DROPLET: Development of a Pharmacodynamic Model for Propofol in Older Adults

Sponsor

Pontificia Universidad Catolica de Chile (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05790720

Collaborator

(none)

Enrollment

Location

Arm

16.1

Anticipated Duration (Months)

3.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Aged	Drug: Propofol	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Pharmacokinetic-pharmacodynamic model that uses the pharmacokinetic parameters of the Eleveld model and new pharmacodynamic parameters derived from frontal EEG in a population older than 65 years.Pharmacokinetic-pharmacodynamic model that uses the pharmacokinetic parameters of the Eleveld model and new pharmacodynamic parameters derived from frontal EEG in a population older than 65 years.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

May 1, 2024

Anticipated Study Completion Date :

Sep 1, 2024

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures

Performance Error (PE) [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 (%).

Secondary Outcome Measures

Median Absolute Performance Error (MDAPE) [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 (%).
Median Prediction Error (MDPE) [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 (%).
Time of Loss of response (LOR) [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).
Time of Burst-suppression (BS) [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).
Time of Return of response (ROR). [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pontificia Universidad Católica de Chile	Santiago	Región Metropolitana	Chile	8330024

Sponsors and Collaborators

Pontificia Universidad Catolica de Chile

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Pontificia Universidad Catolica de Chile

ClinicalTrials.gov Identifier:

NCT05790720

Other Study ID Numbers:

230125002

First Posted:

Mar 30, 2023

Last Update Posted:

Mar 30, 2023

Last Verified:

Feb 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Keywords provided by Pontificia Universidad Catolica de Chile

Propofol

TCI

TIVA

Additional relevant MeSH terms:

Propofol

Study Results

No Results Posted as of Mar 30, 2023