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TRIVASOSTIM

Evaluation of External Trigeminal Nerve Stimulation to Prevent Cerebral Vasospasm after Subarachnoid Hemorrhage Due to Aneurysmal Rupture: A Randomized, Double-Blind Proof-of-Concept Pilot Trial (TRIVASOSTIM Study)

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Year of Publication: 2023

Authors: Philippe Rigoard, Maxime Billot, Maarten Moens, ..., Konstantin V. Slavin

Journal: International Journal of Environmental Research and Public Health

Citation: Int. J. Environ. Res. Public Health 2023, 20, 5836

Link: https://doi.org/10.3390/ijerph20105836

PDF: https://www.researchgate.net/publication...saWNhdGlvbiJ9fQ

Clinical Question

Does external transcutaneous trigeminal nerve stimulation (TNS) decrease the incidence of cerebral infarction related to vasospasm in patients with aneurysmal subarachnoid hemorrhage compared to sham stimulation when assessed by MRI at 3 months?

Bottom Line

In this single-center, double-blind, randomized pilot trial of 60 patients with aneurysmal SAH, 10 days of transcutaneous trigeminal nerve stimulation did not significantly reduce the rate of vasospasm-related cerebral infarction at 3 months compared to sham stimulation (23% vs 27%, p=0.99). No significant differences were observed in functional outcomes, quality of life, or mortality at 6 months. While the pathophysiological rationale based on animal studies and the trigeminovascular system's role in cerebral blood flow regulation was compelling, this proof-of-concept pilot trial was unable to demonstrate that TNS can decrease cerebral infarction secondary to vasospasm. The negative results may be attributed to maintaining stimulation intensity below the paresthesia threshold to preserve double-blinding, potentially underestimating a dose-effect relationship. It would be premature to promote trigeminal system neurostimulation in this context, and further research is needed before clinical application can be recommended.

Major Points

  • Single-center, double-blind, randomized controlled pilot trial with 1:1 randomization
  • 60 patients with aneurysmal SAH enrolled from single French institution (Poitiers University Hospital)
  • 264 patients screened, 111 met inclusion criteria, 60 enrolled, 89 analyzed (1 withdrew consent before intervention)
  • Inclusion criteria: age 18-75 years, aSAH within 48 hours, WFNS grade 1-4, Fisher grade 3-4, aneurysm secured with coiling/surgery
  • 30 patients randomized to active TNS, 30 to sham stimulation
  • Intervention: bilateral transcutaneous electrical stimulation of supratrochlear and supraorbital nerves (ophthalmic division of trigeminal nerve)
  • Stimulation parameters: 20 Hz frequency, intensity adjusted to sub-paresthesia threshold to maintain blinding
  • Non-sedated patients: mean intensity 9.6±2.7 mA (TNS) vs 11.4±1.5 mA (sham), p=0.16
  • Sedated patients: mean intensity 4.9±2.9 mA (TNS) vs 4.3±2.2 mA (sham), p=0.49
  • Treatment duration: 10 days continuous stimulation (days 1-10 after SAH), mean 9.5 days TNS vs 9.9 days sham (p=0.2)
  • Primary endpoint: cerebral infarction on MRI FLAIR at 3 months (or last CT/MRI before death)
  • Primary outcome negative: 23% (7/30) TNS vs 27% (8/30) sham, p=0.99
  • Late infarction (not observed at D6): 10% (3/30) TNS vs 20% (6/30) sham, p=0.47
  • Modified Rankin Scale ≥3 at 6 months: 10% TNS vs 3% sham, p=0.65
  • Glasgow Outcome Scale moderate disability at 6 months: 18% TNS vs 27% sham, p=0.53
  • EQ5D-3L quality of life index at 6 months: 0.79±0.23 TNS vs 0.79±0.22 sham, p=0.99
  • Mortality at 6 months: 7% (2/30) TNS vs 0% sham
  • Perfusion CT abnormality at D6: 40% (12/30) TNS vs 17% (5/30) sham, p=0.084 (trend but not significant)
  • Vasospasm on CT angiography at D6: 47% (14/30) TNS vs 33% (10/30) sham, p=0.43
  • Moderate-severe vasospasm: TNS 43% (13/30) vs sham 27% (8/30)
  • 50% (7/14) of TNS patients and 80% (8/10) of sham patients with vasospasm were asymptomatic
  • No significant differences in secondary complications, serious adverse events, or safety parameters
  • Hydrocephalus occurred in 33% TNS vs 30% sham patients during hospitalization
  • Strong correlation found between vasospasm severity and PCT abnormalities (p<0.0001)
  • 100% of severe vasospasm patients had PCT abnormalities, 53.8% of moderate vasospasm, 5.1% of no/mild vasospasm
  • Significant relationship between WFNS grade and vasospasm occurrence (p=0.016)
  • Study hypothesis based on trigeminovascular system pathophysiology and vasodilator peptide (CGRP) release
  • Stimulation maintained below paresthesia threshold to preserve double-blinding may have limited efficacy

