Author:  Alan Barte, MD, Emergency Medicine Resident, PGY-1
Faculty:  Alexis Cates, DO, Medical Toxicology/Emergency Medicine Attending

The Case:

A 16-year-old female with no known medical history presents to the emergency department (ED) for evaluation after being found unresponsive. She was brought in a car by her family who states that her last known normal was approximately two hours prior to arrival. Per family, she had been alone in her room until a sibling had found her “shaking in the bed and foaming at the mouth.” The shaking episode had lasted approximately one minute with no evidence of incontinence. 

Her family mentions that the patient has had suicidal thoughts in the past and was seeing a psychiatrist until this past summer.  The patient had stopped taking her fluoxetine.  Her family reveals a now empty bottle of diphenhydramine 25mg tablets that was found in the patient’s room. They estimated the container to have had approximately 100 tablets left.  They deny that the patient had any other known co-ingestions.  Other medications in the home include loratadine, ibuprofen, acetaminophen, nifedipine, and “antibiotics” that they could not further characterize. Prior to evaluation in the ED, the patient had received intranasal naloxone by EMS with no response.

Learning Point 1: Anticholinergic Toxicity

Anticholinergic agents work as competitive antagonists against acetylcholine predominately at muscarinic receptors but also minimally at nicotinic receptors. There are many compounds with anticholinergic activity that are both intentionally and unintentionally ingested annually. In 2015 the American Association of Poison Control Centers (AAPCC) reported just under 14,000 reported to poison control centers that year. 

The classic anticholinergic toxidrome can be remembered with a few sayings including “blind as a bat,” “mad as a hatter,” “hot as a hare,” “dry as a bone,” “full as a flask,” and “red as a beet,” which represent mydriasis, confusion, hyperthermia, dry mucous membranes, urinary retention, and flushed skin respectively. Other presentations can include: hypervigilance, agitation, hallucinations, delirium coma, tachycardia, hypertension, tachypnea, decreased bowel sounds, myoclonus, choreoathetosis, and rarely seizures. A helpful pictograph can be seen in Figure 1.  

Figure1: Anticholinergic Toxicity pictogram as seen on LIFTL.com

This can be difficult to differentiate from other toxidromes, but key symptoms such as systemic dryness (e.g. dry mucosal membranes, dry flushed skin, and urinary retention) may help identify anticholinergic toxicity.  Figure 2 includes a helpful table from Up-To-Date that categorizes many of the classic toxidromes.

Figure 2: Common poisoning syndromes as seen on Up-To-Date

The time frame in which signs and symptoms may appear depends on the toxin. The onset usually occurs in the initial one to two hours of ingestion; however, a delayed onset or persisting symptoms are not uncommon. For example, atropine is rapidly absorbed by the gastrointestinal (GI) tract and achieves peak concentrations within two hours.  However, scopolamine toxicity can last for over 24 hours. If the patient has other conditions, a surgical history, or takes medications that have led to decreased peristalsis, this could lead to prolonged absorption in the GI tract which could prolong the effects. 

The case continued…

The patient was evaluated by emergency room physicians and was placed on the monitor.  Oxygen was administered and labs were drawn. An electrocardiogram was performed that showed sinus tachycardia without interval abnormality. On physical exam, the patient was found to have mydriasis, dry flushed skin, and was disoriented and delirious. In conjunction with the medications found with the patient, the clinical diagnosis of anticholinergic toxicity was suspected.

Learning Point 2: Evaluation of anticholinergic toxicity

In any patient with an intentional ingestion and resultant decreased responsiveness, there are a few basic tests that should be ordered following initial resuscitation:

·       Fingerstick glucose – to rule out hypoglycemia or hyperglycemia as a cause of altered mental status

·       Acetaminophen and salicylate concentrations – to evaluate for common co-ingestions

·       EKG – to evaluate for abnormal conduction as a result of a xenobiotic, specifically effects on the QRS and QTc intervals. 

• Recall that diphenhydramine can act as a cardiac toxicant secondary to its blockading effect of the sodium and potassium channels. This can lead to QRS and QTc interval prolongation, respectively.

Additional tests that may be helpful include:

·       Creatinine kinase – evaluate for rhabdomyolysis which can be associated with some anticholinergic agents 

·       Troponin – evaluate for cardiac strain in a critically ill poisoned patient

·       Coagulation studies – in the event there is synthetic liver function abnormalities or other coagulopathies

·      Complete metabolic panel – to evaluate hepatic transaminases, renal function and electrolytes

If the patient has altered mental status, remember “AEIOU TIPS” as a helpful mnemonic for other diagnoses that should be on your differential. But in our case the most likely cause of her decreased responsiveness is related to her ingestion.

The case continued…

Patient was given sodium bicarbonate pushes, fluid resuscitated, and was provided with symptomatic and supportive care. A call to the pharmacy was made to obtain physostigmine, however it was unavailable at the time. Imaging was obtained in the form of a chest x-ray and CT head which both returned negative for acute findings.

Learning Point 3: Management of anticholinergic toxicity

• Initial resuscitation
  • Airway, breathing, circulation
  • Cardiac monitoring
  • Large bore IV access
  • Supplemental oxygen if needed
• Decontamination
  • Activated charcoal can be considered in patients with a secure airway or intact mental status
    • Risks of aspiration, time of ingestion / expected absorption time and the specific xenobiotic should be considered
• Interventions
  • Watch and wait
    • Most patients do well with observation, symptomatic and supportive care
  • Benzodiazepines 
    • Titrate intravenous or intramuscular benzodiazepines for agitation or seizures
    • Avoid medications such as haloperidol as they may worsen clinical toxicity or cardiac conduction effects
  • Physostigmine
    • Consider in the patient where a diagnosis of anticholinergic toxicity is suspected and the patient has moderate symptoms (not requiring intubation)
    • Effects will last only several minutes, and is not curative of the toxicity
    • There are many contraindications: 
      • Bradydysrhythmias 
      • Heart Block (AV and intraventricular)
      • Bronchospasm
    • When appropriate, dosing is 0.5 mg up to 2 mg in an adult, and 0.02 mg / kg up to 0.5 mg in pediatric patients via IV, over 5 minutes
    • Consider consultation with a toxicologist 
  • Sodium bicarbonate 
    • Boluses or infusion can be given for cardiotoxicity due to sodium channel blockade (QRS prolongation)

The case concluded…

It was suspected that the patient had a large pill burden, as she continued to be symptomatic for several hours into days.  She was provided symptomatic and supportive care at the local children’s hospital ICU.  Ultimately, she improved and had psychiatry evaluation upon medical discharge.  

References

Broderick ED, Metheny H, Crosby B. Anticholinergic Toxicity. [Updated 2021 Aug 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534798/

Levine MD. General approach to drug poisoning in adults. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 09, 2021.)

Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 2016 Dec;54(10):924-1109. doi: 10.1080/15563650.2016.1245421. PMID: 28004588.

Su MK, Goldman, M. Anticholinergic poisoning. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 09, 2021.)