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Effect of adrenaline on survival in out-of-hospital cardiac
arrest: A randomised double-blind placebo-controlled trial
Ian...
Article Summary - PICO
Population
 Adult, out-of-hospital cardiac arrest of any cause 2006-
2009
 Resuscitation commence...
Article Summary - PICO
Intervention
 1 mg of IV Epinephrine 1:1000 administered q3min during
resuscitation
 In 10 cc syr...
Article Summary - PICO
Comparison
 Placebo controlled in identical 10 cc vials of NS
 Computer generated randomization
...
Article Summary - PICO
Outcome
 Primary: Survival to hospital discharge
 Secondary:
 Pre-hospital ROSC
 Neurological o...
Rationale
ILCOR includes Epi in ALS resuscitation guidelines despite
there being no randomised placebo-controlled trials i...
Methods
 RCT
 Placebo controlled
 Triple-Blinded
 Data collection on
 Paper PCR which is entered into SPSS statistica...
Methods
 Data reporting consistent with the Utstein definitions
for reporting out of hospital cardiac arrest
 Additional...
Statistics
 Patient/study characteristics: proportions and means
using chi square and t-tests
 Ambulance time intervals:...
Results
 Randomization successful in terms
of
 Age
 Sex
 Location of arrest
 % cardiac etiology
 Rates of Bystander ...
Results
 No significant difference in ITT vs PP analysis
Stated strengths
 First human RCT design
 as opposed to animal RCTs, observations and
nonrandomized/before and after
 P...
Stated Limitations
 Did not meet sample size requirement (by an order of
magnitude) due to last minute drop out of 4 out ...
Stated Limitations
 Only 40% of eligible patients enrolled
 Claim participation of only volunteer paramedics as the
caus...
Author’s conclusions
 The use of adrenaline in cardiac arrest significantly
improves the proportion of patients achieving...
Appraisal
 No conflicts of interest
 Does the study answer a clear question?
 Yes (see PICO)
 Are the results internal...
Are the results valid?
 Cons
 Not powered sufficiently for primary outcome
 Trend suggest increased survival to dischar...
Are the results generalizable?
 50% bystander CPR rates may not be comparable to
our population
 But their overall survi...
Additional considerations
 What kind of post-arrest care was employed in those that
survived?
 Who received therapeutic ...
Questions?
 Thank you for your attention
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Journal Club - EMS - "Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial"

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Summary and Critical Appraisal of:
Jacobs et al,"Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial" Resuscitation 82 (2011) 1138– 1143

Published in: Health & Medicine, Technology
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Journal Club - EMS - "Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial"

