Validation Study of Covariates Model (VaSCoM) for Propofol

Study Overview
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Brief Summary
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Anaesthesia for surgical procedures can be provided using a continuous infusion of intravenous drug. The most commonly used drug for this technique is propofol. Infusion devices programmed with pharmacokinetic models can be used to infuse propofol to achieve a target blood concentration. These pharmacokinetic models predict the rate of distribution of propofol within the body and also the rate at which it is cleared. In practice, the anaesthetist enters patient details such as age, sex and weight as well as a target blood concentration of propofol. The infusion device then infuses propofol at the appropriate rate to achieve this concentration. White and colleagues recently published the Covariates Model for propofol. It is anticipated that this model will have reduced bias and inaccuracy compared to the models in current clinical use. The VaSCoM study has three objectives: Prospective validation of the Covariates Model Modelling of the effect site concentration of propofol Comparison of propofol concentration in venous and arterial blood samples To achieve the above objectives, patients over 18 years of age and undergoing elective non-cardiac surgery will be recruited to the study. Anaesthesia will be delivered using a target controlled infusion device programmed with the Covariates Model for propofol. The target blood concentrations will be set according to a pre-determined schedule and all measurements will be made prior to the start of surgery. Prospective validation of the Covariates Model will be done by comparing blood concentration of propofol predicted by the model to those actually measured. These results will then be compared to the predictions made using the models in current clinical practice. Modelling of the effect site means predicting the concentration of propofol in the brain for a given blood concentration. This will involve using depth of anaesthesia monitors (such as bispectral index) as surrogate markers of brain concentration and comparing this to the predicted and measured blood concentrations of propofol. Finally, important information on the distribution and clearance of propofol can be gained through the comparison of venous and arterial blood samples. In this study, simultaneous sampling of venous and arterial blood will facilitate this comparison.

Official Title
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Validation Study of Covariates Model (VaSCoM) for Propofol

Conditions
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Target Controlled Infusion of Propofol

Intervention / Treatment
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* Drug: Propofol
* Drug: Propofol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged over 18 years ASA I/II Elective non-cardiac surgery expected to last longer than 30 minutes Exclusion Criteria: Patient refusal or unable to consent Premedication, sedative or anaesthetic in the previous 12 hours Pre-operative GCS less than 15 ASA III/IV Allergy to constituents of propofol Excess alcohol intake Drug abuse Mental retardation Difficult airway BMI over 35

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-high-low blood target concentration<br>Patients in the low-high-low group will receive an infusion of propofol with an initial blood target concentration of 2 mcg/ml. After 15 minutes the target will be increased to 5 mcg/ml and after a further 15 minutes the target will be reduced back to 2 mcg/ml for a further 15 to 30 minutes. | Drug: Propofol<br>* Patients in the low-high-low group will receive an infusion of propofol with an initial blood target concentration of 2 mcg/ml. After 15 minutes the target will be increased to 5 mcg/ml and after a further 15 minutes the target will be reduced back to 2 mcg/ml for a further 15 to 30 minutes.<br>|
| Experimental: High-low-high target blood concentration<br>Patients in the high-low-high group will receive an infusion of propofol with an initial blood target concentration of 5 mcg/ml. After 15 minutes the target will be reduced to 2 mcg/ml and after a further 15 minutes the target will be increased back to 5 mcg/ml for a further 15 to 30 minutes. | Drug: Propofol<br>* Patients in the high-low-high group will receive an infusion of propofol with an initial blood target concentration of 5 mcg/ml. After 15 minutes the target will be reduced to 2 mcg/ml and after a further 15 minutes the target will be increased back to 5 mcg/ml for a further 15 to 30 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Performance error of predicted blood propofol concentration (venous blood samples) | Performance error is calculated as: ((Measured blood concentration - Predicted blood concentration)/ Predicted blood concentration) x 100 The median performance error and the absolute performance error can then be calculated as measures of bias and inaccuracy respectively. | 1.5, 5, 16.5, 20, 31.5, 35, 45-60 minutes post infusion start time | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depth of anaesthesia | Depth of anaesthesia (as measured by bispectral index and index of consciousness) will be used as a surrogate marker of propofol effect site concentration. By using complex statistical analysis to compare depth of anaesthesia to measured and predicted blood concentrations, we aim to determine the Keo. This is the rate constant for elimination of propofol from the effect site compartment and will be incorporated to the Covariates Model to predict brain concentration for a given blood concentration of propofol. | 0 to 45-60 minutes post infusion start time | 
| Comparison of performance errors calculated from venous blood samples to performance errors calculated from arterial blood samples | Performance error is calculated as: ((Measured blood concentration - Predicted blood concentration)/ Predicted blood concentration) x 100 | 1.5, 5, 16.5, 20, 31.5, 35, 45-60 minutes post infusion start time | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Propofol, Pharmacokinetics, Pharmacodynamics, Infusion Pumps