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(Circulation. 1997;96:2453-2454.)
© 1997 American Heart Association, Inc.

Articles

Pressor With Promise

Using Vasopressin in Cardiopulmonary Arrest

Sumeet S. Chugh, MBBS; Keith G. Lurie, MD; ; Karl H. Lindner, MD

From The Cardiac Arrhythmia Center, Division of Cardiovascular Medicine, University of Minnesota, Minneapolis (S.S.C., K.G.L.), and the Department of Anesthesiology, Ulm University, Germany (K.H.L.).

Correspondence to Keith G. Lurie, MD, Box 508, 420 Delaware St SE, Minneapolis, MN 55455. E-mail lurie002{at}maroon.tc.umn.edu

Key Words: cardiopulmonary resuscitation • vasopressin • pharmacology • survival

	Introduction

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Despite their widespread use, current methods of cardiopulmonary resuscitation and advanced cardiac life support continue to yield poor results. In the United States, the national average for long-term survival after cardiac arrest in patients with an out-of-hospital arrest remains <5%. Surprisingly, the use of epinephrine, the mainstay of pharmacological therapy in cardiac arrest, is supported only by animal studies and anecdotal case reports. We would like to present evidence that vasopressin, alone or in combination with epinephrine, is more effective than epinephrine in the treatment of cardiopulmonary arrest. Its use during advanced cardiac life support may improve the chances of survival after cardiopulmonary arrest.

	Rationale for the Use of Pressor Agents in Cardiopulmonary Arrest

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All forms of stress elicit an endocrine response. Cardiopulmonary arrest, the ultimate stress,¹ results in the release of endogenous epinephrine and norepinephrine in animals and humans. Systemic vascular resistance increases, with preferential redistribution of blood flow to myocardial and cerebral vessels.² The discovery of this pressor response prompted trials of catecholamines in animal models of cardiac arrest, ultimately leading to the use of epinephrine in human subjects. For more than three decades, epinephrine has been the drug of choice and the major pharmacological intervention in cardiac arrest.

	Does Epinephrine Improve Survival?

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A recent randomized, controlled trial comparing epinephrine with placebo showed that neither high-dose nor standard-dose epinephrine altered survival in cardiac arrest compared with placebo.³ In that study, the immediate survival rate was 8.8%, but only 0.9% patients survived to hospital discharge. Other studies have demonstrated no improvement in survival when low-dose and high-dose (5 to 10 mg) epinephrine were compared.⁴ One concludes from these studies that patients who require epinephrine during cardiopulmonary arrest have uniformly poor survival rates and that furthermore, the use of epinephrine does not improve survival.

	In Search of a Better Pressor

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Of the potential alternatives to epinephrine, vasopressin holds the most promise. In addition to catecholamines, the stress hormone response during cardiac arrest includes release of corticotrophin, cortisol, renin, and vasopressin. When vasopressin levels were measured in patients undergoing cardiopulmonary resuscitation, there was a high degree of correlation between levels of endogenous vasopressin released and the potential for return of spontaneous circulation.² Surprisingly, the converse was observed with endogenous catecholamines: the higher the serum levels of catecholamines, the lower the probability of survival after cardiopulmonary resuscitation.⁵ On the basis of these observations, the use of vasopressin in cardiac arrest was first explored in a porcine model of ventricular fibrillation. Studies were performed in both a closed-chest⁶ and an open-chest pig model.⁷ In both studies, vital-organ blood flow was significantly higher with vasopressin and effects were more prolonged than with epinephrine. In addition, with vasopressin, we observed fewer arrhythmias after cardioversion, and the rate of successful resuscitation was higher. These results may be related, in part, to prior observations that vasopressin is more effective than epinephrine under conditions of low pH and hypoxia.⁸ Thus, in the pig model of ventricular fibrillation, the exogenous administration of vasopressin appears to be significantly better than administration of low, medium, or high doses of epinephrine.

	Human Studies

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Building on these studies, vasopressin has more recently been administered to a small number of patients during refractory cardiac arrest. The first clinical experience in the in-hospital cardiac arrest patient population consisted of a series of case reports.⁹ Eight patients in cardiac arrest received vasopressin (40 U) after all other standard resuscitation measures, including multiple doses of intravenous epinephrine therapy, were ineffective. All eight patients had a return to spontaneous circulation after administration of vasopressin. Three of these eight patients survived to hospital discharge. These findings led to a small, randomized prospective trial in which a direct comparison between vasopressin and epinephrine was made in 40 subjects who presented with out-of-hospital cardiopulmonary arrest.¹⁰ The results showed a doubling of acute resuscitation rates and 24-hour survival with vasopressin as well as a favorable trend in the rate of survival to hospital discharge.

	Pathophysiological Mechanisms

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The mechanism of action of vasopressin during cardiac arrest is poorly understood. Hemodynamic measurements suggest that it causes profound shunting of blood to the heart and brain, away from the muscle, skin, and splanchnic beds. This may be mediated, in part, by release of nitric oxide.^{11 12} In the brain, arginine vasopressin provides significantly more perfusion during cardiopulmonary resuscitation than epinephrine, perhaps secondary to nitric oxide release. Unlike epinephrine, vasopressin continues to cause intense vasoconstriction in the presence of the severe acidosis that accompanies cardiopulmonary arrest,⁸ with a longer duration of action than epinephrine. Unlike epinephrine, which significantly increases myocardial oxygen consumption via ß₁-adrenergic receptor activation, vasopressin enhances myocardial oxygen delivery^{6 7} and may increase cardiac contractility,¹³ without the marked increased in oxygen consumption observed with catecholamines.

