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.
Phase: NA
Conditions: Acute Respiratory Distress Syndrome
Sponsor: Australian and New Zealand Intensive Care Research Centre

 
 
CONFIDENTIAL 
    
 
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. 
 
Chief Investigators: 
              Dr Carol Hodgson 
Australia and New Zealand Intensive Care Research Centre 
Department of Epidemiology and Preventive Medicine 
School of Public Health and Preventive Medicine 
 
 
 
 
Phone: 
 
 Fax: 
 
 Email: 
 
 
Professor Alistair Nichol 
Australia and New Zealand Intensive Care Research Centre 
Department of Epidemiology and Preventive Medicine 
School of Public Health and Preventive Medicine 
Phone: 
 
Fax: 
 
Email: 
 
 
Coordinating Centre:  
 
The Australian & New Zealand Intensive Care Research Centre  
Department of Epidemiology and Preventive Medicine 
School of Public Health and Preventive Medicine, Monash University  
The Alfred Centre, 99 Commercial Road,  
Melbourne, Victoria, 3004 
AUSTRALIA 
Phone: 
 
Fax: 
 
Email: 
 
 

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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................................................ 4 
STUDY ADMINISTRATION STRUCTURE ................................................................................................................... 5 
Coordinating Centre ........................................................................................................................................... 5 
Management Committee ................................................................................................................................... 5 
Training and Education Committee .................................................................................................................... 6 
Steering Committee ............................................................................................................................................ 6 
Contact Details .................................................................................................................................................... 7 
Endorsement ...................................................................................................................................................... 7 
MANAGEMENT COMMITTEE AUTHORISATION ...................................................................................................... 8 
LAY DESCRIPTION.................................................................................................................................................. 10 
ABBREVIATIONS .................................................................................................................................................... 11 
BACKGROUND & RATIONALE................................................................................................................................ 13 
Acute Respiratory Distress Syndrome .............................................................................................................. 13 
ARDS pathophysiology and the effect of mechanical ventilation on organ failure .......................................... 13 
What are the attributes of the “ideal” mechanical ventilation strategy in ARDS ............................................ 14 
PHARLAP pilot randomised controlled trial ...................................................................................................... 15 
Feasibility of an Australasian trial of the PHARLAP strategy in ARDS ............................................................... 16 
Significance ....................................................................................................................................................... 16 
OBJECTIVES ........................................................................................................................................................... 17 
Aim .................................................................................................................................................................... 17 
Hypothesis ........................................................................................................................................................ 17 
STUDY OUTCOME MEASURES .............................................................................................................................. 17 
Primary outcome .............................................................................................................................................. 17 
Secondary outcome .......................................................................................................................................... 17 
Determination of primary outcome ................................................................................................................. 18 
STUDY METHODOLOGY ........................................................................................................................................ 19 
Study outline ..................................................................................................................................................... 19 
Study population .............................................................................................................................................. 19 
Patient screening .............................................................................................................................................. 20 
Informed consent ............................................................................................................................................. 20 
Enrolment and randomisation .......................................................................................................................... 20 
Co-enrolment .................................................................................................................................................... 20 
PARTICIPATING STUDY SITES ................................................................................................................................ 21 
STUDY PROCEDURES ............................................................................................................................................. 22 
Commencement of mechanical ventilation strategy ........................................................................................ 22 
Control group mechanical ventilation .............................................................................................................. 24 
Intervention group (PHARLAP) mechanical ventilation .................................................................................... 27 
Weaning of mechanical ventilation in both groups .......................................................................................... 33 
Fluid management in both groups ................................................................................................................... 34 

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Use of corticosteroids in both groups .............................................................................................................. 35 
Other interventions in both groups .................................................................................................................. 35 
Discontinuation of treatment ........................................................................................................................... 35 
Table of events ................................................................................................................................................. 35 
Laboratory sampling ......................................................................................................................................... 35 
ETHICAL CONSIDERATIONS ................................................................................................................................... 36 
Guiding principles ............................................................................................................................................. 36 
Ethical issues of the study ................................................................................................................................ 36 
DATA MANAGEMENT ........................................................................................................................................... 38 
Data collection methods ................................................................................................................................... 38 
Data variables collected .................................................................................................................................... 38 
Data management ............................................................................................................................................ 39 
Monitoring ........................................................................................................................................................ 39 
Protocol deviations ........................................................................................................................................... 39 
STATISTICAL CONSIDERATIONS ............................................................................................................................ 40 
Power calculations and sample size ................................................................................................................. 40 
Statistical and analytical plan ........................................................................................................................... 40 
Interim analysis ................................................................................................................................................. 40 
Subgroup analyses ............................................................................................................................................ 40 
SAFETY OF SUBJECTS ............................................................................................................................................ 41 
Data Safety Monitoring Committee.................................................................................................................. 41 
Adverse events ................................................................................................................................................. 41 
Serious adverse events ..................................................................................................................................... 41 
FUNDING............................................................................................................................................................... 42 
PUBLICATION ........................................................................................................................................................ 42 
PROJECT TIMELINE................................................................................................................................................ 43 
REFERENCES .......................................................................................................................................................... 44 
APPENDIX 1: PREDICTED BODY WEIGHT (PBW) CALCULATION ............................................................................ 47 
APPENDIX 2: BRONCHOALVEOLAR LAVAGE (BAL) FLUID COLLECTION ................................................................ 48 
Non-bronchoscopic method: ............................................................................................................................ 48 
Bronchoscopic method: .................................................................................................................................... 48 
APPENDIX 3: SCHEDULE OF EVENTS ..................................................................................................................... 50 
APPENDIX 4: APACHE II SEVERITY OF DISEASE CLASSIFICATION .......................................................................... 52 
APPENDIX 5: SHORT FORM 36V2 AUSTRALIAN VERSION ..................................................................................... 55 
APPENDIX 6: EQ5D (ENGLISH VERSION FOR AUSTRALIA) ..................................................................................... 59 
APPENDIX 7: DIFFUSE VERSUS FOCAL ARDS SUBSTUDY ....................................................................................... 61 

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SYNOPSIS 
Background 
 
Acute respiratory distress syndrome (ARDS) is an inflammatory condition of 
the lungs, which is associated with high morbidity and mortality. Tidal 
volume and plateau pressure minimisation have been shown to decrease 
mortality in patients with ARDS. Open lung strategies, including higher 
positive end-expiratory pressure (PEEP) and recruitment manoeuvres, may 
provide an additional benefit, particularly if they are tailored for each 
patient. However, methodological limitations of previous studies may have 
hindered their ability to demonstrate a beneficial effect. 
 
A comprehensive open lung strategy (called PHARLAP) has been designed 
based on recent research, and this includes both tidal volume and plateau 
pressure limitation, as well as a staircase recruitment manoeuvre and 
individualised PEEP titration. In a pilot study this strategy was demonstrated 
to be safe and improved a range of physiological and inflammatory markers 
in patients with ARDS. 
 
Aim 
 
To investigate the clinical efficacy of the PHARLAP strategy compared to 
standard mechanical ventilation in ARDS patients. 
 
Objectives 
 
In a prospective, multi-centre, randomised controlled trial it will be 
determined whether PHARLAP ventilation increases ventilator free days 
compared to standard care. 
 
Methods 
 
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 PEEP 
titration. 
 
Control strategy: Mechanical ventilation based on the ARDSnet protocol 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. A standardised weaning from mechanical 
ventilation guideline will be used in both groups. 
 
Outcomes 
 
The primary outcome is the number of ventilator free days (VFDs) at day 28. 
Secondary outcomes include physiological (PaO2/FiO2 ratio, static lung 
compliance), inflammatory (IL-6 & IL-8 in blood and BAL), clinical (safety, 
length of stay, mortality and quality of life at 6 months) and economic (cost 
effectiveness at 6 months) variables. 
 
 

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STUDY ADMINISTRATION STRUCTURE 
Coordinating Centre 
Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), Department of Epidemiology and 
Preventative Medicine (DEPM) Monash University, Victoria, Australia 
Responsibilities 
• 
Overall management of the study including assistance with HREC applications 
• 
Management of study budget and liaison with funding bodies 
• 
Protocol and case report form (CRF) design and production 
• 
Database design and management 
• 
Protocol training of research coordinators and PHARLAP study team 
• 
Preparation and arrangement of investigator payments 
• 
Study set-up 
• 
Randomisation  
• 
Coordination of data entry and feedback of data enquiries 
• 
Monitoring and close-out site visits 
• 
Organisation of investigator meetings 
• 
Serious adverse event notification 
• 
Data analysis and collaboration on publications 
 
Management Committee 
Responsibilities 
Overseeing all aspects of the study management including: 
• 
Liaison with coordinating centre staff 
• 
Liaison with steering committee 
• 
Liaison with Australian & New Zealand Intensive Care Society Clinical Trials Group 
• 
Liaison with Clinical Informatics and Data Management Unit 
• 
Overseeing funding applications 
• 
Overseeing disbursement & administration of funds 
• 
Ensuring fiscal responsibilities are maintained 
• 
Development and approval of final protocol and study materials 
• 
Development and approval of data collection tools and methods 
• 
General study management issues 
Members 
• 
A/Prof Yaseen Arabi 
 
 
Chairman, Intensive Care Department, King Saud Bin  
 
 
 
 
 
Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia 
• 
Ms Victoria Bennett 
 
 
PHARLAP Project Manager, ANZIC-RC, Monash University 
• 
Prof Andrew Bersten 
 
 
Director Intensive Care, Flinders Medical Centre 

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• 
Prof Jamie Cooper 
 
 
Co-Director, ANZIC-RC, Monash University 
• 
Prof John Fraser  
 
 
Senior Intensivist, The Prince Charles Hospital 
• 
Dr Carol Hodgson 
 
 
Senior Research Fellow, ANZIC-RC, Monash University 
• 
Dr Shay McGuinness 
 
 
Senior Intensivist, Auckland City Hospital 
• 
Ms Lynne Murray 
 
 
Research Manager, ANZIC-RC, Monash University 
• 
Prof Alistair Nichol 
 
 
Professor, ANZIC-RC, Monash University 
• 
Ms Rachael Parke 
 
 
Research Co-ordinator, Auckland City Hospital 
• 
Prof David Tuxen  
 
 
Senior Intensivist, The Alfred Hospital 
• 
Ms Shirley Vallance 
 
 
Research Manager, The Alfred Hospital 
 
Training and Education Committee 
Responsibilities 
• 
Study start-up meetings 
• 
Protocol training to research coordinators and site investigators 
Members 
• 
Ms Victoria Bennett 
• 
Dr Carol Hodgson (co-chair) 
• 
Dr Shay McGuinness 
• 
Ms Rachael Parke 
• 
Prof David Tuxen (co-chair) 
 
Steering Committee 
Responsibilities 
• 
Oversight and advisory role 
• 
Data analysis, collaboration and approval of study publications 
Members 
• 
Management committee (as above) 
• 
Associate Investigators* 
*Local representatives to be appointed once sites confirmed 
 
 
 
 
 

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Contact Details 
Chief investigators 
Co-Chief Investigator 
Dr Carol Hodgson 
Senior Research Fellow – ANZIC-RC 
DEPM, School of Public Health and Preventive Medicine, Monash University 
The Alfred Centre, 99 Commercial Road,  
Melbourne, Victoria, 3004, Australia 
Ph:  
 
Fax: 
 
Email: 
 
 
Co-Chief Investigator 
Professor Alistair Nichol 
Adjunct Professor – ANZIC-RC 
DEPM, School of Public Health and Preventive Medicine, Monash University 
The Alfred Centre, 99 Commercial Road,  
Melbourne, Victoria, 3004, Australia 
Ph: 
 
Fax: 
 
Email: 
 
Coordinating centre 
ANZIC-RC 
DEPM, School of Public Health and Preventive Medicine, Monash University 
The Alfred Centre, 99 Commercial Road,  
Melbourne, Victoria, 3004, Australia  
Project manager 
Ms Victoria Bennett 
PHARLAP Project Manager - ANZIC-RC 
DEPM, School of Public Health and Preventive Medicine, Monash University 
The Alfred Centre, 99 Commercial Road 
Melbourne Victoria, 3004, Australia 
Tel: 
 
Fax: 
 
Mobile: 
  
E-mail: 
 
Endorsement 
The PHARLAP study has been endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials 
Group (ANZICS CTG). 

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LAY DESCRIPTION 
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. 

