Physostigmine for Severe Antimuscarinic Overdose: Pushing Back Against the Stigma

Physostigmine has long been recognized as an antidote to reverse antimuscarinic delirium.

However, its effectiveness, safety profile, and dosing have been disputed in recent years, leading to a decline in its use. Yet a growing amount of more current evidence suggests the toxicity profile associated with physostigmine is misunderstood and occurs when used inappropriately. Despite evidence that physostigmine is undeniably effective in treating the symptoms of confirmed anticholinergic poisoning, its use has plummeted since the early 1980s. Physostigmine became one of a handful of drugs that don’t get the respect they deserve.  

WHAT IS PHYSOSTIGMINE?
Physostigmine is a carbamate acetylcholinesterase inhibitor that is readily capable of crossing the blood-brain barrier due to its tertiary amine properties. Consequently, physostigmine is effective in reversing the peripheral and central effects of anticholinergic toxicity.

WHY THE STIGMA?
Physostigmine was used extensively in the 1960s and ’70s in the treatment of undifferentiated delirium.¹ It was also during the 1970s that it was suggested as a potentially life-saving antidote in tricyclic antidepressant (TCA) toxicity.¹  However, following a report of two deaths during the treatment of tricyclic antidepressant overdoses with physostigmine, opinions rapidly changed.²  The medical community's reaction to these two cases published in Annals of Emergency Medicine in 1980 was dramatic and global, resulting in an almost immediate rejection of physostigmine and movement towards seemingly safer delirium treatment options such as benzodiazepines. The most feared consequence of physostigmine administration includes cardiovascular effects, especially sudden cardiac arrest. However, published reviews of these two cases subsequently suggested the associated fatalities were more likely due to the severe TCA toxicity rather than a consequence of physostigmine administration.^3,4

WHEN IS PHYSOSTIGMINE EFFECTIVE?
In the setting of antimuscarinic toxicity, benzodiazepines have commonly been used to avoid the feared side effects of physostigmine. Despite physostigmine’s effectiveness, it is underutilized due to its safety concerns and short duration of action.⁵ However, when presented with anticholinergic toxicity, in one small study physostigmine controlled agitation and reversed delirium in 97% and 87% of patients, respectively.⁶ This was in stark contrast to benzodiazepines controlling agitation in only 24% of patients while being relatively ineffective in the reversal of delirium.⁶

Why opt in for physostigmine over benzodiazepine?
Physostigmine administration is without significant complication when given to patients in the ED suspected to have antimuscarinic delirium. Its antidotal effects have been reported to cover a range of drugs and different substance intoxications. The variety of drugs include antipsychotics, antihistamines (eg, diphenhydramine), muscle relaxants (eg, alprazolam, cyclobenzaprine, baclofen), antimuscarinic agents and plants including Jimson weed, belladonna, Hell's bells, trumpet flower, and Angels' trumpet.⁷

In addition to the wide coverage, the use of physostigmine has also been studied to reduce the rate of intubation in patients who present with delirium when compared to those treated by benzodiazepines. Endotracheal intubations were performed in patients who ultimately experienced neuromuscular paralysis due to benzodiazepines being ineffective in the control of agitation.⁶

Additionally, physostigmine administration has also been effective in avoiding unnecessary invasive testing and in reducing the length of stay when compared to benzodiazepines. In fact, patients treated initially or only with physostigmine had a lower complication rate and shorter time to recovery than those treated initially or only with benzodiazepines.⁶ The slower recovery rates seen in benzodiazepines could be contributed to the greater incidence of sedation, aspiration, and endotracheal intubations for patients initially treated with benzodiazepines.⁶ Neither of the complications were seen in patients initially treated with physostigmine, and prompt extubation was seen in some patients following physostigmine administration.⁶

How about pediatric populations?
Previous case reports have also shown promising safe and effective use of physostigmine infusions in control of pediatric patients experiencing antimuscarinic delirium and agitation. ^5,12 In one case of imipramine intoxication, a child presented with serious life-threatening coma, hypotension, and cardiac dysrhythmias that were reversed upon the administration of physostigmine.⁸ Physostigmine has been highlighted to be the best agent for treating severe poisoning caused by imipramine and other drugs or plant poisoning that may induce anticholinergic-like toxicity.^8,12

Appropriate dosing
Dosing regimen of physostigmine remains uncertain, but employing a titration approach with low doses administered slowly and extending doses in intervals may minimize the risk of adverse effects. Initial doses can be lowered to 0.5 mg diluted in 10 mL of D₅W or normal saline, infused over the rate of 2-5 minutes while carefully observing the patient for any improvement in presenting symptoms or adverse side effects, as well as continuous cardiac monitoring. ⁹ If the desired effect has not been obtained, then use a titration of additional 0.5 mg doses at 5- to 10- min intervals up to a maximum total dose of 2 mg over the first hour. ⁹ This has been a consistent approach utilized and recommended by other authors, with delirium being found to reverse usually with an initial ≤ 2 mg.^{7, 9}  Pediatric IV dosing is 0.02 mg/kg with a maximum dose of 0.5 mg.  This can be repeated every 5 to 10 minutes until a desired response occurs.  Slow administration (≤ 0.5 mg/minute for pediatric patients) is required to prevent bradycardia, respiratory distress, and seizures. The maximum recommended total dose is 2 mg.¹²

HOW DO I AVOID THE MISUSE OF PHYSOSTIGMINE?
Investigate the symptoms and patient history! Be sure to ask EMS or family members about any possible contact with the drugs in question. This will help narrow down the differential diagnosis and provide you with more confidence when selecting physostigmine as the antidote. If the patient history or drug in question remains unclear, check for the following signs and symptoms: 

Signs and symptoms of cholinergic intoxication
Below are favorable conditions for using physostigmine

• Severe agitation and delirium are of most significance⁶
• Altered mental status, hallucinations⁷
• Drowsiness, obtundation⁷
• Restlessness, tachypnea, tachycardia
• Carphologia (lint-picking behavior), mumbled speech, and inability to follow commands¹⁰
• Dry skin and mucous membranes¹⁰
• Sweating, excessive salivation, bronchorrhea⁹

Be cautious in these cases
Below are unfavorable conditions for using physostigmine

• Very high risk of seizures¹¹
• Known underlying cardiac disease⁹
• Evidence of cardiac toxicity¹¹
• Prolonged QT interval, widened QRS complex¹¹ or QRS greater than 100ms¹¹
• Reactive airway disease
• Intestinal obstruction
• Known TCA poisoning!

If you decide to play it safe and are unsure about using physostigmine as your initial antidote, there is no contraindication in using a benzodiazepine. However, if all alternative methods fail, one should consider the use of cholinesterase inhibitors in anticholinergic delirium resistant to non-pharmacological delirium management.¹¹

TAKE-HOME POINTS

• Physostigmine is useful in treatment of anticholinergic toxicity and appears far superior to benzodiazepines.¹¹
• Do not use physostigmine if TCA toxicity is suspected.
• The optimal risk/benefit in treatment with physostigmine would be to use a titrated dose of 0.5 to 1 mg physostigmine (0.01 – 0.02 mg/kg in children).^11,12

Extra resource
Watch a video of a pediatric patient being treated emergently with physostigmine:  https://youtu.be/6aj-Z8giv1o

REFERENCES

1. Watkins JW, Schwarz ES, Arroyo-Plasencia AM, Mullins ME. The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity. J Med Toxicol. 2015;11(2):179-184. doi:10.1007/s13181-014-0452-x
2. Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980;9(11):588-590. doi:10.1016/S0196-0644(80)80232-0
3. Kulig K, Rumack BH. Physostigmine and asystole. Ann Emerg Med. 1981;10(4):228-229. doi:10.1016/S0196-0644(81)80174-6
4. Suchard JR. Assessing physostigmine’s contraindication in cyclic antidepressant ingestions. J Emerg Med. 2003;25(2):185-191. doi:10.1016/S0736-4679(03)00169-0
5. Wang GS, Baker K, Ng P, et al. A randomized trial comparing physostigmine vs lorazepam for treatment of antimuscarinic (anticholinergic) toxidrome. Clin Toxicol. Published online 2020. doi:10.1080/15563650.2020.1854281
6. Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000;35(4):374-381. doi:10.1016/S0196-0644(00)70057-6
7. Arens AM, Shah K, Al-Abri S, Olson KR, Kearney T. Safety and effectiveness of physostigmine: a 10-year retrospective review *. Clin Toxicol. 2018;56(2):101-107. doi:10.1080/15563650.2017.1342828
8. Wright SP. Usefulness of Physostigmine in Imipramine Poisoning: A Dramatic Response in a Child Resistant to Other Therapy. Clin Pediatr (Phila). Published online 1976. doi:10.1177/000992287601501208
9. Arens AM, Kearney T. Adverse Effects of Physostigmine. J Med Toxicol. 2019;15(3):184. doi:10.1007/S13181-019-00697-Z
10. Boley SP, Olives TD, Bangh SA, Fahrner S, Cole JB. Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center. Clin Toxicol. 2019;57(1):50-55. doi:10.1080/15563650.2018.1485154
11. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium - Theory, evidence and practice. Br J Clin Pharmacol. 2016;81(3):516-524. doi:10.1111/bcp.12839
12. Frascogna N. Physostigmine: is there a role for this antidote in pediatric poisonings? Curr Opin Pediatr. 2007 Apr;19(2):201-5. doi: 10.1097/MOP.0b013e32802c7be1. PMID: 17496766.