Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Timing of onset of gastrointestinal bleeding in the ICU: Protocol for a preplanned observational study.

BACKGROUND: Critically ill patients are at risk of gastrointestinal bleeding, but clinically important gastrointestinal bleeding is rare. The majority of intensive care unit (ICU) patients receive stress ulcer prophylaxis (SUP), despite uncertainty concerning the balance between benefit and harm. For approximately half of ICU patients with gastrointestinal bleeding, onset is early, ie within the first two days of the ICU stay. The aetiology of gastrointestinal bleeding and consequently the balance between benefit and harm of SUP may differ between patients with early vs late gastrointestinal bleeding. METHODS: This is a protocol and statistical analysis plan for a preplanned exploratory substudy of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) randomized clinical trial, comparing intravenous pantoprazole (40 mg once daily) with placebo in 3350 acutely ill adult ICU patients. We will describe baseline characteristics and assess the time to onset of the first clinically important episode of GI bleeding accounting for survival status and allocation to SUP or placebo. In addition, we will describe differences in therapeutic and diagnostic procedures used in patients with clinically important gastrointestinal bleeding according to early vs late bleeding and 90-day vital status. CONCLUSIONS: The study outlined in this protocol will provide detailed information on patient characteristics and the timing of onset of gastrointestinal bleeding in the patients enrolled in the SUP-ICU trial. This may provide additional knowledge and incentives for future studies on which patients benefit from SUP.

Therapeutic bronchoscopy vs. standard of care in acute respiratory failure: a systematic review.

BACKGROUND: We aimed to assess patient-important benefits and harms of therapeutic bronchoscopy vs. standard of care (no bronchoscopy) in critically ill patients with acute respiratory failure (ARF). METHODS: We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) according to the Cochrane Handbook and GRADE methodology, including a predefined protocol (PROSPERO no. CRD42016046235). We included randomized clinical trials (RCTs) comparing therapeutic bronchoscopy to standard of care in critically ill patients with ARF. Two reviewers independently assessed trials for inclusion, extracted data and assessed risk of bias. Risk ratios (RR) with 95% confidence intervals (CI) were estimated by conventional meta-analysis. The risk of random errors was assessed by TSA. Exclusively patient-important outcomes were evaluated. RESULTS: We included five trials (n = 212); all were judged as having high risk of bias. There was no difference in all-cause mortality between therapeutic bronchoscopy and standard of care (TSA adjusted RR 0.39; 95% CI 0.14 to 1.07; I2 0%), and only 3% of the required information size had been accrued. There was no difference in ICU length of stay. A shorter duration of mechanical ventilation was suggested by conventional meta-analysis, however TSA highlighted that only 42% of the required information size had been accrued, indicating high risk of random errors. No trials reported data on adverse events, hospital length of stay, quality of life or performance status. CONCLUSIONS: The quantity and quality of evidence supporting therapeutic bronchoscopy in critically ill patients with ARF is very low with no firm evidence for benefit or harm.

Use of life support in acutely admitted ICU patients. An international cohort study.

BACKGROUND: Use of life support in intensive care unit (ICU) patients has been associated with increased risk of poor outcome. The prognostic importance of the duration of support is less studied. We assessed the use of life support and the association between its duration and 90-day mortality in a contemporary cohort of acutely admitted adult ICU patients. METHODS: We performed a post-hoc analysis of the SUP-ICU 7-day inception cohort study (n = 1034), which was conducted in 97 ICUs in 11 countries. We included patients with an ICU stay of 3 days or more. We assessed the use of life support during the first 3 days in ICU and the crude and adjusted association between its duration and 90-day mortality using logistic regression analyses. RESULTS: We included 690 patients; their 90-day mortality was 23%. During the first 3 days in ICU mechanical ventilation was used in 65%, vasopressors/inotropes in 57% and renal replacement therapy in 13%. Renal replacement therapy for 3 days or more was associated with a higher 90-day mortality as compared with 1 day of renal replacement therapy [odds ratio 6.5 (95% confidence interval 1.3 to 32.8)]. For mechanical ventilation and vasopressors/inotropes the odds ratios were 2.2 [0.9 to 5.3] and 1.2 [0.5 to 2.6], respectively. CONCLUSIONS: Among acutely admitted adult ICU patients, a higher number of days of renal replacement therapy in the initial ICU stay were associated with increased risk of death within 90 days. We did not observe such an association for mechanical ventilation or vasopressor/inotropic therapy.

Lower vs. higher fluid volumes in sepsis-protocol for a systematic review with meta-analysis.

BACKGROUND: Intravenous fluid administration with crystalloids is recommended in the initial management of sepsis. However, the quality of evidence supporting the recommendation on fluid volumes is low, and clinical equipoise exists. Potential benefits of restricting fluid volumes has been suggested, but the overall benefit or harm in patients with sepsis is unknown. Accordingly, we aim to assess patient-important benefits and harms of lower vs. higher fluid volumes in resuscitation of adult patients with sepsis. METHODS/DESIGN: We will conduct a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials comparing different strategies to obtain separation in fluid volumes or balances during resuscitation of adult patients with sepsis. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: The outlined systematic review will provide important data on how patient-important outcomes are affected by higher vs. lower resuscitation fluid volumes in adults with sepsis. Using trial sequential analysis to assess the risk of random errors will increase the validity of the summary estimates calculated and help estimate the required information size for future trials.

Stress ulcer prophylaxis in the intensive care unit trial: detailed statistical analysis plan.

BACKGROUND: In this statistical analysis plan, we aim to provide details of the pre-defined statistical analyses of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. The aim of the SUP-ICU trial is to assess benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the intensive care unit (ICU). METHODS: The SUP-ICU trial is an investigator-initiated, international, multicentre, randomised, blinded, parallel-group trial of intravenously pantoprazole 40 mg once daily vs. placebo in 3350 acutely ill adult ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support, serious adverse reactions, 1-year mortality, and a health economic analysis. Two formal interim analyses will be performed. The statistical analyses will be conducted according to the outlined pre-defined statistical analysis plan. The primary analysis will be a logistic regression analysis adjusted for stratification variables comparing the two intervention groups in the intention-to-treat population. In a secondary analysis, we will additionally adjust the primary outcome for potential random differences in baseline characteristics. The conclusion will be based on the intention-to-treat population. CONCLUSION: Stress ulcer prophylaxis is standard of care in ICUs worldwide, but has never been tested in large high-quality randomised placebo-controlled trials. The SUP-ICU trial will provide important high-quality data on the balance between the benefits and harms of stress ulcer prophylaxis in adult critically ill patients.