The effect of vasopressor dosing on microcirculatory perfusion in preclinical animal models of sepsis: a systematic review and meta-analysis
CCCF ePoster library. James T. Oct 26, 2015; 117364; P15
Tyler E. James
Tyler E. James
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Abstract
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P15


Topic: Basic/Translational Science


The effect of vasopressor dosing on microcirculatory perfusion in preclinical animal models of sepsis: a systematic review and meta-analysis



Tyler E. James, T. James, C. Barron, F. Lamontagne, E. Belley-Cote, H. Yang, D. Fergusson, F. D'Aragon, L. McIntyre, D. Stewart, M. Lalu

Department of Anesthesiology, Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada | Faculty of Medicine, University of Ottawa, Ottawa, Canada | Faculty of Medicine, University of Ottawa, Ottawa, Canada | Department of Medicine, Universite de Sherbrooke, Sherbrooke, Canada | Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada | Faculty of Medicine, Department of Anesthesiology, University of Ottawa, The Ottawa Hospital, Ottawa, Canada | Faculty of Medicine, Clinical Epidemiology Program, University of Ottawa, The Ottawa Hospital, Ottawa, Canada | Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada | Clinical Epidemiology Program, Department of Medicine, The Ottawa Hospital Research Institute, The Ottawa Hosptial, Ottawa, Canada | Regenerative Medicine Program, Department of Cell and Molecular Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada | Department of Anesthesiology, Department of Cell and Molecular Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, Canada

Introduction: Clinical Practice Guidelines suggest titratingvasopressors to achieve a mean arterial blood pressure of at least 65 mm Hg insepsis, however this recommendation has weak supporting evidence (Grade C). Vasopressor-inducedvasoconstriction could potentially restrict blood flow to vital organs andcause harm. Preclinical studies allow for extensive investigation ofvasopressor effects on microcirculation.

Objectives:

We conducted a preclinical systematic review toanswer the question, “In preclinical studies using animal models of sepsis,what is the effect of different vasopressor dosing strategies onmicrocirculatory flow and mortality?”



Methods:

We searched MEDLINE,BIOSIS, and Embase for preclinical studies of sepsis and sepsis models in whichlow vs. high dose vasopressor strategies were compared. Only active comparison studies (randomized,nonrandomized and quasi-randomized) were considered; for incrementaldosing/cross-over designs only the initial dose was considered for analysis Internalvalidity was assessed using a modified version of the Cochrane Risk of BiasAssessment Tool. Construct validity (i.e. “clinical relevance”) was assessedaccording to nine previously published criteria (e.g. adjunct use of fluid resuscitation).Microcirculatory flow and mortality results were pooled using a random effectsmodel and expressed as either ratio of means (RoM) or odds ratios (OR) and 95%confidence intervals (CI). Ratios <1 favor low dose vasopressor.Heterogeneity was evaluated with the I2statistic.



Results:

2785 articles werescreened and 8 articles met eligibility criteria (n=323 animals). Animal modelsincluded sheep (3 studies), hamsters (1), rats (1), pigs (2) and dogs (1). Tomodel disease, studies used endotoxin (5), live bacteria implant (2), or livebacteria infusion (1). Vasopressors used included norepinephrine (3),terlipressin (3), dopamine (2), epinephrine (1) and vasopressin (1). Risk ofbias was unclear in all studies for randomization, allocation concealment, andblinding of personnel; three studies were at high risk of bias for selectiveoutcome reporting and seven studies did not report an a priori sample sizecalculations. Studies incorporated a median of 6 (range 4-8) of 9 suggested constructvalidity criteria to increase clinical relevance (e.g. no studies includedanimals with comorbidities; seven studies included fluid resuscitation). Threeexperiments from two studies examined microcirculatory flow and sevenexperiments in four studies assessed mortality. Low vs. high vasopressor dosinghad no effect on microcirculatory flow (RoM 1.01, 95%CI 0.77-1.32, I2=86%, n=3 experiments); definedsubgroup analysis of experiments that included fluid resuscitation alsodemonstrated no effect on microcirculatory flow (RoM 0.91, 95%CI 0.82-1.01, I2=0%,n=2). Low vs high vasopressor dosing had no apparent effect on overallmortality (OR 0.54, 95%CI 0.19-1.58, I2=0%, n=7). Similarly, noeffect on mortality was seen at predefined time intervals: ≤2 days (OR 0.38, 95%CI0.12-1.21, I2=0%, n=7), >2 to ≤4 days (OR 0.67, 95%CI 0.23-1.92,I2=12%, n=7) and >4 days (OR 0.52, 95%CI 0.15-1.87, I2=16%,n=6).



Conclusion: A limited number of preclinical studies have investigated vasopressordosing strategies in sepsis. Given this limitation, low dose versus highvasopressor dosing had no apparent effect on either microcirculatory flow ormortality


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