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

- Rogue Medic

ILCOR wants the appearance of public comments with less than half the substance

 

The International Liaison Committee on Resuscitation (ILCOR) shows its priorities in the way it handles its problem with public comments.
 

Last week ILCOR posted the two new draft CoSTRs listed below for public comment. It became apparent that the commenting link was broken and those who visited the site could not comment. We apologize for the inconvenience. The commenting link is now fixed and we invite you to comment at ilcor.org/costr.

  • Advanced Airway Management During Adult Cardiac Arrest
  • Vasopressors in Adult Cardiac Arrest
  • As a reminder, the public comment period will close on 4 April 2019.[1]

     

    ILCOR made a mistake that prevented public comments from being submitted for most of the public comment period.

    ILCOR is so interested in your public comments that they have decided to send out an email to let people know that they have the same drop dead date for the comments as before, but this time they might actually be able to get the comments to work. Maybe.

    The lack of evidence of benefit of epinephrine (adrenaline in Commonwealth countries) has lasted over half a century, so what is the rush to get these new guidelines out?

    There is only one outcome that matters – survival without severe brain damage.
     


     

    ILCOR evaluates 23 outcomes.

    ILCOR considers 15 of these outcomes critical, but they are really just 5 outcomes, with some of them repeated over different rhythms. These are (in increasing order of importance to the only one that matters):

    1. For the critical outcome of survival to hospital discharge, 2. For the critical outcome of survival at 3 months, 3. For the critical outcome of favorable neurologic outcome at hospital discharge, 4. For the critical outcome of survival with unfavorable neurologic outcome at 3 months, 5. For the critical outcome of favorable neurologic outcome at 3 months,

    Many of them are repeated for each cardiac arrest rhythm or for each vasopressor, or vasopressor cocktail:

    1. Epinephrine plus vasopressin compared to epinephrine only – Any rhythm 2. Initial vasopressin compared to initial epinephrine – Any rhythm 3. Epinephrine compared to placebo – Non-shockable rhythms 4. Epinephrine compared to placebo – Shockable rhythms 5. Epinephrine compared to placebo – Any initial rhythm

    There is only one outcome that matters – survival without severe brain damage.

    There is only one study that was large enough to answer this:
     

    CONCLUSIONS
    In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.[2]

     

    If the people at ILCOR really think that epinephrine is beneficial in cardiac arrest, they should encourage a much larger study.

    There were 4,000 patients in each group – 4,000 placebo and 4,000 epinephrine.

    Maybe with 8,000 patients in each group, the ever decreasing “trend toward better outcome” will reach significance. Maybe it will be shown to be just another insignificant appearance of a “trend” that is the result of having so few survivors to compare.

    There were only 161 survivors without severe brain damage out of 8,000 cardiac arrest patients – 74 placebo and 87 epinephrine.

    Those resuscitated before receiving epinephrine/placebo were excluded from the study, so this is not a case of EMS that only has a 2% resuscitation rate. The focus on epinephrine is a focus on the patients least likely to be resuscitated and a focus on counterproductive outcomes.

    Almost all of our good outcomes (without severe brain damage) will be without epinephrine, because these resuscitations happen before epinephrine can be give by even the most aggressive epi enthusiast.

    What we are doing is making excuses for memorizing ineffective interventions and requiring their application is a specific way, in order to determine the quality of care. We are promoting fantasy.

    We learned that distracting from the quality of chest compressions is the most deadly thing we can do in resuscitation.

    CPR = only chest compressions – the exception is when the arrest is believed to be due to a respiratory event, such as when the Smurf sign or a respiratory/choking history is present. Chest compressions provide all of the pulmonary resuscitation that a human needs for a non-respiratory event and the respiratory events are not easily missed.

    Why require a whole bunch of skills be applied for such a tiny portion of good outcomes among cardiac arrest patients?

    Why not give up on requiring these skills when the evidence makes it clear that there is no benefit?

    All we are doing is adding cognitive load to make us feel like we are doing something special.

    We could learn something that actually benefits patients, such as how to assess patients when giving high-dose NTG (NiTroGlycerine or GTN GlycerylTriNitrate in Commonwealth countries) for even hypotensive CHF/ADHF (Congestive Heart Failure/Acute Decompensated Heart Failure), where we can make much more of a difference and prevent cardiac arrest, but we don’t.[3],[4],[5]
     


     

    Cognitive load is not just a problem for paramedics and nurses, or med/surg doctors, but also for emergency physicians:

    Cognitive Load and the Emergency Physician
    April 12, 2016
    James O’Shea
    emDocs
    Article

    Why are we distracting everyone from things that do improve the only outcome that matters, in order to promote things that do not improve any outcome that matters?

    Here is what I wrote –
     

    The primary source for the recommendation to keep things the same is a brand new study – PARAMEDIC2.

    This showed no statistically significant improvement in the only outcome that matter – survival without severe brain damage.

    A larger study might show that there is a real improvement – or it may put the epi hypothesis out of its misery.

    I will eventually have a cardiac arrest. If I am resuscitated, whom will ILCOR send to change my diaper, and attend to the other things I can no longer attend to?

    We need evidence of a significant benefit in order to justify distracting everyone from interventions that actually do improve survival without severe brain damage.

    .

     

    The commenting link is now fixed and we invite you to comment at ilcor.org/costr

    Maybe they will pay attention. Dr. Rory Spiegel of EM Nerd has a detailed comment that is also critical of ILCOR’s proposed “strong recommendation” of epinephrine.

    Footnotes:

    [1] Vasopressors in Adult Cardiac Arrest
    Time left for commenting: 11 days 15:49:49
    ILCOR staff
    Created: March 21, 2019 · Updated: March 21, 2019
    Draft for public comment
    Consensus on Science with Treatment Recommendations (CoSTR)
    Vasopressors in Adult Cardiac Arrest page for comments until April 04, 2019 at 06:00 Eastern Time

    [2] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
    Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
    N Engl J Med. 2018 Aug 23;379(8):711-721. doi: 10.1056/NEJMoa1806842. Epub 2018 Jul 18.
    PMID: 30021076

    Free Full Text from N Engl J Med.
     

    In a Bayesian analysis that used an assumption of no benefit from adrenaline, the posterior probability that the absolute rate of survival was at least 1 percentage point higher in the epinephrine group than in the placebo group was 37% (Fig. S3 in the Supplementary Appendix). The probability that the absolute survival rate was at least 2 percentage points higher was 0.2%. With respect to the rate of survival with a favorable neurologic outcome at hospital discharge, the probabilities that the rate was at least 1 or 2 percentage points higher with epinephrine were 1.9% and 0%, respectively (Fig. S4 in the Supplementary Appendix).

     

    The probability of a good outcome (no severe brain damage) is not improved with epinephrine.

    If we want to improve outcomes, we need to look elsewhere, because there is nothing to be gained with epi.

    [3] Intravenous nitrates in the prehospital management of acute pulmonary edema.
    Bertini G, Giglioli C, Biggeri A, Margheri M, Simonetti I, Sica ML, Russo L, Gensini G.
    Ann Emerg Med. 1997 Oct;30(4):493-9.
    PMID: 9326864 [PubMed – indexed for MEDLINE]

    [4] Unreasonable Fear of Hypotension and High-Dose NTG – Part I
    Thu, 29 Aug 2013
    Rogue Medic
    Article

    [5] Unreasonable Fear of Hypotension and High-Dose NTG – Part II
    Wed, 04 Sep 2013
    Rogue Medic
    Article

    .

    ACLS Excuses for Causing Harm with Epinephrine

     

    The next ACLS guidelines are available for review and comment, before they are finalized. The Consensus on Science with Treatment Recommendations (CoSTR) from the International Liaison Committee on Resuscitation (ILCOR) are available for two guidelines:

    Vasopressors in Adult Cardiac Arrest

    Advanced Airway Management During Adult Cardiac Arrest

    We have been using these interventions for so long, that there should be great evidence to show that benefits and harms of both interventions, but there is no good evidence to support either intervention.

    For epinephrine (adrenaline in Commonwealth countries), the most commonly used vasopressor and the only one rally being considered, there is no evidence of actual benefit – increased survival without severe brain damage.

    Nothing else matters.

    There is no valid evidence that increasing any surrogate endpoint improves survival without severe brain damage. The evidence cited by ILCOR shows that epinephrine increases the rate of severe brain damage.
     

    Intervention: Vasopressor or a combination of vasopressors provided intravenously or intraosseously during cardiopulmonary resuscitation.[1]

     

    Here are the outcomes that are supposed to indicate that the patient is better.
     

    Outcomes: Short-term survival (return of spontaneous circulation (ROSC) and survival to hospital admission), mid-term survival (survival to hospital discharge, 28 days, 30 days, or 1 month), mid-term favorable neurological outcomes (Cerebral Performance Category score of 1-2 or modified Rankin Scale 0-3 at hospital discharge, 28 days, 30 days, or 1 month) and long-term favorable and poor (modified Rankin Score 4-5) neurological outcomes (after 1 month).[1]

     

    Is ROSC an improvement?

    We aren’t supposed to ask that question. These are faulty assumption that the guidelines are based on.

    1. Doing something more is better than only doing things supported by valid evidence of improved survival without severe brain damage.

    No.

    How much harm is being caused in this rush to get a pulse back?

    We are supposed to ignore our understanding of research, look at a statistically insignificant “trend”, and extrapolate that statistically insignificant “trend” to support the prejudice that our intervention has not been harmful.

    That is not good science.

    That is not good medicine.
     

    Why aren’t there any studies large enough to show improved survival without severe brain damage for anything other than rapid defibrillation (when indicated VF/pulseless VT) and chest compressions?

    The research has only produced excuses and surrogate endpoint. Surrogate endpoints are for hypothesis generation and sales pitches to the least knowledgeable, but not for treatment guidelines.

    ILCOR has told us this before, but that was because the choice was between large doses of epinephrine and small doses of epinephrine, not between epinephrine and no epinephrine.

    The choice is the same.

    Is the more aggressive intervention helping?

    The answer is the same. No. That is not the conclusion of the evidence.
     

    CONCLUSIONS
    In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.[2]

     

    If the goal is a pulse with more severe brain damage, then epinephrine is the way to go.

    If the goal is increased survival without severe brain damage, we have to keep looking.

    We should limit the use of epinephrine to well controlled research until there is evidence of improvement in outcomes that matter.

    If this evidence is never found, our patients will not have been harmed by epinephrine.

    If this evidence is eventually found, it is something that should have been insisted on decades ago. We should not use wishful thinking and surrogate endpoints to justify interventions that harm patients.

    We used to stop compressions to let the medic/nurse/doctor intubate, or start an IV (IntraVenous) line.

    We knew that the tube was more important.

    We knew that the drugs given through the IV line were more important.

    The 2005 guidelines told us to continue compressions during intubation and during IV attempts and to improve the quality of the compressions.

    That focus on high quality compressions is the only time we have improved outcomes that matter.
     

    CONCLUSIONS: Compared with controls, patients with out-of-hospital cardiac arrest treated with a renewed emphasis on improved circulation during CPR had significantly higher neurologically intact hospital discharge rates.[3]

     

    33 1/3% vs 60% increased survival without severe brain damage.
     

    In 2004, we began a statewide program to advocate chest compression-only CPR for bystanders of witnessed primary OHCA. Over the next five years, we found that survival of patients with a shockable rhythm was 17.7% in those treated with standard bystander CPR (mouth-to-mouth ventilations plus chest compression) compared to 33.7% for those who received bystander chest-compression-only CPR.[4]

     

    18% vs 34% increased survival only – not increased survival without severe brain damage.
     

    In the analysis of MICR [Minimally Interrupted Cardiac Resuscitation] protocol compliance involving 2460 patients with cardiac arrest, survival was significantly better among patients who received MICR than those who did not (9.1% [60/661] vs 3.8% [69/1799]; OR, 2.7; 95% CI, 1.9-4.1), as well as patients with witnessed ventricular fibrillation (28.4% [40/141] vs 11.9% [46/387]; OR, 3.4; 95% CI, 2.0-5.8).[5]

     

    9% vs 4% increased survival only – not increased survival without severe brain damage.
     

    Neurologic outcomes were also better in the patients who received CCR (OR=6.64, 95% CI=1.31 to 32.8).[6]

     

    6 2/3 more likely to have increased survival without severe brain damage. The range is 1 1/3 to almost 33 times, because of the small numbers, but unlike epinephrine, this is statistically significant and supported by other research.

    We are still making excuses for using a drug that causes harm and does not appear to provide a benefit that is greater than the harm. If there is more benefit, it is too small to be measured, even in a study with over 9,000 patients. We do not know which patients benefit and which patients are harmed, so we do not know how to minimize the harm that we cause.

    Our patients deserve better.

    Footnotes:

    [1] Vasopressors in Adult Cardiac Arrest
    Time left for commenting: 11 days 15:49:49
    ILCOR staff
    Created: March 21, 2019 · Updated: March 21, 2019
    Draft for public comment
    Consensus on Science with Treatment Recommendations (CoSTR)
    Vasopressors in Adult Cardiac Arrest page for comments until April 04, 2019 at 06:00 Eastern Time

    [2] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
    Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
    N Engl J Med. 2018 Aug 23;379(8):711-721. doi: 10.1056/NEJMoa1806842. Epub 2018 Jul 18.
    PMID: 30021076

    Free Full Text from N Engl J Med.

    [3] Implementing the 2005 American Heart Association Guidelines improves outcomes after out-of-hospital cardiac arrest.
    Aufderheide TP, Yannopoulos D, Lick CJ, Myers B, Romig LA, Stothert JC, Barnard J, Vartanian L, Pilgrim AJ, Benditt DG.
    Heart Rhythm. 2010 Oct;7(10):1357-62. doi: 10.1016/j.hrthm.2010.04.022. Epub 2010 Apr 24.
    PMID: 20420938

    Free Full Text from Heart Rhythm.

    [4] The cardiocerebral resuscitation protocol for treatment of out-of-hospital primary cardiac arrest.
    Ewy GA.
    Scand J Trauma Resusc Emerg Med. 2012 Sep 15;20:65. doi: 10.1186/1757-7241-20-65. Review.
    PMID: 22980487

    Free Full Text from PubMed Central.

    [5] Minimally interrupted cardiac resuscitation by emergency medical services for out-of-hospital cardiac arrest.
    Bobrow BJ, Clark LL, Ewy GA, Chikani V, Sanders AB, Berg RA, Richman PB, Kern KB.
    JAMA. 2008 Mar 12;299(10):1158-65. doi: 10.1001/jama.299.10.1158.
    PMID: 18334691

    Free Full Text from JAMA.

    [6] Cardiocerebral resuscitation is associated with improved survival and neurologic outcome from out-of-hospital cardiac arrest in elders.
    Mosier J, Itty A, Sanders A, Mohler J, Wendel C, Poulsen J, Shellenberger J, Clark L, Bobrow B.
    Acad Emerg Med. 2010 Mar;17(3):269-75. doi: 10.1111/j.1553-2712.2010.00689.x.
    PMID: 20370759

    Free Full Text from Acad Emerg Med.

    .

    The Grinch Who Stole Reality

     

    And the Grinch, with his Grinch-feet ice cold in the snow, stood puzzling and puzzling, how could it be so?

    It came without ribbons epi.

    It came without tags amio.

    It came without packages oxygen, boxes tubes or bags.

    And he puzzled and puzzled ’till his puzzler was sore. Then the Grinch thought of something he hadn’t before.

    Maybe Christmas living, he thought…doesn’t come from a store drug.

    Maybe Christmas living, perhaps…means a little bit more!

     

    With apologies to Dr. Seuss (Theodore Geisel) for the modification of his parable.

    There are important differences between the minimal criteria for life and the criteria for a meaningful life. Many of us don’t like to think about that, because many of us don’t like thinking. Thinking can be hard. Making excuses for not thinking – priceless (at least, as long as you don’t think about it).

    We have been focusing on the least honest way of reporting outcomes – a pulse – Oooh!, or maybe even 30 days of a pulse – Oood-Ahhh! After all, reality does not support continuing to do what we have been doing. If we admit that we have been causing harm, then we may have to take responsibility for our actions.

    We do not want to take responsibility for our actions. We were only following orders.

    Doctors, PAs (Physician Assistants), NPs (Nurse Practitioners), nurses, paramedics, EMTs, techs, . . . do not want to take responsibility for what we get paid for. Accountability is for people who think – not for us.

    We have blamed science/evidence for requiring that we confront reality. As explained by Dr. Seuss, we want simple answers that do not require understanding. Give us algorithms to mindlessly follow. Give us mnemonics.

    We have been giving epinephrine (adrenaline in Commonwealth countries) for over half a century with no evidence of safety or improvement in the outcome that matters most.

    Why?

    We haven’t wanted to know.

    The first study to look at the effect of placebo vs. epinephrine on neurological survival was cut short – with only a tiny fraction of what would be needed to produce any kind of statistically useful information, except for some of the true believers, who made the same kinds of mistakes that have been made for other discarded treatments – treatments discarded due to failure to work, discarded due to harm, or discarded due to both.

    Don’t study this. Just believe. Belief makes us feel good. Attack science for encouraging understanding.
     

    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.[1]

     

    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.[1]

     

    What was the conclusion produced by the Jacobs study?
     

    CONCLUSION: Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC.[1]

     

    As the homeopaths put their spin on studies that do not really support their claims, people who do not understand science put similar spin on the results of this. For example, if you take a Bayesian approach[2], but distort it to mean that you give extra weight to everything that supports your belief and take away credit from everything else, you can claim that this is an example of science proving that epinephrine works.

    Another way of doing this is to claim that you don’t give the 1 mg dose of epinephrine, therefore the study does not apply to your patients. After all, you are just engaging in a poorly documented, unapproved study, which allows you to think of the survivors as examples of the drug working and make excuses for the rest. Of course, if you don’t give the 1 mg dose of epinephrine, is there any evidence that your treatment is safe or effective? No.

    Rather than insisting that this method of dosing patients be studied, in order to determine if it really is safe or if it really is effective at anything other than getting a pulse in a brain-dead body, claim to be ahead of the science.

    Why find out what is really best for the patients, when there are so many ways of declaring victory and running away?

    In 2018, we had the results of the next study of placebo vs. adrenaline (epinephrine in non-Commonwealth countries, but only Commonwealth countries have bothered to do the research). The conclusion was the same as the conclusion for the only previous study.
     

    CONCLUSIONS: In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.[3]

     

    Has anyone else stated that the use of epinephrine should be limited to controlled trials?

    Not that I know of.

    Everyone else seems to be claiming that giving smaller boluses of epinephrine. or giving titrated infusions of epinephrine is different. Some claim that it is nihilism to refuse to believe in their slightly different treatment – at least until there is undeniable evidence of lack of benefit, or undeniable evidence of harm, or both.

    Requiring evidence of benefit, before using a treatment on a patient is being reasonable.

    Using inadequately studied treatments on people when they are at their most vulnerable is not good medicine.

    A doctor’s oath to Apollo does not include a requirement to perpetuate dogma, but medicine is only slowly starting to focus on what is best for patients, rather than what is best for appearances.

    Dr. Ryan Jacobsen addressed a similar dogma, when he got rid of the long spine board in the system where he was medical director. His description of the evidence applies to epinephrine (bolus, mini-bolus, infusion, patch, inhaler, down the tube, oral, whatever) –

    Other than historical dogma and institutional EMS medical culture we can find no evidence-based reason to continue to use the Long Spine board epinephrine as it currently exists in practice today.[4]

    I changed EMS to medical and the Long Spine board to epinephrine.

    We have good evidence that if your loved one is a laboratory pig, rat, dog, . . . we can kill them and get them back neurologically intact with epinephrine – and with other treatments that have been discarded because they do not have the same effect on humans as on lab animals.

    Let us treat your loved ones like the lab animals we think they are.

    Don’t use EBM (Evidence-Based Medicine), because belief is more important than reality.

    The world is a comedy to those that think; a tragedy to those that feel. – Horace Walpole.

    Keep thinking. Keep demanding evidence. After the nonsense being preached by the believers is exposed, we can improve the outcomes for our patients, because medicine is about doing what is best for the patient, and not about protecting the dogma.

    Footnotes:

    [1] 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. doi: 10.1016/j.resuscitation.2011.06.029. Epub 2011 Jul 2.
    PMID: 21745533

    Free Full Text PDF Download from semanticscholar.org

    [2] Bayesian inference
    Wikipedia
    Article

    [3] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
    Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
    N Engl J Med. 2018 Aug 23;379(8):711-721. doi: 10.1056/NEJMoa1806842. Epub 2018 Jul 18.
    PMID: 30021076

    [4] Johnson County EMS System Spinal Restriction Protocol 2014
    Ryan C. Jacobsen MD, EMT-P, Johnson County EMS System Medical Director
    Jacob Ruthsrom MD, Deputy EMS Medical Director
    Theodore Barnett MD, Chair, Johnson County Medical Society EMS Physicians Committee
    Johnson County EMS System Spinal Restriction Protocol 2014 in PDF format.

    .

    How Bad is Epinephrine (Adrenaline) for Cardiac Arrest, According to the PARAMEDIC2 Study?

     
    Also to be posted on ResearchBlogging.org when they relaunch the site.

    Do we have to stop using epinephrine (adrenaline in Commonwealth countries) for cardiac arrest?
     


     

    PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) compared adrenaline (epinephrine) with placebo in a “randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest”.[1]

    The results showed that 1 mg of epinephrine every 3 – 5 minutes is even worse than I expected, but a lot of the more literate doctors have not been using epinephrine that way. What does this research tell us about their various methods? The podcast REBEL Cast (Rational Evidence Based Evaluation of Literature in Emergency Medicine) has a discussion of this question in REBEL Cast Ep56 – PARAMEDIC-2: Time to Abandon Epinephrine in OHCA?.[2]

    The current ACLS/ILCOR (Advanced Cardiac Life Support/International Liaison Committee on Resuscitation) advice on epinephrine does not state that epinephrine is a good idea, or even require that you give epinephrine to follow their protocol –
     

    The major changes in the 2015 ACLS guidelines include recommendations about prognostication during CPR based on exhaled CO2 measurements, timing of epinephrine administration stratified by shockable or nonshockable rhythms, and the possibility of bundling treatment of steroids, vasopressin, and epinephrine for treatment of in-hospital arrests. In addition, the administration of vasopressin as the sole vasoactive drug during CPR has been removed from the algorithm.[3]

     

    What was the ACLS/ILCOR advice in the 2010 guidelines?
     

    The 2010 Guidelines stated that it is reasonable to consider administering a 1-mg dose of IV/IO epinephrine every 3 to 5 minutes during adult cardiac arrest.[4]

     

    This is in a paragraph that links to the PICO (Population-Intervention-Comparator-Outcomes) question that has been an open question for over half a century – In cardiac arrest, is giving epinephrine better than not giving epinephrine?[5]

    They only considered it reasonable, based on low quality evidence.

    What was the ACLS/ILCOR advice in the 2015 guidelines?
     

    Standard-dose epinephrine (1 mg every 3 to 5 minutes) may be reasonable for patients in cardiac arrest (Class IIb, LOE B-R).[6]

     

    Again, ACLS/ILCOR only considered a dose of epinephrine to be reasonable. Again, this was based on low quality evidence. I am not criticizing the efforts of those who worked on the Jacobs study of adrenaline vs. placebo, because they were stopped by the willfully ignorant opponents of science.[7]

    What about the method of attempting to titrate an infusion to the hemodynamic response, which Dr. Swaminathan and Dr. Rezaie alluded to?

    There is a lot of anecdotal enthusiasm from doctors who use this method, but I do not know of any research that has been published comparing outcomes using this method with anything else. How do we know that the positive reports from doctors are anything other than confirmation bias? We don’t.

    This year is the 200th anniversary of the publication of the very first horror novel – Frankenstein; or, The Modern Prometheus. The doctor in the novel used electricity to raise the dead (and the subjects were very dead). There were no chest compressions in the novel, but it is interesting that we have barely made progress from the fiction imagined by an 18 year old with no medical training, although she did have the opportunity to listen to many of the smartest people in England discuss science. Mary Godwin (later Mary Wollstonecraft Shelley by marriage) was 16 when she started writing the novel.[8]

    We have barely made more progress at resuscitation than a teenager did 200 years ago in a novel. Most of our progress has been in finally admitting that the treatments we have been using have been producing more harm than benefit. Many of us are not even that honest about the harm we continue to cause.

    We dramatically improved resuscitation in one giant leap – when we focused on high quality chest compressions and ignoring the medical theater of advanced life support.

    There are two treatments that work during cardiac arrest – high quality chest compressions and rapid defibrillation.

    Why haven’t we made more progress?

    We have been too busty making excuses for remaining ignorant.

    We need to stop being so proud of our ignorance.

    We now know that amiodarone doesn’t work for cardiac arrest (and is more dangerous than beneficial for ventricular tachycardia – even adenosine appears to be better for VTach), atropine doesn’t work for cardiac arrest, calcium chloride doesn’t work for cardiac arrest (unless it is due to hyperkalemia/rhabdomyolysis), vasopressin doesn’t work for cardiac arrest, high dose epinephrine doesn’t work for cardiac arrest, standard dose epinephrine doesn’t work for cardiac arrest – in other words, we have tried all sorts of drugs, based on hunches and the weakest of evidence, but we still haven’t learned that there isn’t a magic resuscitation drug.

    Should anyone be using any epinephrine to treat cardiac arrest outside of a well controlled study?

    No.

    Also –

    A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest – Part I

    Footnotes:

    [1] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
    Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
    N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMoa1806842. [Epub ahead of print]
    PMID: 30021076

    Free Full Text from NEJM

    All supplementary material is also available at the end of the article at the NEJM site in PDF format –

    Protocol

    Supplementary Appendix

    Disclosure Forms

    There is also an editorial, which I have not yet read, by Clifton W. Callaway, M.D., Ph.D., and Michael W. Donnino, M.D. –

    Testing Epinephrine for Out-of-Hospital Cardiac Arrest.
    Callaway CW, Donnino MW.
    N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMe1808255. [Epub ahead of print] No abstract available.
    PMID: 30021078

    Free Full Text from NEJM

    [2] REBEL Cast Ep56 – PARAMEDIC-2: Time to Abandon Epinephrine in OHCA?
    Anand Swaminathan, MD and Salim Rezaie, MD, FACEP
    July 20, 2018
    Episode 56 and show notes

    [3] Introduction
    Part 7: Adult Advanced Cardiovascular Life Support
    2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
    Mark S. Link, Lauren C. Berkow, Peter J. Kudenchuk, Henry R. Halperin, Erik P. Hess, Vivek K. Moitra, Robert W. Neumar, Brian J. O’Neil, James H. Paxton, Scott M. Silvers, Roger D. White, Demetris Yannopoulos, Michael W. Donnino
    Circulation. 2015;132:S444-S464, originally published October 14, 2015
    https://doi.org/10.1161/CIR.0000000000000261
    Introduction – scroll down to the last paragraph

    [4] Vasopressors in Cardiac Arrest: Standard-Dose Epinephrine
    Part 7: Adult Advanced Cardiovascular Life Support
    2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
    Mark S. Link, Lauren C. Berkow, Peter J. Kudenchuk, Henry R. Halperin, Erik P. Hess, Vivek K. Moitra, Robert W. Neumar, Brian J. O’Neil, James H. Paxton, Scott M. Silvers, Roger D. White, Demetris Yannopoulos, Michael W. Donnino
    Circulation. 2015;132:S444-S464, originally published October 14, 2015
    https://doi.org/10.1161/CIR.0000000000000261
    2010 epinephrine advice

    [5] Epinephrine Versus Placebo
    ILCOR Scientific Evidence Evaluation and Review
    Epinephrine Versus Placebo

     

    Among adults who are in cardiac arrest in any setting (P), does does the use of epinephrine (I), compared with compared with placebo or not using epinephrine (C), change Survival with Favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year, ROSC (O)?

     

    [6] 2015 Recommendation—Updated
    Part 7: Adult Advanced Cardiovascular Life Support
    2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
    Mark S. Link, Lauren C. Berkow, Peter J. Kudenchuk, Henry R. Halperin, Erik P. Hess, Vivek K. Moitra, Robert W. Neumar, Brian J. O’Neil, James H. Paxton, Scott M. Silvers, Roger D. White, Demetris Yannopoulos, Michael W. Donnino
    Circulation. 2015;132:S444-S464, originally published October 14, 2015
    https://doi.org/10.1161/CIR.0000000000000261
    2015 Recommendation—Updated

    [7] 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]

    Free Full Text PDF Download from semanticscholar.org
     

    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.

     

    [8] Frankenstein
    Wikipedia
    Article

    Edited 12-27-2018 to correct link to pdf of Jacobs study in footnote 7.

    .

    A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest – Part I

     
    Also to be posted on ResearchBlogging.org when they relaunch the site.

    The results are in from the only completed Adrenaline (Epinephrine in non-Commonwealth countries) vs. Placebo for Cardiac Arrest study.
     


     

    Even I overestimated the possibility of benefit of epinephrine.

    I had hoped that there would be some evidence to help identify patients who might benefit from epinephrine, but that is not the case.

    PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) compared adrenaline (epinephrine) with placebo in a “randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest”.

    More people survived for at least 30 days with epinephrine, which is entirely expected. There has not been any controversy about whether giving epinephrine produces pulses more often than not giving epinephrine. As with amiodarone (Nexterone and Pacerone), the question has been whether we are just filling the ICUs and nursing home beds with comatose patients.
     

    There was no statistical evidence of a modification in treatment effect by such factors as the patient’s age, whether the cardiac arrest was witnessed, whether CPR was performed by a bystander, initial cardiac rhythm, or response time or time to trial-agent administration (Fig. S7 in the Supplementary Appendix). [1]

     

    The secondary outcome is what everyone has been much more interested in – what are the neurological outcomes with adrenaline vs. without adrenaline?

    The best outcome was no detectable neurological impairment.
     

    the benefits of epinephrine that were identified in our trial are small, since they would result in 1 extra survivor for every 112 patients treated. This number is less than the minimal clinically important difference that has been defined in previous studies.29,30 Among the survivors, almost twice the number in the epinephrine group as in the placebo group had severe neurologic impairment.

    Our work with patients and the public before starting the trial (as summarized in the Supplementary Appendix) identified survival with a favorable neurologic outcome to be a higher priority than survival alone. [1]

     


    Click on the image to make it larger.
     

    Are there some patients who will do better with epinephrine than without?

    Maybe (I would have written probably, before these results), but we still do not know how to identify those patients.

    Is titrating tiny amounts of epinephrine, to observe for response, reasonable? What response would we be looking for? Wat do we do if we observe that response? We have been using epinephrine for over half a century and we still don’t know when to use it, how much to use, or how to identify the patients who might benefit.

    I will write more about these results later

    We now have evidence that, as with amiodarone, we should only be using epinephrine as part of well controlled trials.

    Also see –

    How Bad is Epinephrine (Adrenaline) for Cardiac Arrest, According to the PARAMEDIC2 Study?

    Footnotes:

    [1] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
    Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
    N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMoa1806842. [Epub ahead of print]
    PMID: 30021076

    Free Full Text from NEJM

    All supplementary material is also available at the end of the article at the NEJM site in PDF format –

    Protocol

    Supplementary Appendix

    Disclosure Forms

    There is also an editorial, which I have not yet read, by Clifton W. Callaway, M.D., Ph.D., and Michael W. Donnino, M.D. –

    Testing Epinephrine for Out-of-Hospital Cardiac Arrest.
    Callaway CW, Donnino MW.
    N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMe1808255. [Epub ahead of print] No abstract available.
    PMID: 30021078

    Free Full Text from NEJM

    .

    New Illinois state law will allow basic EMTs to inject epinephrine

     
    EpiPen 1 from Bloomberg dot com
    Image from Bloomberg.com.
     

    0.15 mg (0.15 ml of 1 mg/ml epinephrine) for a child.
    0.3 mg (0.3 ml of 1 mg/ml epinephrine) for an adult.
    Inject deep into the side of the thigh.
    This should not be complicated, but . . . .

    Paramedics have generally been able to give epinephrine injections for anaphylaxis in Illinois and elsewhere. As of January 1, 2017, basic EMTs (Emergency Medical Technicians) in Illinois, who have been able to use the EpiPen autoinjector, will be able to give epinephrine injections the same way paramedics give epinephrine for anaphylaxis.[1],[2]

    Why? The cost of the autoinjector has increased from around $100 to around $600 since 2007, when Mylan bought the EpiPen as part of a group of products from Merck. During that time, the packaging has gone from a single EpiPen to two EpiPens, so that may be one part of the increase.

    The EpiPen, which is currently only made by Mylan, used to have competition from Sanofi. On October 30, 2015, Sanofi recalled their Auvi-Q autoinjectors due to the possibility of dosage inaccuracies.[3] Some people are claiming that the increase in cost is due to the withdrawal of this competitor from the market, but I was able to locate two other competitors in the US, so there is competition.

    Explanations exist; they have existed for all time; there is always a well-known solution to every human problem — neat, plausible, and wrong. H.L. Mencken.

    If only the Sanofi recall caused the price increase, the price would not have been increasing for the past 10 years, but only for the past 10 months. Here is a graph of the price increase before the Sanofi recall.
     

    EpiPen 2 from Bloomberg dot com
    Graph from September 2015 – before the Sanofi recall – from Bloomberg.com.[4]
     

    There are other competitors out there. Adrenaclick by Amedra Pharmaceuticals LLC,[5] and epinephrine injection, USP auto-injector by Lineage Therapeutics Inc.[6] – both located in Horsham, PA and the web sites have the same design, so they may be manufactured in the same facility.
     

    The problems with having basic EMTs giving epinephrine injections are that the education has to be very good and the oversight has to be aggressive. As with naloxone (Narcan), doctors, nurses, and paramedics often give the drug inappropriately, so we know that there is a lot of potential for error.

    The closest children’s hospital only uses autoinjectors, because they do not allow the nurses to draw up epinephrine for anaphylaxis. They probably do not allow the doctors to either, but I did not ask.

    How bad are doctors at diagnosing and treating anaphylaxis?
     

    Senior house officers (SHOs) (n=78) at the start of their accident and emergency (A&E) post were given an anonymous five case history questionnaire, containing one case of true anaphylaxis, and asked to complete the medication they would prescribe. In the case of anaphylaxis, 100% would administer adrenaline (epinephrine) but 55% would do so by the incorrect route. In the remaining cases, 10%–56% would be prepared to administer adrenaline inappropriately. Only 5% were able to indicate the correct route and dose of adrenaline according to Resuscitation Council guidelines (UK). This has implications for training as the survey took place before the start of the A&E posting. Anaphylaxis is over-diagnosed and poorly treated despite Resuscitation Council guidelines.[7]

     

    That was in 2002. Have things improved?
     

    RESULTS:
    68 of 107 (64%) junior doctors completed the questionnaire. All recognised the need for adrenaline in anaphylaxis, but only 74% selected the correct intramuscular route, and 34% the correct route and dose. 82% of junior doctors would inappropriately give adrenaline to the patient who had inhaled a foreign body (case 2). A higher percentage of the 2013 cohort indicated the correct route and dose of adrenaline in anaphylaxis than their 2002 colleagues. However, a greater percentage also selected adrenaline treatment inappropriately in non-anaphylactic case scenarios.

    CONCLUSIONS:
    Despite updated guidelines, junior doctors continue to have poor knowledge about the recognition and management of anaphylaxis, with some still considering inappropriate intravenous adrenaline. More effort should be given to the recognition of anaphylaxis in early medical training.
    [8]

     

    Other research on doctors shows similar inability to come up with the right diagnosis, the right dose, and/or the right route of administration.[9],[10],[11] There are more. My anecdotal experience is that this is also a problem in the US with experienced paramedics and experienced physicians.

    What about the King County epinephrine kit for basic EMTs?
     

    King County epinephrine program to replace epipens 1 from Seattle Times
    Image from the Seattle Times.
     

    With training, EMTs in the program have learned to administer epinephrine efficiently and safely, he said. An EpiPen takes about 45 seconds to administer, start to finish. With the vial and syringe, it’s about 2 minutes, Duren said.[12]

     

    As a paramedic, I am not going to be much faster.
     

    “That sounds reasonable,” Reiter said. “For all but the most severe cases of anaphylaxis, a one-minute time lag is unlikely to make a difference.”[12]

     

    The article suggests that King County is tracking their results carefully, which does not appear to be the case for EMS systems that have first responders giving naloxone. I would still like to see something published in a peer reviewed journal.

    Footnotes:

    [1] New state law will allow EMTs to inject epinephrine
    Dan Petrella
    The Southern Springfield Bureau
    The Southern Illinoisan
    Updated 22 hrs ago
    Article

    [2] New Ill. law to allow all EMTs to use syringes to administer epinephrine – The new law will allow EMTs with basic-level training to use a syringe to administer epinephrine
    By EMS1 Staff
    EMS1.com
    Yesterday at 12:59 PM
    Article

    [3] UPDATED: Sanofi US Issues Voluntary Nationwide Recall of All Auvi-Q® Due to Potential Inaccurate Dosage Delivery
    FDA (Food and Drug Administration – US)
    For Immediate Release
    October 30, 2015
    Recall notice

    [4] How Marketing Turned the EpiPen Into a Billion-Dollar Business – Mylan’s marketing turned the allergy device into a must-have.
    Cynthia Koons and Robert Langreth
    Bloomberg Businessweek
    September 23, 2015 — 10:00 AM EDT
    Article

    [5] How to use Adrenaclick (epinephrine injection, USP auto-injector)
    Adrenaclick by Amedra Pharmaceuticals LLC, Horsham, PA
    Web site

    [6] epinephrine injection, USP auto-injector
    Lineage Therapeutics Inc., Horsham, PA
    Web site

    [7] Proposed use of adrenaline (epinephrine) in anaphylaxis and related conditions: a study of senior house officers starting accident and emergency posts.
    Gompels LL, Bethune C, Johnston SL, Gompels MM.
    Postgrad Med J. 2002 Jul;78(921):416-8.
    PMID: 12151658

    Free Full Text from PubMed Central.

    [8] Correct recognition and management of anaphylaxis: not much change over a decade.
    Plumb B, Bright P, Gompels MM, Unsworth DJ.
    Postgrad Med J. 2015 Jan;91(1071):3-7. doi: 10.1136/postgradmedj-2013-132181.
    PMID: 25573132

    Free Full Text from Postgrad Med J.

    [9] Survey of the use of epinephrine (adrenaline) for anaphylaxis by junior hospital doctors.
    Jose R, Clesham GJ.
    Postgrad Med J. 2007 Sep;83(983):610-1.
    PMID: 17823230

    Free Full Text from PubMed Central

    [10] Anaphylaxis: lack of hospital doctors’ knowledge of adrenaline (epinephrine) administration in adults could endanger patients’ safety.
    Droste J, Narayan N.
    Eur Ann Allergy Clin Immunol. 2012 Jun;44(3):122-7.
    PMID: 22905594

    [11] Treatment of a simulated child with anaphylaxis: an in situ two-arm study.
    O’Leary FM, Hokin B, Enright K, Campbell DE.
    J Paediatr Child Health. 2013 Jul;49(7):541-7. doi: 10.1111/jpc.12276. Epub 2013 Jun 12.
    PMID: 23758136

    Free Full Text from J Paediatr Child Health.

     

    RESULTS:
    Fifty-six junior medical staff participated (90% participation rate). Only 50% of participants administered adrenaline in scenarios of definite anaphylaxis. Adrenaline was more likely to be administered if the scenario included hypotension, where the junior medical officer had previous formal resuscitation training (Advanced Paediatric Life Support) and by medical officers with more years of training.

    CONCLUSION:
    Anaphylaxis is a life-threatening presentation and requires prompt recognition and appropriate adrenaline administration. Junior medical staff may require more emphasis on recognition and prompt adrenaline administration in both undergraduate and in hospital training and education. Simulated scenarios may provide a platform to deliver this training to ultimately improve patient care.

     

    [12] King County drops EpiPen for cheaper kit with same drug
    By JoNel Aleccia
    Seattle Times health reporter
    Originally published January 14, 2015 at 10:05 pm
    Updated January 15, 2015 at 7:00 pm
    Seattle Times
    Article

    .

    Natural Alternatives to the EpiPen, Because We Believe in Parachutes

     

    The evidence for epinephrine (Adrenaline in Commonwealth countries) in anaphylaxis is not the highest quality available, but that does not mean that the use of epinephrine to treat anaphylaxis is not EBM (Evidence Based Medicine).
     

    Evidence Pyramid

    Evidence Pyramid


    Image credit.
     

    The patients are not randomized to placebo vs. epinephrine treatments, but EBM is not limited to placebo studies[1] – unless you believe that the Parachute Study is valid evidence, rather than just satire.[2]

    It is entirely appropriate to use logical fallacy for satire, since humor is not expected to be based on valid evidence. It is definitely not appropriate to use logical fallacy as scientific evidence. Logic is essential to science, while logical fallacy and the avoidance of rational analysis are essential to deception.

    What does the Parachute study have to do with Natural Alternatives to Epipen?[3] The evidence supporting epinephrine is even weaker than the evidence supporting parachutes, since one of the advantages of parachutes is that their use can be adequately studied without using human subjects. Therefore we actually have excellent evidence that parachutes will deploy as expected (with the obvious error bars that apply to valid science), will slow the descent (again, with the obvious error bars that apply to valid science), et cetera.
     

    Even the most dimwitted purveyor of “natural” cures should know that and stay away from “natural” treatments for anaphylaxis, while the smarter snake oil salesmen also know that you can’t afford to mess around with a medical condition that can cause such rapid deterioration from seemingly perfectly health to dead. It’s not good for business.[4]

     

    Ignoring the pathetic absence of evidence for alternative medicine, what is the evidence that epinephrine does improve outcomes?

    There is an excellent discussion of the evidence in an article available for free at PubMed Central.
     

    International guidelines concur that epinephrine (adrenaline) is the medication of first choice in anaphylaxis because it is the only medication that reduces hospitalization and death.[5]

     

    There is no reduction of hospitalization and death with Benadryl (diphenhydramine), with any of the steroids, or with any alternative medicine. Go read the full paper.

    Also, go read the analysis of the problems in the article advocating the use of Natural Alternatives to Epipen at Respectful Insolence.

    Footnotes:

    [1] Evidence based medicine: what it is and what it isn’t.
    Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS.
    BMJ. 1996 Jan 13;312(7023):71-2.
    PMID: 8555924 [PubMed – indexed for MEDLINE]

    Free Full Text from PubMed Central.
     

    Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.

     

    Maybe the opponents of Evidence Based Medicine do not understand that using judgment to apply the best evidence to the patient is essential to EBM.

    [2] Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials.
    Smith GC, Pell JP.
    BMJ. 2003 Dec 20;327(7429):1459-61. Review.
    PMID: 14684649 [PubMed – indexed for MEDLINE]

    Free Full Text from PubMed Central.

    The authors searched the literature for parachute research, but eliminated all studies without control groups, which suggests that EBM has some sort of requirement that all research include a control group. That is one of the logical fallacies employed by the authors for humorous intent.
     

    We excluded studies that had no control group.

     

    Those who cite the parachute study as valid evidence do not seem to understand this sleight of hand. EBM does not exclude studies that have no control group. EBM even includes expert opinion.

    [3] Natural Alternatives to Epipen
    Gazette Review
    Dec 18, 2015
    Adam Trent
    Cached article

    [4] Worst idea ever: “Natural” alternatives to the Epipen
    Respectful Insolence
    Posted by Orac
    December 22, 2015
    Article

    [5] 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.
    Simons FE, Ebisawa M, Sanchez-Borges M, Thong BY, Worm M, Tanno LK, Lockey RF, El-Gamal YM, Brown SG, Park HS, Sheikh A.
    World Allergy Organ J. 2015 Oct 28;8(1):32. doi: 10.1186/s40413-015-0080-1. eCollection 2015.
    PMID: 26525001

    Free Full Text from PubMed Central.

    .

    Should ACLS Recommend the Unknown Based on Weak Evidence?


     
    The AHA (American Heart Association) and ILCOR (International Liaison Committee on Resuscitation) will be meeting tomorrow to finalize the recommendations for the 2015 ACLS (Advanced Cardiac Life Support) guidelines. Here is the comment I submitted on the proposed recommendation for epinephrine (Adrenaline in Commonwealth countries) in cardiac arrest.

    I have not received any information about where to submit SEERS comments, so I am sending this to you. Please forward it to whomever is supposed to receive comments.

    Vasopressors for cardiac arrest (1. Epi v Placebo)
     

    Consensus on Science:
    For all four long term (critical) and short term (important) outcomes, we found one underpowered trial that provided low quality evidence comparing SDE to placebo (Jacobs, 2001, 1138).
    [1]

     

    As a trial that is stated to be underpowered (through no fault of Dr. Jacobs),[2] is there any valid reason the Jacobs study should be considered to be superior to observational studies?
     

    Among 534 subjects, there was uncertain benefit or harm of SDE over placebo for the critical outcomes of survival to discharge [RR 2.12, 95% CI 0.75-6.02, p=0.16] and good neurological outcome defined as CPC of 1-2 [RR 1.73, 95% CI 0.59-5.11, p=0.32].[1]

     

    We do not have good evidence to tell us if this is harmful or beneficial and we do not have any way of determining which patients will be harmed or helped by administration of epinephrine.


     

    However, patients who received SDE had higher rates of the two important outcomes of survival to admission [RR 1.95, 95% CI, 1.34-2.84, p=0.0004] and ROSC in the prehospital setting [RR 2.80, 95% CI 1.78-4.41, p<0.00001] compared to those who received placebo.[1]

     

    Are these surrogate endpoints important?

    How do we know?

    If these surrogate endpoints are important, why is there no valid evidence to support this claim?

    We have a history of being misled by surrogate endpoints. We used to bleed patients and that produced a number of clear benefits in surrogate endpoints.
     

    Physicians observed of old, and continued to observe for many centuries, the following facts concerning blood-letting.

    1. It gave relief to pain. . . . .

    2. It diminished swelling. . . . .

    3. It diminished local redness or congestion. . . . .

    4. For a short time after bleeding, either local or general, abnormal heat was sensibly diminished.

    5. After bleeding, spasms ceased, . . . .

    6. If the blood could be made to run, patients were roused up suddenly from the apparent death of coma. (This was puzzling to those who regarded spasm and paralysis as opposite states; but it showed the catholic applicability of the remedy.)

    7. Natural (wrongly termed ” accidental”) hacmorrhages were observed sometimes to end disease. . . . .

    8. . . . venesection would cause hamorrhages to cease.[3]

     

    We don’t do that any more, because medicine is not supposed to just create a superficial improvement.

    We should not be making any recommendation to treat based on such weak evidence.
     

    The evidence for the routine use of adrenaline is perceived to be at equipoise within the international community of resuscitation scientists requiring re-evaluation19 as suggested by this comprehensive systematic review and meta-analysis. There is a need for well-designed, placebo-controlled, and adequately powered RCTs to evaluate the efficacy of adrenaline and to determine its optimal dosing.11,16,54 The question as to the efficacy of adrenaline for OHCA remains unanswered.[4]

     

    Since the question as to the efficacy of adrenaline for OHCA remains unanswered, we should avoid substituting a bad answer for We don’t know.

    Maybe we should bring back the indeterminate class for these unanswerable questions.
     

    Treatment Recommendation
    Given the observed benefit in short term outcomes, we suggest Standard Dose Epinephrine be administered to patients in cardiac arrest.(weak recommendation, low quality)
    [1]

     

    The benefit is considered important, but that is just an expert opinion, which is the lowest level of evidence.

    A weak recommendation to give a treatment of unknown benefit and unknown harm, based on evidence that is admitted to be of low quality, should not set the standard of care. Even if the guidelines are explicitly stated to not be standards of care, they are adopted as standards of care by the emergency medicine community and by the EMS community.

    We don’t know enough to make a recommendation about epinephrine, or most other treatments, in cardiac arrest.

    We do not need to keep making the same recommendation just because we have made it before. We can leave it up to the treating physician or to the medical director writing the protocols for EMS.
     
     

    See also – Proposed 2015 ACLS Epinephrine Recommendation – Vasopressors for cardiac arrest (1. Epi v Placebo)

    Footnotes:

    [1] Vasopressors for cardiac arrest (1. Epi v Placebo)
    ILCOR Scientific Evidence Evaluation and Review System
    Questions Open for Public Comment
    Closing Date – February 28, 2015
    Question page

    [2] 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]

    Free Full Text PDF Download from semanticscholar.org
     

     

    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.

     

    [3] Blood-Letting
    Br Med J.
    1871 March 18; 1(533): 283–291.
    PMCID: PMC2260507

    [4] Adrenaline for out-of-hospital cardiac arrest resuscitation: a systematic review and meta-analysis of randomized controlled trials.
    Lin S, Callaway CW, Shah PS, Wagner JD, Beyene J, Ziegler CP, Morrison LJ.
    Resuscitation. 2014 Jun;85(6):732-40. doi: 10.1016/j.resuscitation.2014.03.008. Epub 2014 Mar 15.
    PMID: 24642404 [PubMed – in process]

    Edited 12-27-2018 to correct link to pdf of Jacobs study in footnote 2.

    .