Analgesic, Sedative and Antibiotic Pharmacokinetics during Extracorporeal Membrane Oxygenation: Understanding altered pharmacokinetics to improve patient outcomes.

Patients will be eligible for recruitment any time during the ECMO run. Pharmacokinetic samples will be obtained as per the protocol when a new antibiotc ,sedative or analgesic drug is commenced or when an existing sedative or analgesic agent is discontinued by the treating clinician. Sedative and analgesic drugs: Sedative and analgesic drugs will be administered according to local policies at each ICU. As a guide, intravenous Infusions and boluses of morphine (10-30 mg/hr) and midazolam (10-30 mg/hr) titrated to a Richmond Agitation Sedation Scale (RASS) of -3 to -4 and a bispectral index (BIS) of 40-45. Patient ventilator interactions may also be used as a guide to titrate sedation especially in patients on venovenous ECMO. Therapeutic paralysis is at the discretion of the treating clinician and will be guided by neuromuscular monitoring. Additional intravenous sedation if required may be provided with one of the following agents: 1. Propofol (10-200 mg/hr) 2. Dexmeditomedine (1 mcg/kg bolus and 0.1 -1.5 mcg/kg/min) 3. Fentanyl (50-300 mcg/hour) if morphine is discontinued for clinical reasons. 4. Thiopentone ( 100-200 mg/hour)* * Note- Thiopentone is uncommonly used as an ultimate rescue sedative in some patients on ECMO Antibiotics: Antibiotic drug selection and dosing will be at the discretion of the clinician, based on the clinical context and unit guidelines. Doses will be reconstituted in 10 ml of diluent and given as bolus infusion in 50 ml over 30 minutes (except ciprofloxacin and vancomycin – 1-2 hour infusion), or as per local hospital protocols. Sample collection Blood samples will be drawn from an existing arterial line and collected in 2 ml tubes with Lithium Heparin anticoagulant. It is recommended that a closed loop Venous Arterial blood Management Protection system (VAMP, Edward Life sciences, Canada Inc) be used to minimise blood loss during sampling. Minimum sample volume is 2 mls per time point. Another 0.5 mls of blood will be drawn for each additional drug studied. It is unlikely for a patient to be receiving more than 4 study drugs at a given time during PK sampling. Labels and collection tubes will be provided. Sedatives and analgesics: General PK sampling Blood samples will be taken from an existing arterial line at 0, 15, 30, 45, 60, 120, 180, 240, 360 minutes on commencement or cessation of a new sedative drug infusion. Details of drugs, doses and rates of administration to be documented on the data sheet. Antibiotics: All patients will be sampled over a single dosing period during ECMO treatment. Where two or more antibiotics of interest are prescribed for one patient, collect data on timing of administration for both drugs accurately and sample according to the antibiotic with the longer dosing interval. For example vancomycin 1g q12h and piperacillin 4.5g q6h; sample according to the vancomycin 12-hourly dosing schedule. 1. Six-hourly dosing schedule – Blood will be sampled from an existing arterial line at the following time points 0, 15, 30, 45, 60, 90, 120, 180 and 360 minutes. 2. Eight or 12-hourly dosing schedule – Blood samples will be collected from an existing arterial line at the following time points 0, 15, 30, 45, 60, 90, 120, 180 and 480 minutes. Urine specimens: Creatinine clearance for patients not receiving renal replacement therapy: An 8- hour urinary creatinine clearance collection will be obtained and assayed by the local pathology service to determine glomerular filtration rate. For patients receiving RRT the type and dose of the treatment will be documented on the data sheet.