A Selective V(1A) Receptor Agonist, Selepressin, Is Superior to Arginine Vasopressin and to Norepinephrine in Ovine Septic Shock.
OBJECTIVE
Selective vasopressin V(1A) receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V(1A) receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model.


METHODS
Randomized animal study.


METHODS
University hospital animal research laboratory.


METHODS
Forty-six adult female sheep.


METHODS
Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 μg]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70-80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours.


RESULTS
In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals.


CONCLUSIONS
In this clinically relevant model, selepressin, a selective V(1A) receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early.
1Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.2Department of Intensive Care, Sun Yat-sen University Cancer Center, Guangzhou, China.3Clinical & Non-Clinical R&D, Ferring Research Institute, San Diego, CA.4Clinical & Non-Clinical R&D, Ferring Pharmaceuticals A/S, Copenhagen, Denmark.5Department of Biochemistry and Nutrition, Université Libre de Bruxelles, Brussels, Belgium.
Xinrong
X
He
Fuhong
F
Su
Fabio Silvio
FS
Taccone
Régent
R
Laporte
Anne Louise
AL
Kjølbye
Jing
J
Zhang
Keliang
K
Xie
Mouhamed Djahoum
MD
Moussa
Torsten Michael
TM
Reinheimer
Jean-Louis
JL
Vincent
D000818:Animals; D001127:Arginine Vasopressin / Q000627:therapeutic use*; D005260:Female; D009638:Norepinephrine / Q000627:therapeutic use*; D011897:Random Allocation; D017483:Receptors, Vasopressin / Q000819:agonists*; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy*; D012772:Shock, Septic / Q000188:drug therapy / Q000662:veterinary*; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*; D014667:Vasopressins / Q000627:therapeutic use*
D017483:Receptors, Vasopressin; D014662:Vasoconstrictor Agents; C559490:vasopressin, Phe(2)-Ile(3)-Hgn(4)-Orn(iPr)(8)-; D014667:Vasopressins; D001127:Arginine Vasopressin; D009638:Norepinephrine