Grand Rounds: Hearts at the Expense of Brains

Grand Rounds is a new monthly blog series developed by EMS World and FlightBridgeED that will feature top EMS medical directors exploring the intricacies of critical care in EMS practice. In this installment FlightBridgeED Chief Medical Director Jeffrey Jarvis, MD, PM, questions the role of epinephrine in cardiac arrest care. 

Epinephrine has been the foundation of cardiac arrest management for as long as I can remember. Bicarb has come, gone, and considered a comeback, but epi has never changed. This is despite a lack of good evidence that it’s actually effective. This may be changing. An extensive and well-done paper published in the New England Journal of Medicine in 2018 casts this stalwart of emergency medicine in a new light. Let’s look at it in the context of what we already knew.

The first indication that epinephrine might be useful in cardiac arrest was published in 1906.¹ You read that right: The core of the pharmaceutical management of cardiac arrest is built on 114 years of tradition uninhibited by science. This was an experiment in which they induced cardiac arrest in 60 unfortunate dogs of all breeds, ages (yes, they killed puppies!), and weights. They found some benefit to epinephrine. There was no attempt at controls, nor was there any data from human subjects. Even so, 114 years later, we’re essentially doing the same treatment.

There have been multiple observational studies involving epinephrine. Some of these have used case controls of patients who did not get epi.^2–5 The net results of these studies suggest an association between epinephrine and the outcomes of ROSC and survival to hospital admission. There is mixed evidence about epinephrine’s association with the outcome we care most about, neurologically intact survival. In fact, some points to a decrease in functional survival with epinephrine. Because observational studies cannot show causation, we needed randomized controlled trials to see if epinephrine caused better outcomes.

PACA and PARAMEDIC2

We thought we were going to get the RCT we needed in 2011 with the PACA trial.⁶ This was to be a multicenter, multinational study of epinephrine vs. placebo. Unfortunately, for some pretty lame reasons, all but one system pulled out of the trial. The resulting research was therefore underpowered but did provide some useful data.

The study included 601 patients in Perth, Australia, and found that epinephrine increased ROSC and survival to hospital admission. However, it did not increase survival to discharge with a neurologically intact patient. There was a suggestion in this study that patients treated with epinephrine might actually have worse neurologic outcomes, but because the study was underpowered, this was not significant.

PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration In Cardiac Arrest) was a large, well-done double-blinded multicenter study that aimed to answer an important clinical question: In adults with out-of-hospital cardiac arrest not caused by anaphylaxis or asthma, does the use of epinephrine (1 mg every 3–5 minutes) increase 30-day survival compared to placebo?⁷

The study included adults older than 16 treated by an ALS agency for OHCA resistant to initial CPR and defibrillation. It excluded those pregnant, whose arrests came from anaphylaxis or asthma etiology, and who received epi before arrival. The primary outcome was 30-day survival, with secondary outcomes of survival to hospital admission, survival to hospital discharge, neurologically intact survival, and neurologic devastation among survivors. To randomize the epi vs. control, the supplying pharmacy created boxes with 10 syringes of clear solution per numbered box. Each contained either 1 mg of epinephrine 1:10,000 of normal saline.

Discussion

The authors found that epinephrine clearly improved short-term survival but without any difference in neurologically intact survival. In fact, they looked at the proportion of survivors who were neurologically devasted and found 31% in the epinephrine group, compared with 18% in the placebo group. This was almost a twofold increase in adverse outcomes. This is in contrast to the size of the survival advantage they found: just a 0.9% increase in 30-day survival with epinephrine.

They appropriately converted this small increase in short-term survival into the context of the NNT (number needed to treat) and compared it to other components in the chain of survival. The NNT tells us how many patients would need to receive epinephrine to get one additional person with a pulse at 30 days: 112. This is in contrast to NNTs of 5 for early defibrillation, 11 for early recognition, and 15 for bystander CPR. We can also contrast this to the NNH (number needed to harm) of 8 to create one additional neurologically devastated survivor.

There is an interesting concept known as the MCID (minimum clinically important difference). This is determined by surveying patients and providers to assess what difference in outcomes between two treatments would justify adopting the “new” therapy. A multinational study concluded the median difference in cardiac arrest outcomes was a 5% improvement.⁸ So this group suggests a treatment needs to improve outcomes by at least 5% before being adopted, and the largest trial ever of epinephrine in cardiac arrest showed a 0.9% improvement in survival. This obviously does not meet this threshold and raises concern about its continuing use.

It is useful to understand how epinephrine might improve cardiac survival but also decrease neurologically intact survival. The main advantage of epinephrine is felt to be through its alpha effects: It increases peripheral vascular resistance through vasoconstriction. This improves diastolic filling and coronary perfusion pressure. Unfortunately this also leads to microvascular constriction and ischemia. The brain is likely to be more sensitive to this ischemia than the heart. Epinephrine also increases platelet activation, thrombosis, and tachydysrhythmias. These potential adverse events would suggest that patients who survive the initial arrest should be more likely to have a neurologic injury, and in fact, this is what is seen. Of those patients who survive to ICU admission, more than two-thirds die from brain injury.⁹

Takeaways

This was a large, well-done RCT that sought to determine if the way we currently use epinephrine in cardiac arrest improves survival. I think it conclusively tells us that what we are doing now is saving hearts at the expense of brains. I don’t believe that is a good thing. We now have to decide what to do with this information. The NEJM authors have shown us what does not work. We now have to learn and implement what does.

References

1. Crile G, Dolley DH. An experimental research into the resuscitation of dogs killed by anesthetics and asphyxia. J Exp Med, 1906 Dec 21; 8(6): 713–25.

2. Andersen LW, Kurth T, Chase M et al. Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: propensity score matched analysis. BMJ, 2016 Apr 6; 353: i1577.

3. Dumas F, Bougouin W, Geri G, et al. Is epinephrine during cardiac arrest associated with worse outcomes in resuscitated patients? J Am Coll Cardiol, 2014 Dec 9; 64: 2,360–7.

4. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA, 2012 Mar 21; 307: 1,161–8.

5. Shao H, Li CS. Epinephrine in Out‐of‐hospital Cardiac Arrest: Helpful or Harmful? Chin Med J (Engl), 2017; 130: 2,112–6.

6. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation, 2011 Sep; 82: 1,138–43.

7. Perkins GD, Ji C, Deakin CD, et al.; for the PARAMEDIC2 collaborators. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med, 2018; 379: 711–21.

8. 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; 107: 115–20.

9. Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med, 2004 Nov; 30: 2,126–8.

Jeffrey L. Jarvis, MD, MS, EMT-P, FACEP, FAEMS, is chief medical director for FlightBridge ED, EMS medical director for the Williamson County EMS system and Marble Falls Area EMS and an emergency physician at Baylor Scott & White Hospital in Round Rock, Tex. He is board-certified in emergency medicine and EMS. He began his career as a paramedic with Williamson County EMS in 1988 and continues to maintain his paramedic license.