The most appropriate next step in treatment is external evaporative cooling. Hyperthermia occurs most commonly owing to heat stroke, malignant hyperthermia, and neuroleptic malignant syndrome. A temperature greater than 40.0 °C (104.0 °F) and encephalopathy in the setting of environmental heat exposure are characteristic of heat stroke. The majority of patients with nonexertional heat stroke are older than 70 years or have chronic medical conditions. Medications and recreational drugs with anticholinergic, sympathomimetic, and diuretic effects, including alcohol, pose added risk. This patient's advanced age and diuretic use place him at increased risk for nonexertional heat stroke. External evaporative cooling involves removing all clothing and spraying the patient with a mist of lukewarm water while continuously blowing fans on the patient. Ice water immersion is commonly used for patients with exertional heat stroke, who typically are younger and need less monitoring.

Heat stroke is a cause of rhabdomyolysis, but the combination of fever, encephalopathy, and rhabdomyolysis should also raise the possibility of neuroleptic malignant syndrome (NMS) and serotonin syndrome. NMS can be treated with dantrolene or bromocriptine. However, this patient has no muscle rigidity or medication exposure (antipsychotics in particular), which are characteristic of NMS. Therefore, treatment with dantrolene would not be appropriate.

Cyproheptadine is used to treat serotonin syndrome. Although this patient takes sertraline, serotonin syndrome would not be expected to cause severe hyperthermia. Furthermore, characteristic muscle rigidity and neurologic signs, including tremor, hyperreflexia, and clonus, are absent.

N-acetylcysteine is used to treat acetaminophen toxicity, which is a diagnostic consideration in a patient with encephalopathy and a history of depression and possible suicidality. However, acetaminophen overdose is not associated with severe hyperthermia.