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Noninvasive CA Monitoring Validation and Autonomic Modulation in Aneurysmal Subarachnoid Hemorrhage

4. mai 2026 oppdatert av: Noah Jouett, University of Texas Southwestern Medical Center

Non-Invasive Cerebral Autoregulation Monitoring Validation and Autonomic Modulation in Aneurysmal Subarachnoid Hemorrhage: A Two-Component Prospective Study of EVD Clamping Validation, CA Natural History, and the Effects of Cervical Sympathetic Block and Transcutaneous Auricular Vagal Nerve Stimulation on Cerebral Autoregulation Parameters

This is a two-component prospective study of adult aneurysmal subarachnoid hemorrhage (aSAH) patients admitted to the Neurosciences Intensive Care Unit (NSICU) at UT Southwestern Medical Center. Component 1 (active upon IRB approval) validates Brain4Care (B4C) extensometry-derived noninvasive cerebral autoregulation (CA) indices against invasive ICP-derived equivalents in aSAH patients with open external ventricular drains (EVDs), and characterizes the prospective natural history of multi-modal CA parameter evolution through the delayed cerebral ischemia (DCI) window (admission through Day 14). Component 2 (activated upon PI readiness declaration) assesses the within-subject effect of cervical sympathetic block (CSB) and transcutaneous auricular vagal nerve stimulation (taVNS) on CA parameters in enrolled aSAH patients.

Studieoversikt

Status

Har ikke rekruttert ennå

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) affects approximately 35,000 Americans annually and carries a 30-day mortality of approximately 40%. Delayed cerebral ischemia (DCI) - caused by vasospasm, microvascular dysfunction, and impaired cerebrovascular regulation - complicates 25-35% of survivors during the 4-14 day post-rupture window. Cerebral autoregulation (CA) impairment predicts DCI onset and poor neurological outcome. Standard ICP-based CA indices cannot be computed through an open EVD - present in approximately 50-75% of aSAH patients - because the transducer is exposed to ambient pressure. This technical barrier has precluded CA-guided management in the most common clinical aSAH scenario for over two decades.

The autonomic nervous system is a central, understudied regulator of CA in aSAH. Aneurysm rupture produces a massive catecholamine surge coinciding with the early window of CA impairment. We hypothesize that sympathetically-mediated cerebrovascular vasoconstriction contributes to CA failure, and that restoration of sympathovagal balance can shift CA parameters toward a more protective state.

TWO-COMPONENT DESIGN:

COMPONENT 1 - Validation and Natural History (activates immediately upon IRB approval):

A standardized 15-minute EVD clamping protocol (5-minute equilibration plus 10-minute simultaneous invasive/noninvasive CA recording; ICP abort threshold greater than 20 mmHg sustained for 5 or more minutes) is used to validate B4C-derived CA indices (nPRx, nCPPopt, nMx) against invasive ICP-derived equivalents by Bland-Altman analysis and intraclass correlation. NIRS-based MAPopt (TOxA, COx) is characterized as an EVD-independent CA metric. Longitudinal multi-modal CA monitoring proceeds through ICU Day 14 for all enrolled participants.

COMPONENT 2 - Autonomic Modulation (PI readiness-gated):

Within-subject before-after assessment of right-sided cervical sympathetic block (CSB; ultrasound-guided, C6 approach, low-volume ropivacaine) and transcutaneous auricular vagal nerve stimulation (taVNS; 25 Hz, 200-500 microamps, 200 microsecond pulse width via TENS 7000 to cymba conchae; 20-minute sessions twice daily for up to 14 days) on CPPopt, MAPopt, Mx, and CPPopt-MAP deviation. Activation requires documented PI readiness attestation co-signed by a qualified co-investigator or Department Director.

SAFETY (Component 2):

CSB: Continuous cardiac monitoring; pre-procedure coagulation screening (INR 1.5 or less, platelets 50,000/uL or greater within 24 hours); real-time ultrasound guidance. Expected transient ipsilateral Horner syndrome lasting 2-6 hours. Serious adverse event rate less than 0.1% with low-volume technique.

taVNS: Continuous cardiac telemetry; immediate device removal for HR below 50 bpm. Parameters consistent with NAVSaH trial and published taVNS literature.

SIGNIFICANCE: Each aim is independently executable and generates independently publishable results. A positive Component 2 result directly motivates an NIH R01 for a powered randomized trial. A null result establishes the first causal evidence regarding non-modifiability of CPPopt by autonomic intervention, reorienting the field. The study cannot produce a non-informative result.

Studietype

Intervensjonell

Registrering (Antatt)

300

Fase

  • Ikke aktuelt

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiekontakt

Studiesteder

  • Forente stater
    • Texas
      • Dallas, Texas, Forente stater, 75390
        • UT Southwestern Medical Center - Clements University Hospital NSICU
        • Hovedetterforsker:
          • Noah Jouett, DO, PhD
        • Ta kontakt med:
        • Underetterforsker:
          • Ulrike Hoffmann, MD, PhD
        • Underetterforsker:
          • DaiWai Olson, PhD, RN

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

  • Voksen
  • Eldre voksen

Tar imot friske frivillige

Nei

Beskrivelse

Inclusion Criteria (Component 1 - All Enrolled Participants):

  • Age 18 years or older
  • Primary diagnosis of aneurysmal subarachnoid hemorrhage (aSAH), confirmed by imaging
  • Admitted to the NSICU at Clements University Hospital, UT Southwestern Medical Center
  • Informed consent obtained from subject or legally authorized representative (as defined under Texas Health and Safety Code Section 166.039)
  • Brain4Care extensometry sensor placeable at an appropriate cranial site not occluded by surgical dressings or EVD hardware
  • Open EVD with active continuous ICP monitoring (required for EVD clamping sub-protocol only; not required for Aims 2 or 3)

Exclusion Criteria (Component 1):

  • Age younger than 18 years
  • Prisoner status
  • Primary NSICU admission diagnosis other than aSAH
  • Active declination by subject or legally authorized representative
  • Brain4Care sensor not placeable at any accessible cranial site
  • Active clinical deterioration making research monitoring impractical at time of approach
  • Physician-of-record declining research enrollment for clinical reasons
  • Inability to provide informed consent in English
  • Known pregnancy at time of enrollment

Additional Inclusion Criteria for Component 2 (Aim 3 - CSB and taVNS):

  • At least one successful EVD clamping session completed
  • PI documentation of Component 2 operational readiness, co-signed by qualified co-investigator or Department Director
  • INR 1.5 or less and platelet count 50,000/uL or greater within 24 hours prior to each CSB procedure
  • No active infection or cellulitis at right anterolateral neck
  • No known allergy to ropivacaine or amide local anesthetics
  • No contralateral phrenic nerve palsy or severe pre-existing respiratory compromise
  • No cardiac pacemaker or implanted cardiac device contraindicating taVNS
  • No allergy to electrode adhesive materials
  • Continuous cardiac telemetry active and interpretable
  • Resting HR 60 bpm or greater on two readings within 24 hours prior to session
  • No current use of Class I or III antiarrhythmic medications
  • No clinically significant AV conduction abnormality

Additional Exclusion Criteria for Component 2:

  • Prior ipsilateral right-sided cervical surgery, radiation, or known anatomical distortion precluding safe C6 approach
  • Hemodynamic instability with active vasopressor escalation at time of planned CSB
  • Active uncontrolled tachyarrhythmia or bradyarrhythmia at time of taVNS session
  • Physician-of-record declining autonomic modulation procedures for any clinical reason
  • Known or suspected pregnancy

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Grunnvitenskap
  • Tildeling: Ikke-randomisert
  • Intervensjonsmodell: Sekvensiell tildeling
  • Masking: Ingen (Open Label)

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Ingen inngripen: Component 1: CA Monitoring and EVD Clamping Validation
All enrolled aSAH patients. Multimodal CA monitoring (B4C extensometry, NIRS-derived indices, invasive ICP/CPP from EVD where present) throughout ICU Days 1-14. Participants with open EVDs additionally undergo a standardized 15-minute EVD clamping sub-protocol for simultaneous invasive/noninvasive CA index validation, up to one session per 24-hour period. No interventional procedures administered under Component 1.
Eksperimentell: Component 2: Autonomic Modulation (CSB and taVNS)
Component 1 participants meeting Component 2 eligibility criteria after PI readiness declaration. Receive right-sided cervical sympathetic block (CSB; ultrasound-guided, C6) and transcutaneous auricular vagal nerve stimulation (taVNS; cymba conchae, TENS 7000; twice daily 20-minute sessions for up to 14 days). Within-subject before-after assessment of CA parameter effects. CA monitoring from Component 1 continues throughout.
Fremgangsmåte: Right-Sided Cervical Sympathetic Block at C6
Ultrasound-guided right-sided cervical sympathetic block targeting pre-ganglionic cervical sympathetic fibers at the C6 level using low-volume ropivacaine. Real-time ultrasound guidance with aspiration prior to injection. Continuous cardiac monitoring throughout. Coagulation parameters confirmed within 24 hours of each procedure. Expected transient ipsilateral Horner syndrome lasting 2-6 hours.
Andre navn:
  • Stellate Ganglion Block
  • Cervical Sympatholysis
Enhet: Transcutaneous Auricular Vagal Nerve Stimulation (taVNS)
Noninvasive vagal augmentation delivered via electrode placed at the cymba conchae of the right ear using the TENS 7000 device. Parameters: 25 Hz, 200-500 microamps, 200 microsecond pulse width; 20-minute sessions twice daily for up to 14 days (maximum 28 sessions). Continuous cardiac telemetry required; immediate device removal if HR falls below 50 bpm. Intensity set below pain threshold based on participant comfort feedback.
Andre navn:
  • Aurikulær vagusnervestimulering
  • TENS 7000

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Bland-Altman agreement between Brain4Care-derived noninvasive pressure reactivity index (nPRx) and invasive ICP-derived PRx during EVD clamping (Aim 1a)
Tidsramme: During each standardized 15-minute EVD clamping session, up to one session per 24-hour period over ICU Days 1-14
Bland-Altman limits of agreement and intraclass correlation coefficient between Brain4Care (B4C)-derived noninvasive pressure reactivity index (nPRx; unitless, range -1 to +1) and simultaneously acquired invasive ICP-derived PRx during standardized 15-minute EVD clamping sessions. Sessions aborted if ICP exceeds 20 mmHg sustained for 5 or more minutes. Target: 30-50 clamping sessions for Bland-Altman precision.
During each standardized 15-minute EVD clamping session, up to one session per 24-hour period over ICU Days 1-14
Bland-Altman agreement between Brain4Care-derived noninvasive optimal cerebral perfusion pressure (nCPPopt) and invasive ICP-derived CPPopt during EVD clamping (Aim 1b)
Tidsramme: During each standardized 15-minute EVD clamping session, up to one session per 24-hour period over ICU Days 1-14
Bland-Altman limits of agreement and intraclass correlation coefficient between Brain4Care (B4C)-derived noninvasive optimal cerebral perfusion pressure (nCPPopt; reported in mmHg) and simultaneously acquired invasive ICP-derived CPPopt during standardized 15-minute EVD clamping sessions. Sessions aborted if ICP exceeds 20 mmHg sustained for 5 or more minutes. Target: 30-50 clamping sessions for Bland-Altman precision.
During each standardized 15-minute EVD clamping session, up to one session per 24-hour period over ICU Days 1-14
Invasive ICP-derived optimal cerebral perfusion pressure (CPPopt) trajectory through the DCI window in aSAH (Aim 2a)
Tidsramme: ICU admission through Day 14 post-rupture
Prospective characterization of invasive ICP-derived optimal cerebral perfusion pressure (CPPopt; reported in mmHg) trajectory from ICU admission through Day 14 in aSAH patients. Temporal correlation of CPPopt trajectory with DCI onset (clinical and imaging-confirmed) and neurological outcome at discharge, reported as Spearman correlation coefficients.
ICU admission through Day 14 post-rupture
NIRS-derived cerebral oximetry index (COx) trajectory through the DCI window in aSAH (Aim 2b)
Tidsramme: ICU admission through Day 14 post-rupture
Prospective characterization of near-infrared spectroscopy (NIRS)-derived cerebral oximetry index (COx; unitless, range -1 to +1) trajectory from ICU admission through Day 14 in aSAH patients. Temporal correlation of COx trajectory with DCI onset (clinical and imaging-confirmed) and neurological outcome at discharge, reported as Spearman correlation coefficients.
ICU admission through Day 14 post-rupture
Change in invasive ICP-derived optimal cerebral perfusion pressure (CPPopt) before versus after cervical sympathetic block and taVNS (Aim 3a)
Tidsramme: 60 minutes before through 60 minutes after each intervention session
Within-subject paired change in invasive ICP-derived optimal cerebral perfusion pressure (CPPopt; reported in mmHg) comparing a 60-minute pre-intervention monitoring epoch with a 60-minute post-intervention monitoring epoch. Assessed separately for CSB and taVNS. Target: 20-30 paired sessions per intervention for 80% power to detect a shift of 5 mmHg or greater at alpha=0.05 two-sided.
60 minutes before through 60 minutes after each intervention session
Change in NIRS-derived optimal mean arterial pressure (MAPopt) before versus after cervical sympathetic block and taVNS (Aim 3b)
Tidsramme: 60 minutes before through 60 minutes after each intervention session
Within-subject paired change in near-infrared spectroscopy (NIRS)-derived optimal mean arterial pressure (MAPopt; reported in mmHg) comparing a 60-minute pre-intervention monitoring epoch with a 60-minute post-intervention monitoring epoch. Assessed separately for CSB and taVNS. Target: 20-30 paired sessions per intervention for 80% power to detect a shift of 5 mmHg or greater at alpha=0.05 two-sided.
60 minutes before through 60 minutes after each intervention session

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Proportion of monitoring sessions with computable NIRS-derived optimal mean arterial pressure (MAPopt)
Tidsramme: Through ICU Day 14
Percentage of monitoring sessions with computable near-infrared spectroscopy (NIRS)-derived optimal mean arterial pressure (MAPopt), reported as a single proportion. Characterization across EVD-present and EVD-absent aSAH subgroups.
Through ICU Day 14
Bland-Altman agreement between NIRS-derived and Brain4Care-derived optimal mean arterial pressure (MAPopt)
Tidsramme: Through ICU Day 14
Bland-Altman limits of agreement (reported in mmHg) between near-infrared spectroscopy (NIRS)-derived optimal mean arterial pressure (MAPopt) and Brain4Care (B4C) extensometry-derived MAPopt. Characterization across EVD-present and EVD-absent aSAH subgroups.
Through ICU Day 14
Incidence and severity of adverse events (CTCAE grade) related to cervical sympathetic block and taVNS procedures
Tidsramme: During and up to 24 hours after each intervention session
Incidence and characterization of adverse events attributable to CSB (Horner syndrome duration and resolution, local anesthetic systemic toxicity, hematoma, hoarseness, hemodynamic effects) and taVNS (bradycardia, auricular skin irritation, stimulation discomfort). All events classified by Common Terminology Criteria for Adverse Events (CTCAE) grade and reported as incidence per intervention session.
During and up to 24 hours after each intervention session
Change in root mean square of successive R-R interval differences (RMSSD) from continuous ECG before versus after autonomic modulation
Tidsramme: 60 minutes before through 60 minutes after each Component 2 intervention session
Within-subject paired change in RMSSD (reported in milliseconds) derived from continuous ECG monitoring, comparing 60-minute pre-intervention and 60-minute post-intervention epochs for each CSB and taVNS session. RMSSD serves as the primary heart rate variability metric reflecting parasympathetic (vagal) tone. Additional HRV indices (SDNN, LF/HF ratio) reported descriptively as secondary exploratory analyses using the same pre-post epoch comparison.
60 minutes before through 60 minutes after each Component 2 intervention session
Functional status at 90 days assessed by modified Rankin Scale via medical record review
Tidsramme: 90 days post-hospital discharge
Functional and neurological status assessed by modified Rankin Scale (mRS) score via medical record review and/or structured contact at 90 days. Reported as ordinal mRS score (0-6). Correlation with CA index features during the DCI window reported as Spearman correlation coefficients.
90 days post-hospital discharge

Samarbeidspartnere og etterforskere

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Sponsor

University of Texas Southwestern Medical Center

Etterforskere

  • Hovedetterforsker: Noah Jouett, DO, PhD, University of Texas Southwestern Medical Center

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Antatt)

1. juli 2026

Primær fullføring (Antatt)

1. juni 2029

Studiet fullført (Antatt)

1. juni 2030

Datoer for studieregistrering

Først innsendt

18. april 2026

Først innsendt som oppfylte QC-kriteriene

4. mai 2026

Først lagt ut (Faktiske)

11. mai 2026

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

11. mai 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

4. mai 2026

Sist bekreftet

1. april 2026

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • STU20260829

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Nei

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