Epinephrine has been a fundamental therapeutic agent in the management of cardiac arrest since the inception of advanced life support. Despite its ubiquitous use, this practice has never been supported by high quality evidence. With the publication of the PARAMEDIC-2 trial by Perkins et al1, we are now far closer to understanding the true value of epinephrine for out of hospital cardiac arrest (OHCA).
The authors performed a multicenter double-blind RCT, enrolling adult patients who experienced sustained OHCA, in which initial resuscitative attempts were ineffective (defined as no response to initial round of CPR and defibrillation). Patients were randomized to receive 1 mg of epinephrine or a matching syringe of normal saline given IV or IO every 3-5 minutes. Of the 10623 patients screened, 8014 patients were enrolled and included in the final analysis. (4015 patients in the epinephrine group and 3999 patients in the placebo group). As one would expect with an 8000 patient study, the two groups were fairly well balanced. The population study was typical for a cohort of patients experiencing OHCA. The mean age was 69, 65% were male, about 20% of the patients had an initial shockable rhythm, 50% were witnessed by a bystander and 59% received bystander CPR prior to the arrival of EMS.
The authors noted a statistically significant difference in their primary outcome, 30-day survival, which was 3.2% in the epinephrine group and 2.4% in the placebo group (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). This 0.8% absolute difference in survival remained consistent at 3-months (3% vs 2.2%), translated to a NNT of 112 patients to prevent 1 death at 30-days. The authors also reported an increase in the number of patients who were transported to the hospital (50.8% vs 30.7%) and survived to ICU admission (14.1% vs 6.8%).
Although methodologically speaking Perkins et al designed and conducted an almost flawless trial, their selection of a primary outcome is somewhat misleading. Even before this trial the resuscitative properties of epinephrine have been well documented in the literature 2,3,4 (2-4). Study after study has demonstrated that patients who receive epinephrine during cardiac arrest experience ROSC more frequently, are transported to the hospital more often, and are more likely to be admitted to the ICU. Since epinephrine has consistently demonstrated its ability to flog a dying heart into temporary cooperation, the authors primary endpoint was almost a foregone conclusion. In fact, it is somewhat surprising the difference in overall survival was so small (only 0.8%). The question we hoped to glean from PARAMEDIC-2 is what effect does epinephrine have on neurologically intact survival The authors reported no difference in the rate of neurologically intact survival in patients randomized to receive epinephrine vs placebo (2.2% vs 1.9). In fact, the increased survival reported in their primary outcome consisted entirely of patients with severe neurological disability, 31% of the survivors in the epinephrine group had a mRS score of 4 or 5, with only 17% in the placebo group.
While PARAMEDIC-2 does not entirely eliminate the potential benefits of epinephrine administered in drip form, or titrated to a physiological endpoint, these results do not support the continued use of bolus dose epinephrine in patients experiencing OHCA. Not only did the authors fail to demonstrate improvement in neurologically intact survival, epinephrine’s use was associated with a significant increase in critically ill patients without hope of neurological recovery. A heavy cost for such an ineffective therapeutic agent.
Sources Cited:
- EM Nerd-The Case of the Partial Cohort - May 24, 2020
- EM Nerd: The Case of the Sour Remedy Continues - January 20, 2020
- EM Nerd-The Case of the Adjacent Contradictions - December 23, 2019
Hi Rory
Nice summary of the trial. What are your thoughts on organ donation?
It’s potentially beneficial to aggressively resuscitate these patients from the point-of-view of maintaining organ perfusion. If the patient has an unsurvivable brain injury, it’s possible that patient may become an organ donor, either donation following circulatory death or donation after neurological death.
What do you think?
As you said PARAMEDIC2-study gives us no relevant new information we did not know before. More people recieve ROSC and are transfered to the hospital. OK ! CHECK ! Further diagnostic and therapeutic efforts were not evaluated (e.g. protocolled post-cardiac-arrest-care, MTH, cath lab ……….) and this is a major problem i see in many post-CPR trials. Yes you have ROSC, but have you really found and treated the reason for the breakdown ???? If not …… patient will die anyway. Did you reach at least a minimum arterial pressure to keep your brain perfused ? Did you perform at least… Read more »
Agree with Voight that cardiac arrest is a team sport and that patient outcomes are a result of both pre and post arrest care. The study authors published their post-arrest care protocol in the supplementary appendix. It looked great but we have no idea how uniformly it was applied. In daily practice, I see significant variation in care and outcomes between institutions and even individual providers executing the same protocol. If we cut out epi now, we could be cutting out a key therapy that in combination with the application of other current and future therapies could create enough marginal… Read more »
Scott, I wonder if the epi team perhaps had a worse neurological outcome because more patients who would otherwise not have achieved ROSC did on this group and not just all the other theorical causes. I’d also like to know what the post resuscitation care was like namely hypothermia and facility capabilities and if that was appropriately randomized… I also think that 0.8% people are not blown away by becomes a big n when applied across the world given epi, we’ll known and old news not to definitely show patient centered benefit, now actually may show it. I think this… Read more »
I’d have to agree with your observation that we are likely seeing ROSC in patients we wouldn’t have done without epi. The trouble is though that we are would then be giving them epi without evidence of a meaningful benefit. If anything we are likely producing a group of patients with minimal hope or meaningful survival at a huge financial cost to the health system.
Do we think there IS a group of individuals to target for epi, i.e. only respiratory arrest or vtach/vfib arrest? Secondly, since we know high dose epi (5mg) is no better than low dose, how much is ideal? Should we only give 4mg or less and then stop? It may result in less overall survival rates but more significant when taking neuro status into account? What was the average amount of epi given to that arm of the study? How much was given to the pts who achieved ROSC, or survival to discharge? I have a feeling we are just… Read more »
WHAT EVERYONE FAILS TO REALIZE – The epinephrine in all these cases was delivered VERY late in the cardiac arrest. On average of 15 minutes after arrival! (Not sure if they had to weight for arrival of a special unit).
This study is comparing the effects of loading a mostly dead body up with epi and seeing if you can rev the half-dead tissues into temporarily functioning a bit longer.