Clinical trial NCT03098511: CT-Perfusion for Neurological Diagnostic Evaluation
Official title: CT-Perfusion for Neurological Diagnostic Evaluation: a Prospective Canadian Multicenter Diagnostic Test Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Neurological Determination of Death
Keywords: Neurological Determination of Death
Determination of Death
CT-Perfusion scan
Ancillary Test
Organ Donation
Lead sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2017-03-31
Enrollment: 333
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Accuracy of CT-perfusion
timeFrame: CT-Perfusion scan and clinical assessment must be less than 2 hours apart
Secondary outcomes:
measure: Predictive Values
timeFrame: CT-Perfusion scan and clinical assessment must be less than 2 hours apart
measure: Likelihood Ratios
timeFrame: CT-Perfusion scan and clinical assessment must be less than 2 hours apart
measure: Inter-rater Agreement
timeFrame: CT-Perfusion scan and clinical assessment must be less than 2 hours apart
measure: Volume of Distribution
timeFrame: 48 hours
measure: Clearance
timeFrame: 48 hours
measure: Elimination Rate Constant
timeFrame: 48 hours
measure: Concentration-time Curve
timeFrame: 48 hours
measure: Accuracy of CT-perfusion at 6 Months
timeFrame: 6 months
measure: Accuracy of the Predictive Values at 6 Months
timeFrame: 6 months
measure: Accuracy of the Likelihood Ratios at 6 Months
timeFrame: 6 months
measure: Accuracy of the Inter-rater Agreement at 6 Months
timeFrame: 6 months
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Winnipeg
country: Canada
facility: Winnipeg Health Sciences Centre
state: Manitoba
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Brampton
country: Canada
facility: William Osler Health System
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Center
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: St-Michael's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Québec - Université Laval
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
Study officials:
affiliation: Centre hospitalier de l'Université de Montréal (CHUM)
name: Michaël Chassé, MD PhD FRCPC
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba
name: Jai JS Shankar, MD MSc FRCPC
role: PRINCIPAL_INVESTIGATOR
References: