Correspondence

Epinephrine for Out-of-Hospital Cardiac Arrest

N Engl J Med 1999; 340:1763-1765June 3, 1999

Article

To the Editor:

The low success rate of out-of-hospital resuscitation fuels many studies. The excellent study by Gueugniaud et al. (Nov. 26 issue)1 compares the effectiveness of high-dose epinephrine with that of standard-dose epinephrine for out-of-hospital cardiac arrest in a large number of patients. Although high-dose epinephrine resulted more frequently in restoration of spontaneous circulation and admission to the hospital, overall survival (indicated by discharge from hospital) was very low (2.5 percent) and not different between the two groups. Overall, the neurologic outcome of patients surviving to hospital discharge was good but not different between the two groups.

Similar results were reported in studies in the United States and Canada.2,3 Although the rate of bystander cardiopulmonary resuscitation in the current study was much lower than those in the U.S. and Canadian studies (approximately 10 percent vs. 25 to 30 percent), survival rates were similar. In the previous studies, patients with circulatory arrest not related to trauma, hypothermia, drowning, drug overdose, or primary respiratory arrest were included if attempted conversion to a cardiac rhythm providing adequate perfusion failed after two or three countershocks or if they were found to have asystole or nonperfusion. In all these studies, the presence or occurrence of asystole during resuscitation resulted in very poor survival (1 to 2 percent). Advanced resuscitation by means of cardiac pacing in patients with out-of-hospital asystole also has not been shown to improve survival and has resulted in survival rates similar to those in the above-mentioned studies.4 Combining the results of these four studies reveals that in more than 5000 patients, in- or out-of-hospital advanced resuscitation was effective in approximately 3 percent of patients if two or three countershocks did not restore perfusion rhythm or if asystole or nonperfusion was present (Table 1Table 1Survival after Epinephrine for Out-of-Hospital Cardiac Arrest in Patients with or without Syncope.).

It is a good principle when treatment schedules do not result in acceptable outcomes to question these treatment schedules and to study other alternatives. However, from the above-mentioned studies and others, we can conclude that high-dose epinephrine probably does not influence ultimate survival after out-of-hospital cardiac arrest. Furthermore, it can be concluded that failure to restore perfusion rhythm after two or three countershocks in patients with ventricular fibrillation or the occurrence of asystole during out-of-hospital cardiac resuscitation is associated with a very poor prognosis, regardless of the particular treatment approach. Although we should be driven by a desire to give patients the best possible chance of survival, we should also realize that pursuing this objective could inflict harm on patients and their families.

Jan Bakker, M.D., Ph.D.
Hans Rommes, M.D., Ph.D.
Ziekenhuiscentrum Apeldoorn Lukas Hospital, 7300 DS Apeldoorn, the Netherlands

4 References

1. 1

   Gueugniaud P-Y, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med 1998;339:1595-1601
   Full Text | Web of Science | Medline

2. 2

   Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med 1992;327:1051-1055
   Full Text | Web of Science | Medline

3. 3

   Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med 1992;327:1045-1050
   Full Text | Web of Science | Medline

4. 4

   Cummins RO, Graves JR, Larsen MP, et al. Out-of-hospital transcutaneous pacing by emergency medical technicians in patients with asystolic cardiac arrest. N Engl J Med 1993;328:1377-1382
   Full Text | Web of Science | Medline

To the Editor:

The recent report by Gueugniaud et al. raises two major issues of concern and therefore does not eliminate the controversy surrounding the dose of epinephrine used for out-of-hospital cardiac arrest. First, high doses of epinephrine cannot be advocated for the management of prolonged out-of-hospital cardiac arrest solely on the basis of higher rate of return of spontaneous circulation; one must also take into account the ethical and economic aspects of resuscitating patients who have a considerable risk of irreversible multiorgan failure, including brain damage. Indeed, in this study fewer patients in the high-dose group than in the low-dose group were eventually discharged from the hospital.

