Diaphragm Hibernation and Its Driving Factors in Mechanically Ventilated ICU Patients

NCT07819864 | Not Yet Recruiting

• 1 other identifier: NL-011458
• Study Type: observational
• Target: 112
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Patients with invasive mechanical ventilation (IMV) frequently develop diaphragm dysfunction and experience difficult weaning. Recent ex vivo work suggests that a subset of mechanically ventilated ICU patients may exhibit diaphragm hibernation, an energy conserving myosin state that reduces force generation and may lead to a reversible increase in diaphragm strength over time. However, it is unknown whether diaphragm hibernation can be demonstrated in vivo during IMV and which clinical and biological factors are associated with this phenotype. Objective: Primary objective is to determine the driving factors (biomarkers) of diaphragm hibernation during IMV. Secondary objectives are to determine the proportion of ventilated critically ill patients who exhibit diaphragm hibernation during IMV, to investigate inflammatory and metabolic factors and other clinical exposures associated with diaphragm hibernation, and to explore associations between diaphragm hibernation and weaning related and survival outcomes. Study design: Prospective, observational, longitudinal cohort study. Study population: Adult ICU patients receiving IMV, expected to remain mechanically ventilated for at least 72 hours. Intervention (if applicable): Not applicable. This is an observational study. Study specific procedures consist of repeated phrenic nerve magnetic stimulation and additional blood sampling. Main study parameters/endpoints: The primary study parameter is the proportion of participants exhibiting diaphragm hibernation during IMV. Diaphragm hibernation is defined as an increase in stimulated twitch tracheal pressure (Ptr,stim), a measure of diaphragm strength, of at least 10% relative to baseline (Day 0-1) at any follow up assessment (Day 2, 3, 5, or 7) obtained before extubation or death. Ptr,stim will be assessed repeatedly on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participant burden is limited and mainly consists of repeated phrenic nerve magnetic stimulation during a ventilator delivered end expiratory occlusion and additional blood sampling of 9.5 mL per time point, up to a total of 47.5 mL across the study period. Magnetic stimulation is non-invasive and expected discomfort is transient. Rare transient physiological changes may occur and measurements are performed under continuous ICU monitoring and will be postponed or omitted if considered unsafe or interfering with clinical care. Direct benefit for participants is limited, but the study may provide clinically relevant knowledge on diaphragm hibernation and its driving factors. The research questions are specific to diaphragm physiology during IMV in critically ill patients, therefore the study is group related and cannot be performed in a different population.

Conditions

Diaphragm Dysfunction; Weaning Invasive Mechanical Ventilation; Respiratory Failure, ICU

Keywords

Diaphragm; Weaning; Invasive Mechanical Ventilation; Diaphragm Hibernation

Outcome Measures

Primary Outcomes (8)

• Blood C reactive protein level

  C reactive protein will be assessed by blood sample.

  C reactive protein will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Blood procalcitonin level

  Procalcitonin will be assessed by blood sample.

  Procalcitonin will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Blood metabolic biomarkers level

  Metabolic biomarkers will be assessed by blood sample using OLINK Target 96 panel.

  Metabolic biomarkers will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Blood TNF-α level

  TNF-α will be assessed by blood sample.

  TNF-α will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Blood IL-10 level

  IL-10 will be assessed by blood sample.

  IL-10 will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Blood IL-8 level

  IL-8 will be assessed by blood sample.

  IL-8 will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Blood IL-6 level

  IL-6 will be assessed by blood sample.

  IL-6 will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Blood ferritin level

  Ferritin will be assessed by blood sample.

  Ferritin will be assessed on Day 0-1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

Secondary Outcomes (13)

• Proportion of participants exhibiting diaphragm hibernation during invasive mechanical ventilation

  Ptr,stim will be assessed repeatedly on Day 0 to 1, Day 2, Day 3, Day 5, and Day 7, or until extubation or death, whichever occurs first.

• Number of days from intubation to successful extubation

  Collected from study inclusion until Day 28, or ICU/hospital discharge or death, whichever occurs first

• Number of days from first SBT to successful extubation

  Collected from study inclusion until Day 28, or ICU/hospital discharge or death, whichever occurs first

• Incidence of weaning failure

  Collected from study inclusion until Day 28, or ICU/hospital discharge or death, whichever occurs first

• ICU length of stay

  Collected from study inclusion until Day 28, or ICU discharge or death, whichever occurs first

Study Arms (1)

Patients with expected > 3 days of invasive mechanical ventilation

Patients expected \> 3 days of invasive mechanical ventilation will be included in this study. Blood sample and diaphragm strength will be assessed repeatedly, until 7 days after initiation of invasive mechanical ventilation, extubation or death.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population consists of newly admitted adult ICU patients receiving invasive mechanical ventilation, in whom the first study assessment can be performed within 36 hours after initiation of IMV and who are expected to require IMV for at least 3 days.

You may qualify if:

• Age ≥ 18 years.
• Receiving invasive mechanical ventilation at screening.
• Expected to remain mechanically ventilated for ≥ 72 hours from enrolment.
• The first study assessment can be performed within 36 hours after initiation of invasive mechanical ventilation.

You may not qualify if:

• Pre-existing neuromuscular disease affecting the diaphragm (e.g. motor neuron disease, myasthenia gravis, advanced muscular dystrophy, high cervical spinal cord injury) or use of neuromuscular blocker.
• Known phrenic nerve palsy or prior diaphragmatic paralysis.
• Long-term home mechanical ventilation (invasive or non-invasive) prior to ICU admission.
• Post-operative patients after planned diaphragm or phrenic nerve surgery.
• Contraindications to phrenic nerve magnetic stimulation (e.g., unstable cervical spine injury, uncontrolled intracranial hypertension, metallic implants in stimulation area as per manufacturer guidance).
• Pregnancy.
• Participation in another interventional trial that explicitly prohibits co-enrolment or is expected to substantially influence diaphragm function (e.g. experimental neuromuscular blocking strategies), as decided by the principal investigator.

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud University Medical Center (Radboudumc)

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples

MeSH Terms

Conditions

Respiratory Insufficiency

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases

Study Officials

• Jonne Doorduin, PhD

  Radboud University Medical Centre (Radboudumc)

  PRINCIPAL INVESTIGATOR

• Leo Heunks, M.D., PhD

  Radboud University Medical Centre (Radboudumc)

  STUDY CHAIR

Central Study Contacts

Jinyu Zhou, M.sc.

CONTACT

0031626194204; jinyu.zhou@radboudumc.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2026
• First Posted: September 15, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: September 15, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)