Epi for Out-of-Hospital Arrest

In Review

Perkins GD, et al. "A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest". NEJM. 2018. 379:711-721.
PubMed • Full text

Clinical Question

In adult patients that present to paramedics with out-of-hospital arrest in the field, dose acute cardiac life support performed with epinephrine as compared to placebo lead to improved survival and neurological outcome.

Bottom Line

Epinepherine 1mg as administered as part of cardio-pulmonary resuscitation during out of hospital arrest will slightly improve survival but is associated with worsening neurological outcomes.

Major Points

Epinepherine (adrenaline) has been a mainstay of cardiopulmonary resuscitation (CPR) for over half a century. Pharmacologically, along with chest compressions, work towards shunting blood into the central circulation, however, this may be at the cost of microvascular perfusion. Epinepherine may also stimulate the myocardium and induce arrhythmias which would be more problematic in patients with shockable rhythms

This trial conducted in southern Britain including patients from five National Health Service ambulance services randomized 8007 patients to receive either epinepherine 1mg (n=4012) or placebo (n=3995) as part of standard CPR for out-of-hosptial arrest. Their primary outcome was survival at 30 days and their secondary outcomes included length of stay as well as neurological outcomes at 30 days and 3 months. Overall the epinepherine group had improved survival to hospital admission (23% vs. 8%), at 30 days (3.2% vs. 2.4%) or at 3 months (3% vs. 2.2%). Favourable neurological outcomes, however, had no statistical difference at both hospital discharge and at 3 months.

Previous observational trials have demonstrated similar findings to this trial, improvements in ROSC an poor neurological outcomes. The use of epinepherine originally was based on observational trials and animal studies; this prospective, real-world trial has suggested that this may be not support its ongoing use. This trial only tested one dose of epinepherine and a different dose may shown a different outcome for neurological outcomes, however, previous trials have shown no difference in survival, leading to recommendations against these higher doses. This trial is hypothesis generating and may leead to further discussion on use of epinepherine as part of out-of-hospital ACLS.

Guidelines

American Heart Association/International Liaison Committee on Resuscitation (AHA/ILCOR) 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

• Epinepherin 1 mg administered to patients in cardiac arrest
  • after considering the observed benefit in short-term outcomes (ROSC and admission to hospital) and our uncertainty about the benefit or harm on survival to discharge and neurologic outcome.

Design

• Multicenter, randomized, double-blind, placebo-controlled
• N=8007
  • Epinepherine (n=4012)
  • Placebo (n=3995)
• Setting: Five National Health Service ambulance services in the United Kingdom
• Enrollment: December 2014 through October 2017
• Follow-up: 90 days
• Analysis: modified intention-to-treat
• Primary Outcome: Survival to 30 days

Population

Inclusion Criteria

• Adult patients (≥16 years old)
• Out-of-hospital cardiac arrest
• Advanced life support was provided by trial-trained paramedics

Exclusion Criteria

• Known or apparent pregnancy
• Cardiac arrest from anaphylaxis or asthma
• Administration of epinephrine before the arrival of the trial-trained paramedic
  • In one ambulance service, traumatic cardiac arrests were also excluded

Baseline Characteristics

Epinepherine Group displayed

• Demographics: Mean age 69 years, 35% female
• Initial cardiac rhythm: shockable 19%, Non-shockable 78%, Undetermined 2%
• Cause of Cardiac Arrest: Medical 91% Traumatic 2%, Drowning 0.2%, substance overdose 2%, Asphyxia 3%, missing data 2%
• Witness of cardiac arrest: none 37%, Paramedic 11%, Bystander 50%, missing data 1%
• CPR Performed by: Paramedic 11%, bystander 59%, missing data 2%
• Time from: emergency call to ambulance arrival 6min, emergency call to administration of drug 22min, arrival to ambulance departure 50min

Interventions

• 1 mg of epinephrine administered by an intravenous or intraosseous route every 3 to 5 minutes
• Placebo (0.9% Saline)

Outcomes

Comparisons are Epinepherine therapy vs. Placebo therapy.

Primary Outcomes

Survival at 30 days

3.2% vs. 2.4% (OR unadjusted 1.39; 95% CI 1.06-1.82 / OR adjusted 1.47; 95% CI 1.09-1.97)

Secondary Outcomes

Survival to hospital admission

23.8% vs. 8% (OR unadjusted 3.59; 95% CI 3.14-4.12 / OR adjusted 3.83; 95% CI 3.30-4.43)

Length of ICU Stay, median, days(IRQ)

Survived: 7.5(3-15) vs. 7(3.5-12.5)

Died: 2(1-5) vs. 3(1-5)

Length of Hospital stay, median, days(IRQ)

Survived: 21(10-41) cs. 20(9-38)

Died: N/A

Survival to hospital discharge

3.2% vs. 2.3% (OR unadjusted 1.41; 95% CI 0.86-1.61 / OR adjusted 1.19; 95% CI 0.85-1.68)

Favourable neurological outcome at hospital discharge

2.2% vs. 1.9% (OR unadjusted 1.18; 95% CI 0.86-1.87 / OR adjusted 1.19; 95% CI 0.85-1.68)

Survival at 3 months

3% vs. 2.2% (OR unadjusted 1.41; 95% CI 1.07-1.87 / OR adjusted 1.47; 95% CI 1.08-2.00)

Favourable neurological outcome at 3 months

2.1% vs. 1.6% (OR unadjusted 1.31; 95% CI 0.94-1.82 / OR adjusted 1.39; 95% CI 0.97-2.01)

Criticisms

• Estimated survival rate was higher than the results so the power calculation may have been flawed
• Post-arrest in-hospital management was not controlled for nor measured
• Time to drug administration was longer as compared to other trials

Funding

• Health Technology Assessment Programme of the U.K National Institute for Health Research, with legal sponsorship provided by the University of Warwick