Treatment of severe stroke guided by parameters regarding brain protection and neurological recovery

• Register: REBEC
• Last refreshed on: 29 April 2013
• Main ID: RBR-55t5v9
• Date of registration: 01/05/2012
• Primary sponsor: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil
• Public title: Treatment of severe stroke guided by parameters regarding brain protection and neurological recovery
• Scientific title: Multimodal monitoring, inflammation and neuroregeneration in subarchnoid hemorrhage
• Date of first enrolment: 01/03/2012
• Target sample size: 12
• Recruitment status: not yet recruiting
• URL: http://www.ensaiosclinicos.gov.br/rg/RBR-55t5v9/
• Study design: Analytical study, observational, cohort

Countries of recruitment

Brazil

Contacts

• Name: Adriano Nogueira
• Affiliation: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

• Name: Adriano Nogueira
• Affiliation: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Key inclusion & exclusion criteria

Inclusion criteria: Patients of 18 to 65 years of age; have been hospitalized at Clinical Hospital, University of São Paulo Medical School within the first 72 h after the first hemorrhage; presenting Hunt and Hess grade IV or V; presenting anterior circulation aneurysm.
Exclusion criteria: Having undergone some neurosurgical procedure at another facility (e.g. placement of an external ventricular drain) before admission at Clinical Hospital, University of São Paulo Medical School; presenting severe systemic disease; presenting either a Glasgow coma scale score of 3 or pathological posture accompanied by bilateral mydriasis with fixed pupils; unavailable information regarding level of consciousness previously to sedation.

Age minimum: 18Y
Age maximum: 65Y
Gender: -

Health Condition(s) or Problem(s) studied

G00-G99

Nervous system diseases, Subarachnoid hemorrhage
I60

Intervention(s)

Twelve patients will be selected according to the inclusion and the exclusion criteria. All patients will follow the same protocol of treatment. After clinical stabilization and aneurysm occlusion, the catheters of external ventricular drain, brain microdialysis and brain tissue oxygenation will be inserted. Next, the electrodes for electroencephalographic monitoring will be placed on scalp. The external ventricular drain will be used for continuous monitoring of the intracranial pressure and of the brain tissue oxygenation, as well as for CSF collection in the days of catheter placement and removal, and for CSF drainage if necessary for intracranial hypertension treatment. Electroencephalographic and brain tissue oxygenation monitoring will be continuous; the measurement of lactate/pyruvate ratio by brain microdialysis will be carried out hourly. For evaluation of vasospasm, Lindegaard index will be accessed by transcranial Doppler daily. The criteria for removal of the intracranial catheters are: 1) central nervous system infection; 2) three continuous days without sedation and without any alteration in the multimodality monitoring parameters, 3) permanence for seven days. The multimodality monitoring parameters to be controlled are: intracranial pressure > 20 mmHg, brain temperature > or = 37.5°C, brain tissue oxygenation (in the white matter) < 20 mmHg, lactate/pyruvate ratio > 40, decrease in alpha/delta ratio > 50%, Lindegaard index (middle cerebral artery velocity / internal carotid artery velocity) > 6. These parameters will be used to determine the cohorts of this study, namely: 1) cohort #01: patients with altered multimodal monitoring parameters, 2) cohort #02: patients with normal multimodal monitoring parameters. Cohort #02 patients will be managed according to standardized measures for subarachnoid hemorrhage. Regarding cohort #01 patients, to control the multimodality monitoring parameters, clinical measures (e.g. adjustment of arterial blood pressure

Primary Outcome(s)

The primary outcome is the mortality in 90 days after bleeding. Each biomarker mentioned below is a parameter. For each biomarker, a correlation analysis regarding the primary outcome will be carried out. The primary outcome regarding each of the 12 patients included in this project will be evaluated in relation to the presence or absence of altered parameter until 90 days after bleeding. For the continuously measured parameters, the parameter will be regarded as altered if the value of the parameter remained out of the normal range for more than 30 minutes at least once. For the intermittently measured parameters, a parameter will be regarded altered if at least one measurement was out of the normal range.
The type of parameter, the parameters to be evaluated, the frequency of evaluation of the parameters, and the normal values of the parameters are, respectively:
1) Clinical data, body temperature, continuous measurement, altered if > or = 37.5°C;
2) Physiological data, intracranial pressure, continuous measurement, altered if > 20 mmHg;
3) Physiological data, brain temperature, continuous measurement, altered if > or = 37.5°C;
4) Physiological data, brain tissue oxygenation, continuous measurement, altered if < 20 mmHg;
5) Physiological data, metabolic stress, measurement hourly by brain microdialysis, altered if lactate/pyruvate ratio > 40;
6) Physiological data, decrease in alpha/delta ratio > 50%, as measured by electroencephalogram;
7) Physiological data, Lindegaard index (middle cerebral artery velocity / internal carotid artery velocity), daily measurement by transcranial Doppler, altered if > 6;
8) Pro-inflammatory markers in the blood (each marker will be analyzed separately as a predictor); tumor necrosis factor alpha (TNF-alpha), interferon gama (IFN-gama), interleukins (IL-1beta, IL-2, IL-6), matrix metalloproteinases (MMP-2, MMP-9), endothelin, intercellular adhesion molecule-1 (ICAM-1), C reactive protein (CPR); blood collection in the days of external ventricular drain placement and removal, and 7, 14, 21, 28 and 90 days after subarachnoid hemorrhage; normal value for each predictor is specified in datasheet of the immunoenzymatic assay kit;
9) Pro-inflammatory markers in the cerebrospinal fluid (CSF) (each marker will be analyzed separately as a predictor); the same as in item 8; CSF collection during external ventricular drain placement and removal; the normal value will be defined from 15 CSF samples collected due to suspicious of neurological disease (e.g. meningitis, polyradiculoneuritis or subarachnoid hemorrhage) but whose biochemical and cytological results were normal;
10) Anti-inflammatory marker in the blood, IL-10, frequency of collection and value defined as normal according to item 8;
11) Anti-inflammatory marker in the CSF, IL-10, frequency of collection and value defined as normal according to item 9;
12) Neuroregeneration-related markers in the blood (each marker will be analyzed separately as a predictor); brain derived neurotrophic factor, epithelial growth factor, fibroblast growth factor-2, erythropoietin, granulocyte colony stimulating factor, monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor; frequency of collection and values defined as normal according to item 8;
13) Neuroregeneration-related markers in the CSF (each marker will be analyzed separately as a predictor); the same markers as in item 12; frequency of collection and values defined as normal according to item 9.

Secondary Outcome(s)

The secondary outcome is the functional result in 90 days after bleeding. The functional result will be referred to as good prognosis or poor prognosis. Good prognosis corresponds to a score in the modified Rankin scale equal to 0-3. Poor prognosis corresponds to a score in the modified Rankin scale equal to 4-6. The biomarkers to be analyzed as predictors of the secondary outcome are the same biomarkers used for the primary outcome. The analysis of the biomarkers regarding the secondary outcome will be the same as that regarding the primary outcome.

Secondary ID(s)

0573.0.015.000-11

Registro Nº 8084 / Projeto 0585/11

Source(s) of Monetary Support

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil

Secondary Sponsor(s)

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil