Quantification of microcirculatory blood flow: a sensitive and clinically relevant prognostic marker in murine models of sepsis

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.

Laser speckle contrast imaging for assessing microcirculatory changes in multiple splanchnic organs and the gracilis muscle during hemorrhagic shock and fluid resuscitation

“…They reported that stabilization of macrocirculatory hemodynamics, such as the MAP and cardiac output, was likely to occur at the expense of microcirculatory perfusion (Sand et al, 2015). Therefore, macrocirculatory and microcirculatory changes may not be always in the same extent during injury.…”

RETRACTED: Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

“…1,2 Sepsis progression (mortality) is most often attributed to the development of multiple organ failure. In sepsis, inflammation-mediated endothelial activation, defined as a proinflammatory and procoagulant state of the endothelial cells, has been associated with severity of disease.…”

Respiratory gas exchange as a new aid to monitor acidosis in endotoxemic rats: relationship to metabolic fuel substrates and thermometabolic responses

“…; Sand et al. ). Interestingly, there is evidence to suggest that other responses to LPS have distinct time‐courses in anesthetized versus unanesthetized animals.…”

“…), and mouse (Sand et al. ). These studies led to the notion that acidosis is a progressive phenomenon in endotoxic shock, but this notion must still pass scrutiny in studies with better temporal resolution.…”

“…As much as this method is accurate, it provides data with poor temporal resolution. Additionally, the need for serial blood draws has favored experimentation under anesthesia in all species investigated: dog (Jacobs et al 1982;Evans et al 1984), sheep (Dubin et al 2005), pig (Andersson et al 2006), cat (Parratt and Sturgess 1974), rat (Schaefer et al 1995;Scheiermann et al 2011), and mouse (Sand et al 2015). These studies led to the notion that acidosis is a progressive phenomenon in endotoxic shock, but this notion must still pass scrutiny in studies with better temporal resolution.…”