| Description |
The goal of this study was to investigate the bioavailability, efficacy, and safety of inhaled remifentanil, inhaled remimazolam, and combinations of both drugs in mouse, rat, and pig models. Anesthesiology could benefit from efficacious, noninvasively delivered, short acting, and thereby easily titratable analgesic/sedative agents. Remifentanil and remimazolam are potentially advantageous due to their esterase-based metabolism and rapid elimination profiles, particularly to high-risk populations such as obese, elderly, and pediatric populations. Dosing via spontaneous respiration can inherently and safely control the duration and level of sedation and analgesia via patient minute ventilation. There is no inhaled opioid or benzodiazepine currently available for clinical use as an anesthetic agent. It was our hypothesis that remifentanil and remimazolam delivered by inhalation would be rapidly absorbed, pharmacologically active, rapidly cleared, and noninjurious to rodent airways and lungs. We also hypothesized that the pharmacokinetics of inhaled remifentanil in pigs would exhibit similar rapid onset and recovery. Inhaled remifentanil in rats induced profound analgesia with rapid recovery. Inhaled remimazolam in mice produced sedation, while inhaled remimazolam in rats did not produce sedation at the maximum dose able to be achieved in aerosols. Remimazolam delivered in combination with remifentanil potentiated the analgesic response. Pulmonary mechanics and histology showed no irritation or injury by either drug or the combination. Pharmacokinetic analysis of both drugs in rodents were consistent with the pharmacological effects and a study of inhaled remifentanil in pigs demonstrated rapid absorption and clearance of the drug consistent with those reported for intravenous dosing in humans and animals. We have shown that remifentanil and remimazolam, administered alone or in combination, can be a clinically relevant method of anesthesia. These fundamental experiments and results are critical for the future development of formulations for inhalation delivery of these drugs for clinical use. These inhaled drugs could eventually revolutionize the ease and practicality of administering inhaled anesthetic agents, both inside and outside of the operating room. |
