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Trial registered on ANZCTR

Registration number

ACTRN12616001516471

Ethics application status

Approved

Date submitted

31/10/2016

Date registered

3/11/2016

Date last updated

19/12/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

Nasal High-Frequency Oscillation to Improve Respiratory Stability of Preterm Infants: A Randomized Crossover Study

Scientific title

Nasal High-Frequency Oscillation to Improve Respiratory Stability of Preterm Infants: A Randomized Crossover Study

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

The Wiggle Study

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Desaturations and bradycardias related to apnoea of prematurity

Condition category

Condition code

Reproductive Health and Childbirth

Childbirth and postnatal care

Respiratory

Other respiratory disorders / diseases

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Non-invasive high-frequency oscillatory ventilation (nHFO) will be delivered using Hudson binasal prongs (Hudson Respiratory Care Inc, Temecula, California, USA) and a Draeger VN500 ventilator (Draeger Medical System, Luebeck, Germany). Babies will be in prone and 15 degrees head-up tilt position.

The first 30 minutes of nHFO treatment will be defined as washout period. The subsequent 2-hour period will be used for the primary outcome. After 2.5 hours of nHFO treatment, standard care ventilation (CPAP) will be recommenced. The researcher will stay on the bedside during the whole study time to record handling of the infant and other possible influencing factors.

Ventilator settings at the beginning of nHFO:
- Frequency: 8 Hz. Will not be changed during the 2-hour treatment period.
- Mean airway pressure: Previous set CPAP pressure. Will not be changed during the 2-hour treatment period.
- Amplitude: 20 cm H20. Will be adjusted to the smallest amplitude needed for visible chest wall vibration.
- Fraction of inspired oxygen (FiO2): Will be adjusted to maintan oxygen saturation of 91 - 95 percent

The duration of the washout period between treatments will be 30 minutes.

Intervention code [1]

Treatment: Other

Intervention code [2]

Treatment: Devices

Comparator / control treatment

Continuous positive airway pressure (CPAP) will be delivered using Hudson binasal prongs (Hudson Respiratory Care Inc, Temecula, California, USA) and a Draeger VN500 ventilator (Draeger Medical System, Luebeck, Germany). CPAP is the most widely used form of ‘non-invasive’ ventilation in very preterm infants and the current standard of care for the treatment of desaturations and bradycardias.

The first 30 minutes of CPAP treatment will be defined as washout period. The subsequent 2-hour period will be used for the primary outcome.

Ventilator settings at the beginning of CPAP:
- Positive end expiratory pressure: Previous set CPAP pressure. Will not be changed during the 2-hour treatment period.
- Fraction of inspired oxygen (FiO2): Will be adjusted to maintan oxygen saturation of 91 - 95 percent.

Control group

Active

Outcomes

Primary outcome [1]

Difference in the total number of desaturations and bradycardias between CPAP and nHFO treatment during 120-minute recording periods for each therapy.

Timepoint [1]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

An oximetry sensor (LNOP Neo sensor; Masimo, Irvine, California, USA) will be placed around the infant’s wrist or foot and connected to the pulse oximeter (Radical7 V5; Masimo, 2 second averaging mode). Continuous data will be recorded using a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).

Secondary outcome [1]

Difference in fraction of inspired oxygen between CPAP and nHFO treatment.

Timepoint [1]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

The concentration of inspired oxygen will be measured with an oxygen analyser (Teledyne Analytical Instruments, California, USA). The analyser will be inserted into the inspiratory limb of the Draeger VN500 ventilator circuit (Draeger Medical System, Luebeck, Germany) and connected to a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany). Continuous data will be recorded.

Secondary outcome [2]

Difference in peripheral oxygen saturation between CPAP and nHFO treatment.

Timepoint [2]

Secondary outcome [3]

Difference in respiratory rate between CPAP and nHFO treatment.

Timepoint [3]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

Transthoracic impedance with ECG electrodes (Teledyne X2 Philips) placed on the infant’s chest will be used to obtain the respiration signal. The signal will be continuously recorded with a neonatal monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).

Secondary outcome [4]

Difference in heart rate between CPAP and nHFO treatment.

Timepoint [4]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

ECG electrodes (Teledyne X2 Philips) will be placed on the infant’s chest to obtain the ECG signal. The signal will be continuously recorded with a neonatal monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).

Secondary outcome [5]

Difference in the proportion of time spent with oxygen saturations < 80% between CPAP and nHFO treatment.

Timepoint [5]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

An oximetry sensor (LNOP Neo sensor; Masimo, Irvine, California, USA) will be placed around the infant’s wrist or foot and connected to the pulse oximeter (Radical7 V5; Masimo, 2 second averaging mode). Continuous data using a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany) will be used.

Secondary outcome [6]

Difference in the proportion of time spent with heart rates < 80 beats per minute between CPAP and nHFO treatment.

Timepoint [6]

Secondary outcome [7]

Difference in the number of desaturations < 60% and < 80% between CPAP and nHFO treatment.

Timepoint [7]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

An oximetry sensor (LNOP Neo sensor; Masimo, Irvine, California, USA) will be placed around the infant’s wrist or foot and connected to the pulse oximeter (Radical7 V5; Masimo, 2 second averaging mode). Continuous data using a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany) will be used.

Secondary outcome [8]

Difference in the number of bradycardias < 60 beats per minute and < 100 beats per minute between CPAP and nHFO treatment.

Timepoint [8]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

ECG electrodes (Teledyne X2 Philips) will be placed on the infant’s chest to obtain ECG signal. The signal will be continuously recorded with a neonatal monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).

Secondary outcome [9]

Difference in the number of apnoeas requiring stimulation by nursing staff between CPAP and nHFO treatment.

Timepoint [9]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

The researcher who is present during both treatment periods (nHFO and CPAP) will document the number of apnoeas requiring stimulation on a predefined case report form.

Secondary outcome [10]

Difference in regional cerebral oxygenation (rcO2) between the two treatment period measured by near-infrared spectroscopy (NIRS).

Timepoint [10]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

Before the beginning of the study, a near infrared spectroscopy sensor (Fore-Sight Sensor, CAS Med. Medical Systems Inc., Branford, CT, USA) will be placed on the infant’s forehead underneath the CPAP hat. The sensor will not be removed during the whole study period.

Secondary outcome [11]

Difference in the regional ventilation between CPAP and nHFO treatment measured by Electrical Impedance Tomography (EIT).

Timepoint [11]

120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

The EIT system (Swisstom BB2 system, Landquart, Switzerland) includes EIT electrodes that are contained in a belt-like disposable textile patient interface. This EIT belt will be fastened to patient's thorax before beginning of the study and not be removed during the whole study period.

Secondary outcome [12]

Effect of delivered amplitude on regional ventilation measured with Electrical Impedance Tomography (EIT).

Timepoint [12]

The effect of delivered amplitude on EIT will be recorded during nHFO only.

The EIT system (Swisstom BB2 system, Landquart, Switzerland) includes EIT electrodes that are contained in a belt-like disposable textile patient interface. This EIT belt will be fastened to patient's thorax before beginning of the study and not be removed during the whole study period.

Secondary outcome [13]

Difference in Premature Infant Pain Profile (PIPP) between CPAP and nHFO treatment.

Timepoint [13]

PIPP will be assessed by nursing staff at the beginning and at the end of each treatment period and documented manually.

Secondary outcome [14]

Number of changes in ventilator settings.

Timepoint [14]

Will be documented manually during nHFO period only.

The number of changes made on the ventilator (Draeger Medical System, Luebeck, Germany) will be documented manually on a predefined case report form.

Secondary outcome [15]

Safety related events 1:
Transcutaneous carbon dioxide (tcCO2) measurements.

Timepoint [15]

Will be documented manually during nHFO period only.

Before each nHFO washout period, a tcCO2 transducer (M1018A module, Philips Electronics, Andover, Massachusetts, USA) will be placed on the infant’s skin. Given that the tcCO2 transducer needs to be calibrated every two hours, the maximum tcCO2 recording time is limited to 2 hours. Since the baby will be in prone position during both treatment periods and the abdominal area is not available, the transducer will be placed on the back or the lateral thigh. After 120 minutes of recording time (30 minutes before the end of the nHFO treatment period) the transducer will be removed to avoid prolonged application of heat to baby’s skin.

Secondary outcome [16]

Safety related events 2:
Number of events with hypocarbia defined as a tcCO2 < 30 millimetres of mercury (mmHg)

Timepoint [16]

Will be documented during nHFO period only.

Number of events with hypocarbia (TcCO2 transducer: M1018A module, Philips Electronics, Andover, Massachusetts, USA) will be documented manually.

Secondary outcome [17]

Safety related events 3:
Number of hypercarbia defined as a tcCO2 > 60 millimetres of mercury (mmHg)

Timepoint [17]

Will be documented during nHFO period only.

Number of events with hypercarbia (TcCO2 transducer: M1018A module, Philips Electronics, Andover, Massachusetts, USA) will be documented manually.

Secondary outcome [18]

Safety related events 4:
Nasal Trauma Score

Timepoint [18]

Will be documented at the end of nHFO treatment only.

The Nasal Trauma Score will be assessed by nursing stuff and documented manually.

Secondary outcome [19]

Safety related events 5:
Gaseous distension (abdominal girth)

Timepoint [19]

Will be documented at the beginning and at the end of nHFO period.

Abdominal girth will be assessed by nursing stuff and documented manually.

Secondary outcome [20]

Safety related events 6:
Feeding intolerance expressed as the number of vomits.

Timepoint [20]

Will be documented during nHFO period only.

The number of vomits will be documented manually.

Eligibility

Key inclusion criteria

- Gestational age at birth: < 30 weeks
- Postmenstrual age: greater than or equal to 26 and < 34 completed weeks of gestation
- Postnatal age: > 7 days
- Respiratory support: Receiving nasal CPAP and extubated for greater than or equal to 24 hours.

Minimum age

8 Days

Maximum age

10 Weeks

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- Participation in another study that prohibits inclusion
- Nasal trauma and Pressure Injury score greater than or equal to 2 (stage 2: partial thickness skin loss involving epidermis, dermis or both) before study entry

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 1:1. variable block randomisation will be used to ensure balance is achieved over the recruiting period. Sealed consecutively numbered opaque envelopes will be used.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

The sequence of randomisation will be generated by an independent statistician using a randomisation table created by computer software. Sealed consecutively numbered opaque envelopes will be used.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Crossover

Other design features

It is not possible to blind the operator to the non-invasive ventilation mode.

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The primary outcome is the paired difference in the total number of desaturations and bradycardias per 120 minutes of recording time between CPAP and nHFO. The required sample size is therefore dependant on the standard deviation (SD) of these paired differences.
Before we began the study, no data were available to estimate the probable size of this SD. Therefore, we decided to use a generic sample size calculation based on the effect size after consultation with our biostatistician.
For reassurance that our sample size calculation is able to demonstrate an effect size that is clinically relevant, a re-calculation of the sample size was performed after enrolment of the first 20 patients. With a total 40 patients, we will be able to show an effect size of 45%.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

14/11/2016

Actual

17/11/2016

Date of last participant enrolment

Anticipated

30/11/2017

Actual

16/11/2017

Date of last data collection

Anticipated

30/11/2017

Actual

16/11/2017

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

The Royal Women's Hospital - Parkville

Recruitment postcode(s) [1]

3052 - Parkville

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

The Royal Women's Hospital

Address [1]

20 Flemington Road
Parkville VIC 3052

Country [1]

