Attention to Immortal Time Bias in Critical Care Research

Observational studies in critical care medicine offer a popular and practical approach to questions of treatment effectiveness. Although observational research is widely understood to be susceptible to design and interpretation challenges, one well-described source of bias-immortal time bias (ITB)-is frequently present yet often overlooked. ITB may be introduced by study design oversights or mishandled during data analysis. When present, ITB can create inappropriate estimates of the benefit or harm of an exposure or intervention. Studies examining treatments in critically ill patients may be particularly susceptible to ITB, with consequences for clinical adoption and design and initiation of randomized trials. In this Critical Care Perspective, we illustrate the persistent problem of ITB in observational research using recent studies of hydrocortisone, ascorbic acid, and thiamine therapy in patients with sepsis and septic shock. Of the eight studies examined, none contained enough design or reporting elements to rule out the presence of ITB. To mitigate the influence of ITB in future observational studies, we present a novel checklist to help readers assess the features of study design, analysis, and reporting that introduce ITB or obscure its presence. We recommend that commonly used tools designed to evaluate observational research studies should include an ITB assessment.