Cardiorespiratory failure induced by inhalation of aerosolized fentanyl in anesthetized rats

Intravenous rapid injection of fentanyl causes respiratory depression (severe apneas), leading to sudden death, which constitutes the deadliest drug reaction among overdoses of synthetic opioids. Here we asked whether acute inhalation of overdose fentanyl would also result in similar respiratory failure and death. The anesthetized and spontaneously breathing rats with tracheal cannulation were exposed to aerosolized fentanyl at 100 mg/m³ (FNT_H) or 30 mg/m³ (FNT_L) for 10 min. Minute ventilation (V_E), electromyography (EMG) of the internal and external intercostal muscles and thyroarytenoid muscles (EMG_II, EMG_EI, and EMG_TA), heart rate and arterial blood pressure were recorded. During the exposure, FNT_H and FNT_L immediately triggered bradypnea (40 % reduction, p < 0.05) with T_E prolonged and then gradually decreased V_E by 40 % (P < 0.05) after a brief V_E recovery. The initial T_E prolongation (apneas) were characterized by the cessation of EMG_EI activity with enhanced tonic discharges of EMG_TA and EMG_II. After termination of the exposure, the cardiorespiratory responses to FNT_L returned to the baseline values 30 min later, while those to FNT_H were greatly exacerbated (P < 0.05), leading to ventilatory and cardiac arrest occurred 16.4 ± 4.7 min and 19.3 ± 4.5 min respectively after the onset of FNT_H. The ventilatory arrest was featured by cessation of both EMG_EI and EMG_II and augmentation of tonic EMG_TA. Our results suggest that acute exposure to an overdose of fentanyl aerosol leads to death through initially inducing a brief central and upper airway obstructive apnea as well as chest wall rigidity followed by gradual severe hypoventilation, bradycardia and hypotension, and eventual cardiorespiratory arrest in anesthetized rats.