Magic bullets and surrogate biomarkers circa 2009
Abstract
With the discovery almost 25 years ago that administration of tumor necrosis factor-α could produce shock and tissue injury similar to severe sepsis, the fundamental role for cytokines in experimental sepsis was established (1, 2) The dramatic improvement in survival, first seen in mice and then confirmed in primates with bacteremic shock, produced simply by inhibiting a single cytokine (3, 4), resulted in unbridled optimism that sepsis mortality in hospitalized patients could be dramatically reduced. This outlook pervaded the collective conscious for well over two decades, spawned a sundry of biological inhibitors, tested in a multitude of human clinical trials, all with the goal of recapitulating the survival benefit imparted by these “magic bullets” in preclinical animal models (5). Unfortunately, these efforts consumed an enormous amount of energy and financial resources, and demonstrated only minimal benefit to the treatment of human sepsis. Fortunately, the past decade has been spent in self-evaluation (some might also say self-denial), asking why such therapies have not yielded the clinic successes observed with preclinical models. Only now are we beginning to understand the complexity of human sepsis and the limits of our preclinical models (6).
In this issue of Critical Care Medicine, Osuchowski and co-workers (7) argue that although most antisepsis therapies, in general, and anticytokine therapies, in particular, have failed in severe sepsis clinical trials, the…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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