This document discusses subarachnoid hemorrhage (SAH) and vasospasm, which is a common complication of SAH. It provides an overview of the pathophysiology of SAH and vasospasm, involving factors such as nitric oxide, endothelin-1, and oxidative stress. Current standard therapies aim to prevent rebleeding and improve cerebral blood flow, but have limitations. Emerging therapies are being investigated to more effectively treat and prevent 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

9. Newest
Guidelines

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