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Cerebral Autoregulation and COVID-19 (CA-COVID)

Primary Purpose

COVID-19 Acute Respiratory Distress Syndrome, COVID-19 Pneumonia

Status
Recruiting
Phase
Not Applicable
Locations
Greece
Study Type
Interventional
Intervention
NIRS (Near-Infrared Spectroscopy)
Sponsored by
University of Athens
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for COVID-19 Acute Respiratory Distress Syndrome focused on measuring COVID-19, Cerebrovascular circulation, Spectroscopy, Near-Infrared

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Department of Intensive Care Medicine Evaggelismos General HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ICU patients with COVID-19

Arm Description

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.

Outcomes

Primary Outcome Measures

Cerebral autoregulation
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.
Cerebral blood flow
Cerebral blood flow at MAP 65-75 mmHg and MAP 90-100 mmHg by determination of the blood flow index.

Secondary Outcome Measures

Neurologic failure free days
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.
Ventilator free days
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.
Survival to hospital discharge and neurological outcome
Survival to hospital discharge and neurological outcome assessed by the Cerebral Performance Category Score, and the Modified Rankin Scale Score.
Survival to hospital discharge and neurological outcome
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).
Survival to hospital discharge and neurological outcome
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).
Serum Cytokines
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.

Full Information

First Posted
June 15, 2021
Last Updated
May 8, 2023
Sponsor
University of Athens
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1. Study Identification

Unique Protocol Identification Number
NCT04930874
Brief Title
Cerebral Autoregulation and COVID-19
Acronym
CA-COVID
Official Title
Cerebral Autoregulation and Severe Coronavirus Disease 19 [CA-COVID]: A Single-center Physiological Study
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 22, 2021 (Actual)
Primary Completion Date
July 16, 2023 (Anticipated)
Study Completion Date
July 16, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Athens

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19 Acute Respiratory Distress Syndrome, COVID-19 Pneumonia
Keywords
COVID-19, Cerebrovascular circulation, Spectroscopy, Near-Infrared

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
37 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ICU patients with COVID-19
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
NIRS (Near-Infrared Spectroscopy)
Intervention Description
NIRS assessment of cerebral autoregulation and cerebral blood flow
Primary Outcome Measure Information:
Title
Cerebral autoregulation
Description
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.
Time Frame
Days 1-4 of ICU admission
Title
Cerebral blood flow
Description
Cerebral blood flow at MAP 65-75 mmHg and MAP 90-100 mmHg by determination of the blood flow index.
Time Frame
Days 1-4 of ICU admission
Secondary Outcome Measure Information:
Title
Neurologic failure free days
Description
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.
Time Frame
Days 1-60 after ICU admission
Title
Ventilator free days
Description
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.
Time Frame
Days 1-60 after ICU admission
Title
Survival to hospital discharge and neurological outcome
Description
Survival to hospital discharge and neurological outcome assessed by the Cerebral Performance Category Score, and the Modified Rankin Scale Score.
Time Frame
Days 1-60 after ICU admission
Title
Survival to hospital discharge and neurological outcome
Description
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).
Time Frame
Days 1-60 after ICU admission
Title
Survival to hospital discharge and neurological outcome
Description
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).
Time Frame
Days 1-60 after ICU admission
Title
Serum Cytokines
Description
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.
Time Frame
Days 1-7 after ICU admission

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Spyros D Mentzelopoulos, MD, Professor
Phone
+306975304909
Email
sdmentzelopoulos@yahoo.com
First Name & Middle Initial & Last Name or Official Title & Degree
Anastasia Kotanidou, MD, Professor
Phone
+306977077105
Email
akotanid@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Spyros D Mentzelopoulos, MD, Professor
Organizational Affiliation
National and Kapodistrian University of Athens
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Anastasia D Kotanidou, MD, Professor
Organizational Affiliation
National and Kapodistrian University of Athens
Official's Role
Study Chair
Facility Information:
Facility Name
Department of Intensive Care Medicine Evaggelismos General Hospital
City
Athens
State/Province
Attica
ZIP/Postal Code
10675
Country
Greece
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Evaggelismos G Hospital, MD, PhD
Phone
+306975304909
Email
sdmentzelopoulos@yahoo.com
First Name & Middle Initial & Last Name & Degree
Anastasia D Kotanidou, MD, PhD
Phone
+306977077105
Email
akotanid@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
No
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Cerebral Autoregulation and COVID-19

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