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A Selective V1A Receptor Agonist, Selepressin, Is Superior to Arginine Vasopressin and to Norepinephrine in Ovine Septic Shock*

He, Xinrong MD1,2; Su, Fuhong MD, PhD1; Taccone, Fabio Silvio MD, PhD1; Laporte, Régent DVM, MSc, PhD3; Kjølbye, Anne Louise MSc, PhD, MBA4; Zhang, Jing MSc, PhD5; Xie, Keliang MD1; Moussa, Mouhamed Djahoum MD1; Reinheimer, Torsten Michael MSc, PhD4; Vincent, Jean-Louis MD, PhD, FCCM1

doi: 10.1097/CCM.0000000000001380
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Objective: Selective vasopressin V1A receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V1A receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model.

Design: Randomized animal study.

Setting: University hospital animal research laboratory.

Subjects: Forty-six adult female sheep.

Interventions: 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.

Measurements and Main 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 V1A 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.

*See also p. 234.

Current address for Dr. Laporte: Laporte & Associates, LLC, Biotech & Pharma R&D Consultants, San Diego, CA.

Dr. He conducted the experiment, acquired and analyzed the data, and drafted the article. Dr. Su designed and directed the protocol. Dr. Taccone helped perform the experiments, interpret the data, and draft the article. Drs. Laporte, Kjølbye, and Reinheimer participated in the protocol design and critically revised the article. Dr. Zhang carried out the biochemical measurements. Drs. Xie and Moussa helped perform the experiments and acquire the data. Dr. Vincent was involved in the study design and in critically revising the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by a research grant from the International PharmaScience Center, Ferring Pharmaceuticals A/S. The sponsor participated in the protocol design and provided the selepressin used in the study. The sponsor was not involved in performing the experiments or in analyzing the data but did review the article for critical content.

Dr. Laporte received funding from Ferring Research Institute and Ferring International PharmaScience Center and was employed by Ferring Research Institute at the time of the study. Dr. Kjølbye is employed by Ferring Pharmaceuticals A/S. Dr. Reinheimer is employed by Ferring Pharmaceuticals A/S. Dr. Vincent reports that a research grant was paid to the department by International PharmaScience Center, Ferring Pharmaceuticals A/S, during the conduct of the study. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: jlvincen@ulb.ac.be

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