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Trial registered on ANZCTR


Registration number
ACTRN12624001130550
Ethics application status
Approved
Date submitted
28/08/2024
Date registered
18/09/2024
Date last updated
18/09/2024
Date data sharing statement initially provided
18/09/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
An implementation-effectiveness trial to evaluate physiotherapy guideline care in practice and determine whether a course of protocolised physiotherapy ventilator lung hyperinflation treatment, added to guideline care, is feasible, safe, cost-effective and improves patient-important outcomes for ICU patients with severe pneumonia requiring invasive mechanical ventilation.
Scientific title
An implementation-effectiveness trial investigating feasibility, safety and efficacy of Best pRacticE guideline cAre physioTHErapy with the addition of protocolised ventilator lung hyperinflation treatment on patient-important outcomes for critically ill adults intUbated and ventilated with Pneumonia. (BREATHE UP)
Secondary ID [1] 311508 0
None
Universal Trial Number (UTN)
Trial acronym
Breathe Up
Linked study record

Health condition
Health condition(s) or problem(s) studied:
pneumonia 332845 0
Condition category
Condition code
Respiratory 329560 329560 0 0
Other respiratory disorders / diseases
Physical Medicine / Rehabilitation 329561 329561 0 0
Physiotherapy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Guideline physiotherapy care according to van der Lee et al (2024) incorporating a modified ventilator hyperinflation (VHI) treatment by Jacob et al 2021, performed by ICU physiotherapists, at a set daily dosage and frequency of 3 times per day. The VHI technique described by Jacob et al (2021) is based on the individual patient’s estimated inspiratory reserve volume (IRV), to determine the target increase in tidal volume above resting tidal volume which would be safe to deliver to the patient via the ventilator to simulate a deep breath, for the purpose of recruiting atelectatic alveoli via collateral channels to mobilise sputum which can then be cleared via airway suctioning. The following formulae will be used to calculate the estimated IRV as per Jacob et al (2021), using Microsoft Excel, based on each patient’s age, height and weight up to a Body Mass Index (BMI) of 25. Predicted body weight (BMI 25) was used for patients who were overweight or obese.
Estimated IRV (male) =2.89 x height + 0.016 x age - 0.032 x weight - 12.69
Estimated IRV (female) = 1.72 × height - 0.016 x age - 0.022 x weight - 4.91

Patients who are randomised to receive the new VHI treatment will receive four sets of eight to ten breaths, three times per day until extubation or Day 28 in ICU, whichever occurs first. The patient will receive eight to ten breaths per cycle to minimise hyperventilation. An inspiratory time of 3-5 seconds will be used.

In this study, the determined target hyperinflation volume will be limited at a peak pressure of 40cmH2O, which multiple studies have shown to be both effective and safe. Peak pressure is monitored continuously on the ventilator display and reviewed by treating clinicians.

The VHI treatment will be delivered via the patient’s mechanical ventilator using a volume-controlled mode with a decelerating flow pattern, which is pressure limited, with alarms set accordingly to allow the delivery of the treatment VHI breath set to a maximum inspiratory pressure of 40 cmH2O. For patients who have progressed to breathing spontaneously on the ventilator without the need for mandatory ventilator breaths, or who have difficulty with ventilator synchrony, the VHI treatment may be performed using a pressure-support mode of ventilation, where all breaths are triggered by the patient and pressure support is provided to deliver the target volume by the ventilator above the patient’s own breathing effort, up to a pressure limit of 40cmH2O. Research has shown this to be an effective and safe method of delivering VHI treatment in this context and improves patient-ventilator synchrony in patients who are weaning.

Data will be collected at the bedside by the treating clinician regarding each episode of treatment delivered, including the time of treatments, dosage delivered (number of sets and repetitions of breaths), ventilator parameters during treatment, and target and achieved tidal volumes and inspiratory pressures in order to evaluate treatment adherence and fidelity.

Active respiratory physiotherapy treatment, comprising deep breathing exercises and coughing, will be performed daily at a minimum, between extubation and ICU discharge as per guideline care. Once awake and able to participate actively in rehabilitation, muscle strengthening and early mobilisation will be standardised to 20 minutes per day between groups and based on patient’s highest level of function according to the ICU Mobility Scale (IMS).
Intervention code [1] 327963 0
Treatment: Other
Intervention code [2] 327964 0
Rehabilitation
Comparator / control treatment
Guideline physiotherapy care according to van der Lee et al (2024) incorporating varied treatment modes which may include manual hyperinflation using a manual resuscitation bag or conservative VHI using the ventilator, delivered at a variable daily dosage according to the discretion of the treating physiotherapist until extubation.

