Cracking Coma: Towards EEG and MRI Based Precision Medicine After Cardiac Arrest

Rationale: 30-70% of comatose patients admitted to the intensive care unit (ICU) after cardiac arrest never regain consciousness as a result of post anoxic encephalopathy (PAE). Early identification of patients without potential for recovery of brain functioning may prevent inappropriate continuation of medical treatment and improve communication between doctors and patients. However, current diagnostic and prognostic measures can identify only 20-50% of the patients with irreversible brain damage, precluding cerebral recovery and awakening. Also, the pathophysiology of brain damage is largely unclear. New magnetic resonance imaging (MRI) sequences hold potential to substantially improve outcome prediction.

Objectives: 1. To estimate the additional value of early MRI monitoring for the prediction of neurological outcome of comatose patients after cardiac arrest. 2. To gain insight in the pathophysiology of PAE by associating MRI findings with histopathological studies of brain tissue obtained from non-survivors.

Study design: prospective cohort study.

Study population: 100 subsequent comatose patients after cardiac arrest, admitted to the ICU.

Intervention: In addition to standard treatments, patients will undergo MRI of the brain at day 3, 7, and three months after cardiac arrest. A subgroup of patients will be scanned within 24 hours after cardiac arrest, to assess feasibility and to gain more insight in the evolution of brain damage in PAE. Survivors will be followed for one year. Outcome measurements will focus on disabilities, quality of life, and depression. MRI measures will be related to outcome.

Main study parameters/endpoints: The primary outcome measure is neurological outcome, defined as the score on the Cerebral Performance Category (CPC) at six months, dichotomized as good (CPC 1-2 = no or moderate neurological disability) or poor (CPC 3-5 = severe disability, coma, or death). Secondary outcome measures include cognitive functioning, depression, and quality of life at one year, as well as histopathological damage of brain tissue of non-survivors.

Standard procedures:

Patients will be monitored and treated according to guidelines for post out of hospital cardiac arrest treatment as described in local ICU protocols. Patients do not suffer any harm, disadvantage of discomfort while participating in this study.

Standard treatment includes targeted temperature management, hemodynamic monitoring and stabilisation, continuous EEG monitoring, blood sampling through the jugular bulb catheter, Near Infrared Spectroscopy (NIRS), and transcranial doppler (TCD) measurements. The patient's status is repeatedly assessed and treatment is based on the clinical findings.

Additional procedures:

1. MRI A total of 3 MRI scans is planned for each patient: at day 3 ± 1, and day 7 ± 2 after cardiac arrest, and 3 months ± 2 weeks after cardiac arrest. The imaging protocol will consist of structural MRI (including FLAIR and ADC maps) to detect ischemic damage, a 3D T1 for structural analysis and SWI sequences to detect micro bleeds), structural connectivity measurement by DTI, and functional connectivity measurement by resting state BOLD functional MRI. Estimated time to prepare the patient and transport to and from the MRI scanner will be approximately 30 minutes, the scan itself will take approximately 30 minutes, as well. No intravenous contrast agent is used.

   1.1 Acute phase MRI To estimate the feasibility of MRI scanning in the acute phase and to gain more insight in the dynamics of PAE, a subgroup of patients will be scanned within 24 hours after cardiac arrest. Patients will be included in this subgroup dependent on availability of the MRI facility, the clinical stability of the patients and after the patients legal representatives signed informed consent.

   1.2 Transport to the radiology department

   The transport to and from the radiology department will be performed as described in the local protocols on patient transportation. Transport to and from other departments is a frequent procedure in ICU patients. During transport, the patient will be accompanied by a physician and ICU nurse. The MRI scans for this project will be handled as 'elective', which indicates that only patients with a stable hemodynamic and respiratory status will be transported to and undergo the MRI. For this, a patient has to meet all the following criteria:

   A. Hemodynamic stable condition, defined as:
   * mean arterial pressure \> 60 mmHg
   * no or low inotropes or vasopressors (dosage norepinephrine \< 0,3 ug/kg/min and/or dobutamine \< 10 ug/kg/min or equivalent), dosage adjustments less than 0.1 ug/kg/min in the last hour before MRI

   B. Stable cardiac rhythm, defined as:
   * sinus rhythm 50 - 120 beats per minute
   * atrial fibrillation or flutter with ventricle response 60 - 120 per minute

   C. Pulmonary stable condition, defined as:
   * Arterial oxygen saturation \> 95%
   * maximum fraction inspired oxygen \< 60% with maximum level of positive end expiratory pressure of 10 cm H2O
   * peak inspiratory pressure \< 30 cmH2O or \<5 l/min oxygen trough nasal cannula (for patients not on mechanical ventilation)

   Mechanical ventilation during transport and scanning will be provided by an MRI compatible ventilator.

   Extensive monitoring of vital functions will not be interrupted during transport or MRI scanning, by using a mobile trolley with MRI compatible monitoring and ventilation equipment. At all times, a physician and trained ICU nurse will accompany the patient. The medical team accompanying the patient can change treatment during transport and scanning to pursue optimal hemodynamics, pulmonary state, and/or comfort.

   1.3 Clinical evaluation of MRI scans All structural MRI scans will be assessed by a radiologist and results are added to a patient's medical file. Patients and their families will be informed. However, MRI findings will not be taken into account for decisions on withdrawal of treatment. BOLD fMRI and DTI data will be analysed later.
2. Outcome At 3 and 6 months, CPC score will be assessed by a telephone interview by a trained investigator. Additionally, at twelve months, for assessment of cognitive outcome, depression, quality of life, and care giver strain, the patient will be invited to the hospital or visited at his / her place of residence. If a patient dies during the follow-up, the cause of death will be requested from the general practitioner or medical specialist.
3. Post mortem analysis From all patients that die in the hospital after PAE, permission to perform autopsy is sought for. Permission will be asked from the legal representative in the context of current care, after the patient has died. According to current care, brains will be removed and samples fixated within 24 hours at the local pathology departments. On samples from 8 brain areas (sensory- and motor cortex, thalamus, basal ganglia, upper brain stem) evaluation of the agonal state is performed on hematoxylin-eosin staining. Additionally, predefined sections, including all cortical layers and white matter, will be formalin fixed for further analyses.

Eligibility Criteria:
Inclusion Criteria:

* Comatose, defined as Glasgow Coma Score ≤ 8
* Age ≥ 18 years
* Cardiac arrest with a presumed cardiac cause of the arrest or caused by pulmonary embolism
* Admission to ICU

Exclusion Criteria:

* Pregnancy
* Life expectancy \< 24 hours
* Absence of written informed consent (by a legal representative)
* Pre-existing dependency in daily living, defined as CPC score 3 or 4
* Any known progressive brain illness, such as a brain tumor or neurodegenerative disease.
* Known contra-indication for MRI