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CIAN

Continuous Intraarterial Nimodipine Infusion for the Treatment of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Retrospective, Single-Center Cohort Trial

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Year of Publication: 2022

Authors: Andreas Kramer, Moritz Selbach, Thomas Kerz, ..., Carolin Brockmann

Journal: Frontiers in Neurology

Citation: Front. Neurol. 13:829938

Link: https://doi.org/10.3389/fneur.2022.829938

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...r-13-829938.pdf

Clinical Question

Is continuous intraarterial nimodipine infusion safe and effective for treating severe therapy-refractory delayed cerebral ischemia with large vessel vasospasm after aneurysmal subarachnoid hemorrhage?

Bottom Line

Continuous intraarterial nimodipine infusion resulted in favorable outcomes in 76% of patients within 1 year, with acceptable safety profile. The technique may be used to treat patients with severe therapy-refractory delayed cerebral ischemia after SAH.

Major Points

  • Retrospective single-center cohort study of 17 patients treated with CIAN between May 2016 and December 2017
  • CIAN initiated median 9 days after SAH with median duration of 5 days
  • Nimodipine administered at 0.5-2.0 mg/h through microcatheters in extracranial ICA and/or vertebral artery
  • Favorable outcome (GOS 4-5) in 53% at discharge, improved to 76% at 1-year follow-up (follow-up available for 13/17; unchanged GOS from discharge assumed for the 4 missing patients)
  • DCI-related infarctions occurred in 8/17 patients (47%): 5 minor and 3 major
  • One death due to posthemorrhagic cerebral edema
  • Treatment response monitored with TCD, CT perfusion, CT angiography, and DSA
  • All awake patients showed immediate clinical improvement after CIAN initiation
  • Complications included catheter pressure elevation (5 catheters in 4 patients) and accidental removal (2 patients)
  • One patient developed localized cerebral edema possibly due to CIAN
  • Antiplatelet therapy with tirofiban used to prevent catheter-related thromboembolism

Design

Study Type: Retrospective, single-center cohort study

Randomization:

Blinding: Blinded neuroradiologist for reevaluation of radiographic data

Enrollment Period: May 2016 to December 2017

Follow-up Duration: Up to 1 year (median 12 months, range 6-12 months)

Centers: 1

Countries: Germany

Sample Size: 17

Analysis: Descriptive statistics primarily. Correlation analyses using Spearman's rank correlation for ordinal variables, Phi coefficient for binary variables (Chi-Square for significance), and Mann-Whitney U test for combinations of ordinal and binary variables. Statistical significance defined as p ≤ 0.05. R version 4.1.2 used for analysis

Inclusion Criteria

  • Adult patients with aneurysmal subarachnoid hemorrhage
  • Delayed cerebral ischemia with large vessel vasospasm
  • Severe (>75% vessel narrowing on DSA) or diffuse large vessel vasospasm in clinically deteriorating patients
  • In sedated or comatose patients, additional perfusion deficits on CT perfusion required (in the absence of clinical deterioration signs)
  • Persistent clinical symptoms despite short-term intraarterial nimodipine in patients with moderate vasospasm
  • Treatment with CIAN for minimum of 24 hours
  • Treated at University Medical Center Mainz between May 2016 and December 2017

Exclusion Criteria

  • Bleeding causes other than aneurysms
  • CIAN treatment duration less than 24 hours

Baseline Characteristics

CharacteristicControlActive
NoteSingle-arm study, no control group. All patients received CIAN.
Number of patients17
Age, median (range), years54 (38-72)
Female12 (70.6%)
Male5 (29.4%)
Fisher Grade 38 (47.1%)
Fisher Grade 49 (52.9%)
Hunt & Hess, median (range)2 (1-5)
WFNS, median (range)2 (1-5)
GCS at admission, median (range)14 (3-15)
Neurological deficit at admission8 (47.1%)
Aneurysm location - MCA (only)5 (29.4%)
Aneurysm location - AComA (only)4 (23.5%)
Aneurysm location - ICA/PComA (only)3 (17.6%)
Aneurysm location - Multiple3 (17.6%)
Aneurysm location - Other (ACA, VA)2 (11.8%)
Treatment - Endovascular coiling10 (58.8%; includes 1 patient with combined coiling/clipping)
Treatment - Surgical clipping6 (35.3%; includes 1 patient with combined coiling/clipping)
Treatment - WEB device1 (5.9%)
Treatment - Flow-diverting stent1 (5.9%)
Risk factor - Hypertension (aHT)7 (41.2%)
Risk factor - Nicotine4 (23.5%)
Median time SAH to CIAN onset, days9 (3-13)
Median CIAN duration, days5 (1-13)
Vasospasm location - MCA16 (94.1%)
Vasospasm location - ACA13 (76.5%)
Vasospasm location - ICA3 (17.6%)
Severe vasospasm on DSA (>75%)7 (41.2%)
Moderate vasospasm on DSA (50-75%)9 (52.9%)
Short-term IAN prior to CIAN5 (29.4%)
TBA prior to CIAN5 (29.4%; aborted in 4 of 5)

