Individualized Positive End-expiratory Pressure Guided by End-expiratory Lung Volume in the Acute Respiratory Distress Syndrome

NCT04012073 | Terminated Phase 3 DMC FDA Device

• 1 other identifier: ANT-IPE-18-006
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 10

Brief Summary

During the acute respiratory distress syndrome (ARDS), patients' response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP on the basis of patients' individual response is warranted. Measurement of end-expiratory lung volume (EELV) by the nitrogen washin-washout technique, bedside available from recent ICU ventilators, has been shown to reliably estimate PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient's individual requirements. The authors designed an open-label, multicenter, randomized trial to test whether an individualized PEEP setting protocol driven by EELV may improve a composite clinical outcome in patients with moderate-to-severe ARDS.

Conditions

Respiratory Distress Syndrome, Adult

Keywords

Positive end-expiratory pressure; Ventilator-induced lung injury; Mechanical ventilation; Respiratory mechanics

Outcome Measures

Primary Outcomes (1)

• Composite clinical outcome that incorporates ICU mortality, 60-day ventilation-free days (VFD60) and the Area Under the Curve of the InterLeukin-6 serum concentration (IL6AUC) during the first 72 hours of observation

  Composite clinical outcome that incorporates ICU mortality, 60-day ventilation-free days (VFD60) and the Area Under the Curve of the InterLeukin-6 serum blood cytokine concentration (IL6AUC) during the first 72 hours of observation. Every participant in the treatment group will be compared with every participant in the control group and assigned a score resulting from each comparison. Mortality takes precedence over VFD60, which takes precedence over IL6AUC. Two VFD60's will be considered different for the purpose of scoring only if their difference is larger than 5 days. Similarly, two IL6AUC's measurements will be considered different only if their difference exceeds 10% of the smaller of the two. These individual-comparison scores are added up to obtain the cumulative score primary endpoint for each participant. The sum of scores for patients in the treatment group is compared to the sum of scores of subjects in the control group and compared according by use of Mann-Whitney test

  60 days

Secondary Outcomes (34)

• In-ICU mortality

  90 days

• In-Hospital mortality

  90 days

• 90-day mortality

  90 days

• 28-day Ventilator free days

  28 days

• 60-day Ventilator free days

  28 days

Study Arms (2)

IPERPEEP

EXPERIMENTAL

End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial. PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O. In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting. * RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP. * RI\<0.5 will lead to the setting of the lower PEEP value. * In case of RI≥0.5 and \<1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.

Device: Invasive Mechanical ventilation; Drug: Neuromuscular Blocking Agents; Procedure: Prone positioning; Procedure: Resume of spontaneous breathing; Procedure: Rescue treatments; Procedure: Weaning from PEEP; Procedure: Weaning from mechanical ventilation; Procedure: Extubation

EXPRESS

ACTIVE COMPARATOR

PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O

Device: Invasive Mechanical ventilation; Drug: Neuromuscular Blocking Agents; Procedure: Prone positioning; Procedure: Resume of spontaneous breathing; Procedure: Rescue treatments; Procedure: Weaning from PEEP; Procedure: Weaning from mechanical ventilation; Procedure: Extubation

Interventions

Invasive Mechanical ventilation DEVICE

Volume-control ventilation with tidal volume will be set at 6 mL/Kg of predicted body weight, respiratory rate to maintain pH\>7.30 and PaCO2\<50 mmHg and FiO2 will be set to achieve a SpO2\>88-95%. In case of hypercapnia with Ph\<7.30 despite a respiratory rate=30-35, an increase in tidal volume up to 8 ml/kg will be allowed. In both groups, the assigned ventilation protocol will be followed for a minimum of 72 hours from randomization and any time fully controlled ventilation is deemed necessary by the attending physician up to 14 days from randomization. After 14 days from randomization, PEEP will be set according to the clinical practice of each institution. After 72 hours from the study protocol, the PEEP setting protocol according to the assigned treatment will be resumed at any time within 14 days from enrolment if fully controlled ventilation is established, according to the decision of the attending physician in charge.

EXPRESS; IPERPEEP

Neuromuscular Blocking Agents DRUG

All patients will receive NMBA for 48 hours after the enrolment. The decision to stop NMBA administration after 48 hours will be left to the attending physician, but muscle paralysis will be strongly encouraged if PaO2/FiO2 ratio remains lower than 80-100 mmHg. NMBA administration will be resumed anytime deemed necessary by the attending physician.

EXPRESS; IPERPEEP

Prone positioning PROCEDURE

Prone positioning will be used in all enrolled patients as a standard of care: the decision about the timing and the duration of prone position sessions will be left to the attending physician and the time spent by the patient in the prone and in the supine position will be recorded: PEEP will be re-set according to the protocol of the allocated treatment anytime patient's position is changed.

EXPRESS; IPERPEEP

Resume of spontaneous breathing PROCEDURE

Assist/control and assist ventilation will be allowed after 72 hours from the enrolment if deemed appropriate by the attending physician. During spontaneous breathing, PEEP will be set according to the decision of the attending physician and the practice of each institution: however, in order to standardize the treatments, moderate PEEP (10-15 cmH2O) will be encouraged in case of moderate hypoxemia (PaO2/FiO2\<150 mmHg) in control group, while PEEP close to the value set during controlled ventilation according to the treatment protocol but \<15 cmH2O will be suggested in the intervention group. During assist/control and assisted ventilation, PEEP will never be higher than the last PEEP set according to the assigned protocol during controlled ventilation. Fully controlled mechanical ventilation will be resumed any time during the study period if the patient meets the criteria described above or any time deemed necessary by the physicians in charge

EXPRESS; IPERPEEP

Rescue treatments PROCEDURE

Recruitment maneuvers, extracorporeal membrane oxygenation (ECMO), extracorporeal CO2 removal (ECCO2-R) after randomization will be allowed in both groups as rescue therapies and according to the decision of attending physicians: any of these procedures will be accurately recorded on the case report form.

EXPRESS; IPERPEEP

Weaning from PEEP PROCEDURE

In order not to delay weaning from mechanical ventilation, when a patient is managed with assist/control or assist ventilation with PEEP higher than 8 cmH2O, a daily PEEP weaning trial will be performed whether PaO2/FIO2 ratio\>150 mm Hg and FIO2\<0.5: PEEP will be decreased to 8-5 cm H2O and arterial blood gas will be sampled after 20 -0 minutes. Previous ventilatory settings will be resumed if during the procedure transcutaneous oxyhemoglobin saturation decreases below 88%, PaO2/FIO2 falls below 150 mm Hg or if the patient experiences abnormal changes in respiratory rate or other clinical signs suggestive of respiratory distress. When PaO2/FIO2 is no lower than 200 mm Hg at PEEP≤8 cmH2O, the patient will be considered to have acceptable gas exchange on 8-5 cmH2O of PEEP and will be deemed capable to tolerate this setting

EXPRESS; IPERPEEP

Weaning from mechanical ventilation PROCEDURE

A 30-120-minute spontaneous breathing trial will be initiated as the following criteria are met and whether the patient tolerates fully assist ventilation with PEEP≤8 cmH2O for at least 4 hours without experiencing hypoxemia (SpO2\<88% or PaO2/FiO2\<150mmHg): * improvement or resolution of the underlying cause of acute respiratory failure * normal sensorium * correction of arterial hypoxemia (PaO2 ≥ 60 mmHg at a FiO2 ≤ 0.4 with PEEP ≤ 8 cmH2O); * absence of fever (≥ 38 °C) or sepsis; * blood hemoglobin concentration of 7 g/dL or more; * hemodynamic stability For the purpose of the study, success of the spontaneous breathing trial will be defined as presence of the following criteria: * respiratory rate \< 35/min, * arterial oxygen saturation ≥ 90%, * heart rate \< 120/min, * systolic blood pressure \> 90 and \< 160 mmHg * adequate cough. If the spontaneous breathing trial is successful, the patient will be extubated.

EXPRESS; IPERPEEP

Extubation PROCEDURE

Each extubated patient will undergo oxygen therapy via high flow nasal cannula (maximum flows tolerated and FiO2 titrated to obtain 96%\>SpO2\>92%). Pre-emptive noninvasive ventilation (NIV) after extubation will be allowed in prolonged to wean patients (i.e. more than 3 SBT failure or more than 7 days from the first spontaneous breathing trial to being extubated) if deemed necessary by the physician in charge. In case of respiratory failure during oxygen therapy via high flow nasal cannula after extubation and, a rescue NIV trial will be allowed before intubation in both groups at the discretion of the attending physician.

