Subarachnoid hemorrhage and Vasospasm

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Subarachnoid hemorrhage and Vasospasm

  1. 1. SAH  and  Vasospasm:     Emerging  Therapies   Dr. Stuart Wright MD PhD PGY 5 CCM Fellow
  2. 2. Objec9ves   •  Subarachnoid  hemorrhage     •  Vasospasm     •  Pathophysiology   •  Current  therapies   •  Emerging  therapies  
  3. 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. 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. 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. 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  
  7. 7. Newest  Guidelines  
  8. 8. 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  
  9. 9. SAH   •  Outcomes  are  poor   •  Mortality,  50%  from  SAH   •  Morbidity,  15%  severely  disabled   •  Only  20-­‐35%  of  pa9ents  will  have  moderate  to   good  recovery    
  10. 10. 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  
  11. 11. Risk  factors   •  HTN   •  Heavy  alcohol  use   •  Smoking   •  Sympathomime9c  drugs  (cocaine)   •  Previous  ruptured  aneurysm   •  Congenital     –  PCKD   –  Ehlers  Danlos  type  IV  
  12. 12. 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    
  13. 13. Surgical  vs  Endovascular  Treatment  
  14. 14. 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  
  15. 15. Vasospasm   •  Presents  as:   –  New  onset  focal  deficit   –  Unexplained  hydrocephalus   –  Rebleeding   –  Unexplained  increases  in  MAP  (compensatory)  
  16. 16. 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)  
  17. 17. Pathophysiology  
  18. 18. 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  
  19. 19. Nitric  Oxide   •  SAH  inhibi9on  of  NO  synthase   •  ADMA,  endogenous  inhibitor  of  eNOS,  high   with  vasospasm   •  NO  may  reverse  vasocontrictor  ET-­‐1  effects  
  20. 20. 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  
  21. 21. Vasospasm   •  Goals  of  management:   –  Reduce  the  threat  of  ischemic  damage   •  Control  ICP   •  Decreasing  brain  metabolic  rate   •  Improving  CBF  
  22. 22. 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]  
  23. 23. 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)  
  24. 24. Triple  H  Therapy   •  Hypervolemia/  Hemodilu9on/  Hypertension  
  25. 25. 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  
  26. 26. Triple  H  Therapy   •  Side  effects:   –  Pulmonary  edema   –  Cardiac  arrythmia   –  Increased  risk  in  elderly  pa9ents  with  poor  cardiac   reserve  
  27. 27. Triple  H  Therapy   •  1  randomized  trial  of  pa9ents  to  Hypervolemia   versus  normovolemia  post  clipping   •  No  effect  on  CBF  or  vasospasm  
  28. 28. Triple  H  Therapy   •  Cochrane  review  in  2004  confirmed  as  no  solid   evidence  for  volume  expansion  
  29. 29. Triple  H  Therapy   •  Started  with  interven9ons  on  pig  model  and   then  took  protocol  to  pa9ents  post  SAH  
  30. 30. •  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  
  31. 31. Triple  H  Therapy   •  “Standard  triple  H  therapy”  should  be  modified     –  HTN  with  careful  volume  expansion  should  be  the   new  standard  
  32. 32. Sta9ns  !  
  33. 33. 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  
  34. 34. Sta9ns  and  SAH   •  12-­‐fold  increase  in  odds  of  surviving  SAH  if   previously  on  sta9ns  
  35. 35. “Statin treatment reduces need for traditional rescue therapy, and improved outcome in physical and psychosocial function at 6 months”
  36. 36. “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”
  37. 37. BUT…..   •  Various  groups  added  the  therapy  into  their   “standard  care”   •  Now  star9ng  to  get  reports  of  their  outcome   analyses  
  38. 38. “All patients were started on a statin on admission and no clinical difference was noted”
  39. 39. 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  
  40. 40. Magnesium   •  Calcium  antagonist   •  Good  safety  profile   •  Comparable  to  nimodipine  alone   •  No  studies  adding  to  nimodipine  
  41. 41. Magnesium   •  34%  Reduc9on  in  delayed  cerebral  ischemia   •  23%  Reduc9on  in  poor  outcome  at  3  months  
  42. 42. 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  
  43. 43. 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  
  44. 44. EPO   •  May  be  “neuroprotec9ve”   •  May  prevent  vasospasm  by  increasing   ac9va9on  of  eNOS  –  NO  donor   •  S9ll  preliminary  
  45. 45. Conclusion   •  SAH  is  a  devasta9ng  problem  affec9ng   younger  popula9on   •  Vasospasm  is  a  known  poten9ally  modifiable     problem  with  significant  morbidity  and   mortality  
  46. 46. 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  
  47. 47. 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  

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