The NIKI-C Study - A study of plasma pharmacokinetics of nebulized ketamine in post cardiac surgery patients.

This is a single site study, evaluating the pharmacokinetics (PK) of a single dose of nebulized ketamine in post cardiac surgery patients in the intensive care unit (ICU). The study also aims to define the optimal dosing regimens to inform future clinical trials. Design and setting: A minimum 20 post-operative cardiac surgery patients in the ICU that meet the inclusion criteria and none of the exclusion criteria will be recruited. In addition to standard analgesia and sedation prescribed by the treating clinician, each patient will receive nebulized ketamine 0.75mg/kg ideal body weight (IBW). Consent Patients must be able to consent for themselves in order to be eligible for the study. Patients are admitted to the ICU in the later part of the day and extubated later in the evening. The day following surgery patients will be assessed for suitability. Eligible patients will be approached by the Principal Investigator. In consultation with the treating team patients will be assessed for competence prior to approaching for consent. Intervention All patients continue to receive standard of care analgesia (oral, intravenous or epidural) as prescribed by the treating team. A vibrating mesh nebuliser with mouthpiece and exhalation filter will be used to administer the ketamine. The exhalation filter on the nebulizer expiratory port will eliminate the risk of environmental contamination for those present. patients will be shown the nebulizer and given detailed instructions and demonstration regarding the use. For patients on low flow (FiO2 < 0.4) or no oxygen the bacterial filter applied to the exhalation port will reduce fugitive emissions. For patients on high flow nasal cannula (FiO2 < 0.4) the vibrating mesh nebulizer will be inserted in the circuit on the dry side of the humidifier as per current practice. the patient will be requested to wear a surgical mask to cover their mouth and prevent fugitive emissions. Ketamine 0.75mg/kg (based on IBW) rounded to the nearest 5kg will be instilled in the nebulizer chamber to make up to a total of 3mL volume. Nebulization will continue until there is no visible mist. Biological Samples 8 blood samples (3mL each) will be collected into heparinised tubes over two hours (T=0, T+5, +10, +15, +30, +60, +90, +120 minutes) via an existing arterial or central line. A urine creatinine will be performed from time dosing commences until the end of the two hour sampling period. A 1 mL aliquot of urine from the total sample will be retained to determine renal excretion of the study drug. Monitoring Fidelity The qualified research team who are familiar with the study protocol and procedure will be at the bedside throughout the sampling period and will be monitoring for study compliance as per protocol. Data collection is completed by the research team in real time to ensure accuracy and negate the chance of missed data points. A data collection sheet will be completed for all samples collected including time of collection. Nebulization start and stop time is recorded. Medication dose will be calculated and checked by 2 competent clinical personnel at least one of whom will be a study team member. The template medication order will be used to ensure accuracy and consistency across all patients. Clear instructions are provided in the bedside resources for the study team to use that outline sample collection procedure and handling. Study team are highly experienced in these kind of studies and understand the importance of timeliness, correct sample handing and processing and adherence to protocol. A monitoring plan has been established for the study, including a Safety Monitoring Committee (SMC). Protocol adherence will be easily monitored s this is a single site study and the study team will be directly involved in each case. The study will be conducted in accordance with ethical principles consistent with the Declaration of Helsinki, and all relevant national and local guidelines on the ethical conduct of research. The Research team will include experienced research coordinators, intensive care specialists, all with Good Clinical practice (GCP) certification who will have oversight of all study activities and protocol adherence. All data will be directly entered from the source into the REDCap electronic database. the database has the capacity to run validity checks and logic queries to minimise errors. the study monitor will perform 100% source data verification (SDV) for the first patient recruited and 100% SDV on all patients for informed consent in accordance with HREC approval, reportable adverse events as per protocol, clinical outcomes and protocol deviations.