Risk of Misleading Conclusions in Observational Studies of Time-to-Antibiotics and Mortality in Suspected Sepsis

Background: Influential studies conclude that each hour until antibiotics increases mortality in sepsis. However, these analyses often (1) adjusted for limited covariates, (2) included patients with long delays until antibiotics, (3) combined sepsis and septic shock, and (4) used linear models presuming each hour delay has equal impact. We evaluated the effect of these analytic choices on associations between time-to-antibiotics and mortality. Methods: We retrospectively identified 104 248 adults admitted to 5 hospitals from 2015-2022 with suspected infection (blood culture collection and intravenous antibiotics ≤24 h of arrival), including 25 990 with suspected septic shock and 23 619 with sepsis without shock. We used multivariable regression to calculate associations between time-to-antibiotics and in-hospital mortality under successively broader confounding-adjustment, shorter maximum time-to-antibiotic intervals, stratification by illness severity, and removing assumptions of linear hourly associations. Results: Changing covariates, maximum time-to-antibiotics, and severity stratification altered the magnitude, direction, and significance of observed associations between time-to-antibiotics and mortality. In a fully adjusted model of patients treated ≤6 hours, each hour was associated with higher mortality for septic shock (adjusted odds ratio [aOR]: 1.07; 95% CI: 1.04-1.11) but not sepsis without shock (aOR: 1.03;. 98-1.09) or suspected infection alone (aOR:. 99;. 94-1.05). Modeling each hour separately confirmed that every hour of delay was associated with increased mortality for septic shock, but only delays >6 hours were associated with higher mortality for sepsis without shock. Conclusions: Associations between time-to-antibiotics and mortality in sepsis are highly sensitive to analytic choices. Failure to adequately address these issues can generate misleading conclusions.