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

Respiratory Distress Syndrome, Adult Clinical Trial

— IPERPEEP  

Official title:

Individualized Positive End-expiRatory Pressure Guided by End-Expiratory Lung Volume in Moderate-to-severe Acute resPiratory Distress Syndrome.The IPERPEEP Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04012073
• Other study ID #: ANT-IPE-18-006
• Status: Recruiting
• Phase: Phase 3
• Start date: November 1, 2022
• Est. completion date: April 30, 2025

Study information

• Verified date: December 2023
• Source: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Contact: Domenico Luca Grieco
• Phone: +39 06 3015
• Email: dlgrieco[@]outlook.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 132
• Est. completion date: April 30, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lung Injury
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Device:
• 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.

Drug:
• 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.

Procedure:
• 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.

Locations

Country	Name	City	State
Italy	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

Sponsors (4)

Lead Sponsor	Collaborator
Fondazione Policlinico Universitario Agostino Gemelli IRCCS	ClinicalTrialCenter, FerrarioDati, General Electric

Country where clinical trial is conducted

Italy, 

Outcome

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