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ABBREVIATIONS 
A/C = assist/control ventilation  
AKI = acute kidney injury 
ANZIC-RC = Australian & New Zealand Intensive Care Research Centre 
ANZICS CTG = Australia & New Zealand Intensive Care Society Clinical Trials Group 
ARDS = acute respiratory distress syndrome 
ARDSnet = acute respiratory distress syndrome network 
bpm = beats per minute 
CIDMU = clinical informatics data management unit  
cmH2O = centimetres of water 
CPAP = continuous positive airway pressure 
CPMP = committee for proprietary medicinal products 
CT = computed topography 
CXR = chest X-ray 
ECMO = extra corporeal membrane oxygenation 
FiO2 = fraction of inspired oxygen  
GCP = good clinical practice 
HREC = Human Research and Ethics Committee  
ICH = international conference on harmonisation 
ICU = intensive care unit 
IL-6 = plasma interleukin 6 
IL-8 = plasma interleukin 8 
LRM = lung recruitment manoeuvres 
mmHg = millimetres of mercury 
ml/kg = millilitres per kilogram 
NHMRC = National Health and Medical Research Council 
OLS = open lung strategy 
PBW = predicted body weight 
PEEP = positive end expiratory pressure  
PEEPi = intrinsic positive end expiratory pressure 
PaO2 = partial pressure of oxygen in arterial blood 
PaCO2 = partial pressure of carbon dioxide  
Paw = peak airway pressure 
PSV = pressure support ventilation 
RCT = randomised controlled trial 
SAE = serious adverse event  
SaO2 = oxyhaemoglobin saturation measured in arterial blood 

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SBP = systolic blood pressure 
SIMV = synchronised intermittent mandatory ventilation 
SOFA = sequential organ failure assessment score 
SRM = staircase recruitment manoeuvre 
TNF = tumour necrosis factor 
VFDs = ventilator free days 
X-ray = radiograph 

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Inadequate and untitrated PEEP following recruitment manoeuvre 
It is likely that the level of PEEP set after an LRM is important and this should be the minimum required to 
maintain PEEP-dependent re-opening of atelectatic areas while avoiding PEEP-induced lung over-
inflation6,14,20,25,27,28. How best to achieve this has been one of the most vexed questions in critical care27,28. 
Various techniques have been proposed, including a) pulmonary mechanics (i.e. using super-syringe, plateau 
pressure etc)17,29,20, b) CT guided27,32 and c) FiO2/PEEP algorithms6,16. However, these techniques have been 
criticised because they are either clinically impractical, necessitate deep sedation or paralysis, lead to large 
physiological perturbations, introduce dangers related to radiation exposure and patient transport, lack sound 
physiological rationale, or are insensitive to heterogeneous pulmonary lesions (the presence of recruitable vs 
non-recruitable alveoli) and may be injurious (PEEP induced over inflation)23,30,12,27. Oxygen saturation 
measured by pulse oximetry is a familiar, simple and a physiologically sound “yard stick”, for clinicians to 
determine the minimum PEEP needed to maintain recruitment. In brief, the fraction of inspired oxygen (FiO2) 
is adjusted to achieve a saturation of 90-92% (the “shoulder” of the oxyhaemaglobin dissociation curve), a 
point where even small increases in alveolar collapse (de-recruitment) will increase pulmonary shunt and 
reduce oxygenation as detected by a fall in saturation22,26. After adequate recruitment (i.e. the SRM), PEEP is 
reduced in incremental steps until a drop in saturation occurs, the de-recruitment point (Fig. 3). A further LRM 
is then performed to re-expand these newly collapsed alveoli and the PEEP is ‘set’ at the step above the de-
recruitment point (i.e. 2.5 cmH2O higher, Fig 3). This approach has been demonstrated to lead to sustained 
improvements in ARDS patients25,31. While Huh et al demonstrated that PEEP titration resulted in improved 
oxygenation levels and was safe, it did not affect mortality32. Unfortunately, this small study seemed likely to 
have been hindered by an inadequate LRM (max PEEP 25 cmH2O) and a PEEP titration approach which 
permitted insufficient levels of PEEP (i.e. <15 cmH2O) post LRM14. 
Higher plateau pressures in the prior OLS high PEEP groups6,7,20, due to similar tidal volume in both groups may 
also have confounded detection of the potential beneficial effects. In addition, OLS may be beneficial in ARDS 
but not in ALI patients33, suggesting the previous inclusion of ALI patients in prior studies may have diluted 
their potential to detect a protective effect6,7,17. 
Even lower tidal volume and airway pressures 
Amato et al demonstrated that the use of lower tidal volume (6 ml/kg) and plateau airway pressures to 
minimise alveolar strain reduced mortality compared to higher tidal volume (12 ml/kg)17, a finding confirmed 
in the multi-centre ARDSnet study16. Laboratory work34 and recent clinical evidence, including an unpublished 
meta-analysis by Amato (personal communication) demonstrate a correlation between plateau pressure (even 
< 30 cmH2O) and mortality in ARDS. This suggests that even the current “non-injurious” tidal volumes and 
airway pressures which are commonly accepted may be too high and augment lung injury. Plateau airway 
pressures of about 25–28 cmH2O appear to be safer34,35. Reducing tidal volume and plateau pressure therefore 
aims to further minimise alveolar strain, especially in conjunction with an OLS encouraging higher PEEP levels. 
Permissive hypercapnia to facilitate reduced tidal volume and airway pressures 
The tolerance of hypercapnia to limit repetitive alveolar strain (i.e. tidal volume and plateau pressure) has 
been advocated by many36,37. Hypercapnia may also be protective independent of any changes in tidal 
volume38-40. Furthermore, hypercapnia is well tolerated by the critically ill36,37 and the benefit of tightly 
controlling CO2 is questionable and may even augment lung injury41. The ideal OLS should tolerate hypercapnia 
to minimise alveolar strain. 
 
PHARLAP pilot randomised controlled trial  
A pilot trial was conducted to examine the effectiveness and safety of such an Open Lung Strategy, which 
included permissive hypercapnia, stepwise alveolar recruitment manoeuvres (SRM) with PEEP titration 
(titrating against oxygen saturation) and low airway pressure (PHARLAP)31. ARDS patients were randomised to 
PHARLAP (n=10) or control ventilation (n=10) strategies. By design, the PHARLAP group had higher levels of 
PEEP, but not plateau pressures, than the control group. 
Compared to the control group the PHARLAP strategy significantly improved: 
i) Physiological markers: oxygenation (PaO2/FiO2 ratio) and pulmonary mechanics (static lung compliance) over 
7 days, suggesting sustained increases in alveolar recruitment. 

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ii) Systemic inflammatory markers: greater reduction from baseline to day 7 plasma interleukin-8 (IL-8) and 
tumour necrosis factor-alpha (TNFα) suggesting reduced biotrauma. 
iii) Clinical/patient-centred outcomes: Non-significant improvements in VFDs (14.8 v 11.8 days), ICU and 
hospital length of stay and reduced use of hypoxaemic rescue therapies. 
Summary: The PHARLAP ventilation strategy improved lung function (oxygenation, compliance and the use of 
hypoxaemic rescue therapies), reduced systemic inflammation (cytokine concentrations) and was associated 
with non-significant improvements in patient-centred outcomes (although was significantly underpowered to 
detect a difference in these outcomes). 
 
Feasibility of an Australasian trial of the PHARLAP strategy in ARDS 
The ANZICS CTG has the proven ability to conduct large-scale, multi-centre, clinical trials in critically ill 
patients42 and this study has been endorsed by the ANZICS CTG. 
The investigators have an established track record in conducting world-leading studies involving ARDS patients, 
published in the highest impact journals (NEJM, JAMA, AJRCCM)3,4,5,7,17. In addition, they have extensive 
experience conducting large-scale randomised controlled trials of complex critical care interventions (SAFE43, 
Feeding Guidelines study44, DECRA45, ARISE (NCT00975793) and POLAR (NCT00987688)). They have conducted 
a number of laboratory38,39 and clinical studies17,25,26,31 demonstrating the safety and efficacy of the 
components of the PHARLAP study. 
The feasibility of the PHARLAP strategy has been tested in a separate study investigating the adherence to the 
PHARLAP strategy protocol at Prince Charles Hospital (Qld) and Flinders Medical Centre (SA) 
(ACTRN12611000665932). 
A one-month prospective observational study in 2010 determined that 27 patients met the PHARLAP inclusion 
criteria; an average of 1 patient per site per month in Australia and New Zealand. This recruitment rate is 
consistent with previous experience conducting observational3 and interventional7,31, ventilation studies in our 
region. Assuming a recruitment rate of 50% (including refusal of consent), we aim to recruit 150 patients per 
annum, with 25 sites, resulting in a 2¼ year enrolment period. 
 
Significance 
There is substantial experimental evidence, biological rationale, and supportive clinical evidence to suggest the 
efficacy of the PHARLAP ventilation strategy in ARDS. However, mostly because of concern that SRM’s and high 
PEEP may cause barotrauma and haemodynamic instability in critically ill patients, previous trials may have 
been sub-optimally designed to determine the true efficacy of such an OLS. The PHARLAP strategy is more 
intensive, more individual patient tailored and at least as safe as previously studied open lung strategies. In 
addition, the PHARLAP strategy can be delivered by almost any clinician using any conventional mechanical 
ventilator and if proven effective and safe, would be highly applicable for widespread use (including the 
developing world). Given the significance and cost of ARDS, the possible benefits of this strategy, the growing 
number of recommendations for the use of a LRM with elevated levels of PEEP18,19,46, this study is an important 
undertaking. The trial will determine whether the PHARLAP ventilation strategy is effective in increasing 
ventilator free days in patients with ARDS. If the PHARLAP strategy is proven to improve ventilator free days it 
will provide a strong impetus to conduct an international phase III RCT to determine the effects of this strategy 
on mortality. 

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OBJECTIVES 
Aim 
To determine the efficacy of the PHARLAP strategy compared to a control ventilation strategy in increasing 
ventilator free days assessed during the 28 days post randomisation. 
 
Hypothesis 
The PHARLAP strategy group will have a higher number of ventilator free days at day 28 than the control 
group. 
 
STUDY OUTCOME MEASURES 
Primary outcome 
• 
Number of ventilator free days at day 28 post randomisation 
 
Secondary outcome 
• 
Physiological outcomes: 
 
PaO2/FiO2 ratio 
 
Static lung compliance 
• 
Inflammatory outcomes: 
 
Baseline to day 3 change in IL-8 and IL-6 concentrations in broncho-alveolar lavage fluid 
 
Baseline to day 3 change in IL-8 and IL-6 concentrations in plasma 
• 
Clinical/patient-centred efficacy outcomes: 
 
Use of rescue therapies for severe hypoxaemia – inhaled nitric oxide, inhaled prostacyclin, 
prone positioning, high frequency oscillatory ventilation and extracorporeal membrane 
oxygenation (ECMO) 
 
Incidence of acute kidney injury (AKI) 
 
ICU and hospital length of stay 
 
Quality of life assessment (SF-36v2 and EQ-5D) at 6 months 
 
Mortality at ICU/hospital discharge, 28 days, 90 days and 6 months 
 
Cause of death 
• 
Safety outcomes: 
 
Barotrauma 
 
Severe hypotension 
 
Serious adverse effects (SAEs) 
• 
Economic outcomes: 
 
Cost effectiveness analysis at 6 months (based on EQ-5D) 
 

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Determination of primary outcome 
The primary outcome is the number of ventilator free days at day 28 post randomisation, and will be defined 
as the total number of days from day 1 to day 28 on which a patient is alive and receives no assistance from 
mechanical ventilation, if any period of ventilator liberation lasts at least 48 consecutive hours. Study day 1 is 
the day of enrolment and will continue until the end of the daily ICU chart used at that site, or the end of the 
calendar day if electronic data collection systems are used. If patients are on mechanical ventilation for any 
portion of the study day they will be classified as being on mechanical ventilation for that entire study day. To 
be considered truly liberated from mechanical ventilation, the patient will need to have at least 48 consecutive 
hours where they are liberated from mechanical ventilation. This means that if, for example, they have 47 
consecutive hours liberated from mechanical ventilation and then receive mechanical ventilation, none of this 
time will be considered as ventilator free. But if, for example, they have 49 consecutive hours liberated from 
mechanical ventilation and then receive mechanical ventilation, all of this time will be considered as ventilator-
free, to contribute to classification of the ventilator-free status for each study day. Non-invasive mechanical 
ventilation will not be considered assistance if it is provided by face or nasal mask, but will be considered 
assistance if it is provided by tracheostomy. Any patient who dies before weaning from mechanical ventilation 
will be allocated the value of 0 ventilator free days. Any patient who dies after weaning from mechanical 
ventilation (ie. they have at least 48 consecutive hours off mechanical ventilation) but before day 28 will not 
have the days after their death until day 28 considered as a ventilator free day. 

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STUDY METHODOLOGY 
Study outline 
A phase II, multi-centre, prospective, randomised controlled trial. 
 
Study population 
Patients meeting all the inclusion and none of the exclusion criteria in the ICU will be eligible for enrolment. 
Inclusion criteria 
Adult ICU patients who meet all of the following criteria: 
• 
Currently intubated and receiving mechanical ventilation 
• 
Within 72 hours of mechanical ventilation for a diagnosis of ARDS (moderate and severe) based on 
the Berlin definition47 
 
Within 1 week of a known clinical insult or new or worsening respiratory symptoms 
 
Bilateral opacities on CXR which are not fully explained by effusions, lobar/lung collapse or 
nodules 
 
Respiratory failure not fully explained by cardiac failure or fluid overload 
 
PaO2/FiO2 < 200 mmHg with PEEP ≥ 5 cmH2O 
Exclusion criteria 
• 
> 72 hours since diagnosis of ARDS 
• 
> 10 days of continuous mechanical ventilation 
• 
< 16 years of age 
• 
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 < 80 mmHg 
• 
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 
 
 

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Patient screening 
Patients will be screened for eligibility criteria in 25-30 ICUs in Australia and New Zealand. 
 
Informed consent 
Patients will be unable to provide prospective informed consent, as they will be sedated and receiving 
mechanical ventilation. Informed consent will be obtained from the most appropriate Person Responsible, in 
accordance with section 4.4.10 of the NHMRC National Statement, and with variations according to state and 
territory legislations (and also as appropriate for New Zealand). Delayed consent for long-term follow up will 
be sought from the participant when they have suitably recovered capacity. 
 
Enrolment and randomisation 
Site personnel will enrol patients using an internet-based system hosted by the ANZIC Research Centre. 
Randomisation to either the PHARLAP group or the control group will be by permuted blocks and stratified for 
centre and for the cause of ARDS (direct or indirect)48. 
 
Co-enrolment 
Co-enrolment of patients into other interventional studies will be decided by the PHARLAP and the co-
enrolling study management committees on a case-by-case basis. Participants can be co-enrolled in 
observational studies. 

