Cerebral Vasospasm After an Aneurysmal Rupture

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Cerebral Vasospasm After an Aneurysmal Rupture

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Postoperative Angiography
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Postoperative Angiography
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Definitions and Epidemiology

• Typically begins 4-5 days after the hemorrhage
• Angiographic or arterial vasospasm 40 to 70
  the narrowing of cerebral vessels documented by
  angiography or other studies
• Symptomatic vasospasm 20 to 30
• both the clinical picture of delayed onset of
  ischemic neurological deficits associated with
  aneurysmal SAH
• 10-15 die or permanent disability due to
  ischemic deficit

N Engl J Med 354387,2006 Cerebrovascular
disease1997, pp1111-121
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Risk Factors for Symptomatic Vasospasm

• Thick subarachnoid clot on CT
• -gtalmost 60 of patients with thick clots
  develop moderate to severe angiographic vasospasm
• Poor neurological condition on admission
• Cigarette smoking
• Age younger then 35 and older than 65
• Preexisting hypertension
• Incomplete circle of Willis

Neurosurg Focus 21(3)E3,2006
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Modified Fisher Grade
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Pathogenesis of Vasospasm

• Structural Theories
• Proliferative vasculopathy
• Immune vasculopathy
• Vessel wall inflammatory
• Extracellular lattice contraction
• Vasoconstriction Theories
• Free radical lipid peroxidation
• Derangement in eicosanoid production
• Nitric oxide deficit
• Endothelin excess
• Neurogenic factors
• Genetic predisposition
• eNOS gene polymorphism
• Haptoglobin
• APOE protein

Neurology 66634-640.2006 J Cere Blood Flow Metab
24291-7,2004 Neurology 641238-1244,2005
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Pathogenesis of Vasospasm
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Pathogenesis
Cardiovasc res 30493-500,1995
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Timing of Aneurysm Surgery

• Early surgery 48-72 hrs?start 3H therapy
• Good neurological condition ( Hunt and Hess grade
  3
• Large clot with mass effect associated with SAH
• Prevent early rebleeding
• Late surgery 10-14 days
• Poor neurological condition ( Hunt and Hess grade
  4
• Aneurysm difficult to clip
• Significant cerebral edema
• Presence of active vasospasm

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Monitoring of Vasospasm
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TCD for Vasospasm

• Non-invasive measurement for bedside usage
• High inter-observer variability
• Blood-flow velocity depends on more than one
  factor (e.g. vessel diameter, insonation angle,
  cerebral blood volume flow)

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J Neurosurg 96323-330,2002
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Vasospasm in SAH
302 cm/s
106 cm/s
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CT perfusion in detection of cerebral vasospasm

• Accurate, reliable and non-invasive
• Guide the decision to pursue angiography

Neurosurgery 56304-317, 2005 Neurosurg Focus 21
(3)E7, 2006
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Regional blood flow monitor

• CVR (cerebral vascular resistance) rCBF /
  cerebral perfusion pressure
• Bedside continuous monitor

J Neurosurg 9812271234, 2003
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Object of study I

• Early diagnosis of vasospasm by TCD , perfusion
  CT and rCBF monitor
• Predict prognosis and feasibility of operation by
  perfusion CT in poor grade SAH

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Management of Vasospasm

• Nimodipine infusion
• Triple-H therapy hypervolemia, hemodilution,
  hypertension (reverse ischemia)
• Intra-arterial papaverine or nimodipine
  administration (reverse vasospasm)
• Percutaneous transluminal ballon angioplasty
  (reverse vasospasm)

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Evidence-based cerebral vasospasm management
Neurosurg focus 21(3)E8,2006
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Subarachnoid Blood Clot Removal or Lysis

• Surgical removal of subarachnoid clot within
  days of hemorrhage reduces vasospasm
• 10 mg rt-PA is administrated intraoperatively and
  intracisternally immediately after aneurysm
  clipping
• Prevention was significant in the patient with
  thick( Fisher grade 3) SAH on CT

