Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU and HOT-COVID trials: A protocol update.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial was a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure; the Handling Oxygenation Targets in coronavirus disease 2019 (HOT-COVID) tested the same oxygenation targets in patients with confirmed COVID-19. In this study, we aim to evaluate the long-term effects of these oxygenation targets on cognitive and pulmonary function. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: This is the updated protocol and statistical analysis plan of two pre-planned secondary outcomes, the long-term cognitive function, and long-term pulmonary function, in the HOT-ICU and HOT-COVID trials. Patients enrolled in both trials at selected Danish sites and surviving to 1 year after randomisation are eligible to participate. A Repeatable Battery for the Assessment of Neuropsychological Status score and a full-body plethysmography, including diffusion capacity for carbon monoxide, will be obtained. The last patient is expected to be included in the spring of 2024. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on long-term cognitive and pulmonary functions in adult ICU patients with acute hypoxaemic respiratory failure.

Long-term outcomes with haloperidol versus placebo in acutely admitted adult ICU patients with delirium.

PURPOSE: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. METHODS: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values. RESULTS: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS. CONCLUSIONS: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.

Validation of PRE-DELIRIC and E-PRE-DELIRIC in a Danish population of intensive care unit patients-A prospective observational multicenter study.

BACKGROUND: Delirium is a clinical condition characterized by an acute change in brain function and is frequently observed in critically ill patients. The condition has been associated with negative outcomes, making it crucial to identify patients who are at risk. Two recent prediction models have been developed to estimate the risk of delirium in intensive care unit (ICU) patients; the prediction model for delirium (PRE-DELIRIC) and the early prediction model for delirium (E-PRE-DELIRIC). We aimed to perform an external validation of these models in a Danish cohort of critically ill patients. METHODS: We conducted a prospective, observational multicenter study to validate the PRE-DELIRIC and E-PRE-DELIRIC models in a population of patients admitted to four general ICUs in the Zealand Region of Denmark. From January 2022 to January 2023 all adult patients acutely admitted to the participating ICUs were assessed for eligibility. Patients had to be admitted to the ICU for >24 h to be included in the study. Included patients were screened with E-PRE-DELIRIC upon ICU admission and PRE-DELIRIC after 24 h of admission and followed throughout their ICU stay with CAM-ICU delirium assessments. Our primary outcomes were the prognostic accuracy measured by Area Under the Receiver Operating Characteristics (AUROC) and the calibration plot for the E-PRE-DELIRIC and PRE-DELIRIC prediction models. RESULTS: We included 660 patients, of whom 660 were assessed with E-PRE-DELIRIC, and 622 were assessed with PRE-DELIRIC. PRE-DELIRIC showed acceptable discrimination with AUROC of 0.70 (95% CI 0.66 to 0.74) and good calibration. E-PRE-DELIRIC had inadequate discrimination AUROC of 0.63 (95% CI 0.58 to 0.67) and poor calibration. CONCLUSION: In a Danish cohort, we found that the PRE-DELIRIC model demonstrated acceptable performance and E-PRE-DELIRIC demonstrated poor performance. In critically ill adult patients PRE-DELIRIC may be useful in identifying patients at high risk of delirium.

Haloperidol vs. placebo for the treatment of delirium in ICU patients: a pre-planned, secondary Bayesian analysis of the AID-ICU trial.

PURPOSE: The AID-ICU trial was a randomised, blinded, placebo-controlled trial investigating effects of haloperidol versus placebo in acutely admitted, adult patients admitted in intensive care unit (ICU) with delirium. This pre-planned Bayesian analysis facilitates probabilistic interpretation of the AID-ICU trial results. METHODS: We used adjusted Bayesian linear and logistic regression models with weakly informative priors to analyse all primary and secondary outcomes reported up to day 90, and with sensitivity analyses using other priors. The probabilities for any benefit/harm, clinically important benefit/harm, and no clinically important differences with haloperidol treatment according to pre-defined thresholds are presented for all outcomes. RESULTS: The mean difference for days alive and out of hospital to day 90 (primary outcome) was 2.9 days (95% credible interval (CrI) - 1.1 to 6.9) with probabilities of 92% for any benefit and 82% for clinically important benefit. The risk difference for mortality was - 6.8 percentage points (95% CrI - 12.8 to - 0.8) with probabilities of 99% for any benefit and 94% for clinically important benefit. The adjusted risk difference for serious adverse reactions was 0.3 percentage points (95% CrI - 1.3 to 1.9) with 98% probability of no clinically important difference. Results were consistent across sensitivity analyses using different priors, with more than 83% probability of benefit and less than 17% probability of harm with haloperidol treatment. CONCLUSIONS: We found high probabilities of benefits and low probabilities of harm with haloperidol treatment compared with placebo in acutely admitted, adult ICU patients with delirium for the primary and most secondary outcomes.

Thromboembolic and bleeding events in ICU patients with COVID-19: A nationwide, observational study.

