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

Abstract

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 five hospitals from 2015–2022 with suspected infection (blood culture collection and intravenous antibiotics within 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 within 6 h, each hour associated with higher mortality for septic shock (aOR 1.07; 95% CI 1.04–1.11), but not sepsis without shock (aOR 1.03; 0.98–1.09) or suspected infection alone (aOR 0.99; 0.94–1.05). Modeling each hour separately confirmed that every hour delay was associated with increased mortality for septic shock, but only delays of >6 h 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.

Timing of antibiotic treatment identifies distinct clinical presentations among patients presenting with suspected septic shock

“…Another block-randomized controlled trial assessing the impact of pre-hospital antibiotic administration in patients that met SIRS criteria was unable to show a difference in outcomes based on antibiotic timing. In addition, when conducting observational studies using clinical data, the association between antibiotic timing and outcomes can be significantly impacted by time windows, variables, and definitions used to model the relationship, as a recent study by Pak et al has shown 4. Our study demonstrated that, by evaluating suspected septic shock based on antibiotic timing in relation to hypotension onset (instead of ED presentation time), there was significant heterogeneity in sep-sis presentation and treatment timing.…”

“… 14 The study was limited to patients with “suspected septic shock,” defined as a systolic blood pressure (SBP) less than 90 mmHg within 24 h of ED presentation, similar to a recently published article by Pak et al. 4 We excluded those with resolution of hypotension within 30 min of its start to eliminate spurious hypotension. Repeat encounters were treated independently.…”

“…In sepsis, delays in antibiotic administration are associated with increased mortality, particularly after the development of hypotension 1 . Every hour delay in antibiotics after onset of hypotension is associated with an estimated 4%–7% increase in mortality 1–4 . Thus, current guidelines recommend clinicians administer antibiotics within 1 h 5 of shock and/or recognition of sepsis 6,7 …”

“… 1 Every hour delay in antibiotics after onset of hypotension is associated with an estimated 4%–7% increase in mortality. 1 , 2 , 3 , 4 Thus, current guidelines recommend clinicians administer antibiotics within 1 h 5 of shock and/or recognition of sepsis. 6 , 7 …”

Global research trends on sepsis and septic shock during 2003–2022: A data-driven bibliometric analysis

“…A 2023 retrospective study examining 104,248 patients revealed that every hour delay in administering antibiotics correlated with a heightened risk of mortality from septic shock. However, for non-shock patients, delays > 6 h correlate with higher mortality [21]. Inappropriate antibiotic therapy in patients with septic shock is associated with a signi cant increase in mortality.…”