Clinical trial NCT04012073: Individualized Positive End-expiratory Pressure Guided by End-expiratory Lung Volume in the Acute Respiratory Distress Syndrome
Official title: Individualized Positive End-expiRatory Pressure Guided by End-Expiratory Lung Volume in Moderate-to-severe Acute resPiratory Distress Syndrome.The IPERPEEP Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Respiratory Distress Syndrome, Adult
Keywords: Positive end-expiratory pressure
Ventilator-induced lung injury
Mechanical ventilation
Respiratory mechanics
Lead sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Sponsor class: OTHER
Collaborators: name: ClinicalTrialCenter
name: FerrarioDati
name: General Electric
First posted: 2019-07-09
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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
Primary purpose: TREATMENT

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

Eligibility criteria: Eligibility inclusion criteria, according to the ARDS Berlin definition, will be assessed within the first 24 hours from the initiation of invasive mechanical ventilation:

1. Acute respiratory failure within 1 week of a known clinical insult or new or worsening respiratory symptoms;
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:

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.

Primary outcomes:
measure: 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
timeFrame: 60 days
Secondary outcomes:
measure: In-ICU mortality
timeFrame: 90 days
measure: In-Hospital mortality
timeFrame: 90 days
measure: 90-day mortality
timeFrame: 90 days
measure: 28-day Ventilator free days
timeFrame: 28 days
measure: 60-day Ventilator free days
timeFrame: 28 days
measure: Time to successful weaning
timeFrame: 90 days
measure: Time spent on assisted ventilation after the enrolment
timeFrame: 28 days
measure: AUC IL-6
timeFrame: 72 hours
measure: AUC IL-8
timeFrame: 72 hours
measure: AUC TNF
timeFrame: 72 hours
measure: Plateau pressure
timeFrame: 72 hours
measure: Total Lung stress-End-inspiratory transpulmonary pressure derived from elastance ratio
timeFrame: 72 hours
measure: Static stress
timeFrame: 72 hours
measure: Set PEEP
timeFrame: 72 hours
measure: Set PEEP variability
timeFrame: 72 hours
measure: End-expiratory transpulmonary pressure
timeFrame: 72 hours
measure: Dynamic stress-Transpulmonary driving pressure
timeFrame: 72 hours
measure: Respiratory system driving pressure
timeFrame: 72 hours
measure: Respiratory system compliance
timeFrame: 72 hours
measure: Respiratory system compliance normalized to predicted body weight
timeFrame: 72 hours
measure: Lung compliance
timeFrame: 72 hours
measure: Dynamic strain
timeFrame: 30 minutes
measure: Static strain
timeFrame: 30 minutes
measure: Oxygenation
timeFrame: 72 hours
measure: Oxygenation stretch index
timeFrame: 72 hours
measure: Carbon dioxide
timeFrame: 72 hours
measure: Heart rate
timeFrame: 72 hours
measure: Arterial pressure
timeFrame: 72 hours
measure: Simplified organ failure assessment
timeFrame: 28 days
measure: Catecholamine requirements per day
timeFrame: 72 hours
measure: Organ failure
timeFrame: 28 days
measure: Need for rescue recruitment maneuvers
timeFrame: 72 hours
measure: Nedd for rescue extra-corporeal membrane oxygenation
timeFrame: 90 days
measure: Nedd for tracheostomy
timeFrame: 90 days
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Policlinico di Bari
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola
city: Catanzaro
country: Italy
facility: Azienda ospedaliero-universitaria Mater Domini
city: Chieti
country: Italy
facility: SS. Annunziata hospital
city: Ferrara
country: Italy
facility: Azienda ospedaliera universitaria di Ferrara-arcispedale Sant'Anna
city: Genova
country: Italy
facility: Ospedale San Martino
city: Milan
country: Italy
facility: Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Rome
country: Italy
facility: Fondazione Policlinico Universitaro A. Gemelli IRCCS
Study officials:
affiliation: Fondazione Policlinico Universitario A. Gemelli IRCCS; Università Cattolica del Sacro Cuore
name: Massimo Antonelli, MD
role: STUDY_CHAIR
affiliation: Fondazione Policlinico Universitario A. Gemelli IRCCS; Università Cattolica del Sacro Cuore
name: Domenico Luca Grieco, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.