Effects of Two Different Sedation Regimes on Auditory Evoked Potentials and Electroencephalogram (EEG)

Study Overview
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Brief Summary
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Sedation may be necessary in intensive care to facilitate diverse therapeutic interventions, but the use of sedative drugs may increase the risk of delirium and long-term cognitive impairment. Thus the implementation and monitoring of sedation remains difficult despite the use of sedation protocols and clinical sedation scores. Attempts to improve sedation monitoring through the use of the electroencephalogram(EEG) have been disappointing. Derived variables based on the unstimulated EEG fail to predict the response to external stimuli at the clinically most relevant light-to-moderate sedation levels, and the overlap between moderate and deep sedation levels is wide. We have demonstrated that long-latency auditory evoked potentials (ERPs)can be used to avoid deep levels of sedation in healthy volunteers during propofol sedation, independent of the concomitant administration of remifentanil. This approach has a potential clinical application for improved monitoring of sedation. Since the effects of different sedative drugs on the EEG may vary widely, the use of ERPs to monitor sedation needs to be evaluated with different sedative drugs. Therefore we will administer two widely used drug combinations (dexmedetomidine/remifentanil and midazolam/remifentanil) in healthy volunteers and record ERPS and processed EEG during clinical relevant sedation levels

Detailed Description
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Sedation may be necessary in intensive care to facilitate diverse therapeutic interventions, but the use of sedative drugs may increase the risk of delirium and long-term cognitive impairment. Thus the implementation and monitoring of sedation remains difficult despite the use of sedation protocols and clinical sedation scores. Attempts to improve sedation monitoring through the use of the electroencephalogram (EEG) have been disappointing. Derived variables based on the unstimulated EEG fail to predict the response to external stimuli at the clinically most relevant light-to-moderate sedation levels, and the overlap between moderate and deep sedation levels is wide. We have demonstrated that long-latency auditory evoked potentials (ERPs)can be used to avoid deep levels of sedation in healthy volunteers during propofol sedation, independent of the concomitant administration of remifentanil. This approach has a potential clinical application for improved monitoring of sedation. Since the effects of different sedative drugs on the EEG may vary widely, the use of ERPs to monitor sedation needs to be evaluated with different sedative drugs. The alpha-2 agonist dexmedetomidine (dex) has been approved for short-term sedation in surgical intensive care unit (ICU) patients. Preliminary data suggest that the risk of delirium may be substantially reduced when dexmedetomidine is used to produce sedation. Since dexmedetomidine acts via different receptors and brain areas than do benzodiazepines and propofol, its impact on the brain electrophysiology may also be different. The assessment of dexmedetomidine's effects on the EEG and ERPs at various sedation levels has been limited in humans. We hypothesized that the combinations DEXMEDETOMIDINE/REMIFANTANIL (dex/remi) and MIDAZOLAM/REMIFENTANIL (mida/remi) would induce the same changes in EEG and long-latency ERPs during light-to-moderate levels of sedation in healthy subjects, despite the different quality of sedation that they provide. The opioid remifentanil was added because virtually all patients in the ICU have some level of pain and receive an opioid analgesic in combination with a sedative. 10 healthy subjects were assessed with both drug combinations (dex/remi and mida/remi), at least 7 days apart. The sequence of the drug combinations were randomized.

Official Title
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The Effects of Dexmedetomidine/Remifentanil and Midazolam/Remifentanil on Auditory-evoked Potentials and Electroencephalogram at Light-to-moderate Sedation Levels in Healthy Subjects

Conditions
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Conscious Sedation, Deep Sedation, Critical Care

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Midazolam
* Drug: Remifentanil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 years and older healthy Exclusion Criteria: History of problems during anesthesia Impairment of the auditory system

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dex/Remi followed by Mida/Remi<br>Sedation with dexmedetomidine and remifentanil followed by sedation with midazolam and remifentanil separated by one week | Drug: Dexmedetomidine<br>* Infusion of dexmedetomidine<br>Drug: Midazolam<br>* Midazolam infusion<br>Drug: Remifentanil<br>* Infusion of remifentanil<br>|
| Active Comparator: Mida/Remi followed by Dexa/Remi<br>Sedation with midazolam and remifentanil followed by sedation with dexmedetomidine and remifentanil separated by one week | Drug: Dexmedetomidine<br>* Infusion of dexmedetomidine<br>Drug: Midazolam<br>* Midazolam infusion<br>Drug: Remifentanil<br>* Infusion of remifentanil<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amplitudes (in Micro Volts) of Acoustic Event Related Potentials (Time-locked Amplitudes in the Electroencephalogram 100 Milliseconds After the Acoustic Stimulus, Averaged Over 40 Stimuli)Awake and at 3 Different Drug-induced Sedation Levels | Event Related Potentials (time-locked amplitudes in the electroencephalogram 100 milliseconds after the acoustic stimulus, averaged over 40 stimuli) Sedation levels were graded with the Ramsay scale (RS), where the responses of patients to standardized increasing stimuli (voice, then prodding, the pain stimulus) are graded. The higher the number, the deeper is the sedation. RS 6 means no response at all (= anesthesia) | awake + 3 sedation levels (RS2/3/4) (20 minutes each) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BIS-Index Awake and 3 Sedation Levels (RS 2/3/4) | BIS-Index is a dimensionless value ranging from 0-100, indicating fully awake at 100 and a flat-line electroencephalogram at 0. Standard anesthesia creates a BIS-Index range 40-60. The scale is ordinal, not interval. BIS Index is calculated from the EEG by a proprietary algorithm (Aspect Medical Inc.) | awake and 3 sedation levels (RS 2/3/4) 20 min each | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dexmedetomidine, midazolam, remifentanil, Electroencephalography, Event related potentials, BIS, Bispectral Index, Response Entropy, State Entropy