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This study aims to evaluate the efficacy and safety of transcutaneous auricular vagus nerve stimulation (taVNS) in patients with acute intracerebral hemorrhage (ICH). The taVNS intervention will be delivered using the BS-TVNS800-1 transcutaneous electrical stimulation therapy device (KERFUN, Shanxi, China). A total of 186 patients will be randomly assigned in a 1:1 ratio to either the taVNS group or the sham-taVNS group. The primary outcome is the relative volume of perihematoma edema assessed on day 10-14 after randomization. Adverse events associated with taVNS therapy will be systematically evaluated to assess its safety profile.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| taVNS intervention | Active Comparator | Patients will receive taVNS therapy twice daily for 10 consecutive days, in addition to receiving guideline-adherent conventional treatment during hospitalization. |
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| Sham taVNS intervention | Sham Comparator | Patients will receive sham taVNS twice daily for 10 consecutive days, in addition to receiving guideline-adherent conventional treatment during their hospital stay. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| transcutaneous auricular vagus nerve stimulation device | Device | Place the stimulation device on the left auricle and set the stimulation parameters according to the following conditions: a. Waveform: biphase, square wave; b. Wave width: 200 μs; c. Frequency: Alternating between low frequency (4 Hz for 4 s), high frequency (40 Hz for 8 s), and a 4 s pause; d. Intensity: The maximum intensity that induces the strongest sensation the individual can tolerate without causing pain, usually 1.5-3.5 mA; e. Treatment duration: Each treatment lasted 30 minutes, twice daily (8:00, 16:00) for 10 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Volume of perihematoma edema assessed by CT | Relative edema volume. | Day 10-14 after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Autonomic activity assessed by heart rate variability | Heart rate variability (HRV) will be assessed using a 10-minute electrocardiogram (ECG) recorded with a 12-lead ECG Holter (TeleECG BI 12E, Biomedical Instruments Co., Ltd., Shenzhen). HRV indices will be analyzed in both the time domain (e.g., SDNN, RMSSD) and the frequency domain (e.g., LF, HF, LF/HF). | Day 10-14 after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Safety assessment | Adverse events, serious adverse events, death | In the 10-day treatment period |
| Perihematomal blood-brain barrier permeability | Perihematomal blood-brain barrier permeability will be assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI). |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Tiantan Hospital, Capital Medical University | Recruiting | Beijing | Beijing Municipality | 100070 | China |
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| ID | Term |
|---|---|
| D002543 | Cerebral Hemorrhage |
| D000090862 | Neuroinflammatory Diseases |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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The participants and outcome assessors are unaware of the trial grouping.
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| Sham device | Device | The sham taVNS group received the same parameters with a current intensity of 0.06 mA. |
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| Autonomic activity assessed by baroreflex sensitivity | Baroreflex sensitivity (BRS) will be evaluated by noninvasively measuring beat-to-beat signals for 10 min using a servo-controlled plethysmograph (FMS-8A, Delica Medical Equipment Co., Ltd., Shenzhen) placed on the middle finger. | Day 10-14 after randomization |
| National Institutes of Health stroke scale (NIHSS) | NIHSS is used to assess the severity of functional impairment caused by stroke. It consists of 11 test items, with a total score ranging from 0 to 42. A higher score indicates a more severe stroke. | Day 10-14 after randomization |
| GCS (Glasgow Coma Scale) | The GCS is used to assess the level of consciousness in patients, with the total score ranging from 3 to 15. Lower scores indicate more severe impairment. | Day 10-14 after randomization |
| MMSE (Mini-Mental State Examination) | The Mini-Mental State Examination (MMSE) is a widely used cognitive screening tool designed to assess global cognitive function, including orientation, memory, attention, language, and visuospatial skills. Scores range from 0 to 30, with higher scores indicating better cognitive performance. | Day 10-14 after randomization |
| MoCA (Montreal Cognitive Assessment) | The Montreal Cognitive Assessment (MoCA) is another cognitive screening instrument optimized for detecting mild cognitive impairment (MCI) and early dementia. Scores range from 0 to 30, with higher scores indicating better cognitive performance. | Day 10-14 after randomization |
