Effects of COVID-19 Infection and Critical Illness on Diaphragm Tissue Characteristics and Movement, Visualized With MRI

Effects of COVID-19-infection and Mechanical Ventilation on Movement and Tissue Characteristics of the Diaphragm, Visualized by Magnetic Resonance Imaging: a Proof-of-concept Study

COVID-19-infection has a large impact on the respiratory system and possibly on the diaphragm, the main respiratory muscle. In ICU-patients, diaphragm weakness is associated with prolonged ICU-stay, difficult weaning and increased mortality. Our research group recently found evidence for fibrosis and expression of genes involved in fibrosis as well as viral infiltration of the SARS-CoV-2 virus in diaphragm biopsies from COVID-19 ICU patients. This finding suggests a unique manifestation of diaphragm injury in COVID-19 patients after mechanical ventilation. However, it remains unclear what the exact nature and location of diaphragm injury is.

Additionally, it is largely unknown whether this injury affects the movement of the diaphragm, but this might have important clinical implications. Therefore, we aim at visualizing the tissue characteristics and movement of the diaphragm in COVID-19 patients who recently received long-term mechanical ventilation, other ICU patients and healthy controls, using magnetic resonance imaging (MRI). MRI of the diaphragm was already shown feasible in previous research from our group (article currently under review).

New insights in the characteristics of diaphragm weakness and injury in COVID-19 patients and control ICU-patients will contribute to strategies to prevent it and monitor the diaphragm of patients under mechanical ventilation, which can contribute to better patient outcomes.

Study Overview

• Status: Unknown
• Conditions: Covid19; Diaphragm Disease
• Intervention / Treatment: Other: Contrast-enhanced MRI; Other: Measurement of respiratory muscle force

• Study Type: Observational
• Enrollment (Anticipated): 40

Contacts and Locations

• Study Contact: Name: Leo Heunks, Prof. Dr.; Phone Number: (020) 444 4444; Email: l.heunks@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081HV
      • Recruiting
      • Amsterdam UMC, location VUmc
      • Contact: Myrte Wennen, MSc; Phone Number: (020) 444 4444; Email: m.wennen@amsterdamumc.nl
      • Sub-Investigator: Myrte Wennen, MSc
      • Principal Investigator: Leo Heunks, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients that were recently (<= 7 days ago) discharged from the ICU and received mechanical ventilation form the study population with a specific sub group of COVID-19 patients. Healthy, age and gender matched volunteers are selected as control group.

Description

Inclusion criteria

In order to be eligible to participate in this study, a subject in the case group must meet all of the following criteria:

• Invasive mechanical ventilation > 72 hours during current hospital admission
• Admitted for COVID-19-infection (n = 10)
• Currently negative COVID-19 PCR test
• Discharged from the ICU ≤ 7 days ago
• Signed informed consent
• Age ≥ 18 years

In order to be eligible to participate in this study, a subject in the control group must meet all of the following criteria:

• Signed informed consent
• Age ≥ 18 years
• Similar age (max 5 years difference) and gender of one of the subjects in case group

Exclusion criteria

A potential subject for the case group who meets any of the following criteria will be excluded from participation in this study:

• Known history of:

  • Diaphragmatic injury or weakness prior to ICU stay
  • COPD (GOLD IV)
  • Neuromuscular disease (including pathology of the n. phrenicus)
  • Connective tissue disease
  • Chronic use of corticosteroids (>7.5 mg/day for at least 3 months before hospital admission)
  • >10% weight loss within last 6 months prior to ICU admission
• Obesity (BMI > 30 kg/m2 at hospital admission)
• Known pregnancy

• Contraindications for MRI

  • Electrical/metallic implants
  • Claustrophobia
• Unable to hold breath for 10 seconds
• Hierarchical relation with one of the collaborating investigators
• Incapacitation

• Contraindications for the use of a Gadolinium based contrast agent for MRI

  • Known eGFR < 30 ml/min/1.73m2
  • Known history of allergic reactions to an MRI contrast medium
  • Known history of allergic reactions requiring immediate treatment
  • Known history of atopy
  • Asthma These exclusion criteria are based on the guidelines for contrast agents from the European Society for Urogenital Radiology (http://www.esur.org/guidelines/).

Additional exclusion criteria for the case group, subset non-infected patients are:

• History of COVID-19-infection (confirmed with positive test)

Additional exclusion criteria for the control group are:

• History of mechanical ventilation > 24 hours
• History of COVID-19-infection (confirmed with positive test)

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy volunteers; Healthy volunteers, matched by age and gender to patient groups.	Other: Contrast-enhanced MRI; Contrast-enhanced MRI; Other: Measurement of respiratory muscle force; Measurement of the maximum inspiratory and expiratory pressure.
COVID-19 patients; Patients discharged from the ICU after invasive ventilation for COVID-19.	Other: Contrast-enhanced MRI; Contrast-enhanced MRI; Other: Measurement of respiratory muscle force; Measurement of the maximum inspiratory and expiratory pressure.
ICU patients; Patients discharged from the ICU after invasive ventilation for ARDS.	Other: Contrast-enhanced MRI; Contrast-enhanced MRI; Other: Measurement of respiratory muscle force; Measurement of the maximum inspiratory and expiratory pressure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tissue characteristics of the diaphragm	Extracted from contrast enhanced imaging	1 hour
Movement of the diaphragm	Description of the movement of the diaphragm in 4D fashion.	1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative dynamic contrast enhanced imaging of the diaphragm	Application of modelling to describe tissue characteristics of the diaphragm using contrast inflow.	1 hour
Correlation of movement and tissue characteristics of the diaphragm with measurements of maximum inspiratory and expiratory pressure		1 hour
Correlation of movement and tissue characteristics of the diaphragm with clinical parameters	Clinical parameters include ventilator settings, biomarkers for inflammation (CRP, white blood cell count) during ICU admission, daily dosage of drugs known with adverse effects on respiratory muscles, fluid balance, protein intake, primary reason for ICU admission and weaning duration.	1 hour

Other Outcome Measures

Outcome Measure	Time Frame
Correlation of diaphragm tissue characteristics with tissue characteristics of the abdominal muscles	1 hour

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2021
• Primary Completion (Anticipated): January 19, 2023
• Study Completion (Anticipated): January 19, 2023

Study Registration Dates

• First Submitted: January 14, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (Actual): February 3, 2021

Study Record Updates

• Last Update Posted (Actual): March 18, 2021
• Last Update Submitted That Met QC Criteria: March 17, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: MRI; Diaphragm; Mechanical ventilation
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: NL 72271.029.19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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