Autonomic Neuromodulation by Transcutaneous Nerve Stimulation in Acute Ischaemic Stroke.

Study Overview
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Brief Summary
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Autonomic modulation by transcutaneous vagal nerve stimulation in acute ischaemic stroke requiring mechanical thrombectomy: a phase IIa, sham controlled randomised trial.

Detailed Description
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Loss of autonomic variability is strongly associated with adverse outcomes after ischaemic stroke. Removing blood clots from the brain by mechanical thrombectomy has revolutionised the management of stroke, but more than 50% of patients do not regain functional independence.(PMID:26898852) Blood pressure (BP) control is important, since low and high BP (BP variability) are strongly associated with poor patient outcomes after thrombectomy. (PMIDs:32961389;31964286) Autonomic dysfunction causes labile blood pressure. Intact autonomic function is required to control blood pressure and potentially improve recovery after stroke. Impairment of baroreflex autonomic function, due to reduced vagal activity is associated with extreme BP variability, leading to further brain injury and cardiovascular complications.(PMID:30371208) Reduced baroreflex control is related to poor patient outcomes after stroke, independent of absolute blood pressure.(PMID:19834010) Reversing baroreflex and vagal dysfunction is, therefore, widely held to have the potential to improve cardiovascular control and patient outcome in this context.(PMID:19834010) Non-invasive peripheral neuromodulation restores autonomic control. Vagal nerve stimulation improves autonomic control and reverses baroreflex dysfunction (PMIDs:28949064) but this has previously required surgically implanted devices which are expensive and impractical in the context of acute stroke. Afferent Electronic have achieved the same effect as these implantable devices by non-invasive transcutaneous autonomic neuromodulation (TAN). We have used this simple, safe, hand-held, low-cost device to increase vagal activity and baroreflex sensitivity through non-invasive, painless stimulation of nerves located in the outer ear to control blood pressure. Baroreflex sensitivity can be increased at the bedside by TAN for 30 minutes following acute trauma. If this can be replicated in thrombectomy patients, it will aid recovery and rehabilitation through five complementary mechanisms where it has been clinically demonstrated that increasing vagal nerve activity: Restore baroreflex sensitivity; Increase blood flow to ischaemic brain tissue through vagal activation.(PMID:27357059) Dampen cerebral/systemic inflammation.(PMID:26723020); Reduce atrial fibrillation and myocardial injury,(PMIDs:5744003,22739118) which are common after stroke, and independently predict cognitive decline and cardiovascular mortality Allows immediate commencement of vagal nerve stimulation, which has recently been shown to enhance upper-limb rehabilitation.(PMID:33894832) Our proof-of-concept data shows daily TAN reduces BP and BP variability lasting several months even in drug-resistant hypertensive patients. In this proof-of-concept randomised sham-controlled trial, we will examine whether early TAN on presentation for mechanical thrombectomy improves autonomic function in patients with acute ischaemic stroke by reducing blood pressure lability.

Official Title
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Vagal Autonomic Neuromodulation by Transcutaneous Nerve Stimulation in Acute Ischaemic Stroke Requiring Mechanical Thrombectomy.

Conditions
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Ischemic Stroke, Thrombotic Stroke, Autonomic Dysfunction, Autonomic Imbalance

Intervention / Treatment
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* Device: trans-cutaneous auricular sensory stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Undergoing mechanical thrombectomy for acute ischaemic stroke requiring general or sedation. Established hypertensive and/or hypertensive on admission for mechanical thrombectomy [systolic BP >140mmHg; diastolic BP >80mmHg] Exclusion Criteria: Current participation in a clinical trial of a treatment with a similar biological mechanism. Previous enrolment into VANS trial. Anatomical or other contraindication to trans-cutaneous auricular sensory stimulation Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: RCT
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stimulation<br>Electrodes attached bliaterally to tragus nerve region of outer ear, with appropriate device settings to deliver current. | Device: trans-cutaneous auricular sensory stimulation<br>* Transcutaneous auricular sensory stimulation<br>|
| Sham Comparator: Electrode attachment only.<br>Electrodes attached bliaterally to tragus nerve region of outer ear, with device switched off [blinded to operator]. | Device: trans-cutaneous auricular sensory stimulation<br>* Transcutaneous auricular sensory stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure variability | Coefficient of variation of systolic blood pressure | 0-24h after mechanical thrombectomy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systolic and diastolic blood pressure variability in the first 24h after mechanical thrombectomy | Systolic and diastolic blood pressure standard deviation, average real variability, successive variation and residual standard deviation | 0-24h after mechanical thrombectomy | 
| Heart rate variability | Time and frequency domain measures of autonomic cardiac modulation | 0-24h after mechanical thrombectomy | 
| NIH Stroke Scale (NIHSS) | FDA-approved primary outcome measure for stroke in early phase II trials. | recorded before, at 24h and 7 days after mechanical thrombectomy | 
| Organ dysfunction | Clinical need for intravenous pharmacological support for blood pressure [pressors or intravenous antihypertensive medication]; arrythmias; myocardial injury [high sensitivity troponin]; hospital-acquired infection. | First seven days after mechanical thrombectomy. |