Hydroxyzine primarily treats pruritus, anxiety, and insomnia due to its ability to bind histaminic, muscarinic, serotonergic, and dopaminergic receptors. Here, we present a case of rare manifestations of hydroxyzine overdose.CASE PRESENTATION: A 30-year-old female presented after a suicidal attempt with presumptive amlodipine overdose. She was found tachycardic, tachypnic, hypotensive, and lethargic. Urine and serum drug screen was negative. Blood gas revealed a non-anion gap metabolic acidosis. Chest x-ray (CXR) showed no anomalies. ECG revealed sinus tachycardia with normal QT interval. A head CT showed no anomalies. Crystalloid fluid resuscitation was initiated for presumptive amlodipine overdose induced hypotension. Norepinephrine (NE) drip was initiated for distributive shock. Day 1, she complained of excessive thirst and urinary retention; CXR showed bilateral diffuse infiltrates. Echocardiogram revealed left ventricular ejection fraction of 60-65% without wall motion abnormalities or valvulopathy. Day 2, she developed delirium and visual hallucination, warm and dry, intermittent hypotension, large A-a gradient, PaO2/FiO2 ratio <100, and worsening bilateral infiltrates on CXR; consistent with severe ARDS requiring intubation. Clinical presentation was suspicious for anticholinergic toxicity. External records revealed a 120-tablet hydroxyzine 25 mg prescription, and the family provided an update revealing an empty bottle of 90 tabs of hydroxyzine 25mg at home. There was no role for hemodialysis or hemoperfusion. She required maximal support on NE, vasopressin, phenylephrine, and dopamine for worsening distributive shock. Due to persistent anticholinergic symptomatology, two trials of physostigmine were administered with transient avail. Day 3, she required maximal ventilator support for worsening hypoxemia and was referred for ECMO. Day 4, she was slowly weaned off of dopamine, phenylephrine and NE prior to transfer to the ECMO facility. After transfer, she was weaned off of vasopressin, extubated, and discharged home prior to the initiation of ECMO.DISCUSSION: In young adults, hydroxyzine has a 20-hour half life. Our patient ingested about 2 grams of hydroxyzine. The diagnosis of anticholinergic toxicity may be confirmed by resolution or improvement of symptoms during a slow IV injection of 0.5 to 1 mg of physostigmine salicylate. General supportive care and seizure control with physostigmine and diazepam may result in complete recovery within 72 hours.CONCLUSIONS: Hydroxyzine is a safe and effective drug, but life-threatening adverse effects can occur with overdose. Symptoms of toxicity are delirium, seizures, tachycardia, and hypotension. High dose of hydroxyzine may cause ARDS and distributive shock. A postmortem analysis of a confirmed hydroxyzine overdose demonstrated severe pulmonary edema, hyperemia and occasional alveolar hemorrhage.