Don’t be Afraid of Physostigmine

LAST UPDATED July 2, 2019

Physostigmine gets a bad rap, in my opinion. I remember back to my PGY-1 pharmacy residency at UMass when we had a teenage female present with AMS after being found in the woods (Weizberg 2006). She was clearly anticholinergic and the suspected medication, by history, was olanzapine. Physostigmine transformed a delirious patient into one with normal mentation telling us exactly what happened. It was like watching pharmacology in action. It was also the moment when I confirmed the genius of Dr. Ed Boyer and decided to pursue a fellowship in clinical toxicology.

Use in TCA Overdose

Physostigmine used to be part of the ‘coma cocktail,’ until two patients developed asystole in the setting of TCA overdose (Pentel 1980). There was also asystole reported in a 15-year-old (Shannon 1998) and seizures reported in other cases (Knudsen 1984). We understand that the pathophysiology of TCA poisoning is complex, certainly much more than just anticholinergic effects are contributing. Unfortunately, we somewhat overreacted and stopped using physostigmine regularly even when true anticholinergic poisoning was staring at us. The safety of physostigmine use for seizures or cardiotoxicity in the setting of TCA toxicity was difficult to predict (Suchard 2003); newer, higher-quality data suggest it is probably ok for anticholinergic delirium related to TCAs (Rasimus 2018).

Use in Anticholinergic Poisoning

Clearly beneficial: Physostigmine controlled agitation and reversed delirium in 96% and 87% of patients, respectively (Burns 2000). Benzodiazepines controlled agitation in only 24% of patients and were ineffective in reversing delirium.

Physostigmine has also been associated with less ICU admissions (Rosenbaum 2010). In 45 patients receiving the antidote, most were discharged directly from the ED, only 31% required multiple doses, and none required the second dose more than 6.5 hours after the first.

Newer Data

The California Poison Control System published a 10-year retrospective cohort study of 191 hospitalized patients who received physostigmine to reverse an anticholinergic toxidrome (Arens 2018).

What they found

Exposure (n)	Response to Physostigmine
Non-diphenhydramine antihistamines (14), antipsychotics (4), TCAs (3)	21/21 (100%)
Anticholinergic Plants (67)	46/67 (68.7%)
Diphenhydramine (56)	43/56 (64.2%)
Combination products (10)	8/10 (80%)
Other/unknown (37)	22/37 (59.4%)

• 142 patients (74.3%) were treated with physostigmine alone
• 36 patients (18.8%) were discharged directly from the ED (57.6% of patients were admitted to the ICU)
• 182 patients (95.3%) had no documented adverse effects
  • 4 patients experienced emesis
  • 2 patients experienced QTc prolongation
  • 2 patients experienced seizures
  • 1 patient died

application to clinical practice

• Physostigmine appeared effective in the majority of cases.
• Most patients still were admitted to the ICU (contradicting the findings of the 2010 Rosenbaum study).
• Adverse effects were not reported in most cases, though adverse effects are under-reported in poison center data and should not be used, alone, to determine the safety of an intervention.
• The one fatality (massive diphenhydramine – 950 mg) occurred 6 hours after physostigmine administration and was likely unrelated.

More Newer Data

A second poison center study adds strength to the idea that we can use physostigmine safely and effectively in the anticholinergic patient (Boley 2019).

What They Did

• Prospective observational analysis of patients with antimuscarinic delirium
• Quantified rate of delirium improvement with physostigmine compared to non-antidote therapy two hours after treatment
• Adverse events (defined a priori as bradycardia, vomiting, seizures) and resource utilization (intubation and physical restraint) were recorded

What they found

• 154 patients
• Most common exposure classes were antihistamines (68%), analgesics (19%), and antipsychotics (19%)
• Physostigmine administered in 37% of cases (though it was recommended in 81%)
• Delirium control in 79% of patients who received physostigmine versus 36% of those who did not (OR 6.6)
• Adverse events were rare and did not differ significantly between the groups
• Physostigmine was not associated with changes in the incidence of intubation or restraint

Arens et al separately evaluated 161 articles including 2,299 patients to identify adverse effects from physostigmine (Arens 2019). 18% of patients had an adverse effect; most were minor and self-limited (nasuea, vomiting, hypersalivation). 15 patients had seizures and 8 patients had symptomatic bradycardia. Interstingly, there was a much lower rate of adverse effects in patients treated for an overdose of an anticholinergic agent (7.7%) compared with 20.6% of patients with non-anticholinergic agents.

Take Home Points

1. We should stop fearing physostigmine and use it in cases of anticholinergic poisoning (see Dr. Jon Cole’s in-depth review of its us in TCA poisoning)
2. Stock physostigmine in your ED to ensure timely administration

Further Reading

For further reading, please check out the handout from my 2017 American Academy of Emergency Medicine Scientific Assembly talk on Rational Use of Physostigmine and Flumazenil in the ED.