Journal Club Anna Solth ST 1 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 n n n 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 n n 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 n n n n 4 Neurosurgical Centres Randomized, controlled, prospective, double blind study Nimodipine vs Placebo Treatment started within 96 hours Route: po (NG) Dose 60 mg/4° For 21/7 Exclusion Criteria
Methods n n Deterioation was defined as development of focal sign or reduction in GCS Classification of SAH Grade according to WFNS I II IV V GCS 15 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 n n n Effect on BP Progressive reduction in BP over 21 days –NOT significant n n (four breaks of code: x 2 hypotension – both placebo, x 2 jaundice – 1 placebo, 1 nimodipine) n Adverse Effects of Nimodipine Cardiovascular (headache, flushing, 1 hypertension, 1 hypotension) Liver function Rash x 2 (Patients taking placebo had similar adverse effects) n
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 n n 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 bioavaiability higher than po, but similar plasma levels reached. CSF levels are much lower than serum levels No clinical evidence suggesting difference n
Discussion n Higher dose? Nimodipine in angiography –ve SAH? Working mechanism of Nimodipine: unclear
Analysis n Randomized controlled trial Multicentre Double blind n Ib n n
2. Journal
Background: SCS n n n Spinal Cord 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 n n 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 1. Induction of SAH: double haemorrhage. Controls: 0. 9% Saline 2. SCS: Day 0 or Day 5. C 1 level. 3 cycles. 3. Histology: Perfusion fixation with formaldehyde. Measurement of 4. Laser Doppler FLowmetry LDF: via burrholes 5. CBF studies: using 14 C-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 n n 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 n n n Experimental study Small numbers (n=5) Importance of histology measurements?
Thank you!
n n n 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 [Pub. Med - indexed for MEDLINE]
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