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Toxicology Rounds

Physostigmine Doesn't Live Up to Its Unsafe Reputation

Gussow, Leon, MD

doi: 10.1097/01.EEM.0000553469.19609.69
Toxicology Rounds

Dr. Gussow is a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog at www.thepoisonreview.com, follow him on Twitter @poisonreview, and read his past columns at http://bit.ly/EMN-ToxRounds.

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Figure

The antidote physostigmine was first used to treat anticholinergic toxicity in 1864, and by the 1970s, clinicians were commonly administering it for many indications, including poisoning from pure anticholinergic agents and tricyclic antidepressants (TCAs). Some even advocated that emergency physicians include physostigmine as part of the so-called coma cocktail for any patient with significantly decreased mental status.

But things changed. The use of physostigmine had virtually disappeared by the 1990s, and the Association of United States Poison Centers reported in 1997 that only two percent of more than 7,000 patients treated that year for anticholinergic toxicity received physostigmine. What happened?

First off, the clinical abandonment of physostigmine was somewhat surprising because it is one of the most effective and specific antidotes. It is a short-acting carbamate that increases levels of the neurotransmitter acetylcholine in synapses and at muscarinic receptors, overcoming the receptor blockade caused by antimuscarinic agents such as benztropine and scopolamine.

Unlike similar drugs like neostigmine, physostigmine readily crosses the blood-brain barrier, reliably reversing central and peripheral manifestations of the anticholinergic toxidrome. (See table.) Recent research indicates physostigmine is much more effective in controlling anticholinergic-induced agitation and delirium than benzodiazepines are while avoiding oversedation and the need for endotracheal intubation. (Ann Emerg Med 2000;35[4]:374.)

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And It's Gone

So why did physostigmine nearly vanish? This can be traced to a 1980 paper describing two patients who experienced bradycardia and then asystole shortly after receiving physostigmine for severe TCA toxicity, standard treatment at the time. (Ann Emerg Med 1980;9[11]:588.) One patient was resuscitated and recovered; the other apparently suffered hypoxic encephalopathy and died.

These cases were unusual. Both patients had taken massive overdoses of tricyclics and quickly developed seizure activity. Neither was treated with sodium bicarbonate, a now-standard intervention that can prevent or treat TCA-induced dysrhythmias. Despite the authors' contention that physostigmine caused asystole in these cases, it seems more likely this represented the natural evolution of severe TCA overdose. In any case, many clinicians developed a fear of physostigmine after the paper was published, and use of the antidote cratered.

This fear has abated somewhat recently as physostigmine's safety and efficacy in treating anticholinergic agitation and delirium has been studied more, including some research presented at the recent 2018 North American Congress of Clinical Toxicology meeting in Chicago. Sean Boley, MD, of the Minnesota Poison Control System, found that 65 (46%) of 141 patients with antimuscarinic toxidrome treated with physostigmine were significantly less likely to require intubation or ICU admission than those who were not. His three-year single-center retrospective chart review also found no significant differences in adverse events such as vomiting, bradycardia, and seizures between the two groups. Dr. Boley concluded that physostigmine was useful and safe, but noted that the retrospective design made that conclusion less than robust.

A separate study by Dr. Boley and his colleagues found that 57 (34%) of 154 patients with antimuscarinic delirium who were treated with physostigmine experienced more frequent and more rapid control of delirium than those who were not. The one-year prospective analysis also saw no difference between the groups in adverse events, though physostigmine was not associated with a reduced incidence of intubation as in his other review. (Clin Toxicol (Phila) 2018 June 29; http://bit.ly/2zYzvUC.)

Rachel Gorodetsky, PharmD, of D'Youville School of Pharmacy in Buffalo also found that 12 (5%) of 231 patients who received physostigmine had adverse events, including vomiting (8 patients), seizures (3), and bradycardia (1). Her five-year retrospective chart review saw no significant sequelae in the three patients with seizures, and the patient who developed bradycardia did not require any intervention. Forty-eight patients in the study were treated with physostigmine in the surgical recovery room for nonspecific post-anesthetic delirium not related to antimuscarinic exposure. The authors concluded that it is likely unwarranted to avoid physostigmine as an antidote because of concern for adverse effects.

Still, the antidote must be used with caution. Keep these important clinical points in mind:

  • Physostigmine is contraindicated in the seizing patient because it has not demonstrated safe or effective.
  • No real consensus exists, but I believe physostigmine should be avoided for significant cardiac conduction delays (AV block, prolonged QRS interval) and bradycardia.
  • A good response to physostigmine can be diagnostic and avoid the need for additional tests such as CT scan and lumbar puncture in a patient with delirium thought to be caused by exposure to an anticholinergic agent.
  • The adult dose of physostigmine is 0.5-1.0 mg IV given slowly over five minutes and repeated if needed every 15 minutes for a maximum total dose of 2 mg over the first hour.
  • The local poison center should be consulted on any patient who is treated with physostigmine.

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