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Physostigmine Reversal of Dysarthria and Delirium After Iatrogenic Atropine Overdose From a Dental Procedure
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–3, 2018 Ó 2018 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
https://doi.org/10.1016/j.jemermed.2018.02.046
Selected Topics: Toxicology PHYSOSTIGMINE REVERSAL OF DYSARTHRIA AND DELIRIUM AFTER IATROGENIC ATROPINE OVERDOSE FROM A DENTAL PROCEDURE Jon B. Cole, MD, Benjamin S. Orozco, MD, and Ann M. Arens, MD Department of Emergency Medicine, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, Minnesota Reprint Address: Jon B. Cole, MD, Department of Emergency Medicine, Hennepin County Medical Center, University of Minnesota Medical School, 701 Park Avenue, Mail Code RL.240, Minneapolis, MN 55415
, Abstract—Background: Sublingual atropine, dosed at 0.4–0.8 mg, is used by dentists as an antisialogogue to facilitate and increase the speed of procedures. Concentrated ophthalmic atropine drops (10 mg/mL) are commonly used off-label for this purpose. These highly concentrated drops may result in medication errors, atropine toxicity, and the antimuscarinic toxidrome. We report a case of a man who suffered acute delirium and dysarthria (from dry mouth) after an iatrogenic overdose from a dental procedure. His symptoms were initially interpreted as a stroke, but they completely resolved with physostigmine. Case Report: A 57-year-old man presented with acute dysarthria and delirium after a dental procedure; 4 hours earlier he was fitted for a temporary replacement of some premolar/molar teeth. He received sublingual atropine to assist in gingival drying for molding of his prosthesis, but a calculation error resulted in the administration of approximately 113 mg. A stroke evaluation was initially planned; however, 2.5 mg of intravenous physostigmine completely reversed his symptoms. His symptoms reoccurred and were successfully treated twice more with physostigmine; the patient was observed overnight with no additional symptoms and safely discharged the next morning. Why Should an Emergency Physician be Aware of This?: Ophthalmic atropine drops are highly concentrated and may cause an overdose after ingestion of small amounts. This novel case highlights the importance of considering antimuscarinic poisoning in cases of acute
delirium or dysarthria after dental procedures and stands as a reminder to inquire about the use of atropine drops in such cases. Timely recognition of the antimuscarinic toxidrome and appropriate use of physostigmine may prevent unnecessary testing while providing an effective therapy. This case also highlights the need for observation after resolution of delirium treated with physostigmine. Ó 2018 Elsevier Inc. All rights reserved. , Keywords—atropine; iatrogenic; overdose; physostigmine; poisoning; stroke
INTRODUCTION Atropine is described in the dental literature for use as an antisialogogue, with a recommended oral dose range of 0.4–0.8 mg in adults (1). Typically, this is administered as 1–2 drops of ophthalmic atropine (10 mg/mL), which is available in 2-, 5-, or 15-mL bottles (2). Though this use of atropine has occurred for decades and has been shown to increase the speed of dental procedures, ingestion of only a few drops has resulted in toxicity (3,4). Atropine in toxic doses results in manifestation of the antimuscarinic toxidrome. This constellation of signs and symptoms includes tachycardia, mydriasis, delirium, agitation, dry skin, decreased gastrointestinal motility, and urinary retention (5). Toxicity from ophthalmic atropine is sparsely reported, and a literature search reveals no reports of iatrogenic toxicity from atropine used before a dental procedure (6,7).
Presented as a poster at the 2012 North American Congress of Clinical Toxicology in Las Vegas, Nevada, October 1–6, 2012.
RECEIVED: 20 December 2017; FINAL SUBMISSION RECEIVED: 20 February 2018; ACCEPTED: 27 February 2018 1
2
J. B. Cole et al.
Physostigmine is a carbamate that reversibly inhibits acetylcholinesterase, causing increased acetylcholine at terminal nerve endings (8,9). As such, physostigmine counteracts the antimuscarinic toxidrome caused by atropine. Physostigmine has been used since the 19th century to treat atropine toxicity (10). Though its popularity grew inthe1960s and 70s,reportssurfacedin the early 1980s associating asystolewith its use in the treatment of cyclic antidepressant toxicity; the use of physostigmine subsequently declined sharply despite a clear causal link in those reports (8,11,12). Recent literature suggests physostigmine is safer than previously thought (13–18). Moreover, physostigmine has been used to safely treat delirium after ingestion of concentrated atropine eye drops, preventing intubation (6). We describe a unique case of a patient accidentally overdosed on atropine before a dental procedure. He became delirious, suffered dysarthria (from his dry mouth), and presented to an emergency department (ED) where an acute stroke was suspected. Upon recognition of the toxidrome, the patient was subsequently treated with physostigmine, resulting in resolution of symptoms and obviating the need for additional diagnostic evaluation. In this unique case of iatrogenic atropine poisoning, physostigmine provided both therapeutic and diagnostic benefit. CASE REPORT A 57-year-old man was brought to the ED by a concerned coworker because of the man’s acute delirium and dysarthria 4 hours after a dental procedure. The patient’s coworker noted that the patient was ‘‘not acting like himself.’’ He was fidgeting, confused, slurring words, and wandered away during conversation. The patient would later describe feeling inebriated while driving to work after his procedure. He had no known history of psychiatric illness or substance abuse. The patient’s dentist had given him a card disclosing the sublingual use of ophthalmic atropine. The coworker saw the card and was concerned that the patient might be having an allergic reaction to this medication. Later it was learned the patient was being fitted for a temporary replacement of his lower left premolar and molar teeth and, because of the proximity of the parotid duct, the patient was administered sublingual atropine to assist in drying of the gingiva for molding of his prosthesis. Multiple errors subsequently led to an overdose. The treating dentist was unfamiliar with this off-label use and phoned an oral surgery colleague who gave verbal instructions to give 1 mg, which was erroneously interpreted as 1 mL, or half of a 2-mL bottle. In addition, instead of a 2-mL bottle a 15-mL bottle was used; furthermore, the bottle was
given to the patient to self-administer. The patient then self-administered approximately ‘‘three fourths’’ of this 15-mL bottle of 1% atropine, or 113 mg. His initial vital signs were as follows: heart rate 128 beats/min, blood pressure 148/94 mm Hg, temperature 37.7 C, respiratory rate 20 breaths/min, and oxygen saturation 97% on room air. His physical examination was notable for 5-mm minimally reactive pupils, dry mucous membranes, tachycardia, dysarthria, and a distended bladder. He had difficulty following commands but could do so with repeated prompting. He was not oriented to person, place, or time, and had dysarthria. He was moved to a resuscitation room to expedite evaluation of a possible stroke given his acute neurologic signs and symptoms. His initial electrocardiogram showed sinus tachycardia with normal intervals. His blood glucose was 118 mg/dL; there were no remarkable abnormalities on his chemistry panel or venous blood gas analysis. Brain imaging and a consultation with the Neurology Department were planned. The patient was treated with 1 L of normal saline and intravenous (IV) lorazepam 1 mg twice without improvement in his mental status or tachycardia. After consultation with a regional poison center, IV physostigmine 2 mg was given over 6 min. This intervention resulted in rapid improvement of the patient’s mental status; he was drowsy but able to answer questions more appropriately and his dysarthria improved. An additional 0.5 mg IV physostigmine was given over 3 min leading to complete resolution of the patient’s delirium and dysarthria. The patient was amnestic to the events before ED arrival. The patient’ delirium returned 2 h after the initial physostigmine dose. He was treated with another IV physostigmine dose of 2.5 mg with complete resolution of his delirium. Five hours after his first dose of physostigmine, the patient received a third dose (2 mg IV) for recurrence of his delirium and was admitted for observation to a telemetry bed. Physostigmine resolved both his delirium and dysarthria, so no additional evaluation was required; his consultation with the Neurology Department and brain imaging were cancelled. He required no additional doses of physostigmine or medications for sedation and was discharged home the following morning with no sequelae. DISCUSSION Atropine is a tropane alkaloid extracted from several plants of the Solanaceae family; it has been used for centuries to induce mydriasis for cosmetic effect. Currently, atropine is used for therapeutic mydriasis, as well as for its cardiovascular effects. The ophthalmic preparation
