Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000369224
Ethics application status
Approved
Date submitted
25/02/2018
Date registered
12/03/2018
Date last updated
3/03/2023
Date data sharing statement initially provided
13/06/2019
Date results provided
3/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Gas narcosis in hyperbaric environments
Scientific title
Gas narcosis in hyperbaric environments
Secondary ID [1] 293958 0
Nil known
Universal Trial Number (UTN)
U1111-1181-9722
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
gas narcosis 306459 0
Condition category
Condition code
Anaesthesiology 305547 305547 0 0
Other anaesthesiology
Neurological 305548 305548 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In this prospective intervention study a total of 72 participants are needed. There are four parts in this study. Participants can choose to participate in a single part, all four parts or in any combination of the four parts in this study. This will lower the total number of participants needed.

Objective 1 - Developing the qEEG algorithm for narcosis
Nitrous oxide is an anaesthetic gas, which is already narcotic at atmospheric pressure. Therefore, normobaric nitrous oxide is a good substitute for hyperbaric exposure to air during the development of the sensitive qEEG method and the optimization of this measurement method. Increasing doses of nitrous oxide produce a similar pattern of EEG change to nitrogen under hyperbaric conditions. 36 divers will individually breathe 20%, 30% and 40% nitrous oxide in oxygen mixture in the hospital. The mixtures will be administered in a random order. To reduce the possibility of vomiting and nausea caused by the nitrous oxide, participants will be asked to fast 4 hours before the measurement, which commence at 9 am. Dexamethasone can be administered as an anti-emetic. After baseline measurements, the participant starts breathing the nitrous oxide in oxygen mixture from the anaesthetic machine. After 5 minutes of nitrous oxide mixture breathing the EEG, psychometric, CFFF and pupillometry measurements are repeated. Thereafter the participant will breathe 100% oxygen again for 5 minutes to wash out the nitrous oxide. After the measurement the participant will be asked to fill in the Karolinska Sleepiness Scale (KSS) and the Mental Effort Scale (MES). The same measurement will be repeated after 20 minutes of breathing air with a second and third concentration of nitrous oxide. At the end the baseline measurement is repeated.

Objective 2 - Benchmark the algorithm with nitrogen narcosis
In the second objective I will validate the algorithm, developed in objective 1, in the hyperbaric situation. I will do this by comparing the algorithm to the psychometric performance, which will measure known functional deficits. The psychometric tests will measure changes in short-term memory and effects on comprehension of the information processing of the brain. Both are higher cognitive functions that are more affected by gas narcosis. In this part of the study 12 divers will individually have two exposures in a hyperbaric chamber. On one exposure the participant will breathe air, and on the other a heliox mixture of 21% oxygen and balance helium will be breathed. Both gases will be breathed from a built-in breathing mask of the hyperbaric chamber. Each exposure will pause at 25 meters of seawater (msw) equivalent (3.5 ATA) and 50 msw (6 ATA) depths. The two exposures will be performed on different days.
After baseline measurements, the participant will be compressed at a rate of 18 meters a minute, to 3.5 ATA. At 3.5 ATA a next block of measurements will be done beginning with 10 minutes of EEG measurement with the eyes closed, followed by 10 minutes of psychometric and CFFF tests. Next, the participant will be compressed to 6 ATA to repeat the EEG, psychometric and CFFF measurements. After each measurement the participant will be asked to complete the Karolinska Sleepiness Scale (KSS) and the Mental Effort Scale (MES). The decompression will be controlled (including oxygen stops) according to the schedule prescribed by the Canadian Navy decompression tables.

