Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock

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Abstract

Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects.

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Multiple comparison procedures.

Jing Cao, Song Zhang (2014)

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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

James A. Russell, Jean-Louis Vincent, Anne Kjølbye … (2017)

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. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1798-7) contains supplementary material, which is available to authorized users.

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

Xinrong He, Fuhong Su, Fabio Taccone … (2015)

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Author and article information

Journal

Title: JAMA

Abbreviated Title: JAMA

Publisher: American Medical Association (AMA)

ISSN (Print): 0098-7484

Publication date Created: October 15 2019

Publication date (Print): October 15 2019

Volume: 322

Issue: 15

Page: 1476

Affiliations

[1 ]Department of Critical Care Medicine, St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

[2 ]Berry Consultants LLC, Austin, Texas

[3 ]Ferring Pharmaceuticals A/S, Copenhagen, Denmark

[4 ]StraDevo A/S, Kongens Lyngby, Denmark

[5 ]Medical-Surgical Intensive Care Unit, Inserm CIC1435, Dupuytren Teaching Hospital, Limoges, France

[6 ]Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California

[7 ]Los Angeles Biomedical Research Institute, Torrance, California

[8 ]Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California

[9 ]Division of Infectious Diseases, Alpert Medical School of Brown University, Providence, Rhode Island

[10 ]Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark

[11 ]Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

[12 ]Center for Heart Lung Innovation and the Division of Critical Care Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, Canada

[13 ]Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

[14 ]Centre Hospitalier Universitaire d’Angers, Angers, France

[15 ]Nordsjaellands Hospital in Hilleroed, Copenhagen, Denmark

[16 ]Centre Hospitalier Régional, Hopital de La Source, Orléans, France

[17 ]Fondation Hôpital Saint Joseph. Paris, France

[18 ]Medical Intensive Care Unit, Nantes University Hospital, Nantes, France

[19 ]Ghent University Hospital, Ghent, Belgium

[20 ]CHU UCL Manur, Mont-Godinne, Yvoir, Belgium

[21 ]Clinique Saint-Pierre, Ottignies, Belgium

[22 ]Eastern Idaho Regional Medical Center, Idaho Falls

[23 ]Centre Hospitalier Universitaire de Nîmes, Nîmes, France

[24 ]Lariboisière Hospital, Paris-Diderot University, INSERM UMRS-1144, Paris, France

[25 ]Centre Hospitalier Régional et Universitaire de Tours, Tours, France

[26 ]Hopital Cochin, Paris, France

[27 ]Centre Hospitalier Régional et Universitaire de Dijon, Dijon, France

[28 ]Aalborg Universitetshospital, Aalborg, Denmark

[29 ]Ziekenhuis Oost-Limburg, Genk, Belgium

[30 ]Randers Regions Hospital, Randers, Denmark

[31 ]Centre Hospitalier Departemental de Vendee, La Roche sur Yon, France

[32 ]Bispebjerg Hospital, Copenhagen, Denmark

[33 ]Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care, University of Pittsburgh, Pittsburgh, Pennsylvania

[34 ]Associate Editor, JAMA

Article

DOI: 10.1001/jama.2019.14607

PMC ID: 6802260

PubMed ID: 31577035

SO-VID: 1015b14f-b87d-49ed-b9b6-df2ef70b224d

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Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock : The SEPSIS-ACT Randomized Clinical Trial

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Most cited references 10

Multiple comparison procedures.

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

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

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