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Crit Care. 2017 Aug 15;21(1):213. doi: 10.1186/s13054-017-1798-7.

Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients.

Author information

1
Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada. jim.russell@hli.ubc.ca.
2
Department of Intensive Care, ULB Erasme University Hospital (Université Libre de Bruxelles), Route de Lennik 808, B-1070, Brussels, Belgium.
3
Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, DK-2300, Copenhagen, Denmark.
4
Dienst Intensieve Geneeskunde, UZ Brussel, Laarbeeklaan 101, B-1090, Brussels, Belgium.
5
Anaestesiology Department, Hvidovre Hospital, DK-2650, Hvidovre, Denmark.
6
Clinique Universitaire St.-Luc, Service des Soins Intensifs, 10 Avenue Hippocrate, B-1200, Brussels, Belgium.

Abstract

BACKGROUND:

Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients.

METHODS:

This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety.

RESULTS:

A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group.

CONCLUSIONS:

In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation.

TRIAL REGISTRATION:

ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.

KEYWORDS:

Fluid balance; Mechanical ventilation; Norepinephrine; Selepressin; Septic shock; V1A agonist

PMID:
28807037
PMCID:
PMC5557574
DOI:
10.1186/s13054-017-1798-7
[Indexed for MEDLINE]
Free PMC Article

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