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 2 nd 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, 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:  Patients who remained in cardiac arrest after CPR & 1 st 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.

Methods Ethical 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 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!

Results In 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 ) 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 ).

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”.

Results Separate 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