Medical management of vasospasm in subarachnoid hemorrhage patients. Despite targeting multiple pathophysiological mechanisms of DCI and vasospasm, most of the trials did not yield results that could translate to clinical practice. Fasudil and emerging therapies like cisternal irrigation and lumbar drainage combined with intrathecal vasodilators and phosphodiesterase medications showed promising results but need to be tested in a randomized clinical trial for effectiveness.

1. Pharmacological Management
of Cerebral vasospasm in
Subarachnoid hemorrhage
Naresh Mullaguri MD
Neurocritical care fellow

2. Objectives
• Timeline and mechanism of vasospasm
•Choice of medications
•Review of Literature
• Summary
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4. Chugh et al, Neurology India, 2019
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7. VASOSPASM
• 70% of patients will have
angiographic evidence of spasm
• 30% of these patients develop
symptomatic vasospasm
• 50% of these patients will
develop Delayed Ischemic
Neurological Deficits (DIND)
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8. Li et al, World Neurosurgery, 2019
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9. TIMING…
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14. Sehba et al, Molecular Neurobiology 20119/12/19 Naresh Mullaguri, Cleveland clinic Foundation 15

15. • Conventional medical therapies
• Triple H therapy – Focused on vascular resistance, flow viscosity and blood pressure
• Clinical application challenged with emerging evidence.
• HYPERVOLEMIA
• Reported to be ineffective in improving CBF and clinical outcomes compared to NORMOVOLEMIC therapy
• HEMODILUTION
• 3 RCTs reported no significant differences in clinical outcomes but significant increase in adverse effects
• HYPERTENSION
• aims to improve CPP. Through increasing CO, vasopressors, improved CBF and neurological deficits
associated with vasospasm.
• AHA recommends hypertension and euvolemia.
• Only RCT reported equivocal results due to lack of effect and slow recruitment. Recommended to
reconsider current guidelines due to significant side effects including death, pneumothorax, atrial
fibrillation and myocardial infarction.
Gaither et al, Stroke 2018; Findlay, World Neurosurgery 2010
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16. DRUGS FOR VASOSPASM9/12/19 Naresh Mullaguri, Cleveland clinic Foundation 17

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18. CALCIUM CHANNEL BLOCKERS
• Oral Nimodipine – Prophylaxis for DCI. NNT 8
• Mechanism: Blockade of dihydropyridine-type calcium channel. Unclear
mechanism.
• No effect on delayed vasospasm but improved clinical outcome by reducing DCI.
• Recovery of CBF and vasodilation, leading to cerebral protection, observed in
animals.
• IA Nimodipine – rescue therapy.
• Long term IV infusion showed prolonged vasodilation. Systemic hypotension,
vasopressors, infectious complications and increased ICP.
• Meta-analysis – 90% angiographic response, 57% neurological response, 66%
good clinical outcome and 9% mortality. Better outcomes with TCD monitoring.
Abruzzo et al; JNIS 2012;
Ditz et al, WNS 2018;
McGuinness et al., Neurosurg Clin North Am, 2010
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19. Endothelin-1 Antagonists
• Animal studies – recovers CBF when used 60-120 min post SAH
• Clazosentan (CONSCIOUS 3 Phase 3 RCT) – vasospasm and DCI related
morbidity and all cause mortality – Stopped due to non-significant
results.
• Meta-analysis of 27 animal studies - Decreased vasospasm but did
not improve clinical outcomes
• Adverse effects: Pulmonary edema, hypotension and anemia
McDonald et al, Stroke 2012
Liu et al, China Neurosurgery journal, 20169/12/19 Naresh Mullaguri, Cleveland clinic Foundation 20

20. Statins
• HMGCoA reductase inhibitors
• Increases NO synthase in endothelium and vasodilation
• STASH trial – No significant benefits in short and long term
• Meta-analysis of 6 studies – No significant reduced incidence of
vasospasm or poor neurological outcomes but reduced DCI
• Other meta-analysis reported decreased vasospasm but no benefit in DCI,
mortality or favorable outcomes.
Kirkpatrick et al, Lancet Neurology 2014
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21. Magnesium Sulfate
• Ability to cross blood brain barrier and antagonize calcium receptors
• Vasodilation and prevent excitotoxicity
• Animal studies: Mg pretreatment decreases ischemic depolarizations
and reduced ischemic stroke.
• 2 phase 3 RCTs – IMASH and MASH-2 studies IV MgSO4 – found no
difference in clinical outcomes and vasospasm incidence
• Its use as prophylaxis has been excluded
Wong et al, Stroke 2010
Mees et al, Lancet 2012
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22. Vasoactive agents
• Milrinone
• Inhibits calcium channels and PDE- 3
• Continuous intravenous infusion - Vasodilation
• No RCTs exist.
• Retrospective and prospective studies showed decreased DCI, improved GCS,
neurological outcomes.
• Safe at at high doses
• Synergistic with IA Nimodipine for refractory vasospasm
Ghanem et al, Egypt Journal of Anesthesia, 2014
Lannes et al, Canadian Journal of Neurological sciences, 20179/12/19 Naresh Mullaguri, Cleveland clinic Foundation 23

23. Cilostazol
• PDE-3 inhibitor
• Decreases platelet aggregation, vasodilation and anti-inflammatory
effects
• Multiple RCTs and systematic review to date
• Efficacy in reducing vasospasm and DCI
• Reduced poor outcomes and vasospasm related infarctions
Senbokuya et al, J Neurosurgery 2013
Matsuda et al, Cerebrovascular diseases 2016
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24. Sildenafil and Eicosapentanoic acid
• Sildenafil
• Animal study – viable to use for vasodilation. Mechanism by PDE – 5
inhibition.
• Small case series showed increased vessel diameter but no changes in CBF
• Eicosapentanoic acid
• inhibits calcium sensitization in vascular smooth muscle
• Long term use reported low risk of stroke.
• RCT – Decreased DCI but no benefit in long term clinical outcomes.
• Expected finding as endovascular rescue therapy was used in control group.
Dhar et al, Neurocritical care 2016, Atalay et al, Neurosurgery 2016
Yoneda et al, EVAS study, World Neurosurgery 2014
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25. Fasudil
• Rho-kinase inhibitor and vasodilator
• Inhibits protein phosphorylation – affects signal transduction
pathways – reduce vasospasm
• 2 systematic reviews – beneficial in prevention of vasospasm and
cerebral infarction
• Meta-analysis – same results.
• Study comparing it to Nimodipine – No significant difference in
vasospasm but better clinical outcomes in Fasudil group (74.5% vs
61.7%)
• Regularly used as prophylactic treatment in Japan
Liu et al, European Journal of clinical pharmacology 2012
Zhao et al, Neurological medicine Chir (Tokyo) 20119/12/19 Naresh Mullaguri, Cleveland clinic Foundation 26

26. Anti-Oxidants
• Corticosteroids
• Free radical scavengers
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27. Corticosteroids
• Methylprednisolone
• Management of euvolemia, to counteract hyponatremia and fluid loss
• Anti-inflammatory properties
• Animal studies:
• Early use improved CBF and prevented rise in cerebral vascular resistance.
• Reduced lipid peroxidation, preserved anti-oxidant enzyme system.
• One clinical study showed MP with in 24-48 h after SAH X 3 days
improved 1 year functional outcome.
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28. Tirilazad
• < 3 hours after SAH – Prevents CPP and CBF changes.
• Protects microvascular endothelium
• Preserves blood brain barrier
• Clinical trial – Tirilazad 34-48 h after SAH for 10 days showed
improved outcome and decreased mortality in poor grade SAH only in
male patients.
• Meta-analysis – 5 placebo controlled trials found no evidence of
decreased mortality or disability
Kassell et al, J Neurosurgery 1996
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29. Free Radical Scavengers
• Ebselen and Edaravone – Use with in 24 hours
• decrease lipid peroxidation
• Decrease Caspase 3 activation
Limited clinical trial data – beginning 4 days after SAH associated with a trend
towards less vasospasm, cerebral infarction and DCI
Munakata et al, Neurosurgery 2009
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30. Anti-platelet agents
• One animal trial but more clinical data available
• Aspirin and Ticlopidine were most studied
• Prevents vasospasm
• Meta-analysis showed trend towards better outcome in APT treated patients
compared to controls.
• Ticlopidine used after cisternal drainage – reduced platelet aggregation and
improved functional outcome
• Results on Aspirin are contradictory.
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31. Nitric Oxide
• Methods to increase NO bioavailability include
• Intracarotid infusion of NO-saturated saline
• Administration of an NO donor
• Increase eNOS expression/activity - Statins
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32. NO donors
• Nitrosoglutathione
• Nitroglycerin
• NONOate
• GTN
• Recovers CBF, dilates large and small vessels and prevents glutamine excitotoxicity
- Limited trial data.
- Adverse effects – Decrease CPP, hypotension and cyanide toxicity
- Nebivolol
- Selective B1 blocker with NO vasodilatory and anti-oxidant properties
- showed improved vasospasm.
- Hypotension was a complication.
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33. Papaverine
• Prolongs NO mediated mechanisms
• cGMP degradation by Phosphodiesterase
• Extensively used for IA therapy either alone or in combination with
TBA
• Fell out of favor – short acting, required multiple interventions and
decreases PbtO2 and increases ICP.
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34. Rosiglitazone
• PPAR-r agonist
• DM drug
• Decreases vascular smooth muscle remodeling
• Decrease glutamate and oxidative stress with neuroprotective
properties
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35. Hypertonic-Hyperoncotic hydroxyethyl starch
• Only animal study
• Improved vasospasm by reducing endothelial cell water storage
• Increased CBF, decreased ICP and reduced neuronal apoptosis
through early aggressive treatment
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36. Neuroprotective agents
• Erythropoietin
• Anticoagulants – Low dose Heparin
• Tenascin-C knockout
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37. Neuroprotective agents
• Erythropoietin
• Increase brain oxygenation, reduce severity, prevent DCI and improve
outcomes
• Veldeman et al – observed improved PbtO2 in hours after administration in
case series
• Current evidence is limited.
• Low dose heparin infusion – Cochrane review 7 RCTs – no benefit in
clinical outcomes.
Veldeman et al, Bristish J of Anesthesia 2016
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38. Subarachnoid blood load reduction
• Intrathecal Milrinone and Nimodipine therapy
• Pilot study – cisternal drainage and IT Milrinone – feasible, low incidence of
DCI in high grade SAH. No control group, small sample.
• Another study compared IT Milrinone with placebo – Fewer DCI in
intervention group with no improvement in 90 day outcomes.
• IT Nimodipine – RCT 20 patients lavage for 7 days – lower DCI, neurological
improvement and vasospasm (p=0.266).
• Animal study IT Nimodipine and cilostazol – low vasospasm and DCI
Koyanagi et al, J Neurosurgery 2018
Hanggi et al, Cent Eur Neurosurg. 2009
Onal et al, Acta Neurochir suppl. 2011
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39. Lumbar CSF drainage
• Li et al., showed - protective in DCI (OR 0.243; 95% CI 0.119-0.497)
• Systematic review - lower rates of DCI (20% vs 45%; p<0.001) and
higher favorable outcomes (79.4% vs 60.4%; p<0.001) in studies with
comparision groups.
Li et al., China J Emergency Medicine 2015
Panni et al., J Neurosurgical Sciences, 2017
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40. Cisternal irrigation
• Kim et al – Lower vasospasm using papaverine or urokinase compared
with simple drainage. NO long term outcome benefit.
• Other studies showed – fewer DCI and significant relationship
between the number of post operative clots and development of DCI
(OR 6.4; 95% CI 2 - 20) and angiographic vasospasm (OR 2.6; 95% CI
1.4-4.7). mRS of 0-1 in 75.9% at 1 year.
• Cisternal irrigation with lamina terminalis fenestration – reduced
vasospasm incidence, mortality and need for EV rescue treatments.
Kim et al, Neurological sciences 2014
Ota et al, World Neurosurgery 2017
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41. Li et al, World Neurosurgery, 2019
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42. Li et al, World Neurosurgery, 2019
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43. THANK YOU
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