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

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Results
 No significant difference in ITT vs PP analysis

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. 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. 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. 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. 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. 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. 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. 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. Questions?
 Thank you for your attention