Effect of Prone Positioning on Mortality in Patients With Mild to Moderate Acute Respiratory Distress Syndrome. (PROMILD)

Acute respiratory distress syndrome (ARDS) accounts for almost 10% of intensive care units (ICU) admissions. Three ARDS stages have been defined, based on the PaO2/FIO2 ratio measured with positive end-expiratory pressure (PEEP) ≥5 cmH2O: mild (201-300 mmHg), moderate (200-101 mmHg), and severe (≤100mmHg). They represent 30.0%, 46.6%, and 23.4% of ARDS, respectively.

Mechanical invasive ventilation (MV), the cornerstone of ARDS patient care, has a primary goal to protect the lung from ventilator-induced lung injury (VILI). Delivering MV in a prone position (PP) has been shown to improve oxygenation, protect the lung through a better homogenization of lung stress/strain, and stabilize hemodynamics.

A meta-analysis of four randomized controlled trials showed beneficial effect of PP vs. supine position (SP) in the most hypoxemic patients. A fifth randomized controlled trial further showed a significant reduction in mortality with PP in ARDS patients with PaO2/FIO2 <150 mmHg, when neuromuscular blockade and long prone positioning sessions were used. Therefore, PP has since been strongly recommended for ARDS patients with PaO2/FIO2 <150 mmHg. Yet, there is limited evidence in patients with mild to moderate ARDS.

There are, however, strong arguments supporting the need for a new trial in ARDS patients with PaO2/FIO2 in the range 150-300 mmHg:

1. There is no trial that has specifically tested PP in this ARDS subset;
2. PP is safe and has become a standard of care in ICU;
3. Should VILI prevention be a mechanism through which PP improves survival, this should be involved in all ARDS patients;
4. The mortality at hospital discharge in this subset of ARDS remains significant, amounting to 34.9% (95% confidence intervals 31.4-38.5%) in mild and 40.3% (37.4-43.3) in moderate stages;
5. Among 580 patients with mild ARDS at admission to the ICU, in-hospital mortality was 10%, 30%, and 37% for those who improved, persisted, and worsened ARDS, respectively.
6. Finally, PP has been shown to be cost-effective under commonly accepted thresholds.

The hypothesis is that in patients within the 150-300mmHg PaO2/FIO2 range at the time of ARDS diagnosis, PP can reduce mortality as compared to a similar group left in the SP.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome; ARDS; Intensive Care Unit; Mechanical Ventilation
• Intervention / Treatment: Procedure: Patients will receive MV in PP

• Study Type: Interventional
• Enrollment (Anticipated): 656
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laura CHAMBON; Phone Number: +33476768955; Email: lchambon@chu-grenoble.fr
• Study Contact Backup: Name: CRA Sponsor; Phone Number: +33476766862; Email: Arcmoniteur@chu-grenoble.fr

Study Locations

• France
  • Grenoble, France, 38000
    • Recruiting
    • Grenoble University Hospital
    • Principal Investigator: Nicolas Terzi
    • Contact: Roselyne COLLOMB-MURET; Phone Number: +33476767109; Email: rcollombmuret@chu-grenoble.fr
    • Contact: Pierre NICOLAS; Phone Number: +33476767109; Email: pnicolas@chu-grenoble.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age of 18 years or more admitted to ICU.
• ARDS patients meeting the Berlin criteria under invasive mechanical ventilation within the first 24h.
• Mechanically ventilated patients with standard settings: PEEP of 5 cmH2O or more and VT 6 ml/kg PBW and Pplat equal to or below 28-30 cmH2O after intubation.
• PaO2/FIO2 between 150 and 300 mmHg under previous settings within 12 hours after mechanical ventilation standardization.
• Written informed consent obtained from the patient, next of kin/proxy or emergency consent. The patient will be asked to give his consent for the continuation of the trial when his condition will allow.

Exclusion Criteria:

• Contra-indication to PP: spine instability; intracranial pressure greater than 20 mmHg; severe facial trauma; hemodynamic instability
• Non-inclusion criteria related to medical condition: Lung transplant; Burns over more than 20% of body surface; Chronic respiratory failure requiring home oxygen supplementation and/or non-invasive ventilation; Underlying disease with death expectancy within one year;
• Other non-inclusion criteria: Therapeutic limitation; inclusion into another interventional study in intubated and ventilated patients with mortality as primary end-point in the last 30 days; previously included in the same study; prone positioning before inclusion.
• Individuals referred to in Articles L. 1121-5 à L. 1121-7 (pregnant women, persons deprived of freedom, minors), adult individuals under protection of law (L. 1121-8 and L. 1122-1-2) (emergency situations) of public health regulation in France
• Patients not affiliated to social security insurance regimen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients will receive MV in PP; Patients assigned to the intervention group will be turned in PP within the two hours after randomization for at least 16 consecutive hours. Then, patients will be turned in SP. Then, PP sessions are repeated as long as stopping criteria for PP are not met	Procedure: Patients will receive MV in PP; Putting the patient in a prone position
No Intervention: Patients will receive MV in SP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	All-cause mortality 28 days after inclusion	28 days after inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Grenoble
• Investigators: Principal Investigator: Nicolas TERZI, University Hospital, Grenoble

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Anticipated): September 28, 2023
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: September 14, 2021
• First Submitted That Met QC Criteria: September 14, 2021
• First Posted (Actual): September 24, 2021

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: ICU; Intensive Care Unit; ARDS; Acute Respiratory Distress Syndrome; Prone position
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: 38RC20.366

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No