CT-Perfusion for Neurological Diagnostic Evaluation (INDex-CTP)

CT-Perfusion for Neurological Diagnostic Evaluation: a Prospective Canadian Multicenter Diagnostic Test Study

For the purpose of organ donation after neurological determination of death (NDD), death must be declared using a set of standardized clinical criteria. When a full clinical evaluation cannot be completed, additional neuroimaging ancillary testing is required. The ideal ancillary test for NDD would demonstrate no cerebral blood flow, be free of false-positive and false negative results, rapid, safe, readily available, non-invasive, and inexpensive. No current ancillary test for NDD meets these criteria. Computed tomography (CT) perfusion has the characteristics of an ideal test for NDD, but has not been evaluated for routine clinical use for NDD.

The overarching goal of this project is to improve the NDD process by establishing CT-perfusion as the ideal ancillary test. A large prospective Canadian multi-centre diagnostic cohort study will be conducted to validate CT-perfusion for the neurological determination of death.

Specific objectives are:

Primary objective: To determine diagnostic accuracy of CT-perfusion compared to complete clinical evaluation for NDD.

Secondary objectives: 1) To confirm the safety of performing CT-perfusion in critically ill patients suspected of being neurologically deceased; 2) To establish the CT-perfusion inter-rater reliability for NDD; 3) To evaluate the diagnostic accuracy of CT-angiography compared to complete clinical evaluation and to CT-perfusion for NDD; 4) To describe the clearance of commonly used sedatives and narcotics in the setting of NDD; and 5) to investigate biological changes (inflammatory and nanovesicles) that occur in humans during the brain dying process.

Study Overview

• Status: Active, not recruiting
• Conditions: Neurological Determination of Death
• Intervention / Treatment: Diagnostic test: Neurological Diagnostic Evaluation

Detailed Description

The investigators will conduct a large prospective Canadian multi-centre diagnostic cohort study. The primary diagnostic test evaluated will be CT-perfusion. The reference standard will be the complete clinical evaluation of brainstem functions. Comatose patients at high risk of neurological death exempt of confounding factors (e.g. hypothermic patients, use of long-acting sedatives, etc.) will be included. All patients will undergo CT-perfusion of the head (with CT-angiography reconstructions) followed by a complete NDD assessment. Both CT-perfusion and the clinical exam will be performed by independent assessors blinded from each others' interpretation. The primary endpoints will be the sensitivity and specificity of CT-perfusion to confirm NDD. Safety endpoints will be CT-perfusion -related adverse events (i.e. contrast-induced kidney injury, new hemodynamic instability while undergoing CT-perfusion). The true negative, true positive, false negative and false positive for CT-angiography obtained from the CT-perfusion source images when compared to the reference standard as well as when compared to the CT-Perfusion will also be reported. The sensitivity and specificity of CT-angiography compared to the reference standard and to CT-perfusion along with corresponding 95% confidence intervals will be calculated. Individual patient and population pharmacokinetics of analgesics and sedatives will be determined. To better investigate the impact of residual circulating sedative or narcotic levels on the accuracy of CT-Perfusion and CT-Angiography, Receiver Operating Characteristics (ROC) curves for varying levels of narcotic or sedative thresholds and compute the ROC area under the curve for each threshold will be plotted. To assess the immune phenotype, peripheral blood mononuclear cells activation will be evaluated by flow cytometry and cytokines by multiplex analyses. Nanovesicles fraction will be isolated from the plasma by ultracentrifugation and antigenic content and enzymatic activity. The plasma will finally be analysed by ELISAs and multiplex analyses to determine the levels of pro-inflammatory cytokines.

• Study Type: Interventional
• Enrollment (Actual): 333
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Medical Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • Winnipeg Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Queen Elizabeth II Health Sciences Centre
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • William Osler Health System
    • Hamilton, Ontario, Canada
      • Hamilton Health Sciences Center
    • Kingston, Ontario, Canada
      • Kingston General Hospital
    • London, Ontario, Canada
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada
      • The Ottawa Hospital
    • Toronto, Ontario, Canada
      • St-Michael's Hospital
  • Quebec
    • Montreal, Quebec, Canada
      • McGill University Health Centre
    • Montreal, Quebec, Canada
      • Centre hospitalier de l'Université de Montréal (CHUM)
    • Montreal, Quebec, Canada
      • Montreal Neurological Institute and Hospital
    • Quebec City, Quebec, Canada
      • CHU de Québec - Université Laval
    • Sherbrooke, Quebec, Canada
      • Centre Hospitalier Universitaire de Sherbrooke

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Adults 18 years and older
2. Admitted in the intensive care unit with a brain injury
3. Glasgow Coma Scale (GCS) = 3
4. Sedation stopped for at least 6 hours

Exclusion Criteria:

1. Patients with the following contraindications to CT-perfusion will be excluded from the study:

   • Pregnancy
   • Contrast allergy
   • Clinician refuses inclusion because of kidney injury.