	Need for Large-Scale Clinical Trials

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These encouraging results from preliminary studies demand larger clinical trials of this potent vasoconstrictor. Decades of epinephrine use in cardiac arrest (despite lack of definite evidence of benefit) may make this a difficult task. On the basis of the evidence described above, we propose performing a randomized double-blind trial in which epinephrine (1 mg) or vasopressin (40 U) would be administered intravenously after the first dose of epinephrine failed to result in return of spontaneous circulation. If vasopressin has a positive effect on survival, a direct comparison between the two drugs as first-line pressor therapy would follow. Both in-hospital and out-of-hospital trials are needed, but given the different natures of these two populations, there may be a greater impact on survival in the out-of-hospital setting. With the proposed changes in federal regulations on resuscitation research, we are optimistic that a comprehensive clinical evaluation of vasopressin will be feasible in the near future.

	Appeal

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One obvious limitation of resuscitation studies in humans is the inability to obtain informed consent from study subjects. Prolonged debates on this issue have been the Achilles' heel of cardiopulmonary resuscitation research, severely hindering progress in this field.¹⁴ In patients who reach the point at which epinephrine is used for resuscitation, the rate of survival to hospital discharge is <1%.⁴ To improve survival after cardiac arrest, new and promising interventions must be studied in a systematic fashion with the option to waive informed consent in such situations. Although issues of informed consent are vital for protection of patient rights, we propose that in the setting of cardiopulmonary arrest research, the value of assessing vasopressin efficacy in a well-organized clinical trial far outweighs the potential for infringement of patient rights, when they are so near death's door.

	References

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1. Wortsman J, Frank S, Cryer PE. Adrenomedullary response to maximal stress in humans. Am J Med. 1984;77:779-784.[Medline] [Order article via Infotrieve]

2. Lindner KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW, Georgieff M. Stress hormone response during and after cardiopulmonary resuscitation. Anesthesiology. 1992;77:662-668.[Medline] [Order article via Infotrieve]

3. Brown CG, Martin DR, Pepe PE, Stueven H, Cummins RO, Gonzalez E, Jastremski M. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med. 1992;327:1051-1055.[Abstract]

4. Woodhouse SP, Cox S, Boyd P, Case C, Weber M. High dose and standard dose adrenaline do not alter survival, compared with placebo, in cardiac arrest. Resuscitation. 1995;30:243-249.[Medline] [Order article via Infotrieve]

5. Lindner KH, Haak T, Keller A, Bothner U, Lurie KG. Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart. 1996;75:145-150.[Abstract/Free Full Text]

6. Lindner KH, Brinkmann A, Pfenninger EG, Lurie KG, Goertz A, Lindner IM. Effect of vasopressin on hemodynamic variables, organ blood flow and acid-base status in a pig model of cardiopulmonary resuscitation. Anesth Analg. 1993;77:427-435.[Abstract/Free Full Text]

7. Lindner KH, Prengel AW, Pfenninger EG, Lindner IM, Strohmenger HU, Georgieff M, Lurie KG. Vasopressin improves vital organ blood flow during closed-chest cardiopulmonary resuscitation in pigs. Circulation. 1995;91:215-221.[Abstract/Free Full Text]

8. Eichinger MR, Walker BR. Enhanced pulmonary arterial dilatation to arginine vasopressin in the chronically hypoxic rat. Am J Physiol. 1994;267:H2413-H2429.[Abstract/Free Full Text]

9. Lindner KH, Prengel AW, Strohmenger HU, Lurie KG. Vasopressin administration in refractory cardiac arrest. Ann Intern Med. 1996;124:1061-1064.[Abstract/Free Full Text]

10. Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomized comparison of epinephrine and vasopressin in patients in out-of-hospital ventricular tachycardia. Lancet. 1997;349:535-537.[Medline] [Order article via Infotrieve]

11. Russ RD, Walker BR. Role of nitric oxide in vasopressinergic pulmonary vasodilatation. Am J Physiol. 1992;263:H743-H747.

12. Evora PR, Pearson PJ, Schaff HV. Arginine vasopressin induces endothelium-dependent vasodilatation in the pulmonary artery: V1-receptor-mediated production of nitric oxide. Chest. 1995;103:1241-1245.[Abstract/Free Full Text]

13. Chandrashekhar Y, Anand I, Goldsmith S. Arginine vasopressin V1-A receptor mediates positive inotropic effects in normal isolated rat cardiac myocytes. Circulation. 1994;90(suppl I):I-174.

14. Lurie KG, Benditt D. Regulated to death: the matter of informed consent for human experimentation in emergency resuscitation research. Pacing Clin Electrophysiol. 1995;18:1443-1447.[Medline] [Order article via Infotrieve]

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