by Jeff Lapoint
Everyone wins, if winning is being angry – Alexis C. Madrigal
There was a Life in the Fast Lane post in 2016 that chronicled an intrepid clinician justifying beta blocker use in cocaine toxicity. It began with a clinical vignette involving a student who, in attempting to make it through a cram studying session, drank too many energy drinks and then presented to the emergency department with tachycardia and a nasty case of test anxiety. He was successfully treated with metoprolol as the residents stood aghast at the possibility of the “unopposed alpha phenomenon”. The post goes on to describe this physician reaching out to the local toxicologist to participate in a review of this phenomenon:
One toxicologist, who refused to join the systematic review on cocaine despite my multiple attempts (just short of begging), told me, “I don’t care about this topic. Nobody in the field of Toxicology cares either. My mind is made up. I prefer to study more interesting and important topics, like reversal of direct thrombin inhibitors”
Ouch. Because dogma. Or something.
I love this post. It has everything. Heroes! Villains! Logical fallacies! This post is wonderful not because it is correct (it most certainly isn’t) but rather because it perfectly captures almost all the problems with the beta blocker for cocaine debate, albeit by example. Namely, false equivalency. Caffeine toxicity is not the same as cocaine toxicity. Cocaine exposure is not the same as cocaine toxicity. And, failure to demonstrate complications in one population (admitted patients with cocaine positive urine drug screens) does not mean it is safe in a different population (acute cocaine intoxication). In other words, the post falsely equivocates all stimulant toxicity to that of cocaine; falsely equivocates and fails to differentiate between cocaine exposure and cocaine toxicity; and attempts to apply available beta blocker data from the least cocaine toxic patients to all groups.
What toxicologists think (and should be communicating) about cocaine toxicity.
Cocaine toxicity is the result of central monoamine reuptake inhibition, and sodium channel blockade. It makes it so you can’t get those tasty excitatory neurotransmitters out of the synapse. The resultant central and peripheral sympathomimetic excess accounts for much of the observed symptoms (Kloner 1992 PMID:1346509)(Tella 1993 PMID:8229742). Dopaminergic and serotonergic stimulation results in psychomotor agitation (Rich 1991 PMID: 2039099) and hyperthermia, which is among the poorest prognostic indicators in acute cocaine toxicity (Marzuk 1998 PMID: 9628710)(Daras 1995 PMID: 7484066). With the increase of catecholamines comes increases in peripheral sympathetic tone. This means increases in pulse, blood pressure (Goldfrank 1991 PMID:1996800) and vasoconstriction. Add in excess motor activity and you worsen hyperthermia. Let’s not forget that cocaine is also a type IA antidysrhythmic (AKA sodium channel blocker) and prolongs phase 0 of the cardiac conduction cycle. In severe cases this can result in a wide complex tachycardia, ventricular arrhythmia, and cardiovascular collapse (Billman 1990 PMID: 2185973). Type IA agents are voltage sensitive sodium channel blockers that bind more tightly with decreasing pH and increasing heart rate (Wood 2009 PMID: 18815938).
The following are priorities in treating acute cocaine toxicity:
- Control of agitation – benzodiazepines (BZD) do this
- Reduce central-mediated sympathetic tone – BZD do this
- Lower body temperature – BZD, along with active cooling and, in severe cases, paralysis, do this (Jatlow 1979 PMID: 572161)
- Decrease peripheral sympathetic tone – BZD do this indirectly and possibly directly
- Reverse type IA sodium channel blockade effects – sodium bicarbonate does this
- Prevent and treat seizures – BZD do this
- Prevent and treat coronary artery vasoconstriction and myocardial ischemia – BZD and nitrates do this
The reason we advocate for the liberal and judicious use of benzodiazepines in cocaine toxicity is not adherence to some dogma about unopposed alpha stimulation (although there is some evidence to suggest this is a risk) but rather because it is a targeted therapy against the effects of central excitatory neurotransmitters (Goldfrank 1991 PMID:1996800). Benzodiazepines are safe and easily titratable. Unlike beta blockers, they do not affect cardiac conduction or output, an important factor should the patient deteriorate into cardiovascular collapse.
