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

ACP J Club. 1993 May-June;118:76. doi:10.7326/ACPJC-1993-118-3-076

Source Citation

Brown CG, Martin DR, Pepe PE, et al., and the Multicenter High-dose Epinephrine Study Group. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med. 1992 Oct 8;327:1051-5.



To compare mortality and resuscitation outcomes with standard- and high-dose intravenous epinephrine for patients who had a cardiac arrest outside the hospital.


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


6 university hospitals.


Patients > 18 years of age who had cardiopulmonary arrest, defined as absence of both spontaneous respiration and palpable pulse, outside the hospital. Inclusion criteria were ventricular fibrillation based on electrocardiographic tracings (ECGs) despite 3 consecutive countershocks; or ECGs indicating asystole or electromechanical dissociation after either initial countershocks or cardiopulmonary resuscitation, endotracheal intubation, and the establishment of intravenous access. Exclusion criteria were pregnancy; cardiopulmonary arrest associated with trauma, hypothermia, drowning, or drug overdose; primary respiratory arrest; inability to place an endotracheal tube or intravenous line; or presence of clear signs of irreversible cardiac arrest. 1280 patients (mean age 66 y, 66% men) were studied.


All patients were treated according to American Heart Association guidelines except that the initial dose of epinephrine was 0.02 mg/kg for 632 patients and 0.2 mg/kg for 648 patients, both administered by peripheral intravenous injection using prefilled syringes marked in 10-pound increments.

Main outcome measures

Death, successful resuscitation (admission to the emergency department with spontaneous circulation), admission to the hospital, discharge from the hospital, and consciousness at discharge.

Main results

The groups did not differ for survival to discharge, return of spontaneous circulation, successful resuscitation, admission to the hospital, or consciousness at discharge among those who survived to discharge (Table). No adverse effects were associated with high-dose epinephrine. Subgroup analysis showed that, when high-dose epinephrine was given within 10 minutes of arrest, rates of survival to discharge were higher (23% vs 11%, 95% CI -28% to 3%).


No differences were found in mortality, return of spontaneous circulation, hospitalization, or consciousness at discharge between patients who were given standard- and high-dose epinephrine for out-of-hospital treatment of cardiac arrest.

Source of funding: Abbott Laboratories (syringes and epinephrine).

For article reprint: Dr. C.G. Brown, Department of Emergency Medicine, Ohio State University, 108 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA. FAX 614-293-3124.

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

Outcomes High-dose epinephrine Standard-dose epinephrine RBI (95% CI) NNT
Survival to hospital discharge 5% 4% 16% (-30 to 93) Not significant
Return of spontaneous circulation 33% 30% 11% (-5 to 31) Not significant
Successful resuscitation 23% 22% 3% (-16 to 27) Not significant
Admission to hospital 22.3% 21.5% 4% (-15 to 28) Not significant
Conscious at hospital discharge (only patients who survived to discharge [n = 57]) 92% 94% 1.3% (-18 to 20) Not significant

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


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

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


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.