Selective V1-agonism and selective V2-antagonism are superior to arginine vasopressin in ovine septic shock

Introduction

The present study was designed as a prospective, randomized, laboratory experiment to compare the effects of a selective V1-agonist (Phe2-Orn8-vasotocin), a selective V2-antagonist ((propionyl1-D-Tyr(Et)2-Val4-Abu6-Arg8,9)-vasopressin) and arginine vasopressin (AVP), when given as first-line therapy, on hemodynamics, metabolic changes, mesenteric blood flow (Qma) and mortality using a clinically relevant model of septic shock [1].

Methods

Fecal peritonitis was induced in 21 anesthetized, invasively monitored, mechanically ventilated sheep. A combination of crystalloids and 6% hydroxyethyl starch was titrated to maintain constant hematocrit. Following the shock time (ST), defined as mean arterial pressure (MAP) <60 mmHg, sheep were randomly assigned to receive either a continuous infusion of 1 μg/kg/hour V2-antagonist, 0.05 μg/kg/minute V1-agonist or 0.5 mU/kg/minute AVP (n = 7 each). Norepinephrine was titrated up to a maximum of 1 μg/kg/minute to maintain MAP at 70 ± 5 mmHg in all groups. Data are expressed as the mean ± SEM.

Results

No significant differences between groups were detected at baseline and ST. The cardiac index and urine flow were similar between groups. The V1-agonist led to a higher Qma than in both other groups from 5 to 8 hours after ST (P < 0.05 each). Compared with AVP, selective V1-agonism stabilized MAP more effectively and allowed a reduction in cumulative norepinephrine requirements from 4 to 8 hours. The V1-agonist and the V2-antagonist did not differ in these variables. V2-antagonism attenuated the decrease in base excess compared with both other groups and was associated with increased fluid requirements compared with V1-agonism (18 ± 1 vs. 14 ± 1 ml/kg/hour). Compared with AVP, the V1-agonist and the V2-antagonist reduced arterial lactate levels (3.5 ± 0.5 and 4.1 ± 0.3 mmol/l vs. 5.5 ± 0.2 mmol/l, P < 0.02 each) and prolonged survival (13 ± 1 hour and 14 ± 1 hour vs. 10 ± 1 hour; P < 0.01 each).

Conclusion

Whereas V2-antagonism reduced metabolic acidosis, V1-agonism stabilized hemodynamics more effectively compared with AVP. Because of the prolonged survival time, selective V1-agonism and V2-antagonism might be superior to AVP infusion in septic shock. Future studies are warranted to investigate the combination of these two therapeutic strategies.