2. Patients with any of the following confounding factors precluding complete clinical neurological evaluation will be excluded from the study:

   • Cervical fracture above C6
   • Significant facial trauma limiting cranial nerve examination
   • Hypothermia < 34 °C
   • Use of intravenous barbiturates at any time since admission
   • Unresuscitated shock
   • Peripheral nerve or muscle dysfunction or neuromuscular blockade potentially accounting for unresponsiveness
   • Anoxic brain injury < 24h (or 72h if therapeutic hypothermia)
   • Attending physician disagrees to conduct an apnea test
   • Any other abnormalities deemed a confounding factor for NDD by the attending clinician

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Neurological Diagnostic Evaluation; Exams performed according to a determined schedule following admission in the intensive care unit in order to validate CT-perfusion as an accurate ancillary test for neurological diagnostic.

Diagnostic test: Neurological Diagnostic Evaluation; Clinical Data: Demographic data; Daily data (clinical exams, laboratory data); Drug administration; Additional clinical or ancillary neurological determination test Diagnostic Intervention: CT-Perfusion; CT-Angiography reconstructions Reference Standard: - Clinical Neurological Exam Blood Samples (Pharmacokinetics, Inflammatory & Nanovesicles Parameters): At the time of patient enrolment; 6 hours after patient enrolment; At the time of the clinical neurological exam Secondary Outcome measures at 6 months: extended Glasgow Outcome Scale (GOSe); modified Rankin Scale (mRS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accuracy of CT-perfusion	Sensitivity and specificity for brainstem death of CT-perfusion compared to the clinical examination	CT-Perfusion scan and clinical assessment must be less than 2 hours apart

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predictive Values	Positive and negative predictive values between two independent neuroradiology interpretations of CT-perfusion for brainstem death	CT-Perfusion scan and clinical assessment must be less than 2 hours apart
Likelihood Ratios	Positive and negative likelihood ratios between two independent neuroradiology interpretations of CT-perfusion for brainstem death	CT-Perfusion scan and clinical assessment must be less than 2 hours apart
Inter-rater Agreement	Between two independent neuroradiology interpretations of CT-perfusion for brainstem death	CT-Perfusion scan and clinical assessment must be less than 2 hours apart
Volume of Distribution	Volume of distribution from serum concentrations and drug dosing history	48 hours
Clearance	Volume of plasma completely cleared of the drug expressed as mL/min	48 hours
Elimination Rate Constant	Rate at which the drug is removed from the body	48 hours
Concentration-time Curve	Concentration of drug versus time	48 hours
Accuracy of CT-perfusion at 6 Months	Sensitivity and specificity for brainstem death of CT-perfusion compared to the clinical examination for a good mRS score (3 or less) at 6 months	6 months
Accuracy of the Predictive Values at 6 Months	Positive and negative predictive values between two independent neuroradiology interpretations of CT-perfusion for brainstem death for a good mRS score (3 or less) at 6 months	6 months
Accuracy of the Likelihood Ratios at 6 Months	Positive and negative likelihood ratios between two independent neuroradiology interpretations of CT-perfusion for brainstem death for a good mRS score (3 or less) at 6 months	6 months
Accuracy of the Inter-rater Agreement at 6 Months	Between two independent neuroradiology interpretations of CT-perfusion for brainstem death for a good mRS score (3 or less) at 6 months	6 months

Collaborators and Investigators

• Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Michael Chassé, MD PhD FRCPC, Centre hospitalier de l'Université de Montréal (CHUM); Principal Investigator: Jai JS Shankar, MD MSc FRCPC, University of Manitoba

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2017
• Primary Completion (Actual): February 22, 2021
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: March 22, 2017
• First Submitted That Met QC Criteria: March 27, 2017
• First Posted (Actual): March 31, 2017

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Organ Donation; Neurological Determination of Death; Determination of Death; CT-Perfusion scan; Ancillary Test
• Additional Relevant MeSH Terms: Pathologic Processes; Death
• Other Study ID Numbers: CE 16.379

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