Vasopressin versus Epinephrine for Cardiopulmonary Resuscitation
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《新英格兰医药杂志》
To the Editor: We congratulate Wenzel et al. (Jan. 8 issue)1 on their study of vasopressor treatment for out-of-hospital cardiac arrest. The accompanying editorial by McIntyre2 urges an immediate change to resuscitation protocols. The American Heart Association and the International Liaison Committee on Resuscitation are engaged in an evidence-based review of the literature on resuscitation, which will culminate in an international consensus conference in January 2005, followed by treatment recommendations. During this process, more than 250 resuscitation experts analyze and debate all the available data on resuscitation. Expert debate is needed in the interpretation of the post hoc subgroup analyses (e.g., analyses of subgroups based on the initial cardiac rhythm and subgroups given the study drug and additional epinephrine) and the most clinically important outcomes (overall survival and survival with a good neurologic outcome). Enthusiasm for an urgent change in resuscitation protocols based on the study reported by Wenzel et al. must be tempered by the lack of a significant difference between the groups in the rates of survival to hospital admission and survival to hospital discharge. Ten of the 20 survivors in the subgroup that received vasopressin and epinephrine were in a comatose or vegetative state or had severe cerebral disability, as compared with 1 of 5 in the epinephrine group. We urge providers to wait for, and to participate in, the international evidence-evaluation process before changing resuscitation protocols.
Jerry P. Nolan, F.R.C.A.
Royal United Hospital
Bath BA1 3NG, United Kingdom
Vinay Nadkarni, M.D.
Children's Hospital of Philadelphia
Philadelphia, PA 19104-4399
William H. Montgomery, M.D.
Straub Clinic and Hospital
Honolulu, HI 96813
References
Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350:105-113.
McIntyre KM. Vasopressin in asystolic cardiac arrest. N Engl J Med 2004;350:179-181.
To the Editor: We are surprised at the resounding editorial support provided by Dr. McIntyre regarding the study by Wenzel et al., who compared epinephrine and vasopressin for out-of-hospital cardiac arrest. McIntyre states that "these advances should be translated into a new standard of care without delay," but we believe that this endorsement is premature and ignores the negative results of the trial. The only positive result was in the subgroup of patients with asystole; 12 of these patients who received vasopressin, as compared with 4 who received epinephrine, survived to hospital discharge. The P value for this comparison is unimpressive (P=0.04), the numbers are small, and the confidence interval includes unity. Perhaps more important is the depressing cerebral performance scores in each group.
George F. Alvarez, M.D.
David Bihari, M.D.
Prince of Wales Hospital
2034 Sydney, Australia
drgeorgealvarez@hotmail.com
To the Editor: Wenzel and colleagues report that vasopressin was more effective than epinephrine in improving survival to hospital discharge among patients with out-of-hospital cardiac arrest, but only among those who presented with asystole. However, more than 50 percent of long-term survivors in the overall vasopressin group had a neurologic outcome described as severe cerebral disability or worse. Although this result is not statistically different from that among the survivors in the overall epinephrine group, the authors do not report these same figures for the subgroup of most interest — those presenting with asystole. It is likely that neurologic outcomes in this subgroup were worse than those in the overall cohort, and it is possible that any improvement in long-term survival may largely be due to an increase in the number of survivors with a poor neurologic outcome.
Before we choose vasopressin over epinephrine for asystolic cardiac arrest, the authors need to reassure us that improved survival also means improved neurologic outcomes. If we are only increasing the number of patients discharged to nursing homes and other long-term care facilities, we are not doing the public a service.
Kenneth A. Ballew, M.D.
University of Virginia
Charlottesville, VA 22908
kab3n@virginia.edu
To the Editor: I do not share McIntyre's unbridled enthusiasm for vasopressin, for several reasons. First, we are not told the total duration of resuscitation or the total dose of epinephrine used in each group — variables that could account for the differences observed, especially given the possibility of unintentional unmasking of the study drugs because of epinephrine-associated tachycardia. Second, the results of the post hoc analysis of patients given epinephrine after vasopressin should be viewed with great skepticism, as post hoc analyses in other recent trials have taught us.1,2 The only reasonable conclusion is that post hoc results need to be confirmed (or disproved) prospectively. Third, the findings of this large trial do not confirm the reported benefit of vasopressin for ventricular fibrillation in a previous, small trial, which was the basis for the inclusion of vasopressin in the most recent guidelines for advanced cardiac life support.3,4 Another study has failed to demonstrate the superiority of vasopressin.5 McIntyre's recommendation of immediate widespread use of vasopressin is unwarranted and will only discourage the necessary further study of this unproved therapy.
Scott K. Aberegg, M.D., M.P.H.
Johns Hopkins Hospital
Baltimore, MD 21205
scottaberegg@hotmail.com
References
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.
Advanced cardiovascular life support. Section 6. Pharmacology II: agents to optimize cardiac output and blood pressure. Resuscitation 2000;46:155-162.
Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 1997;349:535-537.
Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet 2001;358:105-109.
The authors reply: Despite the worldwide use, for decades, of epinephrine during cardiopulmonary resuscitation, its value with respect to meaningful survival remains unclear.1 We fully agree with Drs. Alvarez and Bihari that the most important end point of a cardiopulmonary-resuscitation attempt is survival with intact neurologic function. As might be expected, 2.2 percent of our patients were in a coma at the time of hospital discharge, but excellent and poor outcomes were similar in the two groups (Table 1). The neurologic outcomes need to be interpreted cautiously because our study was not powered to compare the effect of vasopressin with that of epinephrine on brain function after cardiopulmonary resuscitation. As in a previous study,2 vasopressin followed by epinephrine improved the rate of survival to hospital admission in patients with ventricular fibrillation, but in the present study it resulted in unfavorable neurologic outcomes in 5 of 10 patients who had asystole or pulseless electrical activity. In contrast, none of the patients with asystole or pulseless electrical activity who received 3 mg or more of epinephrine had an unfavorable neurologic outcome, because all of them died. Whether combining vasopressin and epinephrine is beneficial, especially when the medication is administered earlier than it was in our investigation, needs to be confirmed in a prospective study; one study is currently under way in France.
Table 1. Cardiopulmonary Resuscitation in Patients Treated with Vasopressin or Epinephrine Who Had Either Excellent Neurologic Recovery or Coma.
We agree with Dr. Ballew that increasing the number of surviving patients who have an unfavorable neurologic outcome is not useful. Although an unfavorable electrocardiographic finding, such as asystole, may be one important predictor of an unfavorable neurologic outcome, we must remember that the duration of ischemia reflects vital organ injury and that the necessary vasopressor dosage reflects the response to resuscitation efforts. For example, among patients who needed only one or two injections of the study drug, the hospital-discharge rate was 19.5 percent, whereas among patients who required the study drug as well as additional treatment (epinephrine), the hospital-discharge rate was only 4 percent. Since the doses of additional medication were similar in the two groups (median, 5 mg), we do not find any support for Dr. Aberegg's claim of unintentional unmasking due to epinephrine-associated tachycardia. Our study may prove to be a stepping-stone in indicating that vasopressin is a possible alternative to epinephrine in patients with asystole, and particularly in patients who do not have a response to initial treatment with epinephrine. Moreover, we identified promising subgroups, thus encouraging future prospective trials.
Volker Wenzel, M.D.
Medical University Innsbruck
6020 Innsbruck, Austria
volker.wenzel@uibk.ac.at
H. Richard Arntz, M.D.
Free University
12200 Berlin, Germany
Karl H. Lindner, M.D.
Medical University Innsbruck
6020 Innsbruck, Austria
References
Paradis NA, Wenzel V, Southall J. Pressor drugs in the treatment of cardiac arrest. Cardiol Clin 2002;20:61-78.
Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 1997;349:535-537.
The editorialist and a colleague reply: All agree that the study by Wenzel et al. has limitations. Who could expect it to be perfect when it involved 3 countries, 33 communities, and 44 physician-staffed emergency medical service units? Nevertheless, the finding that vasopressin could reestablish effective cardiovascular function in patients with asystole could be seen as the most important outcome of the study, and one that underscores the likelihood that vasopressin has a more favorable effect on the recovery of cardiac electrical and mechanical performance than does epinephrine. Of course, spontaneous circulation needs to be reestablished before brain survival can be hoped for.
The principal criticism of the data presented by Wenzel et al. is that vasopressin may result in too many poor neurologic outcomes. If the poor outcomes had been due to the use of vasopressin, it is likely that they would have been seen in vasopressin-treated patients who had ventricular fibrillation and pulseless electrical activity. That does not appear to be the case. It is more likely that vasopressin, facilitated in some patients by subsequent epinephrine, restored cardiac function after neurologic damage had already occurred. It is highly likely that an extended absence of cerebral perfusion in these patients was responsible for the poor neurologic outcomes. This can be considered neither a negative result (as Alvarez and Bihari suggest) nor a disservice to the public (as Ballew remarks), but rather a favorable cardiovascular response in patients with otherwise refractory cardiac arrest in whom, a priori, the neurologic outcome cannot be predicted.
