Extreme Hyperthermia Following Concomitant Linezolid and Fentanyl: An Atypical Presentation of Serotonin Syndrome in a Critically Ill Patient

On March 15, 2025, a fentanyl infusion was initiated at 10:00 AM for analgesia.An intravenous fentanyl 50-μg bolus was given, followed by a continuous infusion at 50 μg/hour.Linezolid was administered at a dose of 600 mg intravenously as an infusion between 11:00 AM and 2:00 PM.Approximately 1 hour after completion of the linezolid infusion, the patient developed a sudden rise in core temperature to 108°F, confirmed using a nasopharyngeal temperature probe (Figs 1 and2).Neurological examination revealed spontaneous clonus, generalized hyperreflexia, and mydriasis, with depressed consciousness (Glasgow Coma Scale E2VTM2).Despite the severity of hyperthermia, tachycardia was not observed, and the patient had not received sedatives or beta-blockers in the preceding period. IntroductIonSerotonin syndrome (SS) is a drug-induced condition resulting from increased serotonergic activity in the central and peripheral nervous systems.It is classically characterized by neuromuscular excitation, autonomic instability, and altered mental status; however, presentations are frequently incomplete or atypical, particularly in critically ill patients. 1,2 Neuromuscular findings such as clonus and hyperreflexia are considered the most specific diagnostic features and represent the core features of the Hunter Serotonin Toxicity Criteria. 2 Linezolid is a reversible monoamine oxidase inhibitor belonging to the oxazolidinone class of antibiotics and has been increasingly recognized as a precipitant of SS when combined with serotonergic medications. 3,4 Although antidepressants are most commonly implicated, growing evidence suggests that certain opioids, including fentanyl, possess serotonergic activity and may contribute to serotonin toxicity. 45]6 We report a critically ill patient who developed extreme hyperthermia following concomitant administration of linezolid and fentanyl, highlighting diagnostic challenges in the intensive care unit (ICU). case descrIptIonA 60-year-old woman with a known case of hypertension, chronic obstructive pulmonary disease, asthma, and osteoarthritis was admitted with acute gastroenteritis complicated by dehydration, acute kidney injury, septic shock, and encephalopathy.She was intubated prior to transfer to the ICU and required vasopressor support with noradrenaline and vasopressin.A necrotic perineal wound consistent with necrotizing fasciitis necessitated urgent surgical debridement.