Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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A Comparison of Vasopressin and Epinephrine for Out-of-Hospital Cardiopulmonary Resuscitation

Wenzel V, Krismer AC, Arntz HR, et al.

New Engl J Med 2003; 350:105-113. [abstract]

Reviewed by Konstantin Denev MD, Advocate Hope ChildrenÕs Hospital, Oak Lawn, IL

Review posted October 27, 2004

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I. What is being studied?:

The study objective:

To assess the efficacy of vasopressin as an alternative to epinephrine for initial therapy during cardiopulmonary resuscitation for adult, out-of-hospital, cardiac arrest.

The study design:

Prospective, double-blind, muticenter randomised controlled clinical trial conducted in 33 communities.

The patients included:

Adult patients who had out-of-hospital cardiac arrest and presented with ventricular fibrillation, pulseless electrical activity or asystole requiring CPR with vasopressor.

The patients excluded:

1. Successful defibrillation without administration of a vasopressor
2. Documented terminal illness
3. Lack of intravenous access
4. Hemorrhagic shock
5. Pregnancy
6. Traumatic cardiac arrest
7. Age less than 18 years
8. Presence of do-not-resuscitate order.

The interventions compared:

Patients were randomly allocated to receive either 2 ampules of 1 mg epinephrine (Suprarenin) or two ampules of 40 IU vasopressin (Pitressin). Patients who presented with pulseless electrical activity or asystole underwent randomisation immediately; patients with ventricular fibrillation were randomised after the first three attempts of defibrillation had failed. If spontaneous circulation was not restored within three minutes after the first injection of the study drug, the same drug at the same dose was injected again. If spontaneous circulation was still absent, an additional dose of epinephrine was administered at the discretion of the physician managing the CPR.

Additional interventions such as the administration of sodium bicarbonate, atropine, lidocaine, or amiodarone and fibrinolysis were used at the discretion of the physician managing the patient care.

The outcomes evaluated:

The primary end-point of the study was survival to hospital admission and the secondary outcome was survival to hospital discharge.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Investigators and physicians were unaware of the study drug assignment unless decoding became clinically necessary for management in the period after resuscitation. The obtained data were entered into a database system by one investigator and subsequently were crosschecked twice by two other investigators who were unaware of the treatment group assignment.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes, to the primary outcome. All survivors were followed up until the hospital admission. However, 11 patients in the vasopressin group (1.9%) and nine in the epinephrine group (1.5%) were lost to follow-up before hospital discharge. 11 patients in the vasopressin group and 12 patients in the epinephrine group who survived to hospital discharge (19.3% and 20.7%) respectively were lost for follow-up for cerebral performance.

Out of total 1219 patients, 33 were excluded because of missing study drug codes. Given that a difference of 22 patients between the two groups defined the primary positive finding of this study (difference in rate of hospital admission among asystolic patients), this number of exclusions might be significant. In addition, 88 patients who underwent randomization were later shown to meet criteria for exclusion, but they were included into the final analysis on an intention-to-treat basis.

Were patients analyzed in the groups to which they were randomized?

Yes. All patients were kept in their own group for analysis; there were no crossovers.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. The health care workers and the involved investigators were unaware of the study drug assignment. The patients obviously were "blinded" too.

4. Were the groups similar at the start of the trial?

Yes. No significant differences between the two groups were demonstrated in age, sex, and underlying disease.

5. Aside from the experimental intervention, were the groups treated equally?

Additional doses of epinephrine, sodium bicarbonate, atropine, lidocaine, amiodarone and fibrinolysis were administered according to the emergency physician and did not differ between groups. Concurrent therapies can potentially increase the risk for bias but these interventions were medically and ethically justified in the situation of cardiac arrest.

III. What were the results?

1. How large was the treatment effect?

The primary end-point of the study was survival to hospital admission. The rates of hospital admission and survival to discharge were similar between the two treatment groups overall, as well as for patients with ventricular fibrillation and for those with pulseless electrical activity.

Patients in asystole, however, were more likely to survive to hospital admission and to hospital discharge if they were treated with vasopressin than if they had received epinephrine as initial therapy. In this particular group 29% (76 out of 262) patients survived up until the hospital admission vs. 20.3% (54 out of 266) in the epinephrine treated group. Among the patients that survived until the hospital discharge 4.7% (or 12 out of 257) were the survivors in the vasopressin group vs. 1.5% (4 out of 262) in the epinephrine group.

In contrast, there were no significant differences in the rates of hospital admission between the vasopressin group and the epinephrine group either among patients with ventricular fibrillation (46.2 % vs. 43%, P=0.48) or among those with pulseless electrical activity (33.7% vs. 30.5%, P=0.65).

Among the patients in whom spontaneous circulation was not restored with two injections of the study drug, additional treatments with epinephrine resulted in significant increase in the survival rate to hospital admission and discharge in the vasopressin but not in the epinephrine group. (Hospital admission rate 25.7% vs. 16.5%, hospital discharge rate 6.2% vs. 1.7%).

Among patients with asystole

	RR (vasopressin vs epi)	95% CI
Hospital admission	1.4	1.1, 1.9
Hospital discharge	3.1	1.0, 9.4
In those requiring additional epi after two doses of study drug - to hospital admission	1.7	1.1, 2.7
In those requiring additional epi after two doses of study drug - to hospital discharge	12.8	0.7, 222.6

2. How precise was the estimate of the treatment effect?

The CI's are wide for the primary endpoints that were significant. The "landmark" finding of improved rates of hospital discharge in the vasopressin group relied on very small numbers of patients: 12/257 vs. 4/262. The 95% CI for the OR here was 0.1 to 1.0 - very wide (or 1.0 to 9.4 in our calculations of RR to survival for treatment; see Table above). A difference of a couple of patients would have made the OR cross 1 and therefore made the result insignificant.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

When trying to apply the results of this study to our PICU population, several factors should be taken onto consideration. First, in this study pediatric patients were excluded. The patient's age in the vasopressin group was 66.5years ± 14.4 and in the epinephrine group 65.9 years ± 14.2. The cardiovascular history of the patients included into the study (coronary heart disease, hypertension, diabetes) was obviously different than medical history of our pediatric population (congenital cardiac defects). The study demonstrated superior effect of vasopressin compared with epinephrine in patients with asystole and asystole is the most common presenting rhythm in pediatric cardiopulmonary arrest (1). However, the vast majority of pediatric cardiac arrest patients develop cardiac arrest following respiratory arrest; the mechanism of asystole in the two populations is likely to be different. Extrapolating these findings directly to pediatrics, therefore, would be highly speculative.

The study also proved the importance of early (within 10 minutes) basic life support with higher rate of survival among adult patients who received basic life support within 10 minutes after the cardiac arrest. (291 of 665 patients or 43.8% vs. 107 of 517 patients or 20.7%, P < 0.001) How this relates to pediatrics is also unclear.

2. Were all clinically important outcomes considered?

All important outcomes were considered. Survival to hospital admission and discharge along with cerebral performance were considered.

3. Are the likely treatment benefits worth the potential harms and costs?

The study demonstrated better survival in patients with asystole, treated with vasopressin compared with the conventional treatment with epinephrine. The fact that the study was performed in patients at the brink of death precluded the evaluation of any possible adverse effect associated with the study drugs rather than the cardiac arrest. Although a cost analysis was not performed, should the study results be proven with further studies the potentially increased cost is justified.

References

1. Young KD, Gausche-Hill M, McClung CD, Lewis RJ. A prospective, population-based study of the epidemiology and outcome of out-of-hospital pediatric cardiopulmonary arrest. Pediatrics. 2004 Jul;114(1):157-64. [abstract]

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