Does Epinephrine Restart the Heart at the Expense of the Brain?

Patrice Wendling

July 24, 2018

The use of epinephrine, also known as adrenaline, during an out-of-hospital cardiac arrest (OHCA) offered a slight improvement in survival to 30 days but this was offset by worse neurological function in the double-blind PARAMEDIC 2 trial.

"Although more people are alive in the adrenaline group, many of them have sustained severe brain injury as a consequence and have been left in a severely disabled state and by severely disabled state — they're unable to care for themselves," principal investigator, Gavin D. Perkins, MD, Warwick Clinical Trials Unit, University of Warwick, Coventry, UK, told | Medscape Cardiology.

He said it's important the results be reviewed by the International Liaison Committee on Resuscitation (ILCOR), a coalition of seven major resuscitation organizations, but also to have conversations with the wider community because the choices physicians may make need to reflect the values and preferences of patients.

"Certainly when we spoke to patients before this study to ask them what were the most important outcomes, they told us almost universally — 95% — that survival without brain damage was more important than simply surviving alone...So when making practice recommendations, we've got to listen to the public and communities."

Epinephrine has been a cornerstone therapy for OHCA, with usage ranging from 60% to 80% in the UK and 57% to 98% in a recent US study, Perkins noted.

More than 356,000 OHCA arrests occur annually in the United States, with nearly 90% of them fatal, according to the latest statistics from the American Heart Association (AHA).

Publication of the study on July 18 in the New England Journal of Medicine prompted ILCOR to write in a statement that "We anticipate that our newly developed continuous evidence evaluation process will enable ILCOR to respond in a timely manner and rapidly disseminate any revised treatment recommendations."

PARAMEDIC2 is the first randomized controlled trial to identify a long-term survival benefit of epinephrine during cardiac arrest, they say.

Nonetheless, "Both optimal dose and timing of epinephrine during cardiac arrest remain important knowledge gaps," noted ILCOR, citing as study limitations the use of a single fixed dose of epinephrine 1.0 mg every 3 to 5 minutes for all patients and a median of 21 minutes from emergency call to first drug dose.

Commenting for | Medscape Cardiology, Sean van Diepen, MD, an academic cardiologist-intensivist with the University of Alberta, Edmonton, Canada, who was not involved with the study, said, "I do think the trial results give us pause. I think there's the potential that this study can result in a reduction in future epinephrine use for out-of-hospital cardiac arrest."

He added that secondary analyses from this large dataset are also going to be very important, as they may help identify "which patients are more likely to benefit and which patients are more likely to be harmed by this drug."

"The differential survival among subpopulations including those with witnessed arrest and stratified by shockable and nonshockable rhythms really suggests there may be some subgroups that may benefit more," van Diepen said.

Additional analyses are planned to look at subgroups, cost-effectiveness, the impact of adrenaline use on downstream organ donation, and whether time of administration had an effect on the outcomes, Perkins said.

“Whatever these further studies show, I think the main finding of the paper will remain that adrenaline was good for the heart but it was no good for the brain in terms of not finding evidence of improved neurological outcomes,” he said.

Weak Evidence Base

In 2015, ILCOR gave a weak recommendation for epinephrine 1.0 mg during cardiac arrest in adults based on very-low-quality evidence. Observational studies in more than 500,000 patients suggested a benefit with regard to return of spontaneous circulation and hospital admission with epinephrine, but also worse neurologic outcomes.

This prompted ILCOR to call for a randomized trial and the Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC2) trial soon followed.

It randomly assigned 8014 patients with OHCA in the UK to receive epinephrine or saline placebo plus standard care. The median time from emergency call to ambulance arrival was 6.6 minutes in both groups.

More patients in the epinephrine group than in the placebo group had a return to spontaneous circulation during resuscitation (36.3% vs 11.7%), as was the proportion transported to hospital (50.8% vs 30.7%).

At 30 days, 3.2% of patients given epinephrine were alive vs 2.4% of patients treated with placebo (unadjusted odds ratio [OR], 1.39; 95% CI, 1.06 – 1.82).

There was no significant difference between groups in the rate of survival to discharge with a favorable neurologic outcome (modified Rankin score 3 or less), at 2.2% vs 1.9% (unadjusted OR, 1.18; 95% CI, 0.86 – 1.61).

However, severe neurologic impairment (a score of 4 or 5) was almost twice as common among survivors in the epinephrine group as in the placebo group (31.0% vs 17.8%).

Survival to 3 months with a favorable neurologic outcome was 2.1% in the epinephrine group and 1.6% in the placebo group (unadjusted OR, 1.31; 95% CI, 0.94 – 1.82).

Paradoxical Findings

Although the exact reasons are unclear, the literature provides two potential explanations for the adverse outcomes observed with epinephrine use, Perkins said.

"It's possible that adrenaline may have a direct toxic effect on the brain by reducing microvascular blood flow," he said. "Alternatively, the brain is much less resilient to the effects of hypoxia and it's possible that adrenaline is able to restart the heart at a point at which damage has already occurred to the brain that is irreversible."

In an accompanying editorial, Clifton Callaway, MD, PhD, University of Pittsburgh, Pennsylvania, and Michael Donnino, MD, Beth Israel Deaconess, Boston, Massachusetts, write that "The small magnitude of the higher rate of survival and absence of functional recovery will prompt debate about whether epinephrine is truly beneficial for improving meaningful clinical outcomes."

The editorialists note that the results should not be extrapolated to in-hospital cardiac arrest, where epinephrine is typically given a median of 3 minutes after resuscitation rather than the median of 21 minutes in PARAMEDIC2. The results also suggest the need to study smaller doses of epinephrine than were used in the trial (mean total 4.9 mg) to see whether they could promote return of spontaneous circulation with fewer adverse effects.

The major limitation, however, is that the trial did not control for or measure in-hospital treatments, Callaway and Donnino say. Iatrogenic limitation of life support is the most common cause of in-hospital death, while other teams may work harder to treat or reduce injury in the sickest patients in the ICU, thereby minimizing differences in prehospital therapy.

"I think it is a potential source of bias," agreed van Diepen. "From my perspective, the lack of information on in-hospital care including the application of targeted temperature management is important. In addition, they did not have protocolized neuroprognostication for anoxic brain injury or withdrawal-of-care criteria, and these represent additional sources of bias."

Perkins countered that the UK has national resuscitation guidelines for physicians across its intensive care units. Also, he said, a recent national audit they performed showed "reasonable adherence" with the guidelines in terms of therapeutic hypothermia and deferral of neuroprognostication until at least 72 hours. In addition, the postresuscitation care patients receive will reflect the intervention they receive prehospitalization.

Asked what he sees as the biggest limitation, Perkins replied, "What the study doesn't tell us is what the effect would be if alternative doses were used, potentially lower doses or infusions. I think the second thing that it presses us towards is the lack of personalized medicine in resuscitation and often our inability to physiologically titrate treatments against response."

He added, "We are starting to see in the literature this emerging concept where one can either invasively or noninvasively measure things, such as perfusion pressures or end-organ perfusion, and then take a pharmacological treatment — so that your approach will be more of a goal-directed approach rather than a one-size should fit everybody."

The study was funded by the UK National Institute for Health Research; Comprehensive Research Network Intensive Care Foundation and Out of Hospital Cardiac Arrest Registry, which is funded by the British Heart Foundation and Resuscitation Council; and Health Care Wales. Perkins has reported serving as editor of Resuscitation. Callaway has reported being a volunteer for the AHA and participating in writing emergency cardiovascular care guidelines. Donnino has reported being a volunteer for the AHA and participating in the AHA writing group for US guidelines. Donnino has served as vice chair for Advanced Cardiac Life Support at ILCOR. van Diepen has reported no relevant financial relationships.

N Engl J Med. Published online July 18, 2018. Full text, Editorial

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