Open Lung Ventilation in ARDS: The PHARLAP Trial

Australian and New Zealand Intensive Care Research Centre115 enrolled

Overview

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.

340 adult patients who have developed ARDS within the last 72 hours (and within 10 days of commencing mechanical ventilation) will be enrolled in 25- 30 intensive care units (ICUs) and randomly allocated to either the PHARLAP or a control ventilation strategy. PHARLAP strategy: 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 Positive-end expiratory pressure (PEEP) titration. Control strategy: Mechanical ventilation based on the ARDSnet protocol with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and fraction inspired oxygen (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. A standardised weaning from mechanical ventilation guideline will be used in both groups

Study Type

Interventions

PHARLAP mechanical ventilation strategyOTHER

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.

Control group mechanical ventilation strategyOTHER

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.

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

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 chest x-ray (CXR) which are not fully explained by effusions, lobar/lung collapse or nodules * Respiratory failure not fully explained by cardiac failure or fluid overload * Arterial oxygen pressure (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

Locations (27)

Albury/Wodonga

Albury, New South Wales, Australia

Nepean Hospital

Kingswood, New South Wales, Australia

Royal Prince Alfred

Sydney, New South Wales, Australia

Wollongong Hospital

Wollongong, New South Wales, Australia

The Prince Charles Hospital

Brisbane, Queensland, Australia

Flinders Medical Centre

Adelaide, South Australia, Australia

Geelong Hospital

Geelong, Victoria, Australia

The Alfred Hosptial

Melbourne, Victoria, Australia

Adelaide and Meath (Tallaght) Hospital

Dublin, Ireland

Beaumont Hospital

Dublin, Ireland

...and 17 more locations

Outcomes

Primary Outcomes

Number of Ventilator Free Days at Day 28 Post Randomisation

This is the total number of days calculated from day 1 (randomisation) to day 28 on which the patient was alive and received no assistance from invasive mechanical ventilation. Scores range between 0 (no ventilator free days) to 28 (no days on ventilator).

Time frame: 28 days post randomisation

Secondary Outcomes

PaO2/FiO2 Ratio and Static Lung Compliance

PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage). ARDS severity Mild 200-300 / Moderate 100-200 / Severe \<100.

Time frame: Up to day 28 post randomisation

Baseline to Day 3 Change in IL-8 and IL-6 Concentrations in Broncho-alveolar Lavage and Plasma

IL-8 is an important protein related to inflammation, Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response

Time frame: Day 3 post randomisation

Number of Severe Hypotension Events

Hypotension requiring increased vasopressor Days 1-28

Time frame: Up to 28 days post randomisation

Number of Participants With Barotrauma

Evidence of Pneumothorax requiring Drainage

Time frame: 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)

The use of various rescue therapies (each of the therapies is compared between groups - per patient). the various therapies measured are inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO)

Time frame: Within hospital admission

Mortality

At timepoints: day 28

Time frame: at day 28

ICU Length of Stay

The number of days a person stayed in the ICU. A fraction of a day is considered a day

Time frame: From admission to ICU up to 6 months

Incidence of Acute Kidney Injury (AKI)

The incidence of Acute Renal Injury - measured by the use of Continuous Renal Replacement Therapy (CRRT) in each person

Time frame: Within hospital admission

Quality of Life Assessment

SF36v2 will be used Medical Outcomes Study. Scoring the RAND is a two-step process. First, pre-coded numeric values are recoded. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores.

Time frame: 6 months post randomisation

Cost Effectiveness Analysis

This will be based on EQ-5D. EQ-5D is the most widely used health-related quality of life questionnaire in health economic evaluations.\[62\] EQ-5D can be used to derive a set of values that reflect people's opinions of the relative importance of different health problems. These values can be used to derive QALYs for application in cost-effectiveness and cost-utility evaluations.

Time frame: 6 months post randomisation

Hospital Length of Stay

The length of time in days a participant stayed in hospital. A fraction of a day is considered 1 day.

Time frame: From admission up to 6 months