This is what your local toxicologist is considering when you want to talk about cocaine toxicity. It’s not that I don’t want to make the numbers pretty too, it’s just that I want to do so in a fast, safe, titratable fashion that carefully considers a larger view of the underlying pathophysiology.
Cocaine toxicity means cocaine toxicity. Not caffeine toxicity, or methamphetamine toxicity, or even tachycardia resulting from the joy of ordering a motor driven skateboard. Further, when discussing cocaine toxic patients, I don’t include well appearing people with a positive drug screen. In order to have any productive discussion on this issue we have to define the specific segment of the patient population that’s being referred to.
In the LITFL post, the author opens with a patient experiencing mild symptoms from methylxanthine toxicity then cites literature referring to cases of beta blocker use in people with a positive drug screen to reach the ultimate, and ultimately flawed, conclusion that beta blockers are safe in cocaine toxicity.
What’s that? You still think we should use beta blockers here? Fair enough, let’s take a quick look. Cue Jeff Goldblum from Jurassic Park:
You were so preoccupied with whether or not you could that you didn’t stop to think if you should.
The adverse effects of beta blockers in cocaine toxicity are well reported in case studies (Fareed 2007 PMID: 18072171)(Sand 1991 PMID: 1671639). In a classic study, patients undergoing cardiac catheterization were shown to have coronary artery vasospasm when given a beta blocker after cocaine insufflation. Just to reiterate: they gave people intranasal cocaine (Lange 1990 PMID: 1971166). On. The. Cath. Table. Amazing stuff. Only in Texas can this happen.
Critics of this study often point out that the beta blocker was given directly into the coronary artery, a situation that would never happen clinically. True, but these same critics universally fail to acknowledge the implications of this fact; a significant effect was seen with localized dosing – not the systemic dosing they are advocating. High risk patients with recent MI and hypertension were excluded and the patients were all pretreated with oral diazepam (because even that IRB wasn’t completely insane). Critics also cite the low rate of adverse effects (1/10) but conveniently omit that the event was ST elevation with a full occlusion secondary to vasospasm. Propranolol, esmolol, and labetalol all have had adverse cardiovascular effects reported when used in acute cocaine toxicity (Fareed 2007 PMID: 18072171)(Sand 1991 PMID: 1671639)(Lange 1990 PMID: 1971166).
The largest evidence for the safety of beta blockers has been in large retrospective studies and meta-analysis demonstrating the lack of adverse effects in patients that were . . . well, not that sick (Richards 2016 PMID: 26919414). In patients with cocaine positive urine tests, no one died or had a serious adverse effect. The number of patients is indeed impressive, and the authors are thoughtful and prolific publishers. I’ve authored papers with some of them. They are good peeps. Their work gives solid evidence that in patients who aren’t really sick nothing bad happened. Cocaine metabolites are detected in the urine between 48-72 hours after use and as long as several weeks in chronic heavy use. So, how many of these people were really cocaine toxic? And, how in the name of Odin’s beard can we attempt to reasonably extrapolate that data to everyone with cocaine toxicity? How does this work guide us in the ED or in the ICU? Or the critical care paramedic/nursing transport? We don’t always know who is going to deteriorate.
There’s a whole host of other reasons beta blockers may not be ideal therapies for cocaine toxicity. Propranolol can potentiate the sodium channel blockade effects (wide QRS) and inhaled free base cocaine can result in lung damage and bronchospasm making beta blockers less than ideal as their side effects may worsen EKG abnormalities and bronchospasm.
Ultimately, the best argument against beta blockers in cocaine toxicity isn’t the case reports of adverse effects, or literally every recent edition of toxicology and emergency medicine texts written by people who have treated these patients when they present with a core temp of 110F, or even the AHA guidelines recommending against the use of beta blockers in cocaine toxicity (and even in regular ACS with risk factors for shock!). No, the best argument is the availability of a safe, effective treatment with minimal downsides that treats the pathophysiology at its most proximal point and won’t further deterioration in the event of cardiovascular collapse. Dogmatic avoidance of benzodiazepines should be next on the dogmalysis list folks.
Cocaine toxicity is a broad spectrum of complicated pathophysiology. Even the existing flawed data fails to exhibit clear safety and efficacy of beta blockers in patients with cocaine toxicity. Keep the mechanism in mind, aggressively address life threats, and anticipate what you’ll do if the patient crashes. No matter if we are physicians, nurses, or medics, we aren’t technicians trying to make the monitor quiet. Next time you think your local toxicologist is some dogma loving grump, come at the question from this angle. I can almost guarantee a different conversation. And the next time you see the “beta blockers are safe for all cocaine toxicity” post, ask the author if they’d use labetalol first line for pheochromocytoma. Always a good starting off point in the ‘mythical’ unopposed alpha discussion.
Perhaps not surprisingly, I find the characterization of the local toxicologist from LiTFL, although amusing, to be misguided. I get it though. This is certainly a groan-inducing topic for most Medical Toxicologists. Not because we don’t care about the topic, but because we feel people are simply asking the wrong question. It’s the Newman to our Seinfeld.
By failing to engage in these types of discussions we’ve let this topic mutate and morph into a hodgepodge of misinformation. Silence is an especially poor tool of rebuttal in the world of FOAM. We don’t have a dogma problem, we have a communication problem.
In preparation for this piece I went through that old LiTFL post again. The last comment posted in the comments section is from a medical toxicology fellow with a genuine desire to continue the dialogue. Almost ironically, it went unanswered by the post’s author.
James French says
https://academic.oup.com/jcem/article/99/6/1915/2537399 phaeo Mx……
Howard Greller says
You never were very good at counting Alex…
K S says
Could you elaborate on the bit about labetalol and phaeochromocytoma please? As in are you saying it should be first line or not. Many thanks.
Jeff Lapoint says
Thanks for the opportunity to clarify-no, beta blockers should not be used first for pheochromocytoma. I brought this up because people who claim unopposed alpha phenomenon is simply a myth still would use a pure alpha blocker before a beta blocker. It was intended as a cute example to demonstrate that they did in fact believe in unopposed alpha.
To directly answer the question – beta blockers are used in the management of pheochromocytoma, but only after alpha blockade.
Leon Gussow says
This is a very interesting post, but it is populated with so many straw men that it looks like the casting call for a new hip-hop remake of “The Wizard of Oz.” Let’s discuss some of them:
1) “beta-blockers may not be ideal therapies for cocaine toxicities”: I don’t know any toxicologist who would disagree with this statement. Throughout, the author of the post (Dr. Lapoint) argues against mythical toxicologists proposing using beta-blockers as primary treatment of cocaine toxicity, in preference to benzodiazepines. I’m not aware of any toxicologist or author arguing thus.
2) “Dogmatic avoidance of benzodiazepines [in cocaine toxicity] should be next on the dogmalysis list folks.”: Again, no one to my knowledge is advocating avoiding benzodiazepines in cocaine toxicity. The real issue is should beta-blockers be absolutely contraindicated in cocaine toxicity. There is general agreement that there is not enough evidence to answer this definitively.
3) The author seems to suggest that while caffeine isn’t cocaine (I agree!), all beta-blockers are the same: He states that:
“Propranolol, esmolol, and labetalol all have had adverse cardiovascular effects reported when used in acute cocaine toxicity (Fareed 2007 PMID: 18072171)(Sand 1991 PMID: 1671639)(Lange 1990 PMID: 1971166).”
Actually, none of these papers involve the use of labetalol. The Fareed case report described a bad outcome associated with use of metoprolol, Sand’s article involved esmolol, and Lange et al reported a Cath lab study with cocaine and propranolol.
Labetalol is a mixed alpha/beta blocker, and thus fundamentally different from other beta-blockers such as propranolol. Those contending that beta-blockers should not be absolutely contraindicated in this situation generally argue that judicious use of labetalol is reasonable if the patient does not seem to be responding to benzodiazepines, or other possible interventions (such as phentolamine) are not available.
Is the best treatment for a cocaine-toxic patient who appears not to be responding to adequate does of benzodiazepines, and is still hypertensive and tachycardia, more benzodiazepines? We don’t know. We certainly don’t have enough evidence to state dogmatically that labetalol is absolutely contraindicated, or definitely required, in these situations.
Jeff Lapoint says
Thanks for your comments. Aside from some things I think you maybe have missed I pretty much agree with you.
