Pharmacokinetic/Pharmacodynamic Model of Propofol in Children

Study Overview
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Brief Summary
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By measuring plasmatic concentration of propofol at different intervals during surgery of children aged 1 to 12 years old and measuring Bispectral Index (BIS) as a surrogate for cerebral activity, the investigators aim to create a pharmacokinetic/pharmacodynamic model of propofol for children.

Detailed Description
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Propofol is an intravenous anesthetic capable of providing a safe general anesthesia, free from many of the adverse effects associated with inhalation anesthetics (postoperative nausea and vomiting, agitation on awakening, seizures and trigger malignant hyperthermia crisis) and widely used in adults, but even less so in children. This is due to the fact that its pharmacological characteristics have not been clarified at all in the pediatric population. The physiological maturation of different systems in children, as well as changes in body composition and metabolism may determine significant changes in the pharmacokinetics (distribution volumes and clearance) of children. Moreover, within the same age group, variations across different individuals may make even less predictable the pharmacokinetic models currently in use. Indeed, previous work in our group based on these models have shown that propofol dosage required by children to induce general anesthesia is inversely proportional to the age, which could be explained by biases in these models, different sensitivity to propofol at different ages and sizes, etc. The effect of propofol in the brain is described by its pharmacodynamics, but in children this is still in debate. Using a brain activity monitor (BIS), the effect of propofol at the central nervous system can be analyzed under a model of nonlinear mixed effects (NONMEM) and establish the time to peak effect to characterize in detail the pharmacodynamics of this drug. Integrating pharmacokinetic and pharmacodynamic data, a pharmacokinetic/pharmacodynamic (PK/PD) model for the pediatric population can be derived. The aim of this paper is to describe the first PK / PD model of propofol in children, valid for different ages and to analyze them in the context of different body composition parameters. The importance of this study is that its results will publish the missing link in the pediatric pharmacology of propofol, which will encourage more research and more widespread use of this technique in the pediatric population.

Official Title
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Pharmacokinetic/Pharmacodynamic Model of Propofol in Children

Conditions
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Anesthesia

Intervention / Treatment
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* Drug: Propofol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 1 year through 11 years 11 months and 29 days old. American Society of Anesthesiology (ASA) score 1 or 2. Elective surgery of more than 1 hour of expected duration. Written informed consent signed by parents or legal guardians. Oral and written consent in children aged over 7 years old. Exclusion Criteria: Known allergies to study drugs. Use of any medication acting on central nervous system in the last 24 hours previous to surgery. Chronic cardiac, renal, hepatic or neurologic disease that determines abnormal function. Difficult airway (predicted or known). Use of neuraxial anesthesia.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ages 1 year - 3 years 11 months<br>Propofol infusion, measuring of plasmatic levels of propofol through venous sampling | Drug: Propofol<br>* Propofol infusion will be started after inhalational induction by manual infusion by the following scheme: First 15 minutes: 15 mg/kg/min 16 to 30 minutes: 13 mg/kg/min 31 to 60 minutes: 11 mg/kg/min 61 to 120 minutes: 10 mg/kg/min Dose will be titrated to maintain BIS between 40 - 50. Venous sampling for plasmatic levels of propofol measuring will be made at the following moments: 5, 15 and 25 minutes of starting infusion, 1, 3, 5, 7, 9 and 12 minutes of bolus and, 5, 25, 60 and 120 minutes of infusion ended.<br>* Other names: Diprivan;|
| Experimental: Ages 4 years - 8 years 11 months<br>Propofol infusion, measuring of plasmatic levels of propofol through venous sampling | Drug: Propofol<br>* Propofol infusion will be started after inhalational induction by manual infusion by the following scheme: First 15 minutes: 15 mg/kg/min 16 to 30 minutes: 13 mg/kg/min 31 to 60 minutes: 11 mg/kg/min 61 to 120 minutes: 10 mg/kg/min Dose will be titrated to maintain BIS between 40 - 50. Venous sampling for plasmatic levels of propofol measuring will be made at the following moments: 5, 15 and 25 minutes of starting infusion, 1, 3, 5, 7, 9 and 12 minutes of bolus and, 5, 25, 60 and 120 minutes of infusion ended.<br>* Other names: Diprivan;|
| Experimental: Ages 9 years - 11 years 11 months<br>Propofol infusion, measuring of plasmatic levels of propofol through venous sampling | Drug: Propofol<br>* Propofol infusion will be started after inhalational induction by manual infusion by the following scheme: First 15 minutes: 15 mg/kg/min 16 to 30 minutes: 13 mg/kg/min 31 to 60 minutes: 11 mg/kg/min 61 to 120 minutes: 10 mg/kg/min Dose will be titrated to maintain BIS between 40 - 50. Venous sampling for plasmatic levels of propofol measuring will be made at the following moments: 5, 15 and 25 minutes of starting infusion, 1, 3, 5, 7, 9 and 12 minutes of bolus and, 5, 25, 60 and 120 minutes of infusion ended.<br>* Other names: Diprivan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Propofol plasmatic levels | Measured by high pressure liquid chromatography | From start of infusion: 5 min, 15 min, 45 min; from bolus 0 min, 1 min, 3 min, 5 min, 10 min; after infusion 30 min, 60 min, 120 min, 360 min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics | Heart rate and arterial pressure | Entering operating room up to end of anesthesia | 
| Propofol total dose | Measured in milligrams | Start of propofol infusion until it ends | 
| Sevoflurane total dose |  | Start of inhalational induction to zero end tidal concentration | 
| Pulse oximetry |  | Entering operating room up to end of anesthesia | 
| BIS | Depth of anesthesia will be recorded with BIS monitor | Entering operating room up to end of anesthesia | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, pharmacodynamics, propofol, pediatrics