EMCrit Wee – Rob Mac Sweeney on Intra-Arrest Meds

argument

Rob Mac Sweeney is an anaesthetist-intensive care doc. His gig is evidence: analysis, assimilation, and dissemination. Tomorrow, you’ll hear a ton more about the great stuff he does on sites such as Critical Care Reviews. For today, we discuss the topics raised in my recent posting of my SMACC Intra-Arrest Talk.

 

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Comments

  1. Comment on VSE: right now I like to think of Vasopressin, Steroids & Epinephrine like the initial Early Goal Directed Therapy paper – single centre RCT by talented clinicians with impressive results. It’s not the absolute answer, but will guide the way.

    • Brent, Though I don’t disagree with your take-home; remember, they did the single-center RCT years ago, the recent JAMA pub. was a repeat, multi-centre RCT

  2. Here is what Dr. Jacobs, et al. wrote in the paper -

    This study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand and was accordingly powered to detect clinically important treatment effects. Despite having obtained approvals for the study from Institutional Ethics Committees, Crown Law and Guardianship Boards, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services from participating.

    In addition adverse press reports questioning the ethics of conducting this trial, which subsequently led to the involvement of politicians, further heightened these concerns. Despite the clearly demonstrated existence of clinical equipoise for adrenaline in cardiac arrest it remained impossible to change the decision not to participate.

    I have been a very vocal critic of the lack of evidence to support the use of epinephrine in cardiac arrest, but I have not presented the Jacobs study as negative. The study is neutral, because it was decimated by the politicians and the media.

    To view it as positive is also probably a mistake. The average time of EMS arrival was 10 minutes and the outcomes were 2% survival and 4% survival. If that does not reflect the outcomes of your cardiac arrest patient population, then is it relevant? Is 4% survival the goal?

    This may raise a lot of questions, but it does not provide answers. The study is far too is too small to answer the questions, but this is not the fault of Dr. Jacobs.

    The study was designed to be large enough, but research opponents prevented the study from being large enough to avoid the faulty conclusions that small numbers are expected to lead us to. We should not make that mistake.

    The study was neutral.

    The trend is just as irrelevant as having a trend toward the winning lottery number.

    Convince someone to pay me the winning amount for the lottery, based on having some of the right numbers, and I will sing the praises of a trend for you. Until then, the trend is still statistically insignificant for a reason.

    It is too likely to be misleading.

    Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial
    Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL.
    Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2.
    PMID: 21745533 [PubMed - in process]

    http://www.ncbi.nlm.nih.gov/pubmed/21745533

    .

  3. Agree with all of that, and I think Rob and I mentioned why the Jacobs trial was crippled, though the actual quote is very welcome–you don’t see stuff like that written in major journals very often.

    I actually was a thorough disbeliever in epi, from an ebm perspective, up until the Jacobs trial. I now am in a state of equipoise, just as Rob is. We need to be very cognizant of the difference between a trend from a properly powered study=bullshit, vs. a trend like this in a study that recruited 1/8 of it.s patients. The latter certainly doesn’t make the study positive, but I see it as slightly more than neutral as well. I think Rob put it best, “There is a signal there.” Enough signal to do another RCT, enough signal to continue using the med if you want; enough signal to leave it in as a IIB in ACLS.

    Now as to your mention of the 4% survival. Let’s zone in here, this is survival to hospital discharge of OOHCA, AFTER you have already stripped out the VF/VT patients that responded to initial 3 shocks. It is my understanding that these pts did not receive ther. hypothermia either. My gosh, what kind of percentage do you think we can get in these circumstances?

    • I completely agree with more research.

      My criticism of epinephrine, and the many other treatments we have that are not supported by valid evidence, is that we need to find out what works.

      Both type 1 (false positive/excessive gullibility) and type 2 errors (false negative/excessive pessimism) are errors.

      The problem is the lack of adequate evidence. If the evidence is inadequate (as in the Jacobs paper, through no fault of Dr. Jacobs), the analysis is just a derivative – weaker than the original paper.

      On the other hand, a negative trend is something we should pay attention to. Not so much because it is more likely to be true, but because the consequences are likely to be more harmful.

      I forgot that the 4% was after initial defibrillation and without therapeutic hypothermia.

      I think that it is likely that epinephrine does increase survival in some patients, but that we have no valid evidence to tell us which patients.

      I think that it is likely that epinephrine does decrease survival in some patients, but that we have no valid evidence to tell us which patients.

      Your approach of targeting diastolic blood pressure is certainly reasonable – it is in no way any less reasonable than giving epinephrine to everyone dead long enough to be given epinephrine.

      Steroids have been proposed for everything. Cochrane actually tells us that steroids work for spinal injuries, but the review is written by the most positive proponent of steroids.

      http://roguemedic.com/2012/05/cochrane-and-a-significantly-biased-review-of-steroids-for-acute-spinal-cord-injury/

      Ribavarin has also been proposed for everything.

      Skepticism (appropriately waiting for valid evidence to adopt a treatment) is not nihilism.

      Nihilism is ignoring the valid evidence and believing in nothing. Nihilism is no compressions and no defibrillation, because of a belief that nothing works.

      Nihilism (Paint It Black) is the mirror image of interventionism (fans of The Secret – giving everything because What if . . . ?).

      Positive thinking (doing everything) does not save lives any more than negative thinking (doing nothing) saves lives.

      Skepticism is the approach of waiting for enough evidence to be able to present information in a way to convince a disinterested party. We want treatments to work, but putting our fingers on the scale, to try to influence the results in the favor of what we want to be true, is dangerous.

      Skepticism is looking at treatments that do not have valid evidence of benefit and saying, Let’s find out before we expose everyone to this. Medicine is too dangerous to base on unreasonable optimism.

      :-)

      PS – How is the conference?

      .

  4. ha! Dont get so hung up on epinephrine alone!

    the two VSE RCT add weight to the fact that epinephrine has a role in Cardiac arrest. combined with the Jacobs trial, there is enough SIGNAL to certainly say it is reasonable in hospital cardiac arrest and in my view, still has a role in OHCA.

    You dont consider the alternative explanation to why the 4/5 ambulance services chose not to participate in the Jacobs trial….that they were right!

    Rouge, you can argue all you like about lots of other things not holding water and being proven wrong..thats merely a distraction. If you want to argue the EBM extremist view then what Scott says is all true. VSE RCT x 2 all positive for improved neuro outcomes in hospital arrest, Jacobs trial underpowered but signal of benefit. More research we agree is the way forward.

    thats all you can say.

    the evangelistic pulpit bashing is not helpful.

    comparing trends in cardiac arrest trials to lottery numbers is emotively entertaining but has no inherent validity.
    the consequences of one are totally different to the other.

    Lets focus on the science of which gladly there is more

    http://www.bmj.com/content/348/bmj.g3028?etoc

    In hospital arrest of non shockable rhythms , earlier admin of epinephrine is associated with better outcomes including neuro.

    yes I know, retrospective study but large and not causality proving..but the SIGNAL IS consistent !

    eventually enough sIGNALS will be evident that you realise the elephant in the room is that epinephrine is effective in cardiac arrest but not in the way you think now.

    the only way to reach that goal is to make mistakes along the way and learn …but NOT prohibition!

    • ha! Dont get so hung up on epinephrine alone!

      Does epinephrine contribute to the improved outcomes with VSE, or would the outcomes be better with just vasopressin and methylprednisolone? Would a different cocktail be better? We do not know.

      -

      the two VSE RCT add weight to the fact that epinephrine has a role in Cardiac arrest. combined with the Jacobs trial, there is enough SIGNAL to certainly say it is reasonable in hospital cardiac arrest and in my view, still has a role in OHCA.

      The reason the Jacobs paper does not answer that question is that there were too few patients to be able to tell the difference between a genuine trend and the normal statistical variation in outcomes that we should expect.

      -

      You dont consider the alternative explanation to why the 4/5 ambulance services chose not to participate in the Jacobs trial….that they were right!

      Do you really want medically naive politicians and lawyers to overturn doctors medical decisions? Be careful what you wish for.

      As with running a test, the result of a bad decision to test for something does not turn the bad decision into a good decision. That the test found something is just a coincidence. Life is full of coincidences, but we should not make decisions based on the belief that coincidences have meaning.

      -

      . There is equipoise. There is not convincing evidence that there is greater benefit than harm with epinephrine in cardiac arrest.

      That is my point.

      Equipoise means that the refusal to participate was wrong. Make up your mind.

      Perhaps an explanation of what equipoise means, from someone you are not preaching against, might help.

      As Dr. Clifton Callaway, one of the authors of the ACLS guidelines, stated the following about epinephrine in response to the Hagihara paper, which was also after the Jacobs paper.

      The exciting development is that these data create equipoise about the current standard of resuscitation care. The best available observational evidence indicates that epinephrine may be harmful to patients during cardiac arrest, and there are plausible biological reasons to support this observation. However, observational studies cannot establish causal relationships in the way that randomized trials can.

      Questioning the use of epinephrine to treat cardiac arrest.
      Callaway CW.
      JAMA. 2012 Mar 21;307(11):1198-200. doi: 10.1001/jama.2012.313. No abstract available.
      PMID: 22436961 [PubMed - indexed for MEDLINE]

      https://www.ncbi.nlm.nih.gov/pubmed/22436961

      -

      the evangelistic pulpit bashing is not helpful.

      As long as you misrepresent EBM, I will continue to point out the misrepresentations.

      -

      comparing trends in cardiac arrest trials to lottery numbers is emotively entertaining but has no inherent validity.
      the consequences of one are totally different to the other.

      Statistically insignificant trends go both ways. That is why there is statistical analysis of the results.

      A statistically insignificant trend is noise – not signal.

      Noise does not tell us if a treatment works.

      Basing treatments on noise is far more dangerous than basing lottery ticket decisions on noise.

      -

      Lets focus on the science of which gladly there is more

      http://www.bmj.com/content/348/bmj.g3028?etoc

      In hospital arrest of non shockable rhythms , earlier admin of epinephrine is associated with better outcomes including neuro.

      Nowhere in that paper is it demonstrated that any epinephrine is better than no epinephrine.

      Here is what the authors of that paper (including Dr. Clifton Callaway) wrote –

      Despite a strong physiologic rationale and anecdotal reports of efficacy, there are no well controlled trials of epinephrine to assess endpoints such as improved survival and neurologically intact survival. A randomized trial failed to show efficacy for advanced cardiac life support drugs, and extrapolation to the potential lack of efficacy of epinephrine has been suggested; the dose, timing, and even use of epinephrine remains controversial.15-16

      -

      yes I know, retrospective study but large and not causality proving..but the SIGNAL IS consistent !

      The only clear signal is that late epinephrine is more harmful than early epinephrine.

      It may be that epinephrine is beneficial in some patients in cardiac arrest, but we should not assume that this study is a demonstration of benefit compared with no epinephrine.

      eventually enough sIGNALS will be evident that you realise the elephant in the room is that epinephrine is effective in cardiac arrest but not in the way you think now.

      Epinephrine is effective at producing ROSC, but any claim to more than that is speculative.

      Why is it so difficult to just find out what works before we make a treatment standard of care?

      -

      the only way to reach that goal is to make mistakes along the way and learn …but NOT prohibition!

      Why are you misrepresenting what I am writing?

      Where have I insisted on prohibition?

      .

  5. ha! stop living in the past!
    I take it you ignore the last 2 yrs of further research published that Scott and I have cited. lack of evidence does not mean lack of benefit especially when you admit epinephrine improves ROSC. you can give yourself permission to change your dogmatic views of the past.

    • I take it you ignore the last 2 yrs of further research published that Scott and I have cited.

      The statistically insignificant result in the 3 year old Jacobs paper is neutral. It does not support epinephrine.

      Vasopressors in cardiac arrest: a systematic review.
      Larabee TM, Liu KY, Campbell JA, Little CM.
      Resuscitation. 2012 Aug;83(8):932-9. Epub 2012 Mar 15.
      PMID: 22425731 [PubMed - in process]

      In examining the results of the studies of vasopressors, the authors classified the results of the Jacobs paper as neutral. The authors were not impressed by a statistically insignificant trend.

      -

      The last two years of research that you cited?

      A cocktail paper that may demonstrate that vasopressin and methylprednisolone cause more benefit than the harm caused by epinephrine. Again, it is neutral on epinephrine.

      A timing paper that may just demonstrate when epinephrine is most harmful. This is also neutral on epinephrine.

      After over half a century of use, there is not a single study of epinephrine in cardiac arrest that is positive.

      The one study that might have provided an answer was decimated. You seem to praise the people who stopped the study – You dont consider the alternative explanation to why the 4/5 ambulance services chose not to participate in the Jacobs trial….that they were right!

      If you want to claim that epinephrine works, produce evidence, rather than excuses.

      If you want to claim that the authors of neutral studies should have exaggerated the results of their studies, then expect criticism.

      -

      lack of evidence does not mean lack of benefit especially when you admit epinephrine improves ROSC.

      We appear to be harming survival for an improvement in ROSC.

      We do not use high-dose epinephrine, which produces more ROSC than standard dose epinephrine.

      We do not use norepinephrine, which produces more ROSC than standard dose epinephrine.

      Be consistent and go with the treatment that improves ROSC, or admit that ROSC is a misleading surrogate endpoint.

      You can’t credibly use ROSC to support your opinion when you like the result, but ignore ROSC when it does not support your opinion.

      -

      ha! stop living in the past!

      In 2014, the status of epinephrine for cardiac arrest is equipoise, unless you have a study with a positive result.

      Our patients benefit from valid research, not from overly optimistic speculation.

      -

      you can give yourself permission to change your dogmatic views of the past.

      I do change my views, because I am not dogmatic.

      I change my views when there is valid evidence.

      Show me valid evidence, not excuses for the lack of valid evidence.

      .

  6. avoiding the simple question again with dramatics

    do you advocate we abandon epinephrine in cardiac arrest?

    we both agree more study is useful

    do you walk the walk or just talk the talk?

    at least Newman puts his money where his mouth is!

    • Please point out the dramatics.

      Do I walk what walk?

      I admit that we do not know whether epinephrine improves outcomes.

      I am not going to pretend that I know more than I could know in order to behave in a way that you want.

      What does Dr. Newman do that you claim is putting his money where his mouth is?

      .

  7. oh and you dont need evidence to change your view
    its called common sense and being human
    making mistakes in pursuit of improvement is allowed in the human condition
    the dogmatic EBM view that we need to know everything with statistically significant certainty before we make a decision needs to be challenged and I challenge it

    • oh and you dont need evidence to change your view
      its called common sense and being human

      Bleeding patients to get rid of the bad humors was common sense. Evidence demonstrated that common sense was wrong.

      Doctors having to wash their hands between autopsy and delivery of a baby was contrary to common sense. Evidence demonstrated that common sense was wrong.

      Prehospital IV fluids for therapeutic hypothermia was common sense. Evidence demonstrated that common sense was wrong.

      -

      the dogmatic EBM view that we need to know everything with statistically significant certainty before we make a decision needs to be challenged and I challenge it

      This is a fiction that made up by opponents of EBM.

      We know that most treatments based on the rationale of the current understanding of pathophysiology will be more harmful than beneficial, so we should have good evidence that a treatment works before we expose patients to what is expected to be more harmful than beneficial.

      We know that improving surrogate endpoints (ROSC, blood pressure, . . . . ) are low standards that are encouraging, but often misleading. Many of these drugs will be found to be more harmful than beneficial after enough evidence is available.

      We know that many positive studies will be found to be irreproducible, which is why Dr. Rob Mac Sweeney stated that he is hesitant to accept the results of the VSE papers. Listen to this podcast again. He and Dr. Weingart describe some of the problems with accepting treatments on poor evidence or no evidence (common sense).

      We used common sense for millennia with no improvement is outcomes. We applied scientific principles and we began to improve survival.

      You challenge that move away from death by common sense?

      .

  8. Rogue, Tim, we agree to disagree. Scott the host, called time out.
    have some respect

    • I have no problem with that. I did not see Scott’s comment until after I posted my last one. This page does not automatically refresh for me.

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