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

- Rogue Medic

The Second EMS What-if-We’re-Wrong-a-Thon

 

Brandon Oto promoted The First EMS What-if-We’re-Wrong-a-Thon last year, but I was taking a break from blogging at the time, so I did not participate. The idea is to consider a position from the perspective of being wrong.

This is the way science works. An idea (hypothesis) is tested by attempting to prove that it is wrong, rather than attempting to prove that it is true. Unfortunately, not all science is done well. Ideology (politics, religion, nationalism, stereotyping, . . . ) is the opposite of science. The goal of ideologues is to defend the dogma, rather than to find the truth.

Since valid evidence to the contrary is all that I need to change my mind, as I have on ventilation in cardiac arrest, high flow oxygen for just about anything, epinephrine any drug for cardiac arrest, intubation as the gold standard of airway management, et cetera, is to look at something based more on opinion, rather than evidence.
 

What have I been wrong about that I have not yet corrected in writing? Romazicon (flumazenil) is a benzodiazepine antagonist which has the nasty side effect of producing seizures. I have condemned the suggestion that it should be used by EMS, because it is just an ALS (Advanced Life Support) means of trying to correct a BLS (Basic Life Support) problem with the potential for creating ALS problems that would result in even more ALS solutions.[1]
 

In considering the effects of flumazenil, have I put too much emphasis on the adverse effects and not enough emphasis on the ways that the side effects can be prevented or managed?
 

Putting much more emphasis on the side effects, rather than on the benefits is important in pharmacology, because the benefits are usually less than we expect and the serious side effects should be much less frequent than the benefits. If the serious side effects are not much less frequent than the benefits, why use the drug?

The importance of large studies is less in quantifying the benefits, but in having enough data to identify the side effects. The second most famous example of this is the Cardiac Arrhythmia Suppression Trial,[2] which was intended to show which brand of antiarrhythmic drug saved the most lives. The one that saves the most lives is clearly the best and would be marketed aggressively as the best. The result was to demonstrate that the antiarrhythmic drugs were killing people. About 60,000 people, who would not have died at that time, were killed by these drugs. These drugs were the most frequently prescribed drugs in America at that time. All of the best doctors knew that the drugs improved survival – except the drugs were killing patients.

The most famous example of a small rate of serious side effects not being identified until a lot of people were affected is thalidomide.[3] This produced dramatic deformities in the children of mothers who had taken thalidomide for nausea and vomiting of pregnancy. Since the ideas of pure good and pure evil are ideological, rather than real, there are appropriate uses for thalidomide in the treatment of Hansen’s disease (leprosy) and multiple myeloma. Good medicine requires that we balance the benefits and risks in order to increase the probability of an improvement in outcome.
 

What if, in the case of flumazenil, the side effects are both known and manageable?
 
midazolam plus flumazenil = safer qm 2
 

Flumazenil is not as dangerous as I initially thought. I was giving too much emphasis to the problems. I also think that a reasonable case can be made that we should use benzodiazepines more aggressively, while managing airway compromise and oversedation with flumazenil as an occasional supplement to BLS methods such as proper positioning to maintain the airway and stimuli to promote respiratory drive. An IM (IntraMuscular) dose of 10 mg of midazolam (Versed) may be a good starting dose for a small or medium-sized person.

What about seizures? Seizures do occur, but they are not common. Flumazenil is a competitive antagonist, so more benzodiazepine can be given to stop a seizure, but we should not be getting anywhere near that complication. Seizures are not common and only one of the uses of benzodiazepines is to stop seizure activity. There is no good reason to expect seizure activity if we are giving tiny doses (smaller than the recommend doses of flumazenil) to patients who are being sedated with benzodiazepines (the wrong drugs, but often the only ones available to EMS) for agitated delirium and happen to become so sedated that a bad outcome is likely without intervention.[4]

The current issue of the British Journal of Clinical Pharmacology has the theme of the appropriate use of antidotes.
 

Themed issue Antidotes in Clinical Toxicology

Theophrastus Bombastus Paracelsus von Hohenheim (1493–1541) said it all with Dosis sola facit venenum or in modern language “It is the dose, stupid”. So, for a journal of Clinical Pharmacology that as a matter of principle deals with the relation between dose and effect, covering the high end of de (the?) dose – effect relationship is nothing out of the ordinary. This issue is largely about how to treat unfortunate patients who have reached the dark side of the dose–response curve. This can be done by antidotes.[5]

 

This can be done by antidotes.     Not – This must be done by antidotes.

