Diaphragm Hibernation and Its Driving Factors in Mechanically Ventilated ICU Patients (DISSECT)

Diaphragm hIbernation and itS Driving factorS in mEChanically venTilated ICU Patients: the DISSECT Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Diaphragm Dysfunction; Respiratory Failure, ICU; Weaning Invasive Mechanical Ventilation

• Study Type: Observational
• Enrollment (Estimated): 112

Contacts and Locations

• Study Contact: Name: Jinyu Zhou, M.sc.; Phone Number: 0031626194204; Email: jinyu.zhou@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud University Medical Center (Radboudumc)
      • Contact: Jonne Doorduin, PhD; Phone Number: 0031650155757; Email: jonne.doorduin@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• 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.

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants exhibiting diaphragm hibernation during invasive mechanical ventilation	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 to 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 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	Data about number of days from intubation to successful extubation will be retrieved from electronic medical records.	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	Data about number of days from first SBT to successful extubation will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or ICU/hospital discharge or death, whichever occurs first
Incidence of weaning failure	Weaning failure is defined as SBT failure or reintubation within 48 hours. Data will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or ICU/hospital discharge or death, whichever occurs first
ICU length of stay	Data about ICU length of stay will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or ICU discharge or death, whichever occurs first
Hospital length of stay	Data about hospital length of stay will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or hospital discharge or death, whichever occurs first
ICU mortality	Data about ICU mortality will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or ICU discharge or death, whichever occurs first
Hospital mortality	Data about hospital mortality will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or hospital discharge or death, whichever occurs first
Day 28 all-cause mortality	Data about day 28 all-cause mortality will be retrieved from electronic medical records.	Collected from study inclusion until Day 28 or death, whichever occurs first
ICU-free days through day 28	Data about ICU-free days through day 28 will be retrieved from electronic medical records.	Collected from ICU discharge until Day 28 or death, whichever occurs first
Hospital-free days through day 28	Data about hospital-free days through day 28 will be retrieved from electronic medical records.	Collected from hospital discharge until Day 28 or death, whichever occurs first
Time to ICU discharge alive through day 28	Data about time to ICU discharge alive through day 28 will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or ICU discharge or death, whichever occurs first
Time to hospital discharge alive through day 28	Data about time to hospital discharge alive through day 28 will be retrieved from electronic medical records.	Collected from study inclusion until Day 28, or hospital discharge or death, whichever occurs first

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Jonne Doorduin, PhD, Radboud University Medical Centre (Radboudumc); Study Chair: Leo Heunks, M.D., PhD, Radboud University Medical Centre (Radboudumc)

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: September 9, 2026
• First Submitted That Met QC Criteria: September 14, 2026
• First Posted (Actual): September 15, 2026

Study Record Updates

• Last Update Posted (Actual): September 15, 2026
• Last Update Submitted That Met QC Criteria: September 14, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Weaning; Diaphragm; Invasive Mechanical Ventilation; Diaphragm Hibernation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: NL-011458

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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