Open Lung Ventilation in ARDS: The PHARLAP Trial

Not Applicable

Terminated

Conditions: Acute Respiratory Distress Syndrome

Interventions: Other: PHARLAP mechanical ventilation strategy
Other: Control group mechanical ventilation strategy

Registration Number: NCT01667146

Lead Sponsor: Australian and New Zealand Intensive Care Research Centre

Brief Summary: 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.

Detailed Description: 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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 115

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PHARLAP ventilation group	PHARLAP mechanical ventilation strategy	PHARLAP mechanical ventilation strategy
Control group ventilation	Control group mechanical ventilation strategy	Control group mechanical ventilation strategy

Primary Outcome Measures

Name	Time	Method
Number of Ventilator Free Days at Day 28 Post Randomisation	28 days 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).

Secondary Outcome Measures

Name	Time	Method
PaO2/FiO2 Ratio and Static Lung Compliance	Up to day 28 post randomisation	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.
Baseline to Day 3 Change in IL-8 and IL-6 Concentrations in Broncho-alveolar Lavage and Plasma	Day 3 post randomisation	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
ICU Length of Stay	From admission to ICU up to 6 months	The number of days a person stayed in the ICU. A fraction of a day is considered a day
Number of Severe Hypotension Events	Up to 28 days post randomisation	Hypotension requiring increased vasopressor Days 1-28
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	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)
Incidence of Acute Kidney Injury (AKI)	Within hospital admission	The incidence of Acute Renal Injury - measured by the use of Continuous Renal Replacement Therapy (CRRT) in each person
Number of Participants With Barotrauma	Up to 90 days post randomisation	Evidence of Pneumothorax requiring Drainage
Mortality	at day 28	At timepoints: day 28
Quality of Life Assessment	6 months post randomisation	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.
Cost Effectiveness Analysis	6 months post randomisation	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.
Hospital Length of Stay	From admission up to 6 months	The length of time in days a participant stayed in hospital. A fraction of a day is considered 1 day.

Trial Locations

Locations (27): Nepean Hospital
🇦🇺
Kingswood, New South Wales, Australia
Wollongong Hospital
🇦🇺
Wollongong, New South Wales, Australia
Geelong Hospital
🇦🇺
Geelong, Victoria, Australia
The Alfred Hosptial
🇦🇺
Melbourne, Victoria, Australia
Adelaide and Meath (Tallaght) Hospital
🇮🇪
Dublin, Ireland
University Hospital, Lewisham
🇬🇧
London, United Kingdom
Flinders Medical Centre
🇦🇺
Adelaide, South Australia, Australia
Princess Royal University Hospital
🇬🇧
Orpington, Kent, United Kingdom
St Vincents Hospital
🇮🇪
Dublin, Ireland
Albury/Wodonga
🇦🇺
Albury, New South Wales, Australia
Royal Prince Alfred
🇦🇺
Sydney, New South Wales, Australia
The Prince Charles Hospital
🇦🇺
Brisbane, Queensland, Australia
Beaumont Hospital
🇮🇪
Dublin, Ireland
Middlemore Hospital
🇳🇿
Otahuhu, Auckland, New Zealand
University Hospital Limerick
🇮🇪
Limerick, Ireland
Auckland City Hospital (DCCM)
🇳🇿
Auckland, New Zealand
Auckland City Hospital CVICU
🇳🇿
Auckland, New Zealand
Peterborough City Hospital
🇬🇧
Peterborough, Cambridgeshire, United Kingdom
Southmead Hospital
🇬🇧
Bristol, United Kingdom
Hull Royal Infirmary
🇬🇧
Hull, United Kingdom
King's College Hospital
🇬🇧
London, United Kingdom
James Cook University Hospital
🇬🇧
Middlesbrough, United Kingdom
North Middlesex University Hospital
🇬🇧
London, United Kingdom
King Abdulaziz Medical City
🇸🇦
Riyadh, Saudi Arabia
Royal Surrey County Hospital
🇬🇧
Guildford, Surrey, United Kingdom
Mater Misericordiae University Hospital
🇮🇪
Dublin, Ireland
Derriford Hospital
🇬🇧
Plymouth, Devon, United Kingdom