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Lumbar Drainage of CSF

• Reducing the incidence of
• Clinical vasospasm 51-gt17
• Need for angioplasty 45-gt17
• Vasospastic infraction 27-gt7
• Lumbar drainage of CSF after SAH markly reduces
  the risk of clinical vasospasm and its sequelae

J Neurosurg 100215-224,2004
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Animal model of vasospasm

• the injection technique (Solomon et al., 1985)
• endovascular filament model (Bederson et al.
  1995)

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Simvastatin Reduces Vasospasm

• Simvastatin (Zocor) 80 mg daily was used
• Plasma von Willebrand factor and S100ß were
  decreased 3 to 10 days after SAH

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Simvastatin Reduces Vasospasm

• SAH results in endothelial ICAM-1 expressiongt
  perivascular leukocyte migrationgt inflammatory
  cells synthesize endothelin-1gt inactivation of
  nitric oxide (NO)
• Statins have multiple biological properties
  including downregulating inflammation ( decrease
  ICAM-1 expression, inhibiting monocyte and
  endothelial production of ILs, chemokines and
  MMP-9) and upregulating endothelial NO synthase

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NO and vasospasm

• Early events platelet serotonin, thromboxane
  A2IICPgt stop flow phenomenoninflammatory
  response
• Delayed events (gt48 hours)heme gt bilirubin, CO,
  ferrous irongt free radical (lipid
  peroxidation)gteNOS inhibition and ET-1
  synthesis(oxidation of bilirubin to BOXes, then
  increase ADMA)asymmetric dimethylarginine
  (ADMA), an endogenous inhibitor of
  eNOSbilirubin oxidized fragments (BOXes)

Pharmacologytherapeutics 105(2005) 23-56
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Endothelin
Patients in whom angiography revealed diffuse
moderate-to-severe vasospasm had significantly (p
0.05) higher ET levels than other patients
within 24 hours
J. Neurosurg. (92),2000,390-400
ET-1 concentration in CSF showed a significant
increase over time with highest values on day 5
post ictus (p0.03).
Acta Neurochir (Wien) (2005) 147 12711279
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Endothelin

• inhibition of ET-1 biosynthesis (Matsumura et
  a!., 1991), monoclonal antibodies against ET-1
  (Yamauna et a!., 1992), and administration of the
  ET-A receptor antagonist BQ-123 (Cbozel and
  Watanabe,1993) significantly reduced/prevented
  vasospasm following SAH in dogs
• injection of exogenous ET-1 mimics cerebral
  vasospasm after SAH

Acta Neurochir (Wien) (2005) 147 12711279
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Pharmacology Therapeutics 105 (2005) 2356
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Pathogenesis of Vasospasm
TRENDS in Pharmacological Sciences
28(6),2007,252-6
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Endothelin antagonist

• Endothelin concentrations correlate with delayed
  cerebral ischemia and vasospasm after SAH
• Cerebral vasospasm progression suppressed by
  blockage of endothelin B receptor
• Clazosentan (AXV-034343), a selective endothelin
  A receptor antagonist, prevention of cerebral
  vasospasm

J Neurosurg 92390400, 2000
J Neurosurg 106330336, 2007
J Neurosurg 103917, 2005
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Vasospasm as the sole cause of cerebral ischemia?

• the relatively limited role that large arteries
  play in control of CBF
• Lack of correspondence between the sites and
  severity of angiographically confirmed vasospasm
  and cerebral ischemia
• The appearance of cerebral infarcts at autopsy?
  thromboembolism
• The disappointing clinical effects of vasospasm
  therapy

Neurosurg Focus 21(3)E2,2006
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Object of study 2

• Clinical specimen IHC stain for eNOS, integrity
  of endothelium
• CSF study ROS, endothelin, ADMA (urokinase
  irrigation, lumbar drainage)
• Set up animal model of vasospasm

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ADMA (Aysmmetrical dimethylarginine)

• The importance was first recognized by Vallance
  and colleagues in patients with end- stage renal
  disease
• ADMA is not derived from the methylation of free
  L-arginine. Rather, ADMA is generated from
  posttranslational modification of arginine
  residues within a variety of specific proteins
  that are predominantly found in the cell nucleus

