Acute ischemic stroke may result in substantial disability despite timely reperfusion therapy because ischemic and reperfusion-related brain injury can continue before, during, and after restoration of blood flow. This investigator-initiated, prospective, multicenter, randomized, open-label, blinded-endpoint trial will evaluate whether a protocolized Stimulation-Temperature-Oxygen-Positioning (STOP) multimodal neuroprotective strategy added to guideline-based reperfusion therapy and stroke-unit care improves 90-day functional outcome compared with standard care alone. A total of 380 adults with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular therapy within 24 hours of symptom onset or last known well will be randomized in a 1:1 ratio to the STOP strategy plus standard care or standard care alone. The STOP strategy comprises transcutaneous auricular vagus nerve stimulation, protocolized normothermia targeting a body temperature of 37.5 °C or lower, high-flow normobaric oxygen, and dynamic head positioning according to reperfusion treatment and recanalization status. The primary outcome is the ordinal distribution of modified Rankin Scale scores at 90 days after randomization. Blinded assessors will evaluate functional outcomes, and a blinded central imaging core laboratory will adjudicate imaging outcomes. Among participants with anterior-circulation large-vessel occlusion who undergo endovascular therapy, eligible and consenting participants may additionally enter an embedded randomized substudy evaluating selective intra-arterial infusion of 4 °C isotonic saline during thrombectomy.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
380
The STOP strategy comprises four protocolized nonpharmacological interventions added to guideline-based reperfusion therapy and stroke-unit care: (1) taVNS to the left auricular vagus nerve region (0.5 mA, 25 Hz, 200 μs, 20 min every 12 h for 5 days; first session as early as feasible and within 24 h after final reperfusion treatment); (2) temperature management targeting body temperature ≤37.5 °C through 72 h after final reperfusion treatment; (3) high-flow normobaric oxygen initiated as early as possible, preferably before or at reperfusion treatment, at 10 L/min by reservoir mask in non-intubated patients or FiO2 1.0 in intubated patients, for 4 h; and (4) dynamic head positioning: 0° before reperfusion, 30° after mTICI ≥2b, and intermittent -20° Trendelenburg if mTICI \<2b when safe and tolerated. Components may be modified or stopped for safety and must not delay reperfusion therapy.
Participants receive guideline-based reperfusion therapy, including intravenous thrombolysis and/or endovascular therapy when clinically indicated, together with standard stroke-unit care according to contemporary national and institutional guidelines. Standard care may include physiological monitoring and management, antithrombotic and lipid-lowering therapy, management of cerebral edema, dysphagia and aspiration precautions, venous thromboembolism prevention, rehabilitation, clinically indicated oxygen therapy, antipyretic treatment, positioning adjustments, and other rescue treatments. Clinically necessary treatment will not be withheld because of trial participation.
Distribution of disability across the modified Rankin Scale at 90 days
The modified Rankin Scale (mRS) is a 7-category global disability scale ranging from 0 (no symptoms) to 6 (death); lower scores indicate better functional status. The full ordinal distribution will be assessed by a trained evaluator blinded to treatment allocation.
Time frame: Day 90 after randomization
Functional independence at 90 days
Proportion of participants with an mRS score of 0-2. The mRS ranges from 0 (no symptoms) to 6 (death); lower scores indicate better functional status.
Time frame: Day 90 after randomization
Excellent functional outcome at 90 days
Proportion of participants with an mRS score of 0-1. The mRS ranges from 0 (no symptoms) to 6 (death); lower scores indicate better functional status.
Time frame: Day 90 after randomization
All-cause mortality at 90 days
Proportion of participants who have died from any cause.
Time frame: Day 90 after randomization
Change in National Institutes of Health Stroke Scale score from baseline to 24 hours
Change calculated as the 24-hour National Institutes of Health Stroke Scale (NIHSS) score minus the baseline score. The NIHSS ranges from 0 to 42; higher scores indicate greater neurological deficit, so a negative change indicates improvement.
Time frame: Baseline and 24 hours after randomization
Change in National Institutes of Health Stroke Scale score from baseline to day 7 or discharge
Change calculated as the day-7/discharge NIHSS score minus the baseline score. The NIHSS ranges from 0 to 42; higher scores indicate greater neurological deficit, so a negative change indicates improvement.
Time frame: Baseline and Day 7 after randomization or hospital discharge, whichever occurs first
Early neurological improvement at 24 hours
Proportion of participants with a decrease of at least 4 points in NIHSS score from baseline or an NIHSS score of 0-1 at 24 hours. The NIHSS ranges from 0 to 42; lower scores indicate less neurological deficit.
Time frame: 24 hours after randomization
Early neurological deterioration at 24 hours
Proportion of participants with an increase of at least 4 points in NIHSS score from baseline that is not attributable to sedation. The NIHSS ranges from 0 to 42; higher scores indicate greater neurological deficit.
Time frame: 24 hours after randomization
Successful reperfusion at the end of endovascular thrombectomy
Proportion of participants with final modified Thrombolysis in Cerebral Infarction (mTICI) grade 2b, 2c, or 3, adjudicated from the final angiographic run. The mTICI scale ranges from 0 (no perfusion) to 3 (complete perfusion); higher grades indicate better reperfusion.
Time frame: 24 hours after randomization
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