Usefulness of Intravenous Sodium Nitrite During Resuscitation for the Treatment of Out-of-Hospital Cardiac Arrest

Kim, Francis; Dezfulian, Cameron; Empey, Philip E.; Morrell, Matthew R.; Olsufka, Michele; Scruggs, Sue; Kudenchuk, Peter J.; May, Susanne; Maynard, Charles; Sayre, Michael R.; Nichol, Graham

doi:10.1016/j.amjcard.2018.04.060

Cited by 11 publications

(12 citation statements)

References 23 publications

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“…The intervention was not associated with a significant effect on return of spontaneous circulation, rate of rearrest, or requirement for vasopressor support prior to hospital arrival but the 95% CIs did not exclude potentially clinically meaningful differences. Although the intervention was based on promising studies using animal models of cardiac arrest and the results from a phase 1 openlabeled study, 13,14,21 the results of this study do not support the use of sodium nitrite for out-of-hospital cardiac arrest. Experimental animal evidence suggests that increasing nitric oxide bioavailability using pharmacological or genetic mechanisms protects organs during ischemia-reperfusion injury.…”

Section: Discussionmentioning

confidence: 76%

“…13 Based on results from a phase 1, open-label study in 125 patients with out-of-hospital cardiac arrest, a sodium nitrite dose of 45 mg or 60 mg given during resuscitation was sufficient to achieve serum nitrite levels between 10 μM and 20 μM within 10 to 15 minutes after administration. 14 The aim of this randomized trial was to determine whether sodium nitrite given during active resuscitation of patients with out-of-hospital cardiac arrest improved survival to hospital admission.…”

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confidence: 99%

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

Kim

Maynard

Dezfulian

et al. 2021

JAMA

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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 MEASURESThe 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 ϱ; P = .82) and the mean difference for the 60-mg dose vs placebo was −1.3% (1-sided 95% CI, −6.5% to ϱ; 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.

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

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

Kim

Maynard

Dezfulian

et al. 2021

JAMA

Self Cite

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“…The control group was acquired from contemporaneous controls in the paramedic data base of all out-of-hospital cardiac arrests who had received standard of care and did not receive nitrite (n 5 355) during the period the study was open. Interestingly, there was no difference in outcomes (return of spontaneous circulation, rearrest, use of epinephrine, BP, survival to discharge, neurologically favorable survival) between the low-or high-dose nitrite groups or between patients receiving nitrite compared with control patients (Kim et al, 2018). A larger (n 5 1500) randomized placebo-controlled trial is underway comparing two doses of nitrite (45 or 60 mg) and placebo, which should provide a definitive answer as to whether it is useful or not, with primary outcomes of survival to hospital admission and rearrest/epinephrine use prehospital (NCT03452917).…”

Section: F Nitrite and Nitrate In Metabolic Diseasesmentioning

confidence: 91%

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

et al. 2020

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“…Despite adequate serum levels, there were no differences in rate to ROSC, survival or neurological outcome at discharge compared to matched controls. There were no differences in systolic blood pressure or use of noradrenaline (norepinephrine) between both groups ( 112 ).…”

Section: Neuroprotective Treatments Of Comatose Patients After Cardiamentioning

confidence: 93%

Neuroprotective Treatment of Postanoxic Encephalopathy: A Review of Clinical Evidence

2021

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Postanoxic encephalopathy is the key determinant of death or disability after successful cardiopulmonary resuscitation. Animal studies have provided proof-of-principle evidence of efficacy of divergent classes of neuroprotective treatments to promote brain recovery. However, apart from targeted temperature management (TTM), neuroprotective treatments are not included in current care of patients with postanoxic encephalopathy after cardiac arrest. We aimed to review the clinical evidence of efficacy of neuroprotective strategies to improve recovery of comatose patients after cardiac arrest and to propose future directions. We performed a systematic search of the literature to identify prospective, comparative clinical trials on interventions to improve neurological outcome of comatose patients after cardiac arrest. We included 53 studies on 21 interventions. None showed unequivocal benefit. TTM at 33 or 36°C and adrenaline (epinephrine) are studied most, followed by xenon, erythropoietin, and calcium antagonists. Lack of efficacy is associated with heterogeneity of patient groups and limited specificity of outcome measures. Ongoing and future trials will benefit from systematic collection of measures of baseline encephalopathy and sufficiently powered predefined subgroup analyses. Outcome measurement should include comprehensive neuropsychological follow-up, to show treatment effects that are not detectable by gross measures of functional recovery. To enhance translation from animal models to patients, studies under experimental conditions should adhere to strict methodological and publication guidelines.

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Usefulness of Intravenous Sodium Nitrite During Resuscitation for the Treatment of Out-of-Hospital Cardiac Arrest

Cited by 11 publications

References 23 publications

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

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

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

Neuroprotective Treatment of Postanoxic Encephalopathy: A Review of Clinical Evidence

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