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Serious Adverse Events Associated With Vasopressin and Norepinephrine Infusion in Septic Shock*

Anantasit, Nattachai MD1; Boyd, John H. MD, FRCP(C)1,2; Walley, Keith R. MD, FRCP(C)1,2; Russell, James A. MD, FRCP(C)1,2

doi: 10.1097/CCM.0000000000000333
Clinical Investigations

Objective: The frequency, risk factors, and mortality rates of serious adverse events associated with the use of vasopressin and norepinephrine are not clear. The objectives of this study were to determine frequency, risk factors (including candidate gene polymorphisms), and outcomes of serious adverse events in septic shock patients.

Design: Retrospective cohort study using multicenter discovery and single-center validation cohorts.

Setting: ICUs at academic teaching centers.

Patients: Five hundred ninety-seven patients with septic shock in discovery (Vasopressin and Septic Shock trial) and 533 patients in validation (St. Paul’s Hospital) cohorts.

Intervention: Vasopressin and norepinephrine for septic shock.

Measurements and Main Results: The primary outcome variable was 90-day mortality rates of patients with and without serious adverse events. Secondary outcome variables were the association between vasopressor genotype pathway polymorphisms, plasma vasopressin levels, and serious adverse events. Plasma vasopressin concentrations were measured at baseline, 6 hours, 24 hours, 72 hours, and 7 days after vasopressor infusion. Patients with septic shock were genotyped for 268 vasopressor pathway tag single-nucleotide polymorphisms. Serious adverse events occurred in 10.5% and 9.7% of patients in Vasopressin and Septic Shock trial and St. Paul’s Hospital cohorts, respectively. Patients who had serious adverse events had higher mortality (p < 0.01) than patients without serious adverse events (adjusted for age, serum lactate, Acute Physiology and Chronic Health Evaluation II, and maximum dose of norepinephrine day 1) (hazard ratio, 2.97; 95% CI, 2.20–4.00; p < 0.001 and hazard ratio, 1.89; 95% CI, 1.26–2.85; p = 0.002 in Vasopressin and Septic Shock trial and St. Paul’s Hospital, respectively). There was no difference in the area under the plasma vasopressin concentration curve between patients with and without serious adverse events (p = 0.1). The AA genotype of rs28418396 single-nucleotide polymorphism (near the arginine vasopressin receptor 1b gene) was significantly associated with serious adverse events in discovery and validation cohorts (p = 0.001 and p = 0.04, respectively).

Conclusion: Serious adverse events associated with vasopressin and norepinephrine in patients who have septic shock are associated with increased mortality and morbidity. AA genotype of rs28418396 single-nucleotide polymorphism near the arginine vasopressin receptor 1b gene is associated with serious adverse events. The mechanism of this association requires investigation.

Supplemental Digital Content is available in the text.

1Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada.

2Division of Critical Care Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada.

* See also p. 1944.

Registration: ISRCTN94845869.

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 VASST, Canadian Institutes of Health Research (grant number: MCT 44152).

Dr. Boyd is a recipient of a Providence Health Care Research Scholarship. Dr. Walley is employed by the University of British Columbia and has stock options with Sirius Genomics. His institution received grant support from the University of British Columbia and Canadian Institutes of Health Research. Dr. Russell served as board member for Sirius Genomics; consulted for Ferring Pharmaceutical, Grifols, Medimmune, and Astra Zeneca; lectured for Pfizer; has a patent with the University of British Columbia and Sirius Genomics; and has stock options with Sirius Genomics. His institution received grant support from Ferring Pharmaceutical, Astra Zeneca, Sirius Genomics, and Eli Lilly. Dr. Anantasit has disclosed that he does not have any potential conflicts of interest.

For information regarding this article, E-mail: jim.russell@hli.ubc.ca

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins