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

Sponsor

University of Turku (Other)

Overall Status

Completed

CT.gov ID

NCT02624401

Collaborator

University of California, Irvine (Other), University of Michigan (Other), Yale University (Other), University of Helsinki (Other)

160

Enrollment

Location

Arms

14.4

Duration (Months)

11.1

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

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 :

Jan 1, 2016

Actual Primary Completion Date :

Mar 13, 2017

Actual Study Completion Date :

Mar 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dexmedetomidine Intravenous dexmedetomidine using target controlled infusion.	Drug: Dexmedetomidine Intravenous infusion Other Names: Dexdor
Experimental: Propofol Intravenous propofol using target controlled infusion.	Drug: Propofol Intravenous infusion Other Names: Propofol-Lipuro
Experimental: S-ketamine Intravenous S-ketamine using target controlled infusion.	Drug: S-ketamine Intravenous infusion Other Names: Ketanest-S
Experimental: Sevoflurane Inhalational sevoflurane using target controlled inhalation.	Drug: Sevoflurane Inhalation Other Names: Sevorane
Placebo Comparator: Placebo Intravenous saline.	Drug: Placebo Intravenous infusion of saline (Ringer's Acetate)

Outcome Measures

Primary Outcome Measures

Regional cerebral metabolism of glucose [40 min]
Comparison of responsive and unresponsive subjects

Secondary Outcome Measures

EEG [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.
Immunological effects [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.
Metabolomic effects [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.
Gene expression [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.
Psychological well-being [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.
Dream report [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

Drug concentration in plasma or end-tidal [1 hour]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 30 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

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

Exclusion Criteria:

Chronic medication
History of alcohol and/or drug abuse
Strong susceptibility for allergic reactions
Serious nausea in connection with previous anesthesia
Strong susceptibility for nausea
Any use of drugs or alcohol during the 48 hours preceding anesthesia
Use of caffeine products 10-12 hours prior the study
Smoking
Clinically significant previous cardiac arrhythmia / cardiac conduction impairment
Clinically significant abnormality in prestudy laboratory tests
Positive result in the drug screening test
Blood donation within 90 days prior to the study
Participation in any medical study with an experimental drug or device during the preceding 60 days
The study subject has undergone a prior PET or SPECT study
Any contraindication to magnetic resonance imaging (MRI)
Hearing impairment
Detected unsuitability based on MRI scanning results if available before the PET scanning
Sleep disorder or severe sleep problem