Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

The Danger of ROSC – Return Of Spontaneous Circulation

JB responded to Where is the Evidence for Epinephrine in the 2010 ACLS Guidelines with the following comments about the benefits of ROSC (Return Of Spontaneous Circulation) –

The difference being…

ROSC tends to be a useful starting point for return of normal life, even if it doesn’t always lead there.

This is a problem. Any evidence of benefit is given much more weight than evidence of harm.

Suppose you are trying to get into a locked room. You own the room, but you do not have your key. You left $50 in the room. You want to go shopping for groceries.

If you do not get into the room (if you do not get ROSC – Re-Open Shut Chamberdoor), you cannot get your money and buy groceries.

If you use the dynamite that is mysteriously outside your door, you can get in the room (ROSC). Remember, that getting in the room (ROSC) is a prerequisite to getting your money.

Do you use the dynamite on the door?

If Dynamite = ROSC, do you give it a go?


Image credits.

Oh, but this is different!

Is it really different?

We have a problem. We could approach this problem in the least destructive way possible and not use the explosives until we have thoroughly searched for the key.

But we are in a hurry.

Are we providing any real benefit by using epinephrine to blast the heart into action, regardless of the damage epinephrine causes to the brain and heart?

We have no evidence of improved survival with epinephrine, but we do have evidence of worse survival with epinephrine.

Why are we choosing worse survival?

Even if the survival were identical, choosing the more complicated treatment is very bad medicine.

Until there is evidence of a benefit with epinephrine, we should only use epinephrine in randomized, placebo-controlled trials. If there is any benefit from epinephrine, it will probably be small and only in a specially selected group of patients, but we will not know, unless we study it. Maybe epinephrine should only be used after 20 minutes of attempted resuscitation, but if we aren’t improving survival, we are just increasing the hospital costs.

In this post hoc analysis the actual use of adrenaline was associated with increased short-term survival, but with 48% less survival to hospital discharge. This negative association with survival is very similar to the multivariate analysis of observational Swedish registry data where patients receiving adrenaline were 57% less likely to be alive after one month.6 [1]

Highlighting is mine.

Unless you know of a method of achieving return of normal life without first achieving ROSC? I’d be interested to hear it.

You are looking at this backward.

Where is the evidence of improved survival with epinephrine?

Where is the evidence of even survival that just as good as no epinephrine?

ROSC is not the goal. ROSC is just a surrogate endpoint. ROSC can be curing the disease, but killing the patient.

If those x amounts of time was going to turn to death anyway, is it not in the patient’s best interests to give it a go?

If Dynamite = ROSC, do you give it a go?

You assume a lot for a drug that shows decreased survival and worse neurological outcomes in those who do survive.

The burden of proof is on those proposing a treatment.

Show that the treatment is safe.

Show that the treatment works better than placebo.

Don’t just show that the treatment is better at a surrogate endpoint (ROSC), but show that the treatment is better at improving meaningful survival.

Everything else is a distraction – a dangerous distraction.

If you are just resuscitating me to a coma, followed by death in the ICU. Don’t do it.

If you are resuscitating me to a life in a nursing home in front of a TV, wearing diapers and unaware of my surroundings. Don’t do it.

Epinephrine kills brains, when it doesn’t kill the whole patient.

Patient care is not about giving it a go.


Image credit.

In the absence of any studies showing *diminished* return of normal life with adrenaline or other drugs that improve rates of ROSC, I would say that increasing ROSC is giving people the best chance of then taking the next steps along the path to return of normal life (or as I’ve seen it abbreviated – RONF – “return of neurological function”). And thus ethically, at least to my mind, adrenaline is a good idea.

No.

Nonetheless, I agree with your main point. More research needed, and providers/governments/ethics committees/wherever the hold up is need to have the balls to do some proper adrenaline vs placebo studies!

On that we do agree.

I do not see any reason to assume that epinephrine will improve outcomes.

We are just punishing families with false hopes and huge hospital bills and even the torture of having to care for a family member who does not even recognize them anymore.

If we want to convince people that resuscitation is a bad idea, so they sign DNR (Do Not Resuscitate) orders, epinephrine is one way to do it.

Is epinephrine safer than dynamite?

Footnotes:

[1] Outcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial.
Olasveengen TM, Wik L, Sunde K, Steen PA.
Resuscitation. 2011 Nov 22. [Epub ahead of print]
PMID: 22115931 [PubMed – as supplied by publisher]

.

Comments

  1. So I’m curious… I understand where you’re coming from, but are your system protocols written in such a way as to omit Epi? I would wager many attorneys can find experts to state it is standard of care in cardiac arrest patients… Given the strength of your opinions, do you continue to utilize this drug on your arrest patients?

    • I think you are missing one of the points here… Protocols have not yet changed to reflect this current research. That is one obvious issue. But that is very different from saying that “since it is in my protocols, it must be the best for the patient”. Worse than that is delaying or interrupting what works, for the sake of what has not been proven to work at all in the name of protocol. That is another obvious problem. I don’t think anyone, including Rogue, is arguing against following your protocol.. But we must think about what we are doing, and prioritize in such a way that following a protocol that doesn’t work DOES NOT interfere with what does work, namely quality CPR and early defibrillation without interruptions.

      • David B,

        I think you are missing one of the points here… Protocols have not yet changed to reflect this current research.

        The protocols are often written by doctors who look at the ACLS algorithms, rather than read the text. It is not easy to keep up with all of the relevant research.

        It is much easier to trust the AHA to make the right decisions.

        Unfortunately, the AHA has not been earning that trust.

        That is one obvious issue. But that is very different from saying that “since it is in my protocols, it must be the best for the patient”.

        Exactly.

        If the protocols were based on the idea that giving patients unnecessary drugs is bad, then the protocols would be written very differently.

        There is not any reason we should not assume that giving patients unnecessary drugs is good.

        Class IIb does not even come close to necessary.

        Class IIb is not even probably.

        Worse than that is delaying or interrupting what works, for the sake of what has not been proven to work at all in the name of protocol.

        My protocols are written to discourage interruptions to chest compressions, so I just need to document that the priority was the chest compressions.

        I have been on too many codes where the priority seemed to be the interruption of compressions for all sorts of stupidity.

        That is another obvious problem. I don’t think anyone, including Rogue, is arguing against following your protocol.

        No, but there may be a lot of room for variation in how closely we follow the protocol.

        But we must think about what we are doing, and prioritize in such a way that following a protocol that doesn’t work DOES NOT interfere with what does work, namely quality CPR and early defibrillation without interruptions.

        Yes.

        .

        • I suppose that I should clarify, it wasn’t my intention to put protocol up as gospel. I was simply curious if you were operating in a position where it was a viable workaround, and if so, were you minimizing your use of Epi in light of the evidence that is available.

          For what it’s worth, I agree that doing something in the absence of evidence that it’s beneficial, (and in the presence of evidence that it is actually harmful) is flat out wrong. That being said, I’m working in a system where I don’t have the leeway to say I was ensuring CPR was the priority… We have enough hands on scene that the medical director would simply ask why I didn’t just assign someone the role of pill pusher.

          The big problem I think that we run into is, the AHA doesn’t seem to like to 180 on established practices, for reasons only known to them. I think that Epi is so engrained in cardiac resuscitation, that to not do it seems downright insane to many people. I am appreciative of you getting the word out, and I hope that someone will take it seriously enough to study it.

          • txmedic,

            I suppose that I should clarify, it wasn’t my intention to put protocol up as gospel. I was simply curious if you were operating in a position where it was a viable workaround, and if so, were you minimizing your use of Epi in light of the evidence that is available.

            I understand. I also have to work within protocols.

            For what it’s worth, I agree that doing something in the absence of evidence that it’s beneficial, (and in the presence of evidence that it is actually harmful) is flat out wrong. That being said, I’m working in a system where I don’t have the leeway to say I was ensuring CPR was the priority… We have enough hands on scene that the medical director would simply ask why I didn’t just assign someone the role of pill pusher.

            While I am interested in changing the minds of paramedics, I also realize that the most important thing to do is to change the minds of medical directors, since medical directors write the protocols.

            Even more important is to change the minds of the AHA, so that they will stop encouraging the use of epinephrine.

            The big problem I think that we run into is, the AHA doesn’t seem to like to 180 on established practices, for reasons only known to them.

            The AHA just removed atropine from the PEA/Asystole algorithm, so it is possible.

            I think that Epi is so engrained in cardiac resuscitation, that to not do it seems downright insane to many people. I am appreciative of you getting the word out, and I hope that someone will take it seriously enough to study it.

            Thank you. I think the AHA is not doing enough to get the word out, but they are not denying the problems. There are better ways the AHA could deal with this, but the AHA is a committee and there are a bunch of ACLS sub-committees. Committees often resist change. That is one of the reasons, when you hear that something bad happened, that people say they will form a committee to study it. Committees rarely do anything except have meetings.

            The Rogers Commissions examining the Challenger explosion did not want Richard Feynman’s analysis to be included in the official report. Feynman was clear about the problems and what needed to be fixed. That is not what a committee is supposed to do. A committee is supposed to absolve everyone of blame, except for some low level scapegoat.

            Feynman starts his brief appendix (where they tried to hide his conclusions) with –

            Introduction

            [F1] It appears that there are enormous differences of opinion as to the probability of a failure with loss of vehicle and of human life. The estimates range from roughly 1 in 100 to 1 in 100,000. The higher figures come from the working engineers, and the very low figures from management. What are the causes and consequences of this lack of agreement? Since 1 part in 100,000 would imply that one could put a Shuttle up each day for 300 years expecting to lose only one, we could properly ask “What is the cause of management’s fantastic faith in the machinery?”

            He finished with one of the most important statements in the history of risk management –

            For a successful technology, reality must take precedence over public relations, for nature cannot be fooled.

            Volume 2: Appendix F – Personal Observations on Reliability of Shuttle
            Report of the Presidential Commission on the Space Shuttle Challenger Accident (Also known as The Rogers Commission Report)
            by R. P. Feynman
            http://history.nasa.gov/rogersrep/v2appf.htm

            An irony of the attempt to hide Feynman’s statement is that it ended up getting much more attention than the rest of the Rogers Commission Report.

            .

    • TxMedic,

      So I’m curious… I understand where you’re coming from, but are your system protocols written in such a way as to omit Epi?

      No. My protocols do not allow us to omit epinephrine, although the ACLS guidelines do not make epinephrine mandatory.

      It is reasonable to consider administering a 1 mg dose of IV/IO epinephrine every 3 to 5 minutes during adult cardiac arrest (Class IIb, LOE A).

      Epinephrine
      Part 8: Adult Advanced Cardiovascular Life Support
      2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
      Part 8.2: Management of Cardiac Arrest
      Medications for Arrest Rhythms
      Free Full Text Article with links to Free Full Text PDF download

      According to the experts at AHA, it is only reasonable to consider giving epinephrine.

      I would wager many attorneys can find experts to state it is standard of care in cardiac arrest patients…

      Probably.

      The jury would also hear all of the evidence that epinephrine causes more harm.

      The jury would also hear that half as many patients leave the hospital alive when treated with epinephrine as when treated with no drugs.

      The jury would also hear what the AHA states about epinephrine, which is that the best they can come up with after decades of writing guidelines based on the evidence, the drug only has a level of evidence of B and that epinephrine is a Class IIb drug. Only possibly helpful.

      Given the strength of your opinions, do you continue to utilize this drug on your arrest patients?

      I am not a doctor, so I cannot write protocols, but I can delay as much as possible in harming patients.

      .

  2. I stand corrected.

    My understanding of the research was that final outcomes with adrenaline vs without was “no statistically significant difference” as opposed to “worse”, but it appears with what you have cited that that is not the case.

    • JB,

      I stand corrected.

      My understanding of the research was that final outcomes with adrenaline vs without was “no statistically significant difference” as opposed to “worse”, but it appears with what you have cited that that is not the case.

      This is a reanalysis of the data obtained during a study that was using intention to treat analysis. They did not set up the study to analyze the data according to what was actually give, but they found so many protocol violations that they decided to go back and look at the data according to what was actually given.

      We want to be careful in giving too much credit to any post hoc analysis, although I do not see anything ulterior here.

      There continues to be an absence of evidence that epinephrine does anything more than produce more ROSC, and therefore more people dying in the hospital or being discharged to nursing homes.

      This, and the earlier study, do suggest that the benefit from epinephrine is just short-term and that epinephrine produces long-term harm.

      A search of ClinicalTrials.Gov for epinephrine/adrenaline and cardiac arrest does not show any trials for epinephrine vs. placebo, except for the one completed and described in Does Epinephrine Improve Survival from Cardiac Arrest.

      Even though the AHA is admitting a need for this research, nobody seems to be interested. The way to generate interest may be to remove the epinephrine from the guidelines and tell people that they may only use epinephrine in randomized placebo-controlled trials.

      .

  3. As always, RM, this is quality stuff.

    I have a question, though. What is the actual pathophysiology that causes the damage to brain tissue? Assuming that ROSC does happen, how does the Epinephrine that is given (and has a relatively short half-life) cause the kind of tissue damage that you’re talking about? Does it cause furthering hypoxia? Is it chemical? I’m trying to understand this a little better because I’m not sure why the relatively small doses that we use in the field could do the type of damage you describe.

    And this brings another question to mind: what about when Epinephrine is being used in a non-cardiac arrest situation? Specifically, if you’re dealing with someone who is in Anaphylaxis and is being given Epi in the 1:1000 concentration (albeit at a lower dose) for bronchodilation and vasoconstriction, would the concerns you’re talking about regarding tissue damage still apply? Based on the circumstances you’re detailing in your research and analysis, I’m inclined to think they would, but I’m definitely interested to read your thoughts on this.

    I’m asking these questions for a very simple reason: you made me think. You’re really good at that, by the way. And, as I said, I want to understand the “why” more clearly. And since I’ve been a full-time student again, my brain has been engaged much more than it usually is.

    Merry Christmas, and thanks for putting up with pestilent questions 🙂

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