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.
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.
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.
Parallel
Stimulation-Temperature-Oxygen-Positioning (STOP) Multimodal Neuroprotective Strategy
Other interventionThe 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.
Guideline-Based Reperfusion Therapy and Standard Stroke-Unit Care
Other interventionParticipants 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.
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.
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.
All-cause mortality at 90 days
Proportion of participants who have died from any cause.
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.
Hemorrhagic transformation
Proportion of participants with any intracranial hemorrhage or hemorrhagic transformation classified according to the Heidelberg Bleeding Classification by the blinded central imaging core laboratory.
Symptomatic intracranial hemorrhage
Proportion of participants with symptomatic intracranial hemorrhage according to the Heidelberg Bleeding Classification, adjudicated using clinical deterioration and follow-up imaging.
Participants with any adverse event
Proportion of participants experiencing at least one adverse event after randomization. Events will be assessed for seriousness, severity, expectedness, and relationship to study intervention.
Participants with any serious adverse event
Proportion of participants experiencing at least one serious adverse event after randomization.
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