Physostigmine Reversal of Dysarthria and Delirium
has been adopted for use by dentists and oral surgeons to minimize salivation during procedures. Atropine toxicity is characterized by the antimuscarinic toxidrome, which is effectively reversed with physostigmine (5). Though physostigmine’s use may not be common among emergency physicians, it is superior to benzodiazepines for treating antimuscarinic poisoning and has a favorable side effect profile if administered properly as an infusion over 4–6 min (14–16,18,19). The appropriate use of physostigmine may not only help provide an accurate diagnosis; it also frequently obviates the need for more invasive testing, such as lumbar puncture (15). The duration of cholinesterase inhibition of physostigmine is estimated to be 83.7 6 5.2 min, which may be shorter than the expected toxicity after a large atropine overdose, and thus symptoms may recur (20). This case further supports the safety and effectiveness of repeat dosing of physostigmine for recurrent symptoms and the superiority of physostigmine compared with benzodiazepines for antimuscarinic poisoning. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? Ophthalmic atropine drops are highly concentrated and may cause overdose after ingestion of small amounts. This novel case highlights the importance of considering antimuscarinic poisoning in cases of acute delirium or dysarthria after dental procedures and stands as a reminder to inquire about the use of atropine drops in such cases. Timely recognition of the antimuscarinic toxidrome and appropriate use of physostigmine may prevent unnecessary testing while providing an effective therapy. This case also highlights the need for observation after resolution of delirium treated with physostigmine. REFERENCES 1. Kazen DH, Dille JM. An evaluation of atropine as an antisialogogue in dentistry. Oral Surg Oral Med Oral Pathol 1963;16:919–25.
3 2. Akorn-Inc. Atropine sulfate, 15 mL [package insert]. Available at: http://www.akorn.com/documents/catalog/sell_sheets/17478-21515.pdf. Accessed December 18, 2017. 3. Brandt S, Servoss JM, Persily KB. Atropine sulphate—an effective antisialogogue. J Clin Orthod 1981;15:629–34. 4. Hoefnagel D. Toxic effects of atropine and homatropine eyedrops in children. N Engl J Med 1961;264:168–71. 5. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium - theory, evidence and practice. Br J Clin Pharmacol 2016;81:516–24. 6. Stellpflug SJ, Cole JB, Isaacson BA, Lintner CP, Bilden EF. Massive atropine eye drop ingestion treated with high-dose physostigmine to avoid intubation. West J Emerg Med 2012;13:77–9. 7. Bishop AG, Tallon JM. Anticholinergic visual hallucinosis from atropine eye drops. CJEM 1999;1:115–6. 8. Suchard JR. Assessing physostigmine’s contraindication in cyclic antidepressant ingestions. J Emerg Med 2003;25:185–91. 9. Triggle DJ, Michell JM, Filler R. The pharmacology of physostigmine. CNS Drug Rev 1998;4:87–136. 10. Nickalls RW, Nickalls EA. The first use of physostigmine in the treatment of atropine poisoning. A translation of Kleinwachter’s paper entitled’ on the effect of Calabar bean extract as an antidote to atropine poisoning’. Anaesthesia 1988;43:776–9. 11. Stilson M, Kelly K, Suchard J. Physostigmine as an antidote. Cal J Emerg Med 2001;2:47–8. 12. Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 1980;9: 588–90. 13. Arens AM, Shah K, Al-Abri S, Olson KR, Kearney T. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol (Phila) 2018;56:101–7. 14. Rasimas JJ, Sachdeva KK, Donovan JW. Revival of an antidote: bedside experience with physostigmine. J Am Assoc Emerg Psych 2014;12:5–24. 15. 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;35:374– 81. 16. Schneir AB, Offerman SR, Ly BT, et al. Complications of diagnostic physostigmine administration to emergency department patients. Ann Emerg Med 2003;42:14–9. 17. Rosenbaum C, Bird SB. Timing and frequency of physostigmine redosing for antimuscarinic toxicity. J Med Toxicol 2010;6:386–92. 18. Watkins JW, Schwarz ES, Arroyo-Plasencia AM, Mullins ME. Toxicology Investigators Consortium investigators. The use of physostigmine by toxicologists in anticholinergic toxicity. J Med Toxicol 2015;11:179–84. 19. Cole JB, Stellpflug SJ, Ellsworth H, Harris CR. Reversal of quetiapine-induced altered mental status with physostigmine: a case series. Am J Emerg Med 2012;30:950–3. 20. Asthana S, Raffaele KC, Berardi A, et al. Treatment of Alzheimer disease by continuous intravenous infusion of physostigmine. Alzheimer Dis Assoc Disord 1995;9:223–32.
