Mehta, Sangeeta

Importance Eligibility criteria for randomized clinical trials (RCTs) are designed to select clinically relevant patient populations. However, not all eligibility criteria are strongly justified, potentially excluding marginalized groups, and limiting the generalizability of trial findings. Objective To summarize and evaluate the justification of exclusion criteria in published RCTs in critical care medicine. Evidence Review A systematic sampling review of parallel-group RCTs published in the top 5 general internal medicine journals by impact factor ( The Lancet, New England Journal of Medicine, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine ) between January 1, 2018, and February 23, 2023, was conducted. RCTs enrolling adults in intensive care units (ICUs) and RCTs enrolling critically ill patients who required life-sustaining interventions typically initiated in the ICU were included. All study exclusion criteria were categorized as either poorly justified, potentially justified, or strongly justified, adapting previously established criteria, independently and in duplicate. Findings In total, 225 studies were identified, 75 of which were included. The median (IQR) number of exclusion criteria per trial was 19 (14-24), with 1455 total exclusion criteria. Common exclusion criteria were related to the risk of adverse reaction to interventions (302 criteria [20.8%]), followed by inability to obtain consent (120 criteria [8.2%]), and treatment limitation decisions (97 criteria [6.7%]). Most exclusion criteria were either strongly justified (1080 criteria [74.2%]) or potentially justified (297 criteria [20.4%]), whereas 5.4% (78 criteria) were poorly justified. Of the 78 poorly justified exclusion criteria, the most common were pregnancy (19 criteria [24.4%]), communication barriers (11 criteria [14.1%]), lactation (10 criteria [12.8%]), and lack of health insurance (10 criteria [12.8%]). Overall, 45 of 75 studies (60.0%) had at least 1 poorly justified exclusion criteria. Conclusions and Relevance Most exclusion criteria in critical care medicine RCTs were strongly justifiable. Across poorly justified criteria, the most common exclusions were pregnant or lactating persons, those with communication barriers, and individuals without health insurance. This highlights the need to carefully consider exclusion criteria when designing trials to minimize the inappropriate exclusion of participants and enhance generalizability.

ABSTRACT Background: The routine use of empiric combination therapy with aminoglycosides during critical illness is associated with uncertain benefit and increased risk of acute kidney injury. This study aimed to assess the benefits of aminoglycosides in immunocompromised patients with suspected bacterial pneumonia and sepsis. Methods: Secondary analysis of a prospective multicenter study. Adult immunocompromised patients with suspected bacterial pneumonia and sepsis or septic shock were included. Primary outcome was hospital mortality. Secondary outcomes were needed for renal replacement therapy (RRT). Mortality was also assessed in neutropenic patients and in those with confirmed bacterial pneumonia. Results were further analyzed in a cohort matched on risk of receiving aminoglycosides combination. Results: Five hundred thirty-five patients were included in this analysis, of whom 187 (35%) received aminoglycosides in addition to another antibiotic effective against gram-negative bacteria. Overall hospital mortality was 59.6% (58.3% vs. 60.3% in patients receiving and not receiving combination therapy; P = 0.71). Lack of association between mortality and aminoglycosides was confirmed after adjustment for confounders and center effect (adjusted OR 1.14 [0.69–1.89]) and in a propensity matched cohort (adjusted OR = 0.89 [0.49–1.61]). No association was found between aminoglycosides and need for RRT (adjusted OR = 0.83 [0.49–1.39], P = 0.477), nor between aminoglycoside use and outcome in neutropenic patients or in patients with confirmed bacterial pneumonia (adjusted OR 0.66 [0.23–1.85] and 1.25 [0.61–2.57], respectively). Conclusion: Aminoglycoside combination therapy was not associated with hospital mortality or need for renal replacement therapy in immunocompromised patients with pulmonary sepsis.