It is the dose, stupid, is usually translated as The dose makes the poison, or –
 

All things are poison and nothing is without poison, only the dose permits something not to be poisonous. – Paracelsus.
 

Only one article in this issue addresses flumazenil, and that is only as part of a general discussion of antidotes (which also mentions the use of benzodiazepines as the antidote for overdose of amphetamines and other stimulants and for drug induced delirium). The article does encourage caution in the use of flumazenil –
 

For other antidotes, a clinical effect is pharmacologically expected, obvious and rapid (e.g. reversal of coma with flumazenil or naloxone, or resolution of delirium with physostigmine). However, this does not necessarily translate into improved clinical outcomes over supportive care [2]. [6]

 

What if the important safety criteria are using small doses, repeated reassessment, and critical judgment?

Can EMS do that? Our failures with airway management (it is still popular to claim that no evidence of benefit or safety is needed, in spite of the many studies showing harm from intubation) suggest that we cannot, but people keep pointing out that I am an optimist. I think that education can reach many of the dogmatic deniers of science and promoters of emotion over reality.

The use of tiny doses of naloxone (Narcan) to increase the respiratory drive, but not the alertness, of patients with opioid overdoses may result in a sudden increase in level of consciousness and aggression, but that is not typical.

Can we produce better outcomes with judicious use of antidotes in addition to supportive care as a way of managing aggressive use of benzodiazepines? Maybe, but it is not something people seem to want to study. We have given the drug to be reversed and know the dose we gave, so we are not dealing with an unknown overdose. The patient may have ingested other drugs that are unknown, but they tend to be stimulants, which is why we are giving a sedative. The patient may even have taken a benzodiazepine at some point, but more benzodiazepine is not a reason to avoid flumazenil.

The better question is can we improve outcomes for violent patients and for the people who deal with violent patients, with more aggressive use of benzodiazepines and judicious use of flumazenil to minimize the side effects of aggressive benzodiazepine use?

Benzodizepines are the wrong drugs to use for agitated delirium, unless combined with more effective medication. Some EMS providers do not have access to the most effective sedatives, or even the second most effective sedatives. I am limited to benzodiazepines and only in doses that are too low. Adding flumazenil to my scope of practice might help the medical directors to provide better EMS education and more aggressive standing orders.

There is more to write about flumazenil, but this is plenty for today.
 

Also writing in The Second EMS What-if-We’re-Wrong-a-Thon are –

Michael Morse (Rescuing Providence) — asks… what if community paramedicine really is the future of EMS?

Dale Loberger (High Performance EMS) — asks… what if emergency response times don’t really matter all that much?

Amy Eisenhauer (The EMS Siren) — wonders… whether the role of social media in EMS is such a good thing after all.

Ginger Locke — asks… what if video laryngoscopy really is the best first-pass technique for routine endotracheal intubation?

Footnotes:

[1] Flumazenil and EMS – A Box Pandora Should Not Open
Fri, 20 Mar 2009
by Rogue Medic
Article

[2] Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al.

N Engl J Med. 1991 Mar 21;324(12):781-8.
PMID: 1900101 [PubMed – indexed for MEDLINE]

Free Full Text from NEJM.

CONCLUSIONS. There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.

I have written about this in C A S T and Narrative Fallacy and elsewhere.

[3] Thalidomide: the tragedy of birth defects and the effective treatment of disease.
Kim JH, Scialli AR.
Toxicol Sci. 2011 Jul;122(1):1-6. doi: 10.1093/toxsci/kfr088. Epub 2011 Apr 19. Erratum in: Toxicol Sci. 2012 Feb;125(2):613.
PMID: 21507989

Free Full Text from Toxicol Sci.

[4] Excited Delirium: Episode 72 EMS EduCast
Wed, 29 Sep 2010
by Rogue Medic
Article

[5] Issue highlights
British Journal of Clinical Pharmacology
Special Issue: Antidotes in Clinical Toxicology
Volume 81, Issue 3, pages 398–399, March 2016
DOI: 10.1111/bcp.12909
Article

[6] Who gets antidotes? choosing the chosen few.
Buckley NA, Dawson AH, Juurlink DN, Isbister GK.
Br J Clin Pharmacol. 2016 Mar;81(3):402-7. doi: 10.1111/bcp.12894. Epub 2016 Feb 17. Review.
PMID: 26816206

Free Full Text from Br J Clin Pharmacol.

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