Like many of you, I have travelled through the glorious labyrinth of medical learning, initially skipping along, picking the flowers of information, believing wide-eyed anything that I had been taught by my superiors, by textbooks, by journal articles; but as time passed, I began to see that medical truths were not always as concrete as they were made out. Any of you who had the misfortune of teaching advanced cardiac life support a decade ago would have, like me, espoused with great smugness the necessity for using up to 5mg adrenaline per cycle, and failed students if they hadn’t used bretylium at exactly the correct time in an arrest cycle and self-righteously ticked them off for not using a stack of 3 shocks to defibrillate the initial rhythm. Then, usually exactly 5 years later, we would turn around and negate many things we had previously preached, to propagate a new universal truth.
A Medical Reversal, is defined as the situation where a new clinical trial, superior to its predecessors, contradicts current practice. This is not just evidence for replacement, where the current therapy is supplanted by a more up to date practice that is proven to work better, but where a practice which is accepted on the global stage, is proven to be inferior, or possibly harmful.
Today’s theme for the FFFF is Reversals. Medical, and otherwise.
What percentage of published literature constitutes medical reversal?
- This is variable in different journals, but a particularly intriguing paper published in the Archives of Internal Medicine, looked at original articles published over 1 year (2009) in NEJM, and showed that 16% of these fulfilled the definition of ‘reversal’.
- The cynic may argue that papers that get into NEJM are more likely to be sensational, and thus less likely to be true, and more likely to be overturned by further research…
Name 5 drugs or interventions that have been subject to a medical reversal.
- Class 1C anti-arrythmics (flecainide, encainide), in suppression/prevention of ventricular arrythmias in myocardial ischaemia who demonstrated ventricular ectopy. Used routinely because of their intuitive function. The result was, in fact, to kill patients.
- Adrenaline in cardiac arrest. Where does one start?? Low dose, high dose, escalating dose, superior to any other intervention, inferior to swinging a dead cat, intracardiac (thank you Pulp Fiction) ??????
- The use of percutaneous coronary intervention in the stable coronary artery disease. Doesn’t work. Has the message wholly got through to interventional cardiologists yet? – the COURAGE trial.
- Thalidomide – the original medical reversal. Initially marketed as the ‘wonder drug’ for morning sickness, as it was dogmatically believed that drugs could not cross the human placenta, it tragically led to well documented birth defects. It needed the controversial evidence by Australian Obstetrician McBride to cease its routine use (a whole other level of complexity within medical evidence – is this medical Machiavellism?). Now reversed again to be used in multiple myeloma.
- Australian snake antivenom. Based on some laboratory research into the treatment of coagulopathy in envenomation, stocks of antivenom were pulled from many rural and regional centres as they could not afford to keep the massive stocks dictated by the 2004 MJA paper by Yeung et al (recommendation for 10 vials as an initial bolus for VICC associated with brown snake envenomation). Subsequent research reversed this treatment edict, to the point we’re not even sure whether anti venom works at all. Watch this space.
- Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781-8. PubMed PMID: 1900101. [Fulltext]
- Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2. PubMed PMID: 21745533.
- Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012 Mar 21;307(11):1161-8. PubMed PMID: 22436956. [Fulltext]
- Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. Epub 2007 Mar 26. PubMed PMID: 17387127. [Fulltext]
- Yeung JM, Little M, Murray LM, Jelinek GA, Daly FF. Antivenom dosing in 35 patients with severe brown snake (Pseudonaja) envenoming in Western Australia over 10 years. Med J Aust. 2004 Dec 6-20;181(11-12):703-5. PubMed PMID: 15588174.
Let’s move away from the existential reversals to the more literal reversals.
Name two widely available reversal agents that may be more dangerous than the original drugs they are used to reverse?
1. Flumazenil as a reversal agent for benzodiazepines.
- Benzodiazepines will rarely kill you, as long as you’ve got some half decent airway support. Flumazenil, however, has a ferocious reputation for causing status epilepticus, in the vulnerable (particularly the mixed overdose, or the patient with underlying seizure disorder)
2. Protamine as a reversal agent for heparin.
- Well, it’s not actually that dangerous, although it does have a very narrow therapeutic window, and there is the issue of potential anaphylaxis, with hypotension and bronchospasm, but, quite frankly, who really wants to be infused with the sperm of salmon??
Which drug reversal has our academic knickers in a knot at the moment, scrabbling around for reversal agents?
- The brave new class of anticoagulant, feted for its superiority in stroke prevention, with easier administration, less monitoring and less interactions than warfarin, BUT… no CURRENT reversal agent.
- Lots of ‘suggestions’, including withholding next dose, haemodialysis, prothrombinex and factor 7a, however, nothing quite cuts the mustard in the multiply injured, or cerebrally haemorrhaging patient who comes in on dabigatran. For reference, I refer you to three of social media’s superstars (see Q5)
- EM Lit of Note — Rivaroxaban Can Be Reversed, But Not Dabigatran
- Emergency Medicine News — Toxicology Rounds: Dabigatran – The Top 10 Questions
- The Underneaths of EM — Bloody Hell
And, lastly, really, my favourite reversal. A term with which I have only become recently familiar, associated with athleticism beyond the understanding of most of us mere mortals.
The question is: In what sport is a reversal considered a disqualifying event?
- Competitive Eating.
- The International Federation for Competitive Eating, essentially considers a reversal (which apparently is the regurgitation of food, followed by eating the offending bolus, to continue in one’s quest for glory) a disqualification.
- There are, however, different rules around the world, some of which allow this action as permissible.