ARTICLE IN BRIEF
A new report found the administration of epinephrine resulted in a significantly higher rate of survival at 30 days in people who had a cardiac arrest, but their neurological outcomes were not favorable.
The American Heart Association and the European Resuscitation Council guidelines have recommended treatment with epinephrine for successful post-cardiac arrest resuscitation for decades. But a new double-blind study has raised questions about the drug's use in restarting the heart and preserving brain function.
The study, Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest, is the first randomized controlled trial designed to measure the long-term safety and effectiveness of epinephrine as a treatment for out-of-hospital cardiac arrest patients.
It also poses several questions about the timing of the drug's administration and which patients will tend to see more risk/benefit from epinephrine.
Published online on July 18 in the New England Journal of Medicine, the report found the administration of epinephrine 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,” the study authors wrote. 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.
Lead study author, Gavin Perkins, MD, professor of critical care medicine in Warwick Medical School at the University of Warwick in the United Kingdom, told Neurology Today the study should encourage clinicians to focus on treatments that are known to be effective, such as high quality, uninterrupted cardiopulmonary resuscitation (CPR) and early defibrillation.
“Adrenaline may restart the heart but it does not improve survival with a favorable neurological outcome,” he said. “Our advice to clinicians is to follow your national clinical practice guidelines while the implications of our study findings are considered by the International Liaison Committee on Resuscitation and others. The last thing that should happen is for people to interrupt high quality CPR by debating about whether to give adrenaline or not.”
STUDY DESIGN, FINDINGS
For the study, paramedics at five National Health Service ambulance services in the UK administered either 1 mg parenteral epinephrine to 4,015 patients or 0.9 percent saline solution as placebo in 3,999 patients, every three to five minutes with an average of 21 minutes from the emergency call to first drug use, 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 three or less on the modified Rankin scale. The scale ranges from 0 (no symptoms) to six (death).
Patients continued to receive treatment until they achieved a sustained pulse, resuscitation was discontinued, or if care was handed over to clinicians in the hospital. National guidelines were used as the protocol for hospital-based care, which covered targeted temperature management, hemodynamic and ventilatory criteria, and prognostication.
Research paramedics, who were blinded to patients' treatment assignments, assessed outcomes. Study authors recorded serious adverse events, including death, hospitalization, and disability, as trial outcomes. All other adverse events were reported directly to the trial office.
At 30 days, 130 patients (3.2 percent) in the epinephrine intervention group were alive compared with 94 patients (2.4 percent) in the placebo group (p=0.02), for a 39 percent better odds of survival, the researchers reported. Specifically, patients with nonshockable rhythms (adjusted OR 2.15, 95% CI 1.13 to 4.09) experienced better survival with epinephrine, while those with shockable rhythms (adjusted OR 1.33, 95% CI 0.95 to 1.86) showed some benefit. However, there was no significant effect modification by initial rhythm.
The researchers determined that the number of patients who would need to be treated with epinephrine to prevent one death at 30 days was 112.
There were no significant differences in the proportion of patients who survived until hospital discharge with a favorable outcome however. The study authors attributed this to a higher number of patients with severe neurological impairment (a score of four or five on the modified Rankin scale) in the epinephrine-treated group (31 percent versus 17.8 percent, respectively). The findings regarding survival at three months and neurological outcomes at three months were similar.
One of the study limitations was that they tested intermittent 1 mg boluses of epinephrine while other strategies, such as using different doses or dosing intervals, may have produced different results, the researchers noted.
“Alternative strategies might include lower dose, less frequent administration, continuous infusions, or doses titrated against invasively measured blood pressure/end-organ perfusion,” said Dr. Perkins.
The trial was funded by the National Institute for Health Research Health Technology Assessment Programme.
Carolina Maciel, MD, an assistant professor of neurocritical care and vascular neurology in the department of neurology at McKnight Brain Institute of the University of Florida in Gainesville, said the study does not change anything for neurologists. But she said it should open up discussion about current neuroprognostication practices. Neurologists should take this opportunity to think about how they can tailor neuroprognostic assessments and discussions with families and incorporate the values of individuals.
Clinicians should shift their focus to individualize prognosis for neurologic outcomes after cardiac arrest, she said. “Clinicians should ask: What is the individual preference of meaningful recovery. What is an acceptable outcome for them? For some, regaining consciousness, even if you're unable to walk independently, is still an alternative to death. You can achieve a meaningful quality of life despite having a deficit, a greater quality of life than surrogates originally thought.
“It would have been interesting if researchers continued to follow up with those who regained consciousness at six months and at 12 months,” said Dr. Maciel, “to see if they would still have given consent to receive epinephrine.”
Despite a higher survival rate associated with epinephrine in this study, Dr. Maciel said she remains concerned about the drug as a “detrimental vasoconstrictor” to the brain.
Epinephrine makes the arteries tighter and it's nonselective, Dr. Maciel said, which means it can also affect cerebral circulation. “You don't really want to have vasoconstriction in the cerebral circulation at this time when there's such a low perfusion. You actually want vasodilation,” she said.
David M. Greer, MD, MA, FAAN, chair of the department of neurology at Boston University School of Medicine and chief of neurology at Boston Medical Center, shared Dr. Maciel's concern about epinephrine's effects on the brain. “It's a very potent vasoconstrictor,” he told Neurology Today.
Commenting on the severe neurological outcomes associated with epinephrine in the study, Dr. Greer hypothesized that a decrease in cerebral perfusion could have occurred due to vasoconstriction from epinephrine. “Vasoconstriction helps with the coronary perfusion, but it could also be bad at the brain — epinephrine may cause cerebral hypoperfusion,” he said.
Due to epinephrine's unknown effects to the brain, Dr. Maciel suggested a potential shift to interventions that are not only focused on restarting the heart, but also protecting the brain, such as elevating the head during CPR.
Standardized CPR requires the patient to be in a head-down position to maximize blood flow. Focusing on interventions that can maximize brain perfusion while restarting the heart in cardiac arrest, like head-up CPR, could potentially improve neurological outcomes, said Dr. Maciel.
Dr. Perkins disclosed receiving honorarium and travel-related expenses from GSK.