A systematic review to assess the impact of amino acids or their derivatives on skeletal muscle wasting in critically ill patients.

BACKGROUND: It is plausible that supplementation with specific amino acids or metabolites could attenuate skeletal muscle wasting during critical illness. The aim of this systematic review was to explore if amino acids or their derivatives impact skeletal muscle wastage in critically ill adults. METHODS: Four databases were systematically searched to identify randomised control trials which delivered enteral supplemental amino acids, or their metabolites compared with placebo, standard care or no intervention, to critically ill patients and reported outcomes of skeletal muscle mass, plasma amino acids, nitrogen balance, or muscle strength. Two authors independently completed screening, data extraction, and risk of bias assessment using the Cochrane Risk of Bias 2 Tool. A meta-analysis was planned but heterogeneity in the type of intervention used and outcome assessment precluded this. Therefore, data were synthesised using vote counting. RESULTS: Thirty randomised control trials, comprising 1976 patients were included. The most frequently studied interventional amino acid or metabolite was glutamine (n = 12 trials), a combination (n = 9), arginine (n = 6), ß-hydroxy ß-methylbutyrate (HMB) (n = 2) or ornithine (n = 1). Six trials (including 284 participants) measured skeletal muscle following supplementation, four of which used HMB alone or in combination as the intervention. Of these, one trial observed an attenuation of muscle wasting with a combination of amino acids, one observed an exacerbation of muscle wasting with HMB, three trials observed no impact on muscle wasting with HMB or a combination of amino acids and one trial reported no information. CONCLUSION: Six trials have investigated the effect of enteral amino acid or amino acid metabolite supplementation on muscle mass in critically ill. Heterogeneity of interventions, outcome assessments and direction of effects limits the certainty regarding the effect of supplemental amino acids, or their metabolites, on skeletal muscle wasting during critical illness. The trial protocol is registered on PROSPERO (CRD42021275989).

Effect of high versus standard protein provision on functional recovery in people with critical illness (PRECISe): an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in Belgium and the Netherlands.

BACKGROUND: Increased protein provision might ameliorate muscle wasting and improve long-term outcomes in critically ill patients. The aim of the PRECISe trial was to assess whether higher enteral protein provision (ie, 2·0 g/kg per day) would improve health-related quality of life and functional outcomes in critically ill patients who were mechanically ventilated compared with standard enteral protein provision (ie, 1·3 g/kg per day). METHODS: The PRECISe trial was an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in five Dutch hospitals and five Belgian hospitals. Inclusion criteria were initiation of invasive mechanical ventilation within 24 h of intensive care unit (ICU) admission and an expected duration of invasive ventilation of 3 days or longer. Exclusion criteria were contraindications for enteral nutrition, moribund condition, BMI less than 18 kg/m2, kidney failure with a no dialysis code, or hepatic encephalopathy. Patients were randomly assigned to one of four randomisation labels, corresponding with two study groups (ie, standard or high protein; two labels per group) in a 1:1:1:1 ratio through an interactive web-response system. Randomisation was done via random permuted-block randomisation in varying block sizes of eight and 12, stratified by centre. Participants, care providers, investigators, outcome assessors, data analysts, and the independent data safety monitoring board were all blinded to group allocation. Patients received isocaloric enteral feeds that contained 1·3 kcal/mL and 0·06 g of protein/mL (ie, standard protein) or 1·3 kcal/mL and 0·10 g of protein/mL (ie, high protein). The study-nutrition intervention was limited to the time period during the patient's ICU stay in which they required enteral feeding, with a maximum of 90 days. The primary outcome was EuroQoL 5-Dimension 5-level (EQ-5D-5L) health utility score at 30 days, 90 days, and 180 days after randomisation, adjusted for baseline EQ-5D-5L health utility score. This trial was registered with ClinicalTrials.gov (NCT04633421) and is closed to new participants. FINDINGS: Between Nov 19, 2020, and April 14, 2023, 935 patients were randomly assigned. 335 (35·8%) of 935 patients were female and 600 (64·2%) were male. 465 (49·7%) of 935 were assigned to the standard protein group and 470 (50·3%) were assigned to the high protein group. 430 (92·5%) of 465 patients in the standard protein group and 419 (89·1%) of 470 patients in the high protein group were assessed for the primary outcome. The primary outcome, EQ-5D-5L health utility score during 180 days after randomisation (assessed at 30 days, 90 days, and 180 days), was lower in patients allocated to the high protein group than in those allocated to the standard protein group, with a mean difference of -0·05 (95% CI -0·10 to -0·01; p=0·031). Regarding safety outcomes, the probability of mortality during the entire follow-up was 0·38 (SE 0·02) in the standard protein group and 0·42 (0·02) in the high protein group (hazard ratio 1·14, 95% CI 0·92 to 1·40; p=0·22). There was a higher incidence of symptoms of gastrointestinal intolerance in patients in the high protein group (odds ratio 1·76, 95% CI 1·06 to 2·92; p=0·030). Incidence of other adverse events did not differ between groups. INTERPRETATION: High enteral protein provision compared with standard enteral protein provision resulted in worse health-related quality of life in critically ill patients and did not improve functional outcomes during 180 days after ICU admission. FUNDING: Netherlands Organisation for Healthcare Research and Development and Belgian Health Care Knowledge Centre.

