Individualized Positive End-expiratory Pressure Guided by End-expiratory Lung Volume in the Acute Respiratory Distress Syndrome
NCT ID: NCT04012073
Last Updated: 2025-09-30
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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TERMINATED
PHASE3
18 participants
INTERVENTIONAL
2022-11-01
2025-06-30
Brief Summary
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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.
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Detailed Description
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To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume set at 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH2O for thirty minutes (Express PEEP).
Afterwards, a 5-step decremental PEEP trial will be conducted (Express PEEP to PEEP 5 cmH2O), and EELV will be measured at each step. PEEP-induced alveolar recruitment will be calculated for each PEEP range as the difference between PEEP-induced change EELV and the predicted increase in lung volume due to PEEP (PEEP-induced overdistension, equal to the product of respiratory system compliance and PEEP change).
Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or according to the Express strategy (Control arm, PEEP set to achieve a plateau pressure of 28-30 cmH2O).
In both groups, tidal volume size, the use of prone positioning and neuromuscular blocking agents will be standardized.
Primary endpoint of the study is a composite clinical outcome incorporating in-ICU mortality, 60-day ventilator free days and the area under the curve of serum Interleukin 6 over the course of the initial 72 hours.
Primary and secondary endpoints will also be analyzed in subgroups, as defined below:
* ∆EELV5-16/FRC ≥ 73% \[18\] during the PEEP trial
* ∆EELV5-16/FRC \< 73%\[23\] during the PEEP trial
* Recruitment-to-inflation ratio (RI) ≥ 1 and \<1 across the range between the lowest and highest PEEP tested during the PEEP trial
* P/F ratio\<100 mmHg at study inclusion
* IL-6\>400 pg/ml at study inclusion
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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IPERPEEP
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.
Invasive Mechanical ventilation
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.
Neuromuscular Blocking Agents
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.
Prone positioning
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.
Resume of spontaneous breathing
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
Rescue treatments
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.
Weaning from PEEP
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
Weaning from mechanical ventilation
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.
Extubation
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
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
Invasive Mechanical ventilation
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.
Neuromuscular Blocking Agents
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.
Prone positioning
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.
Resume of spontaneous breathing
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
Rescue treatments
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.
Weaning from PEEP
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
Weaning from mechanical ventilation
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.
Extubation
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.
Interventions
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Invasive Mechanical ventilation
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.
Neuromuscular Blocking Agents
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.
Prone positioning
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.
Resume of spontaneous breathing
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
Rescue treatments
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.
Weaning from PEEP
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
Weaning from mechanical ventilation
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.
Extubation
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.
Eligibility Criteria
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Inclusion Criteria
2. Bilateral infiltrates at the chest x-ray or CT scan, not fully explained by effusions, lobar/lung collapse, or nodules;
3. Respiratory failure not fully explained by cardiac failure or fluid overload; objective assessment required to exclude hydrostatic edema if no risk factor present.
4. PaO2/FiO2 ratio≤150 mmHg after 30 mins - 1 hour of mechanical ventilation with PEEP=5 cmH2O.
5. Written informed consent.
Exclusion Criteria
2. Pneumothorax;
3. Acute brain injury;
4. 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;
5. Intubation as a result of an acute exacerbation of chronic pulmonary disease: chronic obstructive pulmonary disease, asthma, cystic fibrosis, etc;
6. Clinically evident intrinsic PEEP (≥2 cmH2O) during screening visit (End-expiratory pause to achieve Flow=0);
7. BMI\>35;
8. BMI\<15 or body weight\<35 Kg;
9. Any chronic disease requiring long-term oxygen therapy or mechanical ventilation at home;
10. Neuromuscular disease of any kind;
11. Severe chronic liver disease (Child-Pugh C or worse);
12. Bone marrow transplantation or chemotherapy-induced neutropenia;
13. History of liver or lung transplant;
14. Decision to withhold life-sustaining treatment;
15. Need for therapy with inhaled nitric oxide due to documented pulmonary arterial hypertension;
16. Life-threatening hypoxemia deemed to require extracorporeal membrane oxygenation (ECMO);
17. Presence of documented barotrauma;
18. High risk of mortality within 3 months from other than ARDS (severe neurological damage, age \>85 years and cancer patients in terminal stages of the disease).
19. Persistent hemodynamic instability, intractable shock (norepinephrine\>1 mcg/kg/h and/or blood lactate\>5 mmol/L and/or considered too hemodynamically unstable for enrolment in the study by the patient's managing physician).
20. More than 24 hours from endotracheal intubation to the time of the screening visit.
18 Years
85 Years
ALL
No
Sponsors
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ClinicalTrialCenter
UNKNOWN
FerrarioDati
UNKNOWN
General Electric
INDUSTRY
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
OTHER
Responsible Party
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Principal Investigators
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Massimo Antonelli, MD
Role: STUDY_CHAIR
Fondazione Policlinico Universitario A. Gemelli IRCCS; Università Cattolica del Sacro Cuore
Domenico Luca Grieco, MD
Role: PRINCIPAL_INVESTIGATOR
Fondazione Policlinico Universitario A. Gemelli IRCCS; Università Cattolica del Sacro Cuore
Locations
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Policlinico di Bari
Bari, , Italy
Policlinico Sant'Orsola
Bologna, , Italy
Azienda ospedaliero-universitaria Mater Domini
Catanzaro, , Italy
SS. Annunziata hospital
Chieti, , Italy
Azienda ospedaliera universitaria di Ferrara-arcispedale Sant'Anna
Ferrara, , Italy
Ospedale San Martino
Genova, , Italy
Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico
Milan, , Italy
Ospedale San Gerardo
Monza, , Italy
Fondazione IRCCS Policlinico San Matteo
Pavia, , Italy
Fondazione Policlinico Universitaro A. Gemelli IRCCS
Rome, , Italy
Countries
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References
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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.
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.
Other Identifiers
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ANT-IPE-18-006
Identifier Type: -
Identifier Source: org_study_id
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