Active respiratory physiotherapy treatment, comprising deep breathing exercises and coughing, will be performed daily at a minimum, between extubation and ICU discharge as per guideline care. Once awake and able to participate actively in rehabilitation, muscle strengthening and early mobilisation will be standardised to 20 minutes per day between groups, and based on patient’s highest level of function according to the ICU Mobility Scale (IMS).
Control group
Active

Outcomes
Primary outcome [1] 339222 0
- Disability
Timepoint [1] 339222 0
Day 90 post randomisation.
Secondary outcome [1] 439133 0
Feasibility
Timepoint [1] 439133 0
3 years post study commencement.
Secondary outcome [2] 439134 0
Safety
Timepoint [2] 439134 0
- Safety will be assessed by a data safety monitoring board (DSMB) at 50% recruitment regarding occurrence of AEs and SAEs
- Inflammatory biomarkers will be assessed at baseline, and Day 7 or ICU discharge.
All AEs and SAEs will be assessed up to 28 days post randomisation.
Secondary outcome [3] 439135 0
- Ventilator free days
Timepoint [3] 439135 0
Day 28 post randomisation.
Secondary outcome [4] 439136 0
Antibiotic free days
Timepoint [4] 439136 0
At day 28 post randomisation
Secondary outcome [5] 439137 0
Vasopressor free days.
Timepoint [5] 439137 0
At day 28 post randomisation.
Secondary outcome [6] 439138 0
Discharge destination.
Timepoint [6] 439138 0
at hospital discharge.
Secondary outcome [7] 439139 0
Mortality
Timepoint [7] 439139 0
At day 28 post randomisation and day 90 post randomisation.
Secondary outcome [8] 439140 0
Days alive and out of hospital
Timepoint [8] 439140 0
Day 90 post randomisation.
Secondary outcome [9] 439141 0
Health-related quality of life
Timepoint [9] 439141 0
Day 90 post randomisation.
Secondary outcome [10] 439778 0
Multidisciplinary staff satisfaction with physiotherapy guideline care.
Timepoint [10] 439778 0
By end of study.

Eligibility
Key inclusion criteria
• ICU admission with diagnosis of pneumonia made by a medical practitioner.
• Aged equal to or greater than 18 years
• Intubated and mechanically ventilated, expected to remain so for equal to or greater than 24 hours, not planned for extubation this calendar day.
• Evidence of consolidation or volume loss on CXR, CT scan or lung ultrasound.
• Evidence of sputum on clinical assessment by a physiotherapist, e.g. auscultation, palpation, endotracheal suction, waveform analysis.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Death imminent or the treating clinician believes that death during this hospital admission is inevitable.
• Treating clinician believes that trial participation is not in the best interests of the patient.
• Receiving invasive mechanical ventilation for greater than 5 days
• Peak airway pressure greater than 35cmH20 consistently for greater than 2 hours
• Progression to severe ARDS according to Berlin Criteria [32]
• Requirement for extracorporeal membrane oxygenation
• Severe bronchospasm
• Undrained pneumothorax or bronchopleural fistula
• Pulmonary haemorrhage
• Lung transplantation or recent lung surgery with bronchial resection
• Unable to communicate in English
• Pregnancy
• Underlying neurological or myopathic condition
• Documented cognitive impairment
• BMI greater than 35
• Hospitalisation for greater than 7 days prior to ICU
• Presence of active cancer or active use of chemotherapeutic agents or neutropenia
• Unlikely to be available for 3-month follow-up (resides overseas)

