by Lewis, Anthony J.;
Lee, Janet S.; Rosengart, Matthew R.
Objective: Our
knowledge of the molecular mechanisms of sepsis has attained exponential
growth. Yet, the pillars of its care remain antibiotics, fluid resuscitation,
and physiologic support of failing organ systems. The inability to bring
biologic breakthroughs to the bedside is not for lack of effort. Over 60
clinical trials of novel therapies, each heavily supported by the momentum of
biologic data suggesting clinical utility, have been conducted and have failed
to identify benefit. This mass of “negative” clinical data abut an equally
towering mound of knowledge of sepsis biology, which collectively have led
investigators to ask, “what happened?”
Data Sources:
Review of published scientific literature via MEDLINE searches using key terms
related to the article topics. Study Selection: Original articles, review
articles, and systematic reviews were considered. Data Extraction: Articles
were selected for inclusion based upon author consensus.
Data Synthesis:
Here, we present a synthetic review of some of the challenges in translating
experimental animal models of sepsis to the bedside. We commence with the
concept that the heterogeneity in the kinetics of the sepsis response serves as
an important, often underappreciated but surmountable, source of translational
impedance. Upon this groundwork, we discuss distinctions between animal
experimentation and clinical trial design in the elements for hypothesis
testing: cohort selection, power and sample size, randomization and blinding,
and timing of intervention. From this concept, we develop a contextual
framework for advancing the paradigm of animal-based investigations to
facilitate science that transitions from molecule to medicine.
Conclusions: A
persistent divide exists between the laboratory and clinical research arenas,
which may be addressable via systematic targeting of identified translational
gaps.
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