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Wednesday, March 4, 2020


Use Epinephrine Judiciously in Cardiac Arrest


The most recent American Heart Association Advanced Cardiac Life Support (ACLS) update published in December recommends that epinephrine be administered to patients in cardiac arrest (class 1 recommendation) every three to five minutes (class 2a recommendation). (Circulation. 2019;140[24]:e881;

At first glance, this is a straightforward, uncontroversial recommendation. We have been giving epinephrine in cardiac arrest for nearly 60 years, ever since Redding and Pearson found that 1.0 mg epinephrine and bicarbonate maximized resuscitation rates in small groups of 10-20 kg mongrel dogs. (Anesth Analg. 1963;42:599.)


Since that time, that same 1.0 mg IV push dose of epinephrine has been recommended for 60-100 kg adults. Studies began in humans in the 1980s that retrospectively looked at epinephrine administration. Though there have been conflicting data throughout the years, 1.0 mg epinephrine every three to five minutes has stood the test of time, and has been the mainstay of pharmacologic drug interventions for shockable and nonshockable cardiac arrests.

Although the ACLS recommendations have been consistent in recommending epinephrine, a number of studies have questioned epinephrine's effectiveness. Ian Stiell, MD, and colleagues evaluated ACLS drugs in 1998, noting "a significant association between unsuccessful resuscitation and the use of epinephrine." (Ann Emerg Med. 1998;32[5]:544.) Ten years later, a study from Norway noted a similar lack of effectiveness of ACLS drugs, particularly epinephrine.

Despite improved short-term survival to hospital admission, no statistically significant improvement in survival to hospital discharge was achieved with the use of epinephrine in cardiac arrest victims. (JAMA. 2009;302[20]:2222; Clinicians relied on data from poorly controlled studies for years and continued to use epinephrine dogmatically. A 2014 meta-analysis analyzing 14 trials of 12,246 patients compared standard-dose epinephrine at 1.0 mg every three to five minutes with placebo, standard-dose epinephrine with high-dose epinephrine, epinephrine with vasopressin, and epinephrine alone with epinephrine combined with vasopressin. Epinephrine demonstrated no benefit in survival to hospital discharge or intact neurological survival in any comparison. (Resuscitation. 2004;85[6]:732.)

Profound Disappointment
The long-awaited PARAMEDIC-2 trial was the first double-blind, placebo-controlled trial to evaluate epinephrine's role in cardiac arrest. (New Engl J Med. 2018;379[8]:711; Four ambulance services across the United Kingdom randomized cardiac arrest patients to receive 1.0 mg IV epinephrine or placebo every three to five minutes. Key variables measured were return of spontaneous circulation, EMS transport to the hospital, and 30-day and 90-day survival. Most importantly, they also measured neurologic outcomes at 30 and 90 days.

Those hoping to see redemption for epinephrine through this study were profoundly disappointed. At first glance, the results were promising. The authors clearly determined that epinephrine administration statistically improved the likelihood of ROSC (36.3% v. 11.7%) and likelihood to be transported to the hospital. They also showed that epinephrine clearly improved 30-day survival with 3.2 percent of epinephrine patients surviving v. 2.4 percent of those patients receiving placebo (OR=1.39; p=0.02). That is where the clear-cut conclusions end, however.

When the authors analyzed favorable neurologic outcomes as defined by a modified Rankin Scale score of 0-3, there was no longer a statistically significant difference (2.2% v. 1.6%). Interestingly, most stroke studies have used a modified Rankin Scale score of 0-2 to qualify good neurologic outcomes, and there was no difference in good neurologic outcome when those criteria were used in this study (1.6% in the epinephrine group v. 1.3% in placebo group). The authors also found there was almost double the number of neurologically devastated patients in the epinephrine group compared with the placebo group (31% v. 17.8%) when they evaluated neurologically devastated patients with a modified Rankin Scale score of 4 and 5.

All the Facts
So why did the AHA continue its endorsement of epinephrine with a Level 1 recommendation? The answer lies in the 90-day data from PARAMEDIC-2. (Circulation. 2019;140[24]:e881;; New Engl J Med. 2018;379[8]:711; They noted a trend at 90 days toward more neurologically intact patients (modified Rankin 0-3) in the epinephrine group compared with the placebo group. This came to a total of three more neurologically intact patients per 1000 patients, and this was only seen in the patients with asystole and PEA, not in those with a shockable rhythm.

But clinicians need to have all the facts before blindly following the AHA recommendations and giving epinephrine every three to five minutes for a prolonged period of time to all patients in cardiac arrest. The 30-day survival in the epinephrine group was marginally better, but this came at great cost. Those who survived were so neurologically devastated that they were likely to linger or die in long-term care facilities, likely at great emotional and financial cost to the family. If this study had been performed in the United States, it would have likely resulted in an even higher percentage of neurologically devastated survivors because we do not have a universal protocol for termination of resuscitation after 20 minutes of asystole or refractory PEA like the United Kingdom.

Our recommendations are based on the available literature. To not violate the standard of care, we believe epinephrine should still be used in cardiac arrest because it is currently recommended as a Level 1 recommendation by the AHA, but we also believe it should be used judiciously because it has the potential to increase the number of neurologically devastated patients. We believe there should be a limit to the amount of epinephrine given in asystolic arrests, especially in unwitnessed arrest patients who do not receive immediate CPR. The termination of resuscitation (TOR) guidelines (unwitnessed, nonshockable rhythm, no ROSC) plus the Jabre criteria (unwitnessed by EMS, nonshockable rhythm, no ROSC after two doses of epinephrine) accurately predict those who are unlikely to benefit from additional resuscitation and are not likely to have any meaningful survival. (Resuscitation. 2020;146:19.)

If a patient has had an asystolic arrest and does not regain a pulse after two to three doses of epinephrine, high-quality CPR, and appropriate oxygenation and ventilation, medical control should be contacted to request termination. We use similar criteria for PEA when it is wide and slow with a heart rate below 25 beats per minute if no reversible cause is present. For ventricular fibrillation, we limit our epinephrine dosing to a single administration after the second defibrillation. We have the benefit of cardiac ultrasound in the ED, and combine the TOR criteria with a lack of cardiac motion. Because studies have shown essentially no survival benefit after five doses of epinephrine (Resuscitation. 2017;117:18), our aim is never to exceed five doses in cardiac arrest. Finally, we strongly believe that each patient's underlying pre-arrest disease state should be a consideration for the duration of resuscitation when pulseless.

After more than half a century of the initial epinephrine studies, we still do not know the exact role (or lack of role) of epinephrine in cardiac arrest. Each day, patients may be receiving suboptimal care because we are not doing large, well-conceived studies on the more than 250,000 cardiac arrests occurring each year in the United States.

Dr. Works completed her emergency medicine residency at Vanderbilt University Medical Center in Nashville and is the currently the EMS fellow there. Dr. Slovis is the chairman of emergency medicine at Vanderbilt University Medical Center, a professor of emergency medicine and medicine, and the medical director of the Metro Nashville Fire Department and Nashville International Airport.

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