Cerebral Oxygenation and Neurological Outcomes FOllowing CriticAL Illness-2 (CONFOCAL-2)

This study is designed to test the hypothesis that poor cerebral perfusion during critical illness is a risk factor for acute and long-term neurological dysfunction among survivors. We use near-infrared spectroscopy to measure brain tissue oxygenation as a non-invasive surrogate marker for cerebral perfusion. Acute neurological dysfunction is defined as the presence of delirium, which is assessed using the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). Chronic neurological dysfunction is defined as having quantitative impairments on robotic testing (KINARM robot) and traditional neuropsychological screening (Repeatable Battery for the Assessment of Neuropsychological Status).

Study Overview

• Status: Recruiting
• Conditions: Delirium; Shock; Critical Illness; Respiratory Failure

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: J. Gordon Boyd, MD, PhD; Phone Number: 6228 613-549-6666; Email: boydj@kgh.kari.net
• Study Contact Backup: Name: Miranda Hunt; Phone Number: 613-549-6666; Email: huntm4@KGH.KARI.NET

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L3V7
      • Recruiting
      • Kingston General Hospital
      • Contact: John G Boyd, MD, PhD; Phone Number: 6228 613-549-6666; Email: 2jgb1@queensu.ca

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

We will be enrolling consecutive patients meeting eligibility criteria from each site in this multi-centred study.

Description

Inclusion

1. Adults ≥ 18 years old

2. Admitted to a critical care unit requiring one or more of the following:

   (a) Respiratory failure requiring invasive mechanical ventilation with an expected duration >24 hours (b) Shock of any etiology. Shock is defined by the need for one of the following vasopressors/inotropes: (i) Dopamine ≥7.5 mcg/kg/min (ii) Dobutamine ≥5 mcg/kg/min (iii) Norepinephrine ≥5 mcg/min (iv) Phenylephrine ≥75 mcg/min (v) Epinephrine at any dose (vi) Milrinone at any dose (if used in conjunction with another agent) (vii) Vasopressin ≥0.03 u/min(if used in conjunction with another agent)

Exclusion:

1. Admission to the ICU > 24 hours
2. Life expectancy <24 hours
3. Admitting diagnosis that affects the central nervous system
4. Any reason that the subject may not be able to participate in the follow up assessments (i.e. limb amputation, paresis, neuromuscular disorders)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Respiratory failure and/or shock; All enrolled patients will undergo 72 hours of monitoring of cerebral oxygenation with near-infrared spectroscopy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional cerebral oxygenation (rSO2) and delirium	Multivariate linear regression will be used to characterize the association between poor cerebral perfusion (as measured using duration of time (minutes) outside of MAPOPT, mean rSO2, and duration of disturbed cerebral autoregulation) and delirium severity to determine if poor cerebral perfusion is an independent predictor of delirium severity. We will estimate the unadjusted effect of each individual predictor on delirium severity (i.e., cumulative CAM-7 scores per patient). The simultaneous multivariate regression model will adjust for the following covariates (sex, a history of hypertension, a history of alcohol abuse, total sedative dose (in midazolam equivalents), total narcotic dose (fentanyl equivalents), severity of illness (APACHE II scores), pre-existing cognitive impairment (CDR score), length of ICU stay, and blood urea nitrogen. The multivariable model will provide the adjusted regression coefficients after controlling for all predictors included in the model.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of secondary outcomes-physiological determinants of cerebral oxygenation	To assess the physiological determinants of rSO2, multiple linear regression will be performed using the patient average of each variable over the 72 hour data collection period. The following predictors will be included in the regression model: heart rate (HR), arterial oxygen saturation (SpO2), MAP, arterial blood gas data (i.e., pH, partial pressure of oxygen, and partial pressure of carbon dioxide), central venous oxygen saturation, and hemoglobin concentration (Hb). In addition, the multivariate model will control for the following covariates associated with cerebral perfusion: sex, age, as well as total sedative, narcotic, and vasopressor dosing. Simultaneous multiple linear regression with adjustment for all aforementioned covariates will be implemented. A within patient repeated measures analysis will also be performed by using the linear mixed effects model with 6 observations per subject reflecting each 12 hour period during the 72 hour data collection period.	72 hours
Cerebral oxygenation as an independent risk factor for long-term cognitive impairment-RBANS	Multiple linear regression analysis will be used to assess if poor cerebral perfusion (i.e. time below MAPOPT, mean rSO2, duration of disturbed cerebral autoregulation) is associated with RBANS global cognition scores at 3- and 12-months post-ICU discharge. We will use the following clinical covariates collected on admission (i.e., pre-existing cognitive impairment, age, severity of illness) and data collected within the first 72 hours of the patients' ICU stay (i.e., narcotic dosing and benzodiazepine dosing). All covariates will be adjusted for in separate regression models for the cognitive outcomes at 3- and 12-months post-ICU discharge. If global cognition is significantly predicted by the impaired cerebral perfusion, we will conduct an exploratory analysis of the RBANS subdomains of cognition (i.e., delay and immediate memory, language, attention, visuospatial/constructional) adjusting for the aforementioned covariates to further explore specific domains of impairment.	3 months and 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time outside optimal MAP	We define the optimal MAP as the MAP at which there is no statistically significant correlation between MAP and rSO2. The time outside the optimal MAP will be calculated, and will be assessed as an independent predictor of delirium, and 3- and 12-month cognitive outcomes.	72h, 3- and 12-months
Robotic quantification of neurological recovery	A the Kingston site, participants will undergo additional neurological assessments with the KINARM robot and associated tasks. This data will be analyzed descriptively	3 and 12 months

Collaborators and Investigators

• Sponsor: Dr. Gordon Boyd
• Collaborators: University Health Network, Toronto; University of Pittsburgh; University of Calgary; University of Ottawa; Western University, Canada; Vancouver General Hospital; Université de Montréal
• Investigators: Principal Investigator: J. Gordon Boyd, MD, PhD, Queen's University

Publications and helpful links

General Publications

• Khan JM, Wood MD, Lee KFH, Maslove D, Muscedere J, English SW, Ball I, Slessarev M, Boyd JG. Delirium, Cerebral Perfusion, and High-Frequency Vital-Sign Monitoring in the Critically Ill. The CONFOCAL-2 Feasibility Study. Ann Am Thorac Soc. 2021 Jan;18(1):112-121. doi: 10.1513/AnnalsATS.202002-093OC. Erratum In: Ann Am Thorac Soc. 2021 Feb;18(2):378.
• Wood MD, Khan J, Lee KFH, Maslove DM, Muscedere J, Hunt M, Scott SH, Day A, Jacobson JA, Ball I, Slessarev M, O'Regan N, English SW, McCredie V, Chasse M, Griesdale D, Boyd JG. Assessing the relationship between near-infrared spectroscopy-derived regional cerebral oxygenation and neurological dysfunction in critically ill adults: a prospective observational multicentre protocol, on behalf of the Canadian Critical Care Trials Group. BMJ Open. 2019 Jun 25;9(6):e029189. doi: 10.1136/bmjopen-2019-029189.

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2017
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: May 1, 2017
• First Submitted That Met QC Criteria: May 2, 2017
• First Posted (Actual): May 5, 2017

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: neurocognitive; near-infrared spectroscopy; cerebral oximetry; post-ICU syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Disease Attributes; Respiratory Insufficiency; Critical Illness
• Other Study ID Numbers: CTO Project ID 0815

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
• product manufactured in and exported from the U.S.: No