| PHQ-9 (Patient Health Questionnaire-9) | The Patient Health Questionnaire-9 (PHQ-9) is a brief, self-report tool validated for screening and monitoring depression severity. Scores range from 0 to 27, with higher scores reflecting greater symptom severity. | Day 10-14 after randomization |
| 90-day National Institutes of Health stroke scale (NIHSS) | NIHSS is used to assess the severity of functional impairment caused by stroke. It consists of 11 test items, with a total score ranging from 0 to 42. A higher score indicates a more severe stroke. | 90 ± 7 days after randomization |
| 90-day modified Rankin Scale (mRS) | The mRS is used to measure the degree of disability or dependence after a stroke. The scale ranges from 0 to 6 and higher scores indicate greater functional impairment. | 90 ± 7 days after randomization |
| 90-day EQ-5D (EuroQol 5-Dimension Questionnaire) score | The EQ-5D is a standardized instrument used to assess health-related quality of life. | 90 ± 7 days after randomization |
| 90-day GCS (Glasgow Coma Scale) | The GCS is used to assess the level of consciousness in patients, with the total score ranging from 3 to 15. Lower scores indicate more severe impairment. | 90 ± 7 days after randomization |
| 90-day MMSE (Mini-Mental State Examination) | The Mini-Mental State Examination (MMSE) is a widely used cognitive screening tool designed to assess global cognitive function, including orientation, memory, attention, language, and visuospatial skills. Scores range from 0 to 30, with higher scores indicating better cognitive performance. | 90 ± 7 days after randomization |
| 90-day MoCA (Montreal Cognitive Assessment) | The Montreal Cognitive Assessment (MoCA) is another cognitive screening instrument optimized for detecting mild cognitive impairment (MCI) and early dementia. Scores range from 0 to 30, with higher scores indicating better cognitive performance. | 90 ± 7 days after randomization |
| 90-day PHQ-9 (Patient Health Questionnaire-9) | The Patient Health Questionnaire-9 (PHQ-9) is a brief, self-report tool validated for screening and monitoring depression severity. Scores range from 0 to 27, with higher scores reflecting greater symptom severity. | 90 ± 7 days after randomization |
| Day 5-7 after randomization |
| Evaluation of glymphatic system | Impairment of the function of the glymphatic system will be assessed by diffusion kurtosis imaging analysis along the perivascular space (DKI-ALPS). | Day 5-7 after randomization |
| Assessment of microglial activation | Microglial activation will be quantified by TSPO-PET/MRI. | Day 7-9 after randomization |
| Interleukin-1β (IL-1β) level in peripheral blood | IL-1β: A pro-inflammatory cytokine (measured in pg/mL) that drives fever, neutrophil activation, and autoimmune responses. It will be detected by ELISA. | Day 10-14 after randomization |
| Interleukin-6 (IL-6) | IL-6: A pro-inflammatory cytokine (pg/mL) involved in acute-phase protein synthesis and B-cell differentiation, and implicated in infections. It will be detected by ELISA. | Day 10-14 after randomization |
| Tumor Necrosis Factor-alpha (TNF-α) | TNF-α is a pro-inflammatory cytokine (pg/mL) which can be detected via ELISA. | Day 10-14 after randomization |
| Interleukin-4 (IL-4) | IL-4 is an anti-inflammatory Th2 cytokine (pg/mL) which will be measured by ELISA. | Day 10-14 after randomization |
| Interleukin-10 (IL-10) | IL-10 is an anti-inflammatory regulator (pg/mL), which will be quantified via ELISA. | Day 10-14 after randomization |
| Transforming Growth Factor-beta (TGF-β) | TGF-β is a multifunctional cytokine (pg/mL) that is involved in regulation of cell growth, differentiation, and apoptosis. It will be detected by ELISA. | Day 10-14 after randomization |
| Neurofilament light chain (NFL) | NFL is a non-specific biological marker representing neuronal injury (measured in pg/mL). It will be measured by ELISA. | Day 10-14 after randomization |
| Monocyte subsets | Classical (CD14++CD16-) differentiate into macrophages for tissue repair, non-classical (CD14+CD16++) patrol vasculature for surveillance, measured in cells/μL by flow cytometry. | Day 10-14 after randomization |
| CD4+ T cells | Coordinate adaptive immunity (helper role, cells/μL) via cytokine secretion and immune activation, assessed by flow cytometry with surface marker staining. | Day 10-14 after randomization |
| CD8+ T cells | Mediate cytotoxicity (cells/μL), quantified using flow cytometry. | Day 10-14 after randomization |
| NK cells | Innate lymphocytes (cells/μL) detected via flow cytometry. | Day 10-14 after randomization |
| B cells | Produce antibodies for humoral immunity (measured in cells/μL), enumerated by flow cytometry (CD19/CD20 markers). | Day 10-14 after randomization |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007249 | Inflammation |