PARAMEDIC-2: A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest - Gavin Perkins
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1) A large randomized controlled trial studied the effects of adrenaline versus placebo for out-of-hospital cardiac arrest (OHCA). 2) The trial found that adrenaline increased the rate of return of spontaneous circulation and survival to hospital admission but did not improve rates of favorable neurological outcome at discharge. 3) The primary outcome of 30-day survival was higher in the adrenaline group, but those who survived in the adrenaline group were more likely to have severe brain damage.
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PARAMEDIC-2: A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest - Gavin Perkins
- 1. V2 29 September 2018
- 2. National Institute for Health Research improving the health and wealth of the nation through research • The trial was funded by the National Institute for Health Research HTA Programme (12/27/126) • The views expressed are those of the authors and not necessarily those of the NHS, NIHR or the Department of Health and Social Care
- 5. Rationale for the trial
- 6. J Crit Care 2014 Restart the heart
- 7. J Crit Care 2014 1 month survival
- 8. Survival with good brain function J Crit Care 2014
- 9. Adrenaline arm Saline (placebo) arm Courtesy of Giuseppe Ristagno, Mechanism 1: Impaired microvascular blood flow
- 10. Mechanism 2: Brain more sensitive to hypoxic ischaemic injury than the heart
- 14. Adrenaline improves long term patient focussed outcomes (neurocognitive function) Risks for Adrenaline outweigh the benefits Strongly Disagree Strongly Disagree Strongly Agree Strongly Agree Perkins Resuscitation 2016 Clinician consensus
- 15. A RCT of adrenaline is needed A RCT should compare adrenaline with: Strongly Disagree Strongly Agree Placebo Beta blocker Low dose Infusion Perkins Resuscitation 2016 Clinician consensus
- 17. Ethical considerations • Sought the views of: – Patients and public – Doctors, nurses and paramedics – Research Ethics Committee – Health Research Authority • Complied with legal and regulatory frameworks
- 18. • Approval for deferred consent from the Research Ethics Committee • Shared information about the trial with the public • Provided a mechanism for a person to indicate they did not want to participate in the trial Ethical approach
- 20. • Primary objective – The primary objective of this trial is to determine the clinical effectiveness of adrenaline in the treatment of OHCA measured as primary outcome: 30 day survival. • Secondary objective – Secondary objectives of the trial are to evaluate the effects of adrenaline on survival, cognitive and neurological outcomes of survivors and to establish the cost- effectiveness of using adrenaline. Objective
- 21. • Inclusion Criteria: – OHCA AND – ALS initiated and / or continued by ambulance service clinician • Exclusion criteria: – Known or apparent pregnancy – Known or apparently <16 years – Anaphylaxis or life threatening asthma – Adrenaline given prior to arrival of ambulance service clinician Eligibility Criteria
- 22. Adrenaline after 3rd shock Airway IV/IO Access Adrenaline
- 23. • Primary outcome – Survival to 30 days post randomisation • Secondary outcomes – Survived event (sustained ROSC, with spontaneous circulation until admission and transfer of care to medical staff at the receiving hospital) – Survival to hospital discharge post randomisation – Neurological outcome (modified Rankin Scale (mRS)) at hospital discharge. – Hospital length of stay post randomisation – Intensive care length of stay post randomisation – Hospital free survival in 30 days post randomisation – ICU free survival in 30 days post randomisation Outcomes
- 24. • Randomisation – opening drug pack – Post randomization exclusions • ROSC • ROLE • Exclusion • Drug administration Randomisation
- 30. 50% bystander witnessed 10% witnessed by paramedics 40% unwitnessed 20% initially shockable rhythms 90% medical cause of cardiac arrest Median time to adrenaline administration 21 minutes Mean dose 5mg
- 31. Return of spontaneous circulation Adrenaline 36.3% n=1457/3975 Placebo 11.7% n=468/3960
- 32. Admitted to hospital Adrenaline 23.8% n=947/3973 Placebo 8.0% n=319/3982 Significantly more in adrenaline group Odds ratio 3.6 (95% CI 3.1-4.1)
- 33. ICU pathway Adrenaline Admitted ICU n=566 (14.1%) Discharged alive from ICU n=152 (3.8%) [n=152/566 (27%)] Placebo Admitted ICU n=270 (6.8%) Discharged alive from ICU n=94 (2.3%) [n=94/270 (34%)]
- 34. Length of stay Adrenaline ICU LOS survivors 7.5d (3-15) ICU LOS non survivors 2d (1-5) Hosp LOS survivors 21 (10-41) Placebo ICU LOS survivors 7.0d (3.5-12.5) ICU LOS non survivors 3d (1-5) Hosp LOS survivors 2 (9-38)
- 36. Survival to 30 days Adrenaline 3.2% n=130/4012 Placebo 2.4% n=94/3995 Significantly more in adrenaline group Odds ratio 1.39 (95% CI 1.06-1.82) P=0.02
- 37. Data source Survival to 30d / discharge OHCAO 3.2% PARAMEDIC1 3.1% Jacobs 2011 4%
- 38. Favourable neurological outcome at discharge Adrenaline 2.2% n=87/4007 Placebo 1.9% n=74/3994 No significant difference Odds ratio 1.18 (95% CI 0.86-1.61)
- 39. Poor neurological outcome Adrenaline 31.0% n=39/126 Placebo 17.8% n=16/90 Significantly more with severe brain damage (mRS 4/5) in adrenaline group Post-hoc comparison Odds ratio 0.51 (95% CI 0.27-0.96)
- 40. Classified by modified Rankin Scale 100% 100% Survivors at hospital discharge Adrenaline (n=126) No adrenaline (n=90)
- 41. 3 month outcomes Adrenaline 3.0% n=121/4009 2.1% n=82/3986 Poor outcome n=16 Missing mRS n=29 Placebo 2.2% n=86/3991 1.6% n=63/3979 Poor outcome n=11 Missing mRS n=20 OR 1.41 (95% CI 1.1-1.9) OR 1.31 (95% CI 0.9-1.8)
- 42. Witnessed None Bystander Paramedic Bystander CPR CPR No CPR Initial rhythm Shockable Non-shockable Cause Medical Non-medical Age Response time Ambulance to drug time Call to drug time P=0.32 P=0.6 P=0.19 P=0.84 P=0.13 P=0.95 P=1.44 P=0.85 Favours Placebo Favours adrenaline
- 43. 10 times 8 times 20 times Adrenaline more effective more effective more effective Reference (1) Comparative effectiveness
- 44. Conclusion Adrenaline can restart the heart but it’s no good for the brain
- 45. Implications for practice Values and preferences of the communities we serve Conversation and dialogue
- 56. ICU free survival to 30 days
- 57. Hospital free survival to 30 days
Editor's Notes
- NO VIDEO or AUDIO
- The slide shows the effect of adrenaline on microvascular blood flow. The images are taken 3 minutes after ROSC in an animal model for cardiac arrest. The left hand slide shows sluggish or stagnant blood flow in the small (microvascular) blood vessels in an animal given adrenaline during the resuscitation attempt. The right hand slide shows intact microvascular blood flow in an animal treated with placebo (no adrenaline). Microvascular blood flow is blood flow in the capillaries which is where gas exchange occurs (as opposed to macrovascular – arteries and veins, which simiply transport blood around the body) The images have been provided by Giuseppe Ristagno specificlly for the use in training materials for the PARAMEDIC-2 trial. Please do not distribute elsewhere as we do not have permission to do so.
- 95% prioritised survival without brain damage
- Adjusted sub-group analyses There was no evidence of an interaction i.e. the effects were consistent across all sub-groups examined