Objective 3 - Measuring oxygen narcosis
Next, I will investigate the narcotic effect of oxygen. I will compare the three different levels of oxygen pressure to evaluate its narcotic potency. Further, I will compare oxygen narcosis to nitrogen narcosis. The measurements obtained in objective 2 while breathing air at 3.5 ATA, have a partial pressure of nitrogen of 2.8 ATA. By comparing the results from these dives where the inspired PO2 is 2.8 ATA (objective 3) and the inspired PN2 is 2.8 ATA (objective 2) the supposed similar narcotic effect can be evaluated. To do this 12 divers will breathe 100% oxygen at the surface (1.0 ATA), 4 msw (1.4 ATA) and 18 msw (2.8 ATA). 1.4 ATA is the operational limit of oxygen for recreational divers. 2.8 ATA is a commonly accepted maximal partial pressure of oxygen in a dry hyperbaric chamber. After baseline measurements, the participant will breathe 100% oxygen from a demand valve mask in the hyperbaric chamber. The EEG and CFFF measurements are repeated. At a rate of 18 meters a minute the diver will be compressed to 1.4 ATA. At 1.4 ATA a next block of measurements will be done; first with 10 minutes of EEG measurement with the eyes closed followed by the CFFF test. The participant will then be compressed to 2.8 ATA to repeat the EEG and CFFF. The diver will be decompressed at 10 meters per minute. Any decompression stops will be based on the needs of the air-breathing investigator as prescribed by the Canadian Navy decompression tables. After each measurement the participant will be asked to fill in the Karolinska Sleepiness Scale (KSS) and the Mental Effort Scale (MES).

Objective 4 – Investigate the magnitude and the physiological mechanism of carbon dioxide narcosis
For this part 12 divers will visit the facility 3 times. Each time they will breath air or heliox (21% oxygen) with three increasing levels of inspired CO2. The increased end-tidal CO2 concentrations will be achieved with prepared gas mixtures with CO2. The CO2 fractions in the gas mixtures are chosen to inflict end-tidal CO2 values that fall within the ranges of 35-45 mmHg (normal range for end-tidal CO2 with no inspired CO2), 45-50 mmHg and 55-60 mmHg. End-tidal CO2 is measured using a sampling line to a gas analyser outside the hyperbaric chamber. Between the two CO2¬-containing breathing mixtures, there will be a 10-minute recovery.

At each exposure the participant will undergo the following measurements:
• 2 minute Psychometric tests (EEG and fNIRS will be recorded simultaneously)
• 1 minute EEG and fNIRS eyes open
• 1 minute EEG and fNIRS eyes closed
• Breath hold (as long as possible at end of exposure)
• Effort and sleepiness questionnaire
• Breathing frequency and flow during exposure and recovery phase

During the normobaric carbon dioxide measurements participants will be breathing air (no added CO2) as baseline measurement. Followed by a heliox mixture (20% oxygen, balance helium) at 1 ATA with subsequently 0% CO2 resulting in end-tidal CO2 between 35-45 mmHg and elevated inspired CO2 levels resulting in end-tidal CO2 values between respectively 45-50 mmHg and 55-60 mmHg.

There will be two hyperbaric exposures in random order. In one session the participant will breathe air at the surface (1.0 ATA) (baseline), air at 50 meter (6 ATA), followed by two air mixtures with elevated levels of inspired CO2. In the other session they will breathe air at the surface (1.0 ATA) (baseline), heliox 20/80 at the surface, heliox 20/80 at 50 meter (6 ATA) and two mixtures with increasing levels of inspired CO2 in heliox, resulting in end-tidal CO2 levels between 45-50 mmHg and 55-60 mmHg. Each elevated inspired CO2¬ exposures is followed by a 10-minute recovery period. The two dives will be at least 48 hours apart. After baseline measurements, the participant will be compressed to 6 ATA at a rate of 10 meters/minute. The diver will be decompressed at 10 meters per minute. Any decompression stops will be prescribed by the Canadian Navy decompression tables. After each measurement the participant will be asked to fill in the Karolinska Sleepiness Scale (KSS) and the Mental Effort Scale (MES).
Intervention code [1] 300228 0
Other interventions
Comparator / control treatment
The measurement before exposure to the specific breathing gas will be used as a control measurement.
Control group
Active

Outcomes
Primary outcome [1] 304687 0
relative change in narcosis depth measured with a to be developed quantitative EEG measurement

