Disorders of consciousness are common after surgery for severe spontaneous intracerebral hemorrhage and are associated with high mortality, disability, and long-term dependence. Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive neuromodulation technique that may enhance arousal-network activity, modulate secondary brain injury, and promote recovery of consciousness.
This multicenter, prospective, double-blind, randomized, sham-controlled trial will enroll 160 adults aged 18 to 75 years who underwent hematoma evacuation within 48 hours after spontaneous intracerebral hemorrhage and have a Glasgow Coma Scale score of 5 to 9 on postoperative day 5 while not sedated. Participants will be assigned 1:1 to active taVNS or sham stimulation for 8 hours once daily for 6 weeks. The primary outcome is the proportion of participants who remain in a disorder of consciousness (unresponsive wakefulness syndrome/vegetative state or minimally conscious state) at postoperative day 90, determined using the Coma Recovery Scale-Revised by blinded assessors.
Nested mechanistic substudies will investigate how taVNS may affect recovery through multimodal assessment of structural and functional brain networks, cerebral perfusion, electrophysiology, autonomic function, and circulating or cerebrospinal-fluid biomarkers. Depending on clinical stability, site capability, sample availability, and additional consent, assessments may include computed tomography, computed tomography angiography and perfusion, structural and functional magnetic resonance imaging, diffusion imaging, arterial spin labeling, electroencephalography, blood samples, and cerebrospinal fluid obtained during clinically indicated procedures.
Spontaneous intracerebral hemorrhage.
Age 18 to 75 years.
Surgical intervention performed within 48 hours after symptom onset.
Glasgow Coma Scale score of 5 to 9 on postoperative day 5 while the participant is not sedated; for intubated participants, the verbal component is scored as 1T.
• Intracranial hemorrhage caused by a confirmed intracranial aneurysm, cerebral vascular malformation, intracranial tumor, arterial thrombosis, or venous thrombosis.
Injury to critical brain structures affecting consciousness, including brainstem hemorrhage or thalamic hemorrhage greater than 20 mL.
Isolated intraventricular hemorrhage.
Severe cardiomyopathy, heart failure, atrial fibrillation, frequent premature beats, second-degree or higher atrioventricular block, or another severe cardiac arrhythmia.
Parallel
Active Transcutaneous Auricular Vagus Nerve Stimulation
DeviceActive taVNS is delivered to the left ear at a frequency of 25 Hz, a pulse width of 500 microseconds, and a current intensity of 0.8-1.5 mA. Stimulation alternates between 30 seconds on and 30 seconds off for a total wearing period of 8 hours once daily. Treatment begins after randomization on postoperative day 5 (±1 day) and continues for 6 weeks.
Sham Transcutaneous Auricular Vagus Nerve Stimulation
DeviceThe sham device is worn at the same left-ear location and for the same schedule as active taVNS (8 hours once daily for 6 weeks), but no electrical current is delivered.
Proportion of Participants With a Disorder of Consciousness at Postoperative Day 90
The proportion of participants classified by the Coma Recovery Scale-Revised (CRS-R) as being in unresponsive wakefulness syndrome/vegetative state (UWS/VS) or a minimally conscious state (MCS- or MCS+). Participants classified as having emerged from the minimally conscious state (eMCS) or as conscious are considered not to have a disorder of consciousness. The day-90 assessment is performed by independent assessors blinded to treatment assignment. A lower proportion indicates a better outcome.
Clinical Consciousness Improvement Response at Postoperative Day 90
The proportion of participants whose CRS-R diagnostic level improves by at least one prespecified category from baseline. Categories are ordered from UWS/VS to MCS-, MCS+, and eMCS/conscious. A higher proportion indicates a better outcome.
Clinical Consciousness Improvement Response at Postoperative Day 28
The proportion of participants whose CRS-R diagnostic level improves by at least one prespecified category from baseline. Categories are ordered from UWS/VS to MCS-, MCS+, and eMCS/conscious. A higher proportion indicates a better outcome.
Ordinal Distribution of Consciousness States at Postoperative Day 90
The overall distribution of CRS-R diagnostic categories: UWS/VS, MCS-, MCS+, and eMCS/conscious. Higher categories indicate better recovery of consciousness.
Change From Baseline in Coma Recovery Scale-Revised Total Score at Postoperative Day 28
The CRS-R comprises auditory, visual, motor, oromotor/verbal, communication, and arousal subscales. The total score ranges from 0 to 23, with higher scores indicating more behaviors consistent with consciousness. Change is calculated as the day-28 score minus the baseline score; a positive change indicates improvement.
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Beijing Tiantan Hospital
Lead sponsor
Beijing Friendship Hospital
Collaborator
First Affiliated Hospital of Fujian Medical University
Collaborator
Liaocheng People's Hospital
Collaborator
