Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest: A Randomized Clinical Trial

Abstract

Importance: Therapeutic delivery of sodium nitrite during resuscitation improved survival in animal models of cardiac arrest, but efficacy has not been evaluated in clinical trials in humans.

Objective: To determine whether parenteral administration of sodium nitrite given by paramedics during resuscitation for out-of-hospital cardiac arrest improved survival to hospital admission.

Design, setting, and participants: Double-blind, placebo-controlled, phase 2 randomized clinical trial including 1502 adults in King County, Washington, with out-of-hospital cardiac arrest from ventricular fibrillation or nonventricular fibrillation. Patients underwent resuscitation by paramedics and were enrolled between February 8, 2018, and August 19, 2019; follow-up and data abstraction were completed by December 31, 2019.

Interventions: Eligible patients with out-of-hospital cardiac arrest were randomized (1:1:1) to receive 45 mg of sodium nitrite (n = 500), 60 mg of sodium nitrite (n = 498), or placebo (n = 499), which was given via bolus injection by the paramedics as soon as possible during active resuscitation.

Main outcomes and measures: The primary outcome was survival to hospital admission and was evaluated with 1-sided hypothesis testing. The secondary outcomes included out-of-hospital variables (rate of return of spontaneous circulation, rate of rearrest, and use of norepinephrine to support blood pressure) and in-hospital variables (survival to hospital discharge; neurological outcomes at hospital discharge; cumulative survival to 24 hours, 48 hours, and 72 hours; and number of days in the intensive care unit).

Results: Among 1502 patients with out-of-hospital cardiac arrest who were randomized (mean age, 64 years [SD, 17 years]; 34% were women), 99% completed the trial. Overall, 205 patients (41%) in the 45 mg of sodium nitrite group and 212 patients (43%) in the 60 mg of sodium nitrite group compared with 218 patients (44%) in the placebo group survived to hospital admission; the mean difference for the 45-mg dose vs placebo was -2.9% (1-sided 95% CI, -8.0% to ∞; P = .82) and the mean difference for the 60-mg dose vs placebo was -1.3% (1-sided 95% CI, -6.5% to ∞; P = .66). None of the 7 prespecified secondary outcomes were significantly different, including survival to hospital discharge for 66 patients (13.2%) in the 45 mg of sodium nitrite group and 72 patients (14.5%) in the 60 mg of sodium nitrite group compared with 74 patients (14.9%) in the placebo group; the mean difference for the 45-mg dose vs placebo was -1.7% (2-sided 95% CI, -6.0% to 2.6%; P = .44) and the mean difference for the 60-mg dose vs placebo was -0.4% (2-sided 95% CI, -4.9% to 4.0%; P = .85).

Conclusions and relevance: Among patients with out-of-hospital cardiac arrest, administration of sodium nitrite, compared with placebo, did not significantly improve survival to hospital admission. These findings do not support the use of sodium nitrite during resuscitation from out-of-hospital cardiac arrest.

Trial registration: ClinicalTrials.gov Identifier: NCT03452917.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Dezfulian reported receiving grants from Mallinckrodt Pharmaceuticals Inc. Dr Sayre reported receiving funding for an EMS fellowship from Stryker Physio-Control. Dr Nichol reported receiving grants from Zoll Medical Corp, Abiomed Inc, and GE Healthcare Inc; receiving personal fees from Zoll Circulation, GE Healthcare Inc, Roche Inc, and Kestra Medical Technologies; and having patents pending for measurement of blood flow during resuscitation and a reperfusion injury–modifying device. No other disclosures were reported.

Figures

Figure 1.. Study Enrollment and Analysis

The study inclusion criteria were patients with out-of-hospital cardiac arrest who received advanced life support by paramedics, those having intravenous or intraosseous access, being aged 18 years or older, and being comatose. DNR indicates do not resuscitate; EMS, emergency medical services. aIndicates an exclusion criterion. bRandomization was stratified by 4 geographic regions in Washington State (South County, Redmond/Bellevue, Seattle, and Shoreline).

Figure 2.. Time to Death by Treatment Group

Observations were censored at hospital discharge. The median observation time was 0.07 days (interquartile range, 0.03-3.81 days).