Vasopressin in Asystolic Cardiac Arrest
http://www.100md.com
《新英格兰医药杂志》
Cardiac arrest remains a major health problem in the United States and other Western nations. Of the approximately 1000 sudden deaths that occur each day in the United States, it is estimated that as many as 20 to 40 percent result from asystolic cardiac arrest.1,2,3 In this issue of the Journal, Wenzel et al.4 demonstrate the success of vasopressin alone and vasopressin followed by epinephrine in refractory asystolic cardiac arrest — an important breakthrough in the science of resuscitation. These advances should be translated into a new standard of care without delay. Medical policymakers should do whatever is necessary to facilitate the orderly implementation of new guidelines based on this new information.
The most common and most treatable rhythm found in patients with cardiac arrest is ventricular fibrillation; in contrast, asystole has been the most refractory to resuscitation attempts. Precise figures for the incidence of the various rhythms associated with cardiac arrest are not available, since the incidence may vary in different study populations. It is likely that ventricular fibrillation is the cause of 60 to 80 percent of cardiac arrests, and asystole the cause of 20 to 40 percent.1,2 In at least one series, asystole was reported as the cause of cardiac arrest in more than 40 percent of cases, and its prevalence has been increasing since 1980.3,5 Pulseless electrical activity may be found in up to 10 percent of patients with cardiac arrest.
A number of theories have been proposed to explain the apparent refractoriness of asystole to resuscitation attempts, including impairment of the automaticity of the sinus node, the malfunction of related conduction pathways secondary to ischemia, the failure of neurogenic innervation of the heart, and the failure of reflex sympathetic performance, among other factors. Although one or another of these mechanisms may or may not be in play in asystole, it is clear that progressive ischemia and acidosis are always present. Epinephrine has been used routinely as the vasoactive drug of choice in asystolic cardiac arrest because of its potency as a vasopressor and because successful resuscitation has been shown to depend on coronary perfusion pressure during resuscitation.6 However, epinephrine and other catecholamines lose much of their effectiveness as vasopressors in a hypoxic, acidotic milieu, and this fact, in addition to the notable rate of failure of epinephrine therapy, has stimulated efforts to identify an effective alternative to epinephrine for use in cardiac arrest.7
In the early 1990s, endogenous vasopressin levels were found to be higher in survivors of cardiac arrest than in patients who died, suggesting that vasopressin could be beneficial in cardiac arrest.8 Subsequent laboratory and clinical studies of the effects of vasopressin in cardiac arrest showed, as Wenzel et al. note, that this agent increased blood flow and oxygen delivery to the heart and the brain, increased the chances of successful resuscitation, and improved neurologic outcomes. In the light of these promising observations, Wenzel et al. undertook a large, multicenter trial to evaluate the effects of vasopressin and epinephrine on survival after out-of-hospital cardiac arrest in adults with ventricular fibrillation, pulseless electrical activity, or asystole.
The study was conducted in 33 communities with 44 physician-staffed emergency medical service units in Austria, Germany, and Switzerland. Patients were randomly assigned to receive either vasopressin (589 patients) or epinephrine (597 patients); they were given the first dose intravenously, and if spontaneous circulation was not reestablished within three minutes after the first dose, a second dose of the same drug at the same dose was injected. If spontaneous circulation was not reestablished even then, doses of epinephrine could be administered to patients in either treatment group at the discretion of the physician.
Surprisingly, among patients with asystole, the rates of restoration of spontaneous circulation and survival to hospital admission were significantly higher after vasopressin therapy than after epinephrine therapy (76 of 262 patients, or 29.0 percent, survived, vs. 54 of 266 patients, or 20.3 percent; P=0.02), and the rate of survival to hospital discharge was significantly higher as well (12 of 257 patients, or 4.7 percent, vs. 4 of 262 patients, or 1.5 percent; P=0.04). This rate of survival after asystolic cardiac arrest may be among the highest yet reported in a major resuscitation trial. It is also notable, although the numbers are small, that the rate of survival to hospital discharge was three times as high in the vasopressin group as in the epinephrine group.
