Faculty Peer Reviewed
A 65-year-old male with a past medical history significant for NYHA class IV heart failure was found by his wife to be unresponsive. Emergency Medical Services was subsequently called and upon arrival, initiated chest compressions and defibrillation for cardiac arrest secondary to ventricular fibrillation. Intravenous access was obtained and despite two episodes of defibrillation, the patient remained in ventricular fibrillation. The patient was given one dose of 40 U of vasopressin followed by 1 mg epinephrine every 3-5 minutes for the persistence of ventricular fibrillation. The patient was transported to the local hospital for further medical management.
In the setting of pulseless cardiac arrest, is there a significant survival advantage to management with vasopressin compared to epinephrine?
Cardiac arrest remains one of the most devastating medical conditions for patients and their families. According to the literature, there are an estimated 400,000 cases of cardiac arrest in the United States annually . Despite the attempts of multiple studies to elucidate the optimal management of cardiac arrest and the implementation of Basic Life Support (BLS) and Advanced Cardiovascular Life Support (ACLS) algorithms, the survival rate following cardiac arrest remains between 2-24% . Given the paucity of evidence in the literature for the proper management strategy, cardiac arrest remains a significant public health dilemma.
There are four recognized cardiac rhythms that produce cardiac arrest: ventricular fibrillation (VF), ventricular tachycardia (VT), pulseless electrical activity (PEA), and asystole . Of these rhythms, ventricular fibrillation accounts for 60-80% of cardiac arrests and is the most treatable rhythm. Conversely, asystole accounts for 20-40% of cardiac arrests and is most often refractory to cardiac resuscitation . Given the significant consequences and sequelae of cardiac arrest, the American Heart Association developed the ACLS protocol to attempt to provide a consistent and optimal management strategy.
It is well-established that the first minutes following cardiac arrest are the most critical to a patient’s survival. The ACLS guidelines recommend Cardiopulmonary Resuscitation (CPR) and defibrillation for cardiac arrest secondary to ventricular tachycardia or fibrillation. If there is persistence of VT/VF subsequent to 1 or 2 episodes of defibrillation, vasopressors are indicated. In cases of nonshockable rhythms, such as PEA or asystole, vasopressors are indicated following the initiation of CPR, once IV access is achieved. Although there have been no placebo-controlled studies demonstrating an increase in neurological survival with any vasopressor agents, there is evidence that vasopressors increase the restoration of spontaneous circulation (ROSC). According to the ACLS guidelines for vasopressor therapy, 1 mg of epinephrine may be given and repeated every 3 to 5 minutes during cardiac arrest. Furthermore, 40 units of vasopressin may be substituted for the first or second dose of epinephrine . Although the ACLS guidelines substantiate the substitution of vasopressin for epinephrine, there is a lack of evidence in the literature that vasopressin increases survival compared to epinephrine.
Vasopressin vs. Epinephrine:
Epinephrine exerts its physiologic effects during cardiac arrest through stimulation of the α-adrenergic receptors, thus inducing vasoconstriction and a subsequent increase in aortic pressure. This systemic vasoconstriction promotes an increase in coronary and cerebral perfusion pressures [5, 6]. Despite these recognized benefits, evidence has shown a negative safety profile of epinephrine, due to its ability to increase myocardial work load, reduce subendocardial perfusion, and induce ventricular arrhythmias . Vasopressin, a nonadrenergic endogenous peptide that induces peripheral, coronary, and renal vasoconstriction via stimulation of the V1 receptors, lacks the adverse effects of epinephrine and has therefore gained much attention as a substitute vasopressor . Another possible advantage is that through V2 receptor stimulation, vasopressin may induce vasodilation and therefore lessen the end-organ hypoperfusion thought to occur with epinephrine .
Although multiple studies have been conducted to determine whether either of these two interventions have a statistically significant survival advantage, the evidence in the literature remains unclear and contradictory. Nevertheless, a study by Wenzel et al. attempted to elucidate the differences in survival between epinephrine, vasopressin, and the concomitant use of both epinephrine and vasopressin. This double-blind, prospective, randomized control trial used the primary and secondary end points of survival to hospital admission and discharge, respectively. Interestingly, there were no significant differences in survival between the epinephrine and vasopressin groups with respect to patients with VF or PEA. Conversely, among patients with cardiac arrest secondary to asystole, patients who received vasopressin had a significantly higher rate of survival to hospital admission and discharge (29.0% vs. 20.3%, P=0.02 and 4.7% vs. 1.5%, P=0.04, respectively) . These findings are supported by the evidence that metabolic derangements, specifically metabolic acidosis, impair the functionality of α-adrenergic receptors, thus diminishing the affect of catecholamines . It is therefore suggested that the superiority findings of vasopressin over epinephrine in asystole is a result of extreme ischemia and acidosis. However, subsequent studies conducted to evaluate the effectiveness of epinephrine and vasopressin in the setting of cardiac arrest have not demonstrated reproducible survival benefits of vasopressin in the setting of any of the four subtypes of cardiac arrest.
Epinephrine + Vasopressin vs. Epinephrine Alone:
Despite the paucity of evidence supporting the superiority of either vasopressor, it has been hypothesized that the combination of both epinephrine and vasopressin may have a synergistic effect. It is well-recognized that concomitant epinephrine and vasopressin increase survival following cardiac arrest in animal subjects . This approach however, has not come to fruition in all but one human subject trial. The findings in the Wenzel et al. study are consistent with those of animal research, supporting vasopressin followed by epinephrine improves ROSC (36.7% vs. 25.9%, P=0.002) and 24-hour survival rates (6.2% vs. 1.7%, P=0.002), compared to epinephrine alone . Regardless of the improved 24-hour survival rate, the rate of patients with neurologic survival at discharge was poor. Consequent studies conducted to further evaluate the role of combination epinephrine and vasopressin have not found an improved outcome over epinephrine alone .
