Clinical toxicology (Philadelphia, Pa.) · 2026
Respiratory and cardiac toxicity of xylazine and fentanyl overdose in rats.
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Lewis Tristan, Judenherc-Haouzi Annick, Reinhardt Amanda, Haouzi Philippe
Аннотация
INTRODUCTION: Xylazine, a veterinary sedative, is an adulterant increasingly found in illicit fentanyl supplies. Yet, the dose-dependent effects of xylazine on fentanyl overdose remain poorly characterized. We sought to determine how xylazine modifies fentanyl-induced mortality, respiratory depression, and cardiovascular dysfunction in rats.
METHODS: Adult male and female Sprague-Dawley rats received non-lethal xylazine alone or combined with fentanyl (150 μg/kg) intravenously. For xylazine, three doses (0.1 mg/kg, 1 mg/kg, or 10 mg/kg) were chosen that produced a dose-dependent transition from a predominantly α2-adrenergic receptor agonist to a non-specific α-adrenergic receptor agonist effect, and are consistent with reported human exposures. Ventilation and pulmonary gas exchange were measured using an open-flow plethysmograph. Cardiovascular function was assessed via telemetry and echocardiography.
RESULTS: Bolus injection of xylazine alone at 0.1 mg/kg produced a typical profile of an α2-adrenergic agonist transitioning to a pronounced and persistent hypertension at 10 mg/kg. Xylazine dose-dependently potentiated the toxicity of fentanyl. Xylazine at 0.1 mg/kg with fentanyl showed no mortality increase (12.5% versus 10.5% fentanyl alone) despite prolonging apnea. Of note, this dose reduced fentanyl-induced rigidity of respiratory muscles and oxygen consumption. Xylazine at 1 mg/kg dramatically increased fentanyl mortality (62.5%), with survivors showing progressive respiratory recovery while non-survivors developed cardiogenic shock secondary to respiratory failure. Xylazine at 10 mg/kg with fentanyl was universally fatal (100%), causing a unique clinical syndrome, consisting of rapid cardiogenic shock leading to a pulseless electrical activity within 2-3 min.
DISCUSSION: Xylazine, when combined with a fentanyl overdose, has no increased mortality at 0.1 mg/kg, exacerbates hypoxemia-driven toxicity on breathing generation and cardiac function at 1 mg/kg, while producing an acute and very rapid lethal cardiocirculatory failure at 10 mg/kg.
CONCLUSION: Xylazine significantly potentiates fentanyl-induced respiratory depression and cardiovascular collapse in a dose-dependent manner in rats.
METHODS: Adult male and female Sprague-Dawley rats received non-lethal xylazine alone or combined with fentanyl (150 μg/kg) intravenously. For xylazine, three doses (0.1 mg/kg, 1 mg/kg, or 10 mg/kg) were chosen that produced a dose-dependent transition from a predominantly α2-adrenergic receptor agonist to a non-specific α-adrenergic receptor agonist effect, and are consistent with reported human exposures. Ventilation and pulmonary gas exchange were measured using an open-flow plethysmograph. Cardiovascular function was assessed via telemetry and echocardiography.
RESULTS: Bolus injection of xylazine alone at 0.1 mg/kg produced a typical profile of an α2-adrenergic agonist transitioning to a pronounced and persistent hypertension at 10 mg/kg. Xylazine dose-dependently potentiated the toxicity of fentanyl. Xylazine at 0.1 mg/kg with fentanyl showed no mortality increase (12.5% versus 10.5% fentanyl alone) despite prolonging apnea. Of note, this dose reduced fentanyl-induced rigidity of respiratory muscles and oxygen consumption. Xylazine at 1 mg/kg dramatically increased fentanyl mortality (62.5%), with survivors showing progressive respiratory recovery while non-survivors developed cardiogenic shock secondary to respiratory failure. Xylazine at 10 mg/kg with fentanyl was universally fatal (100%), causing a unique clinical syndrome, consisting of rapid cardiogenic shock leading to a pulseless electrical activity within 2-3 min.
DISCUSSION: Xylazine, when combined with a fentanyl overdose, has no increased mortality at 0.1 mg/kg, exacerbates hypoxemia-driven toxicity on breathing generation and cardiac function at 1 mg/kg, while producing an acute and very rapid lethal cardiocirculatory failure at 10 mg/kg.
CONCLUSION: Xylazine significantly potentiates fentanyl-induced respiratory depression and cardiovascular collapse in a dose-dependent manner in rats.