Another unexpected result emerged among patients in whom spontaneous circulation could not be restored by the first two doses of either vasopressin or epinephrine. It had been agreed that additional doses of epinephrine could be given at the discretion of the managing physician if spontaneous circulation was not restored by the study drug. There were 732 patients in this category (62 percent of the 1186 study patients), and they were fairly evenly divided between the vasopressin group (373 patients) and the epinephrine group (359 patients). The rates of restoration of spontaneous circulation and survival to hospital admission after additional therapy with epinephrine were significantly higher among patients who were initially treated with vasopressin than among those who were initially treated with epinephrine (96 of 373 patients, or 25.7 percent, survived, vs. 59 of 359 patients, or 16.4 percent; P=0.002), as was the rate of survival to hospital discharge (23 of 369 patients, or 6.2 percent, vs. 6 of 355 patients, or 1.7 percent; P=0.002). This is a remarkable outcome, given that patients in this subgroup could have been deemed to be beyond hope of resuscitation and further resuscitative efforts could have been abandoned at the discretion of the physician.
Epinephrine consumes oxygen, whereas vasopressin increases coronary blood flow and the availability of oxygen to the myocardium.9,10 These dynamics may contribute to the success of vasopressin therapy in asystolic cardiac arrest and the lack of success of epinephrine therapy. Oxygen consumption in ventricular fibrillation may be further accelerated by the increased endogenous catecholamine levels that are characteristically present after cardiac arrest. Additional exogenous epinephrine could be expected to exacerbate hypoxemia and advancing acidosis, both of which would be expected to further impair the vasopressor effects of epinephrine as well. Thus, epinephrine might be not only ineffectual, but also potentially detrimental in early asystolic cardiac arrest, whereas vasopressin appears to be beneficial.
Usually, major changes in the guidelines for resuscitation are adopted at international conferences of experts on cardiopulmonary resuscitation and emergency cardiac care, but such conferences are generally held only at intervals of four to five years. Because of the size and power of the study by Wenzel et al., the dismal rate of resuscitation among patients with asystolic cardiac arrest, and the apparent absence of any added risk of injury to patients who may be treated according to the new therapeutic sequences, practitioners should perhaps be encouraged to incorporate the use of vasopressin into their resuscitation protocols immediately. The best approach to optimizing survival as soon as possible would be to have the appropriate committees of the American Heart Association and the American College of Cardiology convene in order to issue an interim guideline incorporating these important new therapeutic advances.
Source Information
From the Departments of Medicine and Research, Brigham and Women's Hospital, Veterans Affairs Boston Health Care System, and Harvard Medical School — all in Boston.
References
Chambless L, Keil U, Dobson A, et al. Population versus clinical view of case fatality from acute coronary heart disease: results from the WHO MONICA Project 1985-1990. Circulation 1997;96:3849-3859.
Bayes de Luna A, Coumel P, Leclerq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989;117:151-159.
Cobb LA, Fahrenbruch CE, Olsufka M, Copass MK. Changing incidence of out-of-hospital ventricular fibrillation, 1980-2000. JAMA 2002;288:3008-3013.
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.
Iseri LT, Siner EJ, Humphrey SB, Mann S. Prehospital cardiac arrest after arrival of the paramedic unit. JACEP 1977;6:530-535.
Paradis NA, Martin GB, Rivers EP, et al. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106-1113.
Fox AW, May RE, Mitch WE. Comparison of peptide and nonpeptide receptor-mediated responses in rat tail artery. J Cardiovasc Pharmacol 1992;20:282-289.
Lindner KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW, Geogieff M. Stress hormone response during and after cardiopulmonary resuscitation. Anesthesiology 1992;77:662-668.
Paradis NA, Wenzel V, Southall J. Pressor drugs in the treatment of cardiac arrest. Cardiol Clin 2002;20:61-78.
Mayr VD, Wenzel V, Voelckel WG, et al. Developing a vasopressor combination in a pig model of adult asphyxial cardiac arrest. Circulation 2001;104:1651-1656.
