Development of a Pharmacodynamic Model for Propofol in Older Adults

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Aged

Intervention / Treatment
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* Drug: Propofol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Performance Error (PE) | 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) | 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) | 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) | 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) | 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). | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Propofol, TCI, TIVA