Permissive hypercapnia, alveolar recruitment and low airway pressure (PHARLAP)

A protocol for a phase 2 trial in patients with acute respiratory distress syndrome

Carol Hodgson, David Jamie Cooper, Yaseen Arabi, Victoria Bennett, Andrew Bersten, Kathy Brickell, Andrew Davies, Ciara Fahey, John Fraser, Shay McGuinness, Lynne Murray, Rachael Parke, David Tuxen, Shirley Vallance, Meredith Young, Alistair D. Nichol, on behalf of the PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group

Research output: Contribution to journalArticleOtherpeer-review

Abstract

Background: Mechanical ventilation is a life-saving intervention that maintains gas exchange in patients with acute respiratory distress syndrome (ARDS); however, it is associated with high mortality and it may augment, or even initiate, lung injury. An open lung ventilation strategy that combines alveolar recruitment manoeuvres with individually titrated positive end-expiratory pressure (PEEP) and targeting lower tidal volumes, or driving pressures by a permissive approach to hypercapnia, may reduce the lung injury associated with mechanical ventilation. This protocol reports the rationale, study design and analysis plan of the Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) trial. Methods and design: PHARLAP is a phase 2, international, multicentre, prospective, randomised, controlled, parallel-group clinical trial, which aims to determine if staircase alveolar recruitment and individually titrated PEEP, when combined with permissive hypercapnia and low airway pressures, increases ventilator-free days to Day 28 when compared with conventional mechanical ventilation (Acute Respiratory Distress Syndrome Clinical Network [ARDSNet] strategy) in patients with moderate to severe ARDS. This study will enrol 340 patients. The intervention group will receive daily staircase alveolar recruitment manoeuvres with incremental PEEP to a maximum of 40 cmH 2 O and peak pressures to a maximum of 55 cmH 2 O. PEEP will be titrated individually against peripheral oxygen saturation, targeting lower tidal volumes by a permissive approach to hypercapnia. In the control group, patients will receive mechanical ventilation following the ARDSNet-ARMA trial protocol, including PEEP titrated with a PEEP/fraction of inspired oxygen (FiO 2 ) chart. Both groups will receive airway pressures ≤ 30 cmH 2 O and tidal volumes of ≤ 6 mL/kg predicted bodyweight or less. The primary outcome is ventilator-free days to Day 28. Secondary outcomes include oxygenation and lung compliance, intensive care unit (ICU) and hospital length of stay, use of rescue therapies for refractory hypoxaemia, rate of barotrauma, mortality (ICU, hospital and at 28, 90 and 180 days), quality of life and a health economic analysis at 6 months. Discussion: The PHARLAP trial will determine whether the intervention 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 3 trial to determine the effects of this strategy on mortality. Trial registration: ClinicalTrials.gov identifi er NCT01667146.

Original languageEnglish
Pages (from-to)139-149
Number of pages11
JournalCritical Care and Resuscitation
Volume20
Issue number2
Publication statusPublished - 1 Jun 2018

