Clinical trial NCT04819802: MIcrovascular Dysfunction in CRitically Ill cOVID-19 Patients
Official title: Microvascular Flow Alteration and Endothelial Dysfunction in Critically Ill Patient With Covid-19
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Covid-19
Critical Illness
Hemodynamics
SARS-CoV Infection
Keywords: Covid-19
Covid-19 / Pathophysiology
Covid-19 / Virology
Critical illness
Hemodynamics
Intensive Care Units
Microcirculation
Microcirculation / Physiology
Microvessels / Physiopathology
Capillary permeability
Prospective Studies
SARS-CoV-2
SARS-CoV-2 / physiology
Biomarkers / Blood
Glycocalyx / metabolism
Glycocalyx / Pathology
Regional blood flow
Mouth mucosa / Blood supply
Syndecan-1 / Blood
Organ dysfunction scores
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2021-03-29
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult patients admitted to ICU for COVID-19

Brief summary: Microcirculatory dysfunction appears to play a key role in the development of organ failure leading to the death of patients with coronavirus disease 2019 (Covid-19). It is still uncertain today whether this damage is secondary to direct viral infection of endothelial cells or the consequence of the inappropriate inflammatory response induced by the infection. The analysis of endothelial and microcirculatory dysfunctions and glycocalyx degradation therefore appears to be necessary in the understanding of the pathophysiological mechanisms of Covid sepsis and could play a role in the evaluation of the efficacy of certain therapeutics which would aim at improving regional perfusion by decreasing microcirculatory dysfunction.However, the analysis of microcirculatory failure, endothelial dysfunction and glycocalyx degradation has so far only been evaluated in small cohorts, without quantitative analysis of microcirculatory perfusion

Detailed description: The study of pathophysiological mechanisms of cellular penetration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) allows the understanding of organ failures observed in COVID 19. In order to allow its fusion with the cell membrane, SARS-Cov-2 must bind the Angiotensin Converting Enzyme 2 (ACE2) via its Spike protein. This process requires the priming of the viral S protein by a cellular serine protease TMPRSS2. Thus, any cell co-expressing these two receptors is a potential target for the virus. Among all the cells for which this co-expression could be observed, endothelial cells and vascular pericytes seem to be potential targets, whose infection could lead to the development of an endothelial dysfunction responsible for microcirculatory dysfunction. In addition, inappropriate host immune system response observed in Covid-19 with massive production of pro-inflammatory cytokines as IL-6, TNF α and VEGF could lead to endothelial dysfunction through neutrophils, monocytes and macrophages mobilization producing Reactive Oxygen Species that increase endothelium and glycocalyx damages. The resulting pro-adhesive, pro-vasoconstricting and prothrombotic effects could lead to vascular micro-thrombosis, capillary plugging and impairment of capillary flow.

Whether endothelial dysfunction is caused by direct viral cell infection or pro-inflammatory response is uncertain, but various studies have confirmed that endotheliopathy plays a key role in pathophysiological mechanisms in Covid 19.

In the context of critical care, the evaluation of microcirculatory perfusion appears to be a diagnostic tool of major importance. Indeed, microcirculatory dysfunction is directly associated with increased organ failure and mortality in the ICU. In addition, many clinical situations such as sepsis or hemorrhagic shock may be responsible for a loss of hemodynamic coherence between macro and microcirculatory parameters. Thus, the correction of macrohemodynamic parameters (arterial pressure, cardiac output, plasma lactate, central venous oxygen saturation) may be associated with persistent microcirculatory hypoperfusion. It thus appears essential to develop systems for assessing the microcirculation in order to move towards resuscitation guided by microcirculatory objectives.

The aim of this study is to describe the sublingual microcirculation and to evaluate endothelial dysfunction in critically ill patient with Covid-19, and to determine whether there is a correlation between the severity of microcirculatory damage, endothelial dysfunction and clinically important outcomes in ICU. The data will serve to develop strategies for individualized management of high-risk patients screened with microcirculation evaluation.

Eligibility criteria: Inclusion Criteria:

* Adult patient (≥ 18 ans)
* Affiliation to the French social security system
* Patient admitted to ICU within 72 hours before inclusion
* Patient presenting SARS-CoV-2 pneumonia diagnosed by CT scan or by COVID-19 PCR test

Exclusion Criteria:

* Lesions of the oral mucosa

Primary outcomes:
measure: Change in Microvascular flow index (MFI)
timeFrame: At admission, on day 1 and day 2
Secondary outcomes:
measure: Change in perfused vessel density
timeFrame: At admission, on day 1 and day 2
measure: Change in plasma Syndecan-1 levels (in pg/ml)
timeFrame: At admission, on day 1 and day 2
measure: Change in plasma Thrombomodulin levels (in arbitrary units/ml)
timeFrame: At admission, on day 1 and day 2
measure: Change in plasma VEGF-A levels (in arbitrary units/ml)
timeFrame: At admission, on day 1 and day 2
measure: Change in plasma Angiopoietin-2 levels (in ng/ml)
timeFrame: At admission, on day 1 and day 2
measure: Change in cardiac output
timeFrame: At admission, on day 1 and day 2
measure: Blood D-dimer levels (in µg/l)
timeFrame: At admission
measure: Neutrophil to Lymphocyte ratio
timeFrame: At admission
measure: Blood C Reactive Protein levels (in mg/l)
timeFrame: At admission
measure: The ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2)
timeFrame: At admission
measure: The percentage of pulmonary lesions as assessed by computerized tomography (CT) scan
timeFrame: At admission
measure: Mortality
timeFrame: Day 28
measure: Invasive Mechanical ventilation
timeFrame: Day 28
measure: Length of stay in the ICU
timeFrame: Day 28
measure: Acute kidney injury
timeFrame: Day 28
measure: Organ failure
timeFrame: Every day from Day 0 to Day 8, and at Day 28 after inclusion
Other outcomes:
Locations:
city: Le Kremlin Bicêtre
country: France
facility: Surgical Intensive Care Unit - Kremlin Bicêtre Hospital, APHP
Study officials:
affiliation: APHP, Kremlin Bicêtre Hospital
name: Jacques Duranteau, MD, PhD
role: STUDY_DIRECTOR
References: