RX Pad: Mad as a hatter or right on?

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A how-to guide for physostigmine reversal of anticholinergic toxicity.

A 22-year-old female is brought to the Emergency Department for altered mental status by her boyfriend. Vitals: HR 150-160; BP: 146/82; Temp 99.6°F orally. On physical exam her pupils are dilated to 6 mm and sluggishly reactive to light, she has mumbled, disorganized speech and she is picking at the monitor leads and the air in front of her (carphologia).


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Her lips and tongue are dry and are covered with a blue residue, she smells of vomit and has blue-tinged vomitus on her shirt and shorts. She is unable to provide much history. Her boyfriend relates they had an argument while drinking alcohol last night and she locked herself in the bathroom for an hour. At some point in the night, she vomited, and he found her altered just prior to arrival.

Intravenous access is secured, and a bolus of crystalloid is given. An electrocardiogram (ECG) is obtained and notable for sinus tachycardia with a rate of 155 bpm, QRS interval of 92 msec, and QTc interval of 446 msec. She had increased agitation and is given 1 mg of lorazepam intravenously.

What Is Going on Here?

The mnemonic of hot as hare, dry as a bone, blind as a bat, and mad as a hatter comes to mind —  she is exhibiting the signs and symptoms of the anticholinergic toxidrome. The anticholinergic toxidrome is more specifically antimuscarinic in nature with competitive antagonism of acetylcholine occurring at both central and peripheral muscarinic receptors. This toxidrome can be caused by multiple medication classes (antihistamines, antipsychotics, cyclic antidepressants) and botanicals including jimsonweed (Datura stramonium) and deadly nightshade (Atropa belladonna) to name a few.[1]


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Central antimuscarinic toxicity symptoms (excitation, hallucinations, confusion) may persist after peripheral symptoms have resolved; however, central toxicity in the absence of peripheral symptoms has also been described.[1] Mild antimuscarinic toxicity can be treated with redirection, calming surroundings (darkened room and low stimulation environment) and intravenous fluids. Central and significant peripheral antimuscarinic toxicity may need additional treatment modalities, in addition to good supportive care.[2].

Is There an Antidote? What About Physostigmine?

Physostigmine containing beans were used by the Efik people of Old Calabar as part of a trial by ordeal. Those suspected of a crime or witchcraft were made to ingest a concoction produced from the aquatic legume (Physostigma venenosum).  Those deemed innocent swallowed the poison and rapidly vomited while the guilty would die from the resulting symptoms.[1,3]  The most highly active compound in the Calabar bean was named physostigmine and was found to antagonize the effects of atropine and the paralytic curare.

The first use of physostigmine as an antidote was reported in Prague in 1864 by Kleinwatcher who used it to successfully treat several prisoners with severe atropine intoxication.[3] Fast-forward to the 1970s, use of physostigmine gained popularity after the report of successful treatment the delirium of anticholinergic toxicity in a toddler after amitriptyline ingestion.[2]

Anticholinergic toxicity was commonly seen in the 1970s and early empiric use of physostigmine as part of a “coma cocktail” for undifferentiated altered mental status was commonplace.[4,5] The case series published by Pentel and Peterson in 1980 describing two patients suffering asystole following physostigmine injection to treat tricyclic antidepressant overdose largely lead to the abandonment of physostigmine as an antidote for anticholinergic toxicity.[6]


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Mechanism of Action

Physostigmine is a tertiary carbamate that is a short-acting acetylcholinesterase inhibitor. This allows for increased synaptic levels of acetylcholine to overcome the post-synaptic blockade of muscarinic antagonists. The smaller tertiary structure allows physostigmine to cross the blood-brain-barrier to treat the central symptoms of antimuscarinic toxicity. This contrasts with neostigmine and pyridostigmine, whose larger quaternary structures do not allow for significant CNS penetration.[1,7,8]

When given intravenously, the onset of physostigmine is approximately three to five minutes with a clinical duration of effect of 30 to 60 minutes.[9] Historically, the suggested physostigmine dose was 1-2 mg over three to five minutes repeated in 10-15 minutes if no improvement in altered mental status. When an excess of physostigmine is administered, there is a surplus of acetylcholine at various receptors producing cholinergic toxicity. Like any cholinergic overdose, seizures, bradycardia, and excess secretions are possible.[1]

Return From the Scrap Pile?

As previously mentioned, the case series by Pentel and Peterson in 1980 essentially halted the use of physostigmine in antimuscarinic toxicity. Both patients in this case series ingested tricyclic antidepressants (TCA). More ominously, both patients had wide-complex bradycardia and seizures prior to the dose of physostigmine.[6]

Burns, et al. reported 52 consecutive patients treated for antimuscarinic toxicity with either physostigmine alone, benzodiazepines, or physostigmine and benzodiazepines. Use of physostigmine was superior to benzodiazepines in controlling agitation (96% vs 24% respectively). Physostigmine reversed delirium in 87% of patients compared to no reversal of delirium with benzodiazepines.

Patients treated initially with physostigmine required fewer intubations and shorter time to recovery compared to patients treated with benzodiazepines. Importantly, there was no difference in side effects between the groups including seizures, episodes of bradycardia. There were no deaths in the case series. Interestingly, there were four patients with TCA overdose treated with physostigmine without complication (these patients had no QRS prolongation and were given physostigmine six or more hours after ingestion).[7]

Hesitancy and variability in use of physostigmine exists even among toxicologists. Watkins and colleagues queried a database of 815 suffering from anticholinergic toxicity treated by medical toxicologists. Physostigmine was used as the sole treatment in 12.4% of patients compared to 28.7% treated with benzodiazepines alone. There was a significant difference noted in endotracheal intubation in patients treated with physostigmine versus benzodiazepines (1.9% vs 8.4%). Agents causing only anticholinergic toxicity were more likely to receive physostigmine compared to polypharmacy ingestions or agents with multiple effects.[2]

Nguyen, et al. conducted a retrospective observational study at a single institution examining adverse effects in patients given physostigmine. Over a 9-year period, 54 patients received physostigmine for antimuscarinic toxicity. The total mean dose of physostigmine was 2.2 mg with 43% of patients getting an initial dose of 2 mg, and 39% required an additional dose of physostigmine. Five patients experienced clinically significant adverse effects; however, the authors determined no patients had serious adverse effects (cardiac arrest, seizure or symptomatic bradycardia).[8]

A 10-year retrospective review of physostigmine use for reversal of antimuscarinic toxicity in the California Poison Control System by Arens, et al. examined 191 patient encounters. The dosing regimen utilized in this system is 0.5 mg – 1.0 mg over three minutes with additional doses every 5-10 minutes for a total of 2 mg in the first hour.

Physostigmine improved or resolved delirium in 73.3% of patients after an initial dose, 36.1% required additional physostigmine. Adverse effects resulting from physostigmine administration were rare, 4.7% of patients experienced adverse effects. Emesis was the most common in 2.1%. Two patients suffered seizures, and one patient died; however, this death occurred six hours after the dose of physostigmine and the authors felt was unlikely to have contributed.[10]

The Bottom Line

Physostigmine is a short-acting central anticholinesterase inhibitor that is effective in controlling delirium from antimuscarinic toxicity with a similar risk of adverse effects to benzodiazepines or supportive care. It is recommended to obtain an ECG and avoid physostigmine in patients with a QRS interval of greater than 120 msec given concern for TCA ingestion.

Review of the literature supports an initial dose of 0.5 mg- 1mg over 3 to 5 minutes with repeated dosing every 10 to 15 minutes not to exceed a total dose of 2 mg in the first hour.[1,10]  Discussion of the patient with regional poison control center is recommended if physostigmine administration is being considered.

References:
  1. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium – theory, evidence and practice. Br J Clin Pharmacol. 2015;81(3):516-24.
  2. Watkins JW, et al. The use of physostigmine by Toxicologists in anticholinergic toxicity. J Med Toxicol. 2015;11:179-184.
  3. Proudfoot A. The early toxicology of physostigmine: a tale of beans, great men, and egos. Toxicol Rev. 2006;25(2):99-138.
  4. Boley SP, et al. Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center. CliniToxicol. 2019;57(1):50-55.
  5. Hoffman RS and Goldfrank LR. The poisoned patient with altered consciousness: controversies in the use of a ‘coma cocktail’. JAMA. 1995;274(7):562-569.
  6. Pentel P and Peterson CD. Aystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980 Nov;9(11):588-90.
  7. Burns MJ, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000:35(4):374-381.
  8. Nguyen TT, et al. Adverse events from physostigmine: an observational study. Am J Emerg Med. 2018;36:141-2.
  9. Rosenbaum C and Bird SB. Timing and frequency for physostigmine redosing for antimuscarininc toxicity. J Med Toxicol. 2010;6:386-92.
  10. Arens AM, et al. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol. 2018; 56(2):101-7.

ABOUT THE AUTHORS

Dr. Stromberg is an Emergency Physician at Carilion Roanoke Memorial Hospital, a 760-bed Level I trauma center,  and Carilion New River Valley Medical Center, a 146-bed community hospital. He is board certified in Medical Toxicology. He is involved in EM residency education at Carilion and serves as Clerkship Director for Emergency Medicine at Virginia Tech Carilion School of Medicine.  His practice interests include buprenorphine-induction in the Emergency Department and emerging drugs of abuse.

Dr. Schad is an Emergency Medicine clinical pharmacist at Carilion Roanoke Memorial Hospital, a 760-bed Level I trauma center, where she has worked for the last six years since completing her critical care pharmacy residency. She is involved in pharmacy and EM residency education at Carilion and several local schools of pharmacy.  Her practice interests include toxicology and the opioid epidemic.

Dr. McAllister is an Emergency Medicine pharmacist at Carilion Roanoke Memorial Hospital, a 760-bed Level I trauma center, where she has worked for the last 10 years since completing her critical care residency. She is actively involved in Emergency Medicine education through Carilion's EM and pharmacy residency programs, assists in the development of system-wide protocols, and has specific interests in bleeding reversal and toxicology.

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