Unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates

Purpose: Although the definition of septic shock has been standardized, some variation in mortality rates among clinical trials is expected. Insights into the sources of heterogeneity may influence the design and interpretation of septic shock studies. We set out to identify inclusion criteria and baseline characteristics associated with between-trial differences in control group mortality rates. Methods: We conducted a systematic review of RCTs published between 2006 and 2018 that included patients with septic shock. The percentage of variance in control-group mortality attributable to study heterogeneity rather than chance was measured by I-2. The association between control-group mortality and population characteristics was estimated using linear mixed models and a recursive partitioning algorithm. Results: Sixty-five septic shock RCTs were included. Overall control-group mortality was 38.6%, with significant heterogeneity (I-2 = 93%, P < 0.0001) and a 95% prediction interval of 13.5-71.7%. The mean mortality rate did not differ between trials with different definitions of hypotension, infection or vasopressor or mechanical ventilation inclusion criteria. Population characteristics univariately associated with mortality rates were mean Sequential Organ Failure Assessment score (standardized regression coefficient (beta) = 0.57, P = 0.007), mean serum creatinine (beta = 0.48, P = 0.007), the proportion of patients on mechanical ventilation (beta = 0.61, P < 0.001), and the proportion with vasopressors (beta = 0.57, P = 0.002). Combinations of population characteristics selected with a linear model and recursive partitioning explained 41 and 42%, respectively, of the heterogeneity in mortality rates. Conclusions: Among 65 septic shock trials, there was a clinically relevant amount of heterogeneity in control group mortality rates which was explained only partly by differences in inclusion criteria and reported baseline characteristics.