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Trial registered on ANZCTR


Registration number
ACTRN12614001069640
Ethics application status
Approved
Date submitted
22/09/2014
Date registered
7/10/2014
Date last updated
4/03/2019
Date data sharing statement initially provided
4/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimising mechanical ventilation in Intensive Care Unit (ICU)

Scientific title
The effect of Model-based positive end expiratory pressure (PEEP) selection compared to standard practice PEEP selection in the length of mechanical ventilation of respiratory failure patients.
Secondary ID [1] 285099 0
Nil
Universal Trial Number (UTN)
U1111­-1161-­1833
Trial acronym
Clinical Utilisation of Respiratory Elastance: the 'CURE' Study - Optimising PEEP in people on mechanical ventilation
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute respiratory distress syndrome (mild, moderate, severe) 292651 0
Respiratory failure patients requiring mechanical ventilation 293153 0
Condition category
Condition code
Respiratory 292961 292961 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Clinical Protocol
Patients who meet the inclusion criteria will be randomised to intervention or control Patients’ data on both arms will be monitored.

Patients on the intervention will have their ventilation PEEP setting being guided by the bedside computer using the pulmonary elastance model. Patients will undergo Maximum Recruitment Manoeuvre (MaxRM) or PEEP adjustment and Monitoring Procedure (PUMP). MaxRM and PUMP are step-wise PEEP change recruitment manoeuvres (RM). During the RM, PEEP will be adjusted by steps of increase and decrease and the pulmonary elastance of the patient at each PEEP is calculated using the bedside computer.

The protocol will ideally be run for at least 48 hours, and discontinued at the discretion of the clinician when patient lung condition has significantly improved. Data collection will continue until patient is discontinued from mechanical ventilation.


Patient Preparation
1. For the length of mechanical ventilation, patients will be randomised to Control or Intervention using a block randomisation software.

2. For patients randomised for control, they will receive current standard of care of the participating centre.

3. For patients included for intervention, the PEEP and MV will be guided by clinicians using bedside computers.
(i) All patients in the intervention are ventilated using (i) Puritan Bennett PB840 ventilator (Covidien, Boulder, CO, USA) or (ii) Draeger V500 ventilator (Dragerwerk AG & Co. Lubeck, Germany) or (iii) Hamilton Medical G5 ventilator (Bonaduz, Switzerland) using synchronized intermittent mandatory ventilation (SIMV) with volume control while maintaining tidal volume and FiO2 similar to the control group.
(ii) Before the RM, patients may be sedated and paralyzed with muscle relaxants to prevent spontaneous breathing efforts.
(iii) The first RM when the patient is included in the study is a maximum recruitment manoeuvre (MaxRM). This is done at the beginning of the trial by clinicians and only repeated if clinically indicated. Other PEEP adjustments will be a modification of the MaxRM. The PEEP Adjustment and Monitoring Procedure is referred to as a ‘PUMP’, where the change of PEEP is -2 cmH2O to 6 cmH2O of the current PEEP setting The PUMP may be performed by either medical or nursing staff trained in the technique.
(iv) The PEEP adjustment will stop
a. When weaning from mechanical ventilation is considered appropriate, and
b. The patient has transitioned to spontaneous breathing; defined as when the respiratory rate is set to equal or less than 10 breaths per minute and
c. Patient's FiO2 equal or less than 35% and
d. Arterial blood oxygen, PaO2 equal or more than 60mmHg at FiO2 equal or less than 35% for the last 24 hours.
e. After 10 days from study enrolment.
f. At the discretion of the clinician when the patient's lung injury is no longer thought to be delaying their recovery.

4. Data will be collected continuously until the patient is disconnected from the ventilator.


Maximum Recruitment Manoeuvre (MaxRM)
Patients randomised into intervention will immediately receive the following intervention:
1. Patient airway cuff pressure will be increased to 50 cmH2O to prevent leaks during maximum recruitment manoeuvre (MaxRM).
2. The peak airway pressure alarm on the ventilator is set to 55 cmH2O.
3. Prior to the MaxRM, a muscle relaxant with appropriate sedation (eg. fentanyl and/ or propofol) are co-administered.
4. During the MaxRM, PEEP is initially increased in steps of 4 cmH2O above the baseline PEEP level (selected by clinicians) until Peak airway pressure reaches (PIP) equal or more than 45 cmH2O and thereafter, in 2 cmH2O until PIP equal or more than 50 cmH2O.
5. Each PEEP is maintained for 10-15 breathing cycles for calculation of Elastance before a subsequent PEEP increase.
6. After reaching PIP of equal or more than 50 cmH2O, PEEP is reduced by 4 cmH2O steps until initial PEEP setting.
7. Once PEEP has returned to the initial setting, a second RM is performed with PEEP increase steps of 4 cmH2O to the same PIP used in the first RM. PEEP is then decreased by steps of 2 cmH2O until the optimal PEEP level has been obtained. This PEEP will be recommended by bedside computer when the elastance decrement is e equal or less than 5% of the previous value.
8. If the intensive care clinicians do not feel the recommended PEEP level is appropriate, they will have the discretion to select a PEEP of their choice. The clinician will be prompted to record the reasons they have not followed the recommendation.
9. This process will be performed at the beginning of the trial, and only repeated at the clinician’s discretion, e.g. if there has been a possible loss of recruitment following a disconnection from the ventilator.
10. At the end of the MaxRM, the cuff pressure is reduced back to ~30 cmH2O and the ventilator high pressure alarm is set to back to initial setting.


PEEP adjustment and Monitoring Procedure (PUMP)
This procedure is performed when:
i. The patient is turned to supine position or
ii. Every subsequent 6 hours after the first RM or
iii. If the FiO2 is increased by equal or more than 10% or
iv. Anytime at the clinician's discretion
Whichever of (i) –(iv) occurs first triggers a PUMP procedure.
*Usual clinical practice is to turn patients left side to supine to right side every three hours

The procedure for the above PEEP adjustment and monitoring manoeuvres (PUMPs) are as follows:
1. PEEP is first decreased by 2 cmH2O and increased in 2 steps of 4 cmH2O with 10-15 breathing cycles at each step before decreasing back in 4 cmH2O decrements to -2 cmH2O of baseline PEEP.
2. Step 1 is immediately repeated, except the PEEP is reduced in 2 cm decrements.
3. The Bedside computer will recommend the optimal PEEP, at a PEEP higher than minimal elastance at the end of the second PUMP Recruitment Manoeuvre.
4. If the intensive care clinicians do not feel the recommended PEEP level is appropriate, they will have the discretion to select a PEEP of their choice. The clinician will be prompted to record the reasons they have not followed the recommendation.
Intervention code [1] 289946 0
Treatment: Devices
Comparator / control treatment
Patients on standard ventilation practice based on clinicians and hospital practice.

The patients will receive current standard of care, which limits plateau pressure less than or equal to 30 cmH2O while maximising tidal volume, Vt = 4 to 8ml/kg based on predicted body weight using arm demispan.

Positive end expiratory pressure (PEEP) and MV will be selected by clinicians as per standard practice.

FiO2 (fraction of inspired oxygen) will be adjusted as follows: The pulse oximetry recording (SpO2) will be maintained
(i) equal or more than 96% if the FiO2 is equal or more than 30% but less than 40%;
(ii) equal or more than 94% if the FiO2 is equal or more than 40%, but less than 60% and
(iii) 88% - 92% if the FiO2 is equal or more than 60%.

It is very important to standardise oxygen titration to pulse oximetry recordings to ensure robustness of outcomes. Upper and lower SpO2 alarm limits will be set to ensure these guidelines are followed. There is no upper SpO2 limit if the FiO2 is less than 30%.
Control group
Active

Outcomes
Primary outcome [1] 292817 0
Length of mechanical ventilation (LoMV)
Timepoint [1] 292817 0
Duration of patients requiring mechanical ventilation from the time admitted to ICU to the time when patients is weaned.
Primary outcome [2] 292818 0
Area under the curve (AUC) of the Partial pressure of arterial blood oxygen (PaO2) over Fraction of inspired oxygen (FiO2) ratio (PF ratio).

Arterial blood gas is sampled daily and used.
FiO2 at the time when Arterial blood gas is sampled is recorded.

These information are used to calculate the PF ratio at the time when they were sampled.
Timepoint [2] 292818 0
Duration of patients requiring mechanical ventilation from the time admitted to ICU to the time when patients is weaned.
Primary outcome [3] 292819 0
The number of Desaturation events measured as oxygen saturation measured by pulse oxymetry (SPO2) of less than 90%
Timepoint [3] 292819 0
Duration of patients requiring mechanical ventilation from the time admitted to ICU to the time when patients is weaned.
Secondary outcome [1] 309744 0
Area under the curve of the of Oxygen saturation measured using pulse oxymetry (SPO2) over Fraction of inspired oxygen (FiO2) ratio (SPO2/FiO2)

Hourly SPO2 and FiO2 are collected and recorded. These values are used to calculate the SPO2/FiO2 ratio at every hour.
Timepoint [1] 309744 0
Duration of patients requiring mechanical ventilation from the time admitted to ICU to the time when patients is weaned.
Secondary outcome [2] 309745 0
Chest X-ray Murray Index scores over time (subject to data availability: Chest X-ray may not be available)
Timepoint [2] 309745 0
Duration of patients requiring mechanical ventilation from the time admitted to ICU to the time when patients is weaned.


Eligibility
Key inclusion criteria
1. Patients requiring invasive mechanical ventilation (MV) (Intubation or tracheotomy).

2. Patients diagnosed with all acute respiratory distress syndrome (ARDS) severity (PF [oxygen partial pressure to fraction of inspired oxygen] ratio <300mmHg) as per the Berlin Definition (The ARDS Definition Task Force, A. 2012), by intensive care clinicians.

3. Arterial line in situ.

Minimum age
16 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who are likely to be discontinued from MV within 24 hours.

2. Patients with age <16.

3. Patients who have moderate or severe traumatic brain injury, and/or a measured intracranial pressure equal or more than 20 cmH2O.

4. Any medical condition associated with a clinical suspicion of raised intracranial pressure.

5. Patients who have a high spinal cord injury with loss of motor function.

6. Patients who have significant weakness from any neurological disease.

7. Patients who have a Barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema or any intercostal catheter for the treatment of air leak).

8. Patients who have asthma as the primary presenting condition or a history of significant chronic obstructive pulmonary disease.

9. Patients who are moribund and/or not expected to survive for > 72 hours.

10. Patients who are pregnant.

11. Patients who have already received MV for >48 hours (including time spent ventilated in a referring unit).

12. Lack of clinical equipoise by intensive care unit (ICU) medical staff managing the patient.

13. Patients readmitted to ICU within 28 days of the first day entered into the study.

14. Patients readmitted to ICU at any time if they have participated in the study during the same hospital admission.




** Termination criteria for the recruitment manoeuvres
During a recruitment manoeuvre (RM), there are known impacts on the cardiovascular system and respiratory system. Specifically, there is a fall in cardiac output, or blood pressure, or desaturation due to increases of pulmonary shunt. These changes will be anticipated and, inotropes, fluid loading and oxygen therapies maybe initiated to these changes in advance of the RM.

A) Recruitment manoeuvre will not be initiated if the patient care may be compromised from increased sedation and/or use of muscle relaxants.
B) At any time during a recruitment manoeuvre, the RM is terminated if any of the changes below persist for more than 3 minutes:
1. Desaturation with SPO2 less than 88%.
2. New bradycardia (reduction heart rate by 20% and < 60 beats per minute) or,
3. New tachycardia (increase of heart rate by 20% and > 140 beats per minute) or,
4. New arrhythmia leading to (a) or (b) above or,
5. New hypotension (reduction in MAP by 30% or MAP < 60mmHg).

C) Lack of clinical equipoise by the clinician; e.g. when a patient has a low blood pressure and is
thought to be intolerant of PEEP changes.

Intervention will be stopped and will revert to current standard of care when there is lack of clinical
equipoise by the clinician. The clinical reason will be recorded.

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)
Central randomisation using computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
In this study, block randomisation with stratification of APACHE III diagnostic code will be used. Patients eligible for the study with APACHE III diagnostic code 200 (non-operative respiratory diagnosis) and 1300 (post-operative respiratory diagnosis) are separated into a different group. These patients have their primary diagnostic as respiratory disease operative or non-operative and are the primary focus in mechanical ventilation treatment.

After stratification, randomisation will be performed in blocks, where the block sizes are generated using a randomisation program. The program will randomly assign patients into either a control group or intervention group through a random block size.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We used standard sample size calculations for a randomized control trial where the randomization is carried out at the individual patient level. Sample size estimates are based on the primary outcome of reduction in length of mechanical ventilation (LoMV).

A clinically relevant effect size is assumed to be a 25% reduction in the LoMV. Equal allocations to the control and intervention are assumed. One-sided testing for a reduction in LoMV is assumed as only a beneficial effect is expected. A minimum power of 80% and one-sided significance level of 5% is assumed below. The distribution of LoMV in the usual population is heavily skewed to the right. Hence, a Mann-Whitney-Wilcoxon rank sum test for the positive difference in between the control and intervention medians is used below. But these are consistent with a two sample t-test (on the logarithmic scale due to multiplicative reduction) and Kolmogorov-Smirnov test.

A Monte Carlo simulation study based on historical patients’ records is used to determine the minimum sample size required to identify the specified effect size, at the chosen power and significance level. Data for all mechanical ventilated patients in the Christchurch Hospital Intensive care unit (ICU) for 2012 and 2013 were analyzed. The patients’ APACHE 3 diagnostic code and their length of mechanical ventilation were used.

1. A total of 1917 patients were available
2. Exclusion criteria were imposed to obtain an estimated total sample size for the simulation. The exclusion criteria were:
a. patients who are likely to be discontinued from MV within 24 hours;
b. patients who have moderate or severe traumatic brain injury;
c. patients who have a high or spinal cord injury with loss of motor function;
d. patients who have significant weakness from any neurological disease;
e. patients who have acute severe pancreatitis and are expected to be ventilated for more than 10 days; and
f. patients who have asthma as the primary presenting condition.
3. After these exclusions 1022 patients remained. (mean(LoMV)=3.78, sd(LoMV)=7.15, median(LoMV)=1.08)

It is important that all patients who are likely to discontinued from MV in less than 24 hours can be identified in the allocations and excluded from the trial. Inclusion of these individuals leads to approximately a tripling of the required sample size, to achieve the same power and significance level for the prescribed effect size.

Further, patients who are expected to require long term MV (who are not excluded by the other criteria listed above) must also be retained. A-priori identification and exclusion of such long term MV patients (e.g. those likely to require more than 15 days of MV) substantially reduces the power of the test, leading to needing a sample size orders of magnitude higher to achieve the same power and significance level for the prescribed effect size.

A minimum sample size of 130 patients per arm (260 patients in total) is required identify a 25% reduction in the median LoMV, with a power of 80% and one sided significance level of 5%.



Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 6268 0
New Zealand
State/province [1] 6268 0
Canterbury

Funding & Sponsors
Funding source category [1] 289705 0
Government body
Name [1] 289705 0
New Zealand Health Research Council (HRC)
Address [1] 289705 0
Level 3, 110 Stanley Street, Auckland 1010, PO Box 5541, Wellesley Street, Auckland 1441, New Zealand
Country [1] 289705 0
New Zealand
Primary sponsor type
University
Name
University of Canterbury
Address
University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
Country
New Zealand
Secondary sponsor category [1] 288402 0
Hospital
Name [1] 288402 0
Christchurch Hospital
Address [1] 288402 0
2 Riccarton Avenue, Christchurch 4710, New Zealand
Country [1] 288402 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291445 0
Southern Health and Disability Ethics Committee (SHDEC)
Ethics committee address [1] 291445 0
Health and Disability Ethics Committees.
1 the Terrace
PO Box 5013
Wellington
6001
Ethics committee country [1] 291445 0
New Zealand
Date submitted for ethics approval [1] 291445 0
Approval date [1] 291445 0
22/09/2014
Ethics approval number [1] 291445 0
14/STH/132

Summary
Brief summary
Intensive care clinicians use Mechanical Ventilation on a daily basis in the ICU to treat patients with injured lungs. An important setting on the ventilator machines is known as positive end expiratory pressure or PEEP. This controls the pressure in the lung at the end of the breath, and its accuracy is critical in the successful treatment of injured lungs.

Currently, doctors have no standard way of selecting the PEEP for each patient, and use their clinical intuition, or their “gut-feeling”. Different patients have different lungs and as such, selecting PEEP this way might lead to an incorrect PEEP setting for that patient. This might cause the patient to require longer stays in the ICU and/or or further lung injury.

This study aims to evaluate a computer based method of PEEP selection by in a randomised control trial (RCT). A RCT involves a random allocation for your relative or friend under mechanically ventilation to either A) receive standard treatment or B) receive standard treatment with the aid to potentially improve their recovery. The RCT is based on prior research conducted here in the Christchurch ICU. Because this method of PEEP selection is specific to each patient, it is anticipated ventilation better matched to their lungs. This could lead to healthier lungs and as a result, require the patient to spend less time in the ICU.
Trial website
Trial related presentations / publications
Public notes
Standard ventilation practice includes manoeuvres to increase lung recruitment. However, these clinical practices are widely variable and ad-hoc. The recruitment techniques to improve oxygenation and mechanics of ventilation in this proposed study are within the scope of standard ICU clinical practice. The protocols used in this study will standardise these existing interventions to recruit lung volume and titrate PEEP.

Study participants will be unable to consent to participation in this study prior to enrolment as they will be sedated and mechanically ventilated. It is also equally important that patients be commenced in one or the other arm of the RCT at the beginning of MV to ensure a fair comparison and the integrity of the results. We propose to use a delayed consent process which will randomly assign patients to either the intervention or control groups. Retrospective opinions from family members as to whether they believe the patient would wish to participate in the study will be sought as soon as practicable after the start of mechanical ventilation. In our pilot study (currently in progress, Ethics Reference 13/STH/84) it has often not been possible to speak with family members within 48 hours of the start of mechanical ventilation. By this time, it may be too late to see any benefit in optimising lung mechanics over a patient’s stay. We believe the most critical time to maximise lung recruitment is in the first 3-6 hours of the mechanical ventilation, and equally, over the first 1-2 days of MV may also be critical.

This approach has been utilised in several previous, large (RCT) ICU studies such as the NICE study (AKY/04/09/237) the RENAL study (MEC05/10/131) and the CHEST study (MEC09/07/080). We proposed to discuss the study with family/ whanau and provide them with an information sheet and opportunities to answer any questions about the study. An opinion from the family/ whanau will be sought as to whether they believe their relative/ friend/ whanau would agree to participation. If the family/ whanau agrees to their relative/ friend/ whanau participating in the study, they will be asked to sign a statement.

In cases where the family/whanau cannot attend the hospital to sign the statement, their opinion will be obtained by telephone in the first instance. Information about the study will either be made available by emailing them the information sheet and contacting them later by telephone, or the information sheet will be read to them over the telephone. The telephone conversation(s) and their opinions will be documented in the patient’s medical record. As soon as the family/ whanau is able to attend the hospital, they will be asked to sign the statement. If the family are not able to sign a statement during the patient’s time in the ICU, we would give them the option of printing out the statement, signing it, and mailing/ emailing/ faxing it back to us.
If the family/ whanau do not support for their relative/ friend’s continued participation, the relative/friend will cease participation in the study. However, researchers will seek agreement from family/ whanau to use information related to mechanical ventilation collected up until that point. If the family/ whanau does not agree to this request, all information obtained for the study will be destroyed.

The researchers will seek permission form patients who have recovered sufficiently to provide to (i) continue in the study, or (ii) use data already collected. Patients who do not provide permission will be withdrawn from the study and all data collected will be destroyed.

Contacts
Principal investigator
Name 50410 0
A/Prof Geoffrey M Shaw
Address 50410 0
Christchurch Hospital,
2 Riccarton Avenue,
Christchurch 4710
Country 50410 0
New Zealand
Phone 50410 0
+64 (3) 364-1077
Fax 50410 0
Email 50410 0
Geoff.shaw@cdhb.govt.nz
Contact person for public queries
Name 50411 0
Prof J. Geoffrey Chase
Address 50411 0
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 50411 0
New Zealand
Phone 50411 0
(+64) (3) 364 2987 ext 7224
Fax 50411 0
Email 50411 0
geoff.chase@canterbury.ac.nz
Contact person for scientific queries
Name 50412 0
Prof J Geoffrey Chase
Address 50412 0
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 50412 0
New Zealand
Phone 50412 0
(+64) (3) 364 2987 ext 7224
Fax 50412 0
Email 50412 0
geoff.chase@canterbury.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Patients are deindentified for the trial. The trial involves critically ill patients in which we wish not to provide the information to the public.
What supporting documents are/will be available?
No other documents available
Summary results
No Results