1. Journal Club Anna Solth ST1 Neurosurgery Newcastle 14/01/2010 14/01/2010

2. 1. Journal

3. Background: Nimodipine -Calcium Channel Blocker -Binding to L-type voltage gated Calcium Channels -Pharmacokinetics -Bioavaiability100% (iv) 13% (Oral)ioavaiability -Proteinbinding95%Proteinbinding -MetabolismHepaticMetabolism -Half life8-9 hoursHalf life -ExcretionFaeces and UrineExcretion

4. Background: SAH and DIND Delayed Ischaemic Neurologic Deficit (aka clinical vasospasm) Delayed Ischaemic Neurologic Deficit (aka clinical vasospasm) Onset 4-20 days post SAH (peak 7.-10. day) Onset 4-20 days post SAH (peak 7.-10. day) Pathogenesis Pathogenesis Most significant cause of morbidity and mortality if initial SAH is survived 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)“ „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] [Other factors may be: raised ICP due to haematoma/hydrocephalus, hypotension, hypovolaemia, hyponatraemia, iatrogenic]

5. Vasospasm Intima swelling and thickening opening of tight junctions Media necrosis Adventita: inflammation

6. Cerebral Infarction

7. Objective To assess the (prophylactic) effect of Nimodipine on cerebral ischaemina (primary end point) and outcome (secondary end point) after SAH 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 NOT: to assess the influence of Nimodipine on cerebral vasospasm

8. Methods 4 Neurosurgical Centres 4 Neurosurgical Centres Randomized, controlled, prospective, double blind study Randomized, controlled, prospective, double blind study Nimodipine vs Placebo Nimodipine vs Placebo Treatment started within 96 hours Treatment started within 96 hours Route:po (NG) Dose 60mg/4° For 21/7 Exclusion Criteria Exclusion Criteria

9. Methods Deterioation was defined as development of focal sign or reduction in GCS Deterioation was defined as development of focal sign or reduction in GCS Classification of SAH Grade according to WFNS Classification of SAH Grade according to WFNS GCS Neurologic deficit I15- II13-14- III13-14+ IV8-12+/- V3-7+/-

10. Results n=554 (~2 years) Intercentre Variability

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

12. Results

13. Results Effect on BP Effect on BP Progressive reduction in BP over 21 days –NOT significant Progressive reduction in BP over 21 days –NOT significant (four breaks of code: x2 hypotension – both placebo, x2 jaundice – 1 placebo, 1 nimodipine) (four breaks of code: x2 hypotension – both placebo, x2 jaundice – 1 placebo, 1 nimodipine) Adverse Effects of Nimodipine Adverse Effects of Nimodipine Cardiovascular (headache, flushing, 1 hypertension, 1 hypotension) Cardiovascular (headache, flushing, 1 hypertension, 1 hypotension) Liver function Liver function Rash x 2 Rash x 2 (Patients taking placebo had similar adverse effects)

14. 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?

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

16. Discussion Nimodipine povs. iv Nimodipine povs. iv  iv bioavaiability higher than po, but similar plasma levels reached. CSF levels are much lower than serum levels  No clinical evidence suggesting difference

17. Discussion Higher dose? Higher dose? Nimodipine in angiography –ve SAH? Nimodipine in angiography –ve SAH? Working mechanism of Nimodipine: unclear Working mechanism of Nimodipine: unclear

18. Analysis Randomized controlled trial Randomized controlled trial Multicentre Multicentre Double blind Double blind Ib Ib

19. 2. Journal

20. Background: SCS Spinal Cord Stimulation Spinal Cord Stimulation Stimulation of spinal cord causes pain relief Stimulation of spinal cord causes pain relief Intradural electrodes at the level of pain, connected to an external generator Intradural electrodes at the level of pain, connected to an external generator Indications: pain (including angina), dystonia, spasticity Indications: pain (including angina), dystonia, spasticity Trial SCS over several days, Permanent SCS if succesful Trial SCS over several days, Permanent SCS if succesful

21. Hosobuchi Y 1985 10 patients: 10 patients: 5 had cervical spinal cord stimulation 5 had cervical spinal cord stimulation  significant increase in CBF in the hemisphere ipsilateral to the induced paresthesia.  significant increase in CBF in the hemisphere ipsilateral to the induced paresthesia. (5 had thoracic SCS: no effect on CBF) (5 had thoracic SCS: no effect on CBF)

22. Methods Animal model. 71 Rats 1. Induction of SAH: double haemorrhage. Controls: 0.9% Saline 2. SCS: Day 0 or Day5. C1 level. 3 cycles. 3. Histology: Perfusion fixation with formaldehyde. Measurement of BA diameter and cross sectional-area 4. Laser Doppler FLowmetry LDF: via burrholes 5. CBF studies: using 14 C-IMP radiotracer iv during stimulation and quantification in different brain regions

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

24. Results: BA Measurements

25. Results: LDF

26. Results: CBF measurements

27. Results: CBF Measurements

28. Conclusion In this animal model cervical SCS leads to significant vasodilation, improvement in cerbreal blood flow. 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. Spinal cord stimulation may represent a useful adjunct in the treatment of vasospasm.

29. Analysis Experimental study Experimental study Small numbers (n=5) Small numbers (n=5) Importance of histology measurements? Importance of histology measurements?

30. Thank you!

31. Appl Neurophysiol. 1985;48(1-6):372-6. Appl Neurophysiol. 1985;48(1-6):372-6. Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans. Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans. Hosobuchi Y. Hosobuchi Y. Hosobuchi Y 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. 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] PMID: 3879799 [PubMed - indexed for MEDLINE]