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Roy T. Hendley, MS, PharmD PGY-1 Pharmacy Resident The Methodist Hospital Houston, Texas January 21, 2008. Prevention of Vasospasm in Subarachnoid Hemorrhage. Learning Objectives. Assess grading scales and risk for vasospasm Describe Triple H therapy

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Roy T. Hendley, MS, PharmD

PGY-1 Pharmacy Resident

The Methodist Hospital

Houston, Texas

January 21, 2008

Prevention of Vasospasm in Subarachnoid Hemorrhage

learning objectives
Learning Objectives
  • Assess grading scales and risk for vasospasm
  • Describe Triple H therapy
  • Describe the use of calcium channel blockers in vasospasm prevention
  • Describe the evolving role of HMG-CoA Reductase Inhibitors in the management of vasospasm
  • Identify novel therapeutic approaches for management of vasospasm in SAH
cerebrovascular accident classification



Cerebrovascular Accident Classification



Epidural Hemorrhage

Subdural Hemorrhage








Spontaneous Intracerebral Hemorrhage



Subarachnoid Hemorrhage






Basal Ganglia

stroke characteristics 1 12
Stroke Characteristics1-12

SICH = Spontaneous Intracerebral

ISC = Ischemic

sah grading scales
SAH Grading Scales
  • Hunt and Hess (neurological status)
  • WFNS* (Glasgow Coma Scale + motor deficit)
  • Fisher (vasospasm risk)
  • Claassen (ischemia risk 2° to vasospasm)
  • Ogilvy and Carter (predict outcome of therapy)
    • H/H + Fisher + aneurysm size

* World Federation of Neurological Surgeons

fisher grading scale
Fisher Grading Scale

Fisher. Neurosurgery. 1980 Jan;6(1):1-9.

sah management issues
SAH Management Issues
  • Hemorrhage
    • expansion, evacuation, hemostasis
  • Intracranial Pressure (ICP) management
  • Fever reduction
  • Seizure prophylaxis
  • Hyponatremia
    • SIADH vs. Cerebral Salt Wasting
  • Vasospasm prevention
vasospasm theory
Vasospasm Theory
  • Lysed erythrocytes
    • oxyhemoglobin
      • influx of calcium into VSMC causing contraction
      • free radicals forming vasoactive substances
  • Inflammatory response
    • TXA2, leukotrienes and histamine in CSF
  • Sloughing of endothelial cells
    • vasoactive substances reach VSMC
  • Failure of nitric oxide mechanism

Oyama. Crit Care Nurse. 2004 Oct;24(5):58-67.


Development of Delayed Vasospasm


Suhardja. Nat Clin Pract Cardiovasc Med. 2004 Dec;1(2):110-6.

the fisher grading scale is based upon


The Fisher grading scale is based upon:
  • Glasgow Coma Scale
  • CT-defined hemorrhage pattern
  • intraventricular hemorrhage
  • aneurysm size
the vasospasm theory consists of


The vasospasm theory consists of:
  • lysed erythrocytes
  • inflammatory mediators
  • sloughing of endothelial cells
  • failure of nitric oxide mechanism
  • all of the above
the highest incidence of vasospasm occurs after onset of sah


The highest incidence of vasospasm occurs ______ after onset of SAH.
  • 1 - 2 days
  • 1 - 21 days
  • 3 - 14 days
  • 14 - 21 days
vasospasm prevention
Vasospasm Prevention
  • Intracranial pressure (ICP) management
    • Triple H therapy
      • albumin
  • Calcium Channel Blockers
  • HMG-CoA Reductase Inhibitors
  • Milrinone
  • Magnesium sulfate
icp management
ICP Management
  • Fluids
  • Vasopressors to maintain MAP* > 90 mmHg
    • norepinephrine
    • vasopressin
    • phenylephrine
  • Goal: maintain cerebral perfusion
    • CPP** = MAP – ICP
    • normal CPP range: 70 – 100 mmHg

*MAP = mean arterial pressure

**CPP = cerebral perfusion pressure

triple h therapy18
Triple H Therapy
  • Hypertension
  • Hemodilution
  • Hypervolemia
  • Fluids used most often
    • 0.9% NaCl
    • 3% NaCl
    • Albumin 5%


  • Neuroprotective in ischemic stroke
    • hemodiluent
    • antioxidant
    • endothelial cell apoptosis inhibitor
    • maintenance of neuronal metabolism
  • Neuroprotective in SAH
    • modulates calcium, glutathione, TNF-α, nitric oxide and arachidonic acid
    • inhibits apoptosis
    • inhibits adhesion molecules

Suarez. J Neursurg 2004;100:585.

which of the following therapies is not a component of triple h therapy


Which of the following therapies is NOT a component of Triple H therapy:
  • epinephrine 1 mg/min
  • NS 1 liter at 100 ml/hr
  • albumin 5% at 2 ml/min
  • hydralazine 10 mg PO every 8 hours
calcium channel blockers22
Calcium Channel Blockers
  • Dihydropyridine
    • amlodipine (Norvasc®)
    • nicardipine (Cardene®)
    • nimodipine (Nimotop®)
  • Non-dihydropyridine
    • verapamil (Isoptin®)
    • diltiazem (Cardizem®)
nicardipine versus nimodipine
Nicardipine versus Nimodipine
  • Nicardipine
    • significant ability to reduce vasospasms
    • no mortality benefit
  • Nimodipine:
    • greater mortality benefit
    • less ability to reduce vasospasms

Feigin. Neurology 1998; 50:876-883.

