Thursday, March 29, 2012

The Epinephrine Debate

I've been following this for quite some time, and the more I read, the more I learn. The more I learn, the more questions I have. The questions lead to doubts, and the doubts, ironically enough, have lead to my sharing an opinion that I originally thought was a form of heresy.

I use the word "heresy" because anyone who doesn't think about what is being said in any of the research or reporting that has been done on this subject, or is not familiar with it, would likely have the same initial gut reaction I did until I started looking at the research for myself.

The first place I saw the debate was on a fellow blogger's site. I have been following Rogue Medic for a long time - as of this writing, it has to be for close to 6 years. He is from somewhere in the eastern United States, and I don't know how long he's been an EMS provider for, but he's been at it for longer than I have. He is extremely well-written, and while he is somewhat controversial in the opinions he has, he also does his homework and backs up everything that he says, without exception. Some might be offended by his manner - he is rather direct in the way he expresses himself - but it isn't intended to be personal. I had to learn that for myself.

I first read a post he'd written about the use of Epinephrine in cardiac arrest about 2 years ago. The main point of the post was that it should not be used because while it may aid in bringing about the return of spontaneous circulation (ROSC), it can cause harm by doing damage to brain tissue as well as other organs, ultimately causing death in some cases.

I remember my initial reaction when I first read what he wrote. I remember thinking, "huh? Why would he makes statements like this? Is he crazy?" Well, maybe it wasn't in all of those words, but it was a visceral reaction. I mean, when someone makes a statement like that, it's a blow to all of those things that many EMS providers - especially anyone who is qualified to perform Advanced Life Support - whose mantra is to "follow the algorithms and do everything by the numbers." However, I have to say that as I read more and did more of my own investigating, I began to see that what he was saying has merit.

One of the things that he (and others) call for is independent randomized controlled trials of Epinephrine and whether or not it has any real effect on ROSC. To see if anything in the way of studies exists, I went up onto the MEDLINE database and searched on the words "epinephrine cardiac arrest trial", and to my surprise, two articles jumped out at me. Needless to say, I was surprised to see the articles, so I downloaded them and reviewed their content.

A little about Epinephrine first. It is naturally occurring in the human body, both as a hormone and a neurotransmitter. It is secreted in the adrenal gland through the conversion of the amino acid Tyrosine. Known as one of three catecholamines (the other two are Norepinephrine and Dopamine) it is responsible for the "fight or flight" response that is generated through the sympathetic nervous system. It is secreted in small amounts - much smaller than the dosages given externally - but we still have that jolt-like sensation whenever fight-or-flight kicks in. If we get that sensation with what our body produces, imagine what a much larger external dose feels like. An example I can use from personal experience is the dose given from an Epi-Pen, which is at a 1:1000 concentration (for one milligram of fluid the amount of Epinephrine present is .001 milligrams) at 0.4 milligrams. I use one as needed - I am allergic to bee stings and to shellfish. The sensation, even though it works to open air passages, is unpleasant. Heart rate is increased, respiratory rate is increased, nausea and sometimes vomiting occur, and chest pain, although brief, does happen from time to time.

It is no wonder Epinephrine has been described by some as a "heart attack in a vial."

The first article describes a double blind study that was performed in Western Australia. The basic content of this study was that a randomized set of 601 patient with 67 excluded with 271 patients receiving Epinephrine and 262 receiving a placebo. This was done in the context of resuscitation that was being performed on each of these patients including management of their airway and high-quality CPR being performed. The ultimate conclusion that was drawn, based on the results of the study, was that there was no statistically significant difference in the outcome of survival to hospital discharge even though the likelihood of obtaining ROSC increased.

There are a number of limitations and potential sources of error documented in the study. One of the limitations is the number of patients they had; there could have been substantially more available for the study, but four of the five EMS agencies that were supposed to participate didn't. Additionally, there is always human error (when is there not?) to consider, whether it be related to technical problems, clinical issues, or administrative problems, some of these could easily have gotten in the way of getting accurate reporting of results.

The second article was published in 2006 and had a couple of different subjects related to out of hospital cardiac arrest. One was the issue of public access defibrillation. Another was alternative CPR techniques. The third was the use of Epinephrine and Vasopressin compared to Epinephrine only in resuscitation.

Vasopressin is another naturally occurring compound in the human body. Also known as anti-diuretic hormone (ADH), its primary purpose is to become activated when the body's fluid balance is threatened. In higher amounts it has been found to also have properties as a vasoconstrictor, but with a different mechanism of action than Epinephrine - one that is non-adrenergic.

The article hit 5 main points, and from the article, they are as follows - I will address these points within this list:

  • Public access defibrillation programs have been shown to improve survival of cardiac arrest patients treated in public places but not in residential settings
  • The cost effectiveness of public access defibrillation programs depends on the frequency of cardiac arrest at the location where the program is implemented
With the cost of technology diminishing substantially since this was published, I'm inclined to think that these are moot points. The ability to get access to AED's, or automated external defibrillators, is much easier now than it ever used to be, plus for patients with known arryrthmias, being fitted with an automatic internal cardioversion device (AICD) has also become much more commonplace.
  • Vasopressin is superior to Epinephrine in the initial treatment of asystolic cardiac arrest and is equivalent to Epinephrine in the initial treatment of ventricular fibrillation (V-fib) and pulseless electrical activity (PEA)
  • Vasopressin in combination with Epinephrine improves outcome of refractory out-of-hospital cardiac arrest compared to Epinephrine alone
This is all well and good, but the study does not address the issue of survival to hospital discharge  as the previous study did. All it says is pretty much what you see in the bullet points. But in understanding what Vasopressin does, the limited point that the study makes is logical.
  • There is evidence to support the use of compression-only CPR, intra-abdominal compression CPR, and active compression-decompression devices, although large scale trials are needed to demonstrated their effective for out-of-hospital cardiac arrest
Intra-abdominal compression CPR is not something I am personally familiar with. Active devices (Philips' LUCAS device and the Zoll Auto-Pulse are two that I have worked with) work rather effectively even if they appear to be somewhat barbaric in their action. But the key is that they work, and I would imagine independent studies exist that show their effectiveness.

There are a couple of things I have to say to end this post. First, I've looked at some of Rogue Medic's sources (actually, many of them), and as I said earlier in the post, there is a lot of merit in what he says. I really, truly am starting to think that giving someone Epinephrine whose heart is not working properly in the first place does them no favors, and the organizations who make the decisions to propagate the algorithms we are obliged to follow need to take many more looks at what we are doing. Second, there have to be other better ways to treat someone who is in cardiac arrest that are not going to make either not survive their hospital stay or make them wish they were dead if they do. One that is already in place is high-quality CPR - 100 compressions per minute without interruption. Some of the other things we do - good airway management and access to circulation - are nice, but by far this is the most important. And if we're killing the brain's micro-circulation (or that of other vital organs) with Epinephrine, do we want to continue doing that? One would think not...

The only thing I would say to anyone who has read this post and is scratching their head is this: read the articles yourself. And look at Rogue Medic's blog. His cites considerably more sources in his regular posts than I am in this one. And based on what you read, you can simply draw your own conclusions.


Jacobs, I., Finn, J., Jelinek, G., Oxer, H., & Thompson, P. (2011). Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial. Resuscitation, 82, 1138-1143. doi: 10.1016/j.resuscitation.2011.06.029

Richardson, L., Kwun, R., McBurnie, M., and Chason, K. (2006). New Approaches to Out-of Hospital Cardiac Arrest. The Mount Sinai Journal of Medicine, 73(1), 440-448. Retrieved from 

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