Respiratory and cardiac toxicity of xylazine and fentanyl overdose in rats

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: -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: -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.