Higher versus lower oxygenation targets in COVID‐19 patients with severe hypoxaemia (HOT‐COVID) trial: Protocol for a secondary Bayesian analysis

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Background: Supplemental oxygen therapy is central to the treatment of acute hypoxaemic respiratory failure, a condition which remains a major driver for morbidity and mortality in intensive care. Despite several large randomised clinical trials comparing a higher versus a lower oxygenation target for these patients, significant differences in study design impede analysis of aggregate data and final clinical recommendations.Methods: This paper presents the protocol for conducting an individual patient data meta-analysis where full individual patient data according to the intention-to-treat principle will be pooled from the HOT-ICU and HOT-COVID trials in a one-step procedure.The two trials are near-identical in design. We plan to use a hierarchical general linear mixed model that accounts for data clustering at a trial and site level. The primary outcome will be 90-day all-cause mortality while the secondary outcome will be days alive without life-support at 90 days. Further, we outline 14 clinically relevant predefined subgroups which we will analyse for heterogeneity in the intervention effects and interactions, and we present a plan for assessing the credibility of the subgroup analyses. Conclusion:The presented individual patient data meta-analysis will synthesise individual level patient data from two of the largest randomised clinical trials on targeted oxygen therapy in intensive care. The results will provide a re-analysis of the intervention effects on the pooled intention-to-treat populations and facilitate subgroup analyses with an increased power to detect clinically important effect modifications.

Section: Discussionmentioning

confidence: 99%

Section: Choice Of Statistical Modelsmentioning

confidence: 99%

Lower or higher oxygenation targets for acute Hypoxaemic respiratory failure: Protocol for an individual patient data meta‐analysis

Nielsen

Klitgaard

Bruun

et al. 2023

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“…We expect the continuous secondary outcome, days alive without life support, to be skewed (non‐normally distributed) and zero‐inflated. Despite the skewed distribution, this outcome will be analysed using a Bayesian linear regression model, which is robust and adequately allows estimation of the effect measures of interest 17 …”

Section: Methodsmentioning

confidence: 99%

“…We will use Stan's default dynamic Hamiltonian Monte–Carlo sampler with fours chains with at least 10,000 post‐warm‐up samples in total, and at least 1000 bulk/tail effective sample sizes for all parameters. Model adequacy will be assessed as previously described 17,22–24 …”

Section: Methodsmentioning

confidence: 99%

Conservative vs. liberal fluid therapy in septic shock – Protocol for secondary Bayesian analyses of the CLASSIC trial

Sivapalan

Meyhoff

Hjortrup

et al. 2022

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Intravenous (IV) fluids are considered essential in the management of sepsis, and the Surviving Sepsis Campaign guideline suggests at least 30 ml/kg IV fluid volumes should be given initially to adult patients based on low quality evidence. 1 The guideline committee found that there was insufficient evidence to make recommendation on the use of restrictive versus liberal fluid strategy after initial

“…We will employ Bayesian analyses to evaluate the probabilities of various effect sizes that are of interest. This methodology integrates prior beliefs by utilizing an initial prior probability distribution, which is then updated based on the trial data to refine and redistribute probabilities, ultimately forming a posterior probability distribution 25 …”

Section: Introductionmentioning

confidence: 99%

Lower versus higher blood pressure targets in comatose patients resuscitated from out‐of‐hospital cardiac arrest—Protocol for a secondary Bayesian analysis of the box trial

Grand,

Wiberg,

Kjaergaard

et al. 2024

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BackgroundThe management of blood pressure targets during intensive care after out‐of‐hospital cardiac arrest (OHCA) remains a topic of debate. The blood Pressure and Oxygenation Targets After OHCA (BOX) trial explored the efficacy of two different blood pressure targets in 789 patients during intensive care after OHCA. In the primary frequentist analysis, no statistically significant differences were found for neurological outcome after 90 days.MethodsThis protocol outlines secondary Bayesian analyses of 365‐day all‐cause mortality and two secondary outcomes: neurological outcome after 365 days, and plasma neuron‐specific enolase, a biomarker of brain injury, after 48 h. We will employ adjusted Bayesian logistic and linear regressions, presenting results as relative and absolute differences with 95% confidence intervals. We will use weakly informative priors for the primary analyses, and skeptical and evidence‐based priors (where available) in sensitivity analyses. Exact probabilities for any benefit/harm will be presented for all outcomes, along with probabilities of clinically important benefit/harm (risk differences larger than 2%‐points absolute) and no clinically important differences for the binary outcomes. We will assess whether heterogeneity of treatment effects on mortality is present according to lactate at admission, time to return of spontaneous circulation, primary shockable rhythm, age, hypertension, and presence of ST‐elevation myocardial infarction.DiscussionThis secondary analysis of the BOX trial aim to complement the primary frequentist analysis by quantifying the probabilities of beneficial or harmful effects of different blood pressure targets. This approach seeks to provide clearer insights for researchers and clinicians into the effectiveness of these blood pressure management strategies in acute medical conditions, particularly focusing on mortality, neurological outcomes, and neuron‐specific enolase.