Role of selective V1a receptor agonism in ovine septic shock.
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.


METHODS
Randomized controlled laboratory experiment.


METHODS
University animal research facility.


METHODS
: Twenty-four chronically instrumented sheep.


METHODS
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.


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.
Rehberg
Sebastian
S
Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany. Sebastianwillyrehberg@gmail.com
Ertmer
Christian
C
Vincent
Jean-L
JL
Morelli
Andrea
A
Schneider
Mareike
M
Lange
Matthias
M
Van Aken
Hugo
H
Traber
Daniel L
DL
Westphal
Martin
M
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D009638:Norepinephrine / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011659:Pulmonary Gas Exchange; D011897:Random Allocation; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000378:metabolism; D012016:Reference Values; D012756:Sheep; D034561:Sheep, Domestic; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D014668:Vasotocin / Q000494:pharmacology*
D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D014668:Vasotocin; D009638:Norepinephrine