Twenty percent human albumin solution fluid bolus administration therapy in patients after cardiac surgery-II: a multicentre randomised controlled trial.

PURPOSE: After cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT. METHODS: We conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance. RESULTS: Of 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0-19.6) hours with 20% albumin and 10.8 (IQR 0-22.8) hours with crystalloids (difference - 3.8 h, 95% confidence interval [CI] - 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference - 701 mL, 95% CI - 872 to - 530). CONCLUSIONS: In patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy.

Effects of sodium-glucose transporter-2 inhibition on systemic hemodynamics, renal function, and intra-renal oxygenation in sepsis-associated acute kidney injury.

BACKGROUND: People with type 2 diabetes mellitus treated with sodium-glucose transporter-2 inhibitors (SGLT2i) have lower rates of acute kidney injury (AKI). Sepsis is responsible for the majority of AKI in critically ill patients. This study investigated whether SGLT2i is renoprotective in an ovine model of Gram-negative septic AKI. METHODS: Sixteen healthy merino ewes were surgically instrumented to enable measurement of mean arterial pressure, cardiac output, renal blood flow, renal cortical and medullary perfusion, and oxygenation. After a 5-day recovery period, sepsis was induced via slow and continuous intravenous infusion of live Escherichia coli. Twenty-three hours later, sheep were randomized to receive an intravenous bolus of 0.2 mg/kg empagliflozin (n = 8) or a fluid-matched vehicle (n = 8). RESULTS: Empagliflozin treatment did not significantly reduce renal medullary hypoperfusion or hypoxia, improve kidney function, or induce histological changes. Renal cortical oxygenation during the intervention period was 47.6 ± 5.9 mmHg in the empagliflozin group compared with 40.6 ± 8.2 mmHg in the placebo group (P = 0.16). Renal medullary oxygenation was 28.0 ± 18.5 mmHg in the empagliflozin compared with 25.7 ± 16.3 mmHg (P = 0.82). Empagliflozin treatment did not result in significant between-group differences in renal blood flow, kidney function, or renal histopathological changes. CONCLUSION: In a large mammalian model of septic AKI, a single dose of empagliflozin did not improve renal microcirculatory perfusion, oxygenation, kidney function, or histopathology.

Patient-important upper gastrointestinal bleeding in the ICU: A mixed-methods study of patient and family perspectives.

INTRODUCTION: The objective of this study was to create a definition of patient-important upper gastrointestinal bleeding during critical illness as an outcome for a randomized trial. DESIGN: This was a sequential mixed-methods qualitative-dominant multi-center study with an instrument-building aim. In semi-structured individual interviews or focus groups we elicited views from survivors of critical illness and family members of patients in the intensive care unit (ICU) regarding which features indicate important gastrointestinal bleeding. Quantitative demographic characteristics were collected. We analyzed qualitative data using inductive content analysis to develop a definition for patient-important upper gastrointestinal bleeding. SETTING: Canada and the United States. PARTICIPANTS: 51 ICU survivors and family members of ICU patients. RESULTS: Participants considered gastrointestinal bleeding to be important if it resulted in death, disability, or prolonged hospitalization. The following also signaled patient-important upper gastrointestinal bleeding: blood transfusion, vasopressors, endoscopy, CT-angiography, or surgery. Whether an intervention evinced concern depended on its effectiveness, side-effects, invasiveness and accessibility; contextual influences included participant familiarity and knowledge of interventions and trust in the clinical team. CONCLUSIONS: Survivors of critical illness and family members described patient-important upper gastrointestinal bleeding differently than current definitions of clinically-important upper gastrointestinal bleeding.

