Editor’s Note: This article is based on Hagihara A, Manabu H, Abe T, et al., Prehospital Epinephrine Use and Survival Among Patients With Out-of-Hospital Cardiac Arrest. JAMA 2012; 307:1161-1168.¹

Summary

Epinephrine, a mainstay of advanced cardiovascular life support,⁽²⁾ is considered “standard of care” in out-of-hospital cardiac arrest (OHCA). However, data are few confirming its efficacy and the existing data, both experimental and clinical, are conflicting. This study was a prospective, nonrandomized, observational analysis of 417,188 OHCAs occurring in Japan between 2005-2008, using a national database, which sought to determine whether pre-hospital epinephrine use was associated with outcomes including return of spontaneous circulation (ROSC) prior to hospital arrival, survival at 1 month post-arrest, and survival with good or moderate cerebral performance and no, mild, or moderate neurological disability.

Methods

Entry of all OHCA cases into a national registry in Japan is performed in a prospective, nationwide, and population-based manner by the Fire and Disaster Management Agency (FDMA). In addition to extensive data collection regarding the initial arrest care, 1-month follow-up data is collected by the EMS person in charge of each patient with OHCA, who has a face-to-face meeting with the physician who treated that patient at the hospital. If the patient is not at the hospital, the EMS personnel conducts a follow-up search. Epinephrine use is implemented according to the FDMA resuscitation guidelines for emergency lifesaving technicians. Data that met the criteria concerning patient age (>18 years), time course (OHCA prior to EMS arrival), and epinephrine use were analyzed. Also, a propensity score for epinephrine use before hospital arrival was calculated for each patient. Based on propensity score, patients with OHCA who were given epinephrine were compared with unique control patients who were not given epinephrine before hospital arrival.

Results

Between January 1, 2005, and December 31, 2008, 431,968 OHCAs occurred, of which 417,188 met the inclusion criteria. Among all patients, ROSC before hospital arrival was observed in 2786 of 15,030 patients (18.5%) in the epinephrine group and 23,042 of 402,158 patients (5.7%) in the no-epinephrine group (P<.001) with similar findings in the propensity-matched analysis. Use of pre-hospital epinephrine more than doubled the odds of ROSC. In the total sample, the numbers of patients with 1-month survival and survival with good cerebral performance and good neurological outcome respectively, were 805 (5.4%), 205 (1.4%), and 211 (1.4%) with epinephrine and 18,906 (4.7%), 8903 (2.2%), and 8831 (2.2%) without epinephrine (all P<.001). Those receiving epinephrine during OHCA were less than half as likely to be surviving at one month, as well as to be surviving with good cerebral and neurological outcome. Findings were similar in the propensity-matched analysis.

Conclusion

In this large observational study using a national database in Japan, use of prehospital epinephrine was significantly associated with increased chance of return of spontaneous circulation before hospital arrival but decreased chance of survival and good functional outcomes 1 month after the event.

Perspective

Survival from OHCA remains dismally low, with fewer than 8% of arrest victims leaving the hospital, even fewer in most large cities. While some of the high mortality may be accounted for by the lethality of the underlying diseases, there is a five-times differential in survival rates across communities in the US, implying that effective medical interventions appropriately applied can influence survival.⁽³⁾ However, few interventions applied during arrest are based on large bodies of evidence, notably true for the use of epinephrine. There is just one randomized clinical trial (RCT) to date evaluating the use of epinephrine during OHCA, by Jacobs et al.⁽⁴⁾ Findings were similar to the current observational study. In that study, 601 OHCA victims treated by a single ambulance service in Western Australia were randomized to receive epinephrine 1 mg every 3 minutes after the third unsuccessful shock or after the establishment of IV access in the case of non-shockable cardiac arrest rhythms. Similar to the current study, ROSC was higher in the epinephrine group, 23% vs. 8%. Survival to hospital discharge was minimally and non-significantly higher in the epinephrine group, 4% vs. 2%. The small size of that trial left the question unanswered, and thus the current very large, although observational study, brings important information to light on the potential harms resulting from use of epinephrine in OHCA.

