Five Questions With: Dr. Fionna Moore on the PARAMEDIC2 Trial

Epinephrine is the primary drug used during CPR for out-of-hospital cardiac arrest, but its common dose, timing, and indications come primarily from limited animal data. Some experts now question whether it really provides these patients any overall benefit.¹ 

ILCOR (the International Liaison Committee on Resuscitation) was curious too and called for a defining placebo-controlled trial to determine whether epi is safe and effective for OHCA victims. The PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) trial ensued at five U.K. ambulance services, and its results were published in July in the New England Journal of Medicine.² 

In the latest Five Questions With, coinvestigator Dr. Fionna Moore, longtime medical director and recently chief executive for the London Ambulance Service and now executive medical director for the South East Coast Ambulance Service NHS Foundation Trust, helps put the results in perspective. 

EMS World: Prior to this trial, what did the overall body of literature tell us about epinephrine for OHCA? 

Moore: Each year 30,000 people sustain a cardiac arrest in the U.K., and fewer than 1 in 10 survive. The best chance of survival comes if the cardiac arrest is recognized quickly, someone starts cardiopulmonary resuscitation, and defibrillation is applied without delay. 

The use of adrenaline is one of the last things tried in attempts to treat cardiac arrest. It increases blood flow to the heart and increases the chance of restoring a heartbeat. However, it also reduces blood flow in very small blood vessels in the brain, which may worsen brain damage. Observational studies involving over 500,000 patients have reported worse long-term survival and more brain damage among survivors who were treated with adrenaline. 

Despite these issues, until now there have been no definitive studies of the effectiveness of adrenaline as a treatment for cardiac arrest. This led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine if adrenaline is beneficial or harmful as a treatment for out-of-hospital cardiac arrest.

Given the uncertainty about longer-term and functional outcomes, how have EMS docs in the U.K. and U.S. chosen to handle epi for these patients?

The ILCOR, European Resuscitation Council, and Resuscitation Council (U.K.) guidelines all currently reflect giving adrenaline after the third shock in VF/pulseless VT, and as early as possible with a nonshockable rhythm. We will now look to these bodies to consider the results of this very large trial to decide if they feel there is a need to change the existing guidance.

Previously epi had been associated with ROSC in OHCA patients, but not better longer-term survival. The PARAMEDIC2 trial found an associated improvement in 30-day survival—is that the first we’ve seen that? What do you think is behind it?

Anecdotally adrenaline has been associated with improved ROSC rates, and PARAMEDIC2 found a small increase in overall survival at 30 days. However, the concern has always been that the increase in ROSC rates is at odds with improved neurological outcomes. Clearly, as a powerful alpha-1 agent, the impact of adrenaline on the microcirculation within the brain was always a concern. 

There has been previous association of epi with poor neurological outcomes in these patients—why do we think that is, and how do these findings jibe with our existing knowledge about that?

The reasons why more patients survived with adrenaline and yet had an increased chance of severe brain damage are not completely understood. One explanation is that although adrenaline increases blood flow in large blood vessels, it paradoxically impairs blood flow in very small blood vessels and may worsen brain injury after the heart has been restarted. An alternative explanation is that the brain is more sensitive than the heart to periods without blood and oxygen, and although the heart can recover from such an insult, the brain is irreversibly damaged.

What to your mind are the primary take-home points from PARAMEDIC2? Do the findings suggest any tweaks in protocols or approaches to OHCA patients? 

I’d like to reflect the comments of (U.K. resuscitation expert) Professor Jerry Nolan, who said, “This trial has answered one of the longest-standing questions in resuscitation medicine. Taking the results in context of other studies, it highlights the critical importance of the community response to cardiac arrest. Unlike adrenaline, members of the public can make a much bigger difference to survival through learning how to recognize cardiac arrest, perform CPR, and deliver an electric shock with a defibrillator.”

It’s really important that we continue to teach that the most effective treatments are recognizing cardiac arrest and dialing 9-9-9/9-1-1 (which means one extra survivor for every 11 people treated); starting CPR (one extra survivor for every 15 people treated); and public access defibrillation (one extra survivor for every five people treated). Current guidelines advise that adrenaline be given if these initial treatments are unsuccessful. 

References

1. Callaway CW. Epinephrine for cardiac arrest. Curr Opin Cardiol, 2013 Jan; 28(1): 36–42.

2. Perkins GD, Ji C, Deakin CD, et al.; for the PARAMEDIC2 Collaborators. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. NEJM, 2018 Jul 18; https://www.nejm.org/doi/full/10.1056/NEJMoa1806842.