Pharmacology 101: Sodium Nitrite and Cardiac Arrest

Pharmacology 101 is an online column designed to keep EMS providers informed on formularies, dosages, effects, applications, and current research related to medications administered in the prehospital setting. If you have a medication-related question you’d like the author to address, contact editor@emsworld.com.

Out of hospital cardiac arrest (OHCA) is a significant health problem and source of morbidity and mortality. While more than 350,000 episodes occur in America each year, only 7%–20% of victims survive to hospital discharge.^1–4 Unfortunately, our arsenal of medications used in treating OHCA is limited. Thus, the identification of a pharmacological agent with demonstrated efficacy in OHCA could potentially save tens of thousands of lives each year.¹

Sodium nitrite has been a drug of interest in recent years. Animal models have suggested a benefit in survival after cardiac arrest and cytoprotection. The proposed mechanism of action is based on nitrite therapy’s ability to mitigate cellular injury and death, thus protecting the organs from damage when reperfusion is established after ischemia.^2,5 A phase I trial published in 2018 indicated sodium nitrite administration appeared safe and feasible in OHCA.⁵ But the million-dollar question remained: Was it effective for use in OHCA? Could it save lives?

The SNOCAT Trial

Enter the study of interest for this article: Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest: A Randomized Clinical Trial, more easily referenced as the SNOCAT trial, published in JAMA in January 2021. The authors described the results of their double-blind, placebo-controlled phase II randomized clinical trial, which was a follow-up to their initial phase I trial.

The study enrolled patients with OHCA in Seattle and surrounding King County from February 2018 to August 2019. Using a blinded study kit, patients were randomized in a 1:1:1 fashion between sodium nitrite 45 mg, sodium nitrite 60 mg, and placebo, and the contents were administered as soon as possible via intraosseous or intravenous routes. The study did an excellent job of blinding all personnel involved in the process, including paramedics, emergency department staff, inpatient physicians, and nursing staff.

Their primary outcome of interest was survival to hospital admission, which they defined as “formal inpatient assignment and arrival to a hospital ICU bed.” Secondary outcomes included rate of rearrest; use of norepinephrine by paramedics; rate of return of spontaneous circulation; length of ICU stay; cumulative survival to 24 hours, 48 hours, and 72 hours; survival to hospital discharge; and neurological status at hospital discharge.

An impressive total of 1,502 patients over 18 were enrolled, with 1,497 randomized between the three groups. The mean age was 64 years, and about a third of the patients were women. The patients had to be comatose at enrollment and have received advanced life support. Exclusion criteria included trauma, age under 18 years, DNR order, rigor, lividity, lack of coma, incarceration, or pregnancy. Aside from the study medications, standard resuscitation protocols were followed.

What They Found

No statistically significant differences were found for the primary outcome of survival to hospital admission when comparing sodium nitrite 45 mg and 60 mg against placebo. But what if sodium nitrite made a difference elsewhere? The authors also investigated multiple secondary criteria, including the rate of rearrest, return of spontaneous circulation (ROSC), length of ICU stay, survival to 24 hours and hospital discharge, and cerebral disability. Unfortunately, sodium nitrite failed to shine in these measures as well, with no statistically significant differences.

Additional prespecified and post-hoc analyses failed to find any statistically significant differences in several additional measures:

• Time to death;
• Reduction in the first recorded blood pressure level at hospital arrival;
• Sustained hypotension;
• Incidence of withdrawal of life-sustaining support;
• Incidence of cardiac catheterization;
• Incidence of targeted temperature management.

Discussion

This was a well-designed trial that did a good job of minimizing bias while taking promising early human and animal research to the next level. Unfortunately, the lack of statistically significant differences between groups led the authors to conclude “the results of this study do not support the use of sodium nitrite for out-of-hospital cardiac arrest.”²

The authors note some limitations: They consider it possible patients may have been underdosed but remind readers that higher doses of sodium nitrite may cause adverse effects and the doses in their study were chosen based on their phase I data. The study did not have power to detect smaller differences, despite their conservative estimates compared to the robust animal data. A total of 278 patients were not enrolled, exposing the study to enrollment bias. The authors also commented that they were unable to further investigate the subpopulation of patients with ventricular fibrillation due to study design, but their data do not suggest a larger trial would be useful for this purpose.

The authors noted that in contrast to the animal model, which saw administration of sodium nitrite within 12 minutes of asystole, their study had administration times of 25–30 minutes. However, this is consistent with the administration times of other medications.² The journal published commentary from readers who questioned whether there was a relationship between administration times and prognostication, but the authors replied that they did not see differences in hospital outcomes when comparing the lowest 25th percentile of time to drug administration against the highest 25th percentile.^6,7

Future Research

While this study seems to definitively answer the question of whether sodium nitrite is beneficial for OHCA, the further dialogue between the readers and authors may indicate the door has not been slammed shut all the way. Their discussion briefly turned also to the question of in-hospital cardiac arrest. Patients who arrest in-house typically receive cardiovascular life support much more quickly than patients who arrest out-of-hospital. However, the authors noted the etiologies of these arrests differed, and “therefore, the use of sodium nitrite for in-hospital cardiac arrest remains an unanswered question.”^6,7

The views and opinions expressed in this article are those of the author and do not necessarily reflect those of any affiliated people, institutions, or organizations.

References

1. Satty T, Martin-Gill C. Drugs in Out-of-Hospital Cardiac Arrest. Cardiol Clin, 2018; 36(3): 357–66.

2. Kim F, Maynard C, Dezfulian C, et al. Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission after Cardiac Arrest: A Randomized Clinical Trial. JAMA, 2021; 325(2): 138–45.

3. Myat A, Song KJ, Rea T. Out-of-hospital cardiac arrest: current concepts. Lancet, 2018; 391(10,124): 970–9.

4. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics—2018 update: A report from the American Heart Association. Circulation, 2018; 137(12): E67-E492.

5. Kim F, Dezfulian C, Empey PE, et al. Usefulness of Intravenous Sodium Nitrite During Resuscitation for the Treatment of Out-of-Hospital Cardiac Arrest. Am J Cardiol, 2018; 122(4): 554–9.

6. Sang W, Xu F. Effect of Sodium Nitrite on Survival of Cardiac Arrest to Hospital Admission. JAMA, 2021; 325(20): 2,116–8.

7. Kim F, Maynard C, Nichol G. Effect of Sodium Nitrite on Survival of Cardiac Arrest to Hospital Admission—Reply. JAMA, 2021; 325(20): 2,118–9.

Daniel Hu, PharmD, BCCCP, has Doctor of Pharmacy degree and is a critical care and emergency medicine pharmacist. He is a frequent speaker at conferences and has many publications in peer-reviewed journals.