to detect a 2-day increase in the primary outcome, days alive and out of hospital to day 28, chosen with consumer representation. Secondary outcomes include quality of life and fatigue scores at day 28, intensive care unit and hospital lengths of stay, acute kidney injury, and time to resolution of DKA. All analyses will be conducted on an intention-to-treat basis. A prespecified statistical analysis plan will be developed prior to interim analysis. Results and conclusion:The BEST-DKA trial commenced enrolment in March 2024 and should generate results that will determine whether treatment with Plasma-Lyte® 148, compared with saline, results in increased days alive, and out of hospital to day 28 for patients with moderate or severe DKA.

OBJECTIVES:Frailty is associated with poorer outcomes in critical illness, but it is unclear if this relationship is consistent across different body mass index (BMI) levels. DESIGN:A retrospective multicentric registry-based observational study using the Australia New Zealand Intensive Care Society Adult Patient Database. SETTING:Criticallly ill patients admitted to 1170 ICUs between January 1, 2018, and March 31, 2022. PATIENTS:All adults aged 16 years and older with a documented Clinical Frailty Scale (CFS) and BMI. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:The primary outcome was survival up to 3 years following ICU admission. We used Cox proportional hazards models, linear and nonlinear regression models to investigate the association between frailty (defined as CFS, 5-8), in reference to those without frailty, and the mortality risk up to 3 years, and whether this association varied with BMI, after adjusting for key confounders. We included 282,586 patients, of whom 49,070 (17.4%) were frail. Frailty was most prevalent in patients with BMI less than 18.5 kg/m 2 (34.8%), became less frequent as BMI increased, and more prevalent again in BMI greater than or equal to 40 kg/m² (18.8%). Overall, frailty was associated with lower 3-year survival (47.5% vs. 82.2%) and increased mortality (hazard ratio, 1.67; 95% CI, 1.62-1.73). However, the association between frailty and survival was not uniform. The concomitant presence of frailty was associated with progressively larger increases in mortality as BMI categories increased beyond the reference group of 18.5-24.9 kg/m 2 . There was no effect of BMI on the relationship between frailty and mortality for BMI less than 18.5 kg/m 2 . This relationship was consistent in multiple sensitivity analyses. CONCLUSIONS:The association between frailty and outcomes after critical illness differed across BMI categories with a larger increase in the risk of mortality noted at higher BMI levels. Our findings may have implications for managing concurrent obesity, frailty, and critical illness.

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.

Introduction: There is uncertainty around optimal haemodynamic management of community acquired septic shock presenting to the Emergency Department (ED), with current guidelines based on low quality evidence. Prior reviews have included mostly patients with hospital-acquired sepsis in the ICU who have received significant fluid resuscitation prior to randomisation. This review will assess whether restricted fluid administration with earlier vasopressor introduction, compared to liberal fluid administration with the potential for later vasopressor introduction, is associated with reduced mortality and improvements in other outcomes in ED patients with early septic shock. Methods: Systematic review and meta-analysis of randomised controlled trials, conducted according to the PRISMA guidelines. There will be no restriction on language, year of publication or publication status. The population will be adult patients predominantly presenting to ED with septic shock. The intervention will be early vasopressor / restricted fluid resuscitation compared to more liberal fluid resuscitation / later vasopressors. The primary outcome is all cause 90-day mortality, with secondary outcomes related to adverse events, ICU interventions, functional status and quality of life up to six months. We will conduct subgroup analyses by pre-randomisation fluid volume and whether timing of initial vasopressor use was pre-specified. We will search major medical databases using structured searches. Studies will be screened for inclusion by two reviewers independently. Data will be extracted onto standardised forms by two reviewers independently. Differences on inclusion and data extraction will be resolved by consensus. A Bayesian framework will be used as the primary statistical approach, and a frequentist framework as the secondary approach. A random-effect model will be used in the analyses and pooled estimates of effect sizes as risk ratios (RRs) for binary outcomes, and mean differences for continuous outcomes will be presented. We will assess risk of bias using the Cochrane Risk of Bias tool (RoB-2) and assess for publication and incomplete outcome reporting. Certainty of evidence will be assessed using the GRADE approach. Results: We will present the results of the review at national and international scientific meetings, and we will prepare a manuscript for submission for publication in a peer reviewed journal. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This is a protocol for a systematic review, there is no data yet. When there is data it will be available in the published manuscript

