Epinephrine in Out of Hospital Cardiac Arrest - The PARAMEDIC-2 Trial

Background:

For decades the standard of care has been to use epinephrine in out of hospital cardiac arrest. There has long been a thought that it reduces mortality by improving rates of return of spontaneous circulation (ROSC). Indeed, the AHA states in the ACLS guidelines that “Standard-dose epinephrine (1 mg every 3 to 5 minutes) may be reasonable for patients in cardiac arrest.”[1]

However, they give this statement a class 2b level of evidence (weak).

Half of cardiac arrests happen out of hospital. We know that early defibrillation and CPR are critical, but the role of epinephrine has been called into question in several recent trials. [3,4,5,6]

In theory epinephrine increases alpha-1 stimulation. This causes peripheral vasoconstriction, increasing diastolic pressures and improving coronary perfusion. However, the vasoconstriction of the brain’s microcirculation may lead to worsened cerebral hypoxia.

Prior to the PARAMEDIC-2 trial, the question of epinephrine vs no epinephrine had been looked at by about 10 observational studies and 2 clinical trials. In total about 600,000 patients and these papers show increased rates of ROSC and survival to discharge but no difference in neurological outcomes.

In summary: The use of epinephrine in cardiac arrest appears to lead to more ROSC but the effect on neurological outcomes is unclear.

The PARAMEDIC-2 trial [2]:

Study Details:

  • Clinical Question

    • To determine whether epinephrine is beneficial or harmful as a treatment for out-of-hospital cardiac arrest

  • Study Design

    • A randomized, double blind placebo controlled trial

  • Population

    • Out of hospital cardiac arrest patients in the United Kingdom cared for by five specific ambulance groups.

  • Inclusion Criteria

    • Adult patients who had sustained an out-of-hospital cardiac arrest for which advanced life support was provided by paramedics who were trained in the trial protocol.

  • Exclusion Criteria

    • Known or apparent pregnancy, age of < 16 years, cardiac arrest from anaphylaxis or asthma, or the administration of epinephrine before arrival of the trial-trained paramedic.

  • Interventions

    • 1 mg of epinephrine every 3-5 minutes

  • Comparison

    • 0.9% normal saline every 3-5 minutes

  • Primary Outcome

    • Rate of survival at 30 days

  • Secondary Outcomes

    • Rate of survival until hospital admission, the lengths of stay at the hospital and ICU, rates of survival at hospital discharge and at 3 months, and the neurologic outcomes at hospital discharge and at 3 months.

  • Results

 

Epi

Placebo

OR

Primary Outcome

30 d survival

3.2%

2.4%

1.39 (1.06-1.82)

Secondary Outcomes

Survival to hospital admission

23.8%

8.0%

3.59 (3.14-4.12)

Survival to DC

3.2%

2.3%

1.41 (1.08-1.86)

Survival to DC with favorable neuro outcome

2.2%

1.9%

1.18 (0.86-1.61)

Survival at 3 mo

3.0%

2.2%

1.41 (1.07-1.87)

Survival at 3 mo with favorable neuro outcome

2.1%

1.6%

1.31 (0.94-1.82)

Severe Neurologic Impairment

31.0%

17.8%

 

Author’s conclusions

In adults with out of hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.”

 

Our conclusions:

The use of epinephrine in out of hospital cardiac arrest leads to a rather large increase in ROSC but no increased neurological recovery. As a result, the current one-size-fits-all use of epinephrine in non-shockable cardiac arrest should be reconsidered.

To here a more detailed discussion of our analysis and conclusions, please listen to the podcast below:

 

But don’t just take our word for it, check out some of these other amazing podcasts and posts on the trial:

RebelEM: http://rebelem.com/rebel-cast-ep56-paramedic-2-time-to-abandon-epinephrine-in-ohca/

The Resus Room Podcast: https://player.fm/series/the-resus-room/adrenaline-in-cardiac-arrest-paramedic2

The Bottom Line: https://www.thebottomline.org.uk/summaries/icm/paramedic2/

VisualMed: https://visualmed.org/paramedic2-trial-visual-abstract-epinephrine-in-out-of-hospital-cardiac-arrest/


References:

  1. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015 [pdf]

  2. Perkins GD et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. NEJM 2018. [Pubmed]

  3. Hagihara A et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012. [Pubmed]

  4. Jacobs IG et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation 2011.[Pubmed]

  5. Olasveengen T et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 2009.[Pubmed]

  6. Ong M et al. Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest. Annals of Emergency Medicine 2007.[Pubmed]

  7. Patel et al. Association Between Prompt Defibrillation and Epinephrine Treatment With Long-Term Survival After In-Hospital Cardiac Arrest. Circulation 2017 [Pubmed]