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21 
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PARTICIPATING STUDY SITES 
To be confirmed 
• 
Albury Wodonga Health 
• 
CVICU, Auckland City Hospital 
• 
DCCM, Auckland City Hospital 
• 
Austin Hospital 
• 
Barwon Health (Geelong Hospital) 
• 
Flinders Medical Centre 
• 
John Hunter Hospital 
• 
King Abdulaziz Medical City for National Guard (Riyadh) 
• 
Lyell McEwin Hospital 
• 
Middlemore Hospital 
• 
Nepean Hospital 
• 
Northern Hospital 
• 
Launceston 
• 
Prince Charles Hospital 
• 
Royal North Shore 
• 
Royal Prince Alfred 
• 
St Vincents Hospital (Dublin) 
• 
The Alfred Hospital 
• 
Wellington Hospital 
• 
Wollongong Hospital 

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STUDY PROCEDURES 
Commencement of mechanical ventilation strategy 
Patients in both groups should be commenced on the assigned mechanical ventilation strategy as soon as 
possible (but no later than 4 hours) after randomisation. 
Prior to changing the pre-randomisation mechanical ventilation settings to the assigned strategy, 3 tasks need 
to occur in the following order in both groups of patients: 
1. Predicted body weight should be estimated. 
2. Static respiratory compliance should be measured (see below). 
3. Specimens of blood and BAL should be collected (see below) – after static respiratory compliance has 
been measured. 
Estimation of predicted body weight: 
Before setting up the ventilator strategy, the patient’s predicted body weight must be determined. This should 
be estimated using a formula which requires height49 (Appendix 1). If there has been no recent (last few days) 
measurement of height, the height should be estimated using a formula which requires measurement of the 
demi-arm span (Appendix 1). 
Measurement of static respiratory compliance: 
• 
The patient should be adequately sedated (no spontaneous breaths). 
• 
An expiratory pause of 5 seconds should be set to measure intrinsic PEEP (PEEPi). If the 5 second 
pause can not be achieved (because the next breath occurs before the end of the pause), a shorter 
pause should be set. 
• 
Total PEEP is calculated as PEEPi + set PEEP. 
• 
The expiratory pause should be removed, and 30 seconds waited, before a 0.5 second inspiratory 
pause should be set to measure plateau pressure. 
• 
Within the same breath, expired tidal volume and plateau pressure should be measured. 
• 
Static respiratory compliance should be calculated as tidal volume / (plateau pressure – total PEEP). 
Collection of specimens at baseline: 
Patients in both groups should have specimens of blood and bronchoalveolar lavage (BAL) fluid collected prior 
to commencement of the assigned mechanical ventilation strategy. 
The blood specimen should be collected from the arterial line and sent with the BAL specimen to the site’s 
pathology department for appropriate spinning and storage. These will be sent in batches to Flinders Medical 
Centre for measurement of IL-6 and IL-8 levels in both blood and BAL. 
To perform the BAL, we recommend using a bronchoscopic method. Alternatively a non-bronchoscopic 
technique using the KimVent BAL Cath (Bronchial Aspirate Sampling Catheter) can also be used. There are two 
sizes of KimVent BAL Caths – 13F is recommended for a size 7cm ETT and smaller and 16F is recommended for 
a size 7.5cm ETT and larger. These will be provided to all sites by the ANZIC-RC. Whichever method is used, at 
least 10 ml of BAL fluid should be collected. A right-sided BAL is preferred for consistent sampling. 
Appendix 2 includes instructions on how to collect the specimen if a bronchoscopic method is used. It also 
includes instructions on how to perform the non-bronchoscopic technique using the KimVent BAL Cath to 
collect the BAL specimen.  
If the patient has been assigned to the PHARLAP group, this procedure should now be followed as soon as 
possible (but no later than 4 hours after randomisation) by a combined open lung procedure (see below). 
Satisfactory haemodynamic resuscitation may also be required before 4 hours after randomisation. 
If it is not feasible to collect a BAL sample because of limited resources to perform the bronchoscopy or the 
Investigator is unfamiliar with the use of the KimVent BAl cath or it may cause undue delay in recruitment then 

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a BAL sample is not required to be collected once enrolled. We understand that this may occur from time to 
time. However, every attempt should be made to collect the blood sample on all patients. 

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Control group mechanical ventilation 
Initial commencement of mechanical ventilation in the control group 
Mode: After randomisation, patients should be commenced in either Assist/Control (A/C) or Synchronised 
Intermittent Mandatory Ventilation (SIMV). All patients should be commenced in controlled rate ventilation, 
even if this requires additional sedation and/or neuromuscular blocking drugs. The preferred mode is Volume 
Control as follows. 
Tidal Volume: The tidal volume should be set at 6 ml/kg predicted body weight (PBW). The initial respiratory 
rate should be determined by aiming to deliver similar minute ventilation to the pre-randomisation settings. 
The maximum rate is 35 breaths/minute. 
Plateau Pressure: The plateau pressure aim is ≤ 30 cmH2O. If the plateau pressure is > 30 cmH2O, the tidal 
volume should be reduced, but to no less than 4 ml/kg PBW. 
FiO2 and PEEP: The FiO2 and PEEP should be set using the following table of allowable FiO2 and PEEP 
combinations as a guide. The initial setting should be the combination of FiO2 and PEEP that is closest to the 
pre-randomisation settings. The SaO2 aim is 90-95% using the lowest FiO2/PEEP combination to meet this goal. 
The PEEP level in this table represents the PEEP level set on the ventilator, not total or measured PEEP. The 
settings should be as far to the left of this chart as possible, thereby using the lowest combination of FiO2 and 
PEEP possible while maintaining oxygenation within the target range. If the patient has a significant 
desaturation, it is permissible to rapidly increase the PEEP/FiO2 from left to the right of the chart as quickly as 
required to achieve a satisfactory oxygen saturation, then titrate to achieve a SaO2 90 – 95%. 
When both SaO2 and PaO2 measures are available and discordant, PaO2 should take precedence. 
pH: The arterial pH goal for control group patients is pH 7.30-7.45. However there is no actual PaCO2 target 
and it is more important to maintain a tidal volume less than 6 ml/kg and a plateau pressure < 30 cmH2O.  
Acidaemia is permitted unless it is considered clinically relevant, in which case consider the following;  
• 
If pH 7.15-7.30 - increase the set mechanical ventilator rate up to a maximum of 35 breaths/minute or 
until pH > 7.30 or PaCO2 < 25 mmHg.  
• 
If pH < 7.15 - increase the set mechanical ventilator rate, up to a maximum of 35 breaths/minute. 
• 
If pH remains < 7.15 - tidal volume can be increased in 1 ml/kg steps until pH > 7.15 (Pplat target of 30 
may be exceeded). Bicarbonate may be administered if felt clinically indicated. NMB may be 
administered if felt clinically indicated. 
• 
Other mechanical ventilation strategies may be considered, but only after a dose of a neuromuscular 
blocking drug (in addition to suggestions for pH < 7.15). If the acidosis is predominantly metabolic, 
continuous renal replacement therapy may be required at this point. 
If pH > 7.45 and this is considered clinically relevant we suggest decreasing the set mechanical ventilator rate 
(if possible) or decreasing plateau pressure by decreasing tidal volumes (no less than 4ml/kg PBW). 
Alternative mode: Other modes may be considered as a preference by the clinician or because of ventilator 
dysynchrony in A/C volume controlled ventilation. If the main problem is ventilator dysynchrony, the patient 
should first have increased sedation and NMB may be administered if felt clinically indicated. Pressure Control 
mode may be used to deliver rapid inspiratory flow rates which may improve patient-ventilator interaction., 
although Volume Control mode is preferred. When Pressure Control is used, the inspiratory pressure should be 
set to achieve a tidal volume of approximately 6 ml/kg PBW. Plateau pressure in Pressure Control mode is 
considered to be the total pressure (ie. the sum of set inspiratory pressure + PEEP). If the total pressure is ≥ 30 
cmH2O, the inspiratory pressure should be reduced, but to no less than a setting that delivers a tidal volume of 
FiO2 
0.3 
0.4 
0.4 
0.5 
0.5 
0.6 
0.7 
0.7 
0.7 
0.8 
0.9 
0.9 
0.9 
1.0 
PEEP 
(cmH2O) 
5 
5 
 
8 
8 
10 
10 
10 
12 
14 
14 
14 
16 
18 
18-24 

PHARLAP study, Protocol ANZIC-RC/AD002 Version 8.  Dated 25 November 2014 
 
25 
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approximately 4 ml/kg PBW. Whilst Pressure Control mode is being used, tidal volumes should be carefully 
monitored (including the use of mechanical ventilator alarms) with the aim that these remain approximately 
6 ml/kg PBW. 
Neuromuscular blocking drugs: Neuromuscular blocking drugs should be used as judged appropriate by the 
treating clinician and their current unit policies.  
Ongoing mechanical ventilation in the control group 
Goals: The goals of mechanical ventilation should always remain as follows: 
• 
Tidal volume: ≤ 6 ml/kg PBW 
• 
Plateau pressure: ≤ 30 cmH2O (if plateau pressure ≥ 30 cmH2O, reduce tidal volume to 4-6 ml/kg) 
• 
Breath rate: ≤ 35 breaths/minute  
• 
pH: 7.30-7.45 (do not aim for a specific PaCO2) 
• 
SaO2: 90-95% (if PaO2 is available, the aim for this is 60-80 mmHg). When both SaO2 and PaO2 are 
available and discordant, PaO2 should take precedence. 
Titrating the FiO2 and PEEP: The FiO2 and PEEP should be set using the table of allowable FiO2 and PEEP 
combinations as a guide. The PEEP level in this table represents the PEEP level set on the ventilator, not total 
PEEP. The settings should be as far to the left of this chart as possible, thereby using the lowest combination of 
FiO2 and PEEP possible while maintaining oxygenation within the target range. 
If the SaO2 is < 90% (or PaO2 < 60 mmHg, if available), the patient should be changed to the FiO2 and PEEP 
combination to the right of the current settings. If the patient has a significant desaturation, it is permissible to 
rapidly  increase the PEEP/FiO2 from left to the right of the chart as quickly as requiredto achieve a satisfactory 
oxygen saturation, then titrate the PEEP/FiO2 to achieve a SaO2 90 – 95%. 
 
If the SaO2 is > 95% (or PaO2 > 80 mmHg, if available), the patient should be changed to the FiO2 and PEEP 
combination to the left of the current settings. If this leads to a reduction in PEEP, it is preferable not to reduce 
the PEEP again before 4 hours have passed. 
Ventilation during patient transfers: Mechanical ventilation should continue to adhere to this control 
group strategy during patient transfers (to diagnostic or therapeutic procedures outside the ICU) where 
possible. However if the patient receives mechanical ventilation using either a manual (hand-bagging) circuit 
or a transport ventilator that is not practically able to deliver the control group mechanical ventilation settings, 
patients may be ventilated using alternative means whilst away from the ICU. Resumption of control group 
mechanical ventilation should occur as soon as possible after the transfer. 
Specific measurements on Day 3 in the control group 
Patients in both groups should have 2 things measured on day 3: 
1. Static respiratory compliance should be measured (see page 22 for technique). 
2. Specimens of blood and BAL should be collected (see below) – after static respiratory compliance has 
been measured. The BAL should be collected using the same technique as was used at baseline. 
Transition from controlled to spontaneous mechanical ventilation in the control group 
Pressure Support Ventilation (PSV) mode should be used to transition the patient from controlled to 
spontaneous mechanical ventilation. This mode should also be used if there are significant problems using 
controlled ventilation with patient-ventilator dysynchrony, difficulty in meeting aims, or because of strong 
clinician preference. The patients should be in either (1) SIMV Volume/Pressure Control mode with PSV or (2) 
PSV alone. 
FiO2 
0.3 
0.4 
0.4 
0.5 
0.5 
0.6 
0.7 
0.7 
0.7 
0.8 
0.9 
0.9 
0.9 
1.0 
PEEP 
(cmH2O) 
5 
5 
 
8 
8 
10 
10 
10 
12 
14 
14 
14 
16 
18 
18-24 

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In PSV the goals of mechanical ventilation remain as follows: 
• 
Tidal volume: ≤ 6 ml/kg PBW 
• 
Plateau pressure [for controlled breaths]: ≤ 30 cmH2O 
• 
Total pressure [for spontaneous breaths] (ie. set inspiratory pressure + PEEP): ≤ 30 cmH2O 
• 
Breath rate: ≤ 35 breaths/minute 
• 
pH: 7.30-7.45 (do not aim for a specific PaCO2) 
• 
SaO2: 90-95% (if a PaO2 is available, the aim for this is 60-80 mmHg). 
Tidal volume targets should only be relaxed when the patient is clinically stable and receiving FiO2 ≤ 0.5 and 
PEEP ≤ 10 cmH2O. The inspiratory pressure for PSV can be adjusted down to a minimum of 5 cmH2O (if tidal 
volume > 6 ml/kg PBW). If the tidal volume remains > 8 ml/kg PBW, there should be strong consideration to 
increase sedative drugs or to use a neuromuscular blocking drug so that controlled ventilation can replace 
(partially or completely) spontaneous mechanical ventilation. Whilst PSV mode is being used, tidal volumes 
should be carefully monitored (including the use of mechanical ventilator alarms) with the aim that these 
remain approximately 6 ml/kg PBW. 
Management of severe hypoxaemia in the control group 
If control group patients have a PaO2 < 60 mmHg or a SaO2 < 90% whilst receiving an FiO2 and PEEP 
combination in any of the 5 columns at the right end of the FiO2 and PEEP combination table (ie. FiO2 ≥ 0.8 and 
PEEP ≥ 14), hypoxaemic rescue therapies should then be considered. These include prone positioning, inhaled 
nitric oxide, inhaled prostacyclin, high frequency oscillation and extracorporeal membrane oxygenation 
(ECMO), depending on the practice, availability, feasibility in the specific site and appropriateness. 
No recruitment manoeuvres should be performed in control group patients unless there is no other feasible 
hypoxaemic rescue therapy able to be performed. Staircase recruitment manoeuvres should never be 
performed in the control group. 
Resumption of the control group mechanical ventilation strategy should occur as soon as possible. 
Weaning of mechanical ventilation in the control group 
Please see the section below on “Weaning of mechanical ventilation for both groups” 

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Intervention group (PHARLAP) mechanical ventilation 
Initial commencement of mechanical ventilation in the PHARLAP group 
Mode: After randomisation, patients should be commenced in either Assist-Control (A/C) or Synchronised 
Intermittent Mandatory Ventilation (SIMV) using Pressure Control mode. All patients should be commenced in 
controlled rate ventilation, even if this requires additional sedation and/or neuromuscular blocking drugs. The 
PEEP level should remain at the pre-randomisation level. 
The combined open lung procedure in the PHARLAP group (see Figure 1) 
The initial procedure of the PHARLAP mechanical ventilation strategy should be to perform the combined open 
lung procedure which consists of (1) a staircase recruitment manoeuvre (SRM), followed by (2) a PEEP titration 
manoeuvre, and followed by (3) a brief recruitment manoeuvre (see Figure 1). This initial combined open lung 
procedure should be performed within 4 hours of randomisation. 
This will then be followed by PHARLAP strategy mechanical ventilation. 
The combined open lung procedure should be performed after assessment by an intensivist or registrar and 
when haemodynamic resuscitation is complete and circulatory parameters are stable. If vasopressors or 
inotropes are being used, a small transient increase prior to the combined open lung procedure will minimise 
any hypotension. 
The contraindications to a recruitment manoeuvre (both the staircase and the brief manoeuvre) are: 
• 
Mean systemic blood pressure < 60 mmHg despite attempts to augment BP with vasopressors/fluids. 
• 
An active air leak through an intercostal catheter. 
• 
Any radiographical evidence of pneumatoceles, subpleural cysts, or pericardial or mediastinal 
emphysema. 
• 
Subcutaneous emphysema not related to trauma, surgical procedures, or ICU procedures. 
• 
A supraventricular tachycardia associated with a mean systemic blood pressure < 70 mmHg, or any 
ventricular tachycardia. 
If a patient has a contraindication to the combined open lung procedure, all other aspects of PHARLAP 
mechanical ventilation should be continued until the contraindication has resolved (when the combined open 
lung procedure should then be performed). 
The combined open lung procedure should be performed as follows:  
(1) Staircase recruitment manoeuvre (SRM):  
The mechanical ventilator settings should be Pressure Control with an inspiratory pressure of 15 ± 3 cmH2O 
depending on tidal volume achieved (pre-SRM tidal volume target 4-6 ml/kg PBW). The PEEP level should be 
left at the level it had been immediately prior to this procedure. The FiO2 should be adjusted (usually by 
turning it down) until the SaO2 is stable between 90-92%. This may take several (often 15-30 minutes). The 
high pressure alarm should be set to 65 cmH2O and the low tidal volume and minute ventilation alarms 
reduced to < 25% of the current settings. 
Once the FiO2 is stable (ie. no change for 3 minutes), the PEEP should be increased from the pre-randomisation 
baseline to 20 cmH2O. In a stepwise fashion, this should be increased after 2 minutes to 30 cmH2O (for 2 
minutes) and then 40 cmH2O (for 2 minutes), unless there is occurrence of (a) haemodynamic instability 
(defined as heart rate < 40 or > 140 bpm, ventricular tachycardia, or systolic blood pressure (SBP) < 80 mmHg), 
(b) marked oxygen desaturation (SaO2 < 85%) or (c) new air leak through an intercostal catheter. The tidal 
volume should not be adjusted at each PEEP level, unless the tidal volume is > 6 ml/kg PBW. 
The patient may cough or become restless at high PEEP levels. This may be due to expansion of collapsed lung 
and does not require the SRM to be discontinued. Transient reductions in tidal volume and minute ventilation 
are to be expected as the PEEP levels are increased. Sometimes the patient will require additional sedation. 
If haemodynamic instability, marked oxygen desaturation or a new air leak occurs during the SRM, the SRM 
should be abandoned (with no further increases in PEEP occurring above the level where this occurred). If the 

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CONFIDENTIAL 
 
patient is considered to be inadequately haemodynamically resuscitated for their underlying condition, then it 
is preferable if vasopressor or fluid resuscitation should occur over the next 30-60 minutes, and then the 
combined open lung procedure be resumed. If the patient is considered to be adequately haemodynamically 
resuscitated, then fluid loading purely for the SRM should not be undertaken. The PEEP level one level below 
the PEEP level at which the SRM was abandoned should be determined as the maximum tolerated PEEP for 
this specific SRM and the PEEP titration manoeuvre should now occur (i.e. if marked desaturation occurs at 40 
cmH2O the maximum tolerated PEEP should then be determined as 30 cmH2O). The maximum tolerated PEEP 
for the SRM will be determined daily and may be a different value on subsequent days. 
If there is no occurrence of haemodynamic instability, marked oxygen desaturation or new air leak, the PEEP 
should be increased to the highest level of 40 cmH2O. This should be determined as the maximum tolerated 
PEEP for this SRM. 
(2) PEEP titration manoeuvre 
After the final SRM step has been completed (or abandoned, as above), the PEEP should be immediately 
reduced to 25 cmH2O. If, however, the SRM was abandoned at 20 cm H2O, the PEEP titration should begin at 
17.5 cm H2O. The PEEP should be left at this first setting for 3 minutes, then decreased in steps by 2.5 cmH2O 
for 3 minutes at each PEEP level to a minimum of 15 cmH2O (i.e. from 25 to 22.5 to 20 to 17.5 to 15 cmH2O) 
until the de-recruitment PEEP is reached. If the mechanical ventilator does not have 0.5 cmH2O increments, 
round the PEEP up from 22.5 to 23 and 17.5 to 18 cmH2O. The de-recruitment PEEP is defined as the PEEP level 
at which the SaO2 first decreases by ≥ 2%. Once the de-recruitment PEEP has been reached, there should be no 
further reduction in PEEP, and the brief recruitment manoeuvre should now occur. 
The PEEP should not be reduced below 15 cmH2O if desaturation does not occur. In this situation, the PEEP 
should be left on 15 cmH2O and no brief recruitment manoeuvre is required (ie. the combined open lung 
procedure has been completed). 
(3) Brief recruitment manoeuvre 
After this de-recruitment, a 2 minute brief recruitment manoeuvre should be performed (with the inspiratory 
pressure set at 15 ± 3 cmH2O) using the PEEP level that was the maximum tolerated PEEP for the recently 
performed SRM. After this brief recruitment manoeuvre the PEEP should be returned to the level that is 2.5 
cmH2O above the de-recruitment PEEP. If there was no desaturation to determine the de-recruitment PEEP, 
the PEEP should be set at 15 cmH2O and no brief recruitment manoeuvre is required. This final PEEP level 
should be considered the daily optimal PEEP (for the subsequent period - usually 24 hours) until a subsequent 
combined open lung procedure is performed. 
Ventilation settings immediately after the combined open lung procedure 
Plateau pressure, tidal volume and pH: Once the combined open lung procedure has been completed, the 
pressure control level should be reduced to achieve a total pressure (ie. inspiratory pressure + PEEP) ≤ 30 
cmH2O (preferably 25-28 cmH2O) and a tidal volume of 4-6 ml/kg PBW. The tidal volume should be titrated 
down from 6 ml/kg towards 4 ml/kg if possible. The set breath rate should also be reduced aiming for a lowish 
pH (in the range of 7.15-7.30). The actual pH in an individual patient will depend on other factors (including 
level of sedation and other metabolic issues) and should be a clinical decision at the time. 
The mechanical ventilator alarms should be returned to their appropriate settings. 
FiO2 and PEEP: Immediately after the combined open lung procedure, the FiO2 should be decreased until the 
SaO2 is in the target range of 90-95%. One hour after the combined open lung procedure, the SaO2 should be 
noted, and recorded on the bedside PHARLAP study ventilation sheet as the subsequent daily precise SaO2 
target for that day. 
After this 1 hour time point, a SaO2 ≤ 2% below this daily precise SaO2 target should prompt strong 
consideration of re-recruitment using a brief recruitment manoeuvre (with or without an increase in FiO2). 
Over the subsequent hours, the FiO2 should then be decreased (if SaO2 > 95%) or increased (if SaO2 ≤ 2% below 
this daily precise SaO2 target), but the PEEP should not be weaned from the daily optimal PEEP setting. The 
only time the PEEP may be weaned is if there is significant haemodynamic instability, a new air leak through an 
intercostal catheter or if the SaO2 is above the target range (≥ 95%) when the patient has been weaned to FiO2 
≤ 0.4. The daily optimal PEEP will be determined again the next day as part of the daily combined open lung 
procedure. 

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The minimum PEEP in the PHARLAP group is 15 cmH2O. It should only be reduced below 15 cmH2O once the 
patient meets the readiness for weaning criteria (below). 
 
 
 
Neuromuscular blocking drugs: Neuromuscular blocking drugs should be used as judged appropriate by the 
treating clinician and their current unit policies. 
Ongoing mechanical ventilation in the PHARLAP group 
Goals: The goals of mechanical ventilation should always remain as follows: 
• 
Tidal volume: 4-6 ml/kg PBW 
• 
Breath rate: ≤ 35 breaths/minute 
• 
Total pressure (ie. inspiratory pressure + PEEP): ≤ 30 cmH2O (ideal range 25-28 cmH2O) 
• 
SaO2 90-95% (if a PaO2 is available, the aim for this is 60-80 mmHg). Within this range, re-recruitment 
using a brief recruitment manoeuvre is encouraged for reductions in SaO2 of ≥ 2% below the daily 
precise SaO2 target. 
 

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Permissive hypercapnia: The approach should be as follows: 
• 
The tidal volume should be continue to be titrated downwards to achieve a tidal volume 4-6 ml/kg 
PBW and a plateau pressure < 30 cmH2O (ideal range 25-28 cmH2O). The set breath rate should also 
be reduced aiming for a lowish pH (in the range of 7.15-7.30). 
• 
Hypercapnia and acidosis should be tolerated if pH ≥ 7.15. 
• 
If pH < 7.15, the breath rate should be increased in steps of 4 to a maximum of 35 breaths/minute. 
• 
If pH remains < 7.15 (after above), tidal volume should be increased by 1 ml/kg PBW at a time (but to 
a maximum total pressure [ie. inspiratory pressure + PEEP] of 35 cmH2O. 
• 
If pH remains < 7.15 (after above) and the patient is sedated as required, bicarbonate may then be 
considered. If the acidosis is predominantly metabolic, continuous renal replacement therapy may be 
required at this point. 
If pH remains < 7.15 (after above) the tidal volume may be increased further but the PEEP should be reduced 
to maintain Pplat ≤ 35 cmH2O. 
Titrating the FiO2 and PEEP: The PEEP should be left on the daily optimal PEEP determined by the most 
recent combined open lung procedure. The FiO2 should be increased or decreased as required to maintain the 
SaO2 aim. From day 6 onwards (i.e. after the 5 day period of performing combined open lung procedures has 
finished) the optimal PEEP should be set at 15 cmH2O (or higher if clinically appropriate) unless the patient 
meets the readiness for weaning criteria. 
Ongoing recruitment manoeuvres in the PHARLAP group 
Combined open lung procedure: Subsequent combined open lung procedures (each being an SRM, a PEEP 
titration manoeuvre and a brief recruitment manoeuvre) should be performed daily for 5 days, unless the 
patient meets one of the following criteria to omit a combined open lung procedure: 
(a) readiness for weaning criteria are met (see below), 
(b) lack of improvement in static lung compliance criteria are met (on day 3, see below), 
(c) there is a contraindication to a recruitment manoeuvre (see above), or 
(d) it is the 6th day after enrolment (ie. 5 days of combined open lung procedures have occurred). 
The initial combined open lung procedure should be performed within 4 hours of randomisation but 
subsequent combined open lung procedures should be performed during the daytime period (preferably 
during or soon after the morning or ICU ward round) such that one is performed on each consecutive chart day 
(unless the patient meets one of these criteria to omit a combined open lung procedure). 
The daily combined open lung procedure should be performed as it was on the initial occasion, however each 
day there may be a different maximum tolerated PEEP, a different de-recruitment PEEP and a different daily 
optimal PEEP level determined. There should also be a different precise SaO2 target determined 1 hour after 
the combined open lung procedure and which should be the new daily precise SaO2 target. Each of these will 
then remain until a subsequent combined open lung procedure is performed (usually 24 hours later). 
Neither the combined open lung procedure nor independently performed SRMs should be performed at times 
other than this daily morning intervention. 
The lack of improvement in static lung compliance definition will be met if the static lung compliance after the 
staircase recruitment manoeuvre on day 3 is lower than the static lung compliance assessed prior to the 
performance of the initial (day 1) combined open lung procedure. Any patient who meets this criterion will 
have no further combined open lung procedures or brief recruitment manoeuvres and should have the PEEP 
set on 15 cmH2O (or higher if clinically appropriate) unless the patient meets the readiness for weaning 
criteria. 
No combined open lung procedures or brief recruitment manoeuvres should be performed after day 5. If the 
patient has not met readiness for weaning criteria, the optimal PEEP should be set at 15 cmH2O (or higher if 
clinically appropriate) unless the patient meets the readiness for weaning criteria. 

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Desaturation: We recommend patients receive a chest x-ray for significant persistent desaturation to rule 
out barotrauma before a brief recruitment manoeuvre or further combined open lung procedures are 
performed. 
Brief recruitment manoeuvre: A brief recruitment manoeuvre should be performed independently (ie. 
without an SRM and individual PEEP titration) if an oxygen desaturation occurs (≥ 2% below the daily precise 
SaO2 target). This may occur without a clear precipitating event or may occur as a result of (a) an intervention 
(eg. suction, cuff deflation, body position change, coughing episode, waking) or a mechanical ventilator 
disconnection. Disconnections include inadvertent extubations (followed by reintubation), and any inadvertent 
disconnections of the endotracheal tube or tracheostomy tube from the ventilator circuit however brief these 
may be. Disconnections for tracheostomy care and changes of in-line suction catheters should be followed by a 
brief recruitment manoeuvre. Disconnections occurring due to patient transfer for a procedure (eg. radiology 
department, operating theatre) or to move the patient to another ICU bedspace should be followed by a brief 
recruitment manoeuvre only after the patient has been reconnected to the ventilator back in the ICU. For 
example, a transfer to the radiology department may have several associated disconnections (from the ICU 
ventilator, from a transfer ventilator, from a ventilator in the radiology suite, from the transfer ventilator 
again). These should be considered together as one disconnection, and the brief recruitment manoeuvre 
performed only upon return to the ICU with reconnection to the ICU ventilator. If an episode of in-line 
suctioning is performed without a clear disconnection, a brief recruitment manoeuvre is not required. 
Similarly to the combined open lung procedure, independently performed brief recruitment manoeuvres 
should not be performed if:  
(a) readiness for weaning criteria are met (see below), 
(b) lack of improvement in static lung compliance criteria are met (on day 3, see below), 
(c) there is a contraindication to a recruitment manoeuvre (see above), or 
(d) it is the 6th day after enrolment (ie. 5 days of combined open lung procedures have occurred). 
If an oxygen desaturation (≥ 2% below the daily precise SaO2 target) occurs with a clear precipitating event (i.e. 
intervention or ventilator disconnection), the brief recruitment manoeuvre should be performed as follows: 
• 
The PEEP should be increased to the maximum tolerated PEEP determined during the most recently 
performed SRM, left at that level for 2 minutes, and then immediately returned to the daily optimal 
PEEP determined by that same SRM. 
If an oxygen desaturation (≥ 2% below the daily precise SaO2 target) occurs with no clear precipitating event 
(ie. potentially a deterioration in lung function), the brief recruitment manoeuvre should be performed as 
follows: 
• 
The PEEP should be increased to the maximum tolerated PEEP determined during the most recently 
performed SRM, left at that level for 2 minutes, and then immediately returned to 2.5 cmH2O 
(rounded up by 0.5 if the ventilator does not use 0.5 cmH2O settings) higher than the previous daily 
optimal PEEP set during that SRM. 
• 
This new PEEP level should be considered the new daily optimal PEEP level for the subsequent part of 
that day until the next SRM is performed. The FiO2 should then be decreased as required to maintain 
the SaO2 aim. 
• 
The PEEP should not be set higher than 25 cmH2O at any time during the study (with the exception of 
the staircase recruitment manoeuvre). 
Brief recruitment manoeuvres should not be repeated more frequently than 2 hourly and not more than a 
maximum of 4 manoeuvres per 24 hours. 
Ventilation during patient transfers: Mechanical ventilation should continue to adhere to this PHARLAP 
group strategy during patient transfers (to diagnostic or therapeutic procedures outside the ICU) where 
possible. However if the patient receives mechanical ventilation using either a manual (hand-bagging) circuit 
or a transport ventilator that is not practically able to deliver the PHARLAP group mechanical ventilation 
settings, patients may be ventilated using alternative means whilst away from the ICU. Resumption of 
PHARLAP group mechanical ventilation (including performance of a brief recruitment manoeuvre if indicated) 

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should occur as soon as possible after the transfer. A brief recruitment manoeuvre will usually be required (see 
above on this page). 
Specific measurements on Day 3 in the PHARLAP group  
Patients in both groups should have 2 things measured on day 3: 
1. Static respiratory compliance should be measured (see page 22 for technique). 
2. Specimens of blood and BAL should be collected (see below) – after static respiratory compliance has 
been measured. The BAL should be collected using the same technique as was used at baseline. 
If the patient has been assigned to the PHARLAP group, this procedure should now be followed as soon as 
possible by a brief recruitment manoeuvre (see below). 
Transition from controlled to spontaneous mechanical ventilation in the PHARLAP group 
Pressure Support Ventilation (PSV) mode should be used to transition the patient from controlled to 
spontaneous mechanical ventilation. This mode should also be used if there are significant problems using 
controlled ventilation with patient-ventilator dysynchrony, difficulty in meeting aims, or because of strong 
clinician preference. The patients should be in either (1) Pressure Control mode with PSV or (2) PSV alone. 
In PSV the goals of mechanical ventilation remain as follows: 
• 
Tidal volume: 4-6 ml/kg PBW 
• 
Plateau pressure [for controlled breaths]: ≤ 30 cmH2O (ideal range 25-28 cmH2O) 
• 
Total pressure [for spontaneous breaths] (ie. inspiratory pressure + PEEP): ≤ 30 cmH2O (ideal range 
25-28 cmH2O 
• 
Breath rate: ≤ 35 breaths/minute  
• 
pH: > 7.15 (do not aim for a specific PaCO2) 
• 
SaO2: 90-95% (if a PaO2 is available, the aim for this is 60-80 mmHg). 
Tidal volume targets should only be relaxed when the patient is clinically stable and receiving FiO2 ≤ 0.5. The 
inspiratory pressure for PSV can be adjusted down to a minimum of 5 cmH2O (if tidal volume > 6 ml/kg PBW). 
If the tidal volume remains > 8 ml/kg PBW, there should be strong consideration to increase sedative drugs or 
to use a neuromuscular blocking drug so that controlled ventilation can replace (partially or completely) 
spontaneous mechanical ventilation. Whilst PSV mode is being used, tidal volumes should be carefully 
monitored (including the use of mechanical ventilator alarms) with the aim that these remain approximately 
6 ml/kg PBW. 
As lung recovery occurs, the FiO2 should be reduced to maintain the SaO2 in the target range. There should be 
no reductions in PEEP until the SaO2 ≥ 90% whilst receiving FiO2 ≤ 0.4 for 4 continuous hours. 
Management of severe hypoxaemia in the PHARLAP group 
If PHARLAP group patients have a PaO2 < 60 mmHg or a SaO2 < 90% whilst receiving FiO2 ≥ 0.8 and (a) this does 
not improve with a brief recruitment manoeuvre (see procedure above), or (b) a brief recruitment manoeuvre 
is not indicated based on one of the criteria listed above, hypoxaemic rescue therapies should then be 
considered. These include prone positioning, inhaled nitric oxide, inhaled prostacyclin, high frequency 
oscillation, and extracorporeal membrane oxygenation (ECMO), depending on the practice, availability and 
feasibility in the specific site and appropriateness. 
In PHARLAP group patients, no staircase recruitment manoeuvres should be performed other than the 
planned daily combined open lung procedure up until day 5. No brief recruitment manoeuvres should be 
performed in PHARLAP group patients after day 5 unless there is no other feasible hypoxaemic rescue 
therapy able to be performed. 
Resumption of PHARLAP group mechanical ventilation strategy should occur as soon as possible. 
Weaning of mechanical ventilation in the PHARLAP group 
Please see the section below on “Weaning of mechanical ventilation for both groups” 

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Weaning of mechanical ventilation in both groups 
Daily screening of patients in both groups 
Patients should be screened at least once per day for readiness to wean. 
Readiness for weaning 
Patients in both groups will be deemed to have met readiness for weaning criteria when for the first time the 
patient has (1) SaO2 ≥ 90% whilst receiving FiO2 ≤ 0.4 for ≥ 6 continuous hours, and (2) is considered otherwise 
clinically stable. 
• 
If the patient does not meet readiness for weaning criteria, mechanical ventilation aims should 
remain as recommended above for the patient’s group assignment. 
• 
Once a patient meets readiness for weaning criteria the first time, no further recruitment manoeuvres 
(combined open lung procedure or brief recruitment manoeuvres) should be performed in the 
PHARLAP group. If possible, the patient should have the PEEP reduced by 2.5 cmH2O (rounded up by 
0.5 if the ventilator does not use 0.5 cmH2O settings) at a time. Subsequent reductions in PEEP should 
be no sooner than 4 hours after the previous reduction. All other mechanical ventilation aims should 
remain as recommended above for the patient’s group assignment. 
• 
If the patient’s respiratory function deteriorates after weaning criteria has been met the following can 
occur:  
- Control patients: 
- 
Continue using control group ventilation strategy and reassess readiness for weaning the next 
day 
- PHARLAP treatment patients: 
- 
If it is day 2 to 5 and the Cstat did improve then a COLP should be performed and the PEEP 
titrated as per the PHARLAP group protocol. 
- 
If it is after day 5 or the Cstat did not improve on day 3 change the PEEP to the default level 
15cmH20 (may be higher if deemed clinically appropriate) and titrate the FiO2 to maintain 
oxygen saturation ≥ 90% and reassess the readiness for weaning the next day. 
Readiness for unassisted breathing trial 
Patients in both groups will be deemed to have met readiness for an unassisted breathing trial when the 
patient meets all of (1) SaO2 ≥ 90% whilst receiving FiO2 ≤ 0.4 and PEEP ≤ 10 cmH2O for ≥ 6 continuous hours, 
(2) has intact airway reflexes and low amounts of sputum, (3) has a reasonable level of consciousness whilst 
receiving low doses of or no sedative infusions, and (4) is considered otherwise clinically stable and mechanical 
ventilator liberation is considered appropriate (e.g. there is no imminent procedure requiring ongoing 
mechanical ventilation). 
• 
If the patient does not meet readiness for an unassisted breathing trial, mechanical ventilation aims 
should remain as recommended above for the patient’s group assignment, including ongoing 
progressive weaning of PEEP as possible in the PHARLAP group. 
• 
Once a patient meets readiness for an unassisted breathing trial, a period of unassisted breathing 
should commence on the same day. Unassisted breathing is allowing the patient to breathe 
spontaneously on any one of a T-Tube circuit, a tracheostomy mask/hood/shield or a mechanical 
ventilator circuit using CPAP 5 cmH2O with minimal support (ie. PSV ≤ 10 cmH2O). The FiO2 should be 
≤ 0.5. 
Readiness for mechanical ventilator liberation 
Patients in both groups will be deemed to have met readiness for mechanical ventilator liberation criteria if 
after at least 30 minutes of an unassisted breathing trial, the patient meets all of (1) breath rate < 35 
breaths/minute, (2) SaO2 > 90% whilst receiving FiO2 ≤ 0.5, (3) systolic blood pressure > 90 and < 180 mmHg, 
(4) heart rate either (a) < 140 beats/minute or (b) not increased by > 20% since the beginning of the unassisted 

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breathing period, and (5) is considered otherwise clinically stable and mechanical ventilator liberation is not 
considered inappropriate. 
• 
If the patient does not meet readiness for mechanical ventilator liberation criteria, mechanical 
ventilation aims should remain as recommended above for their group assignment until the next day, 
when readiness for weaning should be reassessed. If the unassisted breathing trial led to desaturation 
this may require an increase in FiO2 or PEEP. In the PHARLAP group no further recruitment 
manoeuvres should be performed unless severe desaturation occurs (requiring FiO2 ≥ 0.8). In this 
situation a brief recruitment manoeuvre should be considered. 
• 
Once a patient meets readiness for mechanical ventilator liberation criteria, they should, on the same 
day, be either (1) extubated or (2) placed on a tracheostomy mask/hood/shield for an indefinite 
period. Intermittent periods of mechanical ventilation and tracheostomy mask/hood/shield breathing 
should only occur once it has been deemed clinically necessary by the patient meeting criteria for 
consideration for further invasive mechanical ventilation. 
Consideration for further invasive mechanical ventilation 
Patients in both groups will be deemed to have met consideration for further invasive mechanical ventilation  
if they develop any of (1) hypoxaemia (SaO2 ≤ 90% or PaO2 < 60 mmHg) whilst receiving FiO2 ≥ 0.5, (2) 
respiratory distress (judged clinically), (3) tachypnoea (breath rate > 35 breaths/minute), (4) inability to clear 
airway secretions (judged clinically), (5) upper airway obstruction, or (6) decrease in consciousness (judged 
clinically). 
• 
If the patient does not meet consideration for further invasive mechanical ventilation, they should 
continue indefinitely to receive no invasive mechanical ventilatory support. 
• 
Once a patient meets consideration for further invasive mechanical ventilation after having been 
extubated, reintubation should be considered. Non-invasive ventilation is not recommended after 
recent extubation. If the patient is reintubated, they should continue to receive mechanical 
ventilation as recommended above for their group assignment. In most cases, this should be a brief 
period of controlled ventilation, followed by transition to spontaneous mechanical ventilation. If the 
patient is in the PHARLAP group, no further combined open lung procedures are mandated, although 
a brief recruitment manoeuvre should be considered. The subsequent mechanical ventilator 
disconnection plan should be made with the aim of complete mechanical ventilator liberation as soon 
as possible. 
• 
Once a patient meets consideration for further invasive mechanical ventilation after having been 
placed on a tracheostomy mask/hood/shield, reconnection to the mechanical ventilator should be 
considered. If the patient has invasive mechanical ventilator reconnection, they should continue to 
receive mechanical ventilation as recommended above for their group assignment. In most cases, this 
should be spontaneous mechanical ventilation in pressure support mode. If the patient is in the 
PHARLAP group, no further combined open lung procedures are mandated, although a brief 
recruitment manoeuvre should be considered. The subsequent mechanical ventilator disconnection 
plan should be made with the aim of complete mechanical ventilator liberation as soon as possible. 
 
Fluid management in both groups 
The patient should have the aim of a fluid balance that best suits their clinical state during the first day of the 
study. 
The general aim from day 2 is to ignore the day 1 fluid balance and attempt to achieve a cumulative neutral 
fluid balance thereafter, unless there is a clear indication for a positive or negative fluid balance50.  
If there is an unplanned positive fluid balance it should be corrected by fluid restriction (including 
consideration of concentrated enteral nutrition formulations and diuretics). 
Significant peripheral oedema should be corrected with fluid restriction and diuretics, unless contra-indicated. 
Careful monitoring of renal function and other indices of organ perfusion should occur. 

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If haemodynamic instability occurs during the combined open lung procedure (mainly during the SRM), 
vasopressors should be considered initially. Intravenous fluid boluses should be administered if vasopressor 
requirements increase rapidly. 
 
Use of corticosteroids in both groups 
Steroids should not be used specifically for ARDS after day 751.  
 
Other interventions in both groups 
All other interventions will not be standardised. Given the possibility of confounding by different utilisation 
rates of various interventions between groups, data will be collected on haemodynamics (daily central venous 
pressure, blood pressure and heart rate), fluid balance, pulmonary artery catheter usage, intravenous 
bicarbonate usage, renal replacement therapy usage, neuromuscular blocking drug usage, corticosteroid usage 
and hypoxaemic rescue therapy usage. 
 
Discontinuation of treatment 
Patients in both groups will receive their assigned ventilator strategy until any of the following occur: 
1. The patient is no longer receiving mechanical ventilation 
2. The patient dies or is discharged from the Intensive Care Unit 
3. The patient or surrogate decision-maker withdraws informed consent. 
 
Table of events 
Please see Appendix 3 
 
Laboratory sampling 
Blood (10 ml centrifuged to isolate plasma) and BAL (10 ml taken using the technique described above) 
samples will be collected and stored -80oC at each site at baseline and day 3. Samples will be shipped in 2 
batches to a central processing laboratory (Flinders Medical Centre) for quantification of IL-6, IL-8 and protein 
concentration by blinded laboratory scientists. 
 
 
 
 
 
 
 
 
 

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ETHICAL CONSIDERATIONS 
Guiding principles 
This study is to be performed in accordance with the ethical principles of the Declaration of Helsinki (June 1964 
and amended 1975, 1983, 1989, 1996, 2000, 2008 and Note of Clarification 2002 and 2004), ICH GCP Notes for 
Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with Therapeutic Goods Administration 
comments, NHMRC National Statement on Ethical Conduct in Research Involving Humans (March 2007); the 
New Zealand Interim Good Clinical Research Practice Guidelines (Volume 2 1998 and Volume 3 2000) and ICH 
GCP Notes for Guidance on Good Clinical Practice (CPMP/ICH/135/95). 
 