This post is a response to a post on Litfl. If you haven’t read it, it’s linked in the very first line of my post. That might help with some context. Also check out the comments to that post. Still seeing straw men?
I never said there were toxicologists making these recommendations against benzodiazepines or recommending first line beta blockers but there certainly are physicians out there publishing prolifically and making these claims. Check out my last reference and the paper you reviewed here http://www.thepoisonreview.com/2017/03/01/labetalol-in-acute-cocaine-toxicity-is-it-safe/
I appreciate your point about the references. I’ll double check and fix as necessary.
Hopefully you’ll read the post referenced and revisit here (or click your heels a few times or something).
John Richards says
I find it interesting you write “By failing to engage in these types of discussions we’ve let this topic mutate and morph into a hodgepodge of misinformation. Silence is an especially poor tool of rebuttal in the world of FOAM. We don’t have a dogma problem, we have a communication problem.” – yet it took you nearly 2 years to write something about an article I wrote in 2016? Plus you fail to mention our multiple interactions on Twitter about the topic. Regarding your last sentence – I emailed the Tox Fellow right after the comment and sent him some evidence-based literature.
By the way ALL the cocaine – beta-blocker – unopposed alpha authors got together to publish a paper on the topic. We believed it was the cocaine, not the beta-blocker, causing the phenomenon. You and your cheering section should check it out. It’s based on evidence, not opinion, like your article.
Jeff Lapoint says
Thanks for stopping by. Like I said on Twitter, the statements about silence as a form of rebuttle are not in reference to our communications-which I have enjoyed. Rather, it is a observation about the absence of medical toxicologists on Twitter and in Foamed in general.
Despite what you may think I’m not some unopposed alpha dogma freak- it was barely covered above. The group that set this site up are open minded and care about the best and safest treatment for our patients and the responsible education of our students, residents, and fellows. No matter our opinions, we are all on the same side John.
Here’s the thing- you make this really hard to discuss. What you are recommending is not mainstream and is explicitly recommended against in practically every Emergency Medicine and Medical Toxicology text book. That doesn’t mean you’re wrong. It just means you need to demonstrate a healthy understanding of the rigor and detail involved in convincing people your point.
If you come at medical toxicologists as you did in your life in the fast lane post with examples and evidence that don’t match the conclusions and broad characterizations of our entire specialty you sound more like a zealot that can’t be reasoned with than someone who wants a real dialogue. I know this is not the case after speaking with you but I could see how people could think that even based on your post above. I’m happy to have a great conversation but you need to do what I have asked in my post:
-Define the population you are claiming would benefit. All cocaine toxic patients? All sympathomimetics? All patients for every complaint?
-Show safety in every group from above.
-Now show what you recommend is safe and efficacious.
– Keep it clean and professional. Don’t attack the specialty as a whole again or refer to the physicians taking care of some of the sickest cocaine toxic patients on a regular basis as some biased and unreasonable cheering section. I encourage you to keep an open mind as well. We all have something to learn.
John Richards says
Jeff, there will never be a prospective RCT for patients presenting with extreme cocaine toxicity receiving a beta-blocker, or any other drug for that matter. However, there are cocaine-using patients who come in all the time for chest pain, psychosis, agitation, CHF. The current contraindication is never give beta-blockers to ANY patient using cocaine. I feel that is not based on the evidence available. For example, do we withhold beta-blockers for cocaine-induced CHF patients who occasionally use when it is an AHA/ACC Class I recommended drug? Based on the current contraindication found in textbooks and UpToDate the answer would be “yes” – does that seem right to you?
I would be happy to come down to your EM Residency and give a lecture on this, journal club, or we could record a debate for EMCrit, Tox & Hound, for your colleagues, EM Residents, and anyone else who is interested.
“Keep it clean and professional” – I would ask that you please respect that. Stating I am a “zealot that can’t be reasoned with,” “attack the specialty as a whole again,” and don’t have an “open mind” is untrue and inappropriate. Type in my name in PubMed to read some evidence-based literature on the topic and others, like the CHS article you and I authored together.
When I use to use I was taking 50mg of atenolol but before I started use my I would take 2mg of Xanax and never had any chest pain or bad side affects. I actually use to take more atenolol as I was using to keep my heart rate down …..so why is it that nothing ever happened for years of partying???