Pharmacokinetic/Pharmacodynamic Model of Propofol in Children

Anesthesia Clinical Trial

Official title:

Pharmacokinetic/Pharmacodynamic Model of Propofol in Children

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02544854
• Other study ID #: 15-068
• Status: Recruiting
• Phase: Phase 4
• First received: September 6, 2015
• Last updated: October 10, 2016
• Start date: September 2015
• Est. completion date: December 2016

Study information

• Verified date: October 2016
• Source: Pontificia Universidad Catolica de Chile
• Contact: Ricardo Fuentes, MD
• Phone: 56-9-77648344
• Email: rfuente[@]med.puc.cl
• Is FDA regulated: No
• Health authority: Chile: Comité de Ética Científico
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 2016
• Est. primary completion date: December 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 1 Year to 12 Years

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Anesthesia

Intervention

Drug:
• Propofol
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.

Locations

Country	Name	City	State
Chile	Division de Anestesia - Pontificia Universidad Catolica de Chile	Santiago	Region Metropolitana

Sponsors (1)

Lead Sponsor	Collaborator
Pontificia Universidad Catolica de Chile

Country where clinical trial is conducted

Chile, 

References & Publications (7)

Coppens MJ, Eleveld DJ, Proost JH, Marks LA, Van Bocxlaer JF, Vereecke H, Absalom AR, Struys MM. An evaluation of using population pharmacokinetic models to estimate pharmacodynamic parameters for propofol and bispectral index in children. Anesthesiology. 2011 Jul;115(1):83-93. doi: 10.1097/ALN.0b013e31821a8d80. — View Citation

Fuentes R, Cortínez I, Ibacache M, Concha M, Muñoz H. Propofol concentration to induce general anesthesia in children aged 3-11 years with the Kataria effect-site model. Paediatr Anaesth. 2015 Jun;25(6):554-9. doi: 10.1111/pan.12657. Epub 2015 Apr 16. — View Citation

Gibert S, Sabourdin N, Louvet N, Moutard ML, Piat V, Guye ML, Rigouzzo A, Constant I. Epileptogenic effect of sevoflurane: determination of the minimal alveolar concentration of sevoflurane associated with major epileptoid signs in children. Anesthesiology. 2012 Dec;117(6):1253-61. doi: 10.1097/ALN.0b013e318273e272. — View Citation

Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ. 2011 Jan 1;89(1):46-53. doi: 10.2471/BLT.10.080010. Epub 2010 Sep 10. Review. — View Citation

Kearns GL, Reed MD. Clinical pharmacokinetics in infants and children. A reappraisal. Clin Pharmacokinet. 1989;17 Suppl 1:29-67. Review. — View 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. — View Citation

Rigouzzo A, Servin F, Constant I. Pharmacokinetic-pharmacodynamic modeling of propofol in children. Anesthesiology. 2010 Aug;113(2):343-52. doi: 10.1097/ALN.0b013e3181e4f4ca. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Hemodynamics	Heart rate and arterial pressure	Entering operating room up to end of anesthesia	Yes
Secondary	Propofol total dose	Measured in milligrams	Start of propofol infusion until it ends	No
Secondary	Sevoflurane total dose		Start of inhalational induction to zero end tidal concentration	No
Secondary	Pulse oximetry		Entering operating room up to end of anesthesia	Yes
Secondary	BIS	Depth of anesthesia will be recorded with BIS monitor	Entering operating room up to end of anesthesia	Yes