Ethical issues of the study 
The two major ethical considerations in this study are: 
• 
The enrolment of participants who are unable to provide their own informed consent 
• 
Confidentiality of patient data outside the participating institution 
Informed consent 
The NHMRC National Statement on the Ethical Conduct of Research in Humans  (March 2007) acknowledges in 
Chapter 4.4 that in research studies involving patients who are heavily dependent on medical care, such as the 
patients in this study, it is necessary to assess the efficacy and safety of interventions used in their treatment. 
Patients who are sedated and mechanically ventilated will not be able to provide informed consent. 
Consent will be obtained from the participant’s parent or guardian, a legal surrogate or an organisation 
authorised by law (NS 4.4.10).  The criteria of who may give consent for a patient to take part in medical 
research (and the term with which they may be described) varies at participating sites.  For the purposes of 
this protocol, the descriptor “legal surrogate” describes the person who is legally allowed to give consent for 
the patient. 
The legal surrogate will be invited to consider the patient’s consent for participation after a verbal 
presentation, followed by reading of the “person responsible” information and consent form. There will be 
sufficient time provided for thought, reflection, questions and consultation with others. If the legal surrogate 
provides consent for the patient to participate in the study, they will be asked to sign the consent form.  
In cases where the legal surrogate cannot attend the hospital to sign the consent form within the time 
constraints of the study, consent for patient participation in the study may be obtained over the telephone in 
accordance with local Human Research Ethics Committee guidelines. The telephone conversation will be 
documented in the patient’s medical record. As soon as the legal surrogate is able to attend the hospital they 
will be asked to sign a consent form and note that telephone consent was already provided. 
The legal surrogate will be able to withdraw their consent for the patient to participate in the study at any time 
without any reduction in the quality of care, and if they choose to withdraw the patient, permission will be 
asked to use the data collected up until that time.  
Patients who recover sufficiently to provide their own informed consent will be asked to consent to continue 
in the study or offered the chance to withdraw (as per NS 4.4.14).  If the patient chooses to withdraw from the 
study, they will be asked for permission to use their data up to the time of withdrawal. 
All interaction between research staff and potential or actual participants and their legal surrogate will take 
into consideration the stress or emotional factors associated with critical illness and ensure that the 
dependency of potential participants and their relatives on medical personnel providing treatment does not 
compromise the freedom of decision making to participate (as per NS 4.4.11). 
Confidentiality of patient data 
Patients will be randomised via a secure website and will be allocated a unique study number. The site 
research coordinator will compile an enrolment log including the patient’s name, date of birth, hospital 
identification number, unique study number and date and time of randomisation. Other collected data (using a 
case report form and entered on the study website) will be identified by the unique study number, but will not 

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contain this more identifying personal information. The enrolment log will be kept separately to the case 
report form and the study website, so that the personal information is only kept at the specific enrolling site. 
Contact details of the patient and their family will be collected, including name, address and telephone 
numbers, to allow follow-up assessments to occur. The contact details will be forwarded to the coordinating 
centre, as follow-up assessments (phone interviews) will be performed by the coordinating centre (ANZIC-RC) 
to ensure consistency and accuracy. All data collected in the follow up assessments will be identified by the 
unique study number. The follow up contact details will be kept separately to the case report form and the 
study website. Study data will be entered into a password protected website and database managed by the 
CIDMU (Monash University). None of the personal information will be entered into the database. The contact 
details and study data will be kept in a locked office at both the study site and the coordinating centre. 
Ethics committee approval 
Each participating site will submit this protocol and any other relevant study documentation to the responsible 
local Human Research Ethics Committee (or equivalent).  Approval of the protocol, plans for obtaining 
informed consent, and study-related documents will be obtained prior to the start of the study at each site.  
The site principal investigator will be responsible to ensure that all conditions for approval of the study are met 
and that amendments to the protocol or serious adverse events are also reported to the Human Research 
Ethics Committee (HREC, or equivalent) as required. 
This protocol will also be submitted to the Guardianship Board or similar where this is necessary for legal 
surrogates to provide informed consent for patient participation. The site principal investigator will be 
responsible to obtain such approval from the relevant body prior to obtaining legal surrogate consent. 

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DATA MANAGEMENT 
Data collection methods 
All study-related data will be collected by trained staff at each study site using a paper source document (case 
report form) developed by the coordinating centre. Data will then be entered into an internet-based database 
designed by the CIDMU. Data queries will be automatically generated as they are entered into this database. 
Enrolled patients will be followed up to death or 6 months post-enrolment. Data collection will be restricted 
primarily to those variables necessary to define clinical patient characteristics including: baseline 
demographics, primary diagnoses, physiological parameters, diagnostic interventions, therapeutic 
interventions and documentation of deaths, other serious adverse events, and patient outcomes. 
Patients and/or their legal surrogate will be asked to provide three possible points of contact (home and close 
family contact details) to the research staff prior to discharge. Full protocol data will be collected in all patients 
including those where the study is discontinued prior to the end of the study period. Patients (or a surrogate – 
generally a close family member) who are alive at 6 months after enrolment will be asked to complete a 
questionnaire via post or telephone  by a trained follow-up assessor from the coordinating centre. This follow-
up assessor will use a standardized structured telephone questionnaire52 to measure the QOL assessments EQ-
5D53 and SF- 36v254,55. 
 
Data variables collected 
• 
Demographic data 
• 
Height 
• 
Weight 
• 
Admission diagnosis 
• 
Cause of ARDS 
• 
Classification of ARDS as diffuse or focal (by an independent radiologist) 
• 
PaO2/FiO2 ratio at enrolment 
• 
Barotrauma 
• 
Mode of ventilation 
• 
Ventilation parameters 
• 
ABG results 
• 
Vital signs 
• 
SOFA scores 
• 
Daily fluid balance 
• 
Rescue therapy details 
• 
Co-interventions 
• 
Open lung procedure details 
• 
Ventilation weaning 
• 
Adverse events 
• 
Serious adverse events 
• 
Protocol deviations 
• 
Outcomes – duration of ventilation, length of stay, survival, discharge destination 

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• 
Long term outcomes (at 6 months) – SF36, EQ5D, cost-effectiveness analysis 
Data management 
Data management will be performed by the CIDMU at the Department of Epidemiology and Preventive 
Medicine, Monash University. 
 
Monitoring 
The study will be monitored by a representative of the coordinating centre. Prior to study commencement, a 
start-up teleconference or visit will be conducted at each site. Monitoring of the data collection and protocol 
adherence will occur after study completion for the first intervention and control patient at each site. 
The database will be developed to routinely report queries and protocol violations. Additional queries will be 
generated by the Project Manager following regular reviews of the data. Additional on-site monitoring will also 
be performed if the routine reviews indicate any significant issues at individual sites. Email and telephone 
communication will supplement site visits. 
A monitoring report will be prepared following each visit and reviewed by the management committee. A 
follow up letter will be sent to the principal investigator and research coordinator at the site and will be filed in 
the site investigator file. 
Medical records, any other relevant source documents and the site investigator files will be required to be 
made available to the coordinating centre representative for these monitoring visits during the course of the 
study and at the completion of the study as needed. 
The aims of monitoring visits are to: 
a) Check data accuracy by performing source data verification of the electronic case report form 
against the original source documents 
b) Check for protocol deviations to report these to the Management Committee as necessary 
c) Review primary and secondary outcome data collected for each patient 
d) Confirm the informed consent procedures approved by the site’s HREC have been followed and 
view each original signed consent form 
e) Check data security and access 
f) Review all serious adverse events (SAEs) to allow follow up of all reported SAEs 
g) Review investigator site files for completeness and accuracy 
h) Assist the study staff with any queries or problems they may have in relation to the study 
 
Protocol deviations 
A protocol deviation is an unanticipated or unintentional departure from the expected conduct of an approved 
study that is not consistent with the current research protocol or consent document. A protocol deviation may 
be an omission, addition or change in any procedure described in the protocol. 
Given that investigators are responsible for patient safety and care, they may implement a deviation from, or a 
change of, the protocol to deal with an immediate hazard to trial patients without prior HREC approval. The 
implemented deviation or change must be reported in a protocol deviation form. The deviation must be 
reported by the principal investigator using the case report form so that it can be reported to the coordinating 
centre and the HREC (if applicable). 
 

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STATISTICAL CONSIDERATIONS 
Power calculations and sample size 
Based on data from the PHARLAP pilot study, with 282 subjects this study will have an 80% power to detect a 
difference equal to 33% of a standard deviation (equal to3VFD's) with a two sided p-value of 0.05. To account 
for likely occurrence that VFD will not follow a normal distribution, the sample size has been inflated by 15% to 
324 in accordance with Lehmann56. Allowing for up to a 5% rate for withdrawal or loss to long term follow up, 
340 patients will be enrolled. 
 
Statistical and analytical plan 
Independent senior statisticians at Monash University will perform data analysis. Baseline and outcome 
variables will be compared using Chi-square tests for categorical variables, Student’s t-test for normally 
distributed continuous variables and Wilcoxon rank-sum tests for non-normally distributed continuous 
variables. Duration of ventilation will be analysed using Cox-Proportional Hazards regression with deceased 
patients censored at death, allowing for results to be reported using Kaplan Meier curves. Furthermore, 
duration of ventilation will be stratified into survivors and non-survivors. If as expected, the duration of 
ventilation in each strata is well approximated by a log-normal distribution, this will enable log-transformed 
duration of ventilation to be analysed using parametric analysis (student t-tests) and reported as a ratio 
(95%CI). If normality cannot be achieved then the data would subsequently be analysed non-parametrically. 
Should any baseline imbalances be found to exist between groups, additional sensitivity analysis will be 
performed using Cox Proportional Hazards regression adjusting for imbalanced covariates. All analyses will be 
intention-to-treat. A complete statistical analysis plan will be finalised prior to study completion. 
 
Interim analysis 
One midpoint interim analysis (after primary outcome data is available for 170 patients) will be performed to 
assess accumulated safety data. This will be reported to the Data Safety Monitoring Committee, but will not be 
made available to the Management Committee or to study sites. 
 
Subgroup analyses 
We plan to compare study outcomes in the following pre-specified subgroups: 
(a) Patients with severe ARDS (PaO2/FiO2 < 100) versus patients with moderate ARDS (PaO2/FiO2 100-200 
mmHg) at enrolment. 
(b) Patients with diffuse ARDS versus patients with focal ARDS at enrolment (determined by independent 
radiologists). 
(c) Patients who are responders to the open lung strategy versus patients who are non-responders 
(defined as meeting lack of improvement in static lung compliance definition). 

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SAFETY OF SUBJECTS 
Data Safety Monitoring Committee 
An independent Data Safety Monitoring Committee, comprising experts in clinical trials, biostatistics and 
intensive care will be established. The committee will be responsible for monitoring mortality related to 
serious adverse events, serious adverse events and reviewing the interim safety analysis. 
 
Adverse events 
Adverse events are defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational intervention and does not necessarily have to have a causal relationship with 
this intervention (adapted from the Note for Guidance on Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting (CPMP/ICH/377/95 July 2000).  
It is recognised that the patient population with critical illness and ARDS will experience a number of common 
aberrations in laboratory values, signs and symptoms due to the severity of the underlying illness and the 
impact of standard therapies. These will not necessarily constitute an adverse event unless they require 
significant intervention or are considered to be of concern in the investigator’s clinical judgement. 
In all cases, the condition or disease underlying the symptom, sign or laboratory value should be reported e.g. 
renal failure rather than hyperkalaemia, and agitation rather than self-extubation. 
 
Serious adverse events 
Serious Adverse Events (SAE) are defined in accordance with the Note for Guidance on Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95) (July 2000) as any one of 
the following untoward medical occurrences: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event which may require intervention to prevent one of the previously listed 
outcomes 
In this study all SAEs will be reported if they possibly, probably or causally are related to study enrolment. 
However, consistent with the advice of Cook et al, adverse events already defined and reported as study 
outcomes (mortality) will not be labelled and reported a second time as serious adverse events. 
Reporting of SAEs 
Separate case report forms will be developed to record adverse events and serious adverse events. 
SAEs which occur from the time of enrolment until day 90 follow-up will be reported to the coordinating 
centre via the internet-based SAE form. SAEs should be reported to the coordinating centre within 24 hours of 
study staff becoming aware of the event. 
Minimum information to report will include: 
• 
Patient initials and study number 
• 
Nature of the event 
• 
Commencement and cessation of the event 

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• 
An investigator’s opinion of the relationship between study involvement and the event (unrelated, 
possibly, probably or definitely related). 
• 
Whether treatment was required for the event and what treatment was administered.  
Website address: https://pharlap.org.au 
Telephone Numbers: 
ANZIC-RC: +61 3 99030280 
ANZIC-RC: +61 409367132 
Chief investigator: + 61 419770132 
SAEs must be reported using the study website. The event and report may be discussed with the coordinating 
centre staff or chief investigator if necessary. Coordinating centre staff will be responsible for following-up 
SAEs to ensure all details are available. The site principal investigator is responsible for inform the relevant 
HREC of all SAEs which occur at their site, in accordance with local requirements. 
 
FUNDING 
The PHARLAP study is funded by project grants from the National Health and Medical Research Council 
(NHMRC) (Project grant no APP1021203), the Alfred Hospital, and the Health Research Council of New 
Zealand. The ANZIC-RC will supply infrastructure and administrative support. 
 
PUBLICATION 
The study will be conducted in the name of the PHARLAP investigators, the ANZIC-RC and the Australian and 
New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). The study has been endorsed by the 
ANZICS CTG. The principal publication from the study will be authored as "The PHARLAP Study Investigators for 
the ANZICS CTG”. This will be on behalf of the writing committee and all PHARLAP Investigators with full credit 
being assigned to all collaborating investigators, research coordinators and institutions. Where an individual’s 
name is required for publication it will be that of the writing committee, with the chair of the writing 
committee listed first and subsequent authors listed alphabetically. 
Funding bodies will be acknowledged in the publication. 
Other manuscripts and sub-studies may be authored differently but these must follow the conditions of 
ANZICS CTG endorsement and be approved by the PHARLAP MC. This may lead to manuscripts authored by a 
list of individual authors on behalf of the PHARLAP Study Investigators for the ANZICS CTG. 

PHARLAP study, Protocol ANZIC-RC/AD002 Version 8.  Dated 25 November 2014 
 
44 
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REFERENCES 
1. 
Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators 
 
in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 
 
1999;282:54-61. 
2. 
Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European Consensus conference on 
 
acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial 
 
coordination. Consensus Committee. J Crit Care 1994;9:72-81. 
3. 
Bersten AD, Edibam C, Hunt T, Moran J. Incidence and mortality of acute lung injury and the acute 
 
respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002;165:443-8. 
4. 
Webb SA, Pettila V, Seppelt I, et al. Critical care services and 2009 H1N1 influenza in Australia and 
 
New Zealand. N Engl J Med 2009;361:1925-34. 
5. 
Davies A, Jones D, Bailey M, et al. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) 
 
Acute Respiratory Distress Syndrome. JAMA 2009;302:1888-95. 
6. 
Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in 
 
patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-36. 
7. 
Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment 
 
maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory 
 
distress syndrome: a randomized controlled trial. JAMA 2008;299:637-45. 
8. 
Bersten AD, Cooper DJ. Better supportive care, less ARDS: just do it? Am J Respir Crit Care Med 
 
2011;183:6-7. 
9. 
Li G, Malinchoc M, Cartin-Ceba R, et al. Eight-year trend of acute respiratory distress syndrome: a 
 
population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 2011;183:59-66. 
10. 
Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional 
 
ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure 
 
(CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351-63. 
11. 
Higgins AM, Pettila V, Harris AH, et al. The Critical Care Costs of the Influenza A/H1N1 2009 Pandemic 
 
in Australia and New Zealand. Anaesthesia and Intensive Care 2011 in press;39. 
12. 
Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory 
 
distress syndrome. N Engl J Med 2003;348:683-93. 
13. 
Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory 
 
distress syndrome. N Engl J Med 2006;354:1775-86. 
14. 
Caironi P, Cressoni M, Chiumello D, et al. Lung opening and closing during ventilation of acute 
 
respiratory distress syndrome. Am J Respir Crit Care Med 2010;181:578-86. 
15. 
Morales MM, Pires-Neto RC, Inforsato N, et al. Small airway remodeling in acute respiratory distress 
 
syndrome: a study in autopsy lung tissue. Crit Care 2011;15:R4. 
16. 
The Acute Respiratory Distres Syndrome Network. Ventilation with lower tidal volumes as compared 
 
with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New 
 
Eng J of Med 2000;342:1301-8. 
17. 
Amato MB. Effect of a Protective-Ventilation Strategy on Mortality in the Acute Respiratory Distress 
 
Syndrome. N Eng J Med 1998;338:347-54. 
18. 
Hodgson C, Keating JL, Holland AE, et al. Recruitment manoeuvres for adults with acute lung injury 
 
receiving mechanical ventilation. Cochrane Database Syst Rev 2009:CD006667. 
19. 
Fan E, Wilcox ME, Brower RG, et al. Recruitment maneuvers for acute lung injury: a systematic review. 
 
Am J Respir Crit Care Med 2008;178:1156-63. 
20. 
Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung 
 
injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:646-55. 
21. 
Brower RG, Morris A, MacIntyre N, et al. Effects of recruitment maneuvers in patients with acute lung 
 
injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure. 
 
Crit Care Med 2003;31:2592-7. 
22. 
Lim S-C, Adams AB, Simonson DA, et al. Intercomparison of recruitment maneuver efficacy in three 
 
models of acute lung injury. Crit Care Med 2004;32:2371-7. 
23. 
Tuxen DV, Hodgson CL. Lung recruitment: who, when and how? . Critical Care and Resuscitation 
 
2010;12:141-2. 

PHARLAP study, Protocol ANZIC-RC/AD002 Version 8.  Dated 25 November 2014 
 
45 
CONFIDENTIAL 
 
24. 
Lim C-M, Jung H, Koh Y, et al. Effect of alveolar recruitment maneuver in early acute respiratory 
 
distress syndrome according to antiderecruitment strategy, etiological category of diffuse lung injury, 
 
and body position of the patient. Crit Care Med 2003;31:411-8. 
25. 
Borges JB, Okamoto VN, Matos GF, et al. Reversibility of lung collapse and hypoxemia in early acute 
 
respiratory distress syndrome. Am J Respir Crit Care Med 2006;174:268-78. 
26. 
Hodgson CL, Tuxen DV, Holland AE, et al. A positive response to a recruitment maneuver with PEEP 
 
titration in patients with ARDS, regardless of transient oxygen desaturation during the maneuver. 
 
JICM 2011;26:41-9. 
27. 
Brochard L. New goals for positive end-expiratory pressure in acute respiratory distress syndrome: a 
 
paradigm shift or the end of an area of uncertainty? Am J Respir Crit Care Med 2010;181:528-30. 
28. 
Rouby JJ, Lu Q, Goldstein I. Selecting the right level of positive end-expiratory pressure in patients 
 
with acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:1182-6. 
29. 
Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low 
 
tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: 
 
a randomized, controlled trial. Crit Care Med 2006;34:1311-8. 
30. 
Minneci PC, Eichacker PQ, Danner RL, Banks SM, Natanson C, Deans KJ. The importance of usual care 
 
control groups for safety monitoring and validity during critical care research. Intensive Care Med 
 
2008;34:942-7. 
31. 
Hodgson CL, Nichol, A., Tuxen, D.V., Davies, A.R. et al. A randomised controlled trial of staircase 
 
recruitment manoeuvres, high PEEP and low airway pressure (PHARLAP). Am J Resp Crit Care Med 
 
2010;181:A1686. 
32. 
Huh JW, Jung H, Choi HS, Hong SB, Lim CM, Koh Y. Efficacy of positive end-expiratory pressure 
 
titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress 
 
syndrome. Crit Care 2009;13:R22. 
33. 
Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with 
 
acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. 
 
JAMA 2010;303:865-73. 
34. 
Hager DN, Krishnan JA, Hayden DL, Brower RG. Tidal volume reduction in patients with acute lung 
 
injury when plateau pressures are not high. Am J Respir Crit Care Med 2005;172:1241-5. 
35. 
Terragni PP, Rosboch G, Tealdi A, et al. Tidal hyperinflation during low tidal volume ventilation in 
 
acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175:160-6. 
36. 
Hickling KG. Low volume ventilation with permissive hypercapnia in the Adult Respiratory Distress 
 
Syndrome. Clin Intensive Care 1992;3:67-78. 
37. 
Hickling KG. Lung-protective ventilation in acute respiratory distress syndrome: protection by reduced 
 
lung stress or by therapeutic hypercapnia? Am J Respir Crit Care Med 2000;162:2021-2. 
38. 
Nichol AD, O'Cronin DF, Naughton F, Hopkins N, Boylan J, McLoughlin P. Hypercapnic acidosis reduces 
 
oxidative reactions in endotoxin-induced lung injury. Anesthesiology 2010;113:116-25. 
39. 
Nichol AD, O'Cronin DF, Howell K, et al. Infection-induced lung injury is worsened after renal buffering 
 
of hypercapnic acidosis. Crit Care Med 2009;37:2953-61. 
40. 
Curley G, Contreras MM, Nichol AD, Higgins BD, Laffey JG. Hypercapnia and acidosis in sepsis: a 
 
double-edged sword? Anesthesiology 2010;112:462-72. 
41. 
Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress 
 
syndrome. N Engl J Med 2010;363:1107-16. 
42. 
Jones DA, Cooper DJ, Finfer SR, et al. Advancing intensive care research in Australia and New Zealand: 
 
development of the binational ANZIC Research Centre. Crit Care Resusc 2007;9:198-204. 
43. 
Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for 
 
fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. 
44. 
Doig GS, Simpson F, Finfer S, et al. Effect of evidence-based feeding guidelines on mortality of 
 
critically ill adults: a cluster randomized controlled trial. JAMA 2008;300:2731-41. 
45. 
Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive Craniectomy in Diffuse Traumatic Brain 
 
Injury. N Engl J Med 2011. 
46. 
Kacmarek RM, Kallet RH. Respiratory controversies in the critical care setting. Should recruitment 
 
maneuvers be used in the management of ALI and ARDS? Respir Care 2007;52:622-31. 
47. 
Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin 
 
Definition. JAMA : The Journal of the American Medical Association 2012;307:2526-33. 

PHARLAP study, Protocol ANZIC-RC/AD002 Version 8.  Dated 25 November 2014 
 
46 
CONFIDENTIAL 
 
48. 
Suntharalingam G, Regan K, Keogh BF, Morgan CJ, Evans TW. Influence of direct and indirect etiology 
 
on acute outcome and 6-month functional recovery in acute respiratory distress syndrome. Crit Care 
 
Med 2001;29:562-6. 
49. 
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury 
 
and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. The 
 
New England Journal of Medicine 2000;342:1301-8. 
50. 
Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in 
 
acute lung injury. The New England Journal of Medicine 2006;354:2564-75. 
51. 
Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent 
 
acute respiratory distress syndrome. The New England Journal of Medicine 2006;354:1671-84. 
52. 
Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the 
 
extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma 1998;15:573-85. 
53. 
EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol Group. 
 
Health Policy 1990;16:199-208. 
54. 
Dowdy DW, Eid MP, Dennison CR, et al. Quality of life after acute respiratory distress syndrome: a 
 
meta-analysis. Intensive Care Medicine 2006;32:1115-24. 
55. 
Hawthorne G, Osborne RH, Taylor A, Sansoni J. The SF36 Version 2: critical analyses of population 
 
weights, scoring algorithms and population norms. Qual Life Res 2007;16:661-73. 
56. 
Lehmann EL. Nonparametrics: Statistical methods based on ranks, revised: Prentice Hall; 1998. 
57. 
Cook D, Lauzier F, Rocha MG, Sayles MJ, Finfer S. Serious adverse events in academic critical care 
 
research. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 
 
2008;178:1181-4. 
 
 
 

PHARLAP study, Protocol ANZIC-RC/AD002 Version 8.  Dated 25 November 2014 
 
47 
CONFIDENTIAL 
 
APPENDIX 1: PREDICTED BODY WEIGHT (PBW) CALCULATION 
 
• Male:  
PBW (in kg) = 50 + 0.91 [height (cm) – 152.4] 
 
• Female: 
PBW (in kg) = 45.5 + 0.91 [height (cm) – 152.4] 
 
Ref: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and 
the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. The New England 
Journal of Medicine 2000;342:1301-8. 
 
Use true height if this has been measured accurately in the last few days. If not, use estimated 
height from measurement of the demi-arm span. 
The demi-arm span should be measured using the right arm (preferably) and by measuring between 
the base of the fingers where the middle and ring fingers meet to the sternal notch. The patients’ 
right arm should be extended until it is horizontal with the shoulder. Ensure the wrist is straight. The 
patients’ arm may need to be supported. 
 
The estimated height can then be calculated from the measured demi-arm span as follows: 
 
• Male:  
Height (in cm) = (1.40 X demi-arm span (cm)) + 57.8 
 
• Female: 
Height (in cm) = (1.35 X demi-arm span (cm)) + 60.1 

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APPENDIX 2: BRONCHOALVEOLAR LAVAGE (BAL) FLUID COLLECTION 
Non-bronchoscopic method: 
1. Pre-oxygenate the patient by increasing the FiO2 to 1.0 for 2 minutes. The PEEP should be left on the current 
setting. 
2. Draw up 60 ml of 0.9% saline in appropriate syringes (usually three 20 ml syringes). Prepare a clean 
environment as per the usual site practice for similar interventions. 
3. Connect one of the 0.9% saline syringes to the upper port on the 3 way tap and point the off arrow to the 
other port.  Ensure the blue locking device is open. 
4. Introduce the BAL catheter by forwarding the catheter through connector B so that the catheter tip 
protrudes through the connector before connecting to the endotracheal tube. 
5. Disconnect the in-line suction and ventilator and attach connector B to the endotracheal tube – the catheter 
should be 2 cm into the endotracheal tube. Reconnect the ventilator tubing to connector B. 
6. Advance the catheter until the numbers on the catheter match the numbers on the endotracheal tube. At 
this point the catheter is located exactly at the distal point of the endotracheal tube. 
7. Ensure the white oxygen port on the catheter is orientated to the right. This means that the internal 
catheter will be angled towards the right main bronchus. 
8. Forward the entire catheter another 5 cm and check that the white oxygen port remains orientated to the 
right side. 
9. Flush the catheter with 5 ml 0.9% saline. Lock the blue locking device. 
10. Gently advance the inner catheter until a spongy resistance is noted (ie. the catheter is appropriately 
wedged in a distal bronchus). 
11. Inject the first syringe of 0.9% saline, followed by 5 ml air. With the same syringe, gently hand aspirate the 
BAL, then do the same with subsequent syringes via the 3 way port until a minimum volume of 10ml. is 
obtained. 
12. Withdraw the inner suction catheter until the solid black mark is outside the connector to the endotracheal 
tube. Unlock the blue locking device. Withdraw the entire catheter. Reconnect the in-line suction catheter and 
the original connectors. 
13. Combine the collected BAL fluid from each syringe into a sterile container and label this as a BAL for the 
PHARLAP study. 
14. If the patient has been assigned to the PHARLAP group, this procedure should now be followed as soon as 
possible by a combined open lung procedure (see page 26) if it is day 1 or a BRM if it is day 3. 
 
Bronchoscopic method: 
1. Pre-oxygenate the patient by increasing the FiO2 to 1.0 for 2 minutes. The PEEP should be left on the current 
setting. 
2. Draw up 60 ml of 0.9% saline in appropriate syringes (usually three 20 ml syringes). Prepare a clean 
environment as per the usual site practice for similar interventions. 
3. Wedge the bronchoscope in the appropriate bronchus. 
4. Inject the first syringe of 0.9% saline, followed by 5 ml air. With the same syringe, gently hand aspirate the 
BAL, then do the same with subsequent syringes until a minimum volume of 10 ml is obtained. 

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5. Combine the collected BAL fluid from each syringe into a sterile container and label this as a BAL for the 
PHARLAP study. 
6. If the patient has been assigned to the PHARLAP group, this procedure should now be followed as soon as 
possible by a combined open lung procedure (see page 26) if it is day 1 or a BRM if it is day 3. 
 

