Inhalation of Aerosolized Fentanyl Induces Respiratory Disorder and Sudden Death in Anesthetized Rats

Abstract

In synthetic opioids, fentanyl (FNT) is the deadliest in clinical settings, resulting from respiratory disorder (RD) including ventilatory depression (dVE) and apnea. Rapid intravenous injection of FNT has been reported to cause immediately central and upper airway obstructive apnea that is mediated by vagal afferents in anesthetized rat (Zhuang J et al, 2012 and 2023). Here we asked whether acute inhalation of FNT also induced similar RD. EMGs of the internal and external intercostal muscles and thyroarytenoid muscles (EMGII, EMGEI, and EMGTA), minute ventilation (VE), heart rate and arterial blood pressure were recorded in anesthetized rats exposed to aerosolized FNT for 10 min. Immediately after exposure to FNT at 100 mg/m3, the rats showed apneas and remarkable prolongation of expiratory duration (TE) associated with hypotension and bradycardia. The apneas were characterized by cessation of EMGEI activity (central apnea) with enhanced tonic discharges of EMGTA (vocal closure, i.e., obstructive apnea) and EMGII (expiratory muscle constriction, i.e., chest wall rigidity). After a brief rebound at ~0.5 min exposure when the cardiorespiratory activities almost recovered to the baseline level, the rats presented gradual dVE by reduction of VT and fR, lasting for approximately 10 min. Apneas and ventilatory arrest subsequently occurred, leading to cardiac arrest a few minutes later. In contrast, FNT at 50 mg/m3 initially failed to significantly change VE, but subsequently developed gradual dVE (70% reduction) with significant TE prolongation, bradycardia and hypotension. These cardiorespiratory responses disappeared 30 min later. Our results suggest that acute exposure to a lethal dose of aerosolized FNT initially induces both central and upper airway obstructive apnea followed by dVE and ventilatory arrest, which is responsible for the sudden death in anesthetized rats. Supported by NIH R01 grants HL163512 and DA059063. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.