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Trial registered on ANZCTR


Registration number
ACTRN12619000620123
Ethics application status
Approved
Date submitted
16/04/2019
Date registered
26/04/2019
Date last updated
1/02/2023
Date data sharing statement initially provided
26/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
High flow humidified nasal oxygen versus face mask oxygen for preoxygenation of pregnant women – a prospective randomised controlled crossover study
Scientific title
Comparing the effects of high flow humidified nasal oxygen versus face mask oxygen on expired end tidal oxygen concentration after simulated preoxygenation of pregnant women
Secondary ID [1] 297991 0
None
Universal Trial Number (UTN)
U1111-1231-4043
Trial acronym
HINOP2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pregnancy 312412 0
Preoxygenation 312413 0
Condition category
Condition code
Anaesthesiology 310972 310972 0 0
Anaesthetics
Reproductive Health and Childbirth 310975 310975 0 0
Childbirth and postnatal care
Respiratory 311027 311027 0 0
Normal development and function of the respiratory system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 0: Simulated preoxygenation with face mask oxygen then with high flow humidified nasal oxygen
Group 1: Simulated preoxygenation with high flow humidified nasal oxygen then with face mask oxygen

In order to simulate conditions in our operating theatres, each woman will be placed on an operating table or hospital bed in an optimally ramped position using the Troop™ elevation pillow and with a right lateral pelvic wedge to minimise aortocaval compression. Maternal vital signs (heart rate, blood pressure, respiratory rate and oxygen saturation) will be measured before, during and after each protocol. Fetal heart rate will be measured before and after each protocol.

High flow humidified nasal oxygen protocol
With 10 l.min-1 of room air (FiO2 21%) running in the anaesthetic circuit, a tightly fitting face mask will be applied by a trained investigator (anaesthetist, anaesthetic registrar, medical student, or nurse) and a good seal and ideal fitting will be determined by observing the capnography trace as the woman breathes. (This step may be omitted if the woman undergoes the face mask oxygen protocol first as per her randomization).

The face mask will then be removed. The oxygen concentration in the anaesthetic circuit will be increased to 100% (FiO2 100%) with flows remaining at 10 l.min-1 until the oxygen concentration rises to 100% as determined by real time oxygen analysis on the anaesthetic machine. After this has been achieved, high flow humidified nasal cannulae (Optiflow™ by Fisher & Paykel Healthcare - TGA approved) will be inserted into the woman’s nostrils by the trained investigator (anaesthetist, anaesthetic registrar, medical student, or nurse). The oxygen flow will be commenced (first 30 seconds at 30 l.min-1, then next 150 seconds at 70 l.min-1). Each woman will be instructed to breathe normally with her mouth closed as much as possible. The percentage of time mouth closure is achieved will be recorded to the closest percentage of 0%, 25%, 50%, 75% or 100%. If the maximum (70 l.min-1) flow rate is not tolerated, it will be reduced to 60 l.min-1 and then to 50 l.min-1 before aborting the protocol. At the end of three minutes the woman will be asked to hold her breath in inspiration while the nasal cannulae are quickly removed and the tightly fitting face mask (connected to 10 l.min-1 FiO2 100%) will be applied. The woman will then be asked to exhale normally and breathe normally and the first four etO2 concentration values measured by the end tidal gas analyzer on the anaesthetic machine will be recorded. Other variables including end-tidal carbon dioxide concentration, peak oxygen saturation values and tidal volumes will be recorded.

Face mask oxygenation protocol
With 10 l.min-1 of room air (FiO2 21%) running in the anaesthetic circuit, a tightly fitting face mask will be applied by a trained investigator (anaesthetist, anaesthetic registrar, medical student, or nurse) and a good seal and ideal fitting will be determined by observing the capnography trace as the woman breathes. The face mask will then be removed. The oxygen concentration in the anaesthetic circuit will be increased to 100% (FiO2 100%) with flows remaining at 10 l.min-1 until the oxygen concentration rises to 100% as measured by real time oxygen analysis on the anaesthetic machine. After this has been achieved, the tightly fitting face mask will be applied on the woman by a trained investigator for three minutes observing the capnography trace to ensure a good seal is maintained throughout this time. Each woman will be instructed to breathe normally. The woman will then be asked to exhale normally and breathe normally and the first four etO2 concentration values measured by the end tidal gas analyzer on the anaesthetic machine will be recorded. Other variables including end-tidal carbon dioxide concentration, peak oxygen saturation values and tidal volumes will be recorded.

Between each protocol, the woman will be asked to breathe room air for a minimum of five minutes in order for her etO2 to return to within 10% of her baseline level as assessed by re-application of the face mask (with 10 l.min-1 of room air in the circuit) and oxygen analysis on the anaesthetic machine. This method has been utilized in previous preoxygenation comparison studies in pregnant women to minimize the possibility of a carryover effect between protocols. If the participant’s etO2 has not returned to within 10% of her baseline level at five minutes, she will be asked to continue to breathe room air and her etO2 will be rechecked every two minutes until this criteria has been met. Furthermore, if there is any unaccounted residual carryover effect, our randomized crossover design should evenly spread this across groups.

All data will be recorded on paper forms at time of experiment. Video recordings will be taken of the anaesthetic machine monitor screens (not of the study participants) throughout the procedure. The principal investigator will review each video in full on the day of experiment and any identifying details mentioned in the sound recording will be deleted before storage. Expired oxygen concentration and waveform data will be measured by the gas analyser on our SCIO Oxi Four Plus gas monitor (Drager, Lubeck, Germany) and recorded. First breath end tidal oxygen concentration will be determined from the display and completeness of breath capture determined from interrogation of the waveform.

Comfort level of the standard face mask and the high flow nasal cannulae will be assessed using a three-stage questioning approach. Firstly, the investigator will specify that he/she is interested in comfort related to the specific modality (HFNO or face mask) and not global comfort. Secondly, the participant will be asked their preference (relative comfort) between the two devices. Thirdly, participants will rate both devices using a 5 point word associated scale for comfort levels. This approach encompasses most of the recommendations in a literature review investigating the assessment of comfort in a clinical setting. The women will not undergo general anaesthesia.

Study participants will undergo repeat randomization and the corresponding order of experimental protocols at 6 months from the birth of their baby.
Intervention code [1] 314215 0
Prevention
Comparator / control treatment
Comparator treatment in this instance is face mask oxygen as it represents usual care in our institution's clinical setting

Randomised controlled crossover trial. Participants form their own controls as they undergo both simulated preoxygenation protocols in randomised order determined by their group.
Control group
Active

Outcomes
Primary outcome [1] 319775 0
Expired end tidal oxygen concentration. Expired oxygen concentration and waveform data will be measured by the gas analyser on our SCIO Oxi Four Plus gas monitor (Drager, Lubeck, Germany) and recorded. First breath end tidal oxygen concentration will be determined from the display and completeness of breath capture determined from interrogation of the waveform.
Timepoint [1] 319775 0
First breath after respective protocols completed
(i.e. end of high flow nasal oxygen protocol and end of face mask oxygen protocol). This will be attained at time of recruitment to study (woman in late pregnancy) and repeated at 6 months post-birth.
Secondary outcome [1] 369503 0
Body mass index
- weight will be measured using an analog weighing scale (i.e. in late pregnancy and 6 months post birth)
- height will be measured using a stadiometer in antenatal clinic prior to recruitment to study (this measurement will be used for both testing instances)
Timepoint [1] 369503 0
Weight will be measured just prior to commencement of protocols at both testing instances using an analog weighing scale (i.e. in late pregnancy and 6 months post birth)
Height will be measured using a stadiometer in antenatal clinic prior to recruitment to study (this measurement will be used for both testing instances - i.e. in late pregnancy and 6 months post birth)
Secondary outcome [2] 369504 0
Comfort scores will be measured using a 5 point word associated scale for comfort levels
Timepoint [2] 369504 0
Measured at the end of the protocol. This will be attained at at both testing instances (i.e. in late pregnancy and 6 months post birth)
Secondary outcome [3] 369613 0
End-tidal carbon dioxide concentration (maternal) will be measured by the end-tidal gas analyser on our anaesthetic machine


Timepoint [3] 369613 0
First breath after respective protocols completed
(i.e. end of high flow nasal oxygen protocol and end of face mask oxygen protocol). This will be attained at time of recruitment to study (woman in late pregnancy) and repeated at 6 months post-birth.
Secondary outcome [4] 369614 0
Oxygen saturation values (maternal) will be measured using the pulse oximeter on our anaesthetic machine
Timepoint [4] 369614 0
Before, during & after protocols (i.e. high flow nasal oxygen protocol and face mask oxygen protocol). This will be attained at time of recruitment to study (woman in late pregnancy) and repeated at 6 months post-birth.
Secondary outcome [5] 369615 0
Respiratory rate (maternal) will be measured using clinical assessment
Timepoint [5] 369615 0
Before, during & after protocols (i.e. high flow nasal oxygen protocol and face mask oxygen protocol). This will be attained at time of recruitment to study (woman in late pregnancy) and repeated at 6 months post-birth.
Secondary outcome [6] 369616 0
Heart rate (maternal) will be measured using the pulse oximeter on our anaesthetic machine
Timepoint [6] 369616 0
Before, during & after protocols (i.e. high flow nasal oxygen protocol and face mask oxygen protocol). This will be attained at time of recruitment to study (woman in late pregnancy) and repeated at 6 months post-birth.
Secondary outcome [7] 369617 0
Blood pressure (maternal) will be measured using the non-invasive blood pressure apparatus on our anaesthetic machine
Timepoint [7] 369617 0
Before, during & after protocols (i.e. high flow nasal oxygen protocol and face mask oxygen protocol). This will be attained at time of recruitment to study (woman in late pregnancy) and repeated at 6 months post-birth.
Secondary outcome [8] 369618 0
Heart rate (fetal) will be measured using a doppler ultrasound.
Timepoint [8] 369618 0
Before & after protocols (i.e. high flow nasal oxygen protocol and face mask oxygen protocol). This will be attained at first testing instance (i.e. woman in late pregnancy). It cannot be repeated at post-birth instance.
Secondary outcome [9] 369694 0
Tidal volume measured using volumeter on anaesthetic machine
Timepoint [9] 369694 0
During face mask oxygen protocol only. This will be attained at time of recruitment to study (woman in late pregnancy) and repeated at 6 months post-birth. Tidal volume measurement during high flow nasal oxygen protocol impossible due to nature of apparatus.

Eligibility
Key inclusion criteria
Women in late pregnancy (more than or equal to 36 weeks gestation)
Minimum age
18 Years
Maximum age
50 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Significant nasal pathology, severe systemic disease excluding obesity (as defined by an American Society of Anesthesiologists (ASA) physical status score of 3 or more), preeclampsia of any degree or overwhelming sepsis, in labour, multiple pregnancy

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An investigator not involved in participant recruitment or the study protocol will place the preoxygenation sequence in a sealed opaque envelope (simulated preoxygenation with HFNO then face mask oxygen (even numbers) or simulated preoxygenation with face mask oxygen then HFNO (odd numbers) which will be accessed by the study investigator at the time the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will occur using simple randomisation with a computer-generated random number sequence.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A sample of 100 women will be recruited. Using a power of 90% and a one-sided significance level of 0.025, the standard deviation of 9.09 from our previous study and a non-inferiority bound of 5% etO2 concentration, the required sample size is 70 participants. A previous study utilised a non-inferiority margin of 10% etO2 concentration however we believe that a narrower margin (i.e. half the magnitude) is required to provide strong evidence for a change of practice to HFNO in this context.

We anticipate a 30% drop-out rate including failed complete capture of first breath and non-attendance of women returning in the non-pregnant state to repeat the protocol, thus the proposed sample size of 100. For participants in whom we fail at complete capture of first breath during their pregnant state experiment, their data will be excluded from analysis. For participants who successfully complete their pregnant state experiment but in whom we fail at complete capture of first breath during their non-pregnant state experiment or do not return for this experiment, their data will be included in all analyses except those pertaining to the comparison of pregnant to non-pregnant state figures.

As HFNO confers the additional safety benefit of effective apnoeic oxygenation (assuming no airway obstruction) with the ability to significantly prolong the safe apnoea period4 and face mask oxygen does not, this study has been designed as a non-inferiority trial. Based on the Consolidated Standards of Reporting Trials (CONSORT) statement, in a non-inferiority trial it is conventional to use a one-sided test, but with a stricter threshold for statistical significance (usually alpha = 0.025). If the new technique is worse than the comparator, the outcome will be the same as a two-sided test, but if the new technique is better than the comparator, the null hypothesis would not be rejected.

If there is truly no difference between the standard and experimental treatment, then 70 patients (or 70 data pairs) are required to be 90% sure that the lower limit of a one-sided 97.5% confidence interval (or equivalently a 95% two-sided confidence interval) will be above the non-inferiority limit of -5.

Statistical analysis will be performed with the assistance of the Statistical Consulting Centre and Melbourne Statistical Consulting Platform at the School of Mathematics and Statistics, The University of Melbourne. Experimental data will be analysed using a linear mixed-effects model. We will seek to compare the two modalities for non-inferiority in the late pregnancy state and the post-partum state respectively. We also aim to investigate the effect of pregnancy on adequacy of preoxygenation. Therefore, we will seek to analyse each modality individually to see if participants perform better or worse with either modality depending on whether they are in late pregnancy or post-partum.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
6/08/2019
Actual
6/08/2019
Date of last participant enrolment
Anticipated
20/12/2020
Actual
3/03/2020
Date of last data collection
Anticipated
20/06/2021
Actual
3/03/2020
Sample size
Target
100
Accrual to date
Final
70
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 13633 0
The Royal Women's Hospital - Parkville
Recruitment postcode(s) [1] 26301 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 302515 0
Charities/Societies/Foundations
Name [1] 302515 0
Australian Society of Anaesthetists
Country [1] 302515 0
Australia
Funding source category [2] 302518 0
Hospital
Name [2] 302518 0
Department of Anaesthesia, The Royal Women's Hospital - Parkville
Country [2] 302518 0
Australia
Primary sponsor type
Hospital
Name
Department of Anaesthesia, The Royal Women's Hospital - Parkville
Address
20 Flemington Road, Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 302425 0
None
Name [1] 302425 0
N/A
Address [1] 302425 0
N/A
Country [1] 302425 0
Other collaborator category [1] 280647 0
Individual
Name [1] 280647 0
A/Prof Alicia Dennis
Address [1] 280647 0
Department of Anaesthesia, The Royal Women's Hospital
20 Flemington Road, Parkville VIC 3052
Country [1] 280647 0
Australia
Other collaborator category [2] 280648 0
Individual
Name [2] 280648 0
Prof Philip Peyton
Address [2] 280648 0
Department of Anaesthesia, Austin Health
Studley Road Heidelberg VIC 3084
Country [2] 280648 0
Australia
Other collaborator category [3] 280649 0
Individual
Name [3] 280649 0
Dr Julia Unterscheider
Address [3] 280649 0
Royal Women’s Hospital
20 Flemington Road, Parkville VIC 3052
Country [3] 280649 0
Australia
Other collaborator category [4] 280650 0
Individual
Name [4] 280650 0
Dr Adam Deane
Address [4] 280650 0
Intensive Care Unit, The Royal Melbourne Hospital – City Campus
Grattan Street, Parkville VIC 3050
Country [4] 280650 0
Australia
Other collaborator category [5] 280651 0
Individual
Name [5] 280651 0
Ms Liz Leeton
Address [5] 280651 0
Department of Anaesthesia, The Royal Women's Hospital
20 Flemington Road, Parkville VIC 3052
Country [5] 280651 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303171 0
Royal Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 303171 0
Ethics committee country [1] 303171 0
Australia
Date submitted for ethics approval [1] 303171 0
01/05/2019
Approval date [1] 303171 0
19/07/2019
Ethics approval number [1] 303171 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92730 0
Dr Patrick Tan
Address 92730 0
Department of Anaesthesia, The Royal Women's Hospital
20 Flemington Road, Parkville VIC 3052
Country 92730 0
Australia
Phone 92730 0
+61 3 8345 2381
Fax 92730 0
+61 3 83452379
Email 92730 0
patrickcheefei.tan@thewomens.org.au
Contact person for public queries
Name 92731 0
Patrick Tan
Address 92731 0
Department of Anaesthesia, The Royal Women's Hospital
20 Flemington Road, Parkville VIC 3052
Country 92731 0
Australia
Phone 92731 0
+61 3 8345 2381
Fax 92731 0
+61 3 83452379
Email 92731 0
patrickcheefei.tan@thewomens.org.au
Contact person for scientific queries
Name 92732 0
Patrick Tan
Address 92732 0
Department of Anaesthesia, The Royal Women's Hospital
20 Flemington Road, Parkville VIC 3052
Country 92732 0
Australia
Phone 92732 0
+61 3 8345 2381
Fax 92732 0
+61 3 83452379
Email 92732 0
patrickcheefei.tan@thewomens.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
To maintain participant privacy


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.