 
 
CONFIDENTIAL 
APPENDIX 3: SCHEDULE OF EVENTS 
Assessments/ 
Procedures 
Pre 
Randomisation/
Baseline 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 6 till 
liberation of 
mechanical 
ventilation 
ICU 
discharge 
Hospital 
discharge 
Follow-up 
28 days 
Follow-up 
90 days 
Follow-up 6 
months 
Inclusion & 
Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
data 
X 
 
 
 
 
 
 
 
 
 
 
 
Height & weight 
measurement 
X 
 
 
 
 
 
 
 
 
 
 
 
CXR 
X 
 
 
 
 
 
 
 
 
 
 
 
Download CXR 
image 
X 
 
 
 
 
 
 
 
 
 
 
 
Apache II score 
X 
 
 
 
 
 
 
 
 
 
 
 
Apache III 
diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
SOFA score 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Ventilation 
observations 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Static respiratory 
compliance 
 
X 
 
X 
 
 
 
 
 
 
 
 
Combined open 
lung procedure 
 
X* 
X* 
X* 
X* 
X* 
 
 
 
 
 
 
* Only for patients randomised to PHARLAP treatment group (combined open lung procedure) 

PHARLAP study, Protocol ANZIC-RC/AD002 Version 8.  Dated 25 November 2014 
 
51 
CONFIDENTIAL 
 
Assessments/ 
Procedures 
Pre 
Randomisation/
Baseline 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 6 till 
liberation of 
mechanical 
ventilation 
ICU 
discharge 
Hospital 
discharge 
Follow-up 
28 days 
Follow-up 
90 days 
Follow-up 6 
months 
Sputum sample 
(BAL)  
 
X 
 
X 
 
 
 
 
 
 
 
 
Blood sample 
 
X 
 
X 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serious adverse 
events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Survival status 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
SF36V2 
 
 
 
 
 
 
 
 
 
 
 
X 
EQ5D 
 
 
 
 
 
 
 
 
 
 
 
X 

 
 
CONFIDENTIAL 
APPENDIX 4: APACHE II SEVERITY OF DISEASE CLASSIFICATION 
APACHE II CALCULATION WORKSHEET 
 
The APACHE II score is derived from 3 scoring systems: Part A – Acute Physiology Score, Part B – Age Points, Part C – 
Chronic Health Points 
 
Part A - Acute Physiology Score 
For each of the 12 physiological variables, select the value closest in time, but prior, to the patient meeting the final entry 
criteria for inclusion into the study (T0 hours).  Enter the value in the right hand column. 
 
For exact non-integer data that is not found in any of the given ranges, round the figure up or down to the nearest whole 
number. Eg, 44 years and 3 months is rounded down to ≤ 44 years and assigned 0 points; a calculated MAP of 129.7 is 
rounded up to 130 and assigned 3 points. For integers of xx.5 always round upwards. This is an arbitrary decision but must 
be followed for every patient to ensure consistency. 
 
1. Temperature – this should be a core temperature measurement (rectal, tympanic, oesophageal or via PAC).  Where 
this is not possible, add 0.50C to the oral or axillary temperature 
2. If mean arterial pressure (MAP) is not calculated by monitoring equipment, use the manual sphygmomanometer 
recording of systolic (SBP) and diastolic blood pressure (DBP) to obtain MAP using this equation MAP = (DBP x 2) + 
SBP ÷ 3. 
3. If the patient has an atrial arrhythmia, measure the ventricular response rate (R waves) only to record the heart rate. 
4. A – aDO2 is the difference between the calculated alveolar oxygen tension and the arterial oxygen tension. The 
alveolar oxygen tension is calculated by this equation: AO2 = 713 x FiO2 – PaCO2 x 1.25. The FiO2 here is expressed 
as a proportion of a unit. e.g. 100% FiO2 = 1 and 60% equals 0.6. If the FIO2 (inhaled oxygen concentration) is greater 
than 50%, record the most deranged value for the A – aDO2. If the FIO2 is less than 50% record only the PaO2 (arterial 
oxygen pressure). All measurements are in mmHg. 
5. If ABGs have not been performed, choose the most deranged value for the serum venous bicarbonate (HCO3) in place 
of the arterial pH 
6. To obtain a score for the Glasgow Coma Scale (GCS) use the GCS worksheet provided and subtract the GCS score 
from 15 to arrive at a score on the APACHE worksheet. 
 
Whenever possible, make an attempt to obtain a score for each physiological variable. If one of the 12 variables is not 
available, assign 0 points and make a note of this absence on the APACHE II worksheet. The assumption being made is 
that a test or measurement was not ordered because the status of the patient did not warrant investigation, rather than the 
data was missing. 
 
To complete Part B – assign points to the age range that the patient fits in to. eg, a 48 year old patient would be assigned 
2 points. 
 
 
To complete Part C – first decide if the patient meets any of the criteria provided on the worksheet for a history of severe 
organ insufficiency or immunocompromised. If there is no history, assign 0 points. If there is a history, assign points 
depending on whether the patient is an non-operative emergency admission or an emergency post-operative admission  
 
 
Finally, add the points recorded for each of the 3 parts and enter this total score at question 1.7 The minimum score is 0 
and the maximum score is 71. Keep the completed APACHE II worksheet in the documentation folder for this patient. It 
may be used for quality assurance measures. You will therefore need to print your hospital ID, Patient Initials and Patient 
Study Number on the APACHE worksheet

 
 
CONFIDENTIAL 
APPENDIX 5: SHORT FORM 36V2 AUSTRALIAN VERSION 
INSTRUCTIONS: 
Please answer every question.  Some questions may look like others, but each one is different.  Please take 
the time to read and answer each question carefully by filling in the bubble that best represents your 
response. 
Example: 
This is for your review.  Do not answer this question.  The questionnaire begins with question 1 below. 
For each question you will be asked to fill in a bubble in each line, like this: 
How strongly do you agree or disagree with each of the following statements? 
 
Strongly 
agree 
Agree 
Uncertain Disagree 
Strongly 
disagree 
a)  I enjoy listening to music. 
 
 
 
 
 
b)  I enjoy reading magazines. 
 
 
 
 
 
 
Please begin answering the questions now. 
 
 
1. 
In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
 
2. 
Compared to one year ago, how would you rate your health in general now? 
Much better 
now than  
one year ago 
Somewhat 
better now than 
one year ago 
About the same
 as  
one year ago 
Somewhat 
worse 
 now than  
one year ago 
Much worse 
now than  
one year ago 
 
 
 
 
 
 
Please turn the page and continue. 

PHARLAP study, Protocol ANZIC-RC/AD002 Version 8.  Dated 25 November 2014 
 
59 
CONFIDENTIAL 
 
APPENDIX 6: EQ5D (ENGLISH VERSION FOR AUSTRALIA) 
By placing a tick in one box in each group below, please indicate which statements best describe your own 
health state today. 
 
Mobility 
I have no problems in walking around 
 
 
PLEASE TICK 
I have some problems in walking around 
 
 
ONE BOX 
I am confined to bed 
 
 
 
Personal Care 
I have no problems with personal care 
 
 
 PLEASE TICK 
I have some problems washing or dressing myself 
 
  ONE BOX 
I am unable to wash or dress myself 
 
 
 
Usual Activities (e.g. work, study, housework, family or  
leisure activities) 
I have no problems with performing my usual activities 
 
 
PLEASE TICK 
I have some problems with performing my usual activities 
 
 
ONE BOX 
I am unable to perform my usual activities  
 
 
 
Pain/Discomfort 
 
I have no pain or discomfort 
 
 
PLEASE TICK 
I have moderate pain or discomfort 
 
  
ONE BOX 
I have extreme pain or discomfort 
 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
  
PLEASE TICK 
I am moderately anxious or depressed 
 
  
ONE BOX 
I am extremely anxious or depressed 
 
 

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APPENDIX 7: DIFFUSE VERSUS FOCAL ARDS SUBSTUDY 
This is a study to determine if acute respiratory distress patients with different subtypes behave differently.  
 
Background & rationale 
Patients with different subtypes of ARDS (focal, diffuse and patchy (on Chest X Ray)) may behave differently with application of 
high vs low PEEP depending on the percent of recruitable lung and the amount of stress and strain during PEEP titration/ 
recruitment.  
Patients with diffuse ARDS appear to have more recruitable lungs (1), have a higher inflection point and require higher PEEP levels 
for adequate recruitment without causing over-distension whereas patients with focal ARDS develop over-distension with higher 
levels of PEEP and have less recruitable lungs (2,3). Accordingly, in patients with a focal distribution of loss of aeration (i.e., with 
atelectatic dependent lobes coexisting with aerated nondependent lobes), the use of high PEEP levels (15–20 cm H2O) results in 
minimal alveolar recruitment in the dependent lobes but significant hyperinflation in the nondependent lung lobes. Patients with 
patchy ARDS lie in between the two above mentioned subgroups (Table 1). 
Incidence 
(n=71) 
Mortality rate 
Primary ARDS 
Compliance (ml 
cm H2O-1 ) 
Lower Inflection 
Point (cm H2O) 
Diffuse 
23% (16) 
75% 
82% 
19±9 
8.4±2 
Focal 
36% (26) 
42% 
50% 
41± 21 
4.6±2 
Patchy 
41% (29) 
41% 
79% 
30±15 
6.3±2.7 
Table 1.  Differences between the 3 subgroups of patients with ARDS (Puybasset etal) (2,4,5) 
Patients can be identified a priori as either having focal, patchy or diffuse disease based on their chest radiograph at the time of 
ARDS diagnosis/ study inclusion. The PHARLAP study provides an excellent opportunity to prospectively examine the effect of PEEP 
and recruitment on lung injury in the different subgroups as there will measurement of blood and bronchoalveolar lavage 
cytokines levels as a part of the study.  
 
Objectives 
Aim 
To investigate the effect of recruitment and high (PHARLAP) v low (conventional) PEEP levels on inflammatory markers in different 
subtypes of ARDS (based on CXR). 
Hypothesis 
Patients with diffuse ARDS, when randomized to the recruitment and high PEEP arm, will have lower inflammatory markers when 
compared to patients ventilated with conventional ARDSnet protocol (6) as used in the LOVS study (7). 
 
 
Study outcome measures  
Analyse the inflammatory outcomes based on the radiological type of ARDS.  
Inflammatory markers will be measured by   
• 
Baseline to day 3 change in IL-8 and IL-6 concentrations in non-bronchoscopic broncho-alveolar lavage  
• 
Baseline to day 3 change in IL-8 and IL-6 concentrations in plasma 
 

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Statistical considerations 
As PHARLAP proposes to include 340 patients, based on previous studies (2,4,5,8) about one third of patients will fall into each 
group and this should still leave adequately sized groups of patients with focal, patchy and diffuse to study their influence on the 
PHARLAP primary outcome of number of ventilator free days at day 28 post randomisation, markers of inflammatory mediators, 
and several other secondary outcomes.  With a total of 300 patients in the study based on data from Bersten et al (8) –personal 
communication we will likely get 80-100 patients per subtype, which would mean approximately 40 to 50  patient in each arm per 
subgroup. This should give us a reasonable sample size for each subgroup, and whilst mortality differences or VFDs may be 
unlikely, the potential for differences in other outcomes is reasonable, beside it will generate hypothesis for future studies.   
We plan to analyse the outcomes of the study by utilising the general linear model with each outcome primary and secondary 
outcomes (PHARLAP - primary and secondary outcomes analysed separately as the dependent variable while ventilation strategy 
(PHARLAP / control), CXR coding (diffuse, focal, patchy) will be entered as independent factors. Interaction between ventilation 
strategy and the CXR coding will also be studied in the model. Post Hoc analysis will be done between the various CXR and 
ventilation subgroups (it will compare the outcomes of the CXR subgroups (diffuse, patchy and focal) within and among the 
PHARLAP and control group). 
 
Funding 
Diffuse versus focal substudy is supported by a $34 950 grant (ANZCA) for procurement of the Chest X rays, cost of independent 
radiological scoring, statistical advice and salary support for a research assistant based at the ANZIC-RC.  
 
Publications 
A separate publication following the main publication will be completed in the name of the PHARLAP investigators led by Shailesh 
Bihari and the PHARLAP writing committee.   
 
References 
1. Nieszkowska A, et al. Incidence and regional distribution of lung over inﬂation during mechanical ventilation with positive 
end-expiratory pressure. Crit Care Med 2004; 32:1496–1503  
2. Puybasset L, et al. Regional distribution of gas and tissue in acute respiratory distress syndrome. III. Consequences for the 
effects of positive end-expiratory pressure.  Int Car Med 2000;26:1215-1227 
3. Grasso S, et al. ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure.  Am J 
Respir Crit Care Med 2007;176:761-767 
4. Puybasset L, et al: Regional distribution of gas and tissue in acute respiratory distress syndrome. I. Consequences for lung 
morphology. Intensive Care Med 2000; 26:857–869 
5. Rouby JJ, et al. Regional distribution of gas and tissue in acute respiratory distress syndrome. II. Physiological correlations 
and definition of an ARDS Severity Score. CT Scan ARDS Study Group. Intensive Care Med. 2000 Aug;26(8):1046-56 
6. Brower RG, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress 
syndrome. N Engl J Med 2004;351:327-36 
7. Meade MO, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory 
pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637-45 
8. Bersten AD, et al. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three 
Australian States. Am J Respir Crit Care Med 2002;165:443-8 
 
 
 

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Focal vs diffuse contact details 
1. Shay McGuinness : 
   
CVICU, Auckland City Hospital, Auckland, New Zealand 1010 
2. Shailesh Bihari: 
   
Telephone: 
  
Dept of ICCU, Flinders Medical Centre, Bedford Park, SA, Australia 5042 
3. Andrew Bersten : 
  
Telephone: 
 
Dept of ICCU, Flinders Medical Centre, Bedford Park, SA, Australia 5042 
4. Carol Hodgson : 
  
ANZIC-RC, DEPM, Monash University, Melbourne, VIC, Australia 3004  
5. Alistair Nichol : 
  
ANZIC-RC, DEPM, Monash University, Melbourne, VIC, Australia 3004