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NCT Number: NCT07203781

PEEP-induced Effects on Respiratory dRivE and EFfort

Rationale:

In patients with acute hypoxemic respiratory failure (AHRF), preserving spontaneous breathing during mechanical ventilation offers physiological benefits, but also carries risks. While spontaneous breathing improves gas exchange and limits diaphragm atrophy, strong inspiratory efforts may worsen lung and diaphragm injury. Balancing these factors requires refined and tailored strategies, such as the modulation of PEEP. However, the impact of PEEP on neural respiratory drive and inspiratory effort is very heterogenous, and these two entities have only been studied separately in limited subsets of patients and healthy subjects. Additionally, it remains unclear whether the major determinant of PEEP-induced changes in respiratory drive and effort is represented by variations in diaphragm geometry, lung compliance, or by the presence of expiratory muscles recruitment, which may counteract its effect.

Objective:

The primary objective is to determine the effect of PEEP on diaphragm neuromechanical efficiency (i.e. an index of neural respiratory drive and inspiratory effort) in patients with acute hypoxemic respiratory failure during invasive assisted mechanical ventilation. The secondary objective is to determine the major physiological contributors to PEEP-mediated changes in diaphragm neuromechanical efficiency.

Study design: Prospective, physiological study. Study population: Invasively mechanically ventilated adult patients admitted to the ICU.

Intervention:

For each patient, six different PEEP levels (15-12-10-8-5-2 cmH2O) will be tested during a decremental PEEP trial. During each step, neural respiratory drive, inspiratory effort, expiratory muscle activity, lung inflation pattern through electrical impedance tomography, respiratory muscle geometry and function through ultrasound and surface EMG, gas exchange and hemodynamics data will be collected.

Main study parameters/endpoints:

The primary outcome of the study will be the evaluation of PEEP-mediated changes in diaphragm neuromechanical efficiency (NME).

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Key information

Conditions

ARDS (Moderate or Severe) Acute Hypoxemic Respiratory Failure Hemic and Lymphatic Diseases Immune System Diseases Immunoproliferative Disorders Lymphatic Diseases Lymphoma Lymphoma, Follicular Lymphoma, Non-Hodgkin Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type Respiration Disorders Respiratory Insufficiency Respiratory Tract Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Radboudumc

Nijmegen, Gelderland, 6525 GA, Netherlands

Location status: Recruiting

Location contact

Jonne Doorduin, PhD

CONTACT

[email protected]

06-50155757

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age > 18 years
  • Acute hypoxemic respiratory failure (AHRF) with a PaO2/FiO2-ratio ≤ 200
  • Patient on invasive assisted mechanical ventilation in pressure support mode exhibiting valid inspiratory efforts (occlusion pressure > 5 cmH2O).

Exclusion criteria

  • Pre-existent neuromuscular disease
  • History of chronic respiratory failure requiring long-term oxygen therapy
  • Muscle paralysis
  • Pneumothorax
  • Contra-indication to EIT monitoring (e.g. burns, pacemaker, thoracic wounds limiting electrode placement)
  • Contra-indications for EAdi or oesophageal balloon catheter placement (e.g. history of gastric bypass surgery, gastro-oesophageal junction surgery, oesophageal stricture, recent upper gastrointestinal hemorrhage or known/suspected varices).

Treatment and study plan

PEEP level changes

Other

For each patient, six different PEEP levels (15-12-10-8-5-2 cmH2O) will be tested during a decremental PEEP trial. During each step, neural respiratory drive, inspiratory effort, expiratory muscle activity, lung inflation pattern through electrical impedance tomography, respiratory muscle geometry and function through ultrasound and surface EMG, gas exchange and hemodynamics data will be collected.

Primary outcomes

  1. PEEP-related changes in diaphragm neuromechanical efficiency (NME)

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    The primary endpoint of this study will be the evaluation of PEEP-induced changes in diaphragm neuromechanical efficiency (NME, cmH2O/µV), calculated as the ratio between the change in transdiaphragmatic pressure (representing inspiratory effort in cmH2O and assessed through the use of esophageal and gastric manometry) and the change in diaphragm electrical activity (neural respiratory drive, expressed in µV and measured through diaphragm EMG by a dedicated nasogastric tube) for each inspiration (ΔPdi/ΔEAdi). NME is an index of diaphragm efficiency and of potential electromechanical uncoupling, a key PEEP-mediated effect on the diaphragm. Its assessment combines changes in neural respiratory drive and inspiratory effort after a change in PEEP, which will be assessed individually and combined as a ratio as primary outcome.

