Comparing blood concentrations of intravenous and nebulized sedatives and analgesics in patients who are on mechanical ventilation.

This study is a single site, cross-over study, comparing the plasma pharmacokinetics (PK)s of sedative and analgesic agents with two routes of drug administration in critical care mechanically ventilated patients. In this study 60 patients who meet the inclusion criteria and none of the exclusion criteria will be recruited. In addition to the standard analgesia and sedation prescribed by the treating clinician, each patient will be assigned up to two drugs of investigation at any given time. The drug selection will depend on the following factors: • Exclusion of drugs with known hypersensitivity in the patient. • Exclusion of drugs that patient is already receiving as therapy via any route or frequency. Approach toward selecting study drug will include- 1. Inclusion criteria includes “requiring sedation and or analgesia as per treating team” – high likelihood of receiving at least one of the drugs being tested 2. Drugs that are being administered to the patients will be excluded. For e.g. if the patient is on fentanyl infusion, then fentanyl will not be a study drug. 3. Exclude drugs with known hypersensitivity in the patient e.g. if patient is allergic to morphine then morphine will not be a study drug. 4. May exclude drugs with synergistic effect- eg. if increased risk of hypotension –Dexmedetomidine and Clonidine would preferably not be used together 5. Selection of drug/drugs based on meeting recruitment target for drugs (10 complete sets for each drug – nebulised and Intravenous route) Each drug will be serially administered via one route Intravenous (IV) /nebulised (NEB) and after a minimum washout period of 12 hours following the sampling time, the 2nd route of administration. When enrolment is for two drugs, these will be administered via different routes. For example, if recruited for fentanyl and midazolam, then if fentanyl is administered intravenously, midazolam will be given concurrently via nebulized route initially with the administration routes changed to nebulization and intravenous respectively in the subsequent stage. The initial method of administration for each drug will be determined by a flip of a coin. Based on data from existing studies, the study drugs and their doses according to the route of administration include: Drugs (same for intravenous and nebulized route) Sedative agents Midazolam 5 mg Clonidine 75 µg Dexmedetomidine 50 µg Analgesic agents Fentanyl 50 µg Morphine 5 mg Ketamine 25 mg Intravenous drug administration: Participants will be administered the study drug intravenously via an existing peripheral or central intravenous catheter as per ICU policy and practise. Nebulized administration: A disposable vibrating mesh nebulizer that is currently being used in ICU will be utilised for the nebulization of the study drug. As per current practice, the nebulizer will be placed in the inspiratory limb of the circuit before the Y-piece. If there is a nebulizer in the circuit, only the nebulizer chamber will be replaced and the T-piece will not be changed. The study drugs will be diluted with normal saline. This solution will be instilled in the nebulizer reservoir. Blood samples will be collected over six hours from an existing arterial line or central venous catheter into heparinised tubes. A urine creatinine clearance will be performed over the sampling period up to 8 hour poste commencement of drug and a sample will be kept to determine drug renal excretion. Monitoring fidelity: Protocol adherence will be easily monitored as 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 as all with GCP training and they will have oversight of all study required activities and protocol adherence. All data will be entered directly from the source in to the electronic database. The data base has the capacity to run validity checks and logic queries to minimise errors. De-identified sampling spread sheets uploaded to the data base for validation of sampling time points. Audit of 100% consent, source data verification of essential data points for 20 % of participants.