title: 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.
authors.affiliation: British Heart Foundation Centre for Cardiovascular Research, King's College London, London, United Kingdom;
authors.forename: Claire A
authors.initials: CA
authors.lastname: Sand
authors.affiliation: Pharmacology and Therapeutics, Institute of Pharmaceutical Science, King's College London, London, United Kingdom;
authors.forename: Anna
authors.initials: A
authors.lastname: Starr
authors.affiliation: British Heart Foundation Centre for Cardiovascular Research, King's College London, London, United Kingdom;
authors.forename: Catherine D E
authors.initials: CD
authors.lastname: Wilder
authors.affiliation: British Heart Foundation Centre for Cardiovascular Research, King's College London, London, United Kingdom;
authors.forename: Olena
authors.initials: O
authors.lastname: Rudyk
authors.affiliation: Pharmacology and Therapeutics, Institute of Pharmaceutical Science, King's College London, London, United Kingdom;
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.affiliation: Department of Intensive Care, Guy's & St. Thomas NHS Foundation Trust, London, United Kingdom.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom; and.
authors.forename: David F
authors.initials: DF
authors.lastname: Treacher
authors.affiliation: British Heart Foundation Centre for Cardiovascular Research, King's College London, London, United Kingdom; Pharmacology and Therapeutics, Institute of Pharmaceutical Science, King's College London, London, United Kingdom; manasi.nandi@kcl.ac.uk.
authors.forename: Manasi
authors.initials: M
authors.lastname: Nandi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001794:Blood Pressure / Q000502:physiology; D002302:Cardiac Output / Q000502:physiology; D002432:Cecum / Q000473:pathology; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000502:physiology*; D011379:Prognosis; D012039:Regional Blood Flow / Q000502:physiology*; D018805:Sepsis / Q000473:pathology*
chemical_list: D015415:Biomarkers
keywords: animal models of cardiovascular disease; microcirculation; sepsis; septic shock