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The Edge: The Epinephrine Conundrum Revisited
The Edge is a monthly blog series developed by EMS World and FlightBridgeED that features top EMS medical directors exploring the intricacies of critical care in EMS practice. In this installment FlightBridgeED Chief Medical Director Jeffrey Jarvis, MD, delves further into epinephrine in cardiac arrest.
I wrote about the conundrum of epinephrine in cardiac arrest in this column in March 2020.1 In that article I discussed the landmark PARAMEDIC-2 trial and its challenging conclusion: Epinephrine, as currently recommended in AHA/ILCOR guidelines, results in a small increase in 30-day survival (0.8%) without any difference in the more clinically important neurologically intact survival overall and almost twice as much neurologic devastation among survivors (31.0% vs 17.8%).2
Prior work using surveys of clinical experts calculated a minimum clinically important difference (MCID) of at least 5% for both improved survival and neurologically intact survival for an intervention to be adopted in cardiac arrest.3 The PARAMEDIC-2 trial calculated there is a 0.2% probability of achieving at least 2% improved 30-day survival, a threshold for adoption that is well below the MCID of 5%. To be even more blunt, there was a 0% probability of epinephrine resulting in at least a 2% improved probability of neurologically intact survival. My conclusion from this large, well-done trial was that epinephrine saves the heart at the expense of the brain.
We must always continuously incorporate new evidence into our interpretation of scientific literature. Three new studies published since my last article can help us further our understanding of the role of epinephrine in cardiac arrest.
Time to Epi: Does It Matter?
One of the criticisms of PARAMEDIC-2 was that the time to epinephrine was longer than commonly seen in the U.S. Its authors found a median of 21 minutes from time of the emergency call to the first administration of epinephrine or placebo. Critics have voiced appropriate concern that, because prior observational studies have found time to first epinephrine to be important,4–6 this study may not be useful in determining the role of epinephrine in U.S. out-of-hospital cardiac arrest (OHCA).7 A recent trial examined this question.8
In this secondary analysis of the PARAMEDIC-2 trial, the University of Warwick’s Gavin Perkins and colleagues performed a statistical analysis looking at the influence of time to administration of the study drug (epinephrine or placebo) on each of the outcomes studied: ROSC, 30-day survival, and neurologically intact survival. They excluded patients with unwitnessed arrests (around 38% of 8,000 patients) because of the unknown time from arrest to drug administration. They did this by looking at the interaction between time to drug administration and outcome, controlling for the study drug and other clinically relevant variables such as age, initial rhythm, bystander CPR, etc.
They found, as we already knew, that all outcomes worsen with time. In other words, the longer you are in cardiac arrest before we intervene, the worse you’ll do. This obviously isn’t revelatory. What is important, however, is that the time to epinephrine only mattered in ROSC. It made no difference in 30-day survival or neurologically intact survival. Since ROSC alone is not a patient-oriented outcome, I don’t see this as a meaningful benefit. The author’s conclusion is, “The duration of cardiac arrest, rather than time to drug administration, is the key determinant of outcome.” I think this is a reasonable conclusion and appropriately addresses the criticism of PARAMEDIC-2.
Long-Term Outcomes
The second new study could be considered a continuation of PARAMEDIC-2 that looked at long-term outcomes.9 The University of Warwick’s Kirstie Haywood and colleagues conducted follow-up surveys of survivors from the original trial. Uniquely, they included measures of quality of life and need for assistance with daily activities with their assessment of survival and neurologically intact survival.
Survival outcomes were essentially the same at three and six months as they were at 30 days in the original trial: marginally higher in the epi groups than the placebo groups (0.8% at both time points). There was no difference in neurologically intact survival among all arrests. They also found the higher neurological devastation among survivors seen with epinephrine compared with placebo persisted at three and six months (1.4% and 9.4% between-group differences respectively). While they found no difference in quality of life between the epinephrine and placebo groups as measured on several scales, they did find a larger proportion of patients in the epinephrine group who needed assistance with activities of daily living at both three and six months (16% and 13% differences respectively).
This paper indicated that the conundrum of epinephrine—that is, improving survival at the expense of neurologic function—persisted for up to six months. Interestingly, it also found a clear decrease in quality of life among all survivors of cardiac arrest when compared with the general population.
Impact of Drug Administration Route
The third paper looked at another secondary analysis of the PARAMEDIC-2 trial, this one evaluating the impact of the route of drug administration (IV vs. IO) on outcome.10 Several papers have recently suggested that resuscitation medications may be more effective when given via IV. Notably, a reanalysis of the ALPS trial indicated that amiodarone and lidocaine may improve survival among patients with refractory shockable rhythms when given via IV but not by IO.11 This was a particularly interesting finding in light of the surprising results of the parent trial showing no difference in survival with either medication.12
The University of Bristol’s Jerry Nolan and colleagues calculated the odds ratio of ROSC, 30-day survival, and neurologically intact survival between epinephrine and placebo in the PARAMEDIC-2 trial as a function of the route of administration. They excluded patients who had either an unknown route of administration or received the study drug via both IV and IO routes. After adjusting for the usual confounders (witnessed arrest, bystander CPR, etc.), they found no difference in any outcome. Importantly, they did not record the location of IO access, so they could not assess any potential impact of humeral vs. tibial IO placement. They did find an approximately four-minute faster time from scene arrival to drug administration with IV compared with IO. While this may seem contrary to prior evidence and the experience of IO being faster to establish,13 this trial was performed at a time when the standard guidelines in the U.K. were to establish IV access preferentially, with IO access reserved only for those patients for whom IV access was unsuccessful after two attempts.
