Open Lung Ventilation in ARDS: The PHARLAP Trial (PHARLAP)

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.

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.

Study Overview

• Status: Terminated
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Other: PHARLAP mechanical ventilation strategy; Other: Control group mechanical ventilation strategy

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

• Study Type: Interventional
• Enrollment (Actual): 115
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia
      • Albury/Wodonga
    • Kingswood, New South Wales, Australia, 2747
      • Nepean Hospital
    • Sydney, New South Wales, Australia
      • Royal Prince Alfred
    • Wollongong, New South Wales, Australia, 2500
      • Wollongong Hospital
  • Queensland
    • Brisbane, Queensland, Australia
      • The Prince Charles Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Flinders Medical Centre
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Geelong Hospital
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hosptial
• Ireland
  • Dublin, Ireland
    • Beaumont Hospital
  • Dublin, Ireland
    • Mater Misericordiae University Hospital
  • Dublin, Ireland
    • St Vincents Hospital
  • Dublin, Ireland
    • Adelaide and Meath (Tallaght) Hospital
  • Limerick, Ireland
    • University Hospital Limerick
• New Zealand
  • Auckland, New Zealand, 1142
    • Auckland City Hospital (DCCM)
  • Auckland, New Zealand, 1142
    • Auckland City Hospital CVICU
  • Auckland
    • Otahuhu, Auckland, New Zealand, 1640
      • Middlemore Hospital
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • King Abdulaziz Medical City
• United Kingdom
  • Bristol, United Kingdom
    • Southmead Hospital
  • Hull, United Kingdom
    • Hull Royal Infirmary
  • London, United Kingdom
    • North Middlesex University Hospital
  • London, United Kingdom
    • King's College Hospital
  • London, United Kingdom
    • University Hospital, Lewisham
  • Middlesbrough, United Kingdom
    • James Cook University Hospital
  • Cambridgeshire
    • Peterborough, Cambridgeshire, United Kingdom
      • Peterborough City Hospital
  • Devon
    • Plymouth, Devon, United Kingdom
      • Derriford Hospital
  • Kent
    • Orpington, Kent, United Kingdom
      • Princess Royal University Hospital
  • Surrey
    • Guildford, Surrey, United Kingdom
      • Royal Surrey County Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PHARLAP ventilation group; PHARLAP mechanical ventilation strategy	Other: PHARLAP mechanical ventilation 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 PEEP titration.
Active Comparator: Control group ventilation; Control group mechanical ventilation strategy	Other: Control group mechanical ventilation strategy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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	Day 3 post randomisation
Number of Severe Hypotension Events	Hypotension requiring increased vasopressor Days 1-28	Up to 28 days post randomisation
Number of Participants With Barotrauma	Evidence of Pneumothorax requiring Drainage	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)	Within hospital admission
Mortality	At timepoints: day 28	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	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	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.	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.	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.	From admission up to 6 months

Collaborators and Investigators

• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Collaborators: University College Dublin
• Investigators: Study Chair: Alistair Nichol, PhD, FCICM, Australian and New Zealand Intensive Care Research Centre (ANZIC-RC); Study Chair: Carol Hodgson, PhD, FACP, BAppSc, Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: August 12, 2012
• First Submitted That Met QC Criteria: August 15, 2012
• First Posted (Estimated): August 17, 2012

Study Record Updates

• Last Update Posted (Actual): July 18, 2024
• Last Update Submitted That Met QC Criteria: February 4, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: ANZIC-RC/AD002 Version 8

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The Australian and New Zealand Intensive Care Research Centre (ANZIC RC), Monash University supports the view that:

• Publicly funded research data should be made available with as few restrictions as possible
• Data sharing could enhance public well-being by maximising utilisation of gained knowledge, reducing redundant research and facilitating scientific innovation,
• Data sharing must be responsible, recognise legal, regulatory, ethical and commercial constraints.

The ANZIC-RC has formulated a policy and process to allow appropriate and responsible sharing of research data including prospective and completed studies.

This Policy was guided by, Institute of Medicine principles for responsible sharing of clinical trial data:

• Maximise the benefits of clinical trials
• Minimising the risks of data sharing
• Respect individual participants
• Increase public trust in clinical trials
• Conduct the sharing of trial data in a fair manner
• Appropriately manage conflicts of interest.

• IPD Sharing Time Frame: Is available on request

IPD Sharing Access Criteria

request made to custodian via Australian and New Zealand Intensive Care Research Centre

See ANZIC-RC website term of reference document

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No