This study validates the pharmacodynamic analgesic predictions (effect) given by Minto's remifentanil pharmacokinetic and dynamic model in conscious sedation. This standard model is based on the electroencephalogram (EEG) changes induced by this opioid as a proxy for describing the remifentanil analgesic effect, which might be only valid for high concentrations. Validation of the standard remifentanil model for low concentrations under sedation is needed for safer remifentanil administration.
According to pharmacokinetic and-dynamic (PK/PD) models, the proper use of anesthetics depends on the effect-sites mechanisms and the time-courses of action. This aspect is crucial for the practitioners to target the desired effect-site concentrations of the drugs (drug concentration at brain) by optimizing the drug administration using target control infusion (TCI) systems operating under these model predictions. For more than two decades, the pharmacodynamic properties of remifentanil relied on Minto's model, which is based on processed EEG as the reference to quantify the analgesic effect and effect-site concentration estimate. This remifentanil pharmacodynamic was modeled under conditions administered to volunteers rapidly and at very high doses to induce substantial changes in the spontaneous processed EEG. The experimental concentrations and infusion rates are far from sedative levels, where the EEG has shown a clear response to hypnosis but not to analgesia or nociception. Under the hypothesis that pharmacological models should predict equally well the effects induced by drugs at different concentrations levels, the purpose of this study is to evaluate and validate the pharmacodynamic predictions given by Minto's model in patients under conscious sedation using the algometry as a reference of nociception. The study recruits 100 female patients scheduled for benign gynecological surgery divided into three groups. A group of 35 patients receives a constant TCI effect-site target infusion of 1.5 ng/ml of remifentanil for 25 min. The second group of 35 follow the same protocol with a bolus of 1 mg of midazolam before the remifentanil infusion. The rest configures the control group under saline solution. Experimental data consist of basal algometry (pressure pain threshold) aside from BIS index, blood pressure, and heart rate values and at time-points of 1.5, 5, 10, 15, 18, 20, and 25 minutes after induction. Minto's remifentanil pharmacodynamic model validation relies on comparing the levels and temporal evolution of the algometry measurements during the whole experiment concerning the effect-site estimations provided by the TCI-pump Minto's model.
Study Type
OBSERVATIONAL
Enrollment
100
Group I TCI effect-site target infusion of 1.5 ng/ml of remifentanil.
Group II TCI effect-site target infusion of 1.5 ng/ml of remifentanil + 1 mg Midazolam iv
Group III Control
Ana Abad-Torrent
Barcelona, Spain
Pressure pain threshold (PPT) Baseline
Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry before starting the administration of remifentanil.
Time frame: Baseline
Pressure pain threshold (PPT) 1.5 minutes
Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry 1.5 minutes after starting the administration of remifentanil.
Time frame: 1.5 minutes
Pressure pain threshold (PPT) 5 minutes
Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry 5 minutes after starting the administration of remifentanil.
Time frame: 5 minutes
Pressure pain threshold (PPT) 10 minutes
Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry 10 minutes after starting the administration of remifentanil.
Time frame: 10 minutes
Pressure pain threshold (PPT) 15 minutes
Measurement of pressure pain threshold(0 - 1.000 kPa) by algometry 15 minutes after starting the administration of remifentanil.
Time frame: 15 minutes
Pressure pain threshold (PPT) 18 minutes
Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry 18 minutes after starting the administration of remifentanil.
Time frame: 18 minutes
Pressure pain threshold (PPT) 20 minutes
Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry 20 minutes after starting the administration of remifentanil.
Time frame: 20 minutes
Pressure pain threshold (PPT) 25 minutes
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The algometry technique is used to assess the pain pressure threshold as an analgesic effect of remifentanil concerning Minto's model prediction.
Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry 25 minutes after starting the administration of remifentanil.
Time frame: 25 minutes
Infusion rate
Remifentanil infusion rate (ml/h) administered during the experiment to the patient provided by the TCI system.
Time frame: Continous measurements every 1 second for the whole experiment of 25 minutes
Remifentanil Plasma Concentration (Cp)
Patient's remifentanil plasma concentration (ng/ml) evolution during the experiment given by Minto's model implemented in the TCI system.
