Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP): a protocol for a phase 2 trial in patients with acute respiratory distress syndrome.

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 cmHO and peak pressures to a maximum of 55 cmHO. 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) chart. Both groups will receive airway pressures ≤30 cmHO 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 identifier NCT01667146.