Role of selective V1a receptor agonism in ovine septic shock.

ABSTRACT

OBJECTIVE: The vasopressor effect of arginine vasopressin, a mixed V1a/V2 receptor (V1aR/V2R) agonist, is mediated through the V1aR. Because V2R stimulation may aggravate sepsis-induced vasodilation, fluid accumulation, and microvascular thrombosis, a higher V1aR vs. V2R selectivity might be advantageous. The objective of this study was to elucidate the effects of a first-line therapy with the selective V1aR agonist Phe2-Orn8-Vasotocin vs. arginine vasopressin or norepinephrine on cardiopulmonary hemodynamics and organ function in ovine septic shock. DESIGN: Randomized controlled laboratory experiment. SETTING: University animal research facility. SUBJECTS: Twenty-four chronically instrumented sheep. INTERVENTIONS: After the onset of fecal peritonitis-induced septic shock (mean arterial pressure <60 mm Hg), sheep were randomly assigned to receive first-line treatment with Phe2-Orn8-Vasotocin (0.05 µg·kg·h), arginine vasopressin (0.05 µg·kg·h), or normal saline (each n = 8). In all groups, open-label norepinephrine was additionally titrated up to 1 µg·kg·min to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary. MEASUREMENTS AND MAIN RESULTS: Compared with single norepinephrine therapy, the selective V1aR agonist Phe2-Orn8-Vasotocin reduced norepinephrine requirements (2-6 hrs p < .05 each) and fluid accumulation (p = .043). In addition, mean arterial pressure (6-10 hrs p < .05 each), pulmonary gas exchange (8-10 hrs p < .05 each), and global oxygen transport (10 hrs p < .05 each) were improved by Phe2-Orn8-Vasotocin vs. both other groups. Despite similar preload left ventricular stroke work index was higher in Phe2-Orn8-Vasotocin- than in arginine vasopressin-treated animals (10 hrs p = .02). Metabolic dysfunction (base excess, lactate concentrations) and renal dysfunction (urinary output, creatinine clearance) were attenuated by Phe2-Orn8-Vasotocin infusion when compared with arginine vasopressin and single norepinephrine therapy. Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 and lower 3-nitrotyrosine concentrations in Phe2-Orn8-Vasotocin-treated animals vs. both other groups (p < .05 each). In addition, the selective V1aR agonist Phe2-Orn8-Vasotocin slightly prolonged survival when compared with arginine vasopressin (p = .01) and standard treatment with norepinephrine (p = .003). CONCLUSIONS: Selective V1aR agonism appears to be superior to the V1aR/V2R agonist arginine vasopressin and single norepinephrine infusion for hemodynamic support in septic shock.