Pharmacodynamic Interaction of REMI and DMED

Phase 4

Completed

• Conditions: Anesthesia
• Interventions: Drug: Dexmedetomidine; Drug: Remifentanil

• Registration Number: NCT03143972
• Lead Sponsor: University Medical Center Groningen

Brief Summary

The objective is to map the pharmacokinetic / pharmacodynamic interaction between dexmedetomidine and remifentanil by observing changes in anesthetic depth. These changes will be related to drug concentrations using pharmacokinetic/pharmacodynamic (PKPD) modeling.

Detailed Description

This study is designed to investigate whether the use of a combination of dexmedetomidine and remifentanil is clinically useful to provide anesthesia during surgical and diagnostic procedures and whether it could be used for anesthetic induction. Furthermore the aim is to gain better insights in the required dosing regimens, the inter-individual variability in response towards the combination and the associated side effects. Better characterization of this drug-drug interaction will presumably lead to more precise dosing regimens, which in turn, will lead to a reduction in the occurrence of oversedation, side effects and recovery times.

The objective is to map the pharmacokinetic / pharmacodynamic interaction between dexmedetomidine and remifentanil by observing changes in anesthetic depth, measured by hypnotic and analgesic endpoints such as modified observer's assessment of alertness and sedation scale (MOAA/S), response to electrical stimuli, response to laryngoscopy and electroencephalogram (EEG) derived indices. These effects will be related to drug concentrations using pharmacokinetic/pharmacodynamic (PKPD) modeling.

Study Timeline

• Study First Submitted: 2017-03-14
• Study First Submitted QC: 2017-05-03
• Study First Posted: 2017-05-08
• Study Start: 2017-06-28
• Primary Completion: 2018-02-23
• Study Completion: 2018-02-23
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-16
• Last Update Posted: 2024-04-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• American Society of Anesthesiologists (ASA) Physical Status 1
• No medical history of significance
• No chronic use of medication, drugs, tobacco or more than 20 gr alcohol daily (oral contraceptives excluded).
• Concerning the cognitive function: Volunteers are considered to have sufficient cognitive reserve if they are able to read and comprehend the patient information form, if they can adequately answer the anamnestic questions during the screening process and if they are allowed to provide legitimate written informed consent.
• No selection will be made regarding ethnic background
• No exclusion criterium is present

Exclusion Criteria

• Known intolerance to dexmedetomidine or remifentanil
• Volunteer refusal
• Age < 18 years or >70 years
• Pregnancy, or currently nursing
• Hairstyle with dreadlocks (EEG-monitoring will not be possible)
• Body mass index (BMI) <18 or >30 kg/m2.
• Neurological disorder (epilepsy, the presence of a brain tumor, a history of brain surgery, hydrocephalic disorders, depression needing treatment with anti-depressive drugs, a history of brain trauma, a subarachnoidal bleeding, TIA or cerebral infarct, psychosis or dementia , schizophrenia, alcohol or drug abuse).
• Diseases involving the cardiovascular system (hypertension, coronary artery disease, prior acute myocardial infarction, any valvular and/or myocardial disease involving

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Dexmedetomidine-Remifentanil interaction	Dexmedetomidine	A fixed background dose of dexmedetomidine will be given, this will be calculated after the first 5 subjects completed the dexmedetomidine only session. It will be set to 50% of the observed mean EC50TOL (Tolerance of Laryngoscopy). Remifentanil infusion will be administered by effect site TCI with stepwise increasing targets of 0.5 - 1.0 - 1.5 - 2.0 - 2.5 - 3.0 - 4.0 ng/ml, each lasting for 15 minutes.
Dexmedetomidine only	Dexmedetomidine	Dexmedetomidine will be administered by effect-site TCI according to the Hannivoort model extended with an effect-site rate constant of 0.0428min-1. A stepwise increasing dosing regimen will be given, with concentrations targeting an effect site concentration of 1 ng/ml (40 min), 3 ng/ml (50 min), 4 ng/ml (40 min), 5 ng/ml (40 min) and 8 ng/ml (70 min).
Remifentanil only	Remifentanil	Remifentanil will be administered by effect-site TCI according to the Eleveld model. A stepwise increasing dosing regimen will be given, with concentrations targeting an effect site concentration of 1 ng/ml (12 min), 2 ng/ml (12 min), 3 ng/ml (12 min), 5 ng/ml (12 min) and 7 ng/ml (12 min).
Dexmedetomidine-Remifentanil interaction	Remifentanil	A fixed background dose of dexmedetomidine will be given, this will be calculated after the first 5 subjects completed the dexmedetomidine only session. It will be set to 50% of the observed mean EC50TOL (Tolerance of Laryngoscopy). Remifentanil infusion will be administered by effect site TCI with stepwise increasing targets of 0.5 - 1.0 - 1.5 - 2.0 - 2.5 - 3.0 - 4.0 ng/ml, each lasting for 15 minutes.

Primary Outcome Measures

Name	Time	Method
Tolerance of Laryngoscopy (TOL)	35 - 255 minutes	Tolerance of a laryngoscopy (yes/no) will be tested at the end of each infusion step during both studydays, when MOAA/s is 0 / 1 and will be related to the drug concentration(s).

Secondary Outcome Measures

Name	Time	Method
Electroencephalogram (EEG)	During anesthesia sessions day 1 and day 2	A multichannel electroencephalogram will be recorded
Modified observer's assessment of alertness and sedation scale (MOAA/s)	During anesthesia sessions day 1 and day 2	An hypnotic endpoint measuring depth of anesthesia.
Electrical stimulus	During anesthesia sessions day 1 and day 2	Measuring analgesia by observing response to a standardized electrical stimulus

Trial Locations

Locations (1)

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands