Journal ClubJournal ClubAnna SolthAnna Solth

ST1 NeurosurgeryST1 NeurosurgeryNewcastleNewcastle

14/01/201014/01/2010

1. Journal1. Journal

Background: NimodipineBackground: 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 DINDBackground: SAH and DIND Delayed Ischaemic Neurologic Deficit (aka clinical Delayed Ischaemic Neurologic Deficit (aka clinical

vasospasm)vasospasm) Onset 4-20 days post SAH (peak 7.-10. day)Onset 4-20 days post SAH (peak 7.-10. day) PathogenesisPathogenesis Most significant cause of morbidity and mortality Most significant cause of morbidity and mortality

if initial SAH is survivedif initial SAH is survived „„Ischaemia may be the effect of several factors Ischaemia may be the effect of several factors

and can not be simply attributed to contraction of and can not be simply attributed to contraction of cerebral arteries (vasospasm)“cerebral arteries (vasospasm)“

[Other factors may be: raised ICP due to [Other factors may be: raised ICP due to haematoma/hydrocephalus, hypotension, haematoma/hydrocephalus, hypotension, hypovolaemia, hyponatraemia, iatrogenic]hypovolaemia, hyponatraemia, iatrogenic]

VasospasmVasospasm

Intima swelling and thickening opening of tight junctionsMedia necrosisAdventita: inflammation

Cerebral InfarctionCerebral Infarction

ObjectiveObjective

To assess the (prophylactic) effect of To assess the (prophylactic) effect of Nimodipine on cerebral ischaemina Nimodipine on cerebral ischaemina (primary end point) and outcome (primary end point) and outcome (secondary end point) after SAH(secondary end point) after SAH

NOT: to assess the influence of NOT: to assess the influence of Nimodipine on cerebral vasospasmNimodipine on cerebral vasospasm

MethodsMethods 4 Neurosurgical Centres4 Neurosurgical Centres

Randomized, controlled, prospective, Randomized, controlled, prospective, double blind studydouble blind study

Nimodipine vs PlaceboNimodipine vs Placebo Treatment started within 96 hoursTreatment started within 96 hours Route: po (NG) Dose 60mg/4° For 21/7 Exclusion CriteriaExclusion Criteria

MethodsMethods Deterioation was defined as development of focal sign or reduction Deterioation was defined as development of focal sign or reduction

in GCSin GCS Classification of SAH Grade according to WFNS Classification of SAH Grade according to WFNS

GCSGCS Neurologic deficitNeurologic deficit

II 1515 --

IIII 13-1413-14 --

IIIIII 13-1413-14 ++

IVIV 8-128-12 +/-+/-

VV 3-73-7 +/-+/-

Resultsn=554(~2 years)

Intercentre Variability

ResultsResults

Nimodipine effects poor outcome (secondary) even more significant than cerebral infarction (primary outcome event)

ResultsResults

ResultsResults Effect on BPEffect on BP Progressive reduction Progressive reduction

in BP over 21 days –in BP over 21 days –NOT significantNOT significant

(four breaks of code: x2 (four breaks of code: x2 hypotension – both placebo, x2 hypotension – both placebo, x2 jaundice – 1 placebo, 1 jaundice – 1 placebo, 1 nimodipine)nimodipine)

Adverse Effects of Adverse Effects of NimodipineNimodipine

Cardiovascular Cardiovascular (headache, flushing, 1 (headache, flushing, 1 hypertension, 1 hypertension, 1 hypotension)hypotension)

Liver functionLiver function

Rash x 2Rash x 2(Patients taking placebo (Patients taking placebo

had similar adverse had similar adverse effects)effects)

DiscussionDiscussion

Nimodipine significantly reduces Nimodipine significantly reduces

Cerebral Infarction AND Poor Outcome.Cerebral Infarction AND Poor Outcome.

Effect on outcome greater than Effect on outcome greater than expected from reduction of cerebral expected from reduction of cerebral infarction: Protection against small infarction: Protection against small and diffusely distributed infarcts?and diffusely distributed infarcts?

DiscussionDiscussion

Nimodipine should be given Nimodipine should be given prophylactically to prevent cerebral prophylactically to prevent cerebral infarction and therefore should be infarction and therefore should be started within 96 hours of bleed (it started within 96 hours of bleed (it should be started should be started beforebefore the onset of the onset of vasospasm)vasospasm)

Radiographic vasospasm was not Radiographic vasospasm was not improved in the Nimodipine group improved in the Nimodipine group (results in accordance with previous (results in accordance with previous studies, Allen et al.)studies, Allen et al.)

DiscussionDiscussion

Nimodipine poNimodipine po vs. ivvs. iv iv bioavaiability higher than po, but iv bioavaiability higher than po, but

similar plasma levels reached. CSF similar plasma levels reached. CSF levels are much lower than serum levels are much lower than serum levelslevels

No clinical evidence suggesting No clinical evidence suggesting differencedifference

DiscussionDiscussion

Higher dose?Higher dose? Nimodipine in angiography –ve SAH?Nimodipine in angiography –ve SAH? Working mechanism of Nimodipine: Working mechanism of Nimodipine:

unclearunclear

AnalysisAnalysis

Randomized controlled trialRandomized controlled trial MulticentreMulticentre Double blindDouble blind

IbIb

2. Journal2. Journal

Background: SCSBackground: SCS

Spinal Cord StimulationSpinal Cord Stimulation Stimulation of spinal cord causes pain Stimulation of spinal cord causes pain

reliefrelief Intradural electrodes at the level of Intradural electrodes at the level of

pain, connected to an external pain, connected to an external generatorgenerator

Indications: pain (including angina), Indications: pain (including angina), dystonia, spasticitydystonia, spasticity

Trial SCS over several days, Trial SCS over several days, Permanent SCS if succesfulPermanent SCS if succesful

Hosobuchi Y 1985Hosobuchi Y 1985

10 patients: 10 patients: 5 had cervical spinal cord stimulation5 had cervical spinal cord stimulation significant increase in CBF in the significant increase in CBF in the

hemisphere ipsilateral to the induced hemisphere ipsilateral to the induced paresthesia. paresthesia.

(5 had thoracic SCS: no effect on CBF)(5 had thoracic SCS: no effect on CBF)

MethodsMethodsAnimal model. 71 RatsAnimal model. 71 Rats

1.1. Induction of SAH:Induction of SAH: double haemorrhage. Controls: 0.9% double haemorrhage. Controls: 0.9% SalineSaline

2.2. SCS:SCS: Day 0 or Day5. C1 level. 3 cycles. Day 0 or Day5. C1 level. 3 cycles.

3.3. Histology:Histology: Perfusion fixation with formaldehyde. Perfusion fixation with formaldehyde. Measurement of BA diameter and cross sectional-areaMeasurement of BA diameter and cross sectional-area

4.4. Laser Doppler FLowmetry LDF:Laser Doppler FLowmetry LDF: via burrholes via burrholes

5.5. CBF studies:CBF studies: using using 1414C-IMP radiotracer iv during C-IMP radiotracer iv during stimulation and quantification in different brain regionsstimulation and quantification in different brain regions

Results: BA MeasurementsResults: BA Measurements

Basilar artery diameter. Cross-sectional area. Histological changes: corrugation of internal elastic lamina, vessel wall tickening.

Results: BA MeasurementsResults: BA Measurements

Results: LDFResults: LDF

Results: CBF measurementsResults: CBF measurements

Results: CBF MeasurementsResults: CBF Measurements

ConclusionConclusion

In this animal model cervical SCS In this animal model cervical SCS leads to significant vasodilation, leads to significant vasodilation, improvement in cerbreal blood flow. improvement in cerbreal blood flow.

Spinal cord stimulation may Spinal cord stimulation may represent a useful adjunct in the represent a useful adjunct in the treatment of vasospasm. treatment of vasospasm.

AnalysisAnalysis

Experimental studyExperimental study Small numbers (n=5)Small numbers (n=5) Importance of histology Importance of histology

measurements?measurements?

Thank you!Thank you!

Appl Neurophysiol. 1985;48(1-6):372-6.Appl Neurophysiol. 1985;48(1-6):372-6. Electrical stimulation of the cervical spinal cord Electrical stimulation of the cervical spinal cord

increases cerebral blood flow in humans.increases cerebral blood flow in humans. HosobuchiHosobuchi Y Y.. Ten patients were studied to determine the effect of spinal Ten patients were studied to determine the effect of spinal

cord stimulation on CBF. In 5 patients using a cervical cord stimulation on CBF. In 5 patients using a cervical spinal cord stimulator, the stimulation produced a spinal cord stimulator, the stimulation produced a significant increase in CBF in the hemisphere ipsilateral to significant increase in CBF in the hemisphere ipsilateral to the induced paresthesia. Thoracic cord stimulation, used by the induced paresthesia. Thoracic cord stimulation, used by the other 5 patients, had no effect on CBF. Atropine had no the other 5 patients, had no effect on CBF. Atropine had no effect on the alteration in CBF produced by cervical cord effect on the alteration in CBF produced by cervical cord stimulation. Indomethacin, however, partially blocked the stimulation. Indomethacin, however, partially blocked the effect. These heuristic observations may have implications effect. These heuristic observations may have implications for the future treatment of cerebrovascular insufficiency in for the future treatment of cerebrovascular insufficiency in humans.humans.

PMID: 3879799 [PubMed - indexed for MEDLINE]PMID: 3879799 [PubMed - indexed for MEDLINE]