![Standard
Therapy
• Preven9on
of
rebleed:
– by
securing
intracranial
aneurysm
within
24-‐48h
• Can
allow
SBP
to
rise
to
200
mmHg
• Avoid:
– hypovolemia,
hypotension,
anemia,
fever
and
increased
ICP
• Nimodipine
60
mg
Q4h
PO
for
21
days
– IV
form
in
Europe
but
no
difference
in
clinical
effect
[Kronvall
2009]](https://image.slidesharecdn.com/sahandvasospasm-100119150702-phpapp02/85/Subarachnoid-hemorrhage-and-Vasospasm-24-320.jpg)
Subarachnoid hemorrhage and Vasospasm
- 1. SAH and Vasospasm: Emerging Therapies Dr. Stuart Wright MD PhD PGY 5 CCM Fellow
- 2. Objec9ves • Subarachnoid hemorrhage • Vasospasm • Pathophysiology • Current therapies • Emerging therapies
- 3. Case Scenario • A 45 year old woman, who frequently presents with migraine reports her "worst migraine ever" and on specific ques9oning reports a sudden onset occipital headache now generalised with associated vomi9ng. She requests analgesia and an an9eme9c so that she can "sleep it off at home" and has brought her son to drive her home.
- 4. Clinical Features • Sudden onset HA that lasts 1-‐2 weeks (74%) • Vomi9ng (77%) • Decreased LOC (53%) • Nuchal rigidity (35%) • Focal deficit (15%) • Seizures (7%)
- 5. • Missed because sudden, severe headache is not present in 25% of pa9ents • 1 in 10 with sudden headache, SAH is the cause • Missed in 20-‐50% of pa9ents at first presenta9on
- 6. Diagnosis • CT scan AND lumbar puncture if scan is nega9ve • If SAH is found, it is usually followed with catheter cerebral angio or MR/CT angio to document the anatomic features • CT scan detects 93-‐98% of SAH
- 10. Subarachnoid Hemorrhage • Common and devasta9ng condi9on affec9ng younger pa9ents • Accounts for 3-‐8% of all strokes • Responsible for 25% of years lost due to stroke • 7-‐20 per 100,000 people annually
- 11. SAH • Outcomes are poor • Mortality, 50% from SAH • Morbidity, 15% severely disabled • Only 20-‐35% of pa9ents will have moderate to good recovery
- 12. SAH • Incidence stable over last 4 decades • Incidence increases with age (mean 50 years) • Females more than males (1.6 x) • Black North Americans higher risk than white
- 13. Risk factors • HTN • Heavy alcohol use • Smoking • Sympathomime9c drugs (cocaine) • Previous ruptured aneurysm • Congenital – PCKD – Ehlers Danlos type IV
- 14. Preopera9ve care • Blood pressure should be monitored and controlled – balance of CPP vs HTN induced rebleed • SBP < 160 -‐ one study in 2001 (Ohkuma et al) found rebleeding was more common in those with a systolic blood pressure 160 mm Hg
- 15. Surgical vs Endovascular Treatment
- 16. Vasospasm • Common post-‐opera9ve complica9on: – 3-‐5 days post SAH – Resolu9on over 2-‐4 weeks – Radiographically in 70% of pa9ents – Clinically apparent in 20-‐30% of pa9ents – 50% of symptoma9c pts will progress to infarct – 15-‐20% will have a disabling stroke or die of ischemia
- 17. Vasospasm • Presents as: – New onset focal deficit – Unexplained hydrocephalus – Rebleeding – Unexplained increases in MAP (compensatory)
- 18. Vasospasm Pathogenesis • Likely mul9factorial but involves: – Presence of clot (clot burden and risk of vasospasm) – Blood compounds (Hb, bilirubin oxida9on products) – Induced compounds (endothelin -‐1, nitric oxide)
- 19. Pathophysiology
- 20. Nitric oxide • NO is a potent vasodilator • NO ac9vates guanylyl cyclase to ac9vate cGMP-‐dependent protein kinases • Dephosphoryla9on of myosin, ac9va9on of K+ channels and closure of voltage-‐dependent Ca2+ channels = smooth muscle relaxa9on • Low levels in SAH – free Hb mops up NO
- 21. Nitric Oxide • SAH inhibi9on of NO synthase • ADMA, endogenous inhibitor of eNOS, high with vasospasm • NO may reverse vasocontrictor ET-‐1 effects
- 22. Endothelin-‐1 • ET-‐1 cleaved by endothelin conver9ng enzyme to ac9ve form • Potent vasoconstrictor (ETA ) via G-‐protein secondary messenger • ET-‐1 produced by endothelial cells by ischemia, high in SAH • Lower levels in absence of vasospasm
- 23. Vasospasm • Goals of management: – Reduce the threat of ischemic damage • Control ICP • Decreasing brain metabolic rate • Improving CBF
- 24. Standard Therapy • Preven9on of rebleed: – by securing intracranial aneurysm within 24-‐48h • Can allow SBP to rise to 200 mmHg • Avoid: – hypovolemia, hypotension, anemia, fever and increased ICP • Nimodipine 60 mg Q4h PO for 21 days – IV form in Europe but no difference in clinical effect [Kronvall 2009]
- 25. Standard therapy • Nimodipine • Predominant effect is not through a decrease in angiographic vasospasm • Probably acts through effects on microcircula9on and neuroprotec9on • Nicardipine does reduce vasospasm but did not affect outcome (Haley 1993)
- 26. Triple H Therapy • Hypervolemia/ Hemodilu9on/ Hypertension
- 27. Triple H Therapy • Hypervolemia/ Hemodilu9on/ Hypertension • At first sign of clinical vasospasm: – Hypervolemic hemodilu9on goal hematocrit 33-‐38% – CVP 10-‐12 mmHg (PAWP 15-‐18 mmHg) – SBP 160-‐200 mmHg in clipped aneurysms • Cohort compared to literature standards
- 28. Triple H Therapy • Side effects: – Pulmonary edema – Cardiac arrythmia – Increased risk in elderly pa9ents with poor cardiac reserve
- 29. Triple H Therapy • 1 randomized trial of pa9ents to Hypervolemia versus normovolemia post clipping • No effect on CBF or vasospasm
- 30. Triple H Therapy • Cochrane review in 2004 confirmed as no solid evidence for volume expansion
- 31. Triple H Therapy • Started with interven9ons on pig model and then took protocol to pa9ents post SAH
- 32. • In pigs with intact BBB, neither HTN or hypervolemia had an effect on ICP, CBF or brain oxygena9on • BUT in pa9ents, induced HTN (MAP >130) resulted in inc. CBF and brain oxygena9on • Hypervolemia had minimal to no effect • HHH combo reversed HTN effects on brain oxygena9on
- 33. Triple H Therapy • “Standard triple H therapy” should be modified – HTN with careful volume expansion should be the new standard
- 34. Sta9ns !
- 35. Sta9ns and SAH • Sta9ns not only func9on to lower cholesterol but are also potent NO inducers and down-‐ regulators of inflamma9on • Observa9onal studies of sta9n use in pa9ents were encouraging
- 37. Sta9ns and SAH • 12-‐fold increase in odds of surviving SAH if previously on sta9ns
- 38. “Statin treatment reduces need for traditional rescue therapy, and improved outcome in physical and psychosocial function at 6 months”
- 39. “vasospasm morbidity and mortality reduced by 83 and 75%, respectively” “incidence and severity were reduced by 32%” “duration of vasospasm was shortened by 0.8 days”
- 40. BUT….. • Various groups added the therapy into their “standard care” • Now star9ng to get reports of their outcome analyses
- 41. “All patients were started on a statin on admission and no clinical difference was noted”
- 42. Sta9ns • So what does this mean for the use of Sta9ns: – They don’t appear to be a good rescue tool – But if you were on it for >1 month prior to event there is an 11-‐fold harm reduc9on
- 43. Magnesium • Calcium antagonist • Good safety profile • Comparable to nimodipine alone • No studies adding to nimodipine
- 44. Magnesium • 34% Reduc9on in delayed cerebral ischemia • 23% Reduc9on in poor outcome at 3 months
- 45. Clazosentan • ETA antagonist in Phase II trial • CONSCIOUS-‐1 study • Decreased incidence of vasospasm, DIND, and infarcts on CT in dose-‐dependent manner • BUT, no reduc9on in mortality (underpowered) • CONSCIOUS-‐2, currently enrolling
- 46. NO donors • Gene therapy – way too experimental • Intraventricular administra9on of sodium nitroprusside tried in 10 pa9ents with medically refractory vasospasm – 3 pts had excellent outcome • More to come
- 47. EPO • May be “neuroprotec9ve” • May prevent vasospasm by increasing ac9va9on of eNOS – NO donor • S9ll preliminary
- 48. Conclusion • SAH is a devasta9ng problem affec9ng younger popula9on • Vasospasm is a known poten9ally modifiable problem with significant morbidity and mortality
- 49. Conclusion • Preven9on of vasospasm: – Oral nimodipine is of proven benefit – Star9ng a sta9n – jury s9ll out – If a pa9ent is on a sta9n, con9nue it ASAP • Rescue therapy for vasospasm is beuer coined as “Hypertensive therapy” with judicious volume maintenance
- 50. Conclusion • Magnesium therapy may be of benefit if added to nimodipine or if nimodipine is contraindicated • There are specific targets s9ll under inves9ga9on and therapies in the pipeline but not ready for prime-‐9me