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

Phase 3

Recruiting

• Conditions: Respiratory Distress Syndrome, Adult
• Interventions: 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

• Registration Number: NCT04012073
• Lead Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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.

Detailed Description

ARDS patients with a PaO2/FiO2 ratio equal or below 150 mmHg (during mechanical ventilation with PEEP 5 cmH2O) will be enrolled within 24 hours from endo-tracheal intubation.

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

Study Timeline

• Study First Submitted: 2019-07-04
• Study First Submitted QC: 2019-07-04
• Study First Posted: 2019-07-09
• Study Start: 2022-11-01
• Status Verified: 2023-12
• Last Update Submitted: 2024-01-02
• Last Update Posted: 2024-01-05
• Primary Completion: 2024-12-31
• Study Completion: 2025-04-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 132

Inclusion Criteria

Not provided

Exclusion Criteria

1. Pregnancy;
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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IPERPEEP	Weaning from mechanical ventilation	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.
IPERPEEP	Neuromuscular Blocking Agents	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.
IPERPEEP	Rescue treatments	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.
IPERPEEP	Weaning from PEEP	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.
IPERPEEP	Invasive Mechanical ventilation	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.
IPERPEEP	Extubation	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.
EXPRESS	Prone positioning	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
IPERPEEP	Prone positioning	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.
IPERPEEP	Resume of spontaneous breathing	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.
EXPRESS	Invasive Mechanical ventilation	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
EXPRESS	Weaning from PEEP	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
EXPRESS	Weaning from mechanical ventilation	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
EXPRESS	Neuromuscular Blocking Agents	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
EXPRESS	Rescue treatments	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
EXPRESS	Resume of spontaneous breathing	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
EXPRESS	Extubation	PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O

Primary Outcome Measures

Name	Time	Method
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	60 days	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

Secondary Outcome Measures

Name	Time	Method
60-day Ventilator free days	28 days	The days spent without ventilator assistance within 60 days from randomization
Time to successful weaning	90 days	The time from enrolment to successful liberation from mechanical ventilation
In-Hospital mortality	90 days	Mortality at hospital discharge
AUC IL-6	72 hours	Area under the curve (AUC) of serum interleukin 6 in the initial 72 hours of treatment
Total Lung stress-End-inspiratory transpulmonary pressure derived from elastance ratio	72 hours	Total increase in transpulmonary pressure due to tidal volume and PEEP during the assigned treatment
In-ICU mortality	90 days	Mortality at ICU discharge
90-day mortality	90 days	Mortality at 90 days from randomization
28-day Ventilator free days	28 days	The days spent without ventilator assistance within 28 days from randomization
Arterial pressure	72 hours	Mean arterial pressure during the assigned treatment
Set PEEP variability	72 hours	Ratio of standard deviation to mean PEEP during the assigned treatment
Time spent on assisted ventilation after the enrolment	28 days	The time spent on assisted ventilation on 28-day basis
AUC IL-8	72 hours	Area under the curve (AUC) of serum interleukin 8 in the initial 72 hours of treatment
End-expiratory transpulmonary pressure	72 hours	Directly measured end-expiratory transpulmonary pressure during the assigned treatment
Respiratory system compliance	72 hours	Ratio of tidal volume to respiratory system driving pressure during the assigned treatment
Oxygenation	72 hours	Ratio of PaO2 to FiO2 during the assigned treatment
Oxygenation stretch index	72 hours	Ratio of PaO2/FiO2 to respiratory system driving pressure during the assigned treatment
Carbon dioxide	72 hours	Arterial pressure of CO2 during the assigned treatment
Heart rate	72 hours	Heart rate during the assigned treatment
Organ failure	28 days	Organ failure free days on a 28-day basis, as defined by the simplified organ failure assessment (SOFA)
Need for rescue recruitment maneuvers	72 hours	The proportion of patients needing rescue recruitment maneuvers during the assigned treatment
Plateau pressure	72 hours	Plateau pressure during the assigned treatment
Respiratory system driving pressure	72 hours	The difference between Plateau Pressure and total PEEP during the assigned treatment
AUC TNF	72 hours	Area under the curve (AUC) of serum tumor necrosis factor in the initial 72 hours of treatment
Set PEEP	72 hours	Set PEEP during the assigned treatment
Simplified organ failure assessment	28 days	Simplified organ failure assessment (SOFA) after randomization
Nedd for rescue extra-corporeal membrane oxygenation	90 days	The proportion of patients needing rescue extra-corporeal membrane oxygenation due to persistent hypoxemia
Nedd for tracheostomy	90 days	The proportion of patients needing tracheostomy to enhance the weaning process
Static stress	72 hours	Total increase in transpulmonary pressure due to PEEP during the assigned treatment
Dynamic stress-Transpulmonary driving pressure	72 hours	Total increase in transpulmonary pressure due to tidal volume during the assigned treatment
Respiratory system compliance normalized to predicted body weight	72 hours	Ratio of respiratory system compliance and predicted body weight during the assigned treatment
Lung compliance	72 hours	Ratio of tidal volume to transpulmonary driving pressure during the assigned treatment
Dynamic strain	30 minutes	Ratio of tidal volume to end-expiratory aerated volume (end-expiratory lung volume plus PEEP-induced alveolar recruitment) at study start
Static strain	30 minutes	Ratio of PEEP-induced overdistension volume to end-expiratory aerated volume (end-expiratory lung volume plus PEEP-induced alveolar recruitment) at study start
Catecholamine requirements per day	72 hours	Catecholamin administration ad dosage during the assigned treatment

Trial Locations

Locations (10)

Azienda ospedaliero-universitaria Mater Domini; 🇮🇹 Catanzaro, Italy

Fondazione Policlinico Universitaro A. Gemelli IRCCS; 🇮🇹 Rome, Italy

SS. Annunziata hospital; 🇮🇹 Chieti, Italy

Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico; 🇮🇹 Milan, Italy

Policlinico di Bari; 🇮🇹 Bari, Italy

Fondazione IRCCS Policlinico San Matteo; 🇮🇹 Pavia, Italy

Policlinico Sant'Orsola; 🇮🇹 Bologna, Italy

Azienda ospedaliera universitaria di Ferrara-arcispedale Sant'Anna; 🇮🇹 Ferrara, Italy

Ospedale San Martino; 🇮🇹 Genova, Italy

Ospedale San Gerardo; 🇮🇹 Monza, Italy