Remifentanil Effect-site Prediction by Algometry

Remifentanil Pharmacodynamics During Conscious Sedation From the Algometry Perspective. An Essential Standpoint to be Considered in Opioids Time-course Modelling Validation

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.

Study Overview

• Status: Completed
• Conditions: Conscious Sedation Failure During Procedure
• Intervention / Treatment: Drug: Remifentanil 1 MG Injection [Ultiva]; Device: Algometry; Drug: Midazolam 1 MG/ML Prefilled Syringe; Drug: Saline solution

Detailed Description

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 (Actual): 100

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Ana Abad-Torrent

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

We enrolled 100 female patients scheduled for benign gynaecological surgery. A group of 35 patients received a constant TCI effect-site target infusion of 1.5 ng/ml of remifentanil for 25 min. The second group of 35 followed the same protocol with a bolus of 1 mg of midazolam previous to the remifentanil infusion to evaluate potential anxiolysis effects. The rest configured to the control group.

Algometry was used to quantify pressure pain thresholds regarding basal measurements at time-points of 1.5, 5, 10, 15, 18, 20, and 25 min after induction began beside the blood pressure and heart rate.

Description

Inclusion Criteria:

• Female patients scheduled for benign gynaecological surgery
• 18-80 years old
• ASA I-III

Exclusion Criteria:

• Morbid obesity
• Conduct disorder or anxiety-depressive syndrome
• Chronic treatment with psychotropic drugs or opiates
• Pregnancy
• Alcohol abuse
• Documented allergy to remifentanil or midazolam
• Refusal to participate in the study