Australia

Primary sponsor type

Hospital

Name

The Royal Women's Hospital

Address

20 Flemington Road
Parkville VIC 3052

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Royal Women's Hospital Human Research Ethics Committee

Ethics committee address [1]

Research & Ethics Secretariat
Arthur Hui
20 Flemington Rd
Parkville VIC 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

07/09/2016

Approval date [1]

14/11/2016

Ethics approval number [1]

Summary

Brief summary

Intermittent hypoxia (pulse oximetry saturation <80%) and bradycardia (pulse rate <80 beats per minute) frequently occur in preterm infants, often associated with apnoea of prematurity. Such episodes of hypoxia and re-oxygenation have the potential to trigger a pro-inflammatory cascade leading to multisystem morbidity including retinopathy of prematurity, impaired growth, longer-term cardiorespiratory instability, and poor neurodevelopmental outcome. Widely used treatments such as methylxanthines and continuous positive airway pressure (CPAP) are sometimes insufficient and endotracheal intubation and mechanical ventilation are required. 

Nasal CPAP is the most widely used from of 'non-invasive' ventilation (NIV) in very preterm infants. NIV refers to respiratory support without the need for an endotracheal tube, usually delivered via nasal prongs. Nasal CPAP is an alternative to mechanical ventilation in preterm infants soon after birth. A meta-analysis comparing early CPAP with intubation and mechanical ventilation showed that CPAP reduce the risk of the combined outcome of death or bronchopulmonary dysplasia (BPD). CPAP failure primarily occurs due to AOP, oxygen requirements pre-specified thresholds, and hypercapnia related to hypoventilation. Ventilation failure in infants treated with CPAP may be due to inadequate alveolar ventilation and carbon dioxide elimination.

High-frequency oscillatory ventilation (HFOV) delivered via an endotracheal tube leads to excellent carbon dioxide removal using a tidal volume less than the volume of the dead space. HFOV, which has until recently only been delivered via endotracheal tube, uses oscillations of low amplitude and high frequencies quite different from those of normal respiration. It may cause less lung injury than conventional mechanical ventilation.

The combination of HFOV and NIV could provide lung-protection, improved oxygenation, better gas exchange, and reduced rates of AOP compared to NIV alone. Therefore, we aim to assess the effect of nHFO versus CPAP therapy in very preterm infants born <30 weeks’ gestation on the cumulative event rate of all bradycardias (< 80 bpm) and desaturations (< 80%) during a 120-minute recording period for each therapy.  We hypothesize that in very preterm infants, nHFO is associated with a significant decrease in the number of bradycardias and desaturations compared with CPAP.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Christoph Ruegger

Address

Newborn Research Department
The Royal Women's Hospital
20 Flemington Road
Parkville Melbourne, 3052 VIC

Country

Australia

Phone

+61-477793772

Fax

[email protected]

Contact person for public queries

Name

Christoph Ruegger

Address

Newborn Research Department
The Royal Women's Hospital
20 Flemington Road
Parkville Melbourne, 3052 VIC

Country

Australia

Phone

+61-477793772

Fax

[email protected]

Contact person for scientific queries

Name

Christoph Ruegger

Address

Newborn Research Department
The Royal Women's Hospital
20 Flemington Road
Parkville Melbourne, 3052 VIC

Country

Australia

Phone

+61-477793772

Fax

[email protected]

No information has been provided regarding IPD availability

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

Source	Title	Year of Publication	DOI
Embase	The Effect of Noninvasive High-Frequency Oscillatory Ventilation on Desaturations and Bradycardia in Very Preterm Infants: A Randomized Crossover Trial.	2018	https://dx.doi.org/10.1016/j.jpeds.2018.05.029
Embase	Transmission of oscillatory volumes into the preterm lung during noninvasive high-frequency ventilation.	2021	https://dx.doi.org/10.1164/RCCM.202007-2701OC
Embase	Lung volume distribution in preterm infants on non-invasive high-frequency ventilation.	2022	https://dx.doi.org/10.1136/archdischild-2021-322990

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically