Big thanks to Michelle and Adam for hosting! Also thanks to Mitch K, Katie, Tammy, Maddy, Tim and Ethan for their erudite presentations.
Background: Historically, the only 2 pre-hospital interventions demonstrated to improve survival with good neurologic function after OHCA have been early defibrillation and bystander CPR. Epinephrine, used in cardiac arrest since the 1960s, has consistently been shown to improve ROSC without improving neurologic outcomes.
There are physiologic pros and cons to epi: alpha effects promote vasoconstriction, increasing aortic diastolic pressure and augmenting coronary blood flow and the chance of ROSC. Beta effects can cause dysrythmias, increase myocardial O2 demand and platelet activation, and impair microvascular blood flow leading to long-term organ dysfunction of heart and brain.
Article #1: Perkins GD, Ji G, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest (PARAMEDIC2). NEJM. 2018; 379: 711-721.
This is the largest randomized data set on the use of epinephrine in OHCA. In this pragmatic RCT from the UK and 5 National Health Service ambulance services, a total of 8,014 patients received 1 mg epinephrine every 3-5 minutes vs. placebo for OHCA. Groups were well balanced with regards to baseline characteristics.
The primary outcome was 30-day survival. Secondary outcomes included survival until hospital discharge with a favorable neurologic outcome (modified Rankin scale, mRS ≤ 3). There was a large difference in achieving ROSC favoring epi (36% vs 12%), and at 30 days, significantly higher overall survival in epi patients (3.2% vs 2.4%). However at hospital discharge the same percentage of patients had favorable neuro outcome in both groups (2.2% epi, 1.9% placebo), and more survivors in the epi group had severe neurologic outcomes, mRS 4 or 5 (31% vs 18%).
--Median time from EMS call to epinephrine = 20 minutes (into “metabolic phase” of cardiac arrest). Early epi has been associated with improved outcomes.
--All centers were in the UK, limiting external validity.
--Low overall survival, although this is partially explained by exclusion of >600 patients with ROSC immediately after defibrillation and therefore never needed epi.
--Hospital care was not standardized, although national guidelines were followed.
--No data were reported on baseline neurologic status of patients.
Conclusion: Epinephrine saves bodies, but not brains.
Article #2: Funada A, Goto Y, Tada H et al. Effects of Prehospital Epinephrine Administration on Neurologically Intact Survival in Bystander Witnessed Out-of-Hospital Cardiac Arrest Patients with Non-Shockable Rhythm Depend on Prehospital Cardiopulmonary Resuscitation Duration Required to Hospital Arrival. Heart and Vessels. 2018
Observational trial in Japan of 118,000 patients with bystander witnessed OHCA and non-shockable rhythm, with intent of determining time-dependent effects of pre-hospital epinephrine administration. Due to the organization of the EMS system in Japan, some patients never received pre-hospital epi, and outcomes for this group were based on duration of time from CPR initiation by EMS to hospital arrival. The primary outcome was 1-month survival with good neurologic outcome (cerebral performance category 1 or 2). There was a lot of slicing and dicing, but bottom line was an association of better outcomes if short transport time to the hospital or early epinephrine in the field. The study didn’t include any data on the number of patients with poor neurologic outcomes, and is an observational trial with all limitations intrinsic to a retrospective data set.
Conclusion: Early epi was associated with improved neuro outcomes in witnessed OHCA with non-shockable rhythm in this retrospective observational study.
Article #3: Belletti A, Benedetto U, Putzu A et al. Vasopresors During Cardiopulmonary Resuscitation. A Network Meta-Analysis of Randomized Trials. Critical Care Medicine. 2018; 46(5) e443-e451.
In this network meta-analysis (statistical approach to compare multiple interventions/treatments), 28 RCTs of nearly 15,000 adults with either IHCA or OHCA receiving vasopressors were evaluated to identify preferred vasopressor for the outcomes of ROSC, survival, and survival with good neurologic outcome. PARAMEDIC2 was not included due to timing of publication. Only a combination of epinephrine, vasopressin, and methylprednisolone was associated with increased likelihood of ROSC, and survival with good neurologic outcome. This therapy combination was evaluated in 2 studies in patients with IHCA. When analyzing OHCA arrest studies, no treatment was superior over others. When evaluating shockable rhythm and non-shockable rhythm separately, again there was no vasopressor treatment superior to another. There is no significant randomized evidence to support nor discourage the use of epinephrine during cardiac arrest.
Future of epi? Don’t expect a change in the AHA ACLS recommendations in 2020. Benefits of epinephrine may be time dependent (early is better), rhythm dependent (works better in non-shockable rhythms), and dose-dependent (less may be more). If epi was a new drug being evaluated for use in cardiac arrest, it might be a hard sell, but epi is stocked on EMS rigs around the world, and there are ongoing research efforts to determine how to optimize its use and gain both circulatory and clinical improvement. For example, look for results from a large Korean RCT after 2020 evaluating effect of vasopressin/epinephrine/steroids in OHCA: https://clinicaltrials.gov/ct2/show/NCT03317197