BACKGROUND: Intensive care unit (ICU) patients with Coronavirus disease 2019 (COVID-19) have an increased risk of thromboembolic complications. We describe the occurrence of thromboembolic and bleeding events in all ICU patients with COVID-19 in Denmark during the first and second waves of the pandemic. METHODS: This was a sub-study of the Danish Intensive Care Covid database, in which all patients with SARS-CoV-2 admitted to Danish ICUs from 10th March 2020 to 30th June 2021 were included. We registered coagulation variables at admission, and all thromboembolic and bleeding events, and the use of heparins during ICU stay. Variables associated with thrombosis and bleeding and any association with 90-day mortality were estimated using Cox regression analyses. RESULTS: We included 1369 patients in this sub-study; 158 (12%, 95% confidence interval 10-13) had a thromboembolic event in ICU and 309 (23%, 20-25) had a bleeding event, among whom 81 patients (6%, 4.8-7.3) had major bleeding. We found that mechanical ventilation and increased D-dimer were associated with thrombosis and mechanical ventilation, low platelet count and presence of haematological malignancy were associated with bleeding. Most patients (76%) received increased doses of thromboprophylaxis during their ICU stay. Thromboembolic events were not associated with mortality in adjusted analysis (hazard ratio 1.35 [0.91-2.01, p = .14], whereas bleeding events were 1.55 [1.18-2.05, p = .002]). CONCLUSIONS: Both thromboembolic and bleeding events frequently occurred in ICU patients with COVID-19. Based on these data, it is not apparent that increased doses of thromboprophylaxis were beneficial.

Patient and public involvement in contemporary large intensive care trials: A meta-epidemiological study.

BACKGROUND: Patient and public involvement in randomised clinical trials has received increased focus, including in intensive care trials, but the frequency, method and extent is unknown. This meta-epidemiological study investigated patient and public involvement in contemporary, large ICU trials. METHODS: We systematically searched PubMed for large (≥225 randomised patients), contemporary trials (published between 1 January 2019 and 31 January 2022) assessing interventions in adult patients in ICU settings. Abstracts and full-text articles were assessed independently and in duplicate. Data were extracted using a pre-defined, pilot-tested data extraction form with details on trials, patient and public involvement including categories and numbers of individuals involved, methods of involvement, and trial stage(s) with involvement. Trials authors were contacted as necessary. RESULTS: We included 100 trials, with 18 using patient and public involvement; these were larger and conducted in more centres than trials without patient and public involvement. Among trials with patient and public involvement, patients (in 14/18 trials), clinicians (13 trials), and family members (12 trials) were primarily involved, mainly in the development of research design (15 trials) and development of research focus (13 trials) stages and mostly by discussion (12 trials) and solo interviews (10 trials). A median of 65 individuals (range 1-6894) were involved. CONCLUSIONS: We found patient and public involvement in a fifth of large, contemporary ICU trials. Primarily patients, families, and clinicians were included, particularly in the trial planning stages and mostly through interviews and discussions. Increased patient and public involvement in ICU trials is warranted.

Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia.

PURPOSE: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia.

PURPOSE: We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia. METHODS: Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients. RESULTS: We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93-1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50-80) in the lower oxygenation group versus 67 (50-80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups. CONCLUSION: Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa).

Development of a core outcome set for general intensive care unit patients-A protocol.

INTRODUCTION: Different outcomes are reported in randomised clinical trials (RCTs) in intensive care unit (ICU) patients, and no core outcome set (COS) is available for ICU patients in general. Accordingly, we aim to develop a COS for ICU patients in general. METHODS: The COS will be developed in accordance with the Core Outcome Measures in Effectiveness Trials (COMET) Handbook, using a modified Delphi consensus process and semi-structured interviews involving adults who have survived acute admission to an ICU, family members, clinicians, researchers and other stakeholders. The modified Delphi process will include two steps. Step 1: conduction of a modified Delphi survey, developed and informed by combining the outputs of a literature search of outcomes in previous COSs and semi-structured interviews with key stakeholders. We plan at least two survey rounds to obtain consensus and refine the COS. Step 2: a consensus process regarding instruments or definitions to be recommended for the measurements of the outcomes selected in Step 1. A 'patient and public involvement panel' consisting of a smaller group of patients, family members, clinicians and researchers will be included in the development, analysis and interpretation of the COS. DISCUSSION: The outlined multiple method studies will establish a COS for ICU patients in general, which may be used to increase the standardisation and comparability of results of RCTs conducted in patients in the ICU setting.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

PURPOSE: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.

Delirium in Intensive Care.

Purpose of Review: Delirium in the intensive care unit (ICU) has become increasingly acknowledged as a significant problem for critically ill patients affecting both the actual course of illness as well as outcomes. In this review, we focus on the current evidence and the gaps in knowledge. Recent Findings: This review highlights several areas in which the evidence is weak and further research is needed in both pharmacological and non-pharmacological treatment. A better understanding of subtypes and their different response to therapy is needed and further studies in aetiology are warranted. Larger studies are needed to explore risk factors for developing delirium and for examining long-term consequences. Finally, a stronger focus on experienced delirium and considering the perspectives of both patients and their families is encouraged. Summary: With the growing number of studies and a better framework for research leading to stronger evidence, the outcomes for patients suffering from delirium will most definitely improve in the years to come.