https://doi.org/10.1016/j.jemermed.2018.02.046
Selected Topics: Toxicology PHYSOSTIGMINE REVERSAL OF DYSARTHRIA AND DELIRIUM AFTER IATROGENIC ATROPINE OVERDOSE FROM A DENTAL PROCEDURE Jon B. Cole, MD, Benjamin S. Orozco, MD, and Ann M. Arens, MD Department of Emergency Medicine, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, Minnesota Reprint Address: Jon B. Cole, MD, Department of Emergency Medicine, Hennepin County Medical Center, University of Minnesota Medical School, 701 Park Avenue, Mail Code RL.240, Minneapolis, MN 55415
, Abstract—Background: Sublingual atropine, dosed at 0.4–0.8 mg, is used by dentists as an antisialogogue to facilitate and increase the speed of procedures. Concentrated ophthalmic atropine drops (10 mg/mL) are commonly used off-label for this purpose. These highly concentrated drops may result in medication errors, atropine toxicity, and the antimuscarinic toxidrome. We report a case of a man who suffered acute delirium and dysarthria (from dry mouth) after an iatrogenic overdose from a dental procedure. His symptoms were initially interpreted as a stroke, but they completely resolved with physostigmine. Case Report: A 57-year-old man presented with acute dysarthria and delirium after a dental procedure; 4 hours earlier he was fitted for a temporary replacement of some premolar/molar teeth. He received sublingual atropine to assist in gingival drying for molding of his prosthesis, but a calculation error resulted in the administration of approximately 113 mg. A stroke evaluation was initially planned; however, 2.5 mg of intravenous physostigmine completely reversed his symptoms. His symptoms reoccurred and were successfully treated twice more with physostigmine; the patient was observed overnight with no additional symptoms and safely discharged the next morning. Why Should an Emergency Physician be Aware of This?: Ophthalmic atropine drops are highly concentrated and may cause an overdose after ingestion of small amounts. This novel case highlights the importance of considering antimuscarinic poisoning in cases of acute
delirium or dysarthria after dental procedures and stands as a reminder to inquire about the use of atropine drops in such cases. Timely recognition of the antimuscarinic toxidrome and appropriate use of physostigmine may prevent unnecessary testing while providing an effective therapy. This case also highlights the need for observation after resolution of delirium treated with physostigmine. Ó 2018 Elsevier Inc. All rights reserved. , Keywords—atropine; iatrogenic; overdose; physostigmine; poisoning; stroke
INTRODUCTION Atropine is described in the dental literature for use as an antisialogogue, with a recommended oral dose range of 0.4–0.8 mg in adults (1). Typically, this is administered as 1–2 drops of ophthalmic atropine (10 mg/mL), which is available in 2-, 5-, or 15-mL bottles (2). Though this use of atropine has occurred for decades and has been shown to increase the speed of dental procedures, ingestion of only a few drops has resulted in toxicity (3,4). Atropine in toxic doses results in manifestation of the antimuscarinic toxidrome. This constellation of signs and symptoms includes tachycardia, mydriasis, delirium, agitation, dry skin, decreased gastrointestinal motility, and urinary retention (5). Toxicity from ophthalmic atropine is sparsely reported, and a literature search reveals no reports of iatrogenic toxicity from atropine used before a dental procedure (6,7).
Presented as a poster at the 2012 North American Congress of Clinical Toxicology in Las Vegas, Nevada, October 1–6, 2012.
RECEIVED: 20 December 2017; FINAL SUBMISSION RECEIVED: 20 February 2018; ACCEPTED: 27 February 2018 1
2
J. B. Cole et al.
Physostigmine is a carbamate that reversibly inhibits acetylcholinesterase, causing increased acetylcholine at terminal nerve endings (8,9). As such, physostigmine counteracts the antimuscarinic toxidrome caused by atropine. Physostigmine has been used since the 19th century to treat atropine toxicity (10). Though its popularity grew inthe1960s and 70s,reportssurfacedin the early 1980s associating asystolewith its use in the treatment of cyclic antidepressant toxicity; the use of physostigmine subsequently declined sharply despite a clear causal link in those reports (8,11,12). Recent literature suggests physostigmine is safer than previously thought (13–18). Moreover, physostigmine has been used to safely treat delirium after ingestion of concentrated atropine eye drops, preventing intubation (6). We describe a unique case of a patient accidentally overdosed on atropine before a dental procedure. He became delirious, suffered dysarthria (from his dry mouth), and presented to an emergency department (ED) where an acute stroke was suspected. Upon recognition of the toxidrome, the patient was subsequently treated with physostigmine, resulting in resolution of symptoms and obviating the need for additional diagnostic evaluation. In this unique case of iatrogenic atropine poisoning, physostigmine provided both therapeutic and diagnostic benefit. CASE REPORT A 57-year-old man was brought to the ED by a concerned coworker because of the man’s acute delirium and dysarthria 4 hours after a dental procedure. The patient’s coworker noted that the patient was ‘‘not acting like himself.’’ He was fidgeting, confused, slurring words, and wandered away during conversation. The patient would later describe feeling inebriated while driving to work after his procedure. He had no known history of psychiatric illness or substance abuse. The patient’s dentist had given him a card disclosing the sublingual use of ophthalmic atropine. The coworker saw the card and was concerned that the patient might be having an allergic reaction to this medication. Later it was learned the patient was being fitted for a temporary replacement of his lower left premolar and molar teeth and, because of the proximity of the parotid duct, the patient was administered sublingual atropine to assist in drying of the gingiva for molding of his prosthesis. Multiple errors subsequently led to an overdose. The treating dentist was unfamiliar with this off-label use and phoned an oral surgery colleague who gave verbal instructions to give 1 mg, which was erroneously interpreted as 1 mL, or half of a 2-mL bottle. In addition, instead of a 2-mL bottle a 15-mL bottle was used; furthermore, the bottle was
given to the patient to self-administer. The patient then self-administered approximately ‘‘three fourths’’ of this 15-mL bottle of 1% atropine, or 113 mg. His initial vital signs were as follows: heart rate 128 beats/min, blood pressure 148/94 mm Hg, temperature 37.7 C, respiratory rate 20 breaths/min, and oxygen saturation 97% on room air. His physical examination was notable for 5-mm minimally reactive pupils, dry mucous membranes, tachycardia, dysarthria, and a distended bladder. He had difficulty following commands but could do so with repeated prompting. He was not oriented to person, place, or time, and had dysarthria. He was moved to a resuscitation room to expedite evaluation of a possible stroke given his acute neurologic signs and symptoms. His initial electrocardiogram showed sinus tachycardia with normal intervals. His blood glucose was 118 mg/dL; there were no remarkable abnormalities on his chemistry panel or venous blood gas analysis. Brain imaging and a consultation with the Neurology Department were planned. The patient was treated with 1 L of normal saline and intravenous (IV) lorazepam 1 mg twice without improvement in his mental status or tachycardia. After consultation with a regional poison center, IV physostigmine 2 mg was given over 6 min. This intervention resulted in rapid improvement of the patient’s mental status; he was drowsy but able to answer questions more appropriately and his dysarthria improved. An additional 0.5 mg IV physostigmine was given over 3 min leading to complete resolution of the patient’s delirium and dysarthria. The patient was amnestic to the events before ED arrival. The patient’ delirium returned 2 h after the initial physostigmine dose. He was treated with another IV physostigmine dose of 2.5 mg with complete resolution of his delirium. Five hours after his first dose of physostigmine, the patient received a third dose (2 mg IV) for recurrence of his delirium and was admitted for observation to a telemetry bed. Physostigmine resolved both his delirium and dysarthria, so no additional evaluation was required; his consultation with the Neurology Department and brain imaging were cancelled. He required no additional doses of physostigmine or medications for sedation and was discharged home the following morning with no sequelae. DISCUSSION Atropine is a tropane alkaloid extracted from several plants of the Solanaceae family; it has been used for centuries to induce mydriasis for cosmetic effect. Currently, atropine is used for therapeutic mydriasis, as well as for its cardiovascular effects. The ophthalmic preparation
Physostigmine Reversal of Dysarthria and Delirium
has been adopted for use by dentists and oral surgeons to minimize salivation during procedures. Atropine toxicity is characterized by the antimuscarinic toxidrome, which is effectively reversed with physostigmine (5). Though physostigmine’s use may not be common among emergency physicians, it is superior to benzodiazepines for treating antimuscarinic poisoning and has a favorable side effect profile if administered properly as an infusion over 4–6 min (14–16,18,19). The appropriate use of physostigmine may not only help provide an accurate diagnosis; it also frequently obviates the need for more invasive testing, such as lumbar puncture (15). The duration of cholinesterase inhibition of physostigmine is estimated to be 83.7 6 5.2 min, which may be shorter than the expected toxicity after a large atropine overdose, and thus symptoms may recur (20). This case further supports the safety and effectiveness of repeat dosing of physostigmine for recurrent symptoms and the superiority of physostigmine compared with benzodiazepines for antimuscarinic poisoning. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? Ophthalmic atropine drops are highly concentrated and may cause overdose after ingestion of small amounts. This novel case highlights the importance of considering antimuscarinic poisoning in cases of acute delirium or dysarthria after dental procedures and stands as a reminder to inquire about the use of atropine drops in such cases. Timely recognition of the antimuscarinic toxidrome and appropriate use of physostigmine may prevent unnecessary testing while providing an effective therapy. This case also highlights the need for observation after resolution of delirium treated with physostigmine. REFERENCES 1. Kazen DH, Dille JM. An evaluation of atropine as an antisialogogue in dentistry. Oral Surg Oral Med Oral Pathol 1963;16:919–25.