Despite this four-minute time advantage with IV, there was still no difference in outcomes. This supports the finding in our prior paper that time to epinephrine is not a factor in survival. An important limitation, however, is that the trial was not randomized by route of administration, and over 70% of all patients had the study drug administered via IV.
Bottom Line: What to Do?
IV epinephrine every 3–5 minutes has been a mainstay in cardiac arrest resuscitation since 1906.15 There is significant clinical momentum favoring epinephrine despite a lack of evidence of improved neurologic survival. This is a nice way of saying we still give epinephrine because we’ve always done it this way. These six words are often the greatest impediment to improvement we face. I really had great hopes the PARAMEDIC-2 trial would help us finally answer the question of whether to use epinephrine. I think we actually have greater clarity now, but it is clarity of our conundrum.
We now have pretty convincing evidence that epinephrine improves survival without a difference in neurologic function at the cost of worse neurologic function among those who end up surviving. Trying to translate this research into action is both a clinical and moral challenge. There is clearly some benefit, albeit small, to epinephrine. As many have argued, you can’t have neurologic survival without survival.
The counterargument, though, asks if the small (0.8%) increase in survival is worth a larger increase (13.2%) in neurologic devastation among survivors. I think the ultimate answer to this question will require studies that directly survey patients about which outcome they value most. According to preliminary work described by the PARAMEDIC-2 authors, patients don’t seem to value survival at any cost. In the meantime, I’m left with the conclusion that what we’re doing now isn’t achieving the results I think most patients want.
So what am I doing, as an EMS medical director, with this conundrum? First I try to put the role of epinephrine in the context of other interventions. The number needed to treat (NNT) tells us how many patients need to be treated with an intervention to get one additional outcome. NNT is useful to help us compare the relative impact of different interventions. Using the results of the parent PARAMEDIC-2 trial, Perkins calculated an NNT of 112 with epinephrine vs. placebo to get one additional survivor at 30 days. This means that for every 112 patients given epi, there will be one additional survivor, and 111 will get no benefit. Contrast this with the NNT of other common interventions: bystander CPR: 15, early recognition: 11, early defibrillation: 5. This tells me that whatever I do with epinephrine pales in comparison with our efforts to improve community awareness and intervention.
Bystander CPR and public access defibrillation are far more meaningful interventions than epinephrine. We shouldn’t lose sight of this as we wring our hands about what to do with epi in cardiac resuscitation.
References
1. Jarvis JL. Grand Rounds: Hearts at the Expense of Brains. EMS World, 2020 May; https://www.hmpgloballearningnetwork.com/site/emsworld/article/1223974/grand-rounds-hearts-expense-brains.
2. Perkins GD, Ji C, Deakin CD et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med, 2018; 379: 711–21.
3. Nichol G, Brown SP, Perkins GD et al. What change in outcomes after cardiac arrest is necessary to change practice? Results of an international survey. Resuscitation, 2016 Oct; 107: 115–120.
4. Ewy GA, Bobrow BJ, Chikani V, et al. The time dependent association of adrenaline administration and survival from out-of-hospital cardiac arrest. Resuscitation, 2015; 96: 180–5.
5. Hansen M, Schmicker RH, Newgard CD, et al. Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults. Circulation, 2018; 137(19): 2,032–40.
6. Hayashi Y, Iwami T, Kitamura T, et al. Impact of Early Intravenous Epinephrine Administration on Outcomes Following Out-of-Hospital Cardiac Arrest. Circ J, 2012; 76(7): 1,639–4.
7. Callaway CW, Donnino MW. Testing Epinephrine for Out-of-Hospital Cardiac Arrest. N Engl J Med, 2018; 379(8): 787–8.
8. Perkins GD, Kenna C, Ji C, et al. The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial. Intensive Care Med, 2020; 46(3): 426–36.
9. Haywood KL, Ji C, Quinn T, et al. Long term outcomes of participants in the PARAMEDIC2 randomised trial of adrenaline in out-of-hospital cardiac arrest. Resuscitation, 2021 Mar; 160: 84–93.
10. Nolan JP, Deakin CD, Ji C, et al. Intraosseous versus intravenous administration of adrenaline in patients with out-of-hospital cardiac arrest: a secondary analysis of the PARAMEDIC2 placebo-controlled trial. Intensive Care Med, 2020 May; 46(5): 954–62.
11. Daya MR, Leroux BG, Dorian P, et al. Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest. Circulation, 2020; 141(3): 188–98.
12. Kudenchuk PJ, Leroux BG, Daya M, et al. Antiarrhythmic Drugs for Nonshockable-Turned-Shockable Out-of-Hospital Cardiac Arrest: The ALPS Study (Amiodarone, Lidocaine, or Placebo). Circulation, 2017; 136(22): 2,119–31.
13. Morgan RW, Berg RA. Intraosseous adrenaline for adult out-of-hospital cardiac arrest: Faster access with worse outcomes. Resuscitation, 2020 Apr; 149: 238–9.
14. Grunau B, Kawano T, Scheuermeyer FX, et al. The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest. Ann Emerg Med, 2019; 74(6): 797–806.
15. Crile G, Dolley DH. An Experimental Research Into The Resuscitation of Dogs Killed By Anesthetics and Asphyxia. J Exper Med, 1906; 8(6): 713–25.
Jeffrey L. Jarvis, MD, MS, EMT-P, FACEP, FAEMS, is chief medical director for FlightBridgeED, LLC and cohost of the FlightBridgeED EMS Lighthouse Project Podcast. He also serves as EMS medical director for the Williamson County EMS system and Marble Falls Area EMS and is an emergency physician at Baylor Scott & White Hospital in Round Rock, Tex.
