123

Introduction: The selective vasopressin V1a-receptor agonist selepressin has been shown to decrease platelet activating factor (PAF)-induced capillary leakage and to reverse hypotension in rat and ovine sepsis. Hypothesis: Our hypothesis was that early administration of selepressin (formerly FE 202158) might reduce mortality and organ dysfunction when compared to arginine vasopressin (AVP) or norepinephrine (NE) in the treatment of septic shock. Methods: Twenty-eight fasted, anesthetized, invasively monitored, mechanically ventilated female sheep (28.9 ± 3.5 kg) received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Ringer’s lactate and hydroxyethyl starch (volume ratio = 1:1) were titrated to maintain pulmonary artery occlusion pressure at baseline level throughout the experimental period. When mean arterial pressure (MAP) decreased by 10% from baseline, animals were randomized to receive 0.9% saline (control group, n = 7), 0.25 pmol/kg/min AVP (n = 7), 1 pmol/kg/min selepressin (SEL, n = 7) or 0.5 mcg/kg/min NE (n = 7). In the absence of a response to fluid challenge, all vasopressors were titrated to keep MAP > 70 mmHg. The experiment was continued until death or for a maximum of 30 hours. After death, lung wet/dry ratio was measured. Results: The mean time to start therapy was similar (2.5 hrs) in all four groups. Compared with the other groups, SEL significantly prolonged time to develop hypotension. Both SEL and AVP groups had higher renal blood flow compared with NE and control groups, but only SEL had a significant delay in the development of oliguria. Fluid balance was significantly lower and colloid oncotic pressure higher in the SEL group than in the others. Hypoxemia was significantly delayed in the SEL group as was lactate increase when compared to the other groups. Post-mortem lung wet/dry ratio was significantly lower in the SEL group than in the others. Median survival was significantly prolonged in the SEL group compared with other groups (26 vs 19-23 hours, p<0.001). Conclusions: In this sheep model of septic shock, selepressin improved survival time and organ function when compared to norepinephrine and vasopressin.