Cite this

Hodgson, C., Cooper, D. J., Arabi, Y., Bennett, V., Bersten, A., Brickell, K., ... on behalf of the PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group (2018). Permissive hypercapnia, alveolar recruitment and low airway pressure (PHARLAP): A protocol for a phase 2 trial in patients with acute respiratory distress syndrome. Critical Care and Resuscitation, 20(2), 139-149.
Hodgson, Carol ; Cooper, David Jamie ; Arabi, Yaseen ; Bennett, Victoria ; Bersten, Andrew ; Brickell, Kathy ; Davies, Andrew ; Fahey, Ciara ; Fraser, John ; McGuinness, Shay ; Murray, Lynne ; Parke, Rachael ; Tuxen, David ; Vallance, Shirley ; Young, Meredith ; Nichol, Alistair D. ; on behalf of the 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. In: Critical Care and Resuscitation. 2018 ; Vol. 20, No. 2. pp. 139-149.
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abstract = "Background: Mechanical ventilation is a life-saving intervention that maintains gas exchange in patients with acute respiratory distress syndrome (ARDS); however, it is associated with high mortality and it may augment, or even initiate, lung injury. An open lung ventilation strategy that combines alveolar recruitment manoeuvres with individually titrated positive end-expiratory pressure (PEEP) and targeting lower tidal volumes, or driving pressures by a permissive approach to hypercapnia, may reduce the lung injury associated with mechanical ventilation. This protocol reports the rationale, study design and analysis plan of the Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) trial. Methods and design: PHARLAP is a phase 2, international, multicentre, prospective, randomised, controlled, parallel-group clinical trial, which aims to determine if staircase alveolar recruitment and individually titrated PEEP, when combined with permissive hypercapnia and low airway pressures, increases ventilator-free days to Day 28 when compared with conventional mechanical ventilation (Acute Respiratory Distress Syndrome Clinical Network [ARDSNet] strategy) in patients with moderate to severe ARDS. This study will enrol 340 patients. The intervention group will receive daily staircase alveolar recruitment manoeuvres with incremental PEEP to a maximum of 40 cmH 2 O and peak pressures to a maximum of 55 cmH 2 O. PEEP will be titrated individually against peripheral oxygen saturation, targeting lower tidal volumes by a permissive approach to hypercapnia. In the control group, patients will receive mechanical ventilation following the ARDSNet-ARMA trial protocol, including PEEP titrated with a PEEP/fraction of inspired oxygen (FiO 2 ) chart. Both groups will receive airway pressures ≤ 30 cmH 2 O and tidal volumes of ≤ 6 mL/kg predicted bodyweight or less. The primary outcome is ventilator-free days to Day 28. Secondary outcomes include oxygenation and lung compliance, intensive care unit (ICU) and hospital length of stay, use of rescue therapies for refractory hypoxaemia, rate of barotrauma, mortality (ICU, hospital and at 28, 90 and 180 days), quality of life and a health economic analysis at 6 months. Discussion: The PHARLAP trial will determine whether the intervention 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 3 trial to determine the effects of this strategy on mortality. Trial registration: ClinicalTrials.gov identifi er NCT01667146.",
author = "Carol Hodgson and Cooper, {David Jamie} and Yaseen Arabi and Victoria Bennett and Andrew Bersten and Kathy Brickell and Andrew Davies and Ciara Fahey and John Fraser and Shay McGuinness and Lynne Murray and Rachael Parke and David Tuxen and Shirley Vallance and Meredith Young and Nichol, {Alistair D.} and {on behalf of the PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group}",
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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 & on behalf of the PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group 2018, 'Permissive hypercapnia, alveolar recruitment and low airway pressure (PHARLAP): A protocol for a phase 2 trial in patients with acute respiratory distress syndrome', Critical Care and Resuscitation, vol. 20, no. 2, pp. 139-149.

Permissive hypercapnia, alveolar recruitment and low airway pressure (PHARLAP) : A protocol for a phase 2 trial in patients with acute respiratory distress syndrome. / Hodgson, Carol; Cooper, David Jamie; Arabi, Yaseen; Bennett, Victoria; Bersten, Andrew; Brickell, Kathy; Davies, Andrew; Fahey, Ciara; Fraser, John; McGuinness, Shay; Murray, Lynne; Parke, Rachael; Tuxen, David; Vallance, Shirley; Young, Meredith; Nichol, Alistair D.; on behalf of the PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group.

In: Critical Care and Resuscitation, Vol. 20, No. 2, 01.06.2018, p. 139-149.

Research output: Contribution to journalArticleOtherpeer-review

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T1 - Permissive hypercapnia, alveolar recruitment and low airway pressure (PHARLAP)

T2 - A protocol for a phase 2 trial in patients with acute respiratory distress syndrome

AU - Hodgson, Carol

AU - Cooper, David Jamie

AU - Arabi, Yaseen

AU - Bennett, Victoria

AU - Bersten, Andrew

AU - Brickell, Kathy

AU - Davies, Andrew

AU - Fahey, Ciara

AU - Fraser, John

AU - McGuinness, Shay

AU - Murray, Lynne

AU - Parke, Rachael

AU - Tuxen, David

AU - Vallance, Shirley

AU - Young, Meredith

AU - Nichol, Alistair D.

