Prevalence and representation of comorbidities and multimorbidity in randomised controlled trials in sepsis or septic...

Multimorbidity is prevalent among critically ill patients with sepsis yet remains underreported in critical care randomised controlled trials (RCTs). Inadequate reporting limits the generalisability of findings and the ability to understand whether chronic disease burden modifies treatment effects. We aimed to systematically map and evaluate how comorbidities and multimorbidity are represented, reported, and analysed in RCTs involving Intensive Care (ICU) patients with sepsis or septic shock.

We searched MEDLINE, Embase, CENTRAL, LILACS, Web of Science, medRxiv and clinical trial registries for RCTs between January 1992 and August 2025 for trials enrolling adult ICU patients with sepsis or septic shock. Two reviewers independently screened studies and extracted data using a predefined protocol registered on PROSPERO (CRD42024510506). Trials were categorised according to whether baseline comorbidity information was reported. Reported comorbidities were mapped to a Delphi-derived classification framework.

From 15,830 records, 591 RCTs met inclusion criteria. Of these, 209 trials (35.4%) reported baseline comorbidity data, enrolling a total of 48,429 patients (median 91 per trial). Trials reporting comorbidity information differed systematically from those that did not: they were larger, more likely to have publicly available protocols, more frequently used mortality as a primary outcome, and more often demonstrated low risk of bias in several methodological domains. Reporting of comorbidities increased over time (ρ = 0.80, p < 0.001), with the odds of reporting baseline comorbidity data increasing by approximately 8% per year (OR 1.08, 95% CI 1.06-1.11). Among trials reporting comorbidity data, the most frequently reported conditions were diabetes (86.1% of trials), hypertension (65.1%), chronic kidney disease (56%), and cancer (53.1%). Despite the high prevalence of comorbidities, only four trials (1.9%) explicitly reported multimorbidity and just 12 trials (5.7%) used a structured framework such as the Charlson Comorbidity Index. Nearly 80% of trials excluded participants based on at least one comorbidity.

Baseline comorbidity data are absent from most sepsis RCTs, and trials that report such information differ systematically from those that do not. Standardised frameworks and transparent reporting of comorbidities and multimorbidity are needed to improve representativeness, enable subgroup analyses, and enhance the external validity of sepsis research.