Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock.

Abstract

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.

DESIGN:

Prospective, randomized, controlled laboratory experiment.

SETTING:

University animal research facility.

SUBJECTS:

Twenty-one 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 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.

MEASUREMENTS AND MAIN 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.

• Authors: Sebastian Rehberg, Christian Ertmer, Jean-L Vincent, Hans-U Spiegel, Gabriele Köhler, Michael Erren, Matthias Lange, Andrea Morelli, Jennifer Seisel, Fuhong Su, Hugo Van Aken, Daniel L Traber, Martin Westphal
• Journal: Critical care medicine (Crit Care Med) Vol. 38 Issue 10 Pg. 2016-23 (Oct 2010) ISSN: 1530-0293 [Electronic] United States
• PMID: 20657271 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrazones
• Pyridazines
• Vasoconstrictor Agents
• Arginine Vasopressin
• Simendan
• Norepinephrine

Topics

• Animals
• Arginine Vasopressin (pharmacology)
• Blood Gas Analysis
• Blood Pressure (drug effects, physiology)
• Drug Therapy, Combination
• Hydrazones (pharmacology)
• Lung (drug effects, physiopathology)
• Myocardial Contraction (drug effects, physiology)
• Norepinephrine (pharmacology)
• Pulmonary Wedge Pressure (drug effects, physiology)
• Pyridazines (pharmacology)
• Sheep
• Shock, Septic (drug therapy, physiopathology)
• Simendan
• Vascular Resistance (drug effects, physiology)
• Vasoconstrictor Agents (pharmacology)
• Water-Electrolyte Balance (drug effects, physiology)