Inadequate clinical effect and significant side effects associated with conventional administration of sedative and analgesic agents indicate a need for investigating novel drug delivery. Sub-optimal analgesia and sedation in intensive care causes adverse patient outcomes including impaired sleep in 46%, reduced quality of life, impaired mobility, hospital and or intensive care pain-related readmission costs equating to $1,869 per event, and 30% and 3% incidences of neurological side-effects and respiratory events respectively. Dexmedetomidine and ketamine have sedative-analgesic properties, and intravenous administration is commonly used for both but is associated with low blood pressure and heart rate, and excessive sedation.
Both drugs have previously been used safely, but due to unique advantages of administration via the lung, nebulisation may result in more favourable blood concentrations for safety and clinical effectiveness. Side effects are likely to be minimised, as high peak concentrations following intravenous administration are avoided.
A lack of clinical data on nebulised ketamine and dexmedetomidine limits ability to select appropriate doses for appropriate clinical effects. For this study, mechanical ventilation in the intensive care unit provided the ideal setting to safely evaluate drug delivery systems. Defining lung dose prior to clinical studies is essential, and it was determined that a comparative plasma study of nebulised versus intravenous ketamine and dexmedetomidine would allow the dose equivalency for the intravenous and nebulised administration routes to be derived. The data could then be used to generate dosing guidelines for clinical trials in diverse patient groups.
The Royal Brisbane and Women’s Hospital, Queensland
Dr Julie Lee, Associate Professor Jayesh Dhanani and Associate Professor Victoria Eley
University of Queensland
Professor Jason Roberts
The project was awarded $A66,165 through the ANZCA research grants program for 2022.
The study found that with mechanical ventilation, ketamine and dexmedetomidine can both be effectively nebulised. They both achieved optimal aerosol characteristics, achieving a mean fine particle dose of 30% and bioavailability of 29% (ketamine) and mean fine particle dose of 28% and bioavailability of 35% (dexmedetomidine).
Detailed population pharmacokinetic modelling is now under way, and will inform future clinical trials. Dose calculation in the design of these trials will need to account for the effective bioavailability of the nebulised delivery route. The final population pharmacokinetic modelling will further inform a dosing schedule.
Preliminary comparative pharmacokinetic data suggest lower peak and wider area under the curve, indicating the potential for its use for effective analgesia. Following these results, a phase III pilot feasibility randomised controlled crossover trial with nebulised dexmedetomidine for pain management in burn injury dressing changes has been completed, and a feasibility and plasma pharmacokinetic study of nebulised ketamine in non-ventilated post-operative and trauma patients, as well as in cardiac surgery patients, has commenced. This will lead to a large randomised controlled trial in the future.
Preliminary PK data for ketamine was presented at the annual RBWH research symposium on 6 September 2022.
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