Arms

FieldContinuous Intraarterial Nimodipine Infusion (CIAN)
InterventionNimodipine (0.5-2.0 mg/h, initially 2 mg/h) administered continuously via microcatheters (1.7F) placed in extracranial internal carotid artery (ICA) and/or vertebral artery (VA) through 6F introducer sheath in common femoral artery. Infusion combined with heparin (10 mL/h at 1 IU/mL) for total flow rate of 20 mL/h. Tirofiban (0.4 µg/kg/min for 30 min, then 0.1 µg/kg/min maintenance) for antiplatelet effect. Induced hypertension maintained during CIAN. Nimodipine dose reduced gradually over 1-3 days before stopping. Treatment ended when symptoms resolved and TCD normalized (awake patients) or when PCT/DSA and TCD normalized (sedated patients). Monitoring with daily TCD, routine ECG, cardiac exams, laboratory tests, and serial CT perfusion
DurationMedian 5 days (range 1-13 days)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Two primary endpoints per paper: (1) Glasgow Outcome Scale at discharge (GOS HD) and at follow-up within 1 year (GOS FU); (2) Presence of cerebral infarction on final CT scan prior to discharge (minor: <1/3 vessel territory; major: >1/3 vessel territory)PrimaryGOS 4-5 at discharge: 9/17 (53%) — GOS 5: 8, GOS 4: 1, GOS 3: 4, GOS 2: 3, GOS 1: 1. GOS 4-5 at 1 year: 13/17 (76%) — follow-up available for 13/17 (median 12 months, range 6-12); of those 13, four improved from unfavorable to favorable; the 4 without follow-up were assumed unchanged from discharge (favorable) to derive 13/17. Cerebral infarctions: 8/17 (47%) — minor 5 (29%), major 3 (18%)
Treatment-associated complications (formal secondary endpoint per paper; includes catheter tip thrombosis, catheter occlusion, and vessel dissection)SecondaryNo catheter tip thrombosis observed during CIAN; no vessel occlusions from CIAN catheters; 2 ICA dissections (C2 segment, both left-sided; one during unsuccessful TBA prior to CIAN, one detected after CIAN ended) — neither resulted in vessel occlusion; catheter pressure elevation in 5 catheters across 4 patients (led to 6 catheter replacements in 4 patients); accidental catheter removal in 2 patients
CIAN-related complicationsAdverseCatheter pressure elevation: 5 catheters in 4 patients; Accidental catheter removal: 2 patients; Catheter replacements: 6 in 4 patients; Localized cerebral edema possibly due to CIAN: 1
ICA dissectionAdverse2 (one during TBA before CIAN, one detected after CIAN ended); Both did not result in vessel occlusion
M2 branch perforation during TBAAdverse1 (occurred prior to CIAN)
Hospital-acquired pneumoniaAdverse4 (2 with prolonged weaning and tracheostomy)
Urinary tract infectionAdverse5
Other general complicationsAdverseProlonged weaning without infection: 1; Meningitis: 1; ARDS with pulmonary embolism: 1; Tension pneumothorax: 1; Cholangitis: 1; Temporary cardiomyopathy: 1; Epileptic seizure: 1
DeathAdverse1 (malignant brain edema after multiple infarctions)

Subgroup Analysis

GOS at discharge highly correlated with neurological deficits at admission (r=-0.834, p<0.001), H&H severity (r=-0.753, p<0.001), and GCS at admission (r=0.808, p<0.001). GOS at 1-year follow-up moderately correlated with H&H (r=-0.600, p=0.011), GCS (r=0.552, p=0.022), and neurological deficits (r=-0.563, p=0.006). Infarctions correlated with H&H severity (r=0.650, p<0.001), GCS (r=-0.543, p<0.001), nicotine use (r=0.588, p=0.030), CIAN duration (r=0.656, p=0.004), and hypoperfusion during CIAN (r=0.685, p=0.010)

Criticisms

  • Retrospective single-center design limits generalizability
  • No control group for comparison
  • Small sample size (n=17) limits statistical power
  • Selection bias as protocol weighted cerebral hypoperfusion on PCT heavily for CIAN indication
  • Follow-up data missing for 4/17 patients at 1 year; the reported 76% favorable outcome depends on assuming unchanged GOS from discharge for those 4
  • No routine MRI performed which may have underestimated infarction rates
  • Classification of infarctions by volume doesn't account for eloquent area involvement
  • Long-term follow-up beyond 1 year not available
  • Few patients underwent TBA or short-term intraarterial nimodipine before CIAN, making comparison difficult
  • Open-label treatment without blinding
  • Variability in follow-up imaging timing and protocols
  • Did not use multimodal neuromonitoring (PtiO2, pyruvate metabolism) which some centers employ

Funding

Not explicitly stated in the document

Based on: CIAN (Frontiers in Neurology, 2022)

Authors: Andreas Kramer, Moritz Selbach, Thomas Kerz, ..., Carolin Brockmann

Citation: Front. Neurol. 13:829938

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