Perkins GD, Ji C, Deakin CD, et al.; PARAMEDIC2 Collaborators. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMoa1806842. [Epub ahead of print]
Pablo Avanzas, Consultant in Interventional Cardiology, Hospital Universitario Central de Asturias
Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients. This is a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom. Paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]).
The PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) trial was designed to determine whether epinephrine is beneficial or harmful as a treatment for out-of-hospital cardiac arrest.
Previous trials that have compared standard-dose epinephrine (1 mg) with high-dose epinephrine (5 to 10 mg), with epinephrine and vasopressin, or with placebo have not shown evidence of better outcomes. PARAMEDIC2 trial provides the largest set of randomized data on epinephrine use in out-of-hospital cardiac arrest so far.
In this trial, the use of epinephrine during resuscitation for out-of-hospital cardiac arrest resulted in a significantly higher rate of survival at 30 days than the use of placebo. Patients in the epinephrine group had a higher rate of return of spontaneous circulation, a higher frequency of transport to the hospital, and a higher rate of treatment in the ICU. However, although the rate of survival was slightly better, the trial did not show evidence of a between-group difference in the rate of survival with a favorable neurologic outcome. This result was explained by a higher proportion of patients who survived with severe neurologic disability in the epinephrine group.
The benefit of epinephrine for survival found in this trial should be considered in comparison with other treatments in the chain of survival. The number of patients who would need to be treated with epinephrine to prevent one death after cardiac arrest was 112, as compared with early recognition of cardiac arrest (number needed to treat, 11), CPR performed by a bystander (number needed to treat, 15), and early defibrillation (number needed to treat, 5).
As the editorialist points out, despite having a powerful effect on restoring spontaneous circulation after out-of-hospital cardiac arrest, epinephrine produced only a small absolute increase in survival with no increase in favorable functional recovery as compared with placebo. We now must ponder whether additional treatments after a return of spontaneous circulation could improve functional recovery, whether drug use should differ on the basis of cardiac rhythm, and whether lower doses of epinephrine would be superior to higher doses among patients with out-of-hospital cardiac arrest.