Early Identification of Malignant Brain Edema in laRge Artery oCclusive Stroke After Endovascular Therapy (EMBRACE Study)
Conditions: Endovascular Therapy, Brain Edema, Prediction Model, Ischemic Stroke
Sponsor: Zhejiang Provincial People's Hospital

Early identification of Malignant Brain edema in laRge Artery oCclusive
stroke after Endovascular therapy (EMBRACE study)
Protocol Version Number and Date: 1.0, March 20, 2024

Background
Stroke is a significant global cause of death and disability. Endovascular
thrombectomy (EVT) is currently the best treatment for acute large vessel occlusion
stroke (ALVOS), as it can greatly reduce mortality and improve patient outcomes.
However, only half of patients who undergo EVT achieve functional independence,
and malignant brain edema (MBE), a severe complication, can occur after the
procedure, leading to a poor prognosis. Previous studies have confirmed the
effectiveness of early decompressive hemicraniectomy in reducing morbidity and
mortality in patients with malignant brain edema. Therefore, identifying high-risk
patients for MBE can help clinicians make appropriate triage and early intervention
decisions, potentially saving patients' lives.
Predictive factors for post-ischemic stroke brain edema have been widely discussed,
and reliable early predictive indicators have been identified, such as age, early
consciousness disorders, baseline National Institutes of Health Stroke Scale (NIHSS),
atrial fibrillation, hypertension, baseline blood glucose, and the level of reperfusion
after EVT. Radiological factors, such as the Alberta Stroke Program Early CT Score
(ASPECTS), collateral circulation rating of arteries, venous outflow status, CT
perfusion core infarct volume, perfusion-based collateral status, and clot burden, are
closely associated with the occurrence of MBE post-EVT. However, due to individual
differences and multiple factors affecting MBE, a single factor cannot effectively
predict MBE. Establishing a clinical risk prediction model can effectively identify
high-risk populations for MBE at an early stage.
Aim
To design and validate a predictive model for MBE after EVT.
Design
Study Type: Observational [Patient Registry]
Time Perspective: Prospective

Study population
The study is a multicenter, prospective, observational clinical registry study,
commenced on April 1, 2024, and is expected to end in June 2027. Participants were
ALVOS patients undergoing EVT treatment in neurology departments from multiple
stroke centers. The data from Zhejiang Provincial People's Hospital compose the
model training cohort, while data from other centers serve as an independent external
validation cohort. The protocol of the study has been approved by the human Ethics
Committee of Zhejiang Provincial People’s Hospital (KY2024058). All clinical
investigations will be conducted according to the principles set in the Declaration of
the Helsinki.
Inclusion Criteria:
(1) Age > 18 years old;
(2) Onset of stroke to hospital admission < 24 hours;
(3) Admission with a head CT scan ruling out hemorrhage;
(4) Patients undergoing CT perfusion scan before treatment;
(5) Confirmation of internal carotid artery (ICA) or middle cerebral artery (MCA)
occlusion or tandem occlusion by Digital Subtraction Angiography (DSA) and
subsequent EVT;
(6) complete 3-months follow-up.
Exclusion Criteria:
(1) Poor quality of preoperative CT perfusion imaging;
(2) Posterior circulation occlusion or isolated anterior cerebral artery occlusion;
(3) Presence of other severe diseases such as malignant tumors, severe organ
failure, or other life-threatening conditions with an expected survival period of less
than 90 days;
(4) Incomplete imaging and clinical data.

