Challenging the use of epinephrine during resuscitation from cardiac arrest

Arterial blood gases and other “acute care” biochemical blood tests are frequently ordered during recovery from cardiac arrest. Cardiac arrest, sudden loss of blood flow consequent on cessation of heart activity, is the ultimate medical emergency, frequently exploited for the dramatic nature of its presentation (apparent lifelessness) and treatment by writers of TV medical dramas. 

Return of spontaneous circulation (ROSC), the first step in survival from cardiac arrest depends on rapid (ideally, immediate) initiation of cardiopulmonary resuscitation (CPR), comprising continuous regular chest compressions (heart massage) and assisted ventilation; as well as, if indicated by the presence of ventricular fibrillation or pulseless ventricular tachycardia, prompt electronic conversion of these abnormal cardiac rhythms using externally applied shock to the heart. Delay of just 5 minutes after collapse can result in irreversible hypoxic brain damage, and death may occur if treatment is delayed by 10 minutes. 

Aficionados of the TV medical drama will recognize the above resuscitative measures, and some TV armchair “experts” will additionally recall that the hormone drug epinephrine (alternative name adrenaline) is sometimes used to help stimulate the non-beating heart. 

Although internationally agreed resuscitation guidelines emphasize the prime importance of rapid initiation and uninterrupted continuation of well-defined quality CPR and defibrillation, they also recommend the use of epinephrine (1 mg iv) if initial CPR/defibrillation fails to achieve ROSC. It is recommended that epinephrine at this dosage be delivered every 3-5 minutes for the duration of the resuscitation attempt. Guidelines make clear that continuing CPR should not be interrupted in order to deliver epinephrine, emphasizing the perceived secondary importance of this drug treatment. 

Epinephrine has been employed in resuscitation from cardiac arrest for close to 50 years, despite little formal study evidence of its effectiveness and safety; its continued, time-honored use being based on a sound understanding of its potential beneficial effect (increased cardiac blood flow) in the context of cardiac arrest.

Limited study in recent years has suggested that although epinephrine significantly improves the chance of cardiac-arrest patients achieving ROSC and progressing to postcardiac arrest intensive care, its use is associated with increased risk of paradoxical decreased cerebral blood flow, cerebral ischemia and consequent increased risk of permanent hypoxic brain damage and associated physical and mental disability that all survivors of cardiac arrest may suffer. 

Concern about this apparent potential adverse effect of epinephrine persuaded experts responsible for resuscitation guidelines to call for a placebo-controlled trial to definitively establish if epinephrine is a safe and effective treatment for cardiac arrest. In response, UK researchers planned and conducted the PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest 2) trial.

Now, close to 5 years after it was first conceived, the long-awaited results of PARAMEDIC2, the first-ever randomized, placebo-controlled trial of epinephrine use in cardiac arrest, are recently published.

During an approximate 3-year (2014-2017) study period, paramedics working for five NHS ambulance services across the UK recruited 8014 study patients. All had suffered an out-of-hospital cardiac arrest and failed to achieve ROSC after initial CPR/defibrillation. Each study patient was randomly assigned to receive either iv epinephrine (1 mg every 3-5 minutes) or iv placebo saline solution every 3-5 minutes.

Study design ensured that paramedics were blinded to the treatment (epinephrine or placebo) they were delivering. Apart from this study-defined intervention, all study patients received the same standard paramedic-led treatment for out-of-hospital cardiac-arrest care as defined in current resuscitation guidelines. 

The primary outcome measure was rate of survival at 30 days after the arrest. Secondary outcome measures were: rate of survival to hospital admission (essentially a measure of rate of ROSC “event survival”); length of stay in intensive care; length of stay in hospital; rate of survival to hospital discharge and at 3 months after discharge; and finally, neurological outcome for survivors at hospital discharge and at 3 months after discharge.

The neurological outcome for survivors was individually assessed by research paramedics blinded to the treatment (epinephrine or placebo) that had been delivered to the patient being assessed, using the well-validated modified Rankin Scale (mRS). This allows ranking of the severity of disability resulting from neurological (brain) damage on a six-point scale of 0 to 5; 0 indicating no disability, and 5 most severe disability, summarily defined as “bedridden, incontinent, dependent on constant nursing care and attention”.

Moderate disability (mRS score 3) is summarily defined as “requires some help but able to walk unassisted”. For the purposes of this study, a favorable neurological outcome was defined as an mRS score of 0 to 3; unfavorable neurological outcome was defined as mRS score of 4 or 5. 

Analysis of study results revealed that epinephrine use improves the chances of being alive at 30 days after suffering out-of-hospital cardiac arrest (the primary outcome measure). Of 4012 patients randomized to receive epinephrine, 130 (3.2 %) were alive at 30 days, whereas of 3995 patients randomized to receive placebo, only 94 (2.4 %) were alive at 30 days. Although apparently small, this difference, 3.2 % versus 2.4 %, is statistically significant (P=0.02).

Study results confirm the suggestion that epinephrine use improves the chances of achieving ROSC and surviving to hospital admission (36 % of patients in the epinephrine group versus 11.7 % in the placebo group achieved ROSC; and 23 % in the epinephrine group versus 8 % in the placebo group survived to hospital admission).

Study results, however, also confirm that epinephrine use is associated with higher rate of neurological disability among survivors; 39 of 126 (31 %) patients in the epinephrine group who survived to hospital discharge had an unfavorable neurological outcome (mRS 4 or 5), whereas only 16 of 90 (17.8 %) patients in the placebo group who survived to hospital discharge had such an unfavorable neurological outcome.

This meant that overall, survival with a favorable neurological outcome (mRS 0 to 3) was essentially the same in the two patient groups: 2.2 % of patients in the epinephrine group versus 1.9 % in the placebo group survived to hospital discharge with a favorable neurological outcome; this small % difference is statistically insignificant.

In short, this important study, which has received many plaudits for its design, and generated much discussion, provides the best evidence to date that epinephrine use increases the chance of surviving out-of-hospital cardiac arrest slightly, but doubles the risk that survival will be associated with severe neurological damage and permanent life-changing disability. 

Clearly, these results pose a tricky dilemma. If the ultimate aim of resuscitative treatment of cardiac arrest is survival with minimal or no long-term disability, then results of the study suggest that epinephrine is not indicated; it appears to be no better than placebo. On the other hand, if the ultimate aim of resuscitative treatment is simply to preserve life, without regard for the eventual quality of that life, then evidence suggests that administration of epinephrine is helpful.

A dilemma, indeed, for experts who have to incorporate the results of the trial they called for in the next revision of resuscitation guidelines; and maybe a dilemma, too, for discussion among us TV armchair “experts”?