EXPRESS; IPERPEEP

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Acute respiratory failure within 1 week of a known clinical insult or new or worsening respiratory symptoms;
• Bilateral infiltrates at the chest x-ray or CT scan, not fully explained by effusions, lobar/lung collapse, or nodules;
• Respiratory failure not fully explained by cardiac failure or fluid overload; objective assessment required to exclude hydrostatic edema if no risk factor present.
• PaO2/FiO2 ratio≤150 mmHg after 30 mins - 1 hour of mechanical ventilation with PEEP=5 cmH2O.
• Written informed consent.

You may not qualify if:

• Pregnancy;
• Pneumothorax;
• Acute brain injury;
• Clinical signs of history of decompensated heart failure (New York Heart Association class 3-4 before the acute phase of the disease or documented ejection fraction\<35% or pulmonary capillary wedge pressure\>18 mmHg) or acute coronary syndrome;
• Intubation as a result of an acute exacerbation of chronic pulmonary disease: chronic obstructive pulmonary disease, asthma, cystic fibrosis, etc;
• Clinically evident intrinsic PEEP (≥2 cmH2O) during screening visit (End-expiratory pause to achieve Flow=0);
• BMI\>35;
• BMI\<15 or body weight\<35 Kg;
• Any chronic disease requiring long-term oxygen therapy or mechanical ventilation at home;
• Neuromuscular disease of any kind;
• Severe chronic liver disease (Child-Pugh C or worse);
• Bone marrow transplantation or chemotherapy-induced neutropenia;
• History of liver or lung transplant;
• Decision to withhold life-sustaining treatment;
• Need for therapy with inhaled nitric oxide due to documented pulmonary arterial hypertension;

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead
• ClinicalTrialCenter: collaborator
• FerrarioDati: collaborator
• General Electric: collaborator

Study Sites (10)

Policlinico di Bari

Bari, Italy

Location

Policlinico Sant'Orsola

Bologna, Italy

Location

Azienda ospedaliero-universitaria Mater Domini

Catanzaro, Italy

Location

SS. Annunziata hospital

Chieti, Italy

Location

Azienda ospedaliera universitaria di Ferrara-arcispedale Sant'Anna

Ferrara, Italy

Location

Ospedale San Martino

Genova, Italy

Location

Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico

Milan, Italy

Location

Ospedale San Gerardo

Monza, Italy

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, Italy

Location

Fondazione Policlinico Universitaro A. Gemelli IRCCS

Rome, Italy

Location

Related Publications (2)

• Grieco DL, Maggiore SM, Bellani G, Spadaro S, Spinelli E, Tonetti T, Menga LS, Pozzi M, Battaglini D, Di Mussi R, Bruni A, De Gaetano A, Iovino CG, Brioni M, Mojoli F, Foti G, Volta CA, Pelosi P, Navalesi P, Grasso S, Ranieri VM, Antonelli M; IPERPEEP study group. Individualized positive end-expiratory pressure guided by end-expiratory lung volume in early acute respiratory distress syndrome: study protocol for the multicenter, randomized IPERPEEP trial. Trials. 2022 Jan 20;23(1):63. doi: 10.1186/s13063-021-05993-0.

  PMID: 35057852 DERIVED

• Santa Cruz R, Villarejo F, Irrazabal C, Ciapponi A. High versus low positive end-expiratory pressure (PEEP) levels for mechanically ventilated adult patients with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev. 2021 Mar 30;3(3):CD009098. doi: 10.1002/14651858.CD009098.pub3.

  PMID: 33784416 DERIVED

MeSH Terms

Conditions

Respiratory Distress Syndrome; Ventilator-Induced Lung Injury

Interventions

Neuromuscular Blocking Agents; Prone Position; Airway Extubation

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Injury

Intervention Hierarchy (Ancestors)

Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Posture; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Airway Management; Therapeutics; Investigative Techniques

Study Officials

• Massimo Antonelli, MD

  Fondazione Policlinico Universitario A. Gemelli IRCCS; Università Cattolica del Sacro Cuore

  STUDY CHAIR

• Domenico Luca Grieco, MD

  Fondazione Policlinico Universitario A. Gemelli IRCCS; Università Cattolica del Sacro Cuore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomization will be stratified according to Recruitment/cmH2O ≥ or \< 19 ml/cmH2O across the range between the lowest and highest PEEP tested during the initial PEEP trial

Study Record Dates

• First Submitted: July 4, 2019
• First Posted: July 9, 2019
• Study Start: November 1, 2022
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: September 30, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

IT (10)