Case Presentation: A 57-year-old man with depression and prior suicide attempts presented after being found unresponsive at home with empty bottles of doxepin, amitriptyline, and another unidentified pill bottle. In the ED, he had a GCS of 6, was intubated for airway protection and admitted to MICU. Sodium bicarbonate, fentanyl and propofol infusions were started for tricyclic antidepressant (TCA) toxicity and post-intubation sedation. In the MICU, he developed worsening agitation, hyperthermia with temperature of 104°F, hyperreflexia, clonus, and autonomic instability consistent with serotonin syndrome. Cyproheptadine was started and fentanyl was stopped. He received broad spectrum antibiotics for possible aspiration pneumonia. A comprehensive metabolic panel was normal, salicylate level was mildly elevated at 3.3 mg/dL, a normal acetaminophen level, and a urine drug screen positive for TCAs.By hospital day (HD) 6, clinical status improved to allow extubation and floor transfer. However, the hospitalist noted severe ongoing agitation, hallucinations, and fever that did not respond to acetaminophen. On exam, he had dilated and nonreactive pupils, dry mucous membranes, and one episode of urinary retention were noted; all suggestive of continued antimuscarinic toxicity. Toxicology recommended trial of a rivastigmine patch. Within 6 hours, the patient’s fever, agitation, visual/auditory hallucinations, had resolved. With improved mental status, he reported the other co-ingestion was fluoxetine.
Discussion: This patient presented with typical central (agitation, hallucinations), and peripheral (vasodilation, anhidrosis, urinary retention, mydriasis) manifestations of antimuscarinic toxicity, which are critical for hospitalists to recognize. However, these classic findings manifested on HD 6, which was atypical given the time since initial ingestion. Clonus, rigidity, and autonomic fluctuations were now absent after management of serotonin syndrome in the ICU. We considered meningoencephalitis, alcohol withdrawal, and ICU delirium and considered a lumbar puncture or repeat neuroimaging. However, the elevated temperature not responding to acetaminophen suggested hyperthermia rather than fever. Additionally, the patient rapidly improved after a trial of rivastigmine, rendering additional testing unnecessary. The classic antimuscarinic findings were likely masked during the final day in the ICU due to the use of other sedating medications and manifested more clearly during ward observation.A critical point making sense of this atypical presentation was the report of comorbid fluoxetine overdose. When fluoxetine was first introduced, multiple case reports and pharmacokinetic studies revealed its ability to inhibit CYP2D6, leading to markedly impaired TCA metabolism and prolonged TCA toxicity presenting in patients on stable TCA doses who started fluoxetine.1,2
Conclusions: Hospitalists should keep in mind the possibility of prolonged or delayed anti muscarinic syndrome with comorbid fluoxetine overdose due to delayed TCA metabolism. It is important for hospitalists to recognize anticholinergic toxicity given delayed presentations masked by other sedative medications patients receive in the ICU or ED. Cardiac monitoring, supportive care and benzodiazepines are the mainstay of management for TCA toxicity; reversal agents such as rivastigmine can treat patients with severe manifestations or aid in diagnosis.