Autonomic Neuromodulation by Transcutaneous Nerve Stimulation in Acute Ischaemic Stroke. (VANS)

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

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

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke; Autonomic Dysfunction; Thrombotic Stroke; Autonomic Imbalance
• Intervention / Treatment: Device: trans-cutaneous auricular sensory stimulation

Detailed Description

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:

1. Restore baroreflex sensitivity;
2. Increase blood flow to ischaemic brain tissue through vagal activation.(PMID:27357059)
3. Dampen cerebral/systemic inflammation.(PMID:26723020);
4. Reduce atrial fibrillation and myocardial injury,(PMIDs:5744003,22739118) which are common after stroke, and independently predict cognitive decline and cardiovascular mortality
5. 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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Priya Dias, PhD; Phone Number: +44 (0)20 3594 0349; Email: p.dias@qmul.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, EC1M 6BQ
    • William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Investigators: Principal Investigator: Gareth L Ackland, PhD FRCA, William Harvey Research Institute, Queen Mary University of London

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2023
• Primary Completion (Actual): July 21, 2023
• Study Completion (Actual): July 21, 2023

Study Registration Dates

• First Submitted: June 8, 2022
• First Submitted That Met QC Criteria: June 13, 2022
• First Posted (Actual): June 14, 2022

Study Record Updates

• Last Update Posted (Actual): August 7, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Primary Dysautonomias; Autonomic Nervous System Diseases; Thrombotic Stroke
• Other Study ID Numbers: 314067

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Researchers who provide a methodologically sound proposal approved by an independent review committee intermediary using deidentified data.
• IPD Sharing Time Frame: No end date.
• IPD Sharing Access Criteria: To achieve aims in approved proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No