A Randomized Noninferiority Trial to Compare Enteral to Parenteral Phosphate Replacement on Biochemistry, Waste, and Environmental Impact and Healthcare Cost in Critically Ill Patients With Mild to Moderate Hypophosphatemia.

OBJECTIVES: Hypophosphatemia occurs frequently. Enteral, rather than IV, phosphate replacement may reduce fluid replacement, cost, and waste. DESIGN: Prospective, randomized, parallel group, noninferiority clinical trial. SETTING: Single center, 42-bed state trauma, medical and surgical ICUs, from April 20, 2022, to July 1, 2022. PATIENTS: Patients with serum phosphate concentration between 0.3 and 0.75 mmol/L. INTERVENTIONS: We randomized patients to either enteral or IV phosphate replacement using electronic medical record-embedded program. MEASUREMENT AND MAIN RESULTS: Our primary outcome was serum phosphate at 24 hours with a noninferiority margin of 0.2 mmol/L. Secondary outcomes included cost savings and environmental waste reduction and additional IV fluid administered. The modified intention-to-treat cohort comprised 131 patients. Baseline phosphate concentrations were similar between the two groups. At 24 hours, mean ( sd ) serum phosphate concentration were enteral 0.89 mmol/L (0.24 mmol/L) and IV 0.82 mmol/L (0.28 mmol/L). This difference was noninferior at the margin of 0.2 mmol/L (difference, 0.07 mmol/L; 95% CI, -0.02 to 0.17 mmol/L). When assigned IV replacement, patients received 408 mL (372 mL) of solvent IV fluid. Compared with IV replacement, the mean cost per patient was ten-fold less with enteral replacement ($3.7 [$4.0] vs. IV: $37.7 [$31.4]; difference = $34.0 [95% CI, $26.3-$41.7]) and weight of waste was less (7.7 g [8.3 g] vs. 217 g [169 g]; difference = 209 g [95% CI, 168-250 g]). C O2 emissions were 60-fold less for comparable phosphate replacement (enteral: 2 g producing 14.2 g and 20 mmol of potassium dihydrogen phosphate producing 843 g of C O2 equivalents). CONCLUSIONS: Enteral phosphate replacement in ICU is noninferior to IV replacement at a margin of 0.2 mmol/L but leads to a substantial reduction in cost and waste.

Association between protocol change to a higher-protein formula with lower energy targets and nutrient delivery in critically ill patients with COVID-19: A retrospective cohort study.

BACKGROUND: Guidelines recommend prioritizing protein provision while avoiding excessive energy delivery to critically ill patients with coronavirus disease 2019 (COVID-19), but there are no prospective studies evaluating such a targeted approach in this group. We aimed to evaluate the effect of a "higher-protein formula protocol" on protein, energy, and volume delivery when compared with standard nutrition protocol. METHODS: This was a retrospective cohort study of adult patients with COVID-19 who received mechanical ventilation for >72 h and enteral nutrition. Before October 2021, the standard nutrition protocol for patients was 0.7 ml/kg/h ideal body weight (IBW) of a 63 g/L protein and 1250 kcal/L formula. From October 2021, we implemented a higher-protein formula protocol for patients with COVID-19. The initial prescription was 0.5 ml/kg/h IBW of a 100 g/L protein and 1260 kcal/L formula with greater emphasis on energy targets being directed by indirect calorimetry when possible. Measured outcomes included protein, energy, and volume delivered. RESULTS: There were 114 participants (standard protocol, 48; higher-protein protocol, 66) with 1324 days of nutrition support. The median (95% CI) differences in protein, energy, and volume delivery between targeted and standard protocol periods were 0.08 g/kg/day (-0.02 to 0.18 g/kg/day), -1.71 kcal/kg/day (-3.64 to 0.21 kcal/kg/day) and -1.5 ml/kg/day (-2.9 to -0.1 ml/kg/day). Thirty-three patients (standard protocol, 7; higher-protein protocol, 26) had 44 indirect calorimetry assessments. There was no difference in measured energy expenditure over time (increased by 0.49 kcal/kg/day [-0.89 to 1.88 kcal/kg/day]). CONCLUSION: Implementation of a higher-protein formula protocol to patients with COVID-19 modestly reduced volume administration without impacting protein and energy delivery.

Plasma beta-hydroxy-beta-methylbutyrate availability after enteral administration during critical illness after trauma: An exploratory study.

BACKGROUND: During critical illness skeletal muscle wasting occurs rapidly. Although beta-hydroxy-beta-methylbutyrate (HMB) is a potential treatment to attenuate this process, the plasma appearance and muscle concentration is uncertain. METHODS: This was an exploratory study nested within a blinded, parallel group, randomized clinical trial in which critically ill patients after trauma received enteral HMB (3 g daily) or placebo. Plasma samples were collected at 0, 60, and 180 min after study supplement administration on day 1. Needle biopsies of the vastus lateralis muscle were collected (baseline and day 7 of the HMB treatment intervention period). An external standard curve was used to calculate HMB concentrations in plasma and muscle. RESULTS: Data were available for 16 participants (male n = 12 (75%), median [interquartile range] age 50 [29-58] years) who received placebo and 18 participants (male n = 14 (78%), age 49 [34-55] years) who received HMB. Plasma HMB concentrations were similar at baseline but increased after HMB (T = 60 min: placebo 0.60 [0.44-1.31] µM; intervention 51.65 [22.76-64.72] µM). Paired muscle biopsies were collected from 11 participants (placebo n = 7, HMB n = 4). Muscle HMB concentrations were similar at baseline between groups (2.35 [2.17-2.95]; 2.07 [1.78-2.31] µM). For participants in the intervention group who had the repeat biopsy within 4 h of HMB administration, concentrations were greater (7.2 and 12.3 µM) than those who had the repeat biopsy >4 h after HMB (2.7 and 2.1 µM). CONCLUSION: In this exploratory study, enteral HMB administration increased plasma HMB availability. The small sample size limits interpretation of the muscle HMB findings.

Clinician- and Patient-Identified Solutions to Reduce the Fragmentation of Post-ICU Care in Australia.

BACKGROUND: Critical care survivors experience multiple care transitions, with no formal follow-up care pathway. RESEARCH QUESTION: What are the potential solutions to improve the communication between treating teams and integration of care following an ICU admission, from the perspective of patients, their caregivers, intensivists, and general practitioners (GPs) from diverse socioeconomic areas? STUDY DESIGN AND METHODS: This study included a qualitative design using semi-structured interviews with intensivists, GPs, and patients and caregivers. Framework analysis was used to analyze data and to identify solutions to improve the integration of care following hospital discharge. Patients were previously mechanically ventilated for > 24 h in the ICU and had access to a video-enabled device. Clinicians were recruited from hospital networks and a state-wide GP network. RESULTS: Forty-six interviews with clinicians, patients, and caregivers were completed (15 intensivists, eight GPs, 15 patients, and eight caregivers). Three higher level feedback loops were identified that comprised 10 themes. Feedback loop 1 was an ICU and primary care collaboration. It included the following: (1) developing collaborative relationships between the ICU and primary care; (2) providing interprofessional education and resources to support primary care; and (3) improving role clarity for patient follow-up care. Feedback loop 2 was developing mechanisms for improved communication across the care continuum. It included: (4) timely, concise information-sharing with primary care on post-ICU recovery; (5) survivorship-focused information-sharing across the continuum of care; (6) empowering patients and caregivers in self-management; and (7) creation of a care coordinator role for survivors. Feedback loop 3 was learning from post-ICU outcomes to improve future care. It included: (8) developing comprehensive post-ICU care pathways; (9) enhancing support for patients following a hospital stay; and (10) integration of post-ICU outcomes within the ICU to improve clinician morale and understanding. INTERPRETATION: Practical solutions to enhance the quality of survivorship for critical care survivors and their caregivers were identified. These themes are mapped to a novel conceptual model that includes key feedback loops for health system improvements and foci for future interventional trials to improve ICU survivorship outcomes.

