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A Comparison of High-Dose and Standard-Dose Epinephrine in Children with Cardiac Arrest.

Perondi MBM, Reis AG, Paiva EF, Nadkarni VM, Berg RA.

New Engl J Med 2004; 350:1722-1730. [abstract]

Reviewed by Mahesh Sharma MD, Children's Hospital of Michigan, Wayne State University, Detroit MI

Review posted July 16, 2004

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I. What is being studied?:

The study objective:

To compare high-dose with standard-dose epinephrine as rescue therapy for in-hospital cardiac arrest in children after failure of an initial standard-dose epinephrine.

The study design:

This study was designed as a prospective, randomized double blind trial at a single center and conducted from October 1999 through September 2001.

The patients included:

The patient population was comprised of children who remained in cardiac arrest despite cardiopulmonary resuscitation (CPR) and an initial, standard-dose epinephrine (0.01 mg/kg body weight) during the 23 month study period. In children who had more than one cardiac arrest, only the initial arrest was evaluated.

The patients excluded:

Children with sustained trauma, those whose cardiac arrest had commenced outside the hospital, and those with do-not-resuscitate orders were excluded from the study. Neonates were also excluded.

The interventions compared:

High-dose epinephrine (0.1 mg/kg body weight) was compared to standard-dose epinephrine (0.01 mg/kg body weight). These doses were given for rescue, i.e., after the administration of an initial standard-dose epinephrine (0.01 mg/kg body weight).

The outcomes evaluated:

The primary outcome measure was survival at 24 hours after cardiac arrest. Return of spontaneous circulation (ROSC), survival to hospital discharge, and neurologic status six month after discharge was also evaluated.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, assignment of patients to treatments was randomized by a single study pharmacist who alone had access to treatment packages containing epinephrine solution in either 1:1,000 or 1:10,000 concentrations.

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

Was followup complete?

Yes. All 68 patients who entered the trial were followed up to death or discharge. All the 4 patients discharged were followed up at 6 months for pediatric cerebral performance categorization.

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

Data from all enrolled patients was analyzed in the groups to which the patients were randomized on an intention-to-treat analysis.

However, protocol violations occurred in 18 out of 68 patients. Inadvertent dosing in 10 patients resulted in administration of 0.002 to 0.06 mg/kg body weight of epinephrine. Seven of these 10 patients were in the high-dose group, i.e., should have received 0.1 mg/kg. Three of these 10 were in the standard dose group and were supposed to get 0.01 mg/kg of epinephrine. Eight protocol violations occurred in the standard dose group comprised of 34 patients. These 8 patients received high-dose epinephrine, thus only 2/3rd patients in the standard-group received the standard-dose for rescue.

Secondary questions:

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

Patients, residents, nurses and faculty members were blind to treatment. The members of the research team observing the CPR were also blind to treatment.

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

There was no statistical difference between the high-dose and standard-dose epinephrine group in terms of age, weight, sex, pre-existing disease, cause of arrest (e.g., asphyxia or shock), place of arrest and initial electrocardiographic rhythm.

Although the differences were not statistically significant, in the high-dose epinephrine group, six patients out of 34 had cardiac arrest in the ward where as in the standard-dose epinephrine group, only 1 out of 34 arrested in the ward. All remaining arrests were in the ICU or the emergency department. Further, in the high-dose group, 4 out of 34 patients had ventricular fibrillation or pulseless ventricular tachycardia. In the standard dose group no patient had ventricular fibrillation or pulseless tachycardia.

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

All patients received CPR according to American Heart Association guidelines. Twelve out of 34 patients received > 6 doses of epinephrine in the standard-dose group compared to only 5 out of 34 in the high-dose group, p = 0.05. Further, other treatments following CPR during the post arrest phase, especially inotropes, were not described in the two groups.

III. What were the results?

1. How large was the treatment effect?

The treatment effect was measured by ROSC, survival at 24 hours, and by survival to hospital discharge. ROSC for 20 minutes or less compared to ROSC for > 20 minutes but < 24 hours was not different between the two groups.

Table 1. Survival in the two groups.

		Standard dose (%)	High dose (%)
All patients	Survival to 24 hours	7/34 (21)	1/34 (3)
	Survival to discharge	4/34 (12)	0/34 (0)
Asphyxia patients	Survival to 24 hours	7/18 (39)	0/12 (0)
	Survival to discharge	4/18 (22)	0/12 (0)

After controlling for the differences between the two treatment groups at the time of arrest, the high dose epinephrine group had a substantial odds ratio for death, but the difference from the standard dose group was not significant (odds ratio, 7.9; 97.5% CI 0.9 to 72.5; P = 0.08).

Table 2. Treatment effects for all cardiac arrests, irrespective of cause

High-dose epinephrine rescue	Death at 24 hours	95% Confidence Interval
Absolute Risk Increase	17.9 %	3.1 % to 32.8 %
Number Needed to Harm	6	3 to 32
Relative Risk	1.22	1.02 to 1.46
Relative Risk Increase	0.23	0.02 to 0.46

Table 3. Treatment effects for cardiac arrest secondary to asphyxia

High-dose epinephrine rescue	Death at 24 hours	95% Confidence Interval
Absolute Risk Increase	39 %	11.3% to 66.5%
Number Needed to Harm	3	2 to 9
Relative Risk	1.63	1.1 to 2.3
Relative Risk Increase	0.63	0.1 to 1.32

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

High dose epinephrine in all cardiac arrest patients resulted in an absolute risk increase of death at 24 hours of ~18%; with 95% certainty, the true absolute risk increase could be as low as 3% or as high as 33%. See confidence intervals in Tables 2 and 3 above.

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

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

Yes. The patient population excludes cardiac arrests that occurred out of hospital and newborns. Patients in pediatric intensive care units suffer from cardiac arrests commonly due to asphyxia and shock. Also 49/68 = 72% had asystole as their initial electrocardiographic rhythm, not much different than encountered for in-patient cardiac arrests (1).

Of note, none of these patients in the study were post-operative cardiac surgery patients, so the applicability of these results to that population might be limited.

2. Were all clinically important outcomes considered?

The study analyzed only the initial cardiac arrest in the patient population. Repeated cardiac arrests and their management could influence the 24 hour survival and survival to hospital discharge. The number of repeat arrests, their timings, and distribution in the high-dose and standard-dose groups is not described.

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

There are no treatment benefits demonstrated by using "high-dose" epinephrine (0.1 mg/kg body weight).

References:

1. Reis AG, Nadkarni V, Perondi MB, et al. a prospective Investigation Into the Epidemiology of In-Hospital Pediatric Cardiopulmonary Resuscitation Using the International Utstein Reporting Style. Pediatrics 2002; 109 (2): 200-9. [abstract]

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