Pharmacodynamic Interaction of REMI and DMED (PIRAD)

Pharmacodynamic Interactions Between Remifentanil and Dexmedetomidine (PIRAD)

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.

Study Overview

• Status: Completed
• Conditions: Anesthesia
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Remifentanil

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 Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713EZ
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine only; 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).	Drug: Dexmedetomidine; Single drug administration; Other Names: Dexdor
Experimental: Remifentanil only; 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).	Drug: Remifentanil; Single drug administration; Other Names: Ultiva
Experimental: Dexmedetomidine-Remifentanil interaction; 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.	Drug: Dexmedetomidine; Single drug administration; Other Names: Dexdor; Drug: Remifentanil; Single drug administration; Other Names: Ultiva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerance of Laryngoscopy (TOL)	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).	35 - 255 minutes

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: Michel MR Struys, Prof.Dr., University Medical Center Groningen

Publications and helpful links

General Publications

• Hannivoort LN, Eleveld DJ, Proost JH, Reyntjens KM, Absalom AR, Vereecke HE, Struys MM. Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers. Anesthesiology. 2015 Aug;123(2):357-67. doi: 10.1097/ALN.0000000000000740.
• Ramaswamy SM, Kuizenga MH, Weerink MAS, Vereecke HEM, Struys MMRF, Belur Nagaraj S. Frontal electroencephalogram based drug, sex, and age independent sedation level prediction using non-linear machine learning algorithms. J Clin Monit Comput. 2022 Feb;36(1):121-130. doi: 10.1007/s10877-020-00627-3. Epub 2020 Dec 14.
• Ramaswamy SM, Weerink MAS, Struys MMRF, Nagaraj SB. Dexmedetomidine-induced deep sedation mimics non-rapid eye movement stage 3 sleep: large-scale validation using machine learning. Sleep. 2021 Feb 12;44(2):zsaa167. doi: 10.1093/sleep/zsaa167.
• Belur Nagaraj S, Ramaswamy SM, Weerink MAS, Struys MMRF. Predicting Deep Hypnotic State From Sleep Brain Rhythms Using Deep Learning: A Data-Repurposing Approach. Anesth Analg. 2020 May;130(5):1211-1221. doi: 10.1213/ANE.0000000000004651.
• Ramaswamy SM, Kuizenga MH, Weerink MAS, Vereecke HEM, Struys MMRF, Nagaraj SB. Novel drug-independent sedation level estimation based on machine learning of quantitative frontal electroencephalogram features in healthy volunteers. Br J Anaesth. 2019 Oct;123(4):479-487. doi: 10.1016/j.bja.2019.06.004. Epub 2019 Jul 18.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2017
• Primary Completion (Actual): February 23, 2018
• Study Completion (Actual): February 23, 2018

Study Registration Dates

• First Submitted: March 14, 2017
• First Submitted That Met QC Criteria: May 3, 2017
• First Posted (Actual): May 8, 2017

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Remifentanil; Dexmedetomidine; Pharmacodynamics; Interaction
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Remifentanil; Dexmedetomidine
• Other Study ID Numbers: PIRAD-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Anonimous data might be shared with other research groups

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No