Prevention of Vasospasm in Subarachnoid Hemorrhage

1. Roy T. Hendley, MS, PharmD PGY-1 Pharmacy Resident The Methodist Hospital Houston, Texas January 21, 2008 Prevention of Vasospasm in Subarachnoid Hemorrhage

2. 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

3. Subarachnoid Hemorrhage (SAH)

4. Cerebrovascular Accident Cerebrovascular Accident Classification Stroke Trauma Epidural Hemorrhage Subdural Hemorrhage 70-85% 15-30% Vasospasm Ischemic Hemorrhagic Hypertension AVM Spontaneous Intracerebral Hemorrhage Embolus Thrombus Subarachnoid Hemorrhage Hypoperfusion TIA Aneurysm Cerebellum Pontine Basal Ganglia

5. Stroke Characteristics1-12 SICH = Spontaneous Intracerebral ISC = Ischemic

6. 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

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

8. SAH Management Issues • Hemorrhage • expansion, evacuation, hemostasis • Intracranial Pressure (ICP) management • Fever reduction • Seizure prophylaxis • Hyponatremia • SIADH vs. Cerebral Salt Wasting • Vasospasm prevention

9. 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.

10. Development of Delayed Vasospasm DINDs Suhardja. Nat Clin Pract Cardiovasc Med. 2004 Dec;1(2):110-6.

11. :10 The Fisher grading scale is based upon: • Glasgow Coma Scale • CT-defined hemorrhage pattern • intraventricular hemorrhage • aneurysm size

12. :10 The vasospasm theory consists of: • lysed erythrocytes • inflammatory mediators • sloughing of endothelial cells • failure of nitric oxide mechanism • all of the above

13. :10 The highest incidence of vasospasm occurs ______ after onset of SAH. • 1 - 2 days • 1 - 21 days • 3 - 14 days • 14 - 21 days

14. Therapies to Prevent Vasospasm

15. Vasospasm Prevention • Intracranial pressure (ICP) management • Triple H therapy • albumin • Calcium Channel Blockers • HMG-CoA Reductase Inhibitors • Milrinone • Magnesium sulfate

16. Triple H therapy

17. 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

18. Triple H Therapy • Hypertension • Hemodilution • Hypervolemia • Fluids used most often • 0.9% NaCl • 3% NaCl • Albumin 5%

19. Albumin • 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.

20. :10 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

21. Calcium Channel Blockers

22. Calcium Channel Blockers • Dihydropyridine • amlodipine (Norvasc®) • nicardipine (Cardene®) • nimodipine (Nimotop®) • Non-dihydropyridine • verapamil (Isoptin®) • diltiazem (Cardizem®)

23. 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.

24. Nimodipine • 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

25. :10 Appropriate route(s) of administration fornimodipine used to prevent vasospasm include: • oral • intravenous • both oral & intravenous • intraventricular

26. :10 Nimodipine has demonstrated greater benefit than nicardipine for which of the following: • prevention of vasospasms • mortality • both • neither. Agents have similar outcomes.

27. HMG-CoA Reductase Inhibitors

28. 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

29. Effects of Pravastatin after SAH Primary Endpoints • vasospasm • incidence • severity • duration Secondary Endpoints • DINDs • mortality Tseng Stroke. 2005;36:1627-32.

30. Pravastatin Results Tseng Stroke. 2005;36:1627-32.

31. Pravastatin results (cont’d.) **Data extended to Tseng et al. Stroke. 2007;38:1545-50.

32. Simvastatin Reduces Vasospasm after SAH • Primary Endpoints • Vasospasm • Secondary Endpoints • Markers • von Willebrand factor (vWF) • astrocyte protein S100β Lynch Stroke. 2005;36:2024-26.

33. Simvastatin Results Lynch Stroke. 2005;36:2024-26.

34. S100β mean concentrations 218 pg/ml  69 pg/ml vWF mean concentrations 24ng/ml  14ng/ml Simvastatin Results p < 0.05 p < 0.01

35. Cholesterol-dependent ↓ LDL (oxLDL) Cholesterol-independent 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%

36. Pleiotropic effects of HMG-CoA Reductase Inhibitors Endothelial function Anti-thrombotic Plaque stability Angiogenesis STATINS Anti-inflammatory Immunomodulatory Vascular cytoprotection Anti-oxidant Mason.Clin Sci (Lond). 2003 Sep;105(3):251-66.

37. :10 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

38. New Therapies

39. Milrinone • 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.

40. 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.

41. :10 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

42. Summary of Vasospasm Prevention • Triple H therapy • Nimodipine • HMG-CoA Reductase Inhibitors

43. Acknowledgements • David Romerill, Pharm.D., BCPS • TMH Continuing Pharmacy Education Board

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