Procedures
All ALVOS patients will undergo comprehensive evaluation by neurologists at
admission to the stroke center to obtain baseline data from clinical and laboratory
examinations. Multimodality CT, including head non-contrast CT (NCCT), CT
perfusion (CTP) and CTP-derived multiphase CT angiography (CTA), will be
performed to assess whether patients are eligible for EVT. After EVT, all patients will
be transferred to the neuro-intensive care unit for close perioperative and
postoperative care to ensure stability of vital signs and implementation of
comprehensive monitoring and management. This includes daily neurological
assessments, monitoring of vital signs and oxygenation, and management of
endotracheal intubation. Once the patient's vital signs stabilize or after the patient is
extubated, they will be transferred to the neurology stroke care unit for further
treatment. In principle, this trial does not involve the selection and intervention of
therapeutic drugs. Within 24 hours post-EVT, patients will undergo repeat head
NCCT to exclude hemorrhage and evaluate surgical outcomes. Antiplatelet therapy
may be considered based on the patient's specific condition but should be cautiously
selected in clinical practice and closely monitored to prevent bleeding complications.
In case of signs of hemorrhagic transformation, physicians may adjust the antiplatelet
therapy regimen at their discretion, potentially reducing the dose or delaying
antiplatelet treatment. Additionally, regular in-hospital follow-up head NCCT scans
will be performed on patients at day 3, to monitor disease progression and adjust
treatment plans promptly.
Imaging protocol
Head NCCT is performed on a Toshiba Aquilion 320-slice CT scanner (Toshiba
Medical Systems) using the following acquisition parameters: 120 kV, 128 mAs, scan
coverage of 240 mm, and scan width of 5 mm. Simultaneously, 4-dimensional
time-resolved whole-brain CTA and whole-brain CTP can be acquired. Lohexol (45
mL) (Medrad Stellant D SCT-212; Bayer Healthcare) is injected at a rate of 5

mL/second, followed by a 30 mL saline flush at an injection rate of 4 mL/second. All
perfusion parameters are analyzed using post-processing software.
Radiological assessments
The imaging variables collected in this study involve arterial, venous and perfusion
status variables, including NCCT-ASPECTS, ischemic core volume, the penumbra
volume, collateral status based on CTP and multiphase CTA, clot burden score, and
venous outflow status. Imaging evaluations will be performed by imaging physicians
who are blind to the clinical information.
CT perfusion assessment
Areas with relative cerebral blood flow (rCBF) <30% is defined as the ischemic core.
The penumbra volume is calculated by subtracting the ischemic core volume (lesions
with rCBF <30%) from the perfusion lesion volume (delay time threshold >3
seconds). The collateral index is defined as the volume of tissue with delay time
(DT) >6 s divided by the volume with DT >2 s.
Clot burden score
We use a CBS for the anterior circulation to quantify the extent of ipsilateral
intracranial thrombus, allotting major arteries 10 points for the presence of contrast
opacification on CTA. Two points each is subtracted for the absence of contrast
opacification in the complete cross-section of any part of the proximal M1 segment,
distal M1 segment, or supraclinoid ICA, and 1 point each for M2 branches, A1
segment, and infraclinoid ICA. Partial filling defects suggesting stenosis or
non-occlusive thrombus are rated as patent. A score of 10 indicates the absence of a
visible occlusion on CTA, while a score of 0 indicates occlusion of all major
intracranial anterior circulation arteries.
Venous outflow assessment

The outflow status of the sphenoparietal sinus, superficial middle cerebral veins, and
intracerebral veins will be evaluated. Venous opacification will be graded per vein
using a three-point scale based on baseline CT angiography:
0: Complete absence of cortical vein opacification
1: Moderate opacification (attenuation of one of the target veins on the contralateral
side)
2: Full opacification.
Clinical assessments
We will record the demographic data (gender, age, hypertension, diabetes, history of
atrial fibrillation), site of occlusion, baseline systolic and diastolic blood pressure,
prior IVT administration, baseline NIHSS score, NIHSS score at discharge, modified
Rankin Score (mRS) at discharge, and TOAST stroke etiology (Trial of ORG 10172
in Acute Stroke Treatment) of each participant. Hematological laboratory results will
include baseline glucose, baseline white blood cell count, baseline neutrophil count,
baseline hemoglobin, and platelet count. The EVT operator will record the time from
stroke onset to puncture (OTP), time from puncture to recanalization (PTR), and
degree of blood flow restoration. The occluded vessel will be determined based on
intraoperative angiography results, and reperfusion level will be graded using the
modified Thrombolysis in Cerebral Infarction (mTICI) score, with complete
reperfusion defined as mTICI 2b-3. Clinical assessments will be conducted by
neurologists unaware of the clinical diagnosis.
Study groups

