Episode 74 – Physostigmine and Anticholinergic Toxidrome

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We review this blog post by Bryan Hayes, an ED pharmacist (@PharmERToxGuy), on the use of physostigmine in anticholinergic toxicity.

We review core content on anticholinergic toxicity using Rosen’s Emergency Medicine (9th ed), Tintinalli’s Emergency Medicine (8th ed) and Goldrank’s Toxicology as guides.

Rosh Review Emergency Board Review Questions

A 27-year-old man is brought to the ED by EMS after being found wandering in the street. His BP is 155/70, HR 115, T 37.5°C, RR 16, pulse ox 99% on room air, and finger stick glucose 98. On exam, the patient is confused with mumbling speech. His pupils are 7 mm and nonreactive. His face is flushed. Mucous membranes and skin are dry. Which of the following toxidromes is this patient exhibiting?

A. Anticholinergic

B. Cholinergic

C. Sedative-hypnotic

D. Sympathomimetic

Answer

A. Anticholinergic Toxidrome refers to a constellation of physical findings that can provide important clues in a toxic ingestion. This patient exhibits an anticholinergic toxidrome. Anticholinergics are widely available as over-the-counter cold preparations and sleep aids (diphenhydramine, chlorpheniramine, doxylamine). They also are the basis of the toxicity of jimsonweed. Anticholinergics competitively inhibit acetylcholine in the central and peripheral nervous systems. This classic toxidrome is often described by the phrase “mad as a hatter (altered mental status), blind as a bat (mydriasis), red as a beet (flushed skin), hot as a hare (dry skin due to inability to sweat), dry as a bone (dry mucous membranes).” Other findings include tachycardia, delirium, seizures, and hallucinations. Treatment is mainly supportive with benzodiazepines for agitation and seizures, and cooling for temperature reduction. Gastric decontamination (whole-bowel irrigation or gastric lavage) is often recommended due to the delay in gastric emptying caused by anticholinergics. The use of physostigmine, a reversible cholinesterase inhibitor that will increase synaptic acetylcholine, is controversial and should be administered only in consultation with a toxicologist.

The cholinergic toxidrome (B) is characterized by the mnemonics SLUDGE (salivation, lacrimation, urination, defecation, GI upset, emesis) or DUMBBELS (defecation, urination, miosis, bronchospasm, bronchorrhea, emesis, lacrimation, salivation) and occurs after exposure to organophosphates or carbamates. The sedative-hypnotic toxidrome (C) is seen with benzodiazepines and barbiturates. Clinically, patients exhibit central nervous system and respiratory depression. The sympathomimetic toxidromes (D) can occur after ingestion of cocaine, amphetamines, or decongestants. It typically presents with delirium, paranoia, tachycardia, hypertension, hyperpyrexia, diaphoresis, mydriasis, seizures, and hyperactive bowel sounds. Sympathomimetic and anticholinergic toxidromes are frequently difficult to distinguish. The key difference is that sympathomimetics are associated with diaphoresis, whereas anticholinergics cause dry skin.

A 22-year-old man is brought into the Emergency Department by Emergency Medical Services with altered mental status. He is an agitated man and mumbling incoherent words. His pupils are 6 mm and reactive to light. His axillae are dry. His heart rate is 115 beats/minute and temperature is 101.6 oF. Which of the following is a complication of the antidote used in the treatment of this condition?

A. Asystole

B. Bladder retention

C. QT-interval prolongation

D. Respiratory depression

Answer

Asystole. The mnemonic for the anticholinergic toxidrome is blind as a bat (mydriasis), red as a beet (vasodilation leading to flushing), hot as a hare (hyperthermia), dry as a bone (dry skin and mucosa), mad as a hatter (visual or auditory hallucinations, agitation, and mumbling or incoherent speech), bloated as a toad (ileus and urinary retention), and the heart runs alone (tachycardia). Additionally, anticholinergic toxicity can cause orthostatic hypotension (especially in the elderly), picking behavior, and can lead to seizures, coma, and even death. There are multiple anticholinergic medications, including tricyclic antidepressants, antihistamines, antiparkinson medications, antipsychotics, antispasmodics, belladonna alkaloids, skeletal muscle relaxants, and mydriatics. Antihistamine overdose is the most common cause of anticholinergic toxicity. Treatment is supportive with IV hydration. If the ingestion occurred within one hour, GI decontamination with activated charcoal is reasonable. Benzodiazepines are used for significant agitation and seizures. Good temperature control should be achieved with antipyretics and active cooling is essential. For wide complex tachyarrhythmias, treatment is with sodium bicarbonate. The antidote is physostigmine, a reversible acetylcholinesterase inhibitor. There is, however, a risk of profound bradycardia, seizures, and asystole in patients with widened QRS complexes. This risk is minimal if there is a pure anticholinergic syndrome without concomitant sodium channel blockade, but this is unfortunately not always known. Since the most common cause of anticholinergic toxicity is from diphenhydramine overdose (which causes sodium channel blockade), physostigmine should only be used with the assistance of a medical toxicologist.  