Related Letters:
Vasopressin versus Epinephrine for Cardiopulmonary Resuscitation
Nolan J. P., Nadkarni V., Montgomery W. H., Alvarez G. F., Bihari D., Ballew K. A., Aberegg S. K., Wenzel V., Arntz H. R., Lindner K. H., Sharma G.V.R.K., McIntyre K. M.(Kevin M. McIntyre, M.D., )
The most common and most treatable rhythm found in patients with cardiac arrest is ventricular fibrillation; in contrast, asystole has been the most refractory to resuscitation attempts. Precise figures for the incidence of the various rhythms associated with cardiac arrest are not available, since the incidence may vary in different study populations. It is likely that ventricular fibrillation is the cause of 60 to 80 percent of cardiac arrests, and asystole the cause of 20 to 40 percent.1,2 In at least one series, asystole was reported as the cause of cardiac arrest in more than 40 percent of cases, and its prevalence has been increasing since 1980.3,5 Pulseless electrical activity may be found in up to 10 percent of patients with cardiac arrest.
A number of theories have been proposed to explain the apparent refractoriness of asystole to resuscitation attempts, including impairment of the automaticity of the sinus node, the malfunction of related conduction pathways secondary to ischemia, the failure of neurogenic innervation of the heart, and the failure of reflex sympathetic performance, among other factors. Although one or another of these mechanisms may or may not be in play in asystole, it is clear that progressive ischemia and acidosis are always present. Epinephrine has been used routinely as the vasoactive drug of choice in asystolic cardiac arrest because of its potency as a vasopressor and because successful resuscitation has been shown to depend on coronary perfusion pressure during resuscitation.6 However, epinephrine and other catecholamines lose much of their effectiveness as vasopressors in a hypoxic, acidotic milieu, and this fact, in addition to the notable rate of failure of epinephrine therapy, has stimulated efforts to identify an effective alternative to epinephrine for use in cardiac arrest.7
In the early 1990s, endogenous vasopressin levels were found to be higher in survivors of cardiac arrest than in patients who died, suggesting that vasopressin could be beneficial in cardiac arrest.8 Subsequent laboratory and clinical studies of the effects of vasopressin in cardiac arrest showed, as Wenzel et al. note, that this agent increased blood flow and oxygen delivery to the heart and the brain, increased the chances of successful resuscitation, and improved neurologic outcomes. In the light of these promising observations, Wenzel et al. undertook a large, multicenter trial to evaluate the effects of vasopressin and epinephrine on survival after out-of-hospital cardiac arrest in adults with ventricular fibrillation, pulseless electrical activity, or asystole.
The study was conducted in 33 communities with 44 physician-staffed emergency medical service units in Austria, Germany, and Switzerland. Patients were randomly assigned to receive either vasopressin (589 patients) or epinephrine (597 patients); they were given the first dose intravenously, and if spontaneous circulation was not reestablished within three minutes after the first dose, a second dose of the same drug at the same dose was injected. If spontaneous circulation was not reestablished even then, doses of epinephrine could be administered to patients in either treatment group at the discretion of the physician.
Surprisingly, among patients with asystole, the rates of restoration of spontaneous circulation and survival to hospital admission were significantly higher after vasopressin therapy than after epinephrine therapy (76 of 262 patients, or 29.0 percent, survived, vs. 54 of 266 patients, or 20.3 percent; P=0.02), and the rate of survival to hospital discharge was significantly higher as well (12 of 257 patients, or 4.7 percent, vs. 4 of 262 patients, or 1.5 percent; P=0.04). This rate of survival after asystolic cardiac arrest may be among the highest yet reported in a major resuscitation trial. It is also notable, although the numbers are small, that the rate of survival to hospital discharge was three times as high in the vasopressin group as in the epinephrine group.