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)
Computerised randomisation using REDCap with allocation concealment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
1:1 block randomisation with stratification according to site.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Descriptive statistics will consist of means and standard deviations, or medians and interquartile ranges for continuous data, and frequency distributions for categorical data. Univariate group comparisons will be done using independent t-tests or non-parametric Mann-Whitney U tests for continuous data & Chi-squared or Fisher’s Exact tests for categorical data. Mixed effects generalised linear models, including random effects for patients and site, will be used to examine longitudinal (discharge and 3-months) primary outcome WHODAS 2.0 and secondary outcomes EQ5D-5L and Borg Dyspnoea score. Results will be summarised using estimated mean differences and 95% confidence intervals (CI). Mixed effects logistic regression models will be used to examine longitudinal mortality outcomes, with results summarised using odds ratios (OR) and 95%CI. Ventilator free days will be described using negative binomial models and summarised using estimated means and 95%CIs. Length of stay outcomes will be examined using Kaplan-Meier survival probabilities and described using median (95%CI) days duration, with Log Rank tests used for group comparisons. Cox regression models may be used to derive hazard ratios (HR). Quality-adjusted life years (QALYS) will be calculated using utility scores from the EQ-5D-5L collected at 3-months post randomisation. An a priori subgroup analysis according to site is planned to investigate any between group difference that is site specific. An interim analysis is planned at 50% recruitment to investigate safety and treatment effect on the primary outcome. Data will be analysed using Stata 18.0 (StataCorp LLC, College Station, TX).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
225
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 27034 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [2] 27035 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 43104 0
6009 - Nedlands
Recruitment postcode(s) [2] 43103 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 315799 0
Charities/Societies/Foundations
Name [1] 315799 0
Raine Medical Research Foundation
Country [1] 315799 0
Australia
Funding source category [2] 317280 0
Government body
Name [2] 317280 0
Future Health Research and Innovation Fund
Country [2] 317280 0
Australia
Primary sponsor type
Hospital
Name
South Metropolitan Health Service
Address
Country
Australia
Secondary sponsor category [1] 319558 0
Hospital
Name [1] 319558 0
North Metropolitan Health Service
Address [1] 319558 0
Country [1] 319558 0
Australia
Other collaborator category [1] 283162 0
University
Name [1] 283162 0
The University of Western Australia
Address [1] 283162 0
Country [1] 283162 0
Australia
Other collaborator category [2] 283163 0
University
Name [2] 283163 0
The University of Melbourne
Address [2] 283163 0
Country [2] 283163 0
Australia
Other collaborator category [3] 283164 0
University
Name [3] 283164 0
The Chinese University of Hong Kong
Address [3] 283164 0
Country [3] 283164 0
Hong Kong

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314656 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 314656 0
https://smhs.health.wa.gov.au/Our-research/For-researchers
Ethics committee country [1] 314656 0
Australia
Date submitted for ethics approval [1] 314656 0
26/04/2024
Approval date [1] 314656 0
24/07/2024
Ethics approval number [1] 314656 0

Summary
Brief summary
The aims of this study are:
1. To determine the feasibility (acceptability and fidelity) of implementing the physiotherapy guideline in patients with pneumonia, incorporating a set dosage of ventilator hyperinflation (VHI) treatment, with target volume determined for each patient according to their estimated inspiratory reserve volume, based on height as per Jacob et al (2021).
2. To explore pneumonia phenotypes which demonstrate treatable traits that are amenable to respiratory physiotherapy intervention commenced during the acute period of invasive mechanical ventilation.
3. To determine the effect of a course of VHI treatment method], at a set dosage and frequency of three times daily for the duration of the period that patients are on the mechanical ventilator on symptomatology and patient-centred outcomes.
4. To determine the cost-effectiveness of physiotherapy guideline care incorporating a course of new VHI treatment for pneumonia requiring invasive ventilation in ICU.

It is hypothesised that best practice physiotherapy guideline care, with incorporation of protocolised VHI treatment is safe, feasible and effective in improving patient-important outcomes for critically ill adults requiring invasive mechanical ventilation for pneumonia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 132306 0
Dr Lisa van der Lee
Address 132306 0
Fiona Stanley Hospital, Robin Warren Drive Murdoch, 6150, Western Australlia
Country 132306 0
Australia
Phone 132306 0
+61 08 6152 6547
Fax 132306 0
Email 132306 0
[email protected]
Contact person for public queries
Name 132307 0
Lisa van der Lee
Address 132307 0
Fiona Stanley Hospital, Robin Warren Drive Murdoch, 6150, Western Australlia
Country 132307 0
Australia
Phone 132307 0
+61 08 6152 6547
Fax 132307 0
Email 132307 0
[email protected]
Contact person for scientific queries
Name 132308 0
Lisa van der Lee
Address 132308 0
Fiona Stanley Hospital, Robin Warren Drive Murdoch, 6150, Western Australlia
Country 132308 0
Australia
Phone 132308 0
+61 08 6152 6547
Fax 132308 0
Email 132308 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?
de-identified participant data may be shared with a data transfer agreement.
When will data be available (start and end dates)?
Available following publication with no end date.
Available to whom?
Only researchers who provide a methodologically sound proposal.
Available for what types of analyses?
IDP meta-analyses
How or where can data be obtained?
Subject to approvals by the chief principal investigator.
Email contact: [email protected].


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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