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February - 2021

   

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Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest

F Kim, C Maynard, C Dezfulian, et al JAMA, 2021, 325(2):138-145

Comment

Could nitrite therapy during OHCA limit neurological injury, the most devastating sequelae? There is a plausible mechanism, with animal ischaemic models demonstrating cytoprotective effects, limited cell injury and apoptosis when serum nitrite levels of 190-20 uM are reached. A phase 1 open label study of 125 patients with OHCA found 45mg or 60 mg of sodium nitrite administered during resuscitation was sufficient to achieve serum nitrite levels of 10-20 uM.

This phase 2 RCT of 1502 patients with out-of-hospital cardiac arrest investigates the association of administration of 45 mg or 60 mg of sodium nitrite vs placebo during active resuscitation by paramedics, with improved survival to hospital admission.

They report;

  • 1502 adults with OHCA (VF, VT, non-shockable) in Seattle and King County Washington
  • 1:1:1  IV or intraoessus 45mg SN:60mg SN:placebo delivery by paramedics 
  • Demographic:  mean age 64 years, 34% women, 20- 25% VF/VT, 99% completed trial.
  • Primary outcome survival to hospital admission 41% (45mg) vs 43% (60mg) vs 44% (placebo) - no difference
  • Secondary outcomes - none different including;
    • ROSC (54% vs 59% vs 59%)
    • Use of norepinephrine to support blood pressure
    • Survival to hospital discharge (13% vs 15% vs 15%)
    • Neurological outcomes at hospital discharge - moderate disability or better (12% vs 13% vs 13%)
  • No difference in outcomes when adjust for age, witnessed, rhythm, bystander CPR, location. No difference with other prespecified or posthoc analysis. 

Overall - paramedic administration of 45mg or 60 mg sodium nitrite to patients with OHCA, vs placebo, did not improve survival to hospital admission, or secondary outcomes including survival or neurological recovery in 1502 adults in Seattle.King County.  These findings do not support the use of sodium nitrite during resuscitation from out-of-hospital cardiac arrest.

 

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.

February


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