Tox and Hound – The Physostigma

A very special welcome to our newest hound, Dr. Jon Cole! You can learn more about him here . . .

by Jon Cole

It’s a busy day in the ED. ICU beds are tight, ambulances keep coming, and triage grows at a seemingly exponential rate. Waiting for you are your first three patients, all of whom present some unique challenges:

A 24 year-old woman presents many hours after a quetiapine overdose. Her vital signs are unremarkable, but the resident notes she is obtunded and calculates a Glasgow Coma Scale of 7. The resident orders an ICU bed, prepares to intubate, and remarks “we intubate for a GCS less than 8.”^​1​

A 57-year-old man with no medical or psychiatric history is brought in as a stroke code for “not acting like himself.” He is confused, repeatedly fidgeting, and has distracted, slurred speech, wandering off mid-conversation. Earlier that day he had been to the dentist. While disrobing the patient, a piece of paper is discovered noting he received sublingual atropine during his procedure. A phone call to the dentist reveals a series of potential errors may have led to an atropine overdose. The patient has mumbled, nonsensical speech and repeatedly attempts to remove his monitor leads and pulse ox. IV lorazepam results in no change to his speech or agitation. The neurology team requests a CT stroke series and admission.

A teenage girl with a history of depression and ADHD arrives 8 hours after overdosing on diphenhydramine in a suicide attempt. Her agitation is remarkable. She appears to be responding to vivid hallucinations, and her cries are so loud, they disrupt the entire ED. She receives intermittent doses of lorazepam, which only make her breathing sonorous. However, as soon as she regains consciousness her hallucinations and agitation resume.

What do these patients all have in common? Each has an acute delirium, likely from an anticholinergic agent. If only we had a drug to target the cause of their delirium . . . an “anti-delirium” if you will. In fact, we have such a treatment . . . an oft inappropriately reviled drug called physostigmine.

Delirium from anticholinergic drugs (or more precisely, antimuscarinic drugs – most drugs only antagonize the muscarinic acetylcholine receptors and not the nicotinic acetylcholine receptors – if diphenhydramine was completely “anticholinergic,” it would cause paralysis in overdose) results from blocking muscarinic receptors in the brain. Physostigmine (or physo, for those in the know…) works as an antidote to treat this delirium in a targeted manner. Physo is an acetylcholinesterase inhibitor, so by inhibiting the enzyme that breaks down acetylcholine, physo increases the amount of available acetylcholine at the nerve terminal. With more acetylcholine available to compete with antimuscarinic drugs, more acetylcholine receptors become activated, restoring muscarinic tone, thereby reversing delirium. Although several cholinesterase inhibitors are available for use, physo’s unique chemical structure makes it a useful delirium treatment. Unlike most other “-stigmines,” (e.g., neostigmine) physostigmine is a tertiary (not quaternary) ammonium compound (i.e., its nitrogen ions aren’t charged – see structures). This lack of charge allows it to cross the blood-brain barrier and reverse the delirium.

On a side note, the lack of charge is also what allows it to cross the placenta, as shown by the decrease in heart rate seen on this fetal monitoring strip in a pregnant woman treated with physo.^​2​

The ability to reverse delirium is what led to physostigmine’s trade name: AntiliriumⓇ. I’m not generally a big fan of trade names (though some of them I must admit are quite clever… zolpidem’s AmbienⓇ comes to mind. Ambien is often stylized as AMBien, or “AM” “Bien,” as in “morning” and “good,” as in “good morning.”), but in this case, the trade name is extremely helpful to understand how the drug works. Physostigmine is a drug to reverse antimuscarinic delirium. That is its use; there is no other.

Physostigmine was extremely popular in the 1970’s. Barry Rumack (yes, that Barry Rumack^​3​) presented a poster at the 1975 meeting of the American Academy of Clinical Toxicology entitled “707 cases of anticholinergic poisoning treated with physostigmine.”^​4​ Here’s a quote from another paper describing a personal communication from Dr. Rumack: “…have now had experience with over 700 patients who had anticholinergic findings treated with physostigmine. The results are truly dramatic. The side effects are minimal providing a rapid bolus of physostigmine is not given intravenously.”^​5​ Physostigmine was even a regular component of the “coma cocktail” along with dextrose, oxygen, naloxone and thiamine.^​6​ It’s hard to know if the Doobie Brothers or physo was more popular in 1975.

Antimuscarinics have always been common agents in overdose, but in the 1970s, one particular group of antimuscarinic drugs became even more common: tricyclic antidepressants (TCAs). TCA poisoning is beyond the scope of this post, but there are numerous receptors and ion channels TCAs block to create their unique toxicologic presentation including, to an extent, muscarinic receptors.

Our collective understanding of how to use physostigmine (and how to dress) was different in the 1970s. While everyone understood physo would reverse delirium, its use was advocated for all kinds of neurotoxic effects seen with TCAs, including extrapyramidal effects and seizures.^​5,7​ Physo was also used specifically to treat the cardiovascular effects of TCA overdose.^​8,9​ There is a vivid example of a case report where the authors used massive doses (5-10 mg at a time) of physo to specifically treat bouts of recurrent ventricular tachycardia from a 10 g overdose (combined) of doxepin, imipramine, and desipramine.^​10​ The treating physicians would infuse physo whenever the patient suffered recurrent V-tach until her pulse would slow to the low 100’s. This patient received 70 mg of physostigmine over 4 hours, which is without a doubt the highest dose I have ever heard of.

Then in 1980, a case series of two patients experiencing catastrophic complications after receiving physo for TCA poisoning was published by Pentel and Peterson.^​11​ This paper dramatically changed the thinking about physo. Here are the cases:

A 32-year-old man took 2.3 g of amitriptyline and presented comatose 1 hour later. The patient had a wide QRS (240 ms) with a heart rate of 75 beats/min. He was intubated and then shortly after developed status epilepticus. He was given physo (2 mg) over 3 minutes. Over the next 7 minutes, the patient developed bradycardia and asystole, refractory to atropine. The patient responded to CPR and epinephrine, then received 90 mEq of bicarbonate and was resuscitated. The patient received no bicarbonate prior to arrest.

A 25-year-old man presented one hour after taking 5 g of imipramine and 150 mg of propranolol. He vomited pill fragments and became progressively drowsy. He had two grand mal seizures and after each seizure received 2 mg of physo. Five minutes after his last physo dose, he developed bradycardia unresponsive to 1 mg of atropine that deteriorated to asystole. After 10 minutes of CPR, 1 mg epinephrine, and 90 mEq of bicarbonate ROSC was achieved. However the patient died on hospital day 3. The patient received an unknown amount of bicarbonate “in his fluids” prior to arrest.

In both cases TCA levels were quantified and high. However, propranolol in the second case was never quantified or confirmed. This two-patient series was not the first report of a TCA-induced seizure treated with physo that rapidly deteriorated into a brady-asystolic arrest (Tong et al published such a case in 1976)^​12​, but it had a disproportionate effect on the practice of toxicology.

I don’t know what the Pentel and Peterson had in mind when they published this series; but I can tell you what went through my mind when I wrote a similar paper. When I was a fellow intravenous fat emulsion (IFE, or IntralipidⓇ for those who prefer trade names . . .) was all the rage. It was the new hotness that was going to save all our cardiotoxic arrest patients. National organizations became enthusiastic enough about it that IFE moved up earlier in treatment recommendations.^​13​ As I was finishing my fellowship, I took care of two patients within a few weeks of each other that were eerily similar. Both had MAPs and pulses in the 40s, even on high dose insulin and vasopressors. Thinking “what am I waiting for here?” I gave IFE to both of them, and both of them went into asystole almost immediately. The feeling in the room that the IFE caused the arrest was overwhelming. When we went to publish the cases though, after letting the dust settle, we knew coincidence and/or the natural evolution of the overdose was at least as likely a cause as the IFE.^​14​ The goal of publishing these cases was not to end the use of IFE for overdose, it was simply to report the temporality of the arrests to generate scientific inquiry into a therapy we were collectively enthusiastic about, but did not yet fully understand. Publication bias in case reports usually favors positive outcomes.^​15​ We were attempting to provide some balance. I suspect Pentel and Peterson felt similarly.

There’s a lot of oral history after the publication of the Pentel/Peterson cases, but for various reasons, the use of physostigmine plummeted after the publication of their paper. When I was a toxicology-curious resident and wanted to use physo on a patient, a trusted senior mentor of mine reacted like this: “Physo? That stuff kills people!” According to my faculty at the time, the thinking was that the Pentel/Peterson paper taught us that physo is contraindicated in all TCA overdoses, which led to, “well, we can’t use it in undifferentiated antimuscarinic overdoses because it MIGHT be a TCA,” which then became, “well, even if the history is diphenhydramine overdose, it could be wrong, so we just shouldn’t use it at all.” And thus the stigma about physo – the Physostigma – was born. Credit where credit is due – the term “Physostigma” is an invention of one of our former fellows, Sean Boley, who gave a great talk about this at the 2016 ACMT meeting.

Since the beginning of the current century (it’s been 19 years – I think we can call it the current century now), papers began to appear demonstrating the value of physostigmine, especially compared to toxicology’s favorite hammer for all our nails, benzodiazepines. Toxicologists noted that physo was much better than benzos at reversing delirium and treating agitation (not surprising considering physo treats the underlying cause of the delirium; benzos just cover it up).^​16​ Patients getting physo seemed to have fewer complications and a shorter time to recovery. Toxicologists also lamented the loss of a valuable diagnostic tool – sometimes a head CT or an LP could be avoided if a safe therapy could be given to wake the patient up enough to give a clear history.^​17​

Since practice changed so much after the Physostigma came to be, it’s worth looking at the Pentel/Peterson cases a bit closer with a modern eye. First, these were massive TCA overdoses, and massive TCA overdoses frequently die brady-asystolic deaths naturally.^​18​ This wasn’t necessarily apparent at the time, but it’s clear this is frequently the endgame for fatal TCA cases.^​19​ Second, massive TCA overdoses can easily die, even when we do everything perfectly. Hence the reason we became a ProzacⓇ Nation in the 80s, collectively turning away from TCAs to SSRIs for depression. Third, only one of the two patients got bicarbonate prior to arrest, and “bicarbonate” in fluids is not how we typically utilize bicarbonate today. Today sodium bicarbonate is the standard therapy for a massive TCA overdose with a wide QRS complex and is given as a 1-2 mEq/kg bolus, repeated every 3-5 minutes.^​20​ This bolus-dosing of bicarbonate results in far larger doses than when bicarbonate is given “in fluids.” Even after these patients’ arrests, the bicarbonate given was subtherapeutic based on modern dosing. This is no fault of the authors or the care team at the time. Our understanding of the treatment for TCAs was different then. Especially since one patient co-ingested a beta-blocker like propranolol, which itself can cause a wide QRS on the ECG (through sodium channel blockade) and a brady-asystolic arrest. While the timing of the arrests in this series was suspicious, coincidences do happen, which is why we emphasize frequently that correlation does not equal causation. Post hoc ergo propter hoc, if you prefer Latin. With nearly 40 years of hindsight, another interpretation of these two cases may be that in a massive TCA overdose not treated in time with adequate bicarbonate, asystole may rapidly follow.

In the decades since, more data on physo has emerged. My friend and colleague Annie Arens recently published a systematic review looking at the adverse effects of physostigmine.^​21​ While adverse events were relatively common overall (18%), in addition to the Tong, Pentel and Peterson cases, she and her co-author found only one other case of bradyasystolic arrest following physostigmine out of 2,299 patients.^​22​ This additional patient took up to 9 grams of desipramine and arrived with evidence of shock after multiple seizures and died shortly after receiving physostigmine. Again, this was a massive overdose likely to do poorly regardless; it is unclear if this patient received any bicarbonate or not.

Since Dr. Arens performed her literature search, additional data have been published describing physo’s safety and effectiveness. Dr. Arens herself published a study of 191 patients from the California Poison Control System showing adverse effects were rare and mild, and that physo was frequently effective.^​23​ Nyugen et al reported 54 cases receiving physo at a single institution and found no instances of seizures or cardiac arrest.^​24​ And finally Boley and colleagues published two additional studies this year. In a retrospective study of 141 patients, physostigmine was associated with fewer intubations and ICU admissions, with no difference in adverse events.^​25​ And in a prospective observational Poison Center study of 154 patients, delirium control was superior with physostigmine (79%) versus supportive care (36%), and adverse events were the same in both groups (see our Poison Center guideline below).^​26​ None of these studies identified additional cardiac arrest patients.

So how do we actually use this drug? Here’s how I think about it: Physo is a drug to treat or diagnose delirium. Delirium comes in many forms^​27​, but anticholinergic delirium can present as anything from a coma to agitation with active violence. If delirium is the biggest problem for your patient, physo is likely the right therapy. Benzos solve a lot of problems in toxicology, but in this case, they mostly cover up delirium symptoms instead of treating the underlying problem. It can be used diagnostically to ensure a bigger work-up is not needed. It can also be used to treat delirium. The three patients at the top of this post are all patients I’ve cared for at some point. In the case of the patient from the dental office, physostigmine resolved his delirium and obviated the need for stroke work-up.^​28​ The patient with the quetiapine overdose rapidly improved from her comatose state to a GCS of 15, and both intubation and ICU admission were avoided.^​29​ And the teenager, after receiving physostigmine, was able to tell us that she had vivid, disturbing visual hallucinations that were frightening her. She required no further treatment after physo.

Equally as important is to know when not to use physostigmine. There are some standard contraindications:

• Salicylate allergy (depending on the preparation)
• Intestinal or genitourinary obstruction
• Heart block
• Bradycardia
• Severe asthma

After confirming none of these are present, I typically use physostigmine the way it’s outlined in our Poison Center guideline above. To be clear how we use the guideline, lorazepam is given in addition to bicarbonate if there is evidence of sodium channel blockade on the ECG, since sodium channel blockade on ECG is often a harbinger of seizures.^​30​

Perhaps more important than knowing contraindications, however, is prioritizing your treatments. Remember, physo is AntiliriumⓇ; it is not a treatment for dysrhythmias or seizures (we have far better treatments for both). If you have a patient presenting with hypotension (or other evidence of shock) and evidence of antimuscarinic poisoning, that is a critically ill patient that probably needs intense supportive care. Priorities are intubation, fluids, vasopressors, and bicarbonate if the QRS is wide; the priority is not reversing delirium. This is true whether the overdose is from diphenhydramine, a TCA, an antipsychotic, or any of the myriad of other drugs that cause antimuscarinic poisoning.^​31​

So is TCA poisoning of any kind an absolute contraindication to physostigmine? My take is the answer is no. The primary concern with TCAs and physostigmine is bradyasystolic arrest, but as noted above, there are a lot of other reasons those few cases turned out the way they did, nor are they patients we would recommend physo for today. If a TCA overdose presents to the ED immediately after ingestion, the priority is not usually delirium reversal, it’s usually good supportive critical care. Alternatively, if a TCA overdose presents to the ED much later in their course (such as past the point where peak effects are expected), and is hemodynamically stable but still agitated, physostigmine is a viable option to reverse the delirium. Rasimas et al addressed this issue in a study of 1,197 patients receiving physostigmine, of which 315 were poisoned with TCAs.^​32​ Of these 315, the only adverse events were two episodes of diaphoresis. For a great summary of the TCA/physo question, read this review article.^​33​

Globally speaking, if a patient comes into the ED with hypotension, a wide QRS, and seizures, whether its from diphenhydramine or a TCA (big diphenhydramine overdoses are a lot like TCA overdoses BTW – not surprising considering its structure. It’s basically a TCA), my priority isn’t reversing delirium.

My priority is all the TCA-related critical care things we usually do. If, on the other hand, a patient arrives with mumbled speech, a normal blood pressure, carphologia, and pulling off monitors, whether it’s from diphenhydramine or doxepin, my goal is to fix the delirium, and my therapy of choice is physostigmine. Help me to end the Physostigma.