Trial Outcomes & Findings for Open Lung Ventilation in ARDS: The PHARLAP Trial (NCT NCT01667146)

NCT ID: NCT01667146

Last Updated: 2024-07-18

Results Overview

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).

• Recruitment status: TERMINATED
• Study phase: NA
• Target enrollment: 115 participants
• Primary outcome timeframe: 28 days post randomisation
• Results posted on: 2024-07-18

Participant Flow

Participant milestones

Measure	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.	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.
Overall Study STARTED	58	57
Overall Study COMPLETED	57	56
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	PHARLAP Intervention Arm n=58 Participants 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.	Control Group n=56 Participants 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.	Total n=114 Participants Total of all reporting groups
Age, Continuous	54.2 years STANDARD_DEVIATION 14.0 • n=58 Participants	53.2 years STANDARD_DEVIATION 14.4 • n=56 Participants	53.7 years STANDARD_DEVIATION 14.2 • n=114 Participants
Sex: Female, Male Female	22 Participants n=58 Participants	26 Participants n=56 Participants	48 Participants n=114 Participants
Sex: Female, Male Male	36 Participants n=58 Participants	30 Participants n=56 Participants	66 Participants n=114 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
APACHE II score	23.2 units on a scale STANDARD_DEVIATION 6.8 • n=58 Participants	22.3 units on a scale STANDARD_DEVIATION 7.7 • n=56 Participants	22.8 units on a scale STANDARD_DEVIATION 7.2 • n=114 Participants
BMI	31.3 kg/m^2 STANDARD_DEVIATION 10.1 • n=58 Participants	30.3 kg/m^2 STANDARD_DEVIATION 7.2 • n=56 Participants	30.8 kg/m^2 STANDARD_DEVIATION 8.6 • n=114 Participants

PRIMARY outcome

Timeframe: 28 days 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).

Outcome measures

Measure	PHARLAP Ventilation Group n=57 Participants 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.	Control Group Ventilation n=56 Participants 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.
Number of Ventilator Free Days at Day 28 Post Randomisation	16 days Interval 0.0 to 21.0	14.5 days Interval 0.0 to 21.5

SECONDARY outcome

Timeframe: Up to day 28 post randomisation

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 3 post randomisation

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 28 days post randomisation

Hypotension requiring increased vasopressor Days 1-28

Outcome measures

Measure	PHARLAP Ventilation Group n=57 Participants 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.	Control Group Ventilation n=56 Participants 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.
Number of Severe Hypotension Events	20 events	12 events

SECONDARY outcome

Timeframe: Up to 90 days post randomisation

Evidence of Pneumothorax requiring Drainage

Outcome measures

Measure	PHARLAP Ventilation Group n=57 Participants 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.	Control Group Ventilation n=56 Participants 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.
Number of Participants With Barotrauma	3 Participants	2 Participants

SECONDARY outcome

Timeframe: Within hospital admission

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)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: at day 28

At timepoints: day 28

Outcome measures

Measure	PHARLAP Ventilation Group n=57 Participants 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.	Control Group Ventilation n=56 Participants 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.
Mortality	14 Participants	15 Participants

SECONDARY outcome

Timeframe: From admission to ICU up to 6 months

The number of days a person stayed in the ICU. A fraction of a day is considered a day

Outcome measures

Measure	PHARLAP Ventilation Group n=57 Participants 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.	Control Group Ventilation n=56 Participants 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.
ICU Length of Stay	11.1 days Interval 6.2 to 20.1	13.8 days Interval 6.8 to 22.5

SECONDARY outcome

Timeframe: Within hospital admission

The incidence of Acute Renal Injury - measured by the use of Continuous Renal Replacement Therapy (CRRT) in each person

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 6 months post randomisation

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 6 months post randomisation

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From admission up to 6 months

The length of time in days a participant stayed in hospital. A fraction of a day is considered 1 day.

Outcome measures

Measure	PHARLAP Ventilation Group n=57 Participants 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.	Control Group Ventilation n=56 Participants 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.
Hospital Length of Stay	20.1 Days Interval 8.1 to 37.2	17.9 Days Interval 9.0 to 39.0

Adverse Events

PHARLAP Ventilation Group

Serious events: 23 serious events

Other events: 9 other events

Deaths: 14 deaths

Control Group Ventilation

Serious events: 15 serious events

Other events: 4 other events

Deaths: 17 deaths

Serious adverse events

Measure	PHARLAP Ventilation Group n=58 participants at risk 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.	Control Group Ventilation n=56 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Pneumothorax	5.2% 3/58 • 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	5.4% 3/56 • 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
Cardiac disorders Severe Hypotension	34.5% 20/58 • 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	21.4% 12/56 • 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

Other adverse events

Measure	PHARLAP Ventilation Group n=58 participants at risk 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.	Control Group Ventilation n=56 participants at risk 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.
Metabolism and nutrition disorders refractory acidosis	15.5% 9/58 • 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	7.1% 4/56 • 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

Additional Information

Prof Carol Hodgson

ANZIC - RC, Monash University

Phone: +61 (3) 99030598

Email: carol.hodgson@monash.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place