Vallance P, Leone A, Calver A, et al. Lancet.
1992339572575.
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ADMA

• A Major Cause of Endothelial Dysfunction
• ADMA Regulates Vascular Resistance
• ADMA and Vascular Structure
• Central Role of DDAH

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Biochemical pathway for generation, elimination,
and degradation of ADMA
S-adenosyl-L-methionine (SAM)
S-adenosyl-L-homocysteine (SAH
dimethylarginine dimethylaminohydrolase
protein arginine N-methyltransferases (PRMT types
I and II)
Cooke, J.P. Circulation 109, 18131819 (2004).
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The NOS reaction mechanism.The heme moiety of
the enzyme is colored
Nitric oxide synthase produces NO by catalysing a
five-electron oxidation of a guanidino nitrogen
of L-arginine (L-Arg). Oxidation of L-Arg to
L-citrulline occurs via two successive
monooxygenation reactions producing
N?-hydroxy-L-arginine (NOHLA) as an intermediate.
2 mol of O2 and 1.5 mol of NADPH are consumed per
mole of NO formed
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• Methylation of arginine residues (R) in proteins
  and subsequent proteolysis results in the
  liberation of free methylarginines, including
  asymmetric dimethylarginine (ADMA R-Me2), an
  inhibitor of nitric oxide synthases (NOS).
• ADMA is metabolised by dimethylarginine
  dimethylaminohydrolase (DDAH) to citrulline (CIT)
  and dimethylamine (MA)

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Thanks for your attention !
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Endothelin

• Elevated Endothelin-1 Levels Impair Nitric Oxide
  Homeostasis Through a PKC-Dependent Pathway

Circulation. 2006114suppl II-319I-326.)
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Fisher Grade
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Brain Resuscitation
Conventional GCS, NE ICP oriented Restricted C
rystalloid (-) (-)
Current Trend Cerebral monitor ICP, CPP, CBF
Euvolemia Crystalloid, Colliod Depends
(), ? metabolism
Monitor Target Volume Fluid Pressor Sedatives
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Hunt and Hess Grade
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Postoperative Angiography (1/27)
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TCD for Vasospasm (2)

• VMCA/VICA ratio (Lindegaard index)
• Distinguish states of increased flow in the MCA
  caused by genuine spasm from those caused by
  hyperemia
• Mild vasospasm
• Mean MCA velocity 94 cm/sec
• Peak systolic VMCA/VICA ratio of 3.6
• Moerate-to-severe vasospasm
• Mean MCA velocity 108 cm/sec
• Peak systolic VMCA/VICA ratio of 3.9

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Vasospasm Prevention

• Avoid hypovolemia, hypotension, antihypertensive
  and antifibrinolytic drugs( prevent ischemic)
• Subarachnoid clot removal or lysis with
  fibrinolytic agents( prevent vasospasm)
• Calcium channel blockers and other
  neuroprotectants( prevent ischemic damage)
• 21-Aminosteroid and other antioxidant, lipid
  peroxidation inhibitors and free radical
  scavengers
• Intrathecally administered slow release
  vasodilators (experimental treatment)
• Endothelin inhibitors and antagonist
  (experimental treatment)

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Effect of hypervolemic therapy after subarachnoid
hemorrhage
Stroke. 31383-391, 2000 J neurosurg
98978-984,2003
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Effect of hypervolemic therapy after subarachnoid
hemorrhage
Stroke. 31383-391, 2000 J neurosurg
98978-984,2003
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Effect of Nicardipine Prolonged-Release Implants
on Cerebral Vasospasm
Stroke 200738330-336 Neurosurgery.
200556895902
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CT perfusion in detection of cerebral vasospasm

• Accurate, reliable and non-invasive
• Guide the decision to pursue angiography

Neurosurgery 56304-317, 2005 Neurosurg Focus 21
(3)E7, 2006
53
Intravenous Magnesium in the Treatment of
Patients With Aneurysmal SAH

• MgSO4 calcium antagonist and vasodilator
• Antagonism of N-methyl-D-aspartate receptor

Neurosurgery 581054-1065, 2006