Vasopressin for Out-of-Hospital Cardiac Arrest

Abstract & Commentary

Synopsis: In this randomized, controlled trial, European investigators looked at the role of vasopressin in treating out-of-hospital cardiac arrest. Although the study did not show any benefit of using vasopressin when compared to epinephrine in terms of survival to hospital, this study nonetheless makes a weak argument to use vasopressin in cardiac arrest patients with asystole.

Source: Wenzel V, et al. N Engl J Med. 2004;315:105-113.

In this double-blind, randomized, controlled trial, wenzel and colleagues evaluated the role of intravenous administration of vasopressin to patients experiencing out-of-hospital cardiac arrest. The study took place in European countries in "physician staffed emergency service units." Wenzel et al included all patients with cardiac arrest with pulseless electrical activity (PEA), asystole, or shock-resistant ventricular fibrillation. Patients younger than age 18, do-not-resuscitate (DNR) patients, pregnant patients, those with terminal illness or trauma induced cardiac arrest, and those with hemorrhagic shock or without IV access were excluded.

Randomization took place at the time of diagnosis of asystole or PEA, or after the 3rd failed countershock in patients with ventricular fibrillation. The patients were randomized in blocks of 10 by center, to receive either 2 injections of vasopressin (40 IU, intravenously) or epinephrine (1 mg, intravenously) at 3-minute intervals according to their clinical state. Subsequently, patients could receive 1 mg doses of epinephrine or other medications as the clinical condition warranted. Wenzel et al postulated that there would be no difference in survival to hospital or to discharge from hospital. Wenzel et al calculated that to demonstrate a 25% improvement in discharge from hospital with the drug and 80% power to detect such a difference with two-tailed analysis, 571 patients would be required in each group.

They enrolled 1219 patients and 1186 of them were included in their final analysis. A total of 589 patients received vasopressin and 597 received epinephrine as their initial drug of resuscitation. At baseline, the groups were comparable and equally distributed. Overall, there was no difference in the survival to hospital admission (36.3% with vasopressin, 31.2% with epinephrine; P = .06) or survival to hospital discharge (9.9% both groups; P = .99) between the 2 groups. Spontaneous circulation was restored in 145/589 patients in the vasopressin group and 167/597 patients in the epinephrine group.

When subgroup analysis was performed, the authors did not find any benefit of using vasopressin over epinephrine in patients with ventricular fibrillation, either in restoration of spontaneous circulation (36.8% vs 42.6%), hospital admission (46.2% vs 43%), or survival to hospital discharge (17.8% vs 19.2%). Similarly, in patients with PEA as their initial rhythm, there was no difference in the ability of either drug to restore spontaneous circulation (20.2% vs 20.7%), survival to hospital admission (33.7% vs 30.5%), or survival to hospital discharge (5.9% vs 8.6%).

Wenzel et al found that in the subgroup of patients with asystole, although similar results were seen in establishing spontaneous circulation (16% vs 16.5%), more patients survived to hospital admission (29% vs 20.3% P = 0.02) and discharge from hospital (4.7% vs 1.5 % P = 0.04) when the initial treatment was with vasopressin. There was no statistical difference in the patients’ cerebral function at discharge between the groups. They also looked at all patients in whom spontaneous circulation was not restored with the study drug. There was a trend toward improved survival rate if vasopressin was the initial drug used in resuscitation.

Wenzel et al conclude that vasopressin was similar to epinephrine in the management of ventricular fibrillation and PEA and was superior to epinephrine in patients with asystole. They further suggest that vasopressin followed by epinephrine may be more effective than epinephrine alone in treatment of refractory cardiac arrest.

Comment by Uday B. Nanavaty, MD

At the outset, I conclude, based on this study, that vasopressin has no advantage over epinephrine in patients with out-of-hospital cardiac arrest. This large, randomized clinical trial showed no improvement in the primary outcome, survival to hospital or survival to discharge when vasopressin was compared to epinephrine. In essence, that makes it a negative study in terms of a new therapy, where the new therapy did not improve the outcome when compared to standard treatment. This publication might add to the list of studies and publications that are used to teach clinical researchers and medical students how to read the literature. When a randomized, controlled, double-blind, clinical trial is performed, the only conclusion that has highest reliability and reproducibility is the primary end point. Subgroup analysis can best be used for hypothesis generation.

For example, in this study, the primary end point was survival to hospital admission and survival to discharge. All conclusions about that outcome are reliable, to a certain extent. The subgroup analysis requires a more cautious approach. There are random chances that one of the subgroup will show statistically significant difference. Whether that difference was due to the intervention or just a chance observation is not certain. To reduce the possibility of chance observation, one has to pay a penalty whereby, depending on the number of subgroups you look at, you raise the bar at which point an observation becomes statistically significant. Unfortunately, Wenzel et al did not adjust for these multiple comparisons. Not only that, the subgroup analysis became the major conclusion of the trial’s publication.

Cardiac arrest, commonly referred as Code Blue in US hospitals, is defined as an abrupt cessation of cardiac pump function, which may be reversible by prompt intervention but will lead to death in its absence. In the United States, more than 300,000 people die of sudden cardiac death and, of all the mortality from cardiac causes, as much as 50% may be unexpected. Tremendous effort by large number of organizations and agencies has resulted in nearly uniform care of patients experiencing cardiac arrest. Almost all hospitals in the US use advanced cardiac life support (ACLS) algorithms to manage the cardiac arrest victims. Similar protocols are taught to emergency care providers within and outside the hospital to improve the outcome of cardiac arrest victims. For obvious reasons, patients with "In hospital" cardiac arrest are seen and treated earlier compared to "out of hospital" cardiac arrest patients.

Epinephrine, the most potent vasopressor/stress response molecule, is used to maintain perfusion or improve the circulation when the heart has stopped its pump function. With cessation of circulation and hypoxia, acidosis develops and it is shown in studies that adrenergic agents such as epinephrine and norepinephrine do not remain effective as vasopressor agents. However, larger than physiological doses of epinephrine—1 mg IV—are used, and it is a common experience that, as soon as circulation is established, the effects of intravenously administered vasopressor are seen in a large number of patients in the form of tachycardia, hypertension, and a hyperdynamic circulatory state. Epinephrine doses larger than 1 mg have been tried in randomized control trials and have not been shown to be of any additional benefit. Epinephrine itself, to the best of my knowledge, has not been tried in a placebo controlled study, but it would be unethical at this stage to perform such a study anyway.

Vasopressin, another naturally occurring hormone, has been shown to have vasopressor effects. In animal studies, it has shown promising results in improving survival and neurological outcomes in cardiac arrest models. As is usually the case, a couple of case studies in the 1990s suggested that vasopressin may improve the outcome of patients with cardiac arrest, when all else has failed. Those case series led to a randomized trial of epinephrine compared to vasopressin as an initial agent in shock resistant ventricular fibrillation in out-of-hospital settings. That small trial1 with 40 patients in all, suggested that vasopressin might be highly beneficial in improving the survival of out-of-hospital cardiac arrest patients. A much larger trial2 that included not only shock-resistant ventricular fibrillation but also included patients with PEA and asystole in the in-hospital setting, failed to show any benefit of using vasopressin over epinephrine. However, the American Heart Association, the organization behind the ACLS algorithm, suggested that in shock-resistant ventricular fibrillation, vasopressin, 40 IU intravenously, might be used as an alternate to the first dose of epinephrine. Although one can conclude based on the current study that vasopressin is as effective as epinephrine in all forms of cardiac arrest, the trial really was designed to prove that the drug would have a 25% improvement in outcome. To really establish that vasopressin is equally effective, a much larger study would be needed.

This study, in spite of the bold claim by Wenzel et al, further raises doubt about changing a long-established algorithm. Even though epinephrine has not been tried in randomized controlled trials against placebo, the longstanding algorithm should only be changed if there is substantial benefit from vasopressin. Although the cost per resuscitation may not change much (estimated cost of vasopressin is $14 compared to $1 for epinephrine), it would require a tremendous amount of money to change the algorithm, republish all the literature to train everyone, and then spend $28 more dollars per cardiac arrest patient, without any added benefit of doing so.

References

1. Lindner KH, et al. Lancet. 1997;349:535-537.
2. Stiell IG, et al. Lancet. 2001;358:105-109.

Uday B. Nanavaty, MD, Pulmonary and Critical Care Medicine, Rockville, Maryland, is Associate Editor for Critical Care Alert.