I will use the EEG recordings with the known narcotic effect of nitrous oxide to create a narcosis evaluation tool. This tool will provide an outcome measure on a numerical scale. Out of the many possible qEEG indicators, the subset with the highest correlation with psychometric performance, robustness to noise and interindividual variation will be chosen.
Timepoint [1] 304687 0
baseline (before exposure) and for the duration of 10 minutes during exposure to the breathing gas mixture.
Secondary outcome [1] 342800 0
relative change in higher cognitive functions, measured with two psychometric tests. Both tests are randomly different with each administration to mitigate a learning effect. The Paired Associate Learning (PAL) test is mainly affected by changes in the short-term memory. The Serial Sevens (S77) measures effect on comprehension of the information processing of the brain. Because both are higher cognitive functions they are more affected by gas narcosis. The tests will be performed on a tablet. The test administration program (Mobile Cognition Ltd., Edingburgh, UK) stores the average reaction time and the number of errors made of each test for analysis. Baseline measurements will be regarded as 100% functioning. Subsequent measurements will be transformed to a percentage functioning compared to this baseline measurement.
Timepoint [1] 342800 0
baseline (before exposure) and for the duration of 5 minutes during exposure to the breathing gas gas mixture.
Secondary outcome [2] 342801 0
relative change in narcosis depth measured with critical flicker fusion frequency (CFFF)

During all objectives I will measure the CFFF, because it is an easy to use, non-invasive measurement, which is also useable underwater. During the measurement the participant looks at a small LED light. By changing the flicker frequency one can obtain the fusion frequency, where the participant notes a change from flicker to fusion or the other way around. This flicker fusion frequency is a measurement of impairment caused by narcosis depth. During this study I will measure the CFFF to assess it's capability to measure gas narcosis in divers breathing different gas mixtures.
Timepoint [2] 342801 0
baseline (before exposure) and for the duration of 5 minutes during exposure to the breathing gas gas mixture.
Secondary outcome [3] 344183 0
Subjects will score their alertness / sleepiness by using the Karolinska Sleepiness Scale (KSS) and effort on the Mental Effort Scale (MES) using a VAS questionnaire.
Timepoint [3] 344183 0
After each CFFF measurement the participant will score their alertness and effort of that measurement.
Secondary outcome [4] 348805 0
relative change in narcosis depth measured with pupillometry. During all objectives I will measure the pupillometry, because it is an easy to use, non-invasive measurement, which is also useable underwater. During the measurement the participant looks at a camera with infra-red LEDs. A short light flash will trigger the pupil to contract and dilate. Automatic measurements are taken of this effect.
Timepoint [4] 348805 0
baseline (before exposure) and for 1 minute during exposure to the breathing gas mixture.
Secondary outcome [5] 397683 0
fNIRS
Functional near-infrared spectroscopy (fNIRS) uses near-infrared light emission and detection to measure hemodynamic responses associated with cerebral activation. It provides information on blood volume, flow and oxygenation, similar to functional Magnetic Resonance Imaging (fMRI). This fNIRS system has 18 light sources and 24 detectors placed in the standard 10-20 system on the same headcap as the EEG electrodes. This allows to measure both modalities at the same time. Due to the nature of the fNIRS system it cannot be taken inside a hyperbaric chamber, and will therefore only be used during normobaric measurements. This technique is safe and non-invasive. Analysis of the fNIRS signals will be done offline to compare it to the effects found with EEG.
Timepoint [5] 397683 0
baseline (before exposure) and for the duration of 5 minutes during exposure to the breathing gas gas mixture (objective 4 only).
Secondary outcome [6] 397684 0
Heart rate
The heart rate will be recorded using two additional electrodes on the EEG system. Measure will give insight in the physiological response during the CO2 exposures.
Timepoint [6] 397684 0
baseline (before exposure) and for the duration of 5 minutes during exposure to the breathing gas gas mixture (objective 4 only).
Secondary outcome [7] 397685 0
Breathing rate
The breathing rate will be calculated from the end-tidal carbon dioxide recording during study 4 (CO2). Measure will give insight in the physiological response during the CO2 exposures.
Timepoint [7] 397685 0
baseline (before exposure) and for the duration of 5 minutes during exposure to the breathing gas gas mixture (objective 4 only).

Eligibility
Key inclusion criteria
• Age between 18 and 55 years old
• Written informed consent
• Normal static binocular acuity, corrected or uncorrected
• Normal hearing
• Basic fluency of the English language
• Possession of a valid divers certificate
• Medical fitness for diving according to recreational diver standards.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
A potential subject who meets any of the following criteria will be excluded from participation in this study:
• Current recreational drug use
• Use of psychoactive medication, including anti-histamines
• Mental illness
• Excessive alcohol use (>21 standard alcoholic drinks per week)
• Intake of caffeine-containing beverages over 5 glasses per day
• Smoker

After inclusion a participant will be withdrawn from the study if:
• There is a deviation of the research protocol by the participant
• There is an intake of non-permitted medication
• There is an intake of alcohol 24 hours before the test
• There is an intake of caffeine-containing beverages during the test days
• Less than 6 hours of sleep during the night prior to the test day
• A dive made within 24 hours prior to the an experiment involving hyperbaric exposure
• There are signs or symptoms of decompression illness
• They request to be withdrawn

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
For each of the 4 parts of the study, the participants are in a crossover designed study.
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Sample size calculation
Based on previous studies we will need 12 participants in each group to be able to detect differences between the conditions. Three studies utilising EEG measurements while breathing nitrous oxide (Rampil et al. 1998), air (Pastena et al. 2005; Bevan 1971) and oxygen (Storti et al. 2015), were able to demonstrate differences in the EEG patterns with 13, 10, 13 and 11 participants respectively. Studies showing differences in functioning while breathing nitrogen and oxygen in a hyperbaric chamber (Frankenhaeuser et al. 1963) and while breathing different CO2 concentrations at the surface (Fothergill et al. 1991) both utilised 12 participants. The dataset acquired for the first objective will be divided in two. The first will be used to optimize the algorithm, while the second will be used to test the algorithm. We decided to increase the number of participants by 50% for this objective to have enough statistical power to make the algorithm.

Objective 1 - Creating the qEEG algorithm for narcosis
All EEG data will be analysed off line, using the Matlab software package (Mathworks, Natick, MA, USA). Using this software a quantitative EEG algorithm will be developed that will be responsive for no narcosis to the point of heavily narcotic but still conscious. The algorithm will use the subtle EEG changes, captured by features like the loss of power in the alpha spectrum, global network efficiency and bispectral indexes. During the design of the algorithm, the 100% functioning at baseline on the psychometric tests will be correlated with the baseline score on the qEEG algorithm. The lower percentages of functioning on the psychometric tests while breathing the various concentrations of nitrous oxide will correlate with a higher score on the qEEG algorithm, e.g. more narcosis. Half of the dataset will be used to develop and optimize the algorithm. The other half will be used to test the algorithm.

Objective 2 - Benchmark the algorithm with nitrogen narcosis
The scores calculated by the newly developed qEEG algorithm will be correlated to the percentage of functioning on the psychometric test. If each level of nitrogen exposure shows a high correlation with the qEEG value and functioning on the psychometric tests, the qEEG will be regarded as sensitive for nitrogen narcosis. No differences in qEEG values while breathing heliox suggest qEEG is not affected by pressurisation.

Objective 3 - Measuring oxygen narcosis
Whether oxygen is narcotic will be determined by comparing the three different levels of partial pressure of oxygen. Student's t-test with a two-tailed P value set at .05 will be used to compare the qEEG values at the surface while breathing 100% oxygen, with the qEEG values while breathing 100% oxygen at 1.4 ATA and 2.8 ATA. If the qEEG values increase significantly we can conclude that oxygen is narcotic.

We will also compare oxygen narcosis to nitrogen narcosis. The measurements obtained in objective 2 while breathing air at 3.5 ATA, have a partial pressure of nitrogen of 2.8 ATA. By comparing the results from these dives where the inspired PO2 is 2.8 ATA (objective 3) and the inspired PN2 is 2.8 ATA (objective 2) the supposed similar narcotic effect can be evaluated. We will evaluate this using a Student's t-test with a two-tailed P value set at .05.

Objective 4 - Investigate the magnitude and the physiological mechanism of carbon dioxide narcosis
We will test the hypothesis that elevated CO2 levels are independently narcotic, and also the hypothesis that CO2 can enhance nitrogen narcosis.

First we will compare the qEEG values while breathing Heliox at 1ATA when the PETCO2 lies in the ranges 35-45 mmHg, 45 - 50 mmHg, and 55-60 mmHg. Comparisons will be performed using a Student's t-test with a two-tailed P value set at .05. If the qEEG indicates a progressive and significant increase in narcosis in the higher PETCO2 conditions, then we can conclude that CO2 is narcotic independent of any effect on nitrogen narcosis.

The second hypothesis will evaluate the difference between the qEEG values at 6 ATA while breathing air with a PETCO2 of respectively, 35-45 mmHg, 45 - 50 mmHg, and 55-60 mmHg, and the qEEG values while breathing heliox with a PETCO2 of respectively 35-45 mmHg, 45 - 50 mmHg, and 55-60 mmHg. Comparisons will be performed using a Student's t-test with a two-tailed P value set at .05. When the differences of the qEEG values differ significantly between air and heliox with increasing PETCO2, CO2 is regarded as a mediator of the narcotic effect of nitrogen and/or oxygen. If an increase in PETCO2 is not independently narcotic at the surface or in the heliox dives, but does enhance narcosis in the air dives, it will strongly suggest that it is acting by a synergistic mechanism such as enhancing the nitrogen dose to the brain by causing cerebral vasodilation.

CFFF
The CFFF measures functional impairment, which will be correlated, using a pearson correlation, to the measured effect in the qEEG in each of the objectives.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/07/2018
Actual
9/07/2018
Date of last participant enrolment
Anticipated
1/09/2022
Actual
3/10/2022
Date of last data collection
Anticipated
1/09/2022
Actual
25/10/2022
Sample size
Target
72
Accrual to date
Final
34
Recruitment outside Australia
Country [1] 9557 0
New Zealand
State/province [1] 9557 0
Auckland

Funding & Sponsors
Funding source category [1] 298586 0
Government body
Name [1] 298586 0
Office of Naval Research, US Navy
Country [1] 298586 0
United States of America
Primary sponsor type
Individual
Name
Professor Simon Mitchell
Address
Department of Anaesthesiology,
Auckland City Hospital,
University of Auckland.
2 Park Road,
Grafton, Auckland, 1023
Country
New Zealand
Secondary sponsor category [1] 297751 0
None
Name [1] 297751 0
Address [1] 297751 0
Country [1] 297751 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299551 0
Health and Disability Ethics Committees
Ethics committee address [1] 299551 0
Ethics committee country [1] 299551 0
New Zealand
Date submitted for ethics approval [1] 299551 0
29/06/2016
Approval date [1] 299551 0
08/09/2016
Ethics approval number [1] 299551 0
16/NTA/93

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2416 2416 0 0
/AnzctrAttachments/374440-participant information sheet and consent form Gas Narcosis version 1.2.pdf (Participant information/consent)

Contacts
Principal investigator
Name 80818 0
Prof Simon Mitchell
Address 80818 0
Department of Anaesthesiology,
Auckland City Hospital,
University of Auckland.
2 Park Road,
Grafton, Auckland, 1023
Country 80818 0
New Zealand
Phone 80818 0
+64 9 923 9300
Fax 80818 0
Email 80818 0
[email protected]
Contact person for public queries
Name 80819 0
Xavier Vrijdag MSc
Address 80819 0
Department of Anaesthesiology,
Auckland City Hospital,
University of Auckland.
2 Park Road,
Grafton, Auckland, 1023
Country 80819 0
New Zealand
Phone 80819 0
+64 9 923 9300
Fax 80819 0
Email 80819 0
[email protected]
Contact person for scientific queries
Name 80820 0
Simon Mitchell
Address 80820 0
Department of Anaesthesiology,
Auckland City Hospital,
University of Auckland.
2 Park Road,
Grafton, Auckland, 1023
Country 80820 0
New Zealand
Phone 80820 0
+64 9 923 9300
Fax 80820 0
Email 80820 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Basic demographics
Sleepiness and NASA TLI results
Psychometric test results
EEG recordings
When will data be available (start and end dates)?
6 months after publication of main results
no end date determined
Available to whom?
researchers who provide a methodologically sound proposal at the discretion of Primary Sponsor
Available for what types of analyses?
to achieve the aims in the approved proposal and for meta-analyses
How or where can data be obtained?
access subject to approvals by Principal Investigator


What supporting documents are/will be available?

No Supporting Document Provided



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