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.

TaVNS will be initiated as early as practicable after randomization and may begin before, during, or after reperfusion treatment. The first stimulation session must begin no later than 24 hours after completion of the final reperfusion treatment. Stimulation will be applied to the left auricular region corresponding to the auricular branch of the vagus nerve, using a current intensity of 0.5 mA, frequency of 25 Hz, and pulse width of 200 μs for 20 minutes every 12 hours for five days, with 10 sessions planned. These parameters are based on the NUVISTA regimen. Heart rate, blood pressure, treatment tolerance, and auricular skin condition will be assessed around each session. Symptomatic bradycardia, clinically significant arrhythmia, substantial hemodynamic instability, or clinically relevant local skin injury will prompt interruption or discontinuation of the affected session. Start time, duration, delivered parameters, interruptions, and reasons for discontinuation will be recorded. Hospital discharge or transfer will not be delayed solely to complete the stimulation course; any uncompleted sessions will be documented as reduced treatment exposure rather than protocol withdrawal.

Protocolized temperature management will begin promptly after randomization and continue until 72 hours after completion of the final reperfusion treatment. The target body temperature is ≤37.5°C. For participants treated with IVT alone, the 72-hour period will be anchored to completion of thrombolytic administration; for participants undergoing direct EVT or bridging therapy, it will be anchored to completion of the EVT procedure. Body temperature will be measured at least every 4 hours during the intervention period, with additional measurements when clinically indicated. The measurement site and method will be recorded and, whenever feasible, kept consistent within an individual participant. A temperature >37.5°C will trigger prompt evaluation for infection and other causes of fever and protocol-directed temperature-lowering treatment using antipyretic medication, physical cooling, or both, according to clinical circumstances. Repeated or additional cooling measures may be used when temperature remains above the target. Temperature measurements, interventions, and subsequent response will be recorded. Induction of systemic therapeutic hypothermia is not part of the STOP strategy.

Normobaric oxygen therapy will begin as early as practicable after randomization, preferably before or at initiation of reperfusion treatment, without delaying standard treatment. Nonintubated participants will receive oxygen through a high-concentration reservoir mask at a flow rate of 10 L/min. Participants who are intubated or mechanically ventilated will receive an inspired oxygen fraction of 1.0. Oxygen therapy will continue for four hours from initiation, irrespective of the final reperfusion grade. Peripheral oxygen saturation and respiratory status will be monitored throughout treatment, with oxygen saturation maintained at ≥94%. Clinically significant carbon dioxide retention, worsening respiratory status, or substantial intolerance will prompt adjustment or discontinuation as clinically indicated. Oxygen-delivery device, flow rate, ventilator settings when applicable, start and stop times, and treatment interruptions will be recorded.

Positioning will be adapted to the reperfusion pathway and, for participants undergoing EVT, to the final degree of reperfusion. Participants treated with IVT without subsequent EVT will be maintained in a 0° supine position for 24 hours after completion of thrombolysis. Participants undergoing EVT, including those receiving bridging therapy, will be maintained in a 0° supine position while awaiting thrombectomy and during transfer when feasible. After EVT, participants with successful reperfusion, defined as modified Thrombolysis in Cerebral Infarction (mTICI) grade ≥2b, will be positioned with approximately 30° head elevation for the subsequent 24 hours, whereas those with mTICI <2b will be placed at approximately -20° Trendelenburg position for the subsequent 24 hours when clinically safe and tolerated. For participants managed in a flat or head-down position, development of symptomatic intracranial hemorrhage (sICH), parenchymal hematoma (PH), progressive cerebral edema or raised intracranial pressure, vomiting or aspiration, clinically important respiratory compromise, or another safety concern will prompt discontinuation of the prescribed position and elevation to approximately 30° or another clinically appropriate position. Brief interruptions for feeding, nursing care, diagnostic procedures, rehabilitation, or other necessary clinical activities are permitted. Actual head position, cumulative exposure time, interruptions, and reasons for protocol-directed modification will be recorded.

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.

Among participants with anterior-circulation large-vessel occlusion treated with endovascular therapy, those who achieve successful reperfusion (final mTICI grade 2b-3) and meet the substudy safety criteria may undergo a second centrally concealed 1:1 randomization, stratified by the main-trial STOP assignment, to selective intra-arterial hypothermia or no additional intra-arterial infusion. Participants with vessel perforation, contrast extravasation, definite or strongly suspected procedural intracranial hemorrhage, another serious interventional complication, or another condition considered by the treating interventionist to make additional intra-arterial infusion unsafe will not undergo the second randomization. Additional informed consent may be obtained before EVT on a conditional basis, but eligibility will be reassessed and randomization performed only after EVT has been completed and successful reperfusion confirmed. Participants assigned to hypothermia will receive 300 mL of 0.9% saline at 4 °C through a guiding or intermediate catheter supplying the reperfused vascular territory, infused at 30 mL/min for 10 minutes as soon as practicable after successful reperfusion. Participants assigned to the control group will receive no additional intra-arterial saline infusion. No pre-reperfusion cooling bolus or additional fallback infusion is planned.