Endothelial Function, Inflammation and Organ Dysfunction in COVID-19

Endothelial Function, Inflammation, and Organ Dysfunction in Critically Ill Patients With COVID-19

COVID-19 is a rapidly evolving pandemic with approximately 5% of all patients which require intensive care unit admission. In critically ill patients infected with COVID-19, approximately 15% had severe shock requiring medications to increase blood pressure. It appears that blood vessel tone is altered and microcirculation is not well regulated in patients with COVID-19. The underlying pathophysiology and contributing factors are unknown. The association with subsequent organ dysfunction and outcome is also unclear. Therefore, the investigators aim to investigate serial changes of relevant biomarkers in this population to improve the understanding of this disease, to investigate the association with clinically important outcomes and to find out how best to treat patients. The data will serve to develop strategies for individualised management of this high-risk group.

Study Overview

• Status: Recruiting
• Conditions: Shock; COVID

Detailed Description

COVID-19 is a rapidly evolving pandemic with approximately 5% of all patients requiring admission to an intensive care unit. In critically ill patients infected with COVID-19, acute respiratory distress syndrome (ARDS) is found in 40%, 11.9% required continuous renal replacement therapy (RRT), and 13.4% had vasodilatory shock.

Currently, supportive treatment is the mainstay treatment, with fluid administration and vasopressors for haemodynamic support and lung-protective ventilation in patients with severe respiratory failure.3 Targeted drugs, antiviral therapies, and vaccines are still currently being developed, but there is currently insufficient evidence to recommend any drug over another.

Dysregulation of vasomotor tone and alteration of microcirculatory function are common in patients infected with COVID-19. The underlying pathophysiology and contributing factors are unknown. The association with subsequent organ dysfunction and outcome is also unclear.

Circulating bio-adrenomedullin regulates vascular tone and endothelial permeability during sepsis, and has been shown to associate with 28-day mortality, vasopressor requirement, RRT, and positive fluid balance. Proenkephalin is a biomarker of glomerular function, and was shown to elevate in patients with acute kidney injury (AKI), especially in those with persistent AKI, and major adverse kidney events. Dipeptidyl peptidase 3 (DPP-3) is a myocardial depressant factor, which is involved in angiotensin II cleavage. High DPP-3 levels were associated with severe organ dysfunction and short-term mortality. In critically ill patients, COVID-19 has been reported to be associated with cardiovascular dysfunction and high mortality.

The renin-angiotensin-aldosterone system (RAAS) may be linked to the pathogenesis of COVID-19. The coronavirus receptor utilizes angiotensin converting enzyme 2 (ACE2) to enter target cells. Endogenous angiotensin II is hypothesized to prevent binding of coronavirus to ACE2, causing internalization and downregulation of ACE2, and causing lysosome-mediated destruction of ACE2. There are no human studies in COVID-19 patients to confirm this hypothesis yet.

There is very little knowledge of underlying pathogenesis in patients with COVID-19 and vasodilatory shock. Therefore, the investigators aim to investigate serial changes of relevant biomarkers in this population to give further understanding of this disease and to investigate the association with clinically important outcomes. The data will serve to develop strategies for individualized management of this high-risk group.

• Study Type: Observational
• Enrollment (Anticipated): 82

Contacts and Locations

• Study Contact: Name: Marlies Ostermann, MD, PhD; Phone Number: 83036 0044 207 188 3038; Email: Marlies.Ostermann@gstt.nhs.uk
• Study Contact Backup: Name: Nuttha Lumlertgul, MD, PhD; Phone Number: 83036 0044 207 188 3038; Email: Nuttha.Lumlertgul@gstt.nhs.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 7EH
    • Recruiting
    • Guy's & St Thomas' Hospital
    • Contact: Marlies Ostermann, MD, PhD; Phone Number: 020 71883038; Email: Marlies.Ostermann@gstt.nhs.uk

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Adult COVID-19 patients who are admitted in intensive care units

Description

Inclusion Criteria:

1. Adult patients (≥ 18 years old) admitted to intensive care units
2. Confirmed or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection resulting in coronavirus disease 2019 (COVID-19)

Exclusion Criteria:

None

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
COVID-19 patients; Adult COVID-19 patients admitted to intensive care units

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of plasma bio-adrenomedullin	Change of plasma bio-adrenomedullin	Day 1-7 after intensive care unit admission
Change of plasma proenkephalin	Change of plasma proenkephalin	Day 1-7 after intensive care unit admission
Change of plasma dipeptidyl peptidase-3	Change of plasma dipeptidyl peptidase-3	Day 1-7 after intensive care unit admission
Change of plasma renin	Change of plasma renin	Day 1-7 after intensive care unit admission
Change of plasma angiotensin II	Change of plasma angiotensin II	Day 1-7 after intensive care unit admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of vasodilatory shock	Duration of vasodilatory shock	7 and 28 days
Acute kidney injury	As defined by the Kidney Disease: Improving Global Outcomes criteria	7 and 28 days
Need for renal replacement therapy	Need for renal replacement therapy	7 and 28 days
Duration of ventilation	Duration of ventilation	7 and 28 days
Duration of extracorporeal membrane oxygenation	Duration of extracorporeal membrane oxygenation	7 and 28 days
Mortality	ICU and hospital	28 days

Collaborators and Investigators

• Sponsor: Guy's and St Thomas' NHS Foundation Trust
• Collaborators: King's College Hospital NHS Trust
• Investigators: Principal Investigator: Nuttha Lumlertgul, MD, PhD, Guy's & St Thomas' Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2020
• Primary Completion (Anticipated): July 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: May 27, 2020
• First Submitted That Met QC Criteria: May 27, 2020
• First Posted (Actual): May 29, 2020

Study Record Updates

• Last Update Posted (Actual): August 9, 2021
• Last Update Submitted That Met QC Criteria: August 6, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: 282930

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