REBEL Cast Ep56 – PARAMEDIC-2: Time to Abandon Epinephrine in OHCA?

Background: Epinephrine(adrenaline) has been used in advanced life support in cardiac arrest since the early 1960s. Despite the routine recommendation for its use, evidence to support administration is less than ideal. Although it is clear from multiple observational studies that epinephrine improves return of spontaneous circulation (ROSC) and short-term survival, most evidence suggests an absence of improvements in survival with good neurologic outcomes. In cardiac arrest we want to take advantage of the alpha effects of epinephrine, including peripheral vasoconstriction, and therefore increasing aortic diastolic pressure, which in turn helps augment coronary and cerebral blood flow. On the other hand, we want to avoid the potentially detrimental beta effects including dysrhythmias, decreased microcirculation, and increased myocardial oxygen demand all of which increase the chances of recurrent cardiac arrest and decreased neurologic recovery. The only two interventions in cardiac arrest that have shown improve survival with good neurologic outcomes continue to be high-quality CPR and early defibrillation. The debate over the utility of epinephrine in OHCA has been ongoing for several years now and many providers have been awaiting the results of the PARAMEDIC-2 trial that was just published in the NEJM 2018.

REBEL Cast Episode 56 – PARAMEDIC-2 – Time to Abandon Epinephrine in OHCA?

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What They Did: Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC-2).This was a multicenter, randomized, double-blind, placebo controlled trial involving 8014 patients with OHCA in the United Kingdom

Patients:Adult patients with OHCA receiving ACLS provided by trial-trained paramedics

Intervention:IV epinephrine 1mg q3 – 5min + standard care

Comparison:IV 0.9% normal saline bolus + standard care

Outcomes:

Primary: 30d Survival

Secondary: Survival to Hospital Discharge with Favorable Neurologic Outcome (i.e. mRS ≤3) Survival Until Hospital Admission Length of Stay in the Hospital Length of Stay in the ICU Survival at Hospital Discharge and at 3 Months Neurologic Outcomes at Hospital Discharge and at 3 Months



Exclusion:

Pregnant

Age <16 years

Cardiac arrest from anaphylaxis or asthma

Administration of epinephrine before arrival of a trial-trained paramedic

Traumatic cardiac arrests excluded in one ambulance service

Results:

8014 patients with OHCA 4015 in the IV epinephrine arm (Epi) 3999 in the IV saline placebo arm (Placebo)



Strengths:

Asks a clinically important question

Largest RCT to date on the use of epinephrine in OHCA. Prior to this Jacobs et al trial, which ended prior to complete enrollment was the largest RCT [4]

Large, multicenter, double-blind, placebo controlled trial

Data regarding quality of CPR were obtained with use of defibrillator downloads when available

Outcomes were assessed by research paramedics who were unaware of treatment assignments

Recorded serious adverse events (death, hospitalization, and disability)

Interim data and safety monitoring was performed every 3 months

Patients were well balanced at baseline and had similar concurrent treatments

Limitations:

Hospital-based care, including targeted temperature management, hemodynamic support, ventilatory criteria, and prognostication were not specified in the trial protocol, but did follow national guidelines

Used only 1mg epinephrine q3 – 5min, whereas other dosing strategies might have produced different results

No data on patients baseline neurologic status

The original protocol anticipated a higher survival rate than the one that was observed (6.5% in the placebo group and 7% in the epinephrine group) àSee discussion for elaboration

Information about the quality of CPR was limited to the first 5 minutes of cardiac arrest and involved <5% of enrolled patients

Discussion:

The evidence to date of survival to hospital discharge or long term survival from prior observational studies:

Algorithms for Resuscitation and Post-ROSC Care:

There was a low rate of shockable rhythms in this study (19.2% in Epi arm and 18.7% in the placebo arm). This is evidenced by the extremely low survival rate in this study of 3.2% and 2.4% respectively. However, this is interesting because the authors removed 615 patients who survived after initial management (ie defibrillation -> ROSC). This critique seems to be very prevalent on twitter and should be squashed. Survival was low because those most likely to survive, were removed from study.

CPR was performed in witnessed cardiac arrest in almost 70% of cases

Median time from emergency call to ambulance arrival at the scene was quite quick at about 6 ½ minutes

Median time between emergency call and administration of trial agent 21 minutes.This is an important point, as cardiac arrest is believed to have 3 phases: First 5 min = Electrical Phase (Heart Most Amendable to Defib), Next 10 – 15min = Circulatory Phase, and >20min = Metabolic Phase (Acid-Base Derangements). Epinephrine seems to have its best chances of effect at <20min.

Supraglottic airways were commonly used in this trial in approximately 70% of cases

As per prior observational trials [2 – 9] the use of epinephrine did seem to increase the chances of ROSC (36.3% vs 11.7%).

The authors also make the astute point that number of patients who would need to be treated with epinephrine to prevent one death after cardiac arrest was 112 in this study, but this should also be compared to the things that make a difference in neurologic outcomes which include, CPR performed by a bystander (NNT = 15) and early defibrillation (NNT = 5)

Author Conclusion:“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 a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.”

Clinical Take Home Point: In this well done, multicenter trial epinephrine given at 1mg q3 – 5 minutes increased the chances of ROSC but came at a cost of more ICU usage, more patients with severe neurological disabilities, and no difference in survival with favorable neurological outcome compared to placebo. The use of epinephrine 1mg q 3 – 5 minutes should no longer be part of standard cardiac arrest protocols. Epinephrine should be administered on a case by case basis by experienced providers who perceive that there is a benefit to be had.

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References:

Perkins GD et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. NEJM 2018. [Epub Ahead of Print] Hagihara A et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012. PMID: 22436956 Holmberg M et al. Low chance of survival among patients requiring adrenaline (epinephrine) or intubation after out-of-hospital cardiac arrest in Sweden.Resuscitation2002. PMID: 12104107. Jacobs I et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial.Resuscitation 2011. PMID: 21745533. Olasveengen T et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.JAMA 2009. PMID: 19934423 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. PMID: 17509730 Stiell IG et al. Advanced Cardiac Life Support in Out-of-Hospital Cardiac Arrest in OHCA. NEJM 2004. PMID: 15306666 Nakahara S et al. Evaluation of Pre-Hospital Administration of Adrenaline (Epinephrine) by Emergency medical Services for Patients with Out-of-Hospital Cardiac Arrest in Japan: Controlled Propensity Matched Retrospective Cohort Study. BMJ 2013. PMID: 24326886 Sanghavi P et al. Outcomes after Out-of-Hospital Cardiac Arrest Treated by Basic vs Advanced Life Support. JAMA Intern Med 2015. PMID: 25419698

For More Thoughts on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)