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group I TCI effect-site target infusion of 1.5 ng/ml of remifentanil; Group I of 35 patients received a constant TCI effect-site target infusion of 1.5 ng/ml of remifentanil for 25 min.	Drug: Remifentanil 1 MG Injection [Ultiva]; Group I TCI effect-site target infusion of 1.5 ng/ml of remifentanil.; Other Names: Opioid; Device: Algometry; The algometry technique is used to assess the pain pressure threshold as an analgesic effect of remifentanil concerning Minto's model prediction.; Other Names: Somedic Type II®, Sweden
Group II TCI effect-site target infusion of 1.5 ng/ml of remifentanil + 1 mg Midazolam iv; Group II of 35 patients received a constant TCI effect-site target infusion of 1.5 ng/ml of remifentanil for 25 min with a bolus of 1 mg of midazolam previous to the remifentanil infusion	Drug: Remifentanil 1 MG Injection [Ultiva]; Group I TCI effect-site target infusion of 1.5 ng/ml of remifentanil.; Other Names: Opioid; Device: Algometry; The algometry technique is used to assess the pain pressure threshold as an analgesic effect of remifentanil concerning Minto's model prediction.; Other Names: Somedic Type II®, Sweden; Drug: Midazolam 1 MG/ML Prefilled Syringe; Group II TCI effect-site target infusion of 1.5 ng/ml of remifentanil + 1 mg Midazolam iv; Other Names: Benzodiazepine
Group III Control; Group III of 30 patients. The same TCI system provided the saline solution in the control group under an equivalent simulation profile to the remifentanil administration	Device: Algometry; The algometry technique is used to assess the pain pressure threshold as an analgesic effect of remifentanil concerning Minto's model prediction.; Other Names: Somedic Type II®, Sweden; Drug: Saline solution; Group III Control; Other Names: 0.9% Sodium Chloride Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pressure pain threshold (PPT) Baseline	Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry before starting the administration of remifentanil.	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.	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.	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.	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.	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.	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.	20 minutes
Pressure pain threshold (PPT) 25 minutes	Measurement of pressure pain threshold (0 - 1.000 kPa) by algometry 25 minutes after starting the administration of remifentanil.	25 minutes
Infusion rate	Remifentanil infusion rate (ml/h) administered during the experiment to the patient provided by the TCI system.	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.	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.	Continous measurements every 1 second for the whole experiment of 25 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Single annotation.
Mean arterial pressure (MAP) Baseline	Baseline mean arterial pressure (mmHg) from standard hemodynamic monitor.	Baseline
Mean arterial pressure (MAP) 1.5 min	Measurement of mean arterial pressure (mmHg) 1.5 minutes after starting the administration of remifentanil.	1.5 minutes
Mean arterial pressure (MAP) 5 min	Measurement of mean arterial pressure (mmHg) 5 minutes after starting the administration of remifentanil.	5 minutes
Mean arterial pressure (MAP) 10 min	Measurement of mean arterial pressure (mmHg) 10 minutes after starting the administration of remifentanil.	10 minutes
Mean arterial pressure (MAP) 15 min	Measurement of mean arterial pressure (mmHg) 15 minutes after starting the administration of remifentanil.	15 minutes
Mean arterial pressure (MAP) 18 min	Measurement of mean arterial pressure (mmHg) 18 minutes after starting the administration of remifentanil.	18 minutes
Mean arterial pressure (MAP) 20 min	Measurement of mean arterial pressure (mmHg) 20 minutes after starting the administration of remifentanil.	20 minutes
Mean arterial pressure (MAP) 25 min	Measurement of mean arterial pressure (mmHg) 25 minutes after starting the administration of remifentanil.	25 minutes
Heart Rate (HR) Baseline	Baseline measurement of heart rate (beats/min)	Baseline
Heart Rate (HR) 1.5 min	Measurement of heart rate (beats/min) 1.5 minutes after starting the administration of remifentanil.	1.5 minutes
Heart Rate (HR) 5 min	Measurement of heart rate (beats/min) 5 minutes after starting the administration of remifentanil.	5 minutes
Heart Rate (HR) 10 min	Measurement of heart rate (beats/min) 10 minutes after starting the administration of remifentanil.	10 minutes
Heart Rate (HR) 15 min	Measurement of heart rate (beats/min) 15 minutes after starting the administration of remifentanil.	15 minutes
Heart Rate (HR) 18 min	Measurement of heart rate (beats/min) 18 minutes after starting the administration of remifentanil.	18 minutes
Heart Rate (HR) 20 min	Measurement of heart rate (beats/min) 20 minutes after starting the administration of remifentanil.	20 minutes
Bispectrum (BIS) Baseline	Baseline measurement of EEG Bispectral index (adimensional index from 0- to 100).	Baseline
Bispectrum (BIS) 1.5 minutes	EEG Bispectral index (adimensional index from 0- to 100) 1.5 minutes after starting the administration of remifentanil.	1.5 minutes
Bispectrum (BIS) 5 minutes	EEG Bispectral index (adimensional index from 0- to 100) 5 minutes after starting the administration of remifentanil.	5 minutes
Bispectrum (BIS) 10 minutes	EEG Bispectral index (adimensional index from 0- to 100) 10 minutes after starting the administration of remifentanil.	10 minutes
Bispectrum (BIS) 15 minutes	EEG Bispectral index (adimensional index from 0- to 100) 15 minutes after starting the administration of remifentanil.	15 minutes
Bispectrum (BIS) 20 minutes	EEG Bispectral index (adimensional index from 0- to 100) 20 minutes after starting the administration of remifentanil.	20 minutes
Bispectrum (BIS) 25 minutes	EEG Bispectral index (adimensional index from 0- to 100) 25 minutes after starting the administration of remifentanil.	25 minutes

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Investigators: Principal Investigator: Ana Abad-Torrent, M.D, University Vall d'Hebron Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): May 15, 2020
• Study Completion (Actual): September 30, 2020

Study Registration Dates

• First Submitted: September 15, 2021
• First Submitted That Met QC Criteria: November 1, 2021
• First Posted (Actual): November 10, 2021

Study Record Updates

• Last Update Posted (Actual): November 10, 2021
• Last Update Submitted That Met QC Criteria: November 1, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Remifentanil; Pharmacodynamics; Conscious Sedation; Algometry; TCI Infusion system
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Remifentanil; Midazolam
• Other Study ID Numbers: EPA (AG) 33/2017 (5097)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No