Design

Study Type: Single-center, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept pilot trial

Randomization: 1

Blinding: Double-blind. Randomization performed by specially assigned nurses not involved in patient care using computer-generated allocation list. Research pharmacy prepared blinded trial medication/devices. Patients, treating physicians, outcome assessors blinded. Sham device identical in appearance and displayed current intensity but delivered no electrical stimulation. Three patients unblinded during study: 1 large EVD hematoma (placebo), 1 asymptomatic thrombocytopenia (TNS), 1 femoral artery dissection (placebo)

Enrollment Period: February 2019 to July 2020

Follow-up Duration: 6 months

Centers: 1

Countries: France

Sample Size: 60

Analysis: Intention-to-treat (ITT) analysis on 89 patients (60 randomized, 1 withdrew consent before intervention excluded). Sample size: minimum 30 patients per group (60 total) to detect 30% estimated difference (65% vs 35%) with 80% power using one-tailed Fisher test at 5% risk. Primary endpoint compared using Fisher's exact test. Quantitative outcomes compared using Student's t-test (parametric) or Wilcoxon-Mann-Whitney test (non-parametric) after Shapiro-Wilk normality testing. Qualitative outcomes analyzed using chi-squared or Fisher's exact test. All tests performed at α=5%. Independent DSMB reviewed trial regularly. Statistical analysis performed using SAS version 9.4. Analysis performed by blinded biostatistician and epidemiologist. No interim analysis. No stratification for baseline characteristics

Inclusion Criteria

  • Age 18-75 years
  • Admitted within 48 hours after onset of SAH
  • Ruptured cerebral aneurysm confirmed by CTA or cerebral angiography
  • No progressive psychosis or serious psychotic history requiring hospitalization
  • No progressive cancerous pathology
  • Candidate for aneurysm management by endovascular occlusion or microsurgical exclusion
  • WFNS grade I-IV (1-4) after correction of electrolytes and hydrocephalus
  • Modified Fisher grade 3 or 4
  • Affiliated with health insurance plan
  • Patient or trusted person able to understand and accept study constraints
  • Written informed consent from patient or legally authorized representative

Exclusion Criteria

  • Receiving reinforced protection (minors, pregnant/breastfeeding women, persons deprived of liberty, persons in health/social institutions, adults under legal protection)
  • Proven dementia or neurological/psychiatric history affecting cognitive or motor skills
  • Clinical severity WFNS grade V (very high mortality risk)
  • Intracerebral or intraventricular hemorrhage without subarachnoid component
  • SAH without evidence of aneurysm
  • Unruptured brain aneurysm
  • Contraindication for TENS device placement (electronic pacemaker)
  • Dermatological problems in stimulation area contraindicating TENS patches
  • Previous subarachnoid hemorrhage
  • Age >75 years (one 79-year-old patient included as protocol deviation)

Baseline Characteristics

CharacteristicTNS GroupSham Group
Number3030
Mean age (range), years55.3 ± 9.3 (36-73)59.6 ± 11.5 (27-79)
Female22 (73%)17 (57%)
Male8 (27%)13 (43%)
Height, m165.4 ± 9.5 (145-180)168.8 ± 7.7 (153-185)
Weight, kg72.0 ± 19.8 (45-130)68.8 ± 11.8 (46-92)
BMI, kg/m²26.1 ± 5.9 (18.4-45.0)24.2 ± 4.0 (18.1-36.9)
Median admission time, hours6 (1-32)7 (1-25)
Alcohol abuse5 (17%)4 (13%)
Smoking18 (60%)13 (43%)
Hypertension8 (27%)11 (37%)
WFNS grade at admission - I14 (47%)16 (54%)
WFNS grade at admission - II7 (23%)9 (30%)
WFNS grade at admission - III01 (3%)
WFNS grade at admission - IV9 (30%)4 (13%)
Fisher Grade 36 (20%)6 (20%)
Fisher Grade 419 (63%)22 (73%)
Hydrocephalus8 (27%)9 (30%)
Aneurysm treated with surgery2 (7%)3 (10%)
Aneurysm treated with coiling28 (93%)27 (90%)
Complete aneurysm obliteration24 (80%)22 (73%)

Arms

FieldTrigeminal Nerve Stimulation (TNS)Control
InterventionBilateral transcutaneous electrical nerve stimulation applied to the innervation territory of the supratrochlear and supraorbital nerves (terminal branches of ophthalmic division V1 of trigeminal nerve). Stimulation frequency 20 Hz. Intensity adjusted to sub-paresthesia threshold for non-sedated patients (determined using regular TENS device before blinded device applied). For sedated patients, intensity maintained at 20 mA unless scheduled to stop sedation before day 10, then lower thresholds used to maintain blinding after awakening. Continuous stimulation 24 hours per day for 10 days (days 1-10 after SAH). Electrodes positioned bilaterally over supraorbital area. All patients received standard SAH care including nimodipine. Baseline CTA with CTP at day 3±1, second CTP and CTA at day 8±1 during intervention, MRI with FLAIR at 3 months, clinical evaluation at 6 months. Daily clinical surveillance with Glasgow Coma Scale. Additional CT scans when clinically indicatedIdentical bilateral electrode placement over supratrochlear and supraorbital nerve territories. Sham device identical in appearance to active TNS device and displayed current intensity but delivered no electrical stimulation. Same intensity determination protocol used to maintain blinding. Applied continuously 24 hours per day for 10 days (days 1-10 after SAH). All patients received standard SAH care including nimodipine. Same imaging and follow-up schedule as TNS group: baseline CTA with CTP at day 3±1, second CTP and CTA at day 8±1, MRI with FLAIR at 3 months, clinical evaluation at 6 months
Duration10 days continuous stimulation, 6 months total follow-up10 days sham stimulation, 6 months total follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Presence of cerebral infarction related to vasospasm on MRI FLAIR at 3 months (or on last CT/MRI scan before death), after exclusion of infarcts from other causes (procedure-related, hematoma-related) as primary or relevant cause, or considered not exclusively due to causes other than vasospasm. Assessed by blinded radiologist reviewPrimary27% (8/30), 95% CI not reported23% (7/30), 95% CI not reported3.33%0.99 (Fisher's exact test)
Late cerebral infarction (not observed at day 6 but present at 3 months)Secondary20% (6/30)10% (3/30)0.47
Modified Rankin Scale (MRS) ≥3 at 6 months (unfavorable outcome)Secondary3% (1/30) - one patient with MRS 310% (3/30) - one patient MRS 3, two patients deceased (MRS 6)0.65
Glasgow Outcome Scale (GOS) - moderate disability (GOS II) at 6 monthsSecondary27% (8/30)18% (5/28)0.53
EQ5D-3L Index (quality of life) at 6 monthsSecondaryMean 0.79 ± 0.22 [0.27-1.00] (n=30)Mean 0.79 ± 0.23 [0.25-1.00] (n=28)0.99
EQ5D Visual Analog Scale at 6 monthsSecondaryMean 86 ± 11 [65-100] (n=30)Mean 82 ± 12 [50-100] (n=28)0.26
Mortality at 6 monthsSecondary0% (0/30)7% (2/30) - both deaths unrelated to studyNot reported
Perfusion abnormality on CT perfusion at day 6Secondary17% (5/30)40% (12/30)0.084 (trend but not significant)
Vasospasm presence on CT angiography at day 6Secondary33% (10/30)47% (14/30)0.43
Moderate-severe vasospasm (26-100% arterial diameter reduction)Secondary27% (8/30) moderate-severe combined43% (13/30) moderate-severe combinedNot separately reported
Symptomatic vasospasmSecondary20% (2/10 with vasospasm)50% (7/14 with vasospasm)Not reported
Infarct-related hypodensity on head CT at day 6Secondary13% (4/30)10% (3/30)0.99
Hydrocephalus requiring cerebrospinal fluid drainageSecondary27% (8/30)27% (8/30)0.99
Secondary complications during hospitalizationAdverse33% (10/30)37% (11/30)0.99
HydrocephalusAdverse30% (9/30)33% (10/30)0.99
Serious adverse eventsAdverseNot separately quantified by percentageNot separately quantified by percentageNo significant difference, similar rates
Deaths during study (unrelated to intervention)Adverse02 (1 from hemorrhagic stroke at 119 days, 1 from postoperative empyema at 70 days)Not reported
Patients unblinded for safety reasonsAdverse2 (1 large EVD hematoma, 1 femoral artery dissection)1 (asymptomatic thrombocytopenia)Not reported

Subgroup Analysis

Strong correlation between vasospasm severity and PCT abnormalities: no/mild vasospasm 5.1% (2/39) had PCT abnormality, moderate vasospasm 53.8% (7/13) had PCT abnormality, severe vasospasm 100% (8/8) had PCT abnormality (p<0.0001). Significant relationship between WFNS grade and vasospasm occurrence (p=0.016): WFNS grade 4 patients had highest vasospasm rate (10/14, 71% of grade 4 patients with vasospasm)

Criticisms

  • Single-center study limits generalizability
  • Small sample size (60 patients) - pilot study not powered for definitive efficacy conclusions
  • One patient (79 years old) exceeded age inclusion criterion of 75 years (protocol deviation)
  • Primary endpoint based solely on radiological criteria (MRI FLAIR at 3 months), not clinical examination
  • TNS intensity maintained below paresthesia threshold to preserve blinding may have limited therapeutic effect - potential dose-effect relationship underestimated
  • Stimulation parameters (frequency 20 Hz, intensity) chosen empirically based on previous works without dose-optimization studies
  • No assessment of whether effective dose reached target - no measurement of CGRP levels or other mechanistic biomarkers
  • Three patients unblinded during study (5% of cohort) could introduce bias
  • Higher male proportion in TNS group (27% vs 43%, p=0.02) despite randomization
  • Perfusion CT covered only 4-cm slab at basal ganglia level - could not monitor entire brain for small hypoperfused areas
  • CT perfusion performed only once at day 6 - single timepoint assessment
  • Unexpectedly high perfusion abnormalities in TNS group (40% vs 17%, p=0.084) raises questions about potential adverse effects
  • External TENS targets peripheral nervous system through autonomic ganglia, may not adequately reach central trigemino-cervical complex compared to direct neuraxis stimulation
  • 57.1% of patients with moderate-severe vasospasm were asymptomatic - disconnect between radiological and clinical vasospasm
  • Only radiological definition of DCI used, which may underestimate clinical impact
  • No stratification for baseline characteristics in randomization
  • Study excluded patients with craniotomy/craniectomy, limiting applicability to surgical clipping patients
  • Excluded patients requiring stent-assisted coiling who might benefit from antiplatelet effects
  • Follow-up limited to 6 months - longer-term outcomes unknown
  • Two deaths in TNS group (none in sham) though unrelated to intervention raises safety questions
  • Lower DCI incidence than predicted (23-27% vs expected 50-70%) may indicate early screening effect
  • Pathophysiological mechanism assumes vasodilation via neuropeptide release, but DCI pathophysiology involves multiple factors beyond vessel caliber
  • No measurement of cerebral autoregulation which may be impaired during vasospasm
  • Distinction between clinical and radiological vasospasm difficult - complex neurological symptoms hard to attribute solely to vasospasm
  • Almost half of severe vasospasm patients did not develop DCI - other factors involved beyond vessel narrowing

Funding

No external funding. Study conducted at Poitiers University Hospital. Trial medication (tirofiban for other uses) not applicable - this was TENS device study. Approved by French Agency for Safety of Health Products (ANSM) number 2016-A01144-47 and Ethics Committee CPP West III. FDA IND not applicable (European study)

Based on: TRIVASOSTIM (International Journal of Environmental Research and Public Health, 2023)

Authors: Philippe Rigoard, Maxime Billot, Maarten Moens, ..., Konstantin V. Slavin

Citation: Int. J. Environ. Res. Public Health 2023, 20, 5836

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