Data from experimental studies suggest both potential harms and potential benefits from the use of epinephrine in cardiac arrest. Hemodynamically, in animal studies, epinephrine increases coronary and cerebral perfusion through redirection of peripheral flow.⁽⁵⁾ However, deleterious effects on cerebral microcirculation have been demonstrated, as have reductions in post-arrest myocardial function after use of epinephrine.⁽⁶⁾ From the standpoint of electrical effects, experimental data are conflicting on whether epinephrine facilitates defibrillation⁽⁷⁾ or has no effect.⁽⁵⁾

This study exemplifies the power of a national registry to harness clinical information on very large numbers of patients to provide hypothesis-generating observational data. In Japan, EMS cannot terminate resuscitation in the field, so all arrests are brought to an emergency department, and all OHCA cases are entered in a database run by the national Fire and Disaster Management Agency (FDMA). Not only is extensive data entered at the time of arrest, but EMS is responsible for collecting follow-up information at one month via interviews with treating physicians and searches for discharged patients.⁽¹⁾ The comprehensive data collection, allowing for propensity-scoring analysis in well-matched groups, is an important strength of the study. The collection of data on not just survival but cerebral performance and neurological outcome as well is another strength.

Like any observational study, however, the main limitation of this study is the potential role of unmeasured variables which may confound the associations seen. While the use of epinephrine appears in the FDMA resuscitation guidelines for emergency lifesaving technicians and was incorporated in EMS protocols in Japan in 2006, in this study of over 400,000 OHCAs, only 15,000—less than 5%--received epinephrine. What factors were underlying the decision to administer epinephrine cannot be determined, and definitive data are needed to drive changes in practice. Also, while in this study and the prior RCT, improvement in ROSC did not translate into an improvement in survival, post-arrest care is advancing rapidly, with interventions such as therapeutic hypothermia and the recognition of the importance of post-resuscitation glucose control, and of post-arrest structured protocols, leading to improvements in overall survival.⁽⁸⁾ ROSC is the first step in surviving a cardiac arrest, and as post-arrest care continues to advance, the differential between ROSC and ultimate survival may narrow.

These data are invaluable, however, in creating the equipoise necessary to drive a large, definitive randomized controlled trial of the use of epinephrine in OHCA.⁽⁹⁾ There have been a number of barriers to a trial of this sort. In the Western Australian RCT, four of five planned ambulance services refused to participate as they were unwilling to withhold “standard of care” therapy, resulting in lack of adequate power, and the ethics of the trial were questioned by the press.⁽⁴⁾ Also, funding for resuscitation research has lagged. As pointed out in a recent editorial by Ornato,⁽³⁾ while twice as many Americans die from sudden death as myocardial infarction (310,000/year versus 157,000/year), between 1985 and 2009, the NIH funded more than twenty times the number of studies investigating MI than sudden cardiac arrest (6886 for MI, 257 for sudden death). The current study underscores the critical need for a large RCT of the use of epinephrine in OHCA.

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References

1. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012; 307:1161-8.
2. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, part 7.2: management of cardiac arrest. Circulation 2005; 112(suppl):IV-58-IV-66.
3. Ornato JP, Becker LB, Weisfeldt ML, Wright BA. Cardiac arrest and resuscitation: an opportunity to align research prioritization and public health need. Circulation 2010; 122:1876-9.
4. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation 2011; 82:1138-43.
5. 5. Otto CW, Yakaitis RW. The role of epinephrine in CPR: a reappraisal. Ann Emerg Med 1984; 13:840-3.
6. 6. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ. Epinephrine increases the severity of postresuscitation myocardial dysfunction. Circulation 1995; 92:3089-3093.
7. 7. Suddath WO, Deychak Y, Varghese PJ. Electrophysiologic basis by which epinephrine facilitates defibrillation after prolonged episdoes of ventricular fibrillation. Ann Emerg Med 2001; 38:201-206.
8. 8. Deakin CD, Morrison LJ, Morley PT, Callaway CW, Kerber RE, Kronick SL, Lavonas EJ, et al. Part 8: Advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2010; 81:e93-e174.
9. 9. Callaway CW. Questioning the use of epinephrine to treat cardiac arrest. JAMA 2012; 307:1198-200.

Keywords: Cardiopulmonary Resuscitation, Epinephrine, Hospitals, Out-of-Hospital Cardiac Arrest, Standard of Care

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