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Therapeutics

High-dose epinephrine was no better than standard-dose epinephrine for improving survival after cardiac arrest

ACP J Club. 1993 May-June;118:77. doi:10.7326/ACPJC-1993-118-3-077


Source Citation

Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med. 1992 Oct 8;327:1045-50.


Abstract

Objective

To compare survival for patients with cardiac arrest who are treated with standard- and high-dose epinephrine.

Design

Randomized, double-blind, controlled trial with follow-up to hospital discharge.

Setting

2 university hospitals in Canada.

Patients

All in-hospital and out-of-hospital patients ≥ 16 years of age who had a cardiac arrest and required epinephrine. Exclusion criteria were terminal illness, no cardiopulmonary resuscitation for > 15 minutes, acute trauma, second cardiac arrest during that hospital stay, or cardiac arrest in the operating or recovery room. 650 patients (mean age 66 y, 64% men) were studied with 100% follow-up.

Intervention

All patients were treated according to American Heart Association protocols for advanced cardiac life support except for the epinephrine dosage. 333 patients received standard-dose epinephrine (1 mg), and 317 patients received high-dose epinephrine (7 mg), at 5-minute intervals to a maximum of 5 doses. All additional doses of epinephrine were 1 mg.

Main outcome measures

Successful resuscitation (return of pulse and blood pressure for at least 1 hour), survival to hospital discharge, and neurologic assessment (cerebral performance and modified Mini-Mental State scores). All assessors were blinded to epinephrine dose. Data were collected from chart audits, neurologic assessment, and forms completed by the physician responsible for the resuscitation.

Main results

33 randomized patients were subsequently declared ineligible: Their exclusion or inclusion did not alter results. 52% of the arrests occurred outside the hospital. The mean number of administrations of epinephrine was 2.5. The mean dosages in the standard-dose and high-dose group were 2.5 mg and 17.5 mg, respectively. The standard-dose and high-dose groups did not differ for survival for at least 1 hour (P = 0.12) (Table), survival to hospital discharge (P = 0.38) (Table), neurologic status, or median Mini-Mental State scores. Subgroup analysis failed to show any clinically important benefit from high-dose epinephrine therapy. The subgroup of patients who received high-dose epinephrine > 10 minutes after onset of arrest had a poorer resuscitation rate (11% vs 24%, P = 0.004).

Conclusion

High-dose epinephrine compared with standard-dose epinephrine did not improve survival or neurologic status in patients with cardiac arrest.

Source of funding: Ontario Ministry of Health.

For article reprint: Dr. I.G. Stiell, Clinical Epidemiology Unit, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada. FAX 613-761-9688.


Table. High-dose vs standard-dose epinephrine for cardiac arrest*

Outcomes High-dose epinephrine Standard-dose epinephrine RBR (95% CI) NNH
Survival to 1 h 18% 23% 23% (-5 to 43) Not significant
Survival to hospital discharge 3% 5% 34% (-40 to 69) Not significant

*Abbreviations defined in Glossary; RBR, NNH, and CI calculated from data in article.


Commentary

High-dose and standard-dose epinephrine did not differ in improving outcomes after cardiac arrest outside the hospital

One of the greatest challenges for physicians is to rescue a person from a potentially reversible state of cardiopulmonary arrest. The modern era of cardiopulmonary resuscitation (CPR) evolved from human studies in the 1950s and 1960s. Many highly touted improvements in our resuscitative techniques have appeared in the literature over the past 30 years. They were met with enthusiasm but have failed to improve survival.

The approach of the 2 studies by Brown and Stiell and their colleagues was established in animal models in which high-dose epinephrine apparently improved efficacy. Animal studies, however, are difficult to extrapolate directly to humans because animals have different chest conformities; they have changing CPR mechanics; normal animal heart, lung, and neural axes are involved; and the arrest occurs in a very controlled environment that is optimized for resuscitation.

Recent reports have focused on the dose of epinephrine used for restoration of spontaneous circulation during advanced cardiac life support. Although the standard dose of 1 mg has been used in animal experimentation, the analogous human dose per kilogram would be much higher. This fact has spurred great interest in evaluating the dose response to epinephrine for restoration of cardiocerebral perfusion and improvement of neurologic outcome.

Before proper testing, excitement about higher doses of epinephrine led to their use by clinicians, generating several small case reports and uncontrolled series reporting the benefit. The possibility of improved outcome has even led to a recommendation in the 1992 Adult Advanced Cardiac Life Support Guidelines that high-dose epinephrine is "acceptable" after standard therapy has failed, although its use is "neither recommended nor discouraged" (1).

The studies by Brown and Stiell and their colleagues, although slightly different in their methodologic design, have attempted to answer the question of efficacy of high-dose epinephrine in acute restoration of cardiac stability and long-term neurologic outcome. Although many physicians have hoped for a "magic bullet" from these studies, both have shown clearly that increasing the epinephrine dose to either 0.1 mg/kg or 0.2 mg/kg does not contribute to enhanced resuscitation or improved outcome. In fact, the studies have reconfirmed that survival to hospital discharge is still an extremely poor 3% to 5%.

Interestingly, almost all patients discharged from the hospital had extremely good neurologic function. These studies were not designed, however, to evaluate care after resuscitation. It is possible that patients with poor neurologic function had limitation of life support and were allowed to die rather than to survive with extreme neurologic impairment.

Brown and colleagues retrospectively evaluated a subgroup of patients who may have benefited from high-dose epinephrine. Patients with 10 minutes of arrest who received high-dose epinephrine showed a markedly improved rate of hospital discharge—23% compared with 11% for standard therapy. Brown and coworkers were optimistic about these observations but cautioned that this benefit would need to be verified with appropriate prospective clinical trials. The study by Stiell and associates could not confirm these findings.

The results of these 2 large trials do not support the use of high-dose epinephrine for restoration of spontaneous circulation during cardiopulmonary resuscitation.

Harvey S. Reich, MD
Magee-Women's HospitalPittsburgh, Pennsylvania, USA


Reference

1. Emergency Cardiac Care Committee and Subcommittee, American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Part III—Adult advanced cardiac life support. JAMA. 1992;268: 2199-241.