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The Neural Mechanisms of Anesthesia and Human Consciousness (Part 6)

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ClinicalTrials.gov Identifier: NCT02624401
Recruitment Status : Completed
First Posted : December 8, 2015
Last Update Posted : March 27, 2017
Sponsor:
Collaborators:
University of California, Irvine
University of Michigan
Yale University
University of Helsinki
Information provided by (Responsible Party):
Harry Scheinin, University of Turku

Study Description
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Brief Summary:
Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and electroencephalography (EEG) studies will be carried out to reveal the neural correlates of consciousness. Consciousness of the subjects will be manipulated with anesthetic agents dexmedetomidine, propofol, S-ketamine and sevoflurane. One-hundred-and-sixty (160) healthy male subjects will be recruited to receive EC50 concentration of the anesthetic (40 dexmedetomidine, 40 propofol, 20 S-ketamine, 40 sevoflurane) or placebo (20) while being imaged for cerebral metabolic rate of glucose (CMRglu). Also genetic, immunological and metabolomics samples will be taken and analysed to find possible genetic factors explaining the variability in drug response and to find chemical fingerprints of acute drug effect.

Condition or disease Intervention/treatment Phase
Anesthesia Unconsciousness Drug: Dexmedetomidine Drug: Propofol Drug: S-ketamine Drug: Sevoflurane Drug: Placebo Phase 4

Detailed Description:
The explanation of consciousness poses one of the greatest challenges to science and philosophy in the 21st century. It remains unclear what consciousness is and how it emerges from brain activity. Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and electroencephalography (EEG) studies will be carried out to reveal the neural correlates of consciousness. Consciousness of the subjects will be manipulated with anesthetic agents dexmedetomidine acting through α2-agonism, with propofol and sevoflurane both mainly acting through the enhancement of gamma-aminobutyric acid (GABA) system, and with S-ketamine acting through N-methyl-D-aspartate (NMDA) receptor antagonism. One-hundred-and-sixty (160) healthy male subjects will be recruited to receive EC50 concentration of either dexmedetomidine, propofol, S-ketamine or sevoflurane, or placebo while being imaged for cerebral metabolic rate of glucose (CMRglu). 40 subjects will receive dexmedetomidine, 40 subjects propofol, 20 subjects S-ketamine, 40 subjects sevoflurane and 20 subjects will receive placebo. Also genetic, immunological and metabolomics samples will be taken and analysed to find possible genetic factors explaining the variability in drug response and to find possible immunological and chemical fingerprints of acute drug effect.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Neural Mechanisms of Anesthesia and Human Consciousness (Part 6)
Study Start Date : January 2016
Actual Primary Completion Date : March 13, 2017
Actual Study Completion Date : March 13, 2017
Arms and Interventions
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Arm Intervention/treatment
Experimental: Dexmedetomidine
Intravenous dexmedetomidine using target controlled infusion.
 Drug: Dexmedetomidine
Intravenous infusion
Other Name: Dexdor
Experimental: Propofol
Intravenous propofol using target controlled infusion.
 Drug: Propofol
Intravenous infusion
Other Name: Propofol-Lipuro
Experimental: S-ketamine
Intravenous S-ketamine using target controlled infusion.
 Drug: S-ketamine
Intravenous infusion
Other Name: Ketanest-S
Experimental: Sevoflurane
Inhalational sevoflurane using target controlled inhalation.
 Drug: Sevoflurane
Inhalation
Other Name: Sevorane
Placebo Comparator: Placebo
Intravenous saline.
 Drug: Placebo
Intravenous infusion of saline (Ringer's Acetate)


Outcome Measures
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Primary Outcome Measures :
  1. Regional cerebral metabolism of glucose [ Time Frame: 40 min ]
    Comparison of responsive and unresponsive subjects


Secondary Outcome Measures :
  1. EEG [ Time Frame: 1 hour ]
    64-channel EEG will be recorded and analyzed using time domain, spectral domain, functional connectivity, directed/effective connectivity and graph theoretical analysis methods.

  2. Immunological effects [ Time Frame: 2 hours ]
    Blood samples will be draw at baseline (without drug), at the end of study drug administration and after PET scanning for the measurement of approximately 50 cytokines, chemokines and growth factors.

  3. Metabolomic effects [ Time Frame: 2 hours ]
    Blood samples will be drawn at baseline (without drug), at the end of drug administration and after PET scanning for the measurement of more than 200 serum measures, including lipoprotein subclass distribution and lipoprotein particle concentration, low molecular weight metabolites, such as amino acids, 3-hydroxybutyrate and creatinine, and detailed molecular information on serum lipids, including free and esterified cholesterol, sphingomyelin and fatty acid saturation.

  4. Gene expression [ Time Frame: 2 hours ]
    Blood samples will be collected at baseline (without drug), at the end of drug administration and after PET scanning for the measurement of RNA expression using whole genome microarray-based, massively parallel sequencing or quantitative reverse-transcription polymerase chain reaction based methods.

  5. Psychological well-being [ Time Frame: 2 hours ]
    Psychological well-being and ill-being will be measured with a battery of scientifically validated scales just before initiating the study session and at the end of the study session.

  6. Dream report [ Time Frame: 1 hour ]
    After terminating PET imaging, a structured interview is immediately conducted to verify a recollection or absence of recollection of subjective experiences during possible loss of responsiveness.


Other Outcome Measures:
  1. Drug concentration in plasma or end-tidal [ Time Frame: 1 hour ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male
  2. Age 18-30 years
  3. Good general health i.e. American Society of Anesthesiologists (ASA) physical status I
  4. Fluent in Finnish language
  5. Right handedness
  6. Written informed consent
  7. Good sleep quality

Exclusion Criteria:

  1. Chronic medication
  2. History of alcohol and/or drug abuse
  3. Strong susceptibility for allergic reactions
  4. Serious nausea in connection with previous anesthesia
  5. Strong susceptibility for nausea
  6. Any use of drugs or alcohol during the 48 hours preceding anesthesia
  7. Use of caffeine products 10-12 hours prior the study
  8. Smoking
  9. Clinically significant previous cardiac arrhythmia / cardiac conduction impairment
  10. Clinically significant abnormality in prestudy laboratory tests
  11. Positive result in the drug screening test
  12. Blood donation within 90 days prior to the study
  13. Participation in any medical study with an experimental drug or device during the preceding 60 days
  14. The study subject has undergone a prior PET or SPECT study
  15. Any contraindication to magnetic resonance imaging (MRI)
  16. Hearing impairment
  17. Detected unsuitability based on MRI scanning results if available before the PET scanning
  18. Sleep disorder or severe sleep problem
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02624401


Locations
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Finland
Turku PET Centre
Turku, Finland, FI-20521
Sponsors and Collaborators
University of Turku
University of California, Irvine
University of Michigan
Yale University
University of Helsinki
Investigators
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Principal Investigator: Harry Scheinin, MD Turku PET Centre, University of Turku, Turku, Finland
More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Harry Scheinin, Adjunct Professor, University of Turku
ClinicalTrials.gov Identifier: NCT02624401    
Other Study ID Numbers: LOC-2016
First Posted: December 8, 2015    Key Record Dates
Last Update Posted: March 27, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Unconsciousness
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Dexmedetomidine
Ketamine
Propofol
Sevoflurane
Esketamine
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anesthetics, Intravenous
Anesthetics, General
 Anesthetics
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anesthetics, Dissociative
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Platelet Aggregation Inhibitors