Polymyxin-dextran antiendotoxin pretreatment in an ovine model of normotensive sepsis

Objective: To test the hypothesis that adult sheep pretreated with polymyxin-dextran and then made septic by cecal ligation and perforation would have fewer changes in microvascular integrity and cellular architecture in extrapulmonary organs. Design: Prospective, randomized, double-blind, placebo-controlled animal study. Setting: An animal research facility in a university-affiliate hospital. Subjects: Mature, male Suffolk sheep (32 to 67 kg). Interventions: Animals with chronic indwelling catheters were pretreated with polymyxin B-dextran (6 mg/kg) or placebo (dextran) and an intra-abdominal focus of infection was then produced by cecal ligation and perforation. Treatment (polymyxin a or placebo) was continued every 8 hrs for 48 hrs. Measurements and Main Results: Forty-eight hours after randomization, the polymyxin B-dextran group manifested significantly less pyrexia (p =.04), higher mean arterial pressures (p =.02), less variable serum albumin concentrations (p =.05), and a trend toward decreased lactate concentrations (p =.10). Qualitative morphometry and semiquantitative scoring of tissue from gastrocnemius muscle demonstrated that polymyxin B-dextran-treated sheep had significantly increased total capillary (p =.04) and capillary luminal areas (p =.038) and less mitochondrial swelling and damage (p =.03) compared with the placebo sheep. Conclusions: Pretreatment of sheep in a polymicrobial, peritonitis model of sepsis with polymyxin B-dextran resulted in a significant amelioration of sepsis-induced ultrastructural damage. In placebo-treated control animals, these ultrastructural lesions were associated with a greater severity of sepsis, as measured by the presence of pyrexia, increased lactate concentrations, and less stable blood pressures. These findings justify the investigation of the effects of polymyxin B-dextran in a post onset model of sepsis.