In-person peer support for critical care survivors: The ICU REcovery Solutions cO-Led through surVivor Engagement (ICURESOLVE) pilot randomised controlled trial.

BACKGROUND: Peer support is a promising intervention to mitigate post-ICU disability, however there is a paucity of rigorously designed studies. OBJECTIVES: The objective of this study was to establish feasibility of an in-person, co-designed, peer-support model. METHODS: Prospective, randomised, adaptive, single-centre pilot trial with blinded outcome assessment, conducted at a university-affiliated hospital in Melbourne, Australia. Intensive care unit survivors (and their nominated caregiver, where survivor and caregiver are referred to as a dyad), >18 years of age, able to speak and understand English and participate in phone surveys, were eligible. Participants were randomised to the peer-support model (six sessions, fortnightly) or usual care (no follow-up or targeted information). Two sequential models were piloted: 1. Early (2-3 weeks post hospital discharge) 2. Later (4-6 weeks post hospital discharge). Primary outcome was feasibility of implementation measured by recruitment, intervention attendance, and outcome completion. Secondary outcomes included post-traumatic stress and social support. RESULTS: Of the 231 eligible patients, 80 participants were recruited. In the early model we recruited 38 participants (28 patients, 10 carers; 18 singles, 10 dyads), with an average (standard deviation) age of 60 (18) years; 55 % were female. Twenty-two participants (58 %) were randomised to intervention. Participants in the early intervention model attended a median (interquartile range) of 0 (0-1) sessions (total 24 sessions), with 53% (n = 20) completing the main secondary outcome of interest (Impact of Event Scale) at the baseline and 37 % (n = 14) at the follow-up. For the later model we recruited 42 participants (32 patients, 10 carers; 22 singles, 10 dyads), with an average (standard deviation) age of 60.4 (15.4) years; 50 % were female. Twenty-one participants (50 %) were randomised to intervention. The later intervention model attended a median (interquartile range) of 1 (0-5) sessions (total: 44 sessions), with the main secondary outcome impact of events scale (IES-R) completed by 41 (98 %) participants at baseline and 29 (69 %) at follow-up. CONCLUSIONS: In this pilot trial, a peer-support model that required in-person attendance delivered in a later posthospital phase of recovery appeared more feasible than an early model. Further research should investigate alternative modes of intervention delivery to improve feasibility (ACTRN12621000737831).

Feasibility of Embedding a Randomised Clinical Trial (RCT) into an Electronic Medical Record (EMR) for Patients Admitted to an Intensive Care Unit (ICU).

To establish the feasibility of embedding an RCT into EMR in the ICU, we evaluated the route of phosphate replacement. The EMR screened 207 patients who met the inclusion criteria from 20 April 2022 to 30 June 2022. 162 patients were randomised and 145 patients allocated to treatment. Our study showed that it was feasible to embed screening, randomisation, and treatment allocation for an RCT within an EMR in the ICU.

Perioperative management of long-acting glucagon-like peptide-1 (GLP-1) receptor agonists: concerns for delayed gastric emptying and pulmonary aspiration.

Prescriptions and use of glucagon-like peptide-1 (GLP-1) receptor agonists are increasing dramatically, as indications are expanding from the treatment of diabetes mellitus to weight loss for people with obesity. As GLP-1 receptor agonists delay gastric emptying, perioperative healthcare practitioners could be concerned about an increased risk for pulmonary aspiration during general anaesthesia. We summarise relevant medical literature and provide evidence-based recommendations for perioperative care for people taking GLP-1 receptor agonists. GLP-1 receptor agonists delay gastric emptying; however, ongoing treatment attenuates this effect. The risk of aspiration during general anaesthesia is unknown. However, we advise caution in patients who recently commenced on GLP-1 receptor agonists. After over 12 weeks of treatment, standard fasting times likely suffice to manage the risk of pulmonary aspiration for most otherwise low-risk patients.