3 2. Akorn-Inc. Atropine sulfate, 15 mL [package insert]. Available at: http://www.akorn.com/documents/catalog/sell_sheets/17478-21515.pdf. Accessed December 18, 2017. 3. Brandt S, Servoss JM, Persily KB. Atropine sulphate—an effective antisialogogue. J Clin Orthod 1981;15:629–34. 4. Hoefnagel D. Toxic effects of atropine and homatropine eyedrops in children. N Engl J Med 1961;264:168–71. 5. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium - theory, evidence and practice. Br J Clin Pharmacol 2016;81:516–24. 6. Stellpflug SJ, Cole JB, Isaacson BA, Lintner CP, Bilden EF. Massive atropine eye drop ingestion treated with high-dose physostigmine to avoid intubation. West J Emerg Med 2012;13:77–9. 7. Bishop AG, Tallon JM. Anticholinergic visual hallucinosis from atropine eye drops. CJEM 1999;1:115–6. 8. Suchard JR. Assessing physostigmine’s contraindication in cyclic antidepressant ingestions. J Emerg Med 2003;25:185–91. 9. Triggle DJ, Michell JM, Filler R. The pharmacology of physostigmine. CNS Drug Rev 1998;4:87–136. 10. Nickalls RW, Nickalls EA. The first use of physostigmine in the treatment of atropine poisoning. A translation of Kleinwachter’s paper entitled’ on the effect of Calabar bean extract as an antidote to atropine poisoning’. Anaesthesia 1988;43:776–9. 11. Stilson M, Kelly K, Suchard J. Physostigmine as an antidote. Cal J Emerg Med 2001;2:47–8. 12. Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 1980;9: 588–90. 13. Arens AM, Shah K, Al-Abri S, Olson KR, Kearney T. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol (Phila) 2018;56:101–7. 14. Rasimas JJ, Sachdeva KK, Donovan JW. Revival of an antidote: bedside experience with physostigmine. J Am Assoc Emerg Psych 2014;12:5–24. 15. 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;35:374– 81. 16. Schneir AB, Offerman SR, Ly BT, et al. Complications of diagnostic physostigmine administration to emergency department patients. Ann Emerg Med 2003;42:14–9. 17. Rosenbaum C, Bird SB. Timing and frequency of physostigmine redosing for antimuscarinic toxicity. J Med Toxicol 2010;6:386–92. 18. Watkins JW, Schwarz ES, Arroyo-Plasencia AM, Mullins ME. Toxicology Investigators Consortium investigators. The use of physostigmine by toxicologists in anticholinergic toxicity. J Med Toxicol 2015;11:179–84. 19. Cole JB, Stellpflug SJ, Ellsworth H, Harris CR. Reversal of quetiapine-induced altered mental status with physostigmine: a case series. Am J Emerg Med 2012;30:950–3. 20. Asthana S, Raffaele KC, Berardi A, et al. Treatment of Alzheimer disease by continuous intravenous infusion of physostigmine. Alzheimer Dis Assoc Disord 1995;9:223–32.