COVID-19 Associated Endothelial Dysfunction Study (CAUSED)

L'Étude de la Dysfonction endothéliale Dans la Maladie à COVID-19 Chez Des Patients en Soins Critiques.

SARS-CoV-2 enters human cells through the binding of the spike protein with angiotensin converting enzyme-2 (ACE2), a membrane receptor highly expressed in immune or non-immune cells, and in many organs, including lungs and endothelial cells.

In COVID-19 disease, the infection of endothelial might cause an acute endothelial dysfunction.

The objective of this study is to demonstrate that patients COVID19 (+) hospitalized in ICU present an acute endothelial dysfunction (compared with COVID19 (-) also hospitalized in ICU).

This acute endothelial dysfunction could lead to organ failure, systemic immune dysregulation and thrombosis.

Study Overview

• Status: Completed
• Conditions: Covid19; Microcirculation
• Intervention / Treatment: Diagnostic test: Procedure : Multimodal microvascular assessment at study inclusion

Detailed Description

This cohort study compares 3 exposure cohorts :

Cohort C1 includes COVID19 (+) patients admitted in ICU in whom the diagnosis of COVID19 pneumonia was confirmed.

Cohort C2 includes COVID 19 (-) matched patients also admitted in ICU.

Cohort C3 is a control group. Patients with few comorbidities, ASA 1, recruited during preoperative assessment for elective surgery.

Eligible patients are included within 72 hours of ICU admission (C1, C2) or during the preoperative assessment (C3). Oral consent is needed after complete explanation of the protocol.

During inclusion visit (V0), patient characteristics as treatments, medical history, clinical and biological data are registered.

Microcirculation is assessed for each patient directly after inclusion.

For patients in C1 and C2 a follow-up is planned. This visit (V1) occurs when the patient is discharged from ICU or the day of his death if it occurs in ICU. In case of prolonged stay in ICU, V1 is carried out 2 months after inclusion. During V1, arterial and/or venous thromboembolic events and mortality in ICU is registered.

For Patients in C3, no follow-up is planned.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Angers, France, 49933
    • UH Angers
  • Lyon, France, 69437
    • Hopital E.Herriot - Hospices Civils de Lyon

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria :

• Adult patient (≥ 18 ans)
• Affiliation to the French National Healthcare System
• Voluntary patient who have given oral consent

Cohort C1, COVID19 (+) patients hospitalized in ICU :

• Patient admitted to ICU within 72 hours before inclusion
• Patient presenting SARS-COV2 pneumonia diagnosed by CT scan or by COVID-19 PCR test.

Cohort C2, COVID19 (-) patients hospitalized in ICU :

• Patient admitted to ICU within 72 hours before inclusion
• All COVID19 PCR tests carried out in the 15 days prior inclusion are negative
• All the CT scans possibly performed since the acute event do not show COVID19 pulmonary lesions
• Matching with the cases C1 COVID 19 (+) patients on sex, age (threshold at 65 years), treated hypertension, treated diabetes mellitus.

Cohort C3, elective surgery patients who are not hospitalized in ICU :

• ASA 1 classification (no major comorbidity, a normaly healthy patient)

• Asymptomatic to COVID19 according to French Anesthesiology Society 2020 :

  • No major symptoms among : measured fever > 38°C, dry cough, shortness of breath or high respiratory rate (>20/min), anosmia, ageusia
  • No more than one minor symptom among : sore throat, rhinorrhea, chest pain, myalgia, general alteration or severe tiredness, confusion, disorientation, headache, diarrhea, nausea or/and vomiting, rash/ frostbite/cracking on fingers or hand
• No positive COVID19 PCR test within 15 days prior to inclusion

Non-inclusion criteria :

• Proven sepsis (Procalcitonin >1.0 µg/l) in the 24 hours prior to inclusion
• End-stage kidney disease with dialysis
• Patient with haemodynamic failure treated by norepinephrine
• Patient with traumatic brain injury
• Intubated patient and/or sedated
• Pregnant woman, parturient and nursing mother
• Person restricted in liberty by an administrative or judicial decision
• Patient concerned with admission for psychiatric care
• Adult person subject to a legal protection measure or unable to express consent

Exclusion criteria :

• Cohorts C2 and C3 : positive COVID-19 PCR test within 5 days after inclusion

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Cohort C1; COVID19 (+) ICU patients with COVID19 pneumonia.	Diagnostic test: Procedure : Multimodal microvascular assessment at study inclusion; Vascular occlusion test (VOT) performed on the arm. Measurement of the quality of tissue reperfusion by NIRS on the thenar eminence and the digital perfusion index.; Microcirculation reactivity is measured for each patient with a laser speckle contrast imaging (LSCI) placed on the forearm. Tests will be performed for evaluation of microvascular reactivity: Acetylcholine and Nitroprusside Iontophoresis.; Morphological analysis of the microcirculation by sublingual videomicroscopy.
Other: Cohort C2; COVID19 (-) matched ICU patients	Diagnostic test: Procedure : Multimodal microvascular assessment at study inclusion; Vascular occlusion test (VOT) performed on the arm. Measurement of the quality of tissue reperfusion by NIRS on the thenar eminence and the digital perfusion index.; Microcirculation reactivity is measured for each patient with a laser speckle contrast imaging (LSCI) placed on the forearm. Tests will be performed for evaluation of microvascular reactivity: Acetylcholine and Nitroprusside Iontophoresis.; Morphological analysis of the microcirculation by sublingual videomicroscopy.
Other: Cohort C3; COVID19 (-) ASA 1 non-hospitalized patients	Diagnostic test: Procedure : Multimodal microvascular assessment at study inclusion; Vascular occlusion test (VOT) performed on the arm. Measurement of the quality of tissue reperfusion by NIRS on the thenar eminence and the digital perfusion index.; Microcirculation reactivity is measured for each patient with a laser speckle contrast imaging (LSCI) placed on the forearm. Tests will be performed for evaluation of microvascular reactivity: Acetylcholine and Nitroprusside Iontophoresis.; Morphological analysis of the microcirculation by sublingual videomicroscopy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial function measured by Near-infrared spectroscopy (NIRS)	Measure : Saturation Tissue (StO2) after a vascular occlusion test (VOT)	within 72 hours of admission in Intensive Care Unit (ICU)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial function measured by perfusion index	measure : Perfusion index after a vascular occlusion test (VOT)	within 72 hours of admission in ICU
Microvascular reactivity measured laser speckle contrast imaging	measure : Vasodilation after iontophoresis of Acetylcholine and Nitroprusside	within 72 hours of admission in ICU
Morphological analysis by Sublingual videomicroscopy	measure : Microvascular flow index (MFI)	within 72 hours of admission in ICU
Morphological analysis by Sublingual videomicroscopy	measure : Perfused vessel density (PVD)	within 72 hours of admission in ICU
Inflammatory status	measure : C-reactive protein level	Inclusion
Inflammatory status	measure : neutrophil to lymphocyte ratio	Inclusion
Prothrombotic condition	measure : D-Dimer Level and	Inclusion
Thrombotic events	measure : All arterial and/or venous thromboembolic events since acute episode	Inclusion (V0) up to 8 weeks maximum
Severity of lung disease	measure : PaO2/FiO2 ratio	Inclusion
Severity of lung disease	measure : percentage of pulmonary lesions assessed by CT scan at the ICU admission.	Inclusion
Mortality	measure : Mortality in ICU	Up to 8 weeks after inclusion
Organ failure	measure : Sequential Organ Failure Assessment (SOFA) Score, minimum value 0 and maximum value 24. The higher score means a worse outcome.	Inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Angers

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2021
• Primary Completion (Actual): October 21, 2022
• Study Completion (Actual): December 21, 2022

Study Registration Dates

• First Submitted: February 19, 2021
• First Submitted That Met QC Criteria: February 25, 2021
• First Posted (Actual): February 26, 2021

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: May 3, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• 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: 2021-A00330-41

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