Clinical trial NCT01667146: Open Lung Ventilation in ARDS: The PHARLAP Trial
Official title: 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Acute Respiratory Distress Syndrome
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
Collaborators: name: University College Dublin
First posted: 2012-08-17
Enrollment: 115
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Number of Ventilator Free Days at Day 28 Post Randomisation
timeFrame: 28 days post randomisation
Secondary outcomes:
measure: PaO2/FiO2 Ratio and Static Lung Compliance
timeFrame: Up to day 28 post randomisation
measure: Baseline to Day 3 Change in IL-8 and IL-6 Concentrations in Broncho-alveolar Lavage and Plasma
timeFrame: Day 3 post randomisation
measure: Number of Severe Hypotension Events
timeFrame: Up to 28 days post randomisation
measure: Number of Participants With Barotrauma
timeFrame: Up to 90 days post randomisation
measure: Use of Rescue Therapies for Severe Hypoxaemia - Inhaled Nitric Oxide, Inhaled Prostacyclin, Prone Positioning, High Frequency Oscillatory Ventilation and Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: Within hospital admission
measure: Mortality
timeFrame: at day 28
measure: ICU Length of Stay
timeFrame: From admission to ICU up to 6 months
measure: Incidence of Acute Kidney Injury (AKI)
timeFrame: Within hospital admission
measure: Quality of Life Assessment
timeFrame: 6 months post randomisation
measure: Cost Effectiveness Analysis
timeFrame: 6 months post randomisation
measure: Hospital Length of Stay
timeFrame: From admission up to 6 months
Other outcomes:
Locations:
city: Albury
country: Australia
facility: Albury/Wodonga
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Geelong
country: Australia
facility: Geelong Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hosptial
state: Victoria
city: Dublin
country: Ireland
facility: Adelaide and Meath (Tallaght) Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: St Vincents Hospital
city: Limerick
country: Ireland
facility: University Hospital Limerick
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital
state: Auckland
city: Auckland
country: New Zealand
facility: Auckland City Hospital (DCCM)
city: Auckland
country: New Zealand
facility: Auckland City Hospital CVICU
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Peterborough
country: United Kingdom
facility: Peterborough City Hospital
state: Cambridgeshire
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: Devon
city: Orpington
country: United Kingdom
facility: Princess Royal University Hospital
state: Kent
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: Surrey
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: North Middlesex University Hospital
city: London
country: United Kingdom
facility: University Hospital, Lewisham
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
Study officials:
affiliation: Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)
name: Carol Hodgson, PhD, FACP, BAppSc
role: STUDY_CHAIR
affiliation: Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)
name: Alistair Nichol, PhD, FCICM
role: STUDY_CHAIR
References:
citation: Hodgson CL, Cooper DJ, Arabi Y, King V, Bersten A, Bihari S, Brickell K, Davies A, Fahey C, Fraser J, McGuinness S, Murray L, Parke R, Paul E, Tuxen D, Vallance S, Young M, Nichol A. Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP). A Phase II, Multicenter Randomized Controlled Clinical Trial. Am J Respir Crit Care Med. 2019 Dec 1;200(11):1363-1372. doi: 10.1164/rccm.201901-0109OC.
citation: Hodgson C, Cooper DJ, Arabi Y, Bennett V, Bersten A, Brickell K, Davies A, Fahey C, Fraser J, McGuinness S, Murray L, Parke R, Tuxen D, Vallance S, Young M, Nichol AD; PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP): a protocol for a phase 2 trial in patients with acute respiratory distress syndrome. Crit Care Resusc. 2018 Jun;20(2):139-149.
citation: Bihari S, Bersten A, Paul E, McGuinness S, Dixon D, Sinha P, Calfee CS, Nichol A, Hodgson C; PHARLAP Study Investigators. Acute respiratory distress syndrome phenotypes with distinct clinical outcomes in PHARLAP trial cohort. Crit Care Resusc. 2023 Oct 18;23(2):163-170. doi: 10.51893/2021.2.oa3. eCollection 2021 Jun.