Stimulation-Temperature-Oxygen-Positioning Multimodal Neuroprotection for Acute Ischemic Stroke (STOP)

Reperfusion therapy with intravenous thrombolysis and/or endovascular treatment is the cornerstone of acute ischemic stroke treatment. However, restoration of large-vessel blood flow does not necessarily result in complete tissue recovery. Persistent ischemic injury, microcirculatory dysfunction, neuroinflammation, blood-brain barrier disruption, cerebral edema, and hemorrhagic transformation may contribute to neurological injury before and after reperfusion.

The STOP strategy integrates four nonpharmacological neuroprotective interventions targeting complementary mechanisms. Participants assigned to the STOP group will receive transcutaneous auricular vagus nerve stimulation, protocolized temperature management, high-flow normobaric oxygen, and dynamic head positioning in addition to guideline-based reperfusion therapy and stroke-unit care. All trial interventions must be implemented without delaying intravenous thrombolysis, endovascular therapy, transfer, anesthesia, or other clinically indicated emergency treatment.

Transcutaneous auricular vagus nerve stimulation will be applied to the left auricular region innervated by the auricular branch of the vagus nerve. Recommended stimulation parameters are 0.5 mA current intensity, 25 Hz frequency, and 200 μs pulse width for 20 minutes every 12 hours for 5 days, for a planned total of 10 sessions. The first stimulation will be initiated as early as feasible after randomization and no later than 24 hours after completion of the final reperfusion treatment.

Protocolized temperature management will target a body temperature of 37.5 °C or lower through 72 hours after completion of the final reperfusion treatment. Antipyretic medication, physical cooling, cooling blankets, ice packs, infection assessment, and other clinically appropriate measures may be used when necessary.

High-flow normobaric oxygen will be initiated as early as possible, preferably before or at initiation of reperfusion treatment, without delaying reperfusion therapy. Non-intubated participants will receive oxygen at approximately 10 L/min through a reservoir mask or equivalent high-concentration oxygen delivery device. Intubated or mechanically ventilated participants will receive an inspired oxygen fraction of 1.0, with adjustment permitted for safety. Protocolized high-flow oxygen will continue for a total of 4 hours.

Head position will be dynamically adjusted according to reperfusion treatment and recanalization status. Participants receiving intravenous thrombolysis alone will initially be maintained in the 0° supine position when clinically feasible. Participants undergoing endovascular therapy will generally remain in the 0° supine position before completion of the procedure. After endovascular therapy, participants with successful reperfusion, defined as modified Thrombolysis in Cerebral Infarction grade 2b or higher, will be positioned with approximately 30° head elevation. In participants without successful reperfusion, a -20° Trendelenburg position may be used intermittently when clinically safe and tolerated. Positioning may be modified or discontinued for vomiting, aspiration risk, respiratory compromise, intracranial hemorrhage, cerebral edema, suspected intracranial hypertension, or other safety concerns.

Participants assigned to the control group will receive guideline-based reperfusion therapy and standard stroke-unit care. Clinically indicated oxygen therapy, antipyretic treatment, positioning changes, rescue therapy, and other necessary treatment will not be withheld.

Neurological status will be assessed at baseline, approximately 24 hours after randomization, and at Day 7 or hospital discharge, whichever occurs first. Follow-up CT or MRI will generally be obtained at 24 to 36 hours after reperfusion treatment and again between Day 3 and Day 7. Functional outcome will be assessed at Day 90 by a trained evaluator blinded to treatment allocation.

Among participants with anterior-circulation large-vessel occlusion who undergo endovascular therapy, those who provide additional informed consent may enter an embedded randomized substudy of selective intra-arterial cooling. Participants in the substudy will undergo an independent 1:1 randomization to selective intra-arterial cooling or no selective intra-arterial cooling. When a microcatheter can cross the occlusion, 50 mL of 4 °C isotonic saline will be infused at 10 mL/min before thrombectomy, followed by 300 mL at 30 mL/min after the thrombectomy procedure. If pre-reperfusion infusion cannot be performed, 350 mL may be infused at 30 mL/min after the endovascular procedure. The primary imaging outcome of the embedded substudy is final infarct volume assessed between Day 3 and Day 7 after reperfusion treatment, preferentially using the eligible scan closest to 72 hours.

Inclusion criteria

• Age 18 years or older.
• Clinical diagnosis of acute ischemic stroke.
• Baseline National Institutes of Health Stroke Scale score of 5 to 25.
• CTA, MRA, or DSA confirmation of an intracranial culprit arterial occlusion consistent with the presenting neurological deficit.
• Eligible for guideline-recommended reperfusion therapy and planned to receive, or already initiated, intravenous thrombolysis and/or endovascular therapy.
• Time from symptom onset or last known well to initiation of reperfusion therapy of 24 hours or less.
• Pre-stroke modified Rankin Scale score of 0 or 1.
• Written informed consent provided by the participant or an appropriate legally authorized representative.

Exclusion criteria

• Intracranial hemorrhage on baseline imaging.
• Established cerebral herniation, progressive severe cerebral edema, or an immediate requirement for decompressive surgery before enrollment.
• Severe hypoxemia, severe respiratory failure, or another clinical condition requiring continuous high-concentration oxygen therapy or specialized respiratory support that prevents implementation of the assigned oxygen protocol. Endotracheal intubation or mechanical ventilation alone is not an exclusion criterion.
• Severe hypotension, shock, or other clinically significant hemodynamic instability.
• Active persistent vomiting, inability to adequately protect the airway, severe respiratory distress, or another condition that makes protocolized 0° supine positioning unsafe.
• Clinically significant bradycardia, atrioventricular block, severe arrhythmia, or another condition considered by the investigator to make transcutaneous auricular vagus nerve stimulation inappropriate.
• Severe skin injury, infection, or another local condition at the auricular stimulation site that prevents transcutaneous auricular vagus nerve stimulation.
• Severe systemic infection, sepsis, or another serious acute illness likely to substantially affect short-term prognosis.
• Pregnancy or breastfeeding.
• Severe progressive or terminal disease with expected survival of less than 3 months.
• Current participation in another interventional clinical trial that may affect the assigned intervention or assessment of the primary outcome.
• Any other condition that, in the investigator's judgment, makes trial participation inappropriate.