  1. 1. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial Ian G. Jacobs, Judith C. Finn, George A. Jelinek, Harry F. Oxer, Peter L. Thompson Resuscitation 82 (2011) 1138– 1143 Farooq Khan PGY3 FRCP-EM McGill University
  2. 2. Article Summary - PICO Population  Adult, out-of-hospital cardiac arrest of any cause 2006- 2009  Resuscitation commenced  Province of Western Australia with one major city: Perth  Single EMS service (SJA-WA) with established policy of no drugs during resuscitation protocols prior to study
  3. 3. Article Summary - PICO Intervention  1 mg of IV Epinephrine 1:1000 administered q3min during resuscitation  In 10 cc syringe (total dose up to 10 mg) and followed by 30 cc flush  Administered when indicated  i.e. After 3rd unsuccessful shock  After IV access established in non-shockable cases  By paramedics trained prior to study in  Pharmacology of adrenaline  Overview of trial protocol  Further practice in IV placement  Cardiac arrest simulation exercises
  4. 4. Article Summary - PICO Comparison  Placebo controlled in identical 10 cc vials of NS  Computer generated randomization  Blinded to both paramedic and patient  No other drugs used
  5. 5. Article Summary - PICO Outcome  Primary: Survival to hospital discharge  Secondary:  Pre-hospital ROSC  Neurological outcome (Cerebral Performance Category Score – CPC)  Assessed by independent blinded adjudicators
  6. 6. Rationale ILCOR includes Epi in ALS resuscitation guidelines despite there being no randomised placebo-controlled trials in humans evaluating its efficacy in cardiac arrest  Animal studies have shown that Epi improves coronary and cerebral perfusion  A meta-analysis of high dose versus standard dose Epi did not include a comparison with placebo and showed some benefit of high dose Epi on ROSC but not survival to hospital discharge  Vandycke C, Martens P. High dose versus standard dose epinephrine in cardiacarrest—a meta-analysis. Resuscitation 2000;45:161–6.  Some evidence that Epi is harmful to myocardial function post arrest and cerebral microcirculation
  7. 7. Methods  RCT  Placebo controlled  Triple-Blinded  Data collection on  Paper PCR which is entered into SPSS statistical package  Linked to dispatch data  Compiled into WA Ambulance Service Cardiac Arrest Registry  Outcomes assessed through state-based Emergency, Hospital Morbidity and Mortality data systems  CPC score determined by independent blinded chart review
  8. 8. Methods  Data reporting consistent with the Utstein definitions for reporting out of hospital cardiac arrest  Additional data not routinely part of the PCR,  Randomisation number  Total dose of Epi  IV access achieved or not  Total volume of IV fluids infused  Sample Size Calculation = 2213 patients per group  Planned enrolment of 5000 pts to account for loss to f/u
  9. 9. Statistics  Patient/study characteristics: proportions and means using chi square and t-tests  Ambulance time intervals: means, medians and IQR  Primary and secondary outcomes: OR and 95% CI  Confounders: logistic regression  Subgroups (a priori)  Shockable  Non-shockable
  10. 10. Results  Randomization successful in terms of  Age  Sex  Location of arrest  % cardiac etiology  Rates of Bystander CPR  Initial rhythm  Ambulance response interval  Airway management  Volume of trial drug  Volume of IV fluids  Placebo group had SS not CS higher rate of  witnessed arrests by bystander  Epi group had SS not CS higher rate of  witnessed arrest by paramedic  transport to hospital
  11. 11. Results  No significant difference in ITT vs PP analysis
  12. 12. Stated strengths  First human RCT design  as opposed to animal RCTs, observations and nonrandomized/before and after  Placebo control  as opposed to high-dose vs low-dose  Population with no confounding drugs administered  (e.g. Atropine, amiodarone)  Epi administered in recommended q3min doses  as opposed to single dose  Effective Blinding
  13. 13. Stated Limitations  Did not meet sample size requirement (by an order of magnitude) due to last minute drop out of 4 out of 5 EMS systems initially meant to participate in study  Cited reasons of ethical concerns to withhold “standard of care” meds, despite clear equipoise and IRB approval  Political and Media pressure  Inability to assess the influence of CPR quality or timing of Epi administration during resuscitation  Claim variations in the above reflect clinical practice  Blinding will limit the effect of these factors on outcome
  14. 14. Stated Limitations  Only 40% of eligible patients enrolled  Claim participation of only volunteer paramedics as the cause for this  Potential for selection bias present but mitigated by successful randomization (at least for parameters measured)
  15. 15. Author’s conclusions  The use of adrenaline in cardiac arrest significantly improves the proportion of patients achieving ROSC prehospital, but failed to demonstrate a better survival to hospital discharge, possibly due to inadequate sample size.  Further studies on the role of adrenaline in cardiac arrest are required to determine optimal dose and timing for drug administration.
  16. 16. Appraisal  No conflicts of interest  Does the study answer a clear question?  Yes (see PICO)  Are the results internally valid?  Pros  Well randomized  Concealed, computer generated and groups similar at start  Mitigates selection biases, Hawthorne effects, etc.  Groups treated equally until admission  Good follow-up and ITT analysis  Triple blinded
  17. 17. Are the results valid?  Cons  Not powered sufficiently for primary outcome  Trend suggest increased survival to discharge but numbers are too low  No measurement of CPR quality or time of Epi  Is their claim that this is not relevant justifiable when we know that CPR quality is one of the main factors in determining outcome?  40% eligible patients not enrolled to randomization  May not interfere with results but it would be useful to analyze if they were much different from study sample  10% loss of records
  18. 18. Are the results generalizable?  50% bystander CPR rates may not be comparable to our population  But their overall survival rates are  Can we apply to settings where most paramedics are not trained in IV placement or have enough experience or manpower to do so without compromising CPR?
  19. 19. Additional considerations  What kind of post-arrest care was employed in those that survived?  Who received therapeutic hypothermia?  How many had an easily manageable underlying cause?  How adequately was organ perfusion managed?  How long was the admission post arrest?  Were nosocomial infections involved?  Why don’t more patients admitted to hospital alive = more patients discharged alive and functional  Small numbers and no way to account for this in analysis  Maybe ROSC should be the primary outcome for EMS and survival to hospital discharge is the hospital’s problem  Or does Epi lead to survival of more brain-damaged, lower functioning and more susceptible individuals?
  20. 20. Questions?  Thank you for your attention

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