In the multicenter trial by Gueugniaud et al., 1442 patients were randomized to a combination of epinephrine and vasopressin and 1452 patients were randomized to epinephrine alone. The authors report that there were no treatment-related adverse effects resulting from this study. Furthermore, a posthoc analysis identified that when the initial ECG rhythm was PEA, the patients who received epinephrine alone had a higher rate of survival to hospital discharge (5.8% vs. 0%, P=0.02). However, among patients with an initial ECG rhythm of VF or asystole, there were no significant differences in outcomes between combination therapy and epinephrine alone . These findings further confound the question of whether vasopressin compared to epinephrine or in combination with epinephrine improves survival in the setting of cardiac arrest.
Given that vasopressin has a relatively long half-life of 6 minutes, it is likely that a resulting therapeutic benefit would be from the simultaneous action of both epinephrine and vasopressin . As epinephrine is the standard vasopressor therapy during cardiac arrest, the vasopressin arms of randomized control trials received epinephrine after 3-5 minutes if there was no response to the administration of vasopressin. Despite this hypothesized synergistic effect, the majority of studies in the literature have found no survival benefit to combination therapy over epinephrine alone .
As neither intervention has shown superiority as a monotherapy, the increased cost of vasopressin must be weighed against the incidence of adverse effects of epinephrine. Although it is difficult to analyze management options from a cost-benefit perspective, it must be considered that the cost of 40 U of vasopressin is 15 times greater than that of 1 mg of epinephrine. Healthcare providers must consider that this increase in cost with vasopressin occurs without an evidence-based improvement in survival .
Cardiac arrest remains a significant public health issue despite the focus of research trials and implementation of practice guidelines. Although Advanced Cardiac Life Support is performed by the most highly trained medical professionals, the only interventions shown to significantly increase survival are chest compressions and defibrillation. ACLS guidelines currently recommend that vasopressin may be administered as a replacement of the first or second dose of epinephrine during a cardiac arrest. Given that the overwhelming majority of evidence in the literature does not corroborate an increase in survival with epinephrine and vasopressin combination therapy, it is recommended that either epinephrine or vasopressin be administered as the first dose of vasopressor therapy, followed by repeated doses of epinephrine.
Even if the study by Wenzel et al. is accurate in that vasopressin increases survival to discharge, when cerebral performance of these patients was analyzed, there was no significant improvement in neurological performance . Therefore, future studies are needed to establish the incidence of adverse effects of both vasopressors, thus enabling an objective management decision, given the similar efficacy between both interventions.
Resolution of Case:
The patient in our case received an additional episode of defibrillation with concomitant chest compressions and administration of epinephrine every 3-5 minutes. The subsequent rhythm check demonstrated a perfusing rhythm and the ACLS algorithm was terminated. The patient survived to discharge despite residual neurologic deficits. He was admitted to rehabilitation where he is making modest improvements.
Dr. Oberweis is a 1st year resident at NYU Langone Medical Center
Peer reviewed by Laura Evans, MD, critical care section editor, Clinical Correlations
Image courtesy of Wikimedia Commons.
1. Aung K, Htay T. Vasopressin for Cardiac Arrest: A Systemic Review and Meta-analysis. Arch Intern Med 2005;165:17-24. http://www.ncbi.nlm.nih.gov/pubmed/15642869
2. Sillberg VAH, Perry JJ, Steill IG, Wells GA. Is the combination of vasopressin and epinephrine superior to repeated doses of epinephrine alone in the treatment of cardiac arrest – A systematic review. Resuscitation 2008;79:380-386.
3. American Heart Association. Management of Cardiac Arrest. Circulation 2005;112:IV-58-IV-66.
4. McIntyre KM. Vasopressin in Asystolic Cardiac Arrest. N Engl J Med 2004;350(2):179-181.
5. Yakaitis RW, Otto CW, Blitt CD. Relative importance of α and β adrenergic receptors during resuscitation. Crit Care Med 1979;7:293-296.
6. Michael JR, Guerci AD, Koehler RC, Shi AY, et al. Mechanisms by which epinephrine augments cerebral and myocardial perfusion during cardiopulmonary resuscitation in dogs. Circulation 1984;69:822-835. http://circ.ahajournals.org/cgi/content/short/69/4/822
7. Stroumpoulis K, Xanthos T, Rokas G, Kitsou V, et al. Vasopressin and epinephrine in the treatment of cardiac arrest: an experimental study. Critical Care 2008;12:R40. http://ccforum.com/content/12/1/R40
8. Jing XL, Wang DP, Li H, Li H. Vasopressin and epinephrine versus epinephrine in management of patients with cardiac arrest: a meta-analysis. Signa Vitae 2010;5(1):20-26. http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?ID=12010003760
9. Wenzel V, Krismer AC, Arntz HR, Sitter H, et al. A Comparison of Vasopressin and Epinephrine for Out-of-Hospital Cardiopulmonary Resuscitation. N Engl J Med 2004;350(2): 105-113. http://www.nejm.org/doi/full/10.1056/NEJMoa025431
10. Fox AW, May RE, Mitch WE. Comparison of Peptide and Nonpeptide Receptor-Mediated Responses in Rat Tail Artery. J of Cardiovascular Pharmacology 1992;20:282-289.
11. Gueugniaud PY, David JS, Chanzy E, Hubert H, et al. Vasopressin and Epinephrine vs. Epinephrine Alone in Cardiopulmonary Resuscitation. N Engl J Med 2008;359(2): 21-30.