OPTIMIZATION STRATEGIES FOR DEVELOPMENT OF A RODENT MODEL OF SEVERE HEMORRHAGIC SHOCK.

Abstract

Objective: To demonstrate the use of Taguchiq experimental designs in the development of a rat model of acute hemorrhagic shock. Methods: The focus of the investigation was to identify a subset of therapies (fluid carriers, drugs) that maximize survival time and reduce lactate levels following a 60% volume acute hemorrhage. However, potential confounding factors in any hemorrhage model include choice of critical MAP trigger (for hemorrhage interruption), fluid administration strategy (bolus or pressure titration), and surgeon-specific skills. We implemented Taguchi-type designs in a series of iterative trials investigating survival times and lactate clearance in a rat model of severe hemorrhage shock. These methods are used in quality-control engineering applications to simultaneously assess the effects of multiple variables on an outcome. Designs are characterized by use of orthogonal factor arrays to investigate outcomes and simple performance criteria (mean, standard deviation SD, signal: noise ratio) to quantify outcomes, identify a subset of key factors determining outcome, and reduce unwanted variation from confounding factors. Results: We successfully identified and corrected specific deficiencies in surgical technique. We identified a critical MAP (40 mm Hg); there were significant improvements in both survival times (45 vs >120 min) and lactate clearance (9.2 vs 16 mmol/L at stabilization) with Hextend HX and an artificial HBOC-HS-HX cocktail in comparison to control models. Reduction of the number of potential therapies to investigate and control of extraneous variability in response allows higher sample sizes per group with increased power for detecting therapeutic benefit.