Transcript Journal Club - Newcastle University

Journal Club
Anna Solth
ST1 Neurosurgery
Newcastle
14/01/2010
1. Journal
Background: Nimodipine
-Calcium Channel Blocker
-Binding to L-type voltage gated Calcium Channels
-Pharmacokinetics
-Bioavaiability
100% (iv) 13% (Oral)
-Proteinbinding 95%
-Metabolism
Hepatic
-Half life
8-9 hours
-Excretion
Faeces and Urine
Background: SAH and DIND
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Delayed Ischaemic Neurologic Deficit (aka clinical
vasospasm)
Onset 4-20 days post SAH (peak 7.-10. day)
Pathogenesis
Most significant cause of morbidity and mortality if initial
SAH is survived
„Ischaemia may be the effect of several factors and can
not be simply attributed to contraction of cerebral
arteries (vasospasm)“
[Other factors may be: raised ICP due to
haematoma/hydrocephalus, hypotension, hypovolaemia,
hyponatraemia, iatrogenic]
Vasospasm
Intima swelling and thickening
opening of tight junctions
Media necrosis
Adventita: inflammation
Cerebral Infarction
Objective
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To assess the (prophylactic) effect of
Nimodipine on cerebral ischaemina
(primary end point) and outcome
(secondary end point) after SAH
NOT: to assess the influence of
Nimodipine on cerebral vasospasm
Methods
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4 Neurosurgical Centres
Randomized, controlled, prospective, double
blind study
Nimodipine vs Placebo
Treatment started within 96 hours
Route: po (NG)
Dose 60mg/4°
For 21/7
Exclusion Criteria
Methods
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Deterioation was defined as development of focal sign or reduction in GCS
Classification of SAH Grade according to WFNS
I
II
III
IV
V
GCS
15
13-14
13-14
8-12
3-7
Neurologic deficit
+
+/+/-
Results
n=554
(~2 years)
Intercentre
Variability
Results
Nimodipine effects poor outcome (secondary) even more significant
than cerebral infarction (primary outcome event)
Results
Results
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Effect on BP
Progressive reduction in
BP over 21 days –NOT
significant
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(four breaks of code: x2 hypotension –
both placebo, x2 jaundice – 1 placebo,
1 nimodipine)
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Adverse Effects of
Nimodipine
Cardiovascular
(headache, flushing, 1
hypertension, 1
hypotension)
Liver function
Rash x 2
(Patients taking placebo had
similar adverse effects)
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Discussion
Nimodipine significantly reduces
Cerebral Infarction AND Poor Outcome.
Effect on outcome greater than expected
from reduction of cerebral infarction:
Protection against small and diffusely
distributed infarcts?
Discussion
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Nimodipine should be given
prophylactically to prevent cerebral
infarction and therefore should be started
within 96 hours of bleed (it should be
started before the onset of vasospasm)
Radiographic vasospasm was not
improved in the Nimodipine group (results
in accordance with previous studies, Allen
et al.)
Discussion
Nimodipine po
vs. iv
 iv bioavaiability higher than po, but similar
plasma levels reached. CSF levels are
much lower than serum levels
 No clinical evidence suggesting difference
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Discussion
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Higher dose?
Nimodipine in angiography –ve SAH?
Working mechanism of Nimodipine:
unclear
Analysis
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Randomized controlled trial
Multicentre
Double blind
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Ib
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2. Journal
Background: SCS
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Spinal Cord Stimulation
Stimulation of spinal cord causes pain
relief
Intradural electrodes at the level of pain,
connected to an external generator
Indications: pain (including angina),
dystonia, spasticity
Trial SCS over several days, Permanent
SCS if succesful
Hosobuchi Y 1985
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10 patients:
5 had cervical spinal cord stimulation
 significant increase in CBF in the
hemisphere ipsilateral to the induced
paresthesia.
(5 had thoracic SCS: no effect on CBF)
Methods
Animal model. 71 Rats
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Induction of SAH: double haemorrhage. Controls: 0.9% Saline
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SCS: Day 0 or Day5. C1 level. 3 cycles.
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Histology: Perfusion fixation with formaldehyde. Measurement of
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Laser Doppler FLowmetry LDF: via burrholes
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CBF studies: using 14C-IMP radiotracer iv during stimulation and
BA diameter and cross sectional-area
quantification in different brain regions
Results: BA Measurements
Basilar artery diameter. Cross-sectional area. Histological changes:
corrugation of internal elastic lamina, vessel wall tickening.
Results: BA Measurements
Results: LDF
Results: CBF measurements
Results: CBF Measurements
Conclusion
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In this animal model cervical SCS leads to
significant vasodilation, improvement in
cerbreal blood flow.
Spinal cord stimulation may represent a
useful adjunct in the treatment of
vasospasm.
Analysis
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Experimental study
Small numbers (n=5)
Importance of histology measurements?
Thank you!
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Appl Neurophysiol. 1985;48(1-6):372-6.
Electrical stimulation of the cervical spinal cord
increases cerebral blood flow in humans.
Hosobuchi Y.
Ten patients were studied to determine the effect of spinal
cord stimulation on CBF. In 5 patients using a cervical
spinal cord stimulator, the stimulation produced a
significant increase in CBF in the hemisphere ipsilateral to
the induced paresthesia. Thoracic cord stimulation, used by
the other 5 patients, had no effect on CBF. Atropine had no
effect on the alteration in CBF produced by cervical cord
stimulation. Indomethacin, however, partially blocked the
effect. These heuristic observations may have implications
for the future treatment of cerebrovascular insufficiency in
humans.
PMID: 3879799 [PubMed - indexed for MEDLINE]