Another unexpected result emerged among patients in whom spontaneous circulation could not be restored by the first two doses of either vasopressin or epinephrine. It had been agreed that additional doses of epinephrine could be given at the discretion of the managing physician if spontaneous circulation was not restored by the study drug. There were 732 patients in this category (62 percent of the 1186 study patients), and they were fairly evenly divided between the vasopressin group (373 patients) and the epinephrine group (359 patients). The rates of restoration of spontaneous circulation and survival to hospital admission after additional therapy with epinephrine were significantly higher among patients who were initially treated with vasopressin than among those who were initially treated with epinephrine (96 of 373 patients, or 25.7 percent, survived, vs. 59 of 359 patients, or 16.4 percent; P=0.002), as was the rate of survival to hospital discharge (23 of 369 patients, or 6.2 percent, vs. 6 of 355 patients, or 1.7 percent; P=0.002). This is a remarkable outcome, given that patients in this subgroup could have been deemed to be beyond hope of resuscitation and further resuscitative efforts could have been abandoned at the discretion of the physician.
Epinephrine consumes oxygen, whereas vasopressin increases coronary blood flow and the availability of oxygen to the myocardium.9,10 These dynamics may contribute to the success of vasopressin therapy in asystolic cardiac arrest and the lack of success of epinephrine therapy. Oxygen consumption in ventricular fibrillation may be further accelerated by the increased endogenous catecholamine levels that are characteristically present after cardiac arrest. Additional exogenous epinephrine could be expected to exacerbate hypoxemia and advancing acidosis, both of which would be expected to further impair the vasopressor effects of epinephrine as well. Thus, epinephrine might be not only ineffectual, but also potentially detrimental in early asystolic cardiac arrest, whereas vasopressin appears to be beneficial.
Usually, major changes in the guidelines for resuscitation are adopted at international conferences of experts on cardiopulmonary resuscitation and emergency cardiac care, but such conferences are generally held only at intervals of four to five years. Because of the size and power of the study by Wenzel et al., the dismal rate of resuscitation among patients with asystolic cardiac arrest, and the apparent absence of any added risk of injury to patients who may be treated according to the new therapeutic sequences, practitioners should perhaps be encouraged to incorporate the use of vasopressin into their resuscitation protocols immediately. The best approach to optimizing survival as soon as possible would be to have the appropriate committees of the American Heart Association and the American College of Cardiology convene in order to issue an interim guideline incorporating these important new therapeutic advances.
Source Information
From the Departments of Medicine and Research, Brigham and Women's Hospital, Veterans Affairs Boston Health Care System, and Harvard Medical School — all in Boston.
References
Chambless L, Keil U, Dobson A, et al. Population versus clinical view of case fatality from acute coronary heart disease: results from the WHO MONICA Project 1985-1990. Circulation 1997;96:3849-3859.
Bayes de Luna A, Coumel P, Leclerq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989;117:151-159.
Cobb LA, Fahrenbruch CE, Olsufka M, Copass MK. Changing incidence of out-of-hospital ventricular fibrillation, 1980-2000. JAMA 2002;288:3008-3013.
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.
Iseri LT, Siner EJ, Humphrey SB, Mann S. Prehospital cardiac arrest after arrival of the paramedic unit. JACEP 1977;6:530-535.
Paradis NA, Martin GB, Rivers EP, et al. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106-1113.
Fox AW, May RE, Mitch WE. Comparison of peptide and nonpeptide receptor-mediated responses in rat tail artery. J Cardiovasc Pharmacol 1992;20:282-289.
Lindner KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW, Geogieff M. Stress hormone response during and after cardiopulmonary resuscitation. Anesthesiology 1992;77:662-668.
Paradis NA, Wenzel V, Southall J. Pressor drugs in the treatment of cardiac arrest. Cardiol Clin 2002;20:61-78.
Mayr VD, Wenzel V, Voelckel WG, et al. Developing a vasopressor combination in a pig model of adult asphyxial cardiac arrest. Circulation 2001;104:1651-1656.
Related Letters:
Vasopressin versus Epinephrine for Cardiopulmonary Resuscitation
Nolan J. P., Nadkarni V., Montgomery W. H., Alvarez G. F., Bihari D., Ballew K. A., Aberegg S. K., Wenzel V., Arntz H. R., Lindner K. H., Sharma G.V.R.K., McIntyre K. M.(Kevin M. McIntyre, M.D., )