Models of intensive care unit follow-up care and feasibility of intervention delivery: A systematic review.

BACKGROUND: The optimal model of outpatient intensive care unit (ICU) follow-up care remains uncertain, and there is limited evidence of benefit. RESEARCH QUESTION: The objective of this research is to describe existing models of outpatient ICU follow-up care, quantify participant recruitment and retention, and describe facilitators of patient engagement. STUDY DESIGN & METHODS: A systematic search of the MEDLINE and EMBASE databases was undertaken in June 2021. Two independent reviewers screened titles, abstracts, and full texts against eligibility criteria. Studies of adults with any outpatient ICU follow-up were included. Studies were excluded if published before 1990, not published in English, or of paediatric patients. Quantitative data were extracted using predefined data fields. Key themes were extracted from qualitative studies. Risk of bias was assessed. RESULTS: A total of 531 studies were screened. Forty-seven studies (32 quantitative and 15 qualitative studies) with a total of 5998 participants were included. Of 33 quantitative study interventions, the most frequently reported model of care was in-person hospital-based interventions (n = 27), with 10 hybrid (part in-hospital, part remote) interventions. Literature was limited for interventions without hospital attendance (n = 6), including telehealth and diaries. The median ranges of rates of recruitment, rates of intervention delivery, and retention to outcome assessment for hospital-based interventions were 51.5% [24-94%], 61.9% [8-100%], and 52% [8.1-82%], respectively. Rates were higher for interventions without hospital attendance: 82.6% [60-100%], 68.5% [59-89%], and 75% [54-100%]. Facilitators of engagement included patient-perceived value of follow-up, continuity of care, intervention accessibility and flexibility, and follow-up design. Studies had a moderate risk of bias. INTERPRETATION: Models of post-ICU care without in-person attendance at the index hospital potentially have higher rates of recruitment, intervention delivery success, and increased participant retention when compared to hospital-based interventions. PROSPERO REGISTRATION: CRD42021260279.

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock.

BACKGROUND: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. METHODS: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. RESULTS: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. CONCLUSIONS: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol.

INTRODUCTION: The Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE. METHODS AND ANALYSIS: REVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial. ETHICS AND DISSEMINATION: All participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to - Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION NUMBER: NCT03374800.

Protocol summary and statistical analysis plan for the low oxygen intervention for cardiac arrest injury limitation (LOGICAL) trial.

Background: The effect of conservative vs. liberal oxygen therapy on outcomes of intensive care unit (ICU) patients with hypoxic ischaemic encephalopathy (HIE) is uncertain and will be evaluated in the Low Oxygen Intervention for Cardiac Arrest injury Limitation (LOGICAL) trial. Objective: The objective of this study was to summarise the protocol and statistical analysis plans for the LOGICAL trial. Design setting and participants: LOGICAL is a randomised clinical trial in adults in the ICU who are comatose with suspected HIE (i.e., those who have not obeyed commands following return of spontaneous circulation after a cardiac arrest where there is clinical concern about possible brain damage). The LOGICAL trial will include 1400 participants and is being conducted as a substudy of the Mega Randomised registry trial comparing conservative vs. liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX). Main outcome measures: The primary outcome is survival with favourable neurological function at 180 days after randomisation as measured with the Extended Glasgow Outcome Scale (GOS-E). A favourable neurological outcome will be defined as a GOS-E score of lower moderate disability or better (i.e. a GOS-E score of 5-8). Secondary outcomes include survival time, day 180 mortality, duration of invasive mechanical ventilation, ICU length of stay, hospital length of stay, the proportion of patients discharged home, quality of life assessed at day 180 using the EQ-5D-5L, and cognitive function assessed at day 180 using the Montreal Cognitive Assessment (MoCA-blind). Conclusions: The LOGICAL trial will provide reliable data on the impact of conservative vs. liberal oxygen therapy in ICU patients with suspected HIE following resuscitation from a cardiac arrest. Prepublication of the LOGICAL protocol and statistical analysis plan prior to trial conclusion will reduce the potential for outcome-reporting or analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN12621000518864).