Human sepsis is an intrinsically complex disease. Populations of patients enrolled into clinical trials of novel sepsis therapies are notoriously heterogeneous with respect to the inciting cause of their disease, the co-morbid conditions that define its course, and the acute severity of their initial presentation. This heterogeneity is reflected in strikingly variable mortality risks across studies, and probably, though less clearly-established, in variable response rates to a given intervention. In an accompanying article in this issue of Critical Care, Macias and colleagues argue that the effectiveness of adjuvant sepsis therapies is not dependent on the baseline mortality risk, since the few "positive" trials that have been published show widely divergent placebo mortality rates. But this analysis assumes that biologically distinct interventions will be equally efficacious in clinically diverse populations, and confuses severity as a population descriptor with severity as a surrogate measure of a biologic state in an individual patient. In a pivotal trial of recombinant human activated protein C (rhAPC) in patients with severe sepsis, an aggregate 6% mortality decrement appeared to be the result of negligible efficacy in the least severely ill patients, and considerably greater efficacy in those who were at greatest risk of dying. A larger follow-up study recruiting low risk patients confirmed this impression, showing a convincing absence of benefit in patients who clinicians judged to be less severely ill. If we accept Macias' argument, we are led to the conclusion that rhAPC is of limited use in the management of severe sepsis. On the other hand, if we view severity as a crude surrogate for a particular pathologic state, we would shift our focus to better defining those populations most likely to benefit from intervention, including patients who may not have met criteria for entry in the original PROWESS trial – those with disseminated intravascular coagulation or acute organ dysfunction from causes other than sepsis. Staging systems that stratify heterogeneous patient populations by risk and by potential to benefit from intervention have proven to be essential to the development of multimodal adjuvant treatment for cancer. They will be no less important in the optimal management of sepsis.
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