Pharmacokinetic/Pharmacodynamic Model of Propofol in Children

NCT ID: NCT02544854

Last Updated: 2016-10-12

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-30
• Study Completion Date: 2016-12-31

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.

Conditions

Anesthesia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Blinding Strategy: NONE

Study Groups

Ages 1 year - 3 years 11 months

Propofol infusion, measuring of plasmatic levels of propofol through venous sampling

Group Type: EXPERIMENTAL

Propofol

Intervention Type: DRUG

Propofol infusion will be started after inhalational induction by manual infusion by the following scheme:

1. First 15 minutes: 15 mg/kg/min

2. 16 to 30 minutes: 13 mg/kg/min

3. 31 to 60 minutes: 11 mg/kg/min

4. 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:

1. 5, 15 and 25 minutes of starting infusion,

2. 1, 3, 5, 7, 9 and 12 minutes of bolus and,

3. 5, 25, 60 and 120 minutes of infusion ended.

Ages 4 years - 8 years 11 months

Propofol infusion, measuring of plasmatic levels of propofol through venous sampling

Group Type: EXPERIMENTAL

Propofol

Intervention Type: DRUG

Propofol infusion will be started after inhalational induction by manual infusion by the following scheme:

1. First 15 minutes: 15 mg/kg/min

2. 16 to 30 minutes: 13 mg/kg/min

3. 31 to 60 minutes: 11 mg/kg/min

4. 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:

1. 5, 15 and 25 minutes of starting infusion,

2. 1, 3, 5, 7, 9 and 12 minutes of bolus and,

3. 5, 25, 60 and 120 minutes of infusion ended.

Ages 9 years - 11 years 11 months

Propofol infusion, measuring of plasmatic levels of propofol through venous sampling

Group Type: EXPERIMENTAL

Propofol

Intervention Type: DRUG

Propofol infusion will be started after inhalational induction by manual infusion by the following scheme:

1. First 15 minutes: 15 mg/kg/min

2. 16 to 30 minutes: 13 mg/kg/min

3. 31 to 60 minutes: 11 mg/kg/min

4. 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:

1. 5, 15 and 25 minutes of starting infusion,

2. 1, 3, 5, 7, 9 and 12 minutes of bolus and,

3. 5, 25, 60 and 120 minutes of infusion ended.

Interventions

Propofol

Propofol infusion will be started after inhalational induction by manual infusion by the following scheme:

1. First 15 minutes: 15 mg/kg/min

2. 16 to 30 minutes: 13 mg/kg/min

3. 31 to 60 minutes: 11 mg/kg/min

4. 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:

1. 5, 15 and 25 minutes of starting infusion,

2. 1, 3, 5, 7, 9 and 12 minutes of bolus and,

3. 5, 25, 60 and 120 minutes of infusion ended.

Intervention Type: DRUG

Other Intervention Names

Diprivan

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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Pontificia Universidad Catolica de Chile

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ricardo Fuentes, MD

Role: PRINCIPAL_INVESTIGATOR

Professor

Rose M Heider, MD

Role: PRINCIPAL_INVESTIGATOR

Professor

Locations

Division de Anestesia - Pontificia Universidad Catolica de Chile

Santiago, Santiago Metropolitan, Chile

Site Status: RECRUITING

Countries

Chile

Central Contacts

Ricardo Fuentes, MD

Role: CONTACT

rfuente@med.puc.cl

56-9-77648344

Facility Contacts

Fernando R Altermatt, MSc

Role: primary

fernando.altermatt@gmail.com

56-2-23543270

Hernan E Auad, MD

Role: backup

hernan_auad@hotmail.com

56-2-23543270

References

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Reference Type: BACKGROUND

PMID: 23103557 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 2692939 (View on PubMed)

Fuentes R, Cortinez I, Ibacache M, Concha M, Munoz 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.

Reference Type: BACKGROUND

PMID: 25880448 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 20613468 (View on PubMed)

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Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

PMID: 21346890 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30307663 (View on PubMed)

Other Identifiers

15-068

Identifier Type: -

Identifier Source: org_study_id