Benefit of epinephrine in out-of-hospital cardiac arrest countered by its neurologic effects

Gavin Perkins

Data from PARAMEDIC2 (Prehospital assessment of the role of adrenaline: Measuring the effectiveness of drug administration in cardiac arrest) indicate that epinephrine in adults with an out-of-hospital cardiac arrest significantly improves the rate of 30-day survival compared with placebo. However, the drug is also associated with an increased risk of severe neurologic impairment.

Writing in the New England Journal of Medicine, Gavin D Perkins (Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK) and others report that the evidence for the use of epinephrine in patients who have experienced an out-of-hospital cardiac arrest is mixed—with trials showing no benefit compared with placebo and observational studies indicating higher rates of spontaneous circulation but worse neurological outcome. Therefore, to clarify the evidence in this area, the PARAMEDIC2 was initiated.

In the trial, 8,106 patients who could not be resuscitated with standard methods (cardiopulmonary resuscitation and defibrillation) following an out-of-hospital cardiac arrest were randomised to receive epinephrine (4,015) or placebo (3,999). The primary endpoint was rate of survival at 30 days and secondary endpoints included rate of survival until hospital admission, length of stay in hospital, and neurological outcomes at discharge and at three months.

At 30 days, significantly more patients in the epinephrine group were alive: 3.2% vs. 2.4% for the placebo group (p=0.02). This meant that the number of patients needed to be treated with epinephrine to prevent one death was 112, which the authors note is a much higher number than that seen for early recognition of cardiac arrest (11) or bystander CPR (15). Furthermore, they comment that one life saved for every 112 treated “is less than the minimal clinically important difference that has been defined in previous studies”.

There was no significant difference between in groups in the rate of patients who were discharged with a favourable neurological outcome but severe neurologic impairment—a score of 4 or 5 on the modified Rankin scale—was more common among survivors in the epinephrine group (31% vs. 17.8% for the placebo group). Perkins et al comment that the reasons why epinephrine did not seem to confer a neurological benefit are uncertain but note “one explanation is that although epinephrine increases macroscopic cerebral blood flow, it paradoxically impairs cerebral microvascular blood flow and thus has the potential to worse brain injury after a return of spontaneous circulation”. They add that another explanation for the neurological results is that the brain is “more sensitive to ischaemia and reperfusion injury and less able to functionally recover after restoration of circulation than are the heart and other organs”.

The authors comment that previous work of theirs has shown, according to patients and the general public, “survival with favourable neurological outcome to be a higher priority than survival alone”. “Patients may be less willing to accept burdensome treatments if the chances of recovery are small or the risk of survival with an impaired neurological outcome,” they add.

Perkins comments: “We have found that the benefits of adrenaline [epinephrine] are small—one extra survivor for every 112 patients treated—but the use of adrenaline almost doubles the risk of a severe brain damage amongst survivors.”


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