Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock.
OBJECTIVE
To compare the effects of a first-line therapy of combined arginine vasopressin, levosimendan, and norepinephrine with arginine vasopressin + norepinephrine or norepinephrine alone in ovine septic shock.


METHODS
Prospective, randomized, controlled laboratory experiment.


METHODS
University animal research facility.


METHODS
Twenty-one 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 arginine vasopressin (0.5 mU·kg·min), combined arginine vasopressin (0.5 mU·kg·min) and levosimendan (0.2 μg·kg·min), or normal saline (each n = 7) for 24 hrs. In all groups, open-label norepinephrine was additionally titrated to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary.


RESULTS
Arginine vasopressin + levosimendan + norepinephrine improved left ventricular contractility (higher stroke work indices at similar or lower preload) and pulmonary function (Pao2/Fio2 ratio) when compared with the other groups (p < .05 each). Both nonadrenergic treatment strategies reduced open-label norepinephrine doses. However, only arginine vasopressin + levosimendan + norepinephrine limited fluid requirements and positive fluid balance vs. both other groups (p < .05 each). In addition, arginine vasopressin + levosimendan + norepinephrine increased mixed venous oxygen saturation as compared with arginine vasopressin + norepinephrine. Histologic tissue analyses and pulmonary hemeoxygenase-1 activity revealed no differences among groups. Notably, arginine vasopressin + levosimendan + norepinephrine therapy reduced pulmonary 3-nitrotyrosine levels (p = .028 vs. control animals) as well as urinary protein/creatinine ratio (p < .05 each) and slightly prolonged survival when compared with both other groups (4 hrs vs. arginine vasopressin + norepinephrine: p = .013; 7 hrs vs. norepinephrine alone: p = .003).


CONCLUSIONS
First-line cardiovascular support with combined arginine vasopressin and levosimendan supplemented with norepinephrine improves myocardial, vascular, pulmonary, and renal function as compared with arginine vasopressin + norepinephrine in septic shock.
Rehberg
Sebastian
S
Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany. Sebastian_Rehberg@web.de
Ertmer
Christian
C
Vincent
Jean-L
JL
Spiegel
Hans-U
HU
Köhler
Gabriele
G
Erren
Michael
M
Lange
Matthias
M
Morelli
Andrea
A
Seisel
Jennifer
J
Su
Fuhong
F
Van Aken
Hugo
H
Traber
Daniel L
DL
Westphal
Martin
M
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004359:Drug Therapy, Combination; D006835:Hydrazones / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D011669:Pulmonary Wedge Pressure / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D012756:Sheep; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D000077464:Simendan; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology
D006835:Hydrazones; D011724:Pyridazines; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D000077464:Simendan; D009638:Norepinephrine