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Trial registered on ANZCTR


Registration number
ACTRN12615000766516
Ethics application status
Approved
Date submitted
25/06/2015
Date registered
23/07/2015
Date last updated
23/07/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A pilot study of hypertonic saline in children with chest infections and disabilities
Scientific title
A pilot study comparing inhaled hypertonic to normal saline on the respiratory function of children with neurological impairment and acute lower respiratory tract infection
Secondary ID [1] 286979 0
'Nil known'
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute lower respiratory tract infections 295292 0
Severe neurological impairment 295537 0
Cerebral palsy 295538 0
Condition category
Condition code
Respiratory 295551 295551 0 0
Other respiratory disorders / diseases
Neurological 295552 295552 0 0
Other neurological disorders
Infection 295919 295919 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Salbutamol (200 micrograms) via meter dose inhaler (Ventolin, Allen + Hanburys Respiratory Care), nebulised HTS (6%) 5ml pre-filled syringe (HyperSal6, sodium chloride, 60mg/mL, Royal Children’s Hospital Pharmacy Department), and chest physiotherapy

The treatment order will be randomized and the administrators and participant will be blinded to the type of nebulisation a participant receives. The participant will receive four doses of nebulisation over the two day study period. These will occur in the morning and afternoon on both study days. The type of study nebulisation will vary between days according to the randomization sequence assigned to that participant. There will be the potential to do another two day cycle of the study period for those participants with longer admissions to PICU. Therefore a participant may complete a maximum of two cycles of the two day study period over the course of the trial. For these participants the total intervention period will be 4 days.

Salbutamol will be administered immediately prior to each HTS nebulisation. Salbutamol and the study nebulisation will be administered two times a day prior to the morning and afternoon chest physiotherapy sessions. The nebulization will be delivered via standard pressurized air located at the participant’s bedside with a flow rate of 8 L/min. The nebuliser will be administered until the characteristic mist cannot be visualized and the nebuliser bowl is empty. The circuitry for delivery will be dependent on the type of ventilation a patient is receiving.

Chest physiotherapy will commence within a maximum of 10 minutes after completion of the study nebulisation. Chest physiotherapy treatment has been flexibly defined approximating clinical reality for this heterogeneous participant group. Chest physiotherapy will include standard techniques of percussion, expiratory vibrations, manual hyperinflation, postural drainage, positioning and suction techniques. The chest physiotherapy administered for the participant’s initial chest physiotherapy intervention will be maintained across subsequent study periods where possible. Experienced physiotherapists from grade 1 to grade 4 will administer chest physiotherapy. No students will administer chest physiotherapy. Clinically the application of chest physiotherapy may differ between different therapists. Where possible the physiotherapist administering chest physiotherapy will be held constant between sessions to reduce this variability. A stop watch timer will be used to time chest physiotherapy interventions and ensure compliance with the time frame of the initial chest physiotherapy intervention.

Participants with LRTI on PICU receive three chest physiotherapy sessions per day. All patients will receive three physiotherapy treatments in a day. Only two of these treatments, the morning and afternoon physiotherapy treatments will be included in the study. All participants will receive a third chest physiotherapy session in the evening. This was not included as part of the study intervention due to staffing limitations which would not allow adequate data collection during this period. Prior to the evening physiotherapy treatment, participants will receive a non-blinded normal saline nebuliser without salbutamol administration.

A conservative washout period of approximately 18 hours or more, depending on the time of the afternoon treatment, will be utilized in the study to ensure no carry over effects.

Adherence to the study protocol will be monitored by reviewing medication charts. Any study medications not used will be returned to the hospital pharmacy.
Intervention code [1] 292083 0
Treatment: Drugs
Intervention code [2] 292084 0
Treatment: Other
Comparator / control treatment
Arm 2: Salbutamol (200 micrograms) via meter dose inhaler (Ventolin, Allen + Hanburys Respiratory Care), nebulised NS (0.9%) 5 ml pre-filled syringe (sodium chloride, 9 mg/ mL, Pfizer Pharmaceuticals), and chest physiotherapy

The treatment order will be randomized and the administrators and participant will be blinded to the type of nebulisation a participant receives. The participant will receive four doses of nebulisation over the two day study period. These will occur in the morning and afternoon on both study days. The type of study nebulisation will vary between days according to the randomization sequence assigned to that participant. There will be the potential to do another two day cycle of the study period for those participants with longer admissions to PICU. Therefore a participant may complete a maximum of two cycles of the two day study period over the course of the trial. For these participants the total intervention period will be 4 days.

