Open Lung Ventilation in ARDS: The PHARLAP Trial

NCT01667146 | Terminated Results

• 1 other identifier: ANZIC-RC/AD002 Version 8
• Study Type: interventional
• Target: 115
• Locations: 5 countries
• Sites: 27

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.

Conditions

Acute Respiratory Distress Syndrome

Outcome Measures

Primary Outcomes (1)

• 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).

  28 days post randomisation

Secondary Outcomes (11)

• 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

• Number of Severe Hypotension Events

  Up to 28 days post randomisation

• Number of Participants With 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

Study Arms (2)

PHARLAP ventilation group

EXPERIMENTAL

PHARLAP mechanical ventilation strategy

Other: PHARLAP mechanical ventilation strategy

Control group ventilation

ACTIVE COMPARATOR

Control group mechanical ventilation strategy

Other: Control group mechanical ventilation strategy

Interventions

PHARLAP mechanical ventilation strategy OTHER

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.

PHARLAP ventilation group

Control group mechanical ventilation strategy OTHER

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.

Control group ventilation

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• \> 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

Sponsors & Collaborators

• Australian and New Zealand Intensive Care Research Centre: lead
• University College Dublin: collaborator

Study Sites (27)

Albury/Wodonga

Albury, New South Wales, Australia

Location

Nepean Hospital

Kingswood, New South Wales, 2747, Australia

Location

Royal Prince Alfred

Sydney, New South Wales, Australia

Location

Wollongong Hospital

Wollongong, New South Wales, 2500, Australia

Location

The Prince Charles Hospital

Brisbane, Queensland, Australia

Location

Flinders Medical Centre

Adelaide, South Australia, Australia

Location

Geelong Hospital

Geelong, Victoria, 3220, Australia

Location

The Alfred Hosptial

Melbourne, Victoria, 3004, Australia

Location

Adelaide and Meath (Tallaght) Hospital

Dublin, Ireland

Location

Beaumont Hospital

Dublin, Ireland

Location

Mater Misericordiae University Hospital

Dublin, Ireland

Location

St Vincents Hospital

Dublin, Ireland

Location

University Hospital Limerick

Limerick, Ireland

Location

Middlemore Hospital

Otahuhu, Auckland, 1640, New Zealand

Location

Auckland City Hospital (DCCM)

Auckland, 1142, New Zealand

Location

Auckland City Hospital CVICU

Auckland, 1142, New Zealand

Location

King Abdulaziz Medical City

Riyadh, Saudi Arabia

Location

Peterborough City Hospital

Peterborough, Cambridgeshire, United Kingdom

Location

Derriford Hospital

Plymouth, Devon, United Kingdom

Location

Princess Royal University Hospital

Orpington, Kent, United Kingdom

Location

Royal Surrey County Hospital

Guildford, Surrey, United Kingdom

Location

Southmead Hospital

Bristol, United Kingdom

Location

Hull Royal Infirmary

Hull, United Kingdom

Location

King's College Hospital

London, United Kingdom

Location

North Middlesex University Hospital

London, United Kingdom

Location

University Hospital, Lewisham

London, United Kingdom

Location

James Cook University Hospital

Middlesbrough, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 31356105 BACKGROUND

• 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.

  PMID: 29852853 BACKGROUND

• 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.

  PMID: 38045528 BACKGROUND

MeSH Terms

Conditions

Respiratory Distress Syndrome

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Limitations and Caveats

The power of the study was limited by lower than expected recruitment rates, early termination of the trial (due to the publication of the ART trial), and treatment crossovers. Blinding was not possible within the ICU, staff and relatives were aware of group allocation.

Results Point of Contact

• Title: Prof Carol Hodgson
• Organization: ANZIC - RC, Monash University

carol.hodgson@monash.edu

+61 (3) 99030598

Study Officials

• Carol Hodgson, PhD, FACP, BAppSc

  Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)

  STUDY CHAIR

• Alistair Nichol, PhD, FCICM

  Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr Carol Hodgson

Study Record Dates

• First Submitted: August 12, 2012
• First Posted: August 17, 2012
• Study Start: October 1, 2012
• Primary Completion: October 1, 2017
• Study Completion: March 1, 2018
• Last Updated: July 18, 2024
• Results First Posted: July 18, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Is available on request
• Access Criteria: request made to custodian via Australian and New Zealand Intensive Care Research Centre See ANZIC-RC website term of reference document

Locations

AU (8); IE (5); GB (10); NZ (3); SA (1)