Vasopressin is already an accepted alternative to epinephrine in some settings. The data presented by Wenzel et al. suggest that it could save lives in asystolic patients when epinephrine is ineffective, especially if the time to spontaneous cardiovascular function could be reduced. It is possible that vasopressin could save the lives of many asystolic patients around the world before the next international consensus conference on resuscitation, in January 2005. Why not recommend its use in asystolic patients now, before the conference? Why wait?
G.V.R.K. Sharma, M.D.
Kevin M. McIntyre, M.D., J.D.
Boston VA Health Care System
Boston, MA 02132
Jerry P. Nolan, F.R.C.A.
Royal United Hospital
Bath BA1 3NG, United Kingdom
Vinay Nadkarni, M.D.
Children's Hospital of Philadelphia
Philadelphia, PA 19104-4399
William H. Montgomery, M.D.
Straub Clinic and Hospital
Honolulu, HI 96813
References
Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350:105-113.
McIntyre KM. Vasopressin in asystolic cardiac arrest. N Engl J Med 2004;350:179-181.
To the Editor: We are surprised at the resounding editorial support provided by Dr. McIntyre regarding the study by Wenzel et al., who compared epinephrine and vasopressin for out-of-hospital cardiac arrest. McIntyre states that "these advances should be translated into a new standard of care without delay," but we believe that this endorsement is premature and ignores the negative results of the trial. The only positive result was in the subgroup of patients with asystole; 12 of these patients who received vasopressin, as compared with 4 who received epinephrine, survived to hospital discharge. The P value for this comparison is unimpressive (P=0.04), the numbers are small, and the confidence interval includes unity. Perhaps more important is the depressing cerebral performance scores in each group.
George F. Alvarez, M.D.
David Bihari, M.D.
Prince of Wales Hospital
2034 Sydney, Australia
drgeorgealvarez@hotmail.com
To the Editor: Wenzel and colleagues report that vasopressin was more effective than epinephrine in improving survival to hospital discharge among patients with out-of-hospital cardiac arrest, but only among those who presented with asystole. However, more than 50 percent of long-term survivors in the overall vasopressin group had a neurologic outcome described as severe cerebral disability or worse. Although this result is not statistically different from that among the survivors in the overall epinephrine group, the authors do not report these same figures for the subgroup of most interest — those presenting with asystole. It is likely that neurologic outcomes in this subgroup were worse than those in the overall cohort, and it is possible that any improvement in long-term survival may largely be due to an increase in the number of survivors with a poor neurologic outcome.
Before we choose vasopressin over epinephrine for asystolic cardiac arrest, the authors need to reassure us that improved survival also means improved neurologic outcomes. If we are only increasing the number of patients discharged to nursing homes and other long-term care facilities, we are not doing the public a service.
Kenneth A. Ballew, M.D.
University of Virginia
Charlottesville, VA 22908
kab3n@virginia.edu
To the Editor: I do not share McIntyre's unbridled enthusiasm for vasopressin, for several reasons. First, we are not told the total duration of resuscitation or the total dose of epinephrine used in each group — variables that could account for the differences observed, especially given the possibility of unintentional unmasking of the study drugs because of epinephrine-associated tachycardia. Second, the results of the post hoc analysis of patients given epinephrine after vasopressin should be viewed with great skepticism, as post hoc analyses in other recent trials have taught us.1,2 The only reasonable conclusion is that post hoc results need to be confirmed (or disproved) prospectively. Third, the findings of this large trial do not confirm the reported benefit of vasopressin for ventricular fibrillation in a previous, small trial, which was the basis for the inclusion of vasopressin in the most recent guidelines for advanced cardiac life support.3,4 Another study has failed to demonstrate the superiority of vasopressin.5 McIntyre's recommendation of immediate widespread use of vasopressin is unwarranted and will only discourage the necessary further study of this unproved therapy.
Scott K. Aberegg, M.D., M.P.H.
Johns Hopkins Hospital
Baltimore, MD 21205
scottaberegg@hotmail.com
References
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.
Advanced cardiovascular life support. Section 6. Pharmacology II: agents to optimize cardiac output and blood pressure. Resuscitation 2000;46:155-162.
Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 1997;349:535-537.
Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet 2001;358:105-109.
