Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study.
BACKGROUND
V(2)-receptor (V(2)R) 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 V(2)R-antagonist (Propionyl(1)-D-Tyr(Et)(2)-Val(4)-Abu(6)-Arg(8,9))-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V(1a)R/V(2)R-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 V(2)R-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 V(2)R-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 V(2)R-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 V(2)R-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 V(2)R-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 V(2)R-antagonist group. In addition, the selective V(2)R-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 V(2)R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.
Department of Anesthesiology and Intensive Care, University of Muenster, Albert-Schweitzer-Str, 33, Muenster 48149, Germany. Sebastian_Rehberg@web.de
Sebastian
S
Rehberg
Christian
C
Ertmer
Matthias
M
Lange
Andrea
A
Morelli
Elbert
E
Whorton
Martin
M
Dünser
Anne-Katrin
AK
Strohhäcker
Erik
E
Lipke
Tim G
TG
Kampmeier
Hugo
H
Van Aken
Daniel L
DL
Traber
Martin
M
Westphal
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D017483:Receptors, Vasopressin / Q000819:agonists / Q000502:physiology*; D012756:Sheep; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology
D065092:Antidiuretic Hormone Receptor Antagonists; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin