Clinical trial NCT02544854: Pharmacokinetic/Pharmacodynamic Model of Propofol in Children
Official title: Pharmacokinetic/Pharmacodynamic Model of Propofol in Children
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Anesthesia
Keywords: Pharmacokinetics, pharmacodynamics, propofol, pediatrics
Lead sponsor: Pontificia Universidad Catolica de Chile
Sponsor class: OTHER
First posted: 2015-09-09
Enrollment: 40
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Propofol plasmatic levels
timeFrame: 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 outcomes:
measure: Hemodynamics
timeFrame: Entering operating room up to end of anesthesia
measure: Propofol total dose
timeFrame: Start of propofol infusion until it ends
measure: Sevoflurane total dose
timeFrame: Start of inhalational induction to zero end tidal concentration
measure: Pulse oximetry
timeFrame: Entering operating room up to end of anesthesia
measure: BIS
timeFrame: Entering operating room up to end of anesthesia
Other outcomes:
Locations:
city: Santiago
country: Chile
facility: Division de Anestesia - Pontificia Universidad Catolica de Chile
state: Region Metropolitana
Study officials:
affiliation: Professor
name: Ricardo Fuentes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Professor
name: Rose M Heider, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Panchatsharam S, Callaghan M, Day R, Sury MR. Measured versus predicted blood propofol concentrations in children during scoliosis surgery. Anesth Analg. 2014 Nov;119(5):1150-7. doi: 10.1213/ANE.0000000000000413.
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citation: Fuentes R, Cortinez LI, Contreras V, Ibacache M, Anderson BJ. Propofol pharmacokinetic and pharmacodynamic profile and its electroencephalographic interaction with remifentanil in children. Paediatr Anaesth. 2018 Dec;28(12):1078-1086. doi: 10.1111/pan.13486. Epub 2018 Oct 11.