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Halted by the Management Committee after the publication of the ART Trial
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| Name | Class |
|---|---|
| University College Dublin | OTHER |
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Some people develop the condition called acute respiratory distress syndrome (ARDS). This is a condition where the lungs have become injured from one of a number of various causes, and do not work as they normally do to provide oxygen and remove carbon dioxide from the body. This can lead to a reduced amount of oxygen in the patient's bloodstream. Patients with ARDS are admitted to the intensive care unit (ICU) and need help with their breathing by being connected to a ventilator (breathing machine). ARDS can lead to injury in other organs of the body causing other problems but also death.
Over the past few years, reducing the size of each breath delivered by the ventilator in conjunction with the use of an occasional sustained deep breath called a "recruitment manoeuvre" have been used to try to prevent further damage to the lungs in people with ARDS. This ventilator strategy (termed the PHARLAP strategy) has been shown in a small research study to have some beneficial effects without causing any obvious harm, when compared to a current best practice ventilator strategy. The main beneficial effects of the PHARLAP strategy were to increase the amount of oxygen in the blood and to reduce markers of inflammation (the body reacting to a disease process) in the body. This study was too small to make a strong conclusion, so this study will be much larger and will assess whether patients who have developed ARDS are better off when we use the PHARLAP strategy. Three hundred and forty patients will be enrolled into this study in multiple ICUs across Australia and New Zealand.
The study hypothesis is that the PHARLAP strategy group will have a higher number of ventilator free days at day 28 than the control group.
340 adult patients who have developed ARDS within the last 72 hours (and within 10 days of commencing mechanical ventilation) will be enrolled in 25- 30 intensive care units (ICUs) and randomly allocated to either the PHARLAP or a control ventilation strategy. PHARLAP strategy: Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH > 7.15; daily staircase recruitment manoeuvre and individualised Positive-end expiratory pressure (PEEP) titration.
Control strategy: Mechanical ventilation based on the ARDSnet protocol with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and fraction inspired oxygen (FiO2)/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation. A standardised weaning from mechanical ventilation guideline will be used in both groups
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PHARLAP ventilation group | Experimental | PHARLAP mechanical ventilation strategy |
|
| Control group ventilation | Active Comparator | Control group mechanical ventilation strategy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PHARLAP mechanical ventilation strategy | Other | Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH > 7.15; daily staircase recruitment manoeuvre and individualised PEEP titration. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Ventilator Free Days at Day 28 Post Randomisation | This is the total number of days calculated from day 1 (randomisation) to day 28 on which the patient was alive and received no assistance from invasive mechanical ventilation. Scores range between 0 (no ventilator free days) to 28 (no days on ventilator). | 28 days post randomisation |
| Measure | Description | Time Frame |
|---|---|---|
| PaO2/FiO2 Ratio and Static Lung Compliance | PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage). ARDS severity Mild 200-300 / Moderate 100-200 / Severe <100. | Up to day 28 post randomisation |
| Baseline to Day 3 Change in IL-8 and IL-6 Concentrations in Broncho-alveolar Lavage and Plasma |
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Inclusion Criteria:
Adult ICU patients who met all of the following criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Carol Hodgson, PhD, FACP, BAppSc | Australian and New Zealand Intensive Care Research Centre (ANZIC-RC) | Study Chair |
| Alistair Nichol, PhD, FCICM | Australian and New Zealand Intensive Care Research Centre (ANZIC-RC) | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Albury/Wodonga | Albury | New South Wales | Australia | |||
| Nepean Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31356105 | Background | Hodgson CL, Cooper DJ, Arabi Y, King V, Bersten A, Bihari S, Brickell K, Davies A, Fahey C, Fraser J, McGuinness S, Murray L, Parke R, Paul E, Tuxen D, Vallance S, Young M, Nichol A. Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP). A Phase II, Multicenter Randomized Controlled Clinical Trial. Am J Respir Crit Care Med. 2019 Dec 1;200(11):1363-1372. doi: 10.1164/rccm.201901-0109OC. | |
| 29852853 |
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The Australian and New Zealand Intensive Care Research Centre (ANZIC RC), Monash University supports the view that:
The ANZIC-RC has formulated a policy and process to allow appropriate and responsible sharing of research data including prospective and completed studies.