Salbutamol will be administered immediately prior to each NS nebulisation. Salbutamol and the study nebulisation solution will be administered two times a day prior to the morning and afternoon chest physiotherapy sessions. The nebulisation will be delivered via standard pressurized air located at the participant’s bedside with a flow rate of 8 L/min. The nebuliser will be administered until the characteristic mist cannot be visualized and the nebuliser bowl is empty. The circuitry for delivery will be dependent on the type of ventilation a patient is receiving.

Chest physiotherapy will commence within a maximum of 10 minutes after completion of the study nebulisation. Chest physiotherapy treatment has been flexibly defined approximating clinical reality for this heterogeneous participant group. Chest physiotherapy will include standard techniques of percussion, expiratory vibrations, manual hyperinflation, postural drainage, positioning and suction techniques. The chest physiotherapy administered for the participant’s initial chest physiotherapy intervention will be maintained across subsequent study periods where possible. Experienced physiotherapists from grade 1 to grade 4 will administer chest physiotherapy. No students will administer chest physiotherapy. Clinically the application of chest physiotherapy may differ between different therapists. Where possible the physiotherapist administering chest physiotherapy will be held constant between sessions to reduce this variability. A stop watch timer will be used to time chest physiotherapy interventions and ensure compliance with the time frame of the initial chest physiotherapy intervention.

Participants with LRTI on PICU receive three chest physiotherapy sessions per day. All patients will receive three physiotherapy treatments in a day. Only two of these treatments, the morning and afternoon physiotherapy treatments will be included in the study. All participants will receive a third chest physiotherapy session in the evening. This was not included as part of the study intervention due to staffing limitations which would not allow adequate data collection during this period. Prior to the evening physiotherapy treatment, participants will receive a non-blinded normal saline nebuliser without salbutamol administration.

Adherence to the study protocol will be monitored by reviewing medication charts. Any study medications not used will be returned to the hospital pharmacy.
Control group
Active

Outcomes
Primary outcome [1] 295272 0
Peripheral oxygen saturation/fraction of inspired oxygen ratio (SF ratio). SpO2 will be measured using infant SpO2 sensor (Nellcor, CovidienTM) (3 to 20 kg) or paediatric SpO2 sensor (Nellcor, CovidienTM) (10 to 50 kg) placed on the hand or foot. The sensor will be applied so that the light emitter and photo-detector are placed opposite each other (Philips, 2010). Nursing staff and physiotherapist will ensure the probe provides a consistent SpO2 trace through assessment of the signal quality indicator and pleth waveform (Philips, 2010). Fraction of inspired oxygen will be measured via the ventilator circuitry or oxygen blender for high flow circuitry as appropriate.
Timepoint [1] 295272 0
Baseline, post nebulization, post completion of chest physiotherapy, and 5, 10, 15, 20, 25, 30 minutes post completion of chest physiotherapy.
Secondary outcome [1] 315239 0
Respiratory Rate (RR). RR will be measured via placement of three-lead ECG electrodes (KendallTM, Covidien). Electrodes will be placed directly below the clavicle and near the right shoulder, directly below the left clavicle, and on the left lower abdomen (Philips, 2010). Nursing staff and physiotherapist will ensure good electrode to skin contact and monitor for an appropriate waveform
Timepoint [1] 315239 0
Baseline, post nebulization, post completion of chest physiotherapy, and 5, 10, 15, 20, 25, 30 minutes post completion of chest physiotherapy.
Secondary outcome [2] 315240 0
Transcutaneous carbon dioxide. The equipment for transcutaneous monitoring will be calibrated according to the manufacturer’s instructions prior to each use (Philips, 2010). Calibration will be performed using a Calibration Philips (15210B) or a Radiometer TCC3 calibration unit and gas cylinder. Single participant use membranes will be attached to the probes. These membranes will be changed daily during the study period and also between participants. The physiotherapist or nurse will apply the transcutaneous probes to the thorax 20 min prior to commencement of the study nebulization (Philips, 2010). This time period will allow the probes to reach a steady temperature of 43 degrees and for vascularization to occur (Lagerkvist et al., 2003). The probes will remain in-situ for the entire study period of approximately 90 minutes. The transcutaneous monitoring will be removed 30 minutes post the intervention period after the last time point is recorded and re-applied for the subsequent intervention period occurring the same day.
Timepoint [2] 315240 0
Baseline, post nebulization, post completion of chest physiotherapy, and 5, 10, 15, 20, 25, 30 minutes post completion of chest physiotherapy.
Secondary outcome [3] 315241 0
Heart rate (HR). HR will will be measured via placement of three-lead ECG electrodes (KendallTM, Covidien). Electrodes will be placed directly below the clavicle and near the right shoulder, directly below the left clavicle, and on the left lower abdomen (Philips, 2010). Nursing staff and physiotherapist will ensure good electrode to skin contact and monitor for an appropriate waveform
Timepoint [3] 315241 0
Baseline, post nebulization, post completion of chest physiotherapy, and 5, 10, 15, 20, 25, 30 minutes post completion of chest physiotherapy.
Secondary outcome [4] 315271 0
Transcutanous oxygen. The equipment for transcutaneous monitoring will be calibrated according to the manufacturer’s instructions prior to each use (Philips, 2010). Calibration will be performed using a Calibration Philips (15210B) or a Radiometer TCC3 calibration unit and gas cylinder. Single participant use membranes will be attached to the probes. These membranes will be changed daily during the study period and also between participants. The physiotherapist or nurse will apply the transcutaneous probes to the thorax 20 min prior to commencement of the study nebulization (Philips, 2010). This time period will allow the probes to reach a steady temperature of 43 degrees and for vascularization to occur (Lagerkvist et al., 2003). The probes will remain in-situ for the entire study period of approximately 90 minutes. The transcutaneous monitoring will be removed 30 minutes post the intervention period after the last time point is recorded and re-applied for the subsequent intervention period occurring the same day.
Timepoint [4] 315271 0
Baseline, post nebulization, post completion of chest physiotherapy, and 5, 10, 15, 20, 25, 30 minutes post completion of chest physiotherapy.

Eligibility
Key inclusion criteria
Participants must meet the following criteria:
Be aged between 2 and 18 years of age.
Have a diagnosis of CP GMFCS level IV or V or other neurological impairment with equivalent functional impairment including children with; developmental delay, chromosomal abnormalities, neurodegenerative and metabolic conditions.
Have a clinical diagnosis of LRTI caused by either aspiration pneumonia, bacterial pneumonia, or viral infection.
Must require at least one of oxygen therapy, high flow nasal prongs (HFNP), biphasic positive airway pressure (BIPAP), continuous positive airway pressure (CPAP), or mechanical ventilation.
Minimum age
2 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Acute wheeze associated with severe bronchospasm.
Known intolerance of hypertonic saline within the last 12 months.
Neuromuscular conditions.
Active pulmonary haemorrhage.
Low platelets (less than 20).
Undrained pneumothorax.
High cardiovascular instability.
Requiring extracorporeal membrane oxygenation or high frequency oscillation ventilation.