The authors reply: Despite the worldwide use, for decades, of epinephrine during cardiopulmonary resuscitation, its value with respect to meaningful survival remains unclear.1 We fully agree with Drs. Alvarez and Bihari that the most important end point of a cardiopulmonary-resuscitation attempt is survival with intact neurologic function. As might be expected, 2.2 percent of our patients were in a coma at the time of hospital discharge, but excellent and poor outcomes were similar in the two groups (Table 1). The neurologic outcomes need to be interpreted cautiously because our study was not powered to compare the effect of vasopressin with that of epinephrine on brain function after cardiopulmonary resuscitation. As in a previous study,2 vasopressin followed by epinephrine improved the rate of survival to hospital admission in patients with ventricular fibrillation, but in the present study it resulted in unfavorable neurologic outcomes in 5 of 10 patients who had asystole or pulseless electrical activity. In contrast, none of the patients with asystole or pulseless electrical activity who received 3 mg or more of epinephrine had an unfavorable neurologic outcome, because all of them died. Whether combining vasopressin and epinephrine is beneficial, especially when the medication is administered earlier than it was in our investigation, needs to be confirmed in a prospective study; one study is currently under way in France.
Table 1. Cardiopulmonary Resuscitation in Patients Treated with Vasopressin or Epinephrine Who Had Either Excellent Neurologic Recovery or Coma.
We agree with Dr. Ballew that increasing the number of surviving patients who have an unfavorable neurologic outcome is not useful. Although an unfavorable electrocardiographic finding, such as asystole, may be one important predictor of an unfavorable neurologic outcome, we must remember that the duration of ischemia reflects vital organ injury and that the necessary vasopressor dosage reflects the response to resuscitation efforts. For example, among patients who needed only one or two injections of the study drug, the hospital-discharge rate was 19.5 percent, whereas among patients who required the study drug as well as additional treatment (epinephrine), the hospital-discharge rate was only 4 percent. Since the doses of additional medication were similar in the two groups (median, 5 mg), we do not find any support for Dr. Aberegg's claim of unintentional unmasking due to epinephrine-associated tachycardia. Our study may prove to be a stepping-stone in indicating that vasopressin is a possible alternative to epinephrine in patients with asystole, and particularly in patients who do not have a response to initial treatment with epinephrine. Moreover, we identified promising subgroups, thus encouraging future prospective trials.
Volker Wenzel, M.D.
Medical University Innsbruck
6020 Innsbruck, Austria
volker.wenzel@uibk.ac.at
H. Richard Arntz, M.D.
Free University
12200 Berlin, Germany
Karl H. Lindner, M.D.
Medical University Innsbruck
6020 Innsbruck, Austria
References
Paradis NA, Wenzel V, Southall J. Pressor drugs in the treatment of cardiac arrest. Cardiol Clin 2002;20:61-78.
Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 1997;349:535-537.
The editorialist and a colleague reply: All agree that the study by Wenzel et al. has limitations. Who could expect it to be perfect when it involved 3 countries, 33 communities, and 44 physician-staffed emergency medical service units? Nevertheless, the finding that vasopressin could reestablish effective cardiovascular function in patients with asystole could be seen as the most important outcome of the study, and one that underscores the likelihood that vasopressin has a more favorable effect on the recovery of cardiac electrical and mechanical performance than does epinephrine. Of course, spontaneous circulation needs to be reestablished before brain survival can be hoped for.
The principal criticism of the data presented by Wenzel et al. is that vasopressin may result in too many poor neurologic outcomes. If the poor outcomes had been due to the use of vasopressin, it is likely that they would have been seen in vasopressin-treated patients who had ventricular fibrillation and pulseless electrical activity. That does not appear to be the case. It is more likely that vasopressin, facilitated in some patients by subsequent epinephrine, restored cardiac function after neurologic damage had already occurred. It is highly likely that an extended absence of cerebral perfusion in these patients was responsible for the poor neurologic outcomes. This can be considered neither a negative result (as Alvarez and Bihari suggest) nor a disservice to the public (as Ballew remarks), but rather a favorable cardiovascular response in patients with otherwise refractory cardiac arrest in whom, a priori, the neurologic outcome cannot be predicted.
Vasopressin is already an accepted alternative to epinephrine in some settings. The data presented by Wenzel et al. suggest that it could save lives in asystolic patients when epinephrine is ineffective, especially if the time to spontaneous cardiovascular function could be reduced. It is possible that vasopressin could save the lives of many asystolic patients around the world before the next international consensus conference on resuscitation, in January 2005. Why not recommend its use in asystolic patients now, before the conference? Why wait?
G.V.R.K. Sharma, M.D.
Kevin M. McIntyre, M.D., J.D.
Boston VA Health Care System
Boston, MA 02132