Tag Archives: dci

Cilostazol for DCI Prevention

Cilostazol is a phosphodiesterase III inhibitor which increases cAMP and leads to reversible inhibition of platelet aggregation, vasodilation and inhibition of vascular smooth muscle cell proliferation.  A systematic review was recently published in the Journal of Neurology on the effect of cilostazol on the incidence of delayed cerebral ischemia in subarachnoid hemorrhage (Department of Neurosurgery, West China Hospital).

The meta-analysis included seven studies, all of which were done in Japan:  three were randomized controlled studies, 3 were retrospective studies and one was a prospective study.  Most studies used cilostazol at 200mg per day for 14 days.

studies

Forest plots for the outcomes provided below:

A. Severe angiographic vasospasm

forest plot 1

B. Symptomatic vasospasm

forest plot 2

C. New cerebral infarction

forest plot 3

D. Poor outcome

forest plot 4

E.  Mortality

forest plot 5

Adverse effects related to cilostazol administration in the studies include diarrhea, transaminitis, tachycardia, headaches, hemorrhagic and cardiac events.

The meta-analysis concluded that cilostazol effectively reduced the incidence of severe angiographic vasospasm, symptomatic vasospasm, new cerebral infarction and poor outcome in patients with aneurysmal subarachnoid hemorrhage, but does not reduce mortality significantly.

It is important to note that all of the studies included in the meta-analysis were from one country (Japan), which precludes the generalization of the results to the general population.  Also, none of the patients in the studies received nimodipine, which has not been approved for SAH treatment in Japan.  Whether or not the co-administration of nimodipine would add to or nullify the benefits seen with cilostazol requires further investigation.

Take home message:  should not change current practice, needs further research.

 

References:

Shan, T., Zhang, T., Qian, W., Ma, L., Li, H., You, C. and Xie, X. (2019). Effectiveness and feasibility of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Journal of Neurology.

Uptodate.com. (2019). UpToDate. [online] Available at: https://www.uptodate.com/contents/cilostazol-drug-information?sectionName=Adult&topicId=8872&search=cilostazol&usage_type=panel&anchor=F151445&source=panel_search_result&selectedTitle=1~36&kp_tab=drug_general&display_rank=1#F151413 [Accessed 6 Apr. 2019].

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Relative Alpha Variability

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Reference:

Vespa, Paul M. et al. “Early Detection Of Vasospasm After Acute Subarachnoid Hemorrhage Using Continuous EEG ICU Monitoring”. Electroencephalography and Clinical Neurophysiology 103.6 (1997): 607-615. Web.

DCI Prevention (Failed Interventions)

Here is a list of failed interventions (so far) for DCI prevention in subarachnoid hemorrhage.

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Table was taken from first reference listed below.  The other references listed are the source articles (RCTs) where the table was based from.

Reference

Francoeur, Charles L. and Stephan A. Mayer. “Management Of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage”. Critical Care 20.1 (2016): n. pag. Web.

van den Bergh WM, Algra A, Dorhout Mees SM, van Kooten F, Dirven CMF, van Gijn J, Vermeulen M, Rinkel GJE. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH Study. Stroke. 2006;37:2326–30.

Petruck KC, West M, Mohr G, Weir BK, Benoit BG, Gentilli F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, Cameron S, Tucker WS, Purves GB, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Cleain LJ, Maroun FB, Godon A. Nimodipine treatment in poor-grade aneurysm patients. J Neurosurg. 1988;68:505–17.

Siironen J, Juvela S, Varis J, Porras M, Poussa K, Ilveskero S, Hernesniemi J, Lassila R. No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial. J Neurosurg. 2003;99:953–9.

Tseng M-Y, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ. Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg. 2009;111(1):171–80.

Hasan D, Lindsay KW, Wijdicks EF, Murray GD, Brouwers PJ, Bakker WH, van Gijn J, Vermeulen M. Effect of fludrocortisone acetate in patients with subarachnoid hemorrhage. Stroke. 1989;20(9):1156–61.

Mees SMD, Rinkel GJE, Vandertop WP, Pablo AA, Lavados M, van Kooten F, Kuijsten HAJM, Boiten J, van Oostenbrugge RJ, Salman RA-S, van den Bergh WM. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012;380(9836):44–9.

Gomis P, Graftieaux JP, Sercombe R, Hettler D, Scherpereel B, Rousseaux P. Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2010;112(3):681–8.

Haley EC, Kassell NF, Torner JC. A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1993;78(4):537–47.

Zwienenberg-Lee M, Hartman J, Rudisill N, Madden LK, Smith K, Eskridge J, Newell D, Verweij B, Bullock MR, Baker A, Coplin W, Mericle R, Dai J, Rocke D, Muizelaar JP. Effect of prophylactic transluminal balloon angioplasty on cerebral vasospasm and outcome in patients with fisher grade IIi subarachnoid hemorrhage: Results of a phase II multicenter, randomized, clinical trial. Stroke. 2008;39:1759–65.

Lennihan L, Mayer SA, Fink ME, Beckford A, Paik MC, Zhang H, Wu YC, Klebanoff LM, Raps EC, Solomon RA. Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2000;31:383–91.

Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666–75.

Stepwise Treatment of DCI

Management of DCI is presented here as a three-stage algorithm.  Tier One therapy should be initiated for new DCI which can manifest as neurological deterioration, characteristic imaging findings or MMM abnormalities indicating ischemia.  Tier Two therapy hsould be started in cases of refractory DCI(inadequate reversal of ischemia after first-line therapy.)

 

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Reference:

Francoeur, Charles L. and Stephan A. Mayer. “Management Of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage”. Critical Care 20.1 (2016).

 

Checklist: Predictors of DCI

  • SAH Blood clot:  Volume, location, persistence over time and density
  • Poor clinical condition on admission and loss of consciousness at ictus
  • smoking (strong)
  • diabetes (mod)
  • systemic inflammatory response syndrome (mod)
  • hyperglycaemia (mod)
  • hydrocephalus (mod)
  • hex?
  • history of hypertension?
  • age (inconsistent)

CSF molecules that are possible markers of DCI

  • endothelin-1
  • IL-6
  • some markers of thrombin activation

Serum biomarkers (association, but not validated)

  • TNF
  • IL-6
  • S100β
  • ubiquitin C-terminal hydroxylase 1
  • phosphorylated axonal neurofilament heavy chain
  • matrix metalloproteinases
  • von Willebrand factor
  • endothelin-1
  • vascular endothelial growth factor
  • selectins
  • adhesion molecules

 

Reference

Macdonald, R. Loch. “Delayed Neurological Deterioration After Subarachnoid Haemorrhage”. Nature Reviews Neurology 10.1 (2013): 44-58.

 

How Cortical Spreading Ischemia leads to DCI

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  • cortical neuronal swelling
  • dendrite spine distortion
  • slow changes in brain electrical potential (spreading depolarization)
  • decreased brain electric activity (spreading depression)

Normal Neurovascular Coupling:  Spreading depolarization –> arterioles vasodilate –> hyperemia –> no permanent damage

Abnormal Response:  Spreading depolarization –> inc astrocyte calcium and activation of calcium-activated potassium channels –> arterioles constrict –> waves of cortical hypoperfusion or cortical spreading ischemia

How does this happen?  sodium and calcium influx through multiple ion channels –> loss of electrically negative intraneuronal state –> spreading depolarizations –> prevents action potential formation –> propagates as a wave across cortex –> neurons lack adequate energy supplies to re-establish transmembrane ionic gradients –> cortical spreading ischemia

Subdural strip electrodes studies:

  • 70% of SAH aptients have repetitive cortical spreading depolarizations
  • some patients developed DCI that was spatially and temporally associated with angiographic vasospasm and cortical spreading depolarization
  • patients who had depolarization lasting >60minutes developed infarction on CT or MRI

Cortical spreading ischemia after SAH can be inhibited by nimodipine, NMDA receptor antagonists and prevention of systemic volume depletion

Reference

Macdonald, R. Loch. “Delayed Neurological Deterioration After Subarachnoid Haemorrhage”. Nature Reviews Neurology 10.1 (2013): 44-58.