A Multi-centre Trial of an Open Lung Strategy Including Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure in Patients With Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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Some people develop the condition called acute respiratory distress syndrome (ARDS). This is a condition where the lungs have become injured from one of a number of various causes, and do not work as they normally do to provide oxygen and remove carbon dioxide from the body. This can lead to a reduced amount of oxygen in the patient's bloodstream. Patients with ARDS are admitted to the intensive care unit (ICU) and need help with their breathing by being connected to a ventilator (breathing machine). ARDS can lead to injury in other organs of the body causing other problems but also death. Over the past few years, reducing the size of each breath delivered by the ventilator in conjunction with the use of an occasional sustained deep breath called a recruitment manoeuvre have been used to try to prevent further damage to the lungs in people with ARDS. This ventilator strategy (termed the PHARLAP strategy) has been shown in a small research study to have some beneficial effects without causing any obvious harm, when compared to a current best practice ventilator strategy. The main beneficial effects of the PHARLAP strategy were to increase the amount of oxygen in the blood and to reduce markers of inflammation (the body reacting to a disease process) in the body. This study was too small to make a strong conclusion, so this study will be much larger and will assess whether patients who have developed ARDS are better off when we use the PHARLAP strategy. Three hundred and forty patients will be enrolled into this study in multiple ICUs across Australia and New Zealand. The study hypothesis is that the PHARLAP strategy group will have a higher number of ventilator free days at day 28 than the control group.

Official Title
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A Multi-centre Randomised Controlled Trial of an Open Lung Strategy Including Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure in Patients With Acute Respiratory Distress Syndrome.

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Other: PHARLAP mechanical ventilation strategy
* Other: Control group mechanical ventilation strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult ICU patients who met all of the following criteria: Currently intubated and receiving mechanical ventilation Within 72 Hours of a diagnosis of ARDS (moderate and severe) based on the following Berlin definition: Within 1 week of a known clinical insult or new or worsening respiratory symptoms Bilateral opacities on CXR which are not fully explained by effusions, lobar/lung collapse or nodules Respiratory failure not fully explained by cardiac failure or fluid overload PaO2/FiO2 < 200mmHg with PEEP ≥ 5cmH2O Exclusion Criteria: > 72 hours since diagnosis of ARDS > 10 days of continuous mechanical ventilation Barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema or any intercostal catheter for the treatment of air leak) Significant chest trauma i.e. multiple rib fractures Active bronchospasm or a history of significant chronic obstructive pulmonary disease or asthma Clinical suspicion for significant restrictive lung disease (history of pulmonary fibrosis or suggestive pulmonary function tests) Moderate or severe traumatic brain injury, the presence of an intracranial pressure monitor, or any medical condition associated with a clinical suspicion of raised intracranial pressure Unstable cardiovascular status defined as sustained heart rate < 40 or > 140 bpm, ventricular tachycardia, or SBP < 80mmHg Pregnancy Receiving ECMO Receiving high frequency oscillatory ventilation Death is deemed imminent and inevitable The treating physician believes it is not in the best interest of the patient to be enrolled in the trial Consent not obtained or refused by patient's legal surrogate

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PHARLAP ventilation group<br>PHARLAP mechanical ventilation strategy | Other: PHARLAP mechanical ventilation strategy<br>* Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH > 7.15; daily staircase recruitment manoeuvre and individualised PEEP titration.<br>|
| Active Comparator: Control group ventilation<br>Control group mechanical ventilation strategy | Other: Control group mechanical ventilation strategy<br>* Mechanical ventilation based on the ARDSnet protocol using volume control ventilation with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and FiO2/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of ventilator free days at day 28 post randomisation |  | 28 days post randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PaO2/FiO2 ratio and static lung compliance |  | Up to day 28 post randomisation | 
| Baseline to day 3 change in IL-8 and IL-6 concentrations in broncho-alveolar lavage and plasma |  | Day 3 post randomisation | 
| Incidence of severe hypotension |  | Up to 90 days post randomisation | 
| Incidence of barotrauma |  | Up to 90 days post randomisation | 
| Use of rescue therapies for severe hypoxaemia - inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO) |  | Within hospital admission | 
| Mortality | At timepoints: ICU discharge, hospital discharge, 28 days, 90 days and 6 months | Up to 6 months post randomisation | 
| ICU and hospital length of stay |  | Up to 6 months | 
| Incidence of AKI |  | Within hospital admission | 
| Quality of life assessment | SF36v2 | 6 months post randomisation | 
| Cost effectiveness analysis | Based on EQ-5D | 6 months post randomisation |