Time frame: Continous measurements every 1 second for the whole experiment of 25 minutes
Remifentanil Effect Concentration (Ce)
Patient's remifentanil effect concentration (ng/ml) evolution during the experiment given by Minto's model implemented in the TCI system.
Time frame: Continous measurements every 1 second for the whole experiment of 25 minutes
Age
Apart from standard anthropometric data (Weight, Height, etc), age is of significant relevance for evaluating the possible effect of age on the pharmacodynamic properties of remifentanil and the algometry.
Time frame: Single annotation.
Mean arterial pressure (MAP) Baseline
Baseline mean arterial pressure (mmHg) from standard hemodynamic monitor.
Time frame: Baseline
Mean arterial pressure (MAP) 1.5 min
Measurement of mean arterial pressure (mmHg) 1.5 minutes after starting the administration of remifentanil.
Time frame: 1.5 minutes
Mean arterial pressure (MAP) 5 min
Measurement of mean arterial pressure (mmHg) 5 minutes after starting the administration of remifentanil.
Time frame: 5 minutes
Mean arterial pressure (MAP) 10 min
Measurement of mean arterial pressure (mmHg) 10 minutes after starting the administration of remifentanil.
Time frame: 10 minutes
Mean arterial pressure (MAP) 15 min
Measurement of mean arterial pressure (mmHg) 15 minutes after starting the administration of remifentanil.
Time frame: 15 minutes
Mean arterial pressure (MAP) 18 min
Measurement of mean arterial pressure (mmHg) 18 minutes after starting the administration of remifentanil.
Time frame: 18 minutes
Mean arterial pressure (MAP) 20 min
Measurement of mean arterial pressure (mmHg) 20 minutes after starting the administration of remifentanil.
Time frame: 20 minutes
Mean arterial pressure (MAP) 25 min
Measurement of mean arterial pressure (mmHg) 25 minutes after starting the administration of remifentanil.
Time frame: 25 minutes
Heart Rate (HR) Baseline
Baseline measurement of heart rate (beats/min)
Time frame: Baseline
Heart Rate (HR) 1.5 min
Measurement of heart rate (beats/min) 1.5 minutes after starting the administration of remifentanil.
Time frame: 1.5 minutes
Heart Rate (HR) 5 min
Measurement of heart rate (beats/min) 5 minutes after starting the administration of remifentanil.
Time frame: 5 minutes
Heart Rate (HR) 10 min
Measurement of heart rate (beats/min) 10 minutes after starting the administration of remifentanil.
Time frame: 10 minutes
Heart Rate (HR) 15 min
Measurement of heart rate (beats/min) 15 minutes after starting the administration of remifentanil.
Time frame: 15 minutes
Heart Rate (HR) 18 min
Measurement of heart rate (beats/min) 18 minutes after starting the administration of remifentanil.
Time frame: 18 minutes
Heart Rate (HR) 20 min
Measurement of heart rate (beats/min) 20 minutes after starting the administration of remifentanil.
Time frame: 20 minutes
Bispectrum (BIS) Baseline
Baseline measurement of EEG Bispectral index (adimensional index from 0- to 100).
Time frame: Baseline
Bispectrum (BIS) 1.5 minutes
EEG Bispectral index (adimensional index from 0- to 100) 1.5 minutes after starting the administration of remifentanil.
Time frame: 1.5 minutes
Bispectrum (BIS) 5 minutes
EEG Bispectral index (adimensional index from 0- to 100) 5 minutes after starting the administration of remifentanil.
Time frame: 5 minutes
Bispectrum (BIS) 10 minutes
EEG Bispectral index (adimensional index from 0- to 100) 10 minutes after starting the administration of remifentanil.
Time frame: 10 minutes
Bispectrum (BIS) 15 minutes
EEG Bispectral index (adimensional index from 0- to 100) 15 minutes after starting the administration of remifentanil.
Time frame: 15 minutes
Bispectrum (BIS) 20 minutes
EEG Bispectral index (adimensional index from 0- to 100) 20 minutes after starting the administration of remifentanil.
Time frame: 20 minutes
Bispectrum (BIS) 25 minutes
EEG Bispectral index (adimensional index from 0- to 100) 25 minutes after starting the administration of remifentanil.
Time frame: 25 minutes