Sub-optimal analgesia and sedation in the intensive care setting causes adverse patient outcomes, including impaired sleep in 46 per cent, reduced quality of life, impaired mobility, high economic costs for patient readmission into hospital/intensive care due to pain, besides a 30 per cent incidence of neurological side-effects and respiratory events in 3 per cent. Dexmedetomidine and ketamine have sedative-analgesic properties. Intravenous administration is commonly used for both but is associated with side-effects (low blood pressure, low heart rate and excessive sedation).
Nebulised dexmedetomidine and ketamine have been previously used safely. Due to the unique advantages of administration via the lung, nebulisation of sedative-analgesic medications may result in more favourable blood concentrations for safety and clinical effectiveness. Side effects are likely to be minimised because the high peak concentrations that follow intravenous administration are avoided.
Currently, there are no clinical data on nebulised ketamine and dexmedetomidine which limits our ability to select appropriate doses for appropriate clinical effects. Mechanical ventilation in the intensive care unit provides the ideal setting to evaluate the drug delivery systems in a safe manner. Defining the lung dose prior to clinical studies is essential. A comparative plasma study of nebulised versus intravenous ketamine and dexmedetomidine will allow us to derive the dose equivalency for the two different administration routes (intravenous and nebulised). The data could then be used to generate dosing guidelines for clinical trials in diverse patient groups.
The study results will provide important data to guide dosing for the clinical application of nebulised ketamine and dexmedetomidine. This will be used to provide analgesia and comfort in a non-invasive form in pre-hospital trauma, palliative care, post-operative care, and emergency medicine patients. Thus, this study fulfils an important and urgent requirement for investigation into a novel and non-invasive route of analgesic and sedative administration leading to a positive impact in the field of clinical medicine, health service and research.
- Dr Julie Lee, Associate Professor
- Jayesh Dhanani, Associate Professor
- Victoria Eley, Royal Brisbane and Women’s Hospital, Queensland
- Professor Jason Roberts, University of Queensland
The project was awarded $A66,165 through the ANZCA research grants program for 2022.
Sub-optimal analgesia and sedation in the intensive care setting causes adverse patient outcomes, including impaired sleep in 46%, reduced quality of life, impaired mobility, high economic costs equating to $1869 per readmission into hospital/intensive care due to pain, besides a 30% incidence of neurological side-effects and respiratory events in 3%. Dexmedetomidine and ketamine have sedative-analgesic properties. Intravenous administration is commonly used for both but are associated with side-effects (low blood pressure, low heart rate and excessive sedation).
Nebulised dexmedetomidine and ketamine have been previously used safely. Due to the unique advantages of administration via the lung, nebulisation of sedative-analgesic medications may result in more favourable blood concentrations for safety and clinical effectiveness. Side effects are likely to be minimised because the high peak concentrations that follow intravenous administration are avoided.
However, there was no clinical data on nebulised ketamine and dexmedetomidine which limits our ability to select appropriate doses for appropriate clinical effects. Mechanical ventilation in the intensive care unit provides the ideal setting to evaluate the drug delivery systems in a safe manner. Defining the lung dose prior to clinical studies is essential. A comparative plasma study of nebulised versus intravenous ketamine and dexmedetomidine will allow us to derive the dose equivalency for the two different administration routes (intravenous and nebulised). The data could then be used to generate dosing guidelines for clinical trials in diverse patient groups.
The Results of the study are:
- Nebulized ketamine achieved optimal aerosol characteristics with mechanical ventilation. The mean percentage of fine particle dose (lung dose) achieved was 30%
- Nebulized dexmedetomidine achieved optimal aerosol characteristics with mechanical ventilation. The mean percentage of fine particle dose (lung dose) achieved was 28%
- The bioavailability of nebulized ketamine was 29%. Detailed population pharmacokinetic modelling is underway and will inform future clinical trials.
- The bioavailability of nebulized dexmedetomidine was 35%. Detailed population pharmacokinetic modelling is underway and will inform future clinical trials.
Thus, the results indicate that ketamine and dexmedetomidine can be effectively nebulized. When designing clinical trials using nebulized ketamine and dexmedetomidine, the dose calculation will need to take into account the effective bioavailability of the nebulized route of drug delivery. The final population pharmacokinetic modelling will further inform a dosing schedule.
In conclusion, the study results suggest that nebulized ketamine and dexmedetomidine are able to achieve optimal aerosol characteristics. Preliminary comparative pharmacokinetic data suggest lower peak and wider area under the curve indicating the potential for its use for effective analgesia. Following the results of the study, a phase III pilot feasibility, randomized controlled crossover trial with nebulized dexmedetomidine for pain management in burn injury dressing changes (HREC/2023/MNHB/94679, ACTRN12623001033639) has been commenced in July 2023.
Preliminary PK data for ketamine was presented at the annual RBWH research symposium on 6th September 2022.