Background: Limited literature exists on nutrition practices for long-stay patients in the intensive care unit (ICU). We aimed to compare nutrition practices in the first and second weeks of an ICU admission. Method: A post hoc exploratory analysis of The Augmented vs Routine Approach to Giving Energy Trial (TARGET) randomized controlled trial (RCT) was undertaken. Inclusion criteria were: enrolled in TARGET on day 1 or 2 of ICU admission and ICU length of stay (LOS) >14 days. Clinical characteristics are described, and nutrition delivery and management compared between days 1-7 and 8-14. Data are n (%), mean +/- SD, median (interquartile range [IQR]), or mean difference (MD) and 95% confidence interval (95% CI), with P < 0.05 considered significant. Results: Data from 664 patients were analyzed (56.2 +/- 16.3 years; 61% male; body mass index 29.2 +/- 7.5 kg/m2 and APACHE II 21.9 +/- 8.1). When comparing days 1-7 to 8-14: (1) energy delivery was greater (all sources: 1826 +/- 603 vs 1729 +/- 689 (MD: 97 [95% CI: 52-140] kcal/day, P < 0.001) and nonnutrition sources: 317 +/- 230 vs 192 +/- 197 (MD 125 [95% CI: 111-139] kcal/day; P < 0.001); (2) protein delivery was similar (66 +/- 20 vs 68 +/- 24 (MD: -1.4 [95% CI: -3.2 to 0.4] g/day; P = 0.125]); and (3) fewer patients received parenteral nutrition (PN) (5% vs 9%, P < 0.001) or small intestine feeding (3% vs 8%; P < 0.001). Conclusion: In this post hoc analysis, patients with an ICU LOS >14 days had greater energy delivery and fewer patients received PN or small intestine feeding during days 1-7 than days 8-14. Uncertainty remains regarding whether these data reflect usual practice and the clinical implications of this.

Background:Metabolic acidosis is common in critically ill patients and is associated with increased risk of organ dysfunction, need for renal replacement therapy, and death. Despite its frequency and clinical relevance, the optimal treatment approach remains uncertain. Sodium bicarbonate is often used to correct acidosis, but its risk-benefit profile in this setting is unclear. Objective:To describe the study protocol and statistical analysis plan for the sodium bicarbonate for metabolic acidosis in the intensive care unit (SODa-BIC) trial. Design setting and participants:Protocol for an international, multicentre, randomised, double-blind, parallel-group, superiority adaptive clinical trial. Five hundred (n = 500) adults with metabolic acidosis and receiving a continuous infusion of a vasopressor will be randomly assigned to sodium bicarbonate or placebo in a 1:1 ratio. SODa-BIC started recruiting in April 2023. It is anticipated that recruitment will be completed in 2026. Main outcome measures:The primary outcome will be major adverse kidney events within 30 days (MAKE30). Secondary and tertiary outcomes include 30- and 90-day mortality, receipt of renal replacement therapy, and vasopressor-free and ICU-free days at day 30. All analyses will be conducted on an intention-to-treat basis. Results and conclusions:SODa-BIC will evaluate whether sodium bicarbonate improves clinically meaningful outcomes in critically ill patients with metabolic acidosis. The trial has the potential to inform international practice guidelines and provide robust evidence to guide the treatment of a common and severe condition in the intensive care unit. Registration:Clinicaltrials.gov (NCT05697770).

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:Red blood cell (RBC) transfusion is associated with an increased risk of acute kidney injury (AKI). The extent to which RBC storage affects this association is unclear. We aimed to evaluate the association between storage duration and the occurrence or worsening of any degree of AKI in critically ill patients. STUDY DESIGN AND METHODS:In this pre-planned sub-study of the Standard Issue Transfusion versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) trial, which compared mortality of critically ill patients receiving either the freshest available allogenic RBC unit or standard availability RBC, patients hospitalized in one of the 31 participating sites and who did not have Stage 3 AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) classification were eligible. The primary outcome was the cumulative proportion of patients who developed any degree of new AKI. RESULTS:A total of 899 patients were included. The mean (SD) RBC storage duration was 22.4 (7.4) versus 11.9 (5.4) days in the standard issue RBC and short-storage RBC groups, respectively (p < 0.01). The percentage of patients who developed any stage of new AKI was similar between groups (24.8% in the standard issue RBC group versus 26.1% in the short-storage RBC group; p = 0.66) (Relative Risk 0.95, [95% confidence intervals 0.76-1.19]). There was no difference in secondary outcomes. DISCUSSION:In this pre-planned sub-study of the TRANSFUSE trial, compared with using standard issue RBC, the transfusion of the freshest available RBC was not associated with a decrease in AKI.

Optimal dosing of meropenem and piperacillin/tazobactam in critically ill patients receiving renal replacement therapy (RRT) is uncertain due to variable pharmacokinetics. We aimed to develop generalisable optimised dosing recommendations for these antibiotics. Prospective, multinational pharmacokinetic study including patients requiring various forms of RRT. Independent population PK models were developed, externally validated and applied to perform Monte Carlo dosing simulations using Monolix and Simulx. We calculated the probability that these dosing regimens achieved standard and high therapeutic unbound antibiotic concentrations over 100