Epinephrine in Out-of-Hospital Cardiac Arrest
You are doing an EMS ride-along during your EMS elective and get a call for a 70-
year old male in cardiac arrest. The paramedic hits the lights and sirens and you’re
on scene in five minutes. The ?ire department has already arrived and CPR is in
progress. They tell you that the patient was watching TV with his wife when he
collapsed about 15 minutes prior to their arrival. He did not receive any bystander
CPR and was pulseless and apneic on their arrival.
You and the EMS team take over CPR and bag the patient while hooking up the
monitor. He is found to be in asystole and the paramedic grabs an amp of
epinephrine. You place a supraglottic airway, he gets the epinephrine, and you load
him up while continuing good, uninterrupted chest compressions. He gets two more
rounds of epi en route and gets a pulse back.
On arrival to the ED he has a pulse, is mildly hypotensive, but has no spontaneous
breaths and his pupils are fixed and dilated. You know that giving epinephrine in
cardiac arrest is the standard of care, but wonder what effect it really has: does it
improve ROSC, and if so does it actually improve neurologic function down the road.
You wonder if their is really any evidence to support its use at all. You head to the
computer and start searching. You encounter a prior journal club on this topic from
2015, but wonder if there is any new evidence…
Population: Adult patients with atraumatic out-of-hospital cardiac arrest
Intervention: Intravenous epinephrine administration
Comparison: Standard CPR without epinephrine administration
Outcome: Return of spontaneous circulation, survival to hospital admission, survival to hospital discharge, survival with a good neurologic outcome.
A PubMed search was performed using the search terms “(out-of-hospital cardiac
arrest) AND (epinephrine).” The search was limited to humans, resulting in 248
citations. These were searched and two randomized controlled trials, one
observational trial, and one systematic review were chosen for inclusion. We picked
2 articles we thought were important from the last journal club in January 2015 and
2 new articles, including a randomized control trial, that appeared to represent the
highest quality evidence to date.
Article 2: Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L.
Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 2009 Nov 25;302(20):2222-9.
Article 4: Hansen M, Schmicker RH, Newgard CD, et al; Resuscitation Outcomes
Consortium Investigators. Time to Epinephrine Administration and Survival From
Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults.
Circulation. 2018 May 8;137(19):2032-2040.
As evidence-based medicine has taken root within biomedical research, many
standard practices have been questioned as a look back at the supporting evidence
(or lack thereof) has shown some of them to be closer to tradition than science.
Epinephrine use in out-of-hospital cardiac arrest (OHCA) is one such practice that
has come under fire. Its proposed benefit has been an increase in coronary perfusion
pressure, as demonstrated in animal studies. Consequently, as it was during our last
look at this topic, epinephrine’s use continues to be recommended by the American
Heart Association and the European Resuscitation Council, although wording in the
latter’s guidelines emphasize the lack of evidence in doing so. While high-dose
epinephrine has been shown to improve rates of return of spontaneous circulation
(ROSC), it does not improve the more clinically relevant outcome of survival to
hospital discharge (Gueugniaud 1998, Vandycke 2000). This may be in part due to
reduced microcirculatory cerebral blood flow caused by epinephrine, resulting in
worse neurologic outcomes among survivors.
Past observational studies looking at epinephrine’s utility in OHCA have come to
differing conclusions (Herlitz 1995, Holmberg 2002, Ohshige 2005, Wang 2005, Ong
2007, Yanagawa 2010). In one randomized control trial (Olasveengen 2009), the
authors examined whether any IV medication administration influenced survival to
hospital discharge. The results demonstrated that the IV access group had more
defibrillation attempts (47% vs 37%, respectively; OR, 1.16 [95% CI, 0.74- 1.82]),
more defibrillation shocks (median, 3 [range, 1-22] vs 2 [range, 1-26], respectively;
P =.008), longer CPR duration (22 vs 18 minutes [95% CI, 20-23 vs 17-19), and
higher short-term survival goals such as achieving ROSC (40% vs 25%, OR, 1.99
[95% CI, 1.48-2.67], P< .001) and survival to hospital admission (43% vs 29%, OR,
1.81 [95% CI, 1.36-2.40] P < .001). On the other hand, there was no statistically
significant difference in their primary outcome measure of survival to discharge.
Unfortunately there were several problems with the study including confounding with intention-to-treat analysis (37 of 433 in the no IV access group got epi and 85
of 418 in the IV access group didn’t get epinephrine), selection bias as early ROSC
was put in the no IV access group regardless of allocation, and the possibility of a
type II error due to underpowering the study.
Reardon and Magee noted these shortcomings in their 2013 review paper when
Olasveengen (2012) went back with a post hoc analysis to try and tease out the
relationships between those who received epinephrine and those who did not in the
same data set. After reviewing the current literature for epinephrine in OHCA,
Reardon and Magee and again found the quality and quantity of data to be lacking.
They did point out the quality of the one randomized controlled trial comparing the
use of epinephrine with placebo in the management of OHCA (Jacobs 2011). While
this study demonstrated improvements in survival to hospital discharge with the
use of epinephrine, this result did not achieve statistical significance (OR 2.2, 95% CI
0.7-6.3). The study was afflicted, unfortunately, by a small sample size and was
underpowered to detect a potentially clinically significant improvement in
outcomes. While the investigators initially planned to perform a large study
involving five ambulance services throughout Australia and New Zealand, all but one
service withdrew from the study due to ethical concerns.
In Hansen’s (et al. 2018) paper, they approached the topic from a different
perspective and sought to figure out the relationship between time to epinephrine
administration and survival in adults and children with OHCA and initial
nonshockable rhythms. Because this was a retrospective, secondary analysis of a
large population data set (Resuscitation Outcomes Consortium with an N of 32,101
patients after exclusion criteria applied), they could only comment on association
instead of causation. They were able to demonstrate a statistically significant
association between duration of time from EMS arrival to epinephrine
administration and survival, with a 4% decrease in odds with each additional
minute delayed (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.95–0.98);
epinephrine given greater than 10 minutes after EMS arrival decreased odds of
survival by 18% (OR, 0.82; 95% CI, 0.68–0.98) while unwitnessed arrests with late
epinephrine administration had 37% decrease in survival odds (OR, 0.63; 95% CI,
0.48–0.83, P = 0.02). They also noted CPR process measures were not clinically
significant variables and neither was the route of epinephrine (IV vs. IO). There was
not a separate comparison with the patients who received no epinephrine.
Also in 2018, the much anticipated (in process last journal club) results from the
randomized, double-blinded, placebo controlled PARAMEDIC2 trial were released.
This was the study that Jacobs had intended to perform in 2011, before the
withdrawal of four EMS services. This time they were able to enroll 8014 patients across 5 National Health Service ambulance services in the UK and randomized
patients to receive epinephrine or placebo. PARAMEDIC2 found higher 30-day
survival rates in the epinephrine group (NNT 112, unadjusted OR for survival, 1.39;
95% CI, 1.06-1.82; P = 0.02), but no significant difference in the rate of favorable
neurologic outcome because more survivors had severe neurologic impairment in
the epinephrine group. Additionally, in the pre-trial period they had conducted a
survey of the public which showed 95% of respondents prioritized long-term
survival over short-term survival.
At best, epinephrine is flogging the heart, achieving ROSC in patients who are
otherwise beyond survival. At worst, it is saving the heart and suffocating the brain,
harming or even killing patients who might otherwise be saved. At the very least, it
can be a distraction from the proven measures of high quality compressions and
early defibrillation in a resource limited environment.