SAH  and  Vasospasm:    Emerging  Therapies  

Dr. Stuart Wright MD PhD PGY 5 CCM Fellow

Objec9ves  

•  Subarachnoid  hemorrhage    •  Vasospasm    

•  Pathophysiology  •  Current  therapies  •  Emerging  therapies  

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.  

Clinical  Features  

•  Sudden  onset  HA  that  lasts  1-­‐2  weeks  (74%)  •  Vomi9ng  (77%)  

•  Decreased  LOC  (53%)  •  Nuchal  rigidity  (35%)  •  Focal  deficit  (15%)  •  Seizures  (7%)  

•  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  

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  

Newest  Guidelines  

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  

SAH  

•  Outcomes  are  poor  •  Mortality,  50%  from  SAH  

•  Morbidity,  15%  severely  disabled  

•  Only  20-­‐35%  of  pa9ents  will  have  moderate  to  good  recovery    

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  

Risk  factors  •  HTN  •  Heavy  alcohol  use  •  Smoking  •  Sympathomime9c  drugs  (cocaine)  

•  Previous  ruptured  aneurysm  •  Congenital    

–  PCKD  –  Ehlers  Danlos  type  IV  

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    

Surgical  vs  Endovascular  Treatment  

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  

Vasospasm  

•  Presents  as:  – New  onset  focal  deficit  – Unexplained  hydrocephalus  – Rebleeding  – Unexplained  increases  in  MAP  (compensatory)  

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)  

Pathophysiology  

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  

Nitric  Oxide  

•  SAH  inhibi9on  of  NO  synthase  •  ADMA,  endogenous  inhibitor  of  eNOS,  high  with  vasospasm  

•  NO  may  reverse  vasocontrictor  ET-­‐1  effects  

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  

Vasospasm  

•  Goals  of  management:  – Reduce  the  threat  of  ischemic  damage  

•  Control  ICP  •  Decreasing  brain  metabolic  rate  

•  Improving  CBF  

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]  

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)  

Triple  H  Therapy  

•  Hypervolemia/  Hemodilu9on/  Hypertension  

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  

Triple  H  Therapy  

•  Side  effects:  – Pulmonary  edema  

– Cardiac  arrythmia  –  Increased  risk  in  elderly  pa9ents  with  poor  cardiac  reserve  

Triple  H  Therapy  

•  1  randomized  trial  of  pa9ents  to  Hypervolemia  versus  normovolemia  post  clipping  

•  No  effect  on  CBF  or  vasospasm  

Triple  H  Therapy  

•  Cochrane  review  in  2004  confirmed  as  no  solid  evidence  for  volume  expansion  

Triple  H  Therapy  

•  Started  with  interven9ons  on  pig  model  and  then  took  protocol  to  pa9ents  post  SAH  

•  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  

Triple  H  Therapy  

•  “Standard  triple  H  therapy”  should  be  modified    – HTN  with  careful  volume  expansion  should  be  the  new  standard  

Sta9ns  !  

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  

Sta9ns  and  SAH  

•  12-­‐fold  increase  in  odds  of  surviving  SAH  if  previously  on  sta9ns  

“Statin treatment reduces need for traditional rescue therapy, and improved outcome in physical and psychosocial function at 6 months”

“incidence and severity were reduced by 32%”

“duration of vasospasm was shortened by 0.8 days”

“vasospasm morbidity and mortality reduced by 83 and 75%, respectively”

BUT…..  

•  Various  groups  added  the  therapy  into  their  “standard  care”  

•  Now  star9ng  to  get  reports  of  their  outcome  analyses  

“All patients were started on a statin on admission and no clinical difference was noted”

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  

Magnesium  

•  Calcium  antagonist  •  Good  safety  profile  •  Comparable  to  nimodipine  alone  

•  No  studies  adding  to  nimodipine  

Magnesium  

•  34%  Reduc9on  in  delayed  cerebral  ischemia  •  23%  Reduc9on  in  poor  outcome  at  3  months  

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  

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  

EPO  

•  May  be  “neuroprotec9ve”  •  May  prevent  vasospasm  by  increasing  ac9va9on  of  eNOS  –  NO  donor  

•  S9ll  preliminary  

Conclusion  

•  SAH  is  a  devasta9ng  problem  affec9ng  younger  popula9on  

•  Vasospasm  is  a  known  poten9ally  modifiable    problem  with  significant  morbidity  and  mortality  

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  

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