Abstract
Sepsis and sepsis-associated multiorgan failure represent the major cause of mortality in intensive care units worldwide. Cardiovascular dysfunction, a key component of sepsis pathogenesis, has received much research interest, although research translatability remains severely limited. There is a critical need for more comprehensive preclinical sepsis models, with more clinically relevant end points, such as microvascular perfusion. The purpose of this study was to compare microcirculatory blood flow measurements, using a novel application of laser speckle contrast imaging technology, with more traditional hemodynamic end points, as part of a multiparameter monitoring system in preclinical models of sepsis. Our aim, in measuring mesenteric blood flow, was to increase the prognostic sensitivity of preclinical studies. In two commonly used sepsis models (cecal ligation and puncture, and lipopolysaccharide), we demonstrate that blood pressure and cardiac output are compromised postsepsis, but subsequently stabilize over the 24-h recording period. In contrast, mesenteric blood flow continuously declines in a time-dependent manner and in parallel with the development of metabolic acidosis and organ dysfunction. Importantly, these microcirculatory perturbations are reversed by fluid resuscitation, a mainstay intervention associated with improved outcome in patients. These data suggest that global hemodynamics are maintained at the expense of the microcirculation and are, therefore, not sufficiently predictive of outcome. We demonstrate that microcirculatory blood flow is a more sensitive biomarker of sepsis syndrome progression and believe that incorporation of this biomarker into preclinical models will facilitate sophisticated proof-of-concept studies for novel sepsis interventions, providing more robust data on which to base future clinical trials.
Highlights
SEPSIS IS AN OVERWHELMING systemic inflammatory response to infection that can progress to severe sepsis and, septic shock, characterized by cardiovascular dysfunction, refractory hypotension, and insufficient organ perfusion
The key findings from this study are as follows: 1) Laser speckle contrast imaging can be used in concert with other standard hemodynamic techniques to robustly assess microcirculatory perfusion in septic mice
3) Stabilization of macrocirculatory hemodynamics (MAP and cardiac output (CO)) is likely to occur at the expense of microcirculatory perfusion and is, insufficiently predictive of outcome
Summary
SEPSIS IS AN OVERWHELMING systemic inflammatory response to infection that can progress to severe sepsis and, septic shock, characterized by cardiovascular dysfunction, refractory hypotension, and insufficient organ perfusion. While clinical studies have demonstrated a strong association between microcirculatory perfusion and outcome [15], and microvascular monitoring is increasingly used as a research tool in the clinic [14], preclinical models rarely assess this parameter This may have contributed to the subsequent failure in clinical trials of numerous promising preclinical leads. Sepsis and septic shock are commonly modeled in rodents by systemic administration of a bacterial endotoxin, or through puncture of the cecum to induce polymicrobial peritonitis [40] These models produce pathophysiological alterations similar to those encountered in patients (a profound inflammatory response with disrupted thermoregulation and cardiovascular function). They are widely criticized for their limitations and propensity to generate promising therapies that have later failed in clinical trials [38].
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