Patient Recruitment
Patients are screened for eligibility for the trial by their surgeon. Patients aging from 18 to 70 years old with moderate to severe IVH (Graeb score > 4 points) are eligible for this trial. Imaging examination shows deep brain hemorrhage breaking into the ventricles or primary intraventricular hemorrhage, and the amount of bleeding is large, more than 50% of the lateral ventricle or complete ventricle cast.
Patients are excluded from the trial if they have a history of chronic obstructive pulmonary disease, coronary heart disease, chronic kidney disease, blood disorders, cancer, systemic autoimmune disease, or long-term oral corticosteroids. Patients with following conditions are also excluded: imaging examination showing cerebellum and brain stem hemorrhage; detected cerebrovascular diseases in CTA/MRA/MRV/DSA examinations (choose 1 or 2 examinations); ultra-early (within 72 hours) or late enhanced MRI suggesting the presence of brain tumors; history of coagulopathy or long-term oral anticoagulant.
Setting
The study is performed at neurosurgical centers from 4 tertiary hospitals from different parts of China. The organizer will set up an expert panel of 4–6 people to ensure that each participating site has the ability to perform the proper surgical technique.
First, the site applying to participate in the study needs to provide at least two unedited endoscopic IVH evacuation surgery videos and two EVD videos, and provide data of at least 5 cases for endoscopic IVH evacuation surgery and EVD (including preoperative imaging data, surgical records, and postoperative imaging data). The expert panel will judge whether the applicant has the qualification to participate in the study based on the above information.
The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist is provided in Additional file1.
Randomization
Weadopt a central randomization method based on the stratification of each clinical trial center, based on the mobile client randomization tool “Randomization Allocation Tool” (RAT) to achieve random assignment of two surgical methods. If the subject is qualified for the trial and signs the informed consent form, the investigator authorized by each center can input the relevant information of the corresponding subject in the mobile phone client. After the random administrator approves the confirmation, the assigned group is immediately fed back to the researcher’s mobile phone, and the researcher performs the prescribed surgical treatment according to the specified group. The method generates a random allocation sequence in advance and can effectively prevent selection bias.
Procedure
The patient in endoscopic group was placed in the supine position and under general anesthesia. Endoscopy was performed using a rigid endoscope (Karl Storz, German). The side with more hemorrhage was taken as the surgical side and a transverse incision of about 3 cm in length was performed 1–2 cm in front of the coronal suture, 2–3 cm beside the midline. Then, a bone window with a diameter of 2–3 cm was made and we cross-incised the dura mater. Next, the surgeons inserted the endoport into the lateral ventricle, which constituted the endoscopic operative channel. The hematoma was removed by a technique using irrigation and aspiration. After exposing the choroid plexus of the lateral ventricle, surgeons should strive to clear the hematoma in the third ventricle through the interventricular orifice. At the same time, the blood clots could be removed with grasping forceps and if there was bleeding, bipolar coagulation could be used to stop bleeding. During the operation, the veins, choroid plexus and ventricular wall should be carefully protected and blood clots that were closely adhering to the choroid plexus were not required to be completely removed. The third ventriculostomy and pellucid septostomy should be performed if possible. The ventricular drainage catheter was placed on the surgical side. The dura and skin were closed in a routine manner. An immediate postoperative CT scan was obtained to assess the residual hematoma. Six hours after surgery, we administered 20,000 U urokinase with 5 ml saline every 8 hours through the catheter and the catheter was closed for 1 hour to allow drug–clot interaction and then reopened to allow for gravitational drainage. Subsequent CT scans were done for any safety concern or every 24 hours. Administration of urokinase was stopped when the CT scans showed that the circulation of cerebrospinal fluid is unobstructed. When CT scans showed that the intracerebral hematoma was significantly reduced and the circulation of cerebrospinal fluid is unobstructed, the catheter could be clamped for 24 h. If there was no acute intracranial pressure increase, the catheter could then be removed.
