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JOURNAL CLUB

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:

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JOURNAL CLUB

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  1. JOURNAL CLUB A Comparison of High-Dose and Standard-dose Epinephrine in Children with Cardiac Arrest NEJM 350;17April 22, 2004 By Norah A A Al Khathlan M.D.

  2. 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.

  3. 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.”

  4. 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.

  5. 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.

  6. What is being studied ? Exclusion criteria: • Neonates. • Trauma cases. • Those with cardiac arrests commencing outside the hospital. • Those with DNR orders. • Subsequent arrests.

  7. 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.

  8. 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).

  9. What is being studied ? Outcome measured: Survival at 24hrs post cardiac arrest. Survivors were additionally followed post discharge for neurological deficits

  10. KAAUH-JEDDAH

  11. 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.

  12. 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.

  13. 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.

  14. 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%.

  15. 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.

  16. JEDDAH

  17. 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.

  18. 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!

  19. 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

  20. 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).

  21. 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”.

  22. 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

  23. 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?

  24. 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

  25. RIYADH

  26. Finally….weaknesses!! • Small sample size: • Power of 75%  Unacceptable. • C.I. • Protocol violations: Contamination. ? bias • Population studied: • monitored & witnessed arrests. • no cardiac disease

  27. THANK YOU

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