6th June 2004 By Norah A A Al Khathlan M.D.

JOURNAL CLUB

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

NEJM 350;17April 22, 2004

What is being studied ?

The Study Objective: To compare the use of high-dose epinephrine

0.1mg/kg with standard-dose 0.01mg/kg for the 2nd dose of epinephrine (i.e.,the rescue dose) during resuscitation following in-hospital cardiac arrest in children.Conducted at the Children’s institute: 122-bed tertiary care center.

More than 6000 pts/yr. No trauma or cardiac surgery.

What is being studied ?

Hypothesis:“ In children who had an in-hospital cardiac arrest,

rescue therapy with high-dose epinephrine( HDE) as compared with continued use of the standard dose, would improve the rate of survival at 24 hrs.”

“ the difference will be more clearly demonstrable in patients with asphyxia-precipitated arrests.”

What is being studied ?

Study design:

Prospective, randomized, double-blind trial. The trial included 68 children

The primary outcome measure was survival 24hrs after the arrest.

What is being studied ?

Inclusion criteria:• All Children who remain in cardiac arrest despite CPR

& an initial standard-dose of epinephrine (0.01mg/kg).• All children as above between October 31,1999, to

September 30, 2001. • Only the initial cardiac arrest was evaluated if more

than one occurred.

What is being studied ?

Exclusion criteria: • Neonates.• Trauma cases.• Those with cardiac arrests commencing outside the

hospital.• Those with DNR orders.• Subsequent arrests.

What is being studied ?

Definition of cardiac arrest: The cessation of mechanical cardiac activity,

determined on the basis of the absence of a palpable pulse and the presence of unresponsiveness and apnea.

What is being studied ?

Interventions compared:Patients who remained in cardiac arrest despite CPR and

an initial standard-dose of epinephrine (0.01mg/kg) were randomized to receive:Standard-dose epinephrine (0.01mg/kg/dose).High-dose epinephrine (0.1mg/kg/dose).

What is being studied ?

Outcome measured:

Survival at 24hrs post cardiac arrest.

Survivors were additionally followed post discharge for neurological deficits

Methods Randomization was provided by computer: “random-number generator” Single pharmacist prepared treatment packages:

Each with 10 x 1ml vials of epinephrine in a solution of 1: 1000 or 1:10000.

Patients who remained in cardiac arrest after CPR & 1st dose of epinephrine “routinely stocked”, received 0.1ml/kg of the experimental solution which provided : 0.01mg/kg/dose if it was of 1:10000 solution. 0.1mg/kg/dose if it was of 1:1000 solution.

Methods All further doses were provided from the same

treatment package. Only the study pharmacist had access to

information pertaining to concentration of epinephrine used.

CPR team provided CPR as per AHA guidelines without interference from research team.

MethodsEthical issues:

The study was exempted from the requirement of an informed consent because of:

The unexpected & sudden nature of cardiac arrests.

Both dose strategies are recommended by AHA.

An informed consent was required & obtained for continued follow-up after discharge.

Methods

Sample size:Previous experience:

2 year period expected to yield approximately 70 patients.

24 hrs survival after 2 standard doses of epinephrine was ~ 20%.

24 hrs survival after rescue therapy with high-dose epinephrine increased from 0% to 50%.

With 34 patients in each group the power to detect an improvement from 20 to 50 % was 75%.

Methods Statistical analysis:

Intention to treat basis. 1ry outcome was 24hrs survival. Data from patients with arrests 2ry to asphyxia and those from arrests

2ry to shock were analysed separately. StatView 5.0 & Stata 7.0 software. Chi-square analysis or Fisher’s exact test for disrete variables and

unpaired t-tests for continuous variables. All reported P values are two-sided. Multiple logistic-regression analysis were used for differences between

groups. Some protocol violation still occurred requiring further analysis.

Results 185 patients with cardiac arrests.

117 met exclusion criteria.67 cases due to DNR orders.

68 children were enrolled & randomly assigned to:High-dose treatment regimen (34 patients).Standard-dose regimen (34 patients).

Protocol violations in 18 of 68 cases. The two groups were generally similar before

arrest.

Results Protocol violations In 18 out of 68 cases:

10 cases had deviations from recommended doses.3 in the standard-dose group.7 in the high-dose group.Doses ranged between 0.002 to 0.06mg/kg/dose.

8 cases of the standard-dose group were given high doses at some point.

7 of these were > 20kg used up the experimental dose!

ResultsIn general: Prior to arrest:

Nearly all arrests, 96% were witnessed. 78% were on cardiac monitors. 68% were on ventilators. 53% were with Catecholamine infusions.

During resuscitation: More patients in high-dose group received 2-3 doses. (19 vs. 11). More in standard-dose received > 6 doses. ( 12 vs. 5). Both findings were statistically significant P value 0.05

Results Rate of survival at 24 hrs was lower in HDE group,

P=0.05 (C.I. 1.0-397.0)

However the above refers to “unadjusted odds ratio” !!

After adjustment by multiple logistic-regression analysis for differences between the 2 treatments …..difference is not statistically significant P=0.08 (C.I. 0.9-72.5).

Results None of the HDE group survived to hospital discharge as

compared with 4 of the 34 in SDE group. P = 0.11

But… “ the two treatment groups did not differ significantly in terms of ROSC or the rate of survival to hospital discharge”.

ResultsSeparate analysis for those with asphyxia related arrests. For those with asphyxia related arrests n= 30 :

none of the 12 in HDE survived at 24hrs. 7 out of 18 in SDE survived at 24hrs. P =0.02

38 patients had arrests precipitated by shock 22 in HDE 16 in SDE

Results

Analysis after exclusion of all protocol violations:Survival is lower in HDE 1 of 27 as compared to 6 of 23 in SDE P =0.04

Is this an acceptable way of analysis?

Results Of those with “no protocol violations” and arrests

precipitated by asphyxia:24 hrs survival in HDE group (0 of 8).6 of 13 in SDE group. P = 0.04

Finally….weaknesses!! Small sample size:

Power of 75% Unacceptable. C.I. Protocol violations: Contamination. ? bias Population studied:

monitored & witnessed arrests.no cardiac disease