Secondary outcomes

  1. PEEP-induced changes in inspiratory effort

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    Inspiratory effort will be assessed through esophageal pressure monitoring and expressed in cmH2O.

  2. PEEP-induced changes in neural respiratory drive

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    Neural respiratory drive will be assessed through the monitoring of the electrical activity of the diaphragm, performed with the use of a dedicated nasogastric tube equipped with electrodes and expressed in µV.

  3. PEEP-induced effects on partitioned respiratory system mechanics

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    Respiratory mechanics assessed through ventilator and esophageal/gastric manometry, inlcuding end-expiratory, end-inspiratory and driving transpulmonary pressure (expressed in cmH2O).

  4. PEEP induced effects on tidal volume

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    Changes in expired tidal volume will be monitored from the ventilator (expressed in mL)

  5. PEEP-induced effects on end-expiratory lung impedance

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    End-expiratory lung impedance will be assessed with electrical impedance tomography (EIT) and expressed in arbitrary units and as percentage change from baseline.

  6. PEEP-induced effects on amount of pendelluft

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    Pendelluft will be examined through electrical impedance tomography monitoring and expressed as % of total tidal impedance variation.

  7. PEEP-induced changes in diaphragm thickening fraction assessed through ultrasound

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected once within the last 10 minutes of each step.

    Diaphragm thickening fraction will be assessed and expressed in %, through the formula: (End-inspiratory thickness - End-expiratory thickness) / End-expiratory thickness × 100.

  8. PEEP-induced effects on internal oblique muscle thickening fraction

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected once within the last 10 minutes of each step.

    Internal oblique muscle thickening fraction will be measured through ultrasound and expressed in %, with the following formula: (End-inspiratory thickness - End-expiratory thickness) / End-expiratory thickness × 100.

  9. PEEP-induced changes in gastric pressure during expiration

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    Expiratory muscle activity will be assessed through monitoring of gastric pressure swings during expiration and expressed in cmH2O.

  10. PEEP-induced changes in abdominal wall muscles expiratory activity

    Time frame: Measurements will be conducted throughout the protocol at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected recording the last 10 minutes of each step.

    Abdominal wall muscles expiratory activity will be assessed and quantified through the use of surface EMG of the abdominal wall, and expressed in µV.

  11. PEEP-induced effects on gas exchange

    Time frame: Measurements will be conducted throughout the protocol at baseline and at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected once in the last 10 minutes of each step.

    Effects on gas exchange, including PaO2 and PaCO2 monitoring (mmHg), will be evaluated through arterial blood gas monitoring.

  12. PEEP-induced effects on arterial blood pressure

    Time frame: Measurements will be conducted throughout the protocol at baseline and at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected once in the last 10 minutes of each step.

    Hemodynamics will be assessed through standard invasive blood pressure and will include the recording of systolic, diastolic and mean arterial blood pressure (mmHg).

  13. PEEP-induced effects on heart rate

    Time frame: Measurements will be conducted throughout the protocol at baseline and at each of the 6 PEEP levels tested: 15, 12, 10, 8, 5 and 2 cmH2O. Each PEEP step will last 30 minutes, and measurements will be collected once in the last 10 minutes of each step.

    Heart rate will be monitored and expressed in beats per minute.

Study contacts

Contact information is provided by the study sponsor or research team.

Tommaso Rosà, M.D.

CONTACT

[email protected]

06-50155757

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Collaborators

  • Catholic University of the Sacred Heart

Registry information

Official study title

Unraveling PEEP-induced Effects on Respiratory dRivE and EFfort in Acute Hypoxemic Respiratory Failure: the REEF Study

Acronym: REEF

Important dates

Study start
2025
Primary completion
2026
Study completion
2026
First posted
Oct 2, 2025
Registry last updated
Nov 17, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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