Patient and public involvement in contemporary large intensive care trials: Protocol for a meta-epidemiological study.

BACKGROUND: Patient and public involvement (PPI) in randomized clinical trials (RCTs) has increased in recent years but remains the exception rather than the rule. We aim to assess the frequency and extent of PPI in large, contemporary RCTs conducted in an intensive care setting. METHODS AND DESIGN: We will conduct a meta-epidemiological study of RCTs conducted in intensive care settings published since 2019 and assess their use of PPI. We will extract trial characteristics and verify the use of PPI with trial authors unless specifically stated in the published paper. The primary outcome will be the proportion of trials that use PPI. Secondary outcomes will explore which groups are consulted, at which stage of the trial process this occurs, and by what means these opinions are collected and implemented. DISCUSSION: This meta-epidemiological study will provide an important insight into the use of PPI in large, contemporary intensive care trials. We wish to reveal ways in which patient involvement could be incorporated more broadly and purposefully here and help to empower clinicians, researchers and patients to collaborate further on future research processes and goals.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial.

BACKGROUND: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. METHODS: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. RESULTS: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: -1.1 days, 95% CI -9.5 to 7.3, P = .79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. CONCLUSIONS: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

Translation of the updated clinical frailty scale 2.0 into Danish and implications for cross-sectoral reliability.

The Clinical Frailty Scale, which provides a common language about frailty, was recently updated to version 2.0 to cater for its increased use in areas of medicine usually involved in the care and treatment of older patients. We have previously translated the Clinical Frailty Scale 1.2 into Danish and found inter-rater-reliability to be excellent for primary care physicians, community nurses, and hospital doctors often involved in cross-sectoral collaborations. In this correspondence we present the Danish translation and cultural adaption of the Clinical Frailty Scale 2.0. Our recent findings on cross-sectoral inter-rater reliability for the Clinical Frailty Scale 1.2 are likely also applicable for the Clinical Frailty Scale 2.0.

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.

Characteristics, interventions, and longer term outcomes of COVID-19 ICU patients in Denmark-A nationwide, observational study.

BACKGROUND: Most data on intensive care unit (ICU) patients with COVID-19 originate in selected populations from stressed healthcare systems with shorter term follow-up. We present characteristics, interventions and longer term outcomes of the entire, unselected cohort of all ICU patients with COVID-19 in Denmark where the ICU capacity was not exceeded. METHODS: We identified all patients with SARS-CoV-2 admitted to any Danish ICU from 10 March to 19 May 2020 and registered demographics, chronic comorbidities, use of organ support, length of stay, and vital status from patient files. Risk factors for death were analyzed using adjusted Cox regression analysis. RESULTS: There were 323 ICU patients with confirmed COVID-19. Median age was 68 years, 74% were men, 50% had hypertension, 21% diabetes, and 20% chronic pulmonary disease; 29% had no chronic comorbidity. Invasive mechanical ventilation was used in 82%, vasopressors in 83%, renal replacement therapy in 26%, and extra corporeal membrane oxygenation in 8%. ICU stay was median 13 days (IQR 6-22) and hospital stay 19 days (11-30). Median follow-up was 79 days. At end of follow-up, 118 had died (37%), 15 (4%) were still in hospital hereof 4 in ICU as of 16 June 2020. Risk factors for mortality included male gender, age, chronic pulmonary disease, active cancer, and number of co-morbidities. CONCLUSIONS: In this nationwide, population-based cohort of ICU patients with COVID-19, longer term survival was high despite high age and substantial use of organ support. Male gender, age, and chronic co-morbidities, in particular chronic pulmonary disease, were associated with increased risk of death.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists. METHODS: The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals. DISCUSSION: The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock. METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116. FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]). INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock. FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

Effect of intermediate care on mortality following emergency abdominal surgery. The InCare trial: study protocol, rationale and feasibility of a randomised multicentre trial.

BACKGROUND: Emergency abdominal surgery carries a 15% to 20% short-term mortality rate. Postoperative medical complications are strongly associated with increased mortality. Recent research suggests that timely recognition and effective management of complications may reduce mortality. The aim of the present trial is to evaluate the effect of postoperative intermediate care following emergency major abdominal surgery in high-risk patients. METHODS AND DESIGN: The InCare trial is a randomised, parallel-group, non-blinded clinical trial with 1:1 allocation. Patients undergoing emergency laparotomy or laparoscopic surgery with a perioperative Acute Physiology and Chronic Health Evaluation II score of 10 or above, who are ready to be transferred to the surgical ward within 24 h of surgery are allocated to either intermediate care for 48 h, or surgical ward care. The primary outcome measure is all-cause 30-day mortality. We aim to enrol 400 patients in seven Danish hospitals. The sample size allows us to detect or refute a 34% relative risk reduction of mortality with 80% power. DISCUSSION: This trial evaluates the benefits and possible harm of intermediate care. The results may potentially influence the survival of many high-risk surgical patients. As a pioneer trial in the area, it will provide important data on the feasibility of future large-scale randomised clinical trials evaluating different levels of postoperative care. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01209663.