Development of a Pharmacodynamic Model for Propofol in Older Adults (DROPLET)

November 20, 2023 updated by: Pontificia Universidad Catolica de Chile

Development of a Pharmacodynamic Model for Propofol in Older Adults (Development phaRmacodynamic mOdel Propofol oLdEr adulTs: DROPLET)

The goal of this pharmacodynamic study is to develop a model for Propofol administration for older adults (>65 years). The main objective is to create a model based on a new pharmacodynamic parameter, derived from frontal electroencephalogram (EEG), to admininster Propofol in older adults. With this new model, the investigators aim to:

  • Evaluate the relationship between the plasmatic concentration, described by the Eleveld pharmacokinetic model, versus the effect of the drug represented with a new parameter derived from the intraoperative frontal EEG.
  • To validate the predictive ability of Eleveld's pharmacokinetic-pharmacodynamic model, based on the bispectral index (BIS), compared to the new model based on a parameter derived from intraoperative frontal EEG.

Participants will be asked to answer preoperative questionnaires, receive a Propofol intravenous infusion concomitantly with continuous BIS and EEG monitoring, and to be evaluated for clinical sings of loss and return of consciousness.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

The administration of intravenous anesthetics in the elderly population requires adequate titration to avoid deleterious effects derived from overdosing or underdosing. Older patients show greater sensitivity to similar doses of propofol compared to younger patients. In addition, there is extensive interindividual variability among older patients, which would also explain the different responses to the same dose of drugs. This variability would be secondary to differences in comorbidities and physiological age, in contrast to chronological age, which would not explain the differences found in response to anesthetics in these patients.

One way in which an attempt has been made to make the doses of anesthetics in different patients comparable is the use of models that predict what infusion rate is required to maintain a given concentration at the site of drug action. The relationship between a propofol effect site concentration (Ce) with a given effect can be represented by pharmacodynamic (PD) models. Recently, Eleveld et al. created a pharmacokinetic-pharmacodynamic (PKPD) model for the administration of intravenous propofol in a population of wide ages, including neonates to older patients. However, the pharmacodynamic parameter used in this model was the BIS index, which has been questioned for its use in older adults. In addition, the creation of this PD model only included 3 patients older than 70 years, so the underrepresentation of this age group in the construction of the model could affect its performance, making it even more difficult to correctly predict the effect in this population.

Anesthetic drugs exert their desired hypnotic effect on the brain. Brain electrical activity can be monitored non-invasively by recording electrical potential on the cranial surface using electrodes. The electroencephalographic (EEG) changes observed with the administration of anesthetics are usually systematic across different patients. These have been described and have been used to identify different phases of anesthetic "depth" or hypnosis. In addition, the representation of the EEG signal by means of a spectrogram has facilitated the incorporation of this information into commercial EEG monitors that previously only included highly processed indices such as the BIS.

Within the EEG patterns of the spectrogram described for anesthetic maintenance with propofol, the alpha (8-12 Hz) and delta (1-4 Hz) oscillations stand out. However, the power of alpha oscillations decreases with age and with other changes that are associated with age, such as decreased cognitive ability, increased comorbidities and brain vulnerability. Therefore, guiding our administration of propofol based on obtaining a pattern of alpha predominance appears to be difficult in this aged population.

The general objective of this work is to build a PKPD model that uses the pharmacokinetic parameters of the Eleveld model and new pharmacodynamic parameters derived from the frontal EEG in a population older than 65 years. Our hypothesis is that the Eleveld PKPD model, modified with this new pharmacodynamic parameter, will predict better the hypnotic effect of propofol than the original Eleveld PKPD model, in adult patients older than 65 years.

The creation of a PKPD model of propofol for the population over 65 years of age would allow a better titration of this drug to avoid possible deleterious effects secondary to its under or overdosage.

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Chile
    • Región Metropolitana
      • Santiago, Región Metropolitana, Chile, 8330024
        • Pontificia Universidad Catolica de Chile
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

65 years to 99 years (Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients undergoing non-cardiac elective surgery requiring general anesthesia
  • American Society of Anesthesiologists Physical Status I to III

Exclusion Criteria:

  • Patients undergoing emergency surgery
  • Neurosurgical patients
  • History of alcohol abuse or recreational drug use
  • Known allergie to Propofol
  • Body mass index ≥ 35 Kg m-2
  • Unstable heart failure

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention
Patients older than 65 years of age will receive an intravenous infusion of Propofol with prespecified plasma targets. During its administration, registration of BIS values, frontal electroencephalography, and clinical signs of consciousness will be performed. Two models will be created and compared retrospectively: BIS (Eleveld Validation) and EEG Frontal Marker (New model).
Drug: Propofol
Patients older than 65 years of age will receive an intravenous infusion of Propofol with prespecified plasma targets. During its administration, registration of BIS values, frontal electroencephalography, and clinical signs of consciousness will be performed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Performance Error (PE)
Time Frame: Intravenous infusion start to one minute after start of burst suppression in EEG
Difference between the measured (according to Eleveld) and predicted concentrations, divided by the predicted concentration. Multiplied by 100. Unit of measure: percentage (%).
Intravenous infusion start to one minute after start of burst suppression in EEG

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Median Absolute Performance Error (MDAPE)
Time Frame: Intravenous infusion start to one minute after start of burst suppression in EEG
Median Absolute Performance Error (MDAPE) is the median PE and is a measure of how close the predicted concentration is to the measured concentration (Accuracy). Unit of measure: percentage (%).
Intravenous infusion start to one minute after start of burst suppression in EEG
Median Prediction Error (MDPE)
Time Frame: Intravenous infusion start to one minute after start of burst suppression in EEG
Median Prediction Error (MDPE) is a measure of the overall bias of the predictions; it indicates whether the model systematically overshoots or undershoots the target. Unit of measure: percentage (%).
Intravenous infusion start to one minute after start of burst suppression in EEG
Time of Loss of response (LOR)
Time Frame: Intravenous infusion start to one minute after start of burst suppression in EEG
Loss of response (LOR) is defined as the time when patients stop responding to verbal commands, light tactile stimulation, and the eyelid reflex. Unit of measure: time (seconds).
Intravenous infusion start to one minute after start of burst suppression in EEG
Time of Burst-suppression (BS)
Time Frame: Intravenous infusion start to one minute after start of burst suppression in EEG
Burst-suppression (BS) consists of alternating episodes of isoelectric flat EEG periods with bursts of slow waves, including systemic and quasiperiodic variation where high voltage and isoelectric periods have variations between and within bursts. Unit of measure: time (seconds).
Intravenous infusion start to one minute after start of burst suppression in EEG
Time of Return of response (ROR).
Time Frame: Intravenous infusion start to one minute after start of burst suppression in EEG
Return of response (ROR) is defined as the response to verbal stimulation and mild tactile stimulation. Unit of measure: time (seconds).
Intravenous infusion start to one minute after start of burst suppression in EEG

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Pontificia Universidad Catolica de Chile

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 1, 2023

Primary Completion (Estimated)

May 1, 2024

Study Completion (Estimated)

September 1, 2024

Study Registration Dates

First Submitted

March 2, 2023

First Submitted That Met QC Criteria

March 16, 2023

First Posted (Actual)

March 30, 2023

Study Record Updates

Last Update Posted (Estimated)

November 21, 2023

Last Update Submitted That Met QC Criteria

November 20, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 230125002

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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