Use it!

Epinephrine has been included in advanced life support algorithms since the birth of modern CPR in the 1960s. Animal and human studies demonstrate that epinephrine increases both cerebral and myocardial blood flow. Epinephrine increases the aortic diastolic pressure when injected during cardiac arrest, thereby increasing coronary perfusion pressure. Chest compressions, while lifesaving, can compress the thoracic inlet, limiting cerebral perfusion. The alpha vasoconstrictive effects of epinephrine shunt blood from the periphery to the central circulation, augmenting blood flow through the carotid and coronary arteries. Observational data of in-hospital cardiac arrest patients demonstrates an association between improved neurologically intact survival with shorter time to epinephrine. 

Randomized clinical trial data further demonstrate that epinephrine improves the rate of return of spontaneous circulation (ROSC) when compared to placebo. The PARAMEDIC-2 trial published in August 2018 in the New England Journal of Medicine, is the largest randomized controlled trial of epinephrine versus placebo to date, yet the time to epinephrine was prolonged relative to prior studies (21.5 minutes versus 10 minutes). Therefore, we must question whether this is a fair trial of epinephrine when the evidence base suggests that earlier epinephrine improves outcome. Despite this limitation, epinephrine improved survival to every time point from hospital admission to three months. However, due to the very low overall survival in the epinephrine and placebo groups (3.2% and 2.4%, respectively), the trial simply was not powered to evaluate the secondary outcome of neurological disability. 

Unlike other randomized controlled trials of epinephrine in cardiac arrest, the PARAMEDIC-2 trial did not control or report the proportion of patients in each group that received targeted temperature management (TTM), an intervention that has been proven to increase neurologically intact survival. Furthermore, there was no standardization of post-acute care with respect to exposure to premature withdrawal of life-sustaining therapies (WLST) prior to three days. Therefore, we are left wondering if there was a disparity between groups for successful achievement of targeted temperature management or adherence to international guidelines that recommend neuro-prognostication be delayed at least three days for accurate differentiation of irreversible brain injury from delayed clearance of sedation, analgesia and neuromuscular blockade. Recent observational data shows that while two-thirds of patients have “early awakening” at a median time of one day, one-third of patients have “late awakening” at a median time of five days, where the majority were observed to have good neurologic outcome.  

Ultimately, the current evidence does not adequately examine the impact of epinephrine on neurologically intact survival. To cast aside a therapy that improves survival in cardiac arrest, we must have definitive evidence that it worsens neurologic outcome, which currently does not exist. Future trials must either standardize post-arrest care with an algorithm similar to the TTM trial or at least report the proportion of patients exposed to TTM and premature WLST. Ideally, a blinded physician would utilize EEG, MRI and SSEP to assess neurologic function prior to making statements regarding neurologic prognosis that can trigger the self-fulfilling prophecy of premature WLST that results in a poor outcome (death), no matter whether a patient is merely sedated from delayed clearance or irreversibly brain injured.   

The controversy surrounding epinephrine in cardiac arrest is alive and well. We will examine the opposing arguments against epinephrine in a future post. Stay tuned!

References:

Cronberg T, Rundgren M, Wethall E, et al. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology. 2011;77:623-630. 

Donnino M, Salciccioli J, Howell M, et al. Time to administration of epinephrine and outcome after in-hospital cardiac arrest with shockable rhythms: retrospective analysis of large in-hospital data registry. BMJ. 2014;348:1-9. 

Elmer J, Torres C, Aufderheide TP, et al. Association of early withdrawal of life-sustaining therapy for perceived neurological prognosis with mortality after cardiac arrest. Resuscitation. 2016;102:127-135. 

Jacobs I, Finn J, Jelinek G, Oxer H, Thompson P. Effect of survival on out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011;82:1138-1148. 

Michael J, Guerci A, Koehler C, et al. Mechanisms by which epinephrine augments cerebral and myocardial perfusion during cardiopulmonary resuscitation in dogs. Circulation. 1984;69(4):822-835. 

Nielsen N, Wetterslev J, Cronberg T, et al. TTM trial Investigators. Targeted temperature management at 33°Cversus 36°C after cardiac arrest. NEJM. 2013;369(23):2197-2206.  

Olasveengen T, Sunde K, Brunborg C, Thosen J, Steen P, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 2009;302(20):2222-2229. 

Paradis N, Martin G, Rosenberg J, et al. The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA. 1991;265:1139-1144. 

Perkins GD, Deakin CD, Nolan JP, et al. PARAMEDIC2 Collaborators. A randomized trial of epinephrine in out-of-hospital cardiac arrest. NEJM. 2018;379(8):711-721. 

Rey A, Rossetti A, Miroz JP, Eckert P, Oddo M. Late awakening in survivors of postanoxic coma: early neurophysiologic predictors and association with ICU and long-term neurologic recovery. Crit Care Med. 2019;47(1):85-92. 

Rossetti A, Rabinstein A, Oddo M. Neurological prognostication of outcome in patients in coma after cardiac arrest. Lancet Neurology. 2016;15:597-609. 

Taccone F, Cronberg T, Friberg H, et al. How to assess prognosis after cardiac arrest and therapeutic hypothermia. Critical Care. 2014;202(18):1-12.