The patient in EVD group was placed in the supine position and under general anesthesia. The bilateral external ventricular drainage was performed regularly and the unilateral drainage was performed only when one lateral ventricular has little hematoma and the circulation of cerebrospinal fluid is unobstructed. Surgeons usually selected the point 1–2 cm before the coronal suture of the bleeding side and 2–3 cm next to the midline as the puncture point and punctured inwardly along the plane of the puncture point and the line of the ear. The surgeons used a soft catheter with a guide needle to puncture in depth of about 5 cm and then pulled out the guide needle. The next step was to fix the drainage catheter and suture the scalp incision. Postoperative CT was done immediately to confirm positioning of the soft catheter and stability of the hematoma. Six hours or more after catheter placement, we administered 20,000 U urokinase with 5 ml saline every 8 hours and the catheter was closed for 1 hour to allow drug–clot interaction and then reopened to allow for gravitational drainage. Subsequent CT scans were done for any safety concern or every 24 hours. Administration of urokinase was stopped when the CT scans showed that the circulation of cerebrospinal fluid is unobstructed. When CT scans showed that the intracerebral hematoma was significantly reduced and the circulation of cerebrospinal fluid is unobstructed, the catheter could be clamped for 24 h. If there was no acute intracranial pressure increase, the catheter could then be removed.
Outcome Measures
The primary outcome measure is the survival rate of patients at 12 months postoperatively. (Enrollment and assessments in the trial were shown in Table 1)
In addition, secondary outcome measures include treatment-related morbidity, as evaluated by the incidence of:
Postoperative patient survival (OS).
Modified Rankin score (preoperative, one month, three months, six months, 12 months).
Proportion of patients who need ventricular-peritoneal shunt Incidence of postoperative hydrocephalus.
Postoperative intracranial infection.
Hospital stays.
Hospitalization expenses.
Table 1 Enrollment and assessments in the trial
Item
|
Screening period
|
Follow-up
|
Operation day
|
1 day after operation
|
7 day after operation
|
2 weeks after operation
|
1 month after operation
|
3 months after operation
|
6 months after operation
|
12 months after operation
|
Informed consent
|
X
|
|
|
|
|
|
|
|
|
Collect demographic data
|
X
|
|
|
|
|
|
|
|
|
Collect medical history
|
X
|
|
|
|
|
|
|
|
|
Physical examination
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Blood routine examination
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Blood biochemical examination
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Routine urine test
|
X
|
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Brain CT scan
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Brain MRI
|
X
|
|
|
|
|
X
|
X
|
X
|
X
|
CTA/ MRA/ MRV/ DSA(Choose 1 or 2 items)
|
X
|
|
|
|
|
|
|
|
|
HIV、HBV、HCV screening
|
X
|
|
|
|
|
|
|
|
|
Graeb score
|
X
|
X
|
X
|
X
|
X
|
X
|
|
|
|
Glasgow Coma Scale
|
X
|
X
|
X
|
X
|
X
|
X
|
|
|
|
Inclusion/Exclusion criteria
|
X
|
|
|
|
|
|
|
|
|
Randomization
|
X
|
|
|
|
|
|
|
|
|
Survival rate at 12 months postoperatively
|
|
|
|
|
|
|
|
|
X
|
Modified Rankin Scale
|
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Postoperative patient survival (OS)
|
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Postoperative Complications
|
|
□
|
□
|
□
|
□
|
□
|
□
|
□
|
□
|
Statistical analysis
The OS curves will be estimated using the Kaplan–Meier method. The primary comparison of survival distributions will be performed with the log rank test. Secondary analyses will adjust for prognostic factors using appropriate regression models (e.g., Cox proportional hazards model). All measures of efficacy will be compared by an intention-to-treat analysis including all randomized patients.
Continuous variables will be assessed for normality and equality of variances between groups. Discrete variables will be summarized by frequencies/proportions. For continuous variables, analysis of variance and/or regression will be used, where appropriate. If assumptions for these tests are violated, alternative nonparametric tests will be used. Difference between groups with respect to discrete variables will be evaluated by using c2 tests.