AU - on behalf of the PHARLAP Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Mechanical ventilation is a life-saving intervention that maintains gas exchange in patients with acute respiratory distress syndrome (ARDS); however, it is associated with high mortality and it may augment, or even initiate, lung injury. An open lung ventilation strategy that combines alveolar recruitment manoeuvres with individually titrated positive end-expiratory pressure (PEEP) and targeting lower tidal volumes, or driving pressures by a permissive approach to hypercapnia, may reduce the lung injury associated with mechanical ventilation. This protocol reports the rationale, study design and analysis plan of the Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) trial. Methods and design: PHARLAP is a phase 2, international, multicentre, prospective, randomised, controlled, parallel-group clinical trial, which aims to determine if staircase alveolar recruitment and individually titrated PEEP, when combined with permissive hypercapnia and low airway pressures, increases ventilator-free days to Day 28 when compared with conventional mechanical ventilation (Acute Respiratory Distress Syndrome Clinical Network [ARDSNet] strategy) in patients with moderate to severe ARDS. This study will enrol 340 patients. The intervention group will receive daily staircase alveolar recruitment manoeuvres with incremental PEEP to a maximum of 40 cmH 2 O and peak pressures to a maximum of 55 cmH 2 O. PEEP will be titrated individually against peripheral oxygen saturation, targeting lower tidal volumes by a permissive approach to hypercapnia. In the control group, patients will receive mechanical ventilation following the ARDSNet-ARMA trial protocol, including PEEP titrated with a PEEP/fraction of inspired oxygen (FiO 2 ) chart. Both groups will receive airway pressures ≤ 30 cmH 2 O and tidal volumes of ≤ 6 mL/kg predicted bodyweight or less. The primary outcome is ventilator-free days to Day 28. Secondary outcomes include oxygenation and lung compliance, intensive care unit (ICU) and hospital length of stay, use of rescue therapies for refractory hypoxaemia, rate of barotrauma, mortality (ICU, hospital and at 28, 90 and 180 days), quality of life and a health economic analysis at 6 months. Discussion: The PHARLAP trial will determine whether the intervention 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 3 trial to determine the effects of this strategy on mortality. Trial registration: ClinicalTrials.gov identifi er NCT01667146.

AB - Background: Mechanical ventilation is a life-saving intervention that maintains gas exchange in patients with acute respiratory distress syndrome (ARDS); however, it is associated with high mortality and it may augment, or even initiate, lung injury. An open lung ventilation strategy that combines alveolar recruitment manoeuvres with individually titrated positive end-expiratory pressure (PEEP) and targeting lower tidal volumes, or driving pressures by a permissive approach to hypercapnia, may reduce the lung injury associated with mechanical ventilation. This protocol reports the rationale, study design and analysis plan of the Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) trial. Methods and design: PHARLAP is a phase 2, international, multicentre, prospective, randomised, controlled, parallel-group clinical trial, which aims to determine if staircase alveolar recruitment and individually titrated PEEP, when combined with permissive hypercapnia and low airway pressures, increases ventilator-free days to Day 28 when compared with conventional mechanical ventilation (Acute Respiratory Distress Syndrome Clinical Network [ARDSNet] strategy) in patients with moderate to severe ARDS. This study will enrol 340 patients. The intervention group will receive daily staircase alveolar recruitment manoeuvres with incremental PEEP to a maximum of 40 cmH 2 O and peak pressures to a maximum of 55 cmH 2 O. PEEP will be titrated individually against peripheral oxygen saturation, targeting lower tidal volumes by a permissive approach to hypercapnia. In the control group, patients will receive mechanical ventilation following the ARDSNet-ARMA trial protocol, including PEEP titrated with a PEEP/fraction of inspired oxygen (FiO 2 ) chart. Both groups will receive airway pressures ≤ 30 cmH 2 O and tidal volumes of ≤ 6 mL/kg predicted bodyweight or less. The primary outcome is ventilator-free days to Day 28. Secondary outcomes include oxygenation and lung compliance, intensive care unit (ICU) and hospital length of stay, use of rescue therapies for refractory hypoxaemia, rate of barotrauma, mortality (ICU, hospital and at 28, 90 and 180 days), quality of life and a health economic analysis at 6 months. Discussion: The PHARLAP trial will determine whether the intervention 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 3 trial to determine the effects of this strategy on mortality. Trial registration: ClinicalTrials.gov identifi er NCT01667146.

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