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.