training set
To determine potential predictive factors, imaging and clinical parameters will be
enrolled into LASSO regression analysis, which effectively eliminated several
irrelevant or multicollinearity independent variables to reduce high-dimensional data.
The multivariable logistic regression analysis will be applied to determine the

variables predicting MBE, and the results will be used to create a predictive model
based on the training set.

validation set
The predictive model will be further validated in the validation set.
Outcome assessment
Primary Outcome Measures:
The occurrence of MBE: Patients developed MBE within 3 days post-EVT
Secondary Outcome Measures:
1. The follow-up mRS scores of enrolled patients at 90 days since stroke onset.
2. Evidence of parenchymal hemorrhage (PH type) on cranial imaging during
hospitalization.
Sample size
In this study, predictive model will be constructed using the EVT database from
Zhejiang Provincial People's Hospital as a training cohort, and prospective data from
other centers will be used to validate the performance of predictive model. We will
randomly select 70% of the patients from the Stroke Center EVT database at Zhejiang
Provincial People's Hospital as the training cohort, while the remaining 30% will
constitute the internal validation cohort. Within the training cohort, our aim will be to
analyze imaging and clinical parameters when constructing the predictive model.
Given the requirement of at least 10 events per candidate variable for model
establishment, a minimum of 200 MBE patients is necessary in the training cohort to
ensure stable model estimation. Based on a study design with a sample ratio of 7:3 for
the training and internal validation sets, at least 290 MBE patients will be required in
this study at Zhejiang Provincial People's Hospital. The external validation set will
require 100-200 positive samples; considering an approximate 20% incidence rate of
MBE in anterior circulation EVT patients, this study will need to include at least 1950
EVT patients.

Statistical analysis
Compare baseline clinical and imaging data of EVT patients with and without MBE
across the training, internal validation, and external validation sets. Continuous
variables conforming to a normal distribution will be described using means and
standard deviations, while those not conforming will be described using medians and
quartiles. Categorical variables will be expressed as percentages.
In the training set, factors influencing MBE will be analyzed. Continuous variables
will be analyzed using Student's t-test or Mann-Whitney U test, while categorical
variables will be analyzed using chi-square test and Fisher's exact test. Collinearity
among variables will be assessed using Variance Inflation Factors (VIFs), where VIF
<10 and Tolerance >0.1 indicate no significant collinearity. Variables with a
significance level of P <0.1 in univariate analysis will be incorporated into logistic
regression analysis using forward stepwise selection method, and odds ratios (ORs)
and 95% confidence intervals (CIs) will be calculated. Factors with P < 0.05 will be
included as independent predictors of MBE in the model. After constructing the
predictive model, it will be converted into a dynamic nomogram and deployed on a
webpage, generating a dynamic nomogram URL.
The dynamic nomogram URL will be used to externally validate EVT data from other
stroke centers and will collect data. The area under the receiver operating
characteristic (ROC) curve (AUC) will be used to evaluate the ability of the predictive
model to identify high-risk MBE patients after EVT in the training, internal and
external validation sets, and corresponding 95% CIs will be calculated. Calibration
plots and the Hosmer-Lemeshow goodness-of-fit test will assess the consistency
between actual MBE occurrence and predicted MBE risk probability in EVT patients.
Decision curve analysis (DCA) will determine the clinical net benefit of the model at
different risk threshold probabilities in the three sets.
Statistical analyses will be performed using IBM SPSS Statistics software (version

26.0; IBM Corporation, Armonk, NY, USA) and R software (version 4.3.1, R
Development Core Team, Vienna, Austria).