This document summarizes various treatments for cerebral vasospasm following subarachnoid hemorrhage. It discusses conventional therapies like triple H therapy and notes emerging evidence questioning their effectiveness. It then reviews several medications that have been used for vasospasm, including calcium channel blockers, endothelin receptor antagonists, statins, magnesium sulfate, and various vasoactive agents. It also discusses other potential treatments like anti-oxidants, anti-platelet agents, nitric oxide donors, and various neuroprotective agents. Surgical interventions like lumbar CSF drainage and cisternal irrigation are also summarized as methods that may help reduce subarachnoid blood load and lower rates of delayed cerebral ischemia.

1. CEREBRALVASOSPASM

2. Objectives
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• Timeline and mechanism ofvasospasm
•Choice of medications
•Review of Literature
• Summary

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4. Chughet al, Neurology India,2019
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6. VASOSPASM
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• 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)

7. Liet al, World Neurosurgery,2019
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8. TIMING…
NareshMullaguri, ClevelandclinicFoundation 9/12/19 10

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12. • Conventional medical therapies
• Triple Htherapy – Focusedon vascular resistance, flow viscosity and bloodpressure
• Clinical application challenged with emergingevidence.
• HYPERVOLEMIA
• Reported to be ineffective in improving CBFand clinical outcomes compared to NORMOVOLEMICtherapy
• HEMODILUTION
• 3 RCTsreported no significant differences in clinical outcomes but significant increase in adverse effects
• HYPERTENSION
• aims to improve CPP.Through increasing CO,vasopressors, improved CBFand neurological deficits
associatedwith vasospasm.
• AHArecommends hypertension and euvolemia.
• Only RCTreported 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 myocardialinfarction.
Gaither et al, Stroke 2018; Findlay, World Neurosurgery2010
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13. DRUGS FORVASOSPASM
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15. CALCIUM CHANNELBLOCKERS
• Oral Nimodipine – Prophylaxis for DCI.NNT8
• Mechanism: Blockade of dihydropyridine-type calcium channel.Unclear
mechanism.
• No effect on delayed vasospasm but improved clinical outcome by reducingDCI.
• Recoveryof CBFand vasodilation, leading to cerebral protection, observedin
animals.
• IANimodipine – rescue therapy.
• Longterm IVinfusion showed prolonged vasodilation. Systemichypotension,
vasopressors, infectious complications and increasedICP.
• Meta-analysis – 90%angiographic response, 57%neurological response, 66%
good clinical outcome and 9%mortality. Better outcomes withTCDmonitoring.
Abruzzo et al; JNIS2012;
Ditz et al, WNS2018;
McGuinness et al., Neurosurg Clin North Am,2010
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16. Endothelin-1Antagonists
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• Animal studies – recovers CBFwhen used 60-120 min post SAH
• Clazosentan (CONSCIOUS3 Phase3 RCT)– vasospasmand DCIrelated
morbidity and all causemortality – Stopped due to non-significant
results.
• Meta-analysis of 27 animal studies - Decreasedvasospasmbut did
not improve clinicaloutcomes
• Adverse effects: Pulmonary edema, hypotension and anemia
McDonald et al, Stroke2012
Liu et al, China Neurosurgery journal,2016

17. Statins
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• HMGCoAreductase inhibitors
• Increases NOsynthase in endothelium and vasodilation
• STASHtrial – No significant benefits in short and longterm
• Meta-analysis of 6 studies – No significant reduced incidence of
vasospasmor poor neurological outcomes but reducedDCI
• Other meta-analysis reported decreased vasospasmbut no benefit inDCI,
mortality or favorableoutcomes.
Kirkpatrick et al, Lancet Neurology2014

18. MagnesiumSulfate
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• Ability to crossblood brain barrier and antagonize calciumreceptors
• Vasodilation and prevent excitotoxicity
• Animal studies: Mg pretreatment decreasesischemic depolarizations
and reduced ischemic stroke.
• 2 phase 3 RCTs– IMASHand MASH-2studies IVMgSO4– found no
difference in clinical outcomes and vasospasmincidence
• Its useasprophylaxis hasbeen excluded
Wonget al, Stroke2010
Mees et al, Lancet2012

19. Vasoactiveagents
• Milrinone
• Inhibits calcium channels and PDE-3
• Continuous intravenous infusion -Vasodilation
• No RCTsexist.
• Retrospective and prospective studies showed decreased DCI,improved GCS,
neurological outcomes.
• Safeat highdoses
• Synergistic with IANimodipine for refractoryvasospasm
Ghanemet al, Egypt Journal of Anesthesia,2014
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20. Cilostazol
• PDE-3inhibitor
• Decreasesplatelet aggregation, vasodilation and anti-inflammatory
effects
• Multiple RCTsand systematic review to date
• Efficacy in reducing vasospasm andDCI
• Reduced poor outcomes and vasospasm related infarctions
Senbokuya et al, JNeurosurgery 2013
Matsuda et al, Cerebrovascular diseases2016
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21. Sildenafiland Eicosapentanoicacid
• Sildenafil
• Animal study – viable to usefor vasodilation. Mechanism by PDE–5
inhibition.
• Small caseseries showed increased vesseldiameter but no changesin CBF
• Eicosapentanoic acid
• inhibits calcium sensitization in vascular smoothmuscle
• Longterm usereported low risk ofstroke.
• RCT– Decreased DCIbut no benefit in long term clinicaloutcomes.
• Expected finding asendovascular rescue therapy wasused in control group.
Dhar et al, Neurocritical care 2016,Atalay et al, Neurosurgery2016
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22. Fasudil
• Rho-kinase inhibitor and vasodilator
• Inhibits protein phosphorylation – affects signaltransduction
pathways – reduce vasospasm
• 2 systematic reviews – beneficial in prevention of vasospasmand
cerebral infarction
• Meta-analysis – same results.
• Study comparing it to Nimodipine – No significant difference in
vasospasmbut better clinical outcomes in Fasudil group (74.5%vs
61.7%)
• Regularly used asprophylactic treatment in Japan
Liu et al, European Journal of clinical pharmacology2012
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23. Anti-Oxidants
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• Corticosteroids
• Freeradical scavengers

24. Corticosteroids
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• Methylprednisolone
• Management of euvolemia, to counteract hyponatremia and fluidloss
• Anti-inflammatory properties
• Animal studies:
• Early useimproved CBFand prevented rise in cerebral vascularresistance.
• Reduced lipid peroxidation, preserved anti-oxidant enzymesystem.
• Oneclinical study showed MPwith in 24-48 h after SAHX3 days
improved 1 year functional outcome.

25. Tirilazad
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• <3 hours after SAH– Prevents CPPand CBFchanges.
• Protects microvascular endothelium
• Preservesblood brain barrier
• Clinical trial –Tirilazad 34-48 h after SAHfor 10 daysshowed
improved outcome and decreased mortality in poor grade SAHonly
in male patients.
• Meta-analysis – 5 placebo controlled trials found no evidenceof
decreased mortality or disability
Kassellet al, JNeurosurgery 1996

26. FreeRadicalScavengers
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• Ebselenand Edaravone– Usewith in 24 hours
• decrease lipid peroxidation
• Decrease Caspase3 activation
Limited clinical trial data – beginning 4 daysafter SAHassociated with atrend
towards lessvasospasm,cerebral infarction andDCI
Munakata et al, Neurosurgery2009

27. Anti-plateletagents
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• Oneanimal trial but more clinical dataavailable
• Aspirin and Ticlopidine were most studied
• Prevents vasospasm
• Meta-analysis showed trend towards better outcome in APTtreatedpatients
compared to controls.
• Ticlopidine used after cisternal drainage – reduced platelet aggregationand
improved functional outcome
• Results on Aspirin arecontradictory.

28. NitricOxide
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• Methods to increase NObioavailability include
• Intracarotid infusion of NO-saturatedsaline
• Administration of an NOdonor
• Increase eNOSexpression/activity -Statins

29. NOdonors
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• Nitrosoglutathione
• Nitroglycerin
• NONOate
• GTN
• RecoversCBF,dilates large and small vesselsand prevents glutamine excitotoxicity
- Limited trial data.
- Adverse effects – DecreaseCPP,hypotension and cyanide toxicity
- Nebivolol
- Selective B1blocker with NOvasodilatory and anti-oxidant properties
- showed improved vasospasm.
- Hypotension wasa complication.

30. Papaverine
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• Prolongs NOmediated mechanisms
• cGMPdegradation by Phosphodiesterase
• Extensively used for IAtherapy either alone or incombination with
TBA
• Fell out offavor – short acting, required multiple interventions and
decreasesPbtO2 and increases ICP.

31. Rosiglitazone
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• PPAR-ragonist
• DM drug
• Decreasesvascular smooth muscle remodeling
• Decreaseglutamate and oxidative stress with neuroprotective
properties

32. Hypertonic-Hyperoncotichydroxyethylstarch
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• Only animal study
• Improved vasospasmby reducing endothelial cell waterstorage
• Increased CBF,decreased ICPand reduced neuronal apoptosis
through early aggressivetreatment

33. Neuroprotectiveagents
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• Erythropoietin
• Anticoagulants – Low dose Heparin
• Tenascin-C knockout

34. Neuroprotectiveagents
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• Erythropoietin
• Increase brain oxygenation, reduce severity, prevent DCIand improve
outcomes
• Veldeman etal – observed improved PbtO2in hours after administration in
caseseries
• Current evidence islimited.
• Low dose heparin infusion – Cochrane review 7 RCTs– no benefit in
clinical outcomes.
Veldeman et al, Bristish Jof Anesthesia2016

35. Subarachnoidblood loadreduction
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• Intrathecal Milrinone and Nimodipine therapy
• Pilot study – cisternal drainage and ITMilrinone – feasible, low incidenceof
DCIin high grade SAH.No control group, smallsample.
• Another study compared ITMilrinone with placebo – Fewer DCIin
intervention group with no improvement in 90 day outcomes.
• ITNimodipine – RCT20 patients lavage for 7 days– lower DCI,neurological
improvement and vasospasm(p=0.266).
• Animal study ITNimodipine and cilostazol – low vasospasm andDCI
Koyanagi et al, JNeurosurgery 2018
Hanggiet al, Cent EurNeurosurg. 2009
Onal et al,Acta Neurochir suppl.2011

36. LumbarCSFdrainage
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• Liet al., showed - protective in DCI(OR0.243; 95%CI 0.119-0.497)
• Systematic review - lower rates of DCI(20%vs45%;p<0.001) and
higher favorable outcomes (79.4%vs60.4%; p<0.001) in studies with
comparision groups.
Liet al., China JEmergency Medicine 2015
Panni et al., JNeurosurgical Sciences,2017

37. Cisternalirrigation
• Kim et al – Lower vasospasmusing papaverine or urokinase compared
with simple drainage. NOlong term outcomebenefit.
• Other studies showed – fewer DCIand significant relationship
between the number of post operative clots and development of DCI
(OR6.4; 95%CI2 - 20) and angiographic vasospasm(OR2.6; 95%CI
1.4-4.7). mRSof 0-1 in 75.9%at 1year.
• Cisternal irrigation with lamina terminalis fenestration – reduced
vasospasmincidence, mortality and need for EVrescuetreatments.
Kim et al, Neurological sciences 2014
Ota et al, World Neurosurgery 2017
D9/1e2/A19guiar,Acta Neurochir suppl. 2013 41

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Liet al, World Neurosurgery,2019

39. Liet al, World Neurosurgery,2019
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40. THANKYOU
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