  • MOA:
    • dihydropyridine blocks calcium influx through L-type calcium channels
  • Dose: 60 mg orally every 4 hours for 21 days
    • if NPO, extract liquid and flush through NGT
  • Adverse effects:
    • hypotension  cardiovascular collapse
appropriate route s of administration for nimodipine used to prevent vasospasm include


Appropriate route(s) of administration fornimodipine used to prevent vasospasm include:
  • oral
  • intravenous
  • both oral & intravenous
  • intraventricular
nimodipine has demonstrated greater benefit than nicardipine for which of the following


Nimodipine has demonstrated greater benefit than nicardipine for which of the following:
  • prevention of vasospasms
  • mortality
  • both
  • neither. Agents have similar outcomes.
hmg coa reductase inhibitor trials
HMG-CoA Reductase Inhibitor Trials

↑ Nitric Oxide (NO)

Attenuated vasospasm and DINDs after induced SAH

Dose dependent increase in NO independent of LDL

Restored endothelial function independent of LDL and NO

effects of pravastatin after sah
Effects of Pravastatin after SAH

Primary Endpoints

  • vasospasm
    • incidence
    • severity
    • duration

Secondary Endpoints

  • DINDs
  • mortality

Tseng Stroke. 2005;36:1627-32.

pravastatin results
Pravastatin Results

Tseng Stroke. 2005;36:1627-32.


Pravastatin results (cont’d.)

**Data extended to Tseng et al. Stroke. 2007;38:1545-50.

simvastatin reduces vasospasm after sah
Simvastatin Reduces Vasospasm after SAH
  • Primary Endpoints
    • Vasospasm
  • Secondary Endpoints
    • Markers
      • von Willebrand factor (vWF)
      • astrocyte protein S100β

Lynch Stroke. 2005;36:2024-26.

simvastatin results
Simvastatin Results

Lynch Stroke. 2005;36:2024-26.

simvastatin results34

mean concentrations

218 pg/ml  69 pg/ml


mean concentrations

24ng/ml  14ng/ml

Simvastatin Results

p < 0.05

p < 0.01

summary of hmg coa reductase inhibitors for vasospasm prevention

↓ LDL (oxLDL)


Nitric Oxide restoration

Summary of HMG-CoA Reductase Inhibitors for Vasospasm Prevention
  • ↓ Incidence vasospasm 42-58%
  • ↓ DINDs 14 days – 6 months
  • ↓ Mortality 75%
  • ↓ VMCA (EC function) 30%
  • ↓ need for rescue therapy 37%

Pleiotropic effects of HMG-CoA Reductase Inhibitors

Endothelial function


Plaque stability





Vascular cytoprotection


Mason.Clin Sci (Lond). 2003 Sep;105(3):251-66.



JG, a 55-year-old Caucasian female, presented to the emergency department (ED) reporting a sudden onset of "the worst headache of my life." A CT scan revealed a SAH due to a ruptured aneurysm which was then repaired. Medication orders at admission included nimodipine, norepinephrine and albumin. The physician consults pharmacy to dose the HMG-CoA Reductase Inhibitor for vasospasm prevention. Based on current literature, your recommendation is:

  • Somatostatin 10 mg PO daily
  • Sandostatin 30 mg PO daily
  • Simvastatin 80 mg PO daily
  • Pravastatin 10 mg PO daily
  • MOA: PDE III inhibitor
    • vasodilating and inotropic properties
  • Dosing:
    • load: 8 mg over 30 minutes
    • infusion: 0.5 – 1.5 mcg/kg/min for 14 days
  • Administration: Intra-arterial then intravenous
  • Contraindications:
    • HR > 100 bpm
    • 20% decrease in blood pressure

Fraticelli. Stroke. 2008 Mar;39(3):893-8.

magnesium sulfate
Magnesium Sulfate
  • MOA:
    • neuroprotective and vasodilatory effects
    • impedes formation of reactive O2 species
    • inhibits platelet aggregation
  • Dose:
    • 12 g in 500 mL of 0.9% NaCl
    • infused intravenously at rate of 21 mL/hour
  • Goal:
    • serum magnesium: 3 - 4 mg/dL

Muroi. Surg Neuro 2008;69:33-9.



JG’s condition began to worsen post-aneurysm repair. JG was intubated and an extraventricular drain was immediately placed to manage hydrocephalus. CPP 50 mmHg (nl: 70-100 mmHg) MAP 75 mmHg (nl: 90-110 mmHg) ICP 25 mmHg (nl: 0-10 mmHg)Which of the following medications would NOT be used to INCREASE the CPP?

  • nimodipine IV
  • lisinopril
  • norepinephrine
  • albumin
  • A & B
summary of vasospasm prevention
Summary of Vasospasm Prevention
  • Triple H therapy
  • Nimodipine
  • HMG-CoA Reductase Inhibitors
  • David Romerill, Pharm.D., BCPS
  • TMH Continuing Pharmacy Education Board

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