References:

  1. Arens AM, et al. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol. 2017 Jul 13:1-7. [Epub ahead of print] PMID 28703024
  2. “Anticholinergics.” Rosen’s Emergency Medicine. 9th ed.  Chapter 145
  3. “Anticholinergics.” Tintinalli’s Emergency Medicine: A Comprehensive Review. 8th ed. Chapter 202.

Episode 73 – Gastroparesis & Biliary Pathology

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Dr. Salim Rezzaie of RebelEM wrote a blog post on HUGS – Haloperidol for Gastroparesis.  This study had significant methodologic limitations but provides some interesting insight into a practice that many providers have adopted – using haloperidol for gastroparesis. A tiny RCT by Roldan and colleagues also looked at this practice and found promising results, although the study was very small.  Haloperidol has also been used in cannabinoid hyperemesis but literature on this is limited to case reports/series. 

Core Content

We review biliary colic, cholecystitis, and cholangitis using Tintinalli (8th ed) Chapter 79 and Rosen’s Emergency Medicine (9th ed) Chapter 80 as guides.

Rosh Review Emergency Board Review Questions

A 60-year-old woman presents with two days of right upper quadrant abdominal pain constant in nature and associated with subjective fever, nausea, and vomiting. Vital signs are temperature of 38.1°C, heart rate 87, blood pressure 140/80 mm Hg, respiratory rate 14, and oxygen saturation of 99% on room air. Her abdomen is soft with right upper quadrant tenderness and a positive Murphy’s sign. Which of the following tests is most sensitive and specific in diagnosing this patient’s condition?

A. Computed tomography scan with intravenous contrast

B. Hepatobiliary iminodiacetic acid (HIDA) scan

C. MRI with gadolinium

D. Ultrasound

Answer

This patient has suspected acute cholecystitis and requires an imaging study for confirmation. Hepatobiliary iminodiacetic acid (HIDA) scanning is considered the most sensitive and specific test for diagnosing acute cholecystitis. IDA is administered intravenously, taken up by hepatocytes, and excreted into the bile canaliculi. Failure to obtain an outline of the gallbladder within one hour proves cystic duct obstruction and, in the appropriate clinical setting, confirms the diagnosis of acute cholecystitis. Visualization of the gallbladder and common duct within one hour has a high negative predictive value. A HIDA scan is usually obtained when the ultrasound study is equivocal.

Computed tomography scan with intravenous contrast (A) can identify cholecystitis with a reported sensitivity of 92% and specificity of 99%. It is most useful in cases of emphysematous and hemorrhagic cholecystitis. MRI with gadolinium (C) provides similar diagnostic yield to CT scan. Ultrasound (D) is most useful in the ED setting because it is a quick, noninvasive test. Its sensitivity and specificity, however, are lower than a HIDA scan’s for pathology-confirmed cholecystitis. Ultrasound findings and a clinical exam consistent with acute cholecystitis are highly predictive, and many such patients will undergo cholecystectomy without further diagnostic testing.

 

References:

  1. Ramirez R, Stalcup P, Croft B, Darracq MA. Haloperidol undermining gastroparesis symptoms (HUGS) in the emergency department. Am J Emerg Med. 2017; 35(8):1118-1120. [pubmed]
  2. Roldan CJ, Chambers KA, Paniagua L, Patel S, Cardenas-Turanzas M, Chathampally Y. Randomized Controlled Double-blind Trial Comparing Haloperidol Combined With Conventional Therapy to Conventional Therapy Alone in Patients With Symptomatic Gastroparesis. Acad Emerg Med. 2017; In Press[pubmed]
  3. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient have acute cholecystitis? JAMA. 2003; 289(1):80-6. [pubmed]
  4. Jain A, Mehta N, Secko M. History, Physical Examination, Laboratory Testing, and Emergency Department Ultrasonography for the Diagnosis of Acute Cholecystitis. Acad Emerg Med.. 2017; 24(3):281-297. [pubmed]
  5. Hwang H, Marsh I, Doyle J. Does ultrasonography accurately diagnose acute cholecystitis? Improving diagnostic accuracy based on a review at a regional hospital.   J Surg. 2014 Jun; 57(3): 162–168. [pubmed]