Second, since “all” the patients were treated according to standard American Heart Association and European Resuscitation Council guidelines, except for the epinephrine injections, it is unclear how the patients were assigned to standard cardiopulmonary resuscitation or nonstandard, active compression–decompression cardiopulmonary resuscitation. Subgroups defined by a characteristic measured after randomization can lack comparability in another characteristic, such as the proportion of patients whose initial cardiac rhythm was ventricular fibrillation. Therefore, the absence of differences between the subgroups may not be a true effect of treatment but rather the result of differences in the base-line characteristics of the patients that led to an odd response or to the development of side effects.1

Finally, it is noteworthy that the results of this study are in accordance with other studies.2,3

Patrick R. Martens, M.D.
Akademisch Ziekenhuis Sint Jan Hospital, 8000 Brugge, Belgium

3 References

1. 1

   Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-98
   CrossRef | Web of Science | Medline

2. 2

   Martens PR, Mullie A. The availability of 10 mg epinephrine vialsfor cardiac arrest: a retrospective analysis. Resuscitation 1991;22:219-228
   CrossRef | Web of Science | Medline

3. 3

   Behringer W, Kittler H, Sterz F, et al. Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med 1998;129:450-456
   Web of Science | Medline

Author/Editor Response

The authors and a colleague reply:

To the Editor: Bakker and Rommes question the wisdom of providing advanced cardiac life support to patients who have cardiac arrest outside the hospital because of the poor prognosis, especially in patients with asystole. We agree that the poor results raise important economic and ethical issues, but we do not think that this problem is easy to solve, for several reasons. First, in our study, excluding patients with asystole from advanced cardiac life support would have resulted in the death of 37 percent of all the patients who were discharged alive from the hospital. Second, since most patients with irreversible brain damage die within 24 hours, the economic cost is limited. Third, some of these brain-dead patients can be organ donors, an argument that must be strongly considered before concluding that advanced cardiac life support is futile, even in patients with asystole.

We agree with Dr. Martens that our study did not definitely prove that high-dose epinephrine must be used for prehospital cardiac arrest, only because a higher rate of return of spontaneous circulation was observed. In contrast, our study suggests that a low dose is better when ventricular fibrillation is present and that a high dose is better when the rhythm is asystole. Although we included 3327 patients, the size of our study was too small for us to be able to detect an effect on discharge from the hospital. Indeed, more than 42,500 patients would have been required to demonstrate a significant difference in the number of patients discharged from the hospital (with an alpha of 0.05 and a beta of 0.01).1 The size of such a study would far exceed that of all previously performed studies of cardiac arrest. Therefore, until such a large study can be performed, we suggest that our results regarding the return of spontaneous circulation (an intermediate end point) should be considered in most recommendations about the use of epinephrine in cardiac arrest (e.g., the guidelines of the American Heart Association and the European Resuscitation Council).

The randomization was clearly described in the Methods section. This was a double-blind randomized study, and there was no possibility that the emergency physician could recognize the treatment assigned to the patient. We indicated that only some centers used active compression–decompression cardiopulmonary resuscitation (but used it for all the patients treated in those centers). Therefore, we do not think that any bias could have affected the results. Of course, because the use of active compression–decompression was not randomly assigned, we must analyze with caution the results shown in Table 6. Nevertheless, it should be emphasized that our finding agrees with the results of a randomized study by Plaisance et al.,2 indicating that survival was increased with the use of active compression–decompression cardiopulmonary resuscitation.

Pierre-Yves Gueugniaud, M.D., Ph.D.
Hôpital Edouard Herriot, 69437 Lyons CEDEX 03, France

Pierre Mols, M.D., Ph.D.
Centre Hospitalier Universitaire Saint-Pierre, 1000 Brussels, Belgium

Jean-Charles Pannetier, M.D.
Hôpital Edouard Herriot, 69437 Lyons CEDEX 03, France

2 References

1. 1

   Casagrande JT, Pike MC. An improved approximate formula for calculating sample sizes for comparing two binomial distributions. Biometrics 1978;34:483-486
   CrossRef | Web of Science | Medline

2. 2

   Plaisance P, Adnet F, Vicaut E, et al. Benefit of active compression-decompression cardiopulmonary resuscitation as a prehospital advanced cardiac life support: a randomized multicenter study. Circulation 1997;95:955-961
   Web of Science | Medline

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