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)
Eligible participants will be identified by the principle investigator and other members of the physiotherapy team by reviewing the daily PICU medical handover list and attendance at the weekday morning handover meetings. Participant recruitment will occur from Monday to Friday. After reviewing current admissions, potential participants will be screened for the relevant inclusion and exclusion criteria. For those participants fulfilling the criteria, the principle investigator and another member of the physiotherapy team will approach a parent or legal guardian for consent to participate in the study. If the parent or legal guardian is not present, the request for consent will be made by phone call. For parents of children who do not speak English an interpreter will be used. When obtaining consent the voluntary nature of participation will be emphasized. In the first instance, recruitment will be undertaken by a clinician not involved in delivering the treatment intervention. However this may not always be possible to avoid, due to the small nature of the study and small number of physiotherapists involved in delivering the treatment intervention. During recruitment the voluntary nature of participation in the study will be described verbally and via the parent/guardian information statement and consent form. Families of participants will be re-assured that if they do not participate it will not affect the standard of care they receive or their relationship with the physiotherapy department. The medical team will be informed if a child is recruited into the trial. If a participant already enrolled in the trial is discharged from PICU to the ward but subsequently re-admitted to PICU on the same admission they would be eligible for another study period if they had only completed once cycle of the intervention period and would not need to be re-consented.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The person obtaining consent for participation in the trial will not be aware of the randomization sequence. The treating physiotherapist will contact pharmacy and provide the pharmacist with the name of the consented participant. The pharmacist will then allocate the participant to a treatment sequence by which they are randomly exposed to HTS and physiotherapy or NS and physiotherapy. The randomization sequences will be generated by Monash University using computer sequence randomization, prior to study commencement. Only the allocating officer in pharmacy will have access to the sequence of treatments for each participant.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
This pilot study will be a single centre trial utilizing a randomized crossover design. The study will compare the use of HTS (6%) and chest physiotherapy to NS (0.9%) and chest physiotherapy on short-term respiratory outcomes. The treatment order will be randomized and the administrators and participant will be blinded to the type of nebulisation a participant receives. The participant will receive four doses of nebulisation over the two day study period. These will occur in the morning and afternoon on both study days. The type of study nebulisation will vary between days according to the randomization sequence assigned to that participant. There will be the potential to do another two day cycle of the study period for those participants with longer admissions to PICU. Therefore a participant may complete a maximum of two cycles of the two day study period over the course of the trial. For these participants the total intervention period will be 4 days.
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Mean and standard deviations will be calculated for all outcomes for the hypertonic saline and normal saline groups. Analysis to compare groups will be done using linear regression with repeated measures and robust standard errors. Statistical analysis will be done using Stata data analysis and statistical software (Statacorp LP).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
25/06/2015
Actual
25/06/2015
Date of last participant enrolment
Anticipated
1/12/2015
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 3915 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 9829 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 291454 0
Hospital
Name [1] 291454 0
Paediatric Intensive Care Unit
The Royal Children's Hospital Melbourne
Country [1] 291454 0
Australia
Primary sponsor type
Hospital
Name
Paediatric Intensive Care Unit, Royal Children's Hospital Melbourne
Address
50 Flemington Road
Parkville
Victoria
3052
Country
Australia
Secondary sponsor category [1] 290131 0
None
Name [1] 290131 0
Address [1] 290131 0
Country [1] 290131 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293003 0
Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 293003 0
Ethics committee country [1] 293003 0
Australia
Date submitted for ethics approval [1] 293003 0
16/03/2015
Approval date [1] 293003 0
02/06/2015
Ethics approval number [1] 293003 0
35070 A
Ethics committee name [2] 293004 0
Monash University Human Research Ethics Committee
Ethics committee address [2] 293004 0
Ethics committee country [2] 293004 0
Australia
Date submitted for ethics approval [2] 293004 0
05/06/2015
Approval date [2] 293004 0
08/06/2015
Ethics approval number [2] 293004 0
CF15/2303 - 2015000930

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

Contacts
Principal investigator
Name 57990 0
Miss Clare McKinnon
Address 57990 0
Royal Children's Hospital
50 Flemington Road
Parkville
Victoria
3052
Country 57990 0
Australia
Phone 57990 0
+613 9345 5522
Fax 57990 0
Email 57990 0
[email protected]
Contact person for public queries
Name 57991 0
Clare McKinnon
Address 57991 0
Royal Children's Hospital
50 Flemington Road
Parkville
Victoria
3052
Country 57991 0
Australia
Phone 57991 0
+613 9345 5522
Fax 57991 0
Email 57991 0
[email protected]
Contact person for scientific queries
Name 57992 0
Clare McKinnon
Address 57992 0
Royal Children's Hospital
50 Flemington Road
Parkville
Victoria
3052
Country 57992 0
Australia
Phone 57992 0
+613 9345 5522
Fax 57992 0
Email 57992 0
[email protected]

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