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.

• Authors: Sebastian Rehberg, Christian Ertmer, Jean-L Vincent, Andrea Morelli, Mareike Schneider, Matthias Lange, Hugo Van Aken, Daniel L Traber, Martin Westphal
• Journal: Critical care medicine (Crit Care Med) Vol. 39 Issue 1 Pg. 119-25 (Jan 2011) ISSN: 1530-0293 [Electronic] United States
• PMID: 20890184 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Vasopressin
• Arginine Vasopressin
• Vasotocin
• Norepinephrine

Topics

• Animals
• Arginine Vasopressin (pharmacology)
• Blood Gas Analysis
• Disease Models, Animal
• Female
• Hemodynamics (drug effects, physiology)
• Immunohistochemistry
• Kaplan-Meier Estimate
• Norepinephrine (pharmacology)
• Oxygen Consumption (drug effects, physiology)
• Pulmonary Gas Exchange
• Random Allocation
• Receptors, Vasopressin (agonists, metabolism)
• Reference Values
• Sheep
• Sheep, Domestic
• Shock, Septic (drug therapy, mortality, pathology)
• Survival Rate
• Vasotocin (pharmacology)