Investigating the impact of body composition on the activity of propofol in babies, infants and children undergoing anaesthesia.

The aim of this study is to investigate the influence of body composition on propofol pharmacokinetics and pharmacodynamics in neonates infants and children (0-15 years). This will be a prospective population based PKPD study to examine the influence of body composition on propofol pharmacokinetics in neonates infants and children. Participants will include 50 neonates infants and children aged 0-15 years undergoing surgical procedures at Starship Children’s Hospital. Children undergoing cardiac or liver transplant surgery will not be included. This study will include both obese and non-obese children. A case report form (CRF) will be used to collect details for each case. These will include patient demographics, details of the surgical procedure and the timing of drug and surgical events. Details such as dose and timing of dose will be recorded for other drugs including inhalational anaesthetics and opioids. This information will be used to assess the effects of these drugs given in combination. The time at which each blood sample is taken will be recorded. A copy of the final anaesthetic record will be obtained for the study records, but all identifying information will be removed. The patients recruited into this study will be a sample of convenience which will depend on the theatre schedule and the availability of the researcher on any given day. Informed consent will be obtained from the children’s parents or legal guardian before being enrolled into the study. Body composition will be measured in all participants using skin fold thickness and bioimpedance analysis with the ImpediMed Imp-DF50 instrument. These measures will be taken at the bedside before or after surgery, or in the operating room while the participant is anaesthetised before their surgery begins. These methods are both rapid (they will take approximately 10 minutes) and non-invasive. The skinfold thickness calliper measures a pinch of skin at a precise location to determine the subcutaneous fat layer. Body composition can be estimated from this information using predictive equations. The biceps, triceps, subscapular and suprailiac skinfolds will be measured. These will be located using standard anatomical landmarks to ensure consistency between participants. The triceps skin fold will be located midway between the acromion and olecranon process on the posterior surface of the right arm. The biceps skin fold will be located at the same level on the anterior surface, in line with the cubital fossa. The subscapular skin fold will be measured approximately 2 cm below the inferior angle of the scapula at a 45-degree angle. The suprailiac skinfold will be located approximately 2 cm above the iliac crest at the anterior of the axillary line. We intend to supplement these measures with dual X-ray absorptiometry (DXA) or air displacement plethysmography (ADP) wherever possible. The DXA scan requires the participant to remain still for approximately 5 minutes. The entire clinic visit in which a DXA scan could be obtained should take no longer than 20 minutes. DXA scanning will be an optional extra measure of body composition. It will be at the parents’ discretion as to whether they think their child would remain still for the duration of the scan. DXA provides both whole-body and regional estimates of body composition and has the ability to separate muscle from FFM and calculate bone mineral density. The Pea Pod (Cosmed, Rome, Italy) is a commercially available device which has shown to be useful for determining body composition in neonates and infants < 8 kg using air displacement plethysmography. It is a is a three-compartment measure that determines fat mass, total body water and non-aqueous solids. Measurement of body composition using the PeaPod will be offered at the parents’ discretion. All body composition measurements will be obtained by a study researcher who is completing this study as part of a PhD. Study measurements can be taken at a time prior or following surgery, whenever is convenient for participants and their families. Anaesthetic treatment will be in accordance with the Australian and New Zealand College of Anaesthetists (ANZCA) standards. Doses and time of doses will be recorded in these cases on the study CRF for inclusion in analysis. Anaesthesia will be induced by inhalation of sevoflurane or an intravenous bolus dose of propofol. Anaesthesia will be maintained with a propofol infusion using an Alaris® PK syringe pump (Cardinal Health, Alaris Products, Basingstoke, UK). BIS and infusion data will be recorded during the anaesthetic through the routine automated monitoring system SaferSLEEP® (Auckland, New Zealand) and from the Alaris PK syringe pump. The maintenance dose rate of propofol administered will be at the discretion of the consulting anaesthetist. This may be either through automatic infusions based on existing PK models, or a manual infusion regimen. The delivery of propofol is in accordance with routine clinical care. Real time infusion and BIS data will be recorded and transferred from the SaferSLEEP® monitor to a study computer. Infusion data could include time, target concentration, dose and dose rate. BIS data will include time, minimum and maximum BIS values, and the average signal quality index (SQI). Inspired and end tidal sevoflurane concentration may also be recorded. A maximum of 5 mL arterial or venous blood will be taken from participants. This will be obtained from the existing indwelling arterial or venous catheter. An optimal design study will guide the times samples are obtained in order to provide the most accurate estimates of the PK parameter CL and the parameter Ffat. The duration of blood sampling is dependent on the duration of the surgical procedure. Samples are unlikely to be obtained more than one hour after cessation of propofol due to logistics (i.e. patients transferred into recovery and onto the ward). Patients will be observed from the time they are brought into theatre (this is to collect baseline information prior to propofol administration) until the last sample is obtained after the infusion is stopped. This study will record bispectral index (BIS), a modified form of electroencephalography (EEG) used to assess depth of sedation. This is routinely collected during surgical procedures to minimise accidental anaesthetic awareness and the risks associated with deep anaesthesia. Blood samples will be analysed by high performance liquid chromatography (HPLC) to determine plasma concentrations of propofol. Selective and sensitive methods for the analysis of propofol concentrations in blood have been developed and validated in terms of recovery, linearity, lower limit of quantification and precision and accuracy. The total concentration of propofol will be measured. Propofol samples will be analysed by the Burns Trauma & Critical Care Research Centre, University of Queensland, Brisbane, Australia.