Cerebral Autoregulation and COVID-19 (CA-COVID)

December 16, 2024 updated by: Spyros D. Mentzelopoulos, University of Athens

Cerebral Autoregulation and Severe Coronavirus Disease 19 [CA-COVID]: a Single-center Physiological Study

This study aims to assess cerebral autoregulation by near-infrared spectroscopy (NIRS) in patients with severe coronavirus disease 19 (COVID-19). Results on COVID-19 participants will be compared with prior results of patients with septic shock and cardiac arrest, who participated in NCT03649633 and NCT02790788, respectively.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Background and Rationale:

Septic encephalopathy is a serious complication of sepsis / septic shock. In postmortem, human brain samples, two forms of neuraxonal injury have been described, namely, scattered ischemic lesions and diffuse injury. Prior evidence suggests that cerebral autoregulation is impaired in patients with septic shock, and this may render the central nervous system more vulnerable to direct ischemic damage, especially during episodes of hypotension. Recent observational data suggest that impaired cerebral autoregulation is associated with death within 3 months in patients with septic shock. Near-infrared spectroscopy (NIRS) constitutes an established method of noninvasive assessment of cerebral autoregulation and also provides the capability of semiquantitative assessment of regional cerebral blood flow. Severe coronavirus disease (COVID-19) is characterized by hypoxemia due to pneumonia, thromboembolic events that often affect the cerebral and pulmonary vascular network, vasodilatory shock and multiorgan failure. Pathophysiological mechanisms have features in common with those of septic shock and include "cytokine storm", diffuse vascular endothelial involvement, micro- and macro-vascular thrombosis and dysregulation of micro-circulation and vascular tone. In the present study, the following 3 hypotheses will be tested: 1. Cerebral autoregulation is likely to be severely impaired or even abolished in patients with COVID-19 who require admission to an Intensive Care Unit (ICU). In addition, the correlation between the NIRS Tissue Oxygenation Index and the mean arterial pressure may be stronger in COVID-19 compared to septic shock and comparable to that determined after cardiac arrest. 2. Cerebral autoregulation is likely to be associated with known COVID-19 severity markers such as lymphopenia and elevated C-reactive protein (CRP), ferritin, delta dimers (D-dimers) and lactate dehydrogenase (LDH) 3. The early (ie on ICU days 1 and 3) absence of cerebral autoregulation is likely to be associated with residual neurological deficits.

METHODS:

NIRS monitoring will be performed for approximately 90 minutes at 2 mean blood pressure levels (MAP, i.e. 65-70 mmHg and 95-100 mmHg) within 12-48 hours and 60-84 hours after admission to the ICU for severe COVID-19 infection. Autoregulation will be assessed using Tissue Oxygenation Index values and mean arterial pressure (MAP) values in a regression analysis and will be considered sufficient if the relative Pearson correlation coefficient is less than 0.3 Cerebral blood flow will be assessed by blood flow index (BFI) determination after intravenous infusion of 5 mg indocyanine.

ICU Protocol: All COVID-19 patients participating in this study will be treated in a standardized manner that includes: An intermediate dose of Enoxaparin, e.g. 4000 units x 2 subcutaneously 2. Treatment with remdesivir and dexamethasone 3. Up to 2 broad-spectrum antibiotics to treat possibly co-existing bacterial respiratory tract infection 4. A conservative fluid management strategy 5. A protective ventilation strategy in a semirecumbent position 5. Anesthesia with Midazolam, Propofol and Remifentanil 7. Enteral nutrition that will start within 24 hours after admission to the ICU, 8. Permissive hyperglycemia (blood glucose 150-200 mg / dL).

Data Collection and Patient Monitoring:

Monitoring of patients during the first 10 days after inclusion in the study will include 1) Determination and recording of hemodynamic parameters and hemodynamic support, blood gases and arterial blood lactate at 9 p.m. 2) Blood sampling at 24-48, 72 hours and 7 days after inclusion in the study for determination of serum cytokines and 3) Daily recording of laboratory values, fluid balance and administration. The results of 2-4 daily determinations of blood glucose will be recorded and then the incidence of hyperglycemia (defined as blood glucose in excess of 200 mg) will be analyzed. Follow-up until day 60 after inclusion in the study will include organic failures and the number of days without mechanical ventilatory assistance. Finally, the length of stay in the ICU, the date of discharge from the hospital and the morbidity and complications throughout the patient's treatment until discharge from the hospital will be recorded.

Predefined comparisons: The severity of cerebral autoregulation disturbance in patients with COVID-19 will be compared with the cerebral autoregulation disturbance in 1) patients with septic shock (n = 32, NCT03649633, www.clinicaltrials.gov) and 2) cardiac arrest (n = 30, NCT02790788, www.clinicaltrials.gov). Also, other -pre-specified -by the respective research protocols- patient monitoring variables will be compared between the aforementioned groups of patients.

Names / degrees of Associates:

Alexandros Kouvarakos, Physiotherapist; Eirini Patsaki, Physiotherapist; Sotirios Malachias, MD, PhD; Charikleia Vrettou, MD, PhD; Stylianos Kokkoris, MD, PhD; Prodromos Temperikidis, MD, PhD; Aggeliki Kannavou, MD, PhD; George Adamos, MD, PhD

Study Type

Interventional

Enrollment (Actual)

7

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Greece
    • Attica
      • Athens, Attica, Greece, 10675
        • Department of Intensive Care Medicine Evaggelismos General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Admission to ICU and endotracheal intubation/mechanical ventilation for severe COVID-19 infection

Exclusion Criteria:

  • Age <18 years
  • Pregnancy
  • Patients with a terminal underlying disease who are unlikely to survive until discharge from the hospital
  • Patients with acquired immunodeficiency and ("pre-COVID") lymphocyte Cluster Differentiation 4+ count <50 / μL
  • Patients with COVID-19 who have been transferred from another hospital
  • Patients with a history of allergic reaction
  • Use of prone position to facilitate mechanical ventilation
  • Absence of signed informed consent from a first degree relative

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ICU patients with COVID-19
NIRS monitoring will be performed for approximately 90 minutes at 2 mean blood pressure levels (MAP, ie 65-70 mmHg and 95-100 mmHg) within 12-48 hours and 60-84 hours after admission to the ICU for severe COVID-19 infection. Autoregulation will be assessed using Tissue Oxygenation Index values and mean arterial pressure values in a regression analysis and will be considered sufficient if the relative Pearson correlation coefficient is less than 0.3. Cerebral blood flow will be assessed by blood flow index determination after intravenous infusion of 5 mg indocyanine.
Other: NIRS (Near-Infrared Spectroscopy)
NIRS assessment of cerebral autoregulation and cerebral blood flow

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cerebral autoregulation
Time Frame: Days 1-4 of ICU admission
The tissue oxygenation index of the frontal cortex will be determined (at a rate of 180 measurements / min) while increasing MAP from a minimum of 65-75 mmHg to a maximum of 90-100 mmHg by changing the vasopressor infusion rate. Cooncurrent changes in MAP will also be recorded. Subsequently, linear regression between MAP and the Tissue Oxygenation Index will be performed. A Pearson correlation coefficient of >0.3 will be considered as "absence" of autoregulation of the cerebral vasculature.
Days 1-4 of ICU admission
Cerebral blood flow
Time Frame: Days 1-4 of ICU admission
Cerebral blood flow at MAP 65-75 mmHg and MAP 90-100 mmHg by determination of the blood flow index.
Days 1-4 of ICU admission

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurologic failure free days
Time Frame: Days 1-60 after ICU admission
Days without neurologic failure throughout the 60-day follow-up period. Patients with a Glasgow Coma Scale of <9 will be considered to have neurological failure.
Days 1-60 after ICU admission
Ventilator free days
Time Frame: Days 1-60 after ICU admission
Days without mechanical ventilatory assistance throughout the 60-day follow-up period. On any given day of follow-up, patients will be considered as "ventilator-free" only if there is no need for respiratory support within the preceding 24 hours.
Days 1-60 after ICU admission
Survival to hospital discharge and neurological outcome
Time Frame: Days 1-60 after ICU admission
Survival to hospital discharge and neurological outcome assessed by the Cerebral Performance Category Score, and the Modified Rankin Scale Score.
Days 1-60 after ICU admission
Survival to hospital discharge and neurological outcome
Time Frame: Days 1-60 after ICU admission
Survival to hospital discharge and neurological outcome assessed by the Cerebral Performance Category (CPC) Score. The CPC Score ranges from 1 to 5, with 1 corresponding to the best possible outcome (i.e. patient able to work and lead a normal life), and 5 corresponding to the worst possible outcome (i.e. brain death).
Days 1-60 after ICU admission
Survival to hospital discharge and neurological outcome
Time Frame: Days 1-60 after ICU admission
Survival to hospital discharge and neurological outcome assessed by the Modified Rankin Scale (mRS) Score. The mRS ranges from 0, corresponding to the best possible outcome (i.e. no symptoms related to a neurological deficit), to 6 corresponding to the worst possible outcome (i.e. death).
Days 1-60 after ICU admission
Serum Cytokines
Time Frame: Days 1-7 after ICU admission
Tumor Necrosis Factor alpha, Interleukin (IL)-1 beta, IL-6, IL-8, and IL-10 levels at 24-48, 72 hours and 7 days after enrollment. Plasma concentrations of all the aforementioned cytokines will be expressed in picograms per milliliter.
Days 1-7 after ICU admission

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Athens

Investigators

  • Principal Investigator: Spyros D Mentzelopoulos, MD, Professor, National and Kapodistrian University of Athens
  • Study Chair: Anastasia D Kotanidou, MD, Professor, National and Kapodistrian University of Athens

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 22, 2021

Primary Completion (Actual)

September 16, 2022

Study Completion (Actual)

September 16, 2022

Study Registration Dates

First Submitted

June 15, 2021

First Submitted That Met QC Criteria

June 16, 2021

First Posted (Actual)

June 18, 2021

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

December 16, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CA-COVID 196/10-6-2021

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on COVID-19 Pneumonia

Clinical Trials on NIRS (Near-Infrared Spectroscopy)

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Japan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe