Epinephrine and the Paramedic-2 trial: Is it time to pull our starting pitcher?

New research questions whether pharmacotherapy in cardiac arrest is effective at ROSC and long-term survival

If ALS versus BLS in cardiac arrest resuscitation was a Little League game, we’d be awful close to calling the game for BLS based on the mercy rule.

In 1999, the ARREST trial demonstrated amiodarone to be more effective than placebo at achieving ROSC in out-of-hospital cardiac arrest [1]. In 2002, the ALIVE trial demonstrated amiodarone also beat the pants off our traditional ventricular antiarrhythmic, lidocaine [2]. What it wasn’t proven to do, however, was result in improved survival to hospital discharge.

Or, as I’ve often pointed out to my students, “Administration of amiodarone to VF patients has been demonstrated to be significantly better than lidocaine or placebo at temporarily resuscitating a corpse long enough to run up a huge bill in the ICU, and then die anyway.”

In recent years, we’ve begun to turn a critical eye toward administration of the one drug we’ve clung to through all those changes – epinephrine.
In recent years, we’ve begun to turn a critical eye toward administration of the one drug we’ve clung to through all those changes – epinephrine. (Photo/Wikimedia Commons)

OPALS in 2004 demonstrated that ALS care for out-of-hospital cardiac arrest (OHCA) did not improve outcomes when compared to BLS resuscitation with AEDs.

It only took 10 years or so after that for AHA/ILCOR to grudgingly conclude that the evidence supporting antiarrhythmic therapy in VF arrest was very weak, and that it might be acceptable to forego antiarrhythmic therapy entirely, taking an individual problem-solving approach instead.

We dropped routine administration of atropine in cardiac arrest, tacitly acknowledging the fact that asystolic cardiac arrest is a reliable sign of death, and not simply hypo-atropenia.

Is epinephrine any more effective?

In recent years, we’ve begun to turn a critical eye toward administration of the one drug we’ve clung to through all those changes – epinephrine – but the supporting evidence is not looking good. If we return to my Little League analogy, epinephrine would be our ace pitcher we’re hoping to keep the BLS hitters in check until our ALS problem-solving interventions can get us back into the game.

And folks, our ace pitcher is getting shelled.

We’ve had several studies questioning the efficacy of epinephrine in cardiac arrest, and the recent publication of the Paramedic-2 trial in the United Kingdom represents the first large-scale, multi-center RCT sufficiently powered to study the question [3-6].

The Paramedic-2 Trial

Paramedic-2 was a large-scale, multi-center randomized controlled trial conducted at five different EMS agencies in the United Kingdom. The study randomized 8,014 OHCA patients, after initial CPR and defibrillation, into two groups; epinephrine 1 mg 1:10,000 every 3-5 minutes plus standard ILCOR resuscitation guidelines, and placebo (0.9 percent saline) plus standard ILCOR resuscitation guidelines. The epinephrine arm enrolled 4,015 patients while the placebo arm enrolled 3,999 patients. Excluded from the study were:

  • Pregnant patients.
  • Patients under age 16.
  • Cardiac arrest from anaphylaxis or asthma (presumably more likely to have better outcomes with epinephrine).
  • Administration of epinephrine before arrival or a trial-trained paramedic.
  • Traumatic cardiac arrest (at one agency).

It’s also important to note that 615 OHCA patients were screened from inclusion because they achieved ROSC prior to randomization. The exclusion of these patients – the most likely survivors in cardiac arrest resuscitation – likely account for the lower overall survival rates in the study.

The trial was powered to measure a primary outcome of 30-day survival of OHCA, with several secondary outcomes. Among these, survival to discharge and 30-day survival with low neurological impairment, and ROSC rates have generated the most discussion.

The epinephrine arm had 128 patients (3.2 percent) survive to hospital discharge versus 91 (2.3 percent) in the placebo group. At 30 days, 3.2 percent of the epinephrine group was still alive versus 2.4 percent of the placebo group.  Significantly more epinephrine patients achieved ROSC (947 or 23 percent) versus placebo patients (319 or 8.0 percent).

However, the higher ROSC and survival numbers in the epinephrine group are tempered by significantly worse neurological outcomes. A higher number of epinephrine patients had poor neurological outcomes, enough so that the percentages of favorable neurological outcomes were not statistically significant when compared to placebo (2.2 percent at discharge and 2.1 percent at 30 days for epinephrine versus 1.9 percent and 1.6 percent for placebo).

So what do these numbers mean for your practice?

An unfortunate fact of scientific research is that it often raises as many questions as it answers, but it is still the best way of gaining understanding of the world in which we live. Proponents of epinephrine in cardiac arrest will rightfully point out that the significantly higher ROSC rates in the epinephrine arm are promising. To achieve meaningful outcomes in cardiac arrest, we must first restore a pulse, and unquestioningly epinephrine does that better than placebo.

Critics, however, will just as correctly point out, “At what price ROSC? If it doesn’t result in patients surviving with a high quality of life, what is the point?”

The truth, as usual, is probably equidistant from the extremes, and finding the sweet spot for epinephrine administration will likely require further study. At this point, it seems increasingly clear that routine administration of epinephrine is not beneficial to favorable long-term outcomes, which raises the following questions:

  • Are the pressor effects of epinephrine, and their expected increase in cerebral perfusion pressure outweighed by suppression of microcirculation?
  • Is 1 mg even the right dose?
  • Should we be titrating it in infusions, based upon patient weight, arterial pressures, or end-tidal capnography?
  • Would epinephrine be more effective if administered in the appropriate timeframe?

We have understood for some time that there are three phases of cardiac arrest;

  1. Electrical (0-5 minutes).
  2. Circulatory (6-20 minutes).
  3. Metabolic (>20 minutes).  

In the paramedic-2 trial, the median time interval between arrest and administration of the study drug was 21 minutes, well into the metabolic phase of arrest. Would earlier administration during the circulatory phase, where increased systemic vascular resistance would presumably be beneficial, show better results for epinephrine?

All of these questions can only be answered with further study, but it seems increasingly likely that soon, we’ll be administering epinephrine to fewer patients, at a dose and interval yet to be determined.

It might just be time to make epinephrine our closer, or trot him out only against left-handed batters, rather than keep him as our starting pitcher.

This article, originally published on July 25, 2018, has been updated. 

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