This Policy was guided by, Institute of Medicine principles for responsible sharing of clinical trial data:
Is available on request
request made to custodian via Australian and New Zealand Intensive Care Research Centre
See ANZIC-RC website term of reference document
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| ID | Title | Description |
|---|---|---|
| FG000 | PHARLAP Ventilation Group | PHARLAP mechanical ventilation strategy PHARLAP mechanical ventilation strategy: Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH > 7.15; daily staircase recruitment manoeuvre and individualised PEEP titration. |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 25, 2014 |
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| Control group mechanical ventilation strategy | Other | Mechanical ventilation based on the ARDSnet protocol using volume control ventilation with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and FiO2/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation. |
|
IL-8 is an important protein related to inflammation, Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response |
| Day 3 post randomisation |
| Number of Severe Hypotension Events | Hypotension requiring increased vasopressor Days 1-28 | Up to 28 days post randomisation |
| Number of Participants With Barotrauma | Evidence of Pneumothorax requiring Drainage | Up to 90 days post randomisation |
| Use of Rescue Therapies for Severe Hypoxaemia - Inhaled Nitric Oxide, Inhaled Prostacyclin, Prone Positioning, High Frequency Oscillatory Ventilation and Extracorporeal Membrane Oxygenation (ECMO) | The use of various rescue therapies (each of the therapies is compared between groups - per patient). the various therapies measured are inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO) | Within hospital admission |
| Mortality | At timepoints: day 28 | at day 28 |
| ICU Length of Stay | The number of days a person stayed in the ICU. A fraction of a day is considered a day | From admission to ICU up to 6 months |
| Incidence of Acute Kidney Injury (AKI) | The incidence of Acute Renal Injury - measured by the use of Continuous Renal Replacement Therapy (CRRT) in each person | Within hospital admission |
| Quality of Life Assessment | SF36v2 will be used Medical Outcomes Study. Scoring the RAND is a two-step process. First, pre-coded numeric values are recoded. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores. | 6 months post randomisation |
| Cost Effectiveness Analysis | This will be based on EQ-5D. EQ-5D is the most widely used health-related quality of life questionnaire in health economic evaluations.[62] EQ-5D can be used to derive a set of values that reflect people's opinions of the relative importance of different health problems. These values can be used to derive QALYs for application in cost-effectiveness and cost-utility evaluations. | 6 months post randomisation |
| Hospital Length of Stay | The length of time in days a participant stayed in hospital. A fraction of a day is considered 1 day. | From admission up to 6 months |
| Kingswood |
| New South Wales |
| 2747 |
| Australia |
| Royal Prince Alfred | Sydney | New South Wales | Australia |
| Wollongong Hospital | Wollongong | New South Wales | 2500 | Australia |
| The Prince Charles Hospital | Brisbane | Queensland | Australia |
| Flinders Medical Centre | Adelaide | South Australia | Australia |
| Geelong Hospital | Geelong | Victoria | 3220 | Australia |
| The Alfred Hosptial | Melbourne | Victoria | 3004 | Australia |
| Adelaide and Meath (Tallaght) Hospital | Dublin | Ireland |
| Beaumont Hospital | Dublin | Ireland |
| Mater Misericordiae University Hospital | Dublin | Ireland |
| St Vincents Hospital | Dublin | Ireland |
| University Hospital Limerick | Limerick | Ireland |
| Middlemore Hospital | Otahuhu | Auckland | 1640 | New Zealand |
| Auckland City Hospital (DCCM) | Auckland | 1142 | New Zealand |
| Auckland City Hospital CVICU | Auckland | 1142 | New Zealand |
| King Abdulaziz Medical City | Riyadh | Saudi Arabia |
| Peterborough City Hospital | Peterborough | Cambridgeshire | United Kingdom |
| Derriford Hospital | Plymouth | Devon | United Kingdom |
| Princess Royal University Hospital | Orpington | Kent | United Kingdom |
| Royal Surrey County Hospital | Guildford | Surrey | United Kingdom |
| Southmead Hospital | Bristol | United Kingdom |
| Hull Royal Infirmary | Hull | United Kingdom |
| King's College Hospital | London | United Kingdom |
| North Middlesex University Hospital | London | United Kingdom |
| University Hospital, Lewisham | London | United Kingdom |
| James Cook University Hospital | Middlesbrough | United Kingdom |
| Background |
| Hodgson C, Cooper DJ, Arabi Y, Bennett V, Bersten A, Brickell K, Davies A, Fahey C, Fraser J, McGuinness S, Murray L, Parke R, Tuxen D, Vallance S, Young M, Nichol AD; PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP): a protocol for a phase 2 trial in patients with acute respiratory distress syndrome. Crit Care Resusc. 2018 Jun;20(2):139-149. |
| 38045528 | Background | Bihari S, Bersten A, Paul E, McGuinness S, Dixon D, Sinha P, Calfee CS, Nichol A, Hodgson C; PHARLAP Study Investigators. Acute respiratory distress syndrome phenotypes with distinct clinical outcomes in PHARLAP trial cohort. Crit Care Resusc. 2023 Oct 18;23(2):163-170. doi: 10.51893/2021.2.oa3. eCollection 2021 Jun. |
| 42020568 | Derived | Wildi K, Bihari S, Bersten A, Dixon DL, Paul E, McGuinness S, Hodgson C, Nichol A, Chataway T, Colella AD, Gebhard CE, Chegeni N, Matigian N, LiBassi G, Passmore M, Bouquet M, Ritchie A, Suen J, Fraser J; PHARLAP Study Investigators. Early differential protein expression in blood and bronchoalveolar fluid among ARDS phenotypes. Sci Rep. 2026 Apr 22;16(1):18748. doi: 10.1038/s41598-026-43956-0. |
| Control Group Ventilation |
Control group mechanical ventilation strategy Control group mechanical ventilation strategy: Mechanical ventilation based on the ARDSnet protocol using volume control ventilation with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and FiO2/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | PHARLAP Intervention Arm | PHARLAP strategy (21) included pressure control mode, Tidal Volume (VT) of 4-6 ml/kg, and plateau airway pressures <28cm H2O (online supplement). Patients underwent daily maximal RMs with PEEP titration (a combined open lung procedure [COLP]) for up to the first 5 days The COLP was performed as follows. A staircase RM (SRM) was applied in pressure control ventilation at 15 6 3 cm H2O, with the PEEP increased to 20 cm H2O, then 30 cm H2O, and then 40 cm H2O for 2 minutes each. This step was followed by decremental PEEP titration from 25 cm H2O in 2.5-cm H2O steps for 3 minutes until the SpO2 decreased by 2% or more or to a minimum of 15 cm H2O PEEP if desaturation did not occur. Last, a brief RM returned the PEEP to a level 2.5 cm H2O above the level of desaturation. Airway pressures were minimized with permissive hypercapnia and targeting VT and plateau pressures ,6 ml/kg and ,28 cm H2O, respectively. Brief RMs could be performed throughout the day in case of hypoxemia (online supplement). The study's weaning protocol included daily assessments to identify patients who met weaning criteria and were suitable for a spontaneous breathing trial (online supplement) (24). After a successful spontaneous breathing trial, the ICU clinician reviewed the patient with a view to prompt extubation. |
| BG001 | Control Group | patients were ventilated according to the Acute Respiratory Distress Syndrome Network's low-VT/low PEEP ventilation protocol (4), including volume control mode, VT of 6 ml/kg, plateau airway pressures <30 cm H2O, and the low PEEP strategy (Table E2). RMs were not permitted. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
| |||||||||||||||
| APACHE II score | Acute Physiology and Chronic Health Evaluation II (APACHE II) is a measure of disease severity derived from 3 scores: A) Physiology Score, 12 physiological variables assigned values between 0 (normal) and 4 (high or low abnormal range); B) Age; ranging 0 (44yrs or less) to 6 (75yrs or more); and C) Chronic Health; based on patients medical history with values from 0 (no history) to 5 (non-operative or emergency post-operative patients). Sub-scales are added to determine an overall score between 0 and 71, with increasing scores indicating increased risk of hospital death | Median | Standard Deviation | units on a scale |
| ||||||||||||||
| BMI | Mean | Standard Deviation | kg/m^2 |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Ventilator Free Days at Day 28 Post Randomisation | This is the total number of days calculated from day 1 (randomisation) to day 28 on which the patient was alive and received no assistance from invasive mechanical ventilation. Scores range between 0 (no ventilator free days) to 28 (no days on ventilator). | Posted | Median | Inter-Quartile Range | days | 28 days post randomisation |
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| Secondary | PaO2/FiO2 Ratio and Static Lung Compliance | PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage). ARDS severity Mild 200-300 / Moderate 100-200 / Severe <100. | Not Posted | Jan 2025 | Up to day 28 post randomisation | Participants | |||||||||||||||||||||||||||||||||
| Secondary | Baseline to Day 3 Change in IL-8 and IL-6 Concentrations in Broncho-alveolar Lavage and Plasma | IL-8 is an important protein related to inflammation, Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response | Not Posted | Jan 2025 | Day 3 post randomisation | Participants | |||||||||||||||||||||||||||||||||
| Secondary | Number of Severe Hypotension Events | Hypotension requiring increased vasopressor Days 1-28 | Posted | Number | events | Up to 28 days post randomisation |
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| Secondary | Number of Participants With Barotrauma | Evidence of Pneumothorax requiring Drainage | Posted | Count of Participants | Participants | Up to 90 days post randomisation |
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| Secondary | Use of Rescue Therapies for Severe Hypoxaemia - Inhaled Nitric Oxide, Inhaled Prostacyclin, Prone Positioning, High Frequency Oscillatory Ventilation and Extracorporeal Membrane Oxygenation (ECMO) | The use of various rescue therapies (each of the therapies is compared between groups - per patient). the various therapies measured are inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO) | Not Posted | Jan 2025 | Within hospital admission | Participants | |||||||||||||||||||||||||||||||||
| Secondary | Mortality | At timepoints: day 28 | Posted | Count of Participants | Participants | at day 28 |
|
| |||||||||||||||||||||||||||||||
| Secondary | ICU Length of Stay | The number of days a person stayed in the ICU. A fraction of a day is considered a day | Posted | Median | Inter-Quartile Range | days | From admission to ICU up to 6 months |
|
| ||||||||||||||||||||||||||||||
| Secondary | Incidence of Acute Kidney Injury (AKI) | The incidence of Acute Renal Injury - measured by the use of Continuous Renal Replacement Therapy (CRRT) in each person | Not Posted | Jan 2025 | Within hospital admission | Participants | |||||||||||||||||||||||||||||||||
| Secondary | Quality of Life Assessment | SF36v2 will be used Medical Outcomes Study. Scoring the RAND is a two-step process. First, pre-coded numeric values are recoded. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores. | Not Posted | Jan 2025 | 6 months post randomisation | Participants | |||||||||||||||||||||||||||||||||
| Secondary | Cost Effectiveness Analysis | This will be based on EQ-5D. EQ-5D is the most widely used health-related quality of life questionnaire in health economic evaluations.[62] EQ-5D can be used to derive a set of values that reflect people's opinions of the relative importance of different health problems. These values can be used to derive QALYs for application in cost-effectiveness and cost-utility evaluations. | Not Posted | Jan 2025 | 6 months post randomisation | Participants | |||||||||||||||||||||||||||||||||
| Secondary | Hospital Length of Stay | The length of time in days a participant stayed in hospital. A fraction of a day is considered 1 day. | Posted | Median | Inter-Quartile Range | Days | From admission up to 6 months |
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Adverse events will be collected from randomisation up until the 90 day follow up, up to 90 days in total
Patients with critical illness and ARDS will experience a number of common aberrations in lab values, signs and symptoms due to the severity of underlying illness and the impact of standard therapies. These do not necessarily constitute an adverse event unless they require significant intervention or are of concern in the investigator's clinical judgement.
Primary outcome data (all-cause mortality) not available for one participant in the intervention group, drew to withdrawn consent
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | PHARLAP Ventilation Group | PHARLAP mechanical ventilation strategy PHARLAP mechanical ventilation strategy: Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH > 7.15; daily staircase recruitment manoeuvre and individualised PEEP titration. | 14 | 57 | 23 | 58 | 9 | 58 |
| EG001 | Control Group Ventilation | Control group mechanical ventilation strategy Control group mechanical ventilation strategy: Mechanical ventilation based on the ARDSnet protocol using volume control ventilation with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and FiO2/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation. | 17 | 56 | 15 | 56 | 4 | 56 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Requiring chest tube |
| |
| Severe Hypotension | Cardiac disorders | Systematic Assessment | requiring a change in vasopressors |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| refractory acidosis | Metabolism and nutrition disorders | Systematic Assessment | acidosis refractory to normal mangament |
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The power of the study was limited by lower than expected recruitment rates, early termination of the trial (due to the publication of the ART trial), and treatment crossovers. Blinding was not possible within the ICU, staff and relatives were aware of group allocation.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof Carol Hodgson | ANZIC - RC, Monash University | +61 (3) 99030598 | carol.hodgson@monash.edu |
| Feb 19, 2023 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 18, 2013 | Mar 15, 2022 | ICF_001.pdf |
| ID | Term |
|---|---|
| D012128 | Respiratory Distress Syndrome |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |
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