Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study

Introduction

V₂-receptor (V₂R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V₂R-antagonist (Propionyl₁-D-Tyr(Et)₂-Val₄-Abu₆-Arg_8,9)-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V_1aR/V₂R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock.

Methods

After the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V₂R-antagonist (1 μg/kg per hour), AVP (0.05 μg/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 μg/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary.

Results

Compared to AVP- and placebo-treated animals, the selective V₂R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V₂R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V₂R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V₂R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V₂R-antagonist group. In addition, the selective V₂R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025).

Conclusions

Selective V₂R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.