Tag Archives: vasospasm

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].

Images of Vasospasm

This is a review of an interesting study from 1997 (published in Stroke) that illustrates how vasospastic arteries in a rat subarachnoid hemorrhage model looks like under the scanning electron microscope.

The researchers injected hemolysate (lysed autologous blood) into the cisterna magna of male Sprague-Dawley rats.  After ten minutes, a polymer resin casting medium was injected intravenously.  Once the resin has casted, the tissue and bones were corroded using NaOH solution, until only the vascular cast remains.  The casts were visualized under scanning electron microscope, and the following images were derived:

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Basilar artery of:  A.  saline-injected control rats;  B. hemolysate-injected rats;  arrowheads = PICA;  note the narrowing and corrugation seen in the basilar artery of the hemolysate-injected rats.

Capture.JPG Other major arteries were also observed to be in vasospasm.  (note corrugation in these arteries)

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Vasospasm (demonstrated as corrugation in the casted vessels) is seen in the major arteries (A) as well as the small arteries (B).

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High magnification showing “corrugation” of the basilar artery.  The arrows point to nuclear indentations which correspond the the endothelial cell nucleus.  (see below0

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The researchers also performed conventional SEM.  A and B are normal vessels while C and D are hemolysate-induced vasospastic blood vessels.   A and C are low magnification, B and D are high magnification.

The normal vessels (A) show that the inner surface is very smooth and the vessel wall is thin, and (B) the endothelial nuclei are clearly observed, projecting into the inner surface at regular intervals of 10-20 um.

The vasospastic vessels (C) shows that the smooth muscle layer is thicker, corrugation is observed and (D) many humps are sandwiched and flattened between hills formed by the endothelial cells.

Cast model shows corrugation, characteristic folds of endothelial cells at regular intervals and indentations of endothelial cell nuclei at each peak of those folds.  These indentations correspond to the humps seen in conventional SEM analysis.  The mechanical force of corrugation compressed the endothelial cells, flattened their nuclei and likely disturbed their function.  These physical alterations cause narrowing of the vessels, disturbs local blood flow, and may disturb blood coagulation and adhesion of WBC and platelets to the endothelium.  This may be a mechanism that explains thrombus inflammation and inflammatory response in these diseased vessels.

Their research also showed that arteries exposed to greater amount of hemolysate exhibit more severe vasospasm.

Reference:

Ono, S. et al. “Three-Dimensional Analysis Of Vasospastic Major Cerebral Arteries In Rats With The Corrosion Cast Technique”. Stroke 28.8 (1997): 1631-1638.

Post-traumatic Cerebral Vasospasm

3 phases after severe head injury:

1. hypoperfusion and cerebral ischemia (24h)
2. rebound hyperemia (24-72h)
3.  post-traumatic vasospasm (4-14d)

Methods to detect Post-trauma Vasospasm
1. Cerebral angio
2. TCD
3. AVDO2 – cerebral arteriovenous difference of oxygen – lower value suggests hyperaemia
4. xenon clearance method / cerebral perfusion studies
5. shape of TCD waveform – no dicrotic notch in hyperaemia

Lindegaard ratio:  ratio between mean velocity in MCA and mean velocity in cervical ICA, if 3 or more then the high intracranial velocity likely to be due to vasospasm

Incidence of post-traumatic vasospasm:  (see tables below)
10-39% in anigio studies (done once post-trauma)
higher in TCD studies (multiple evaluations because noninvasive, so incidence is bloated)

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*Presence of SAH did not correlate with inc incidence of post-trauma vasospasm (37.9% vs 31.3% p=0.34)
*Thick layers of subarachnoid blood on CT had a tendency to develop post-trauma vasospasm (44.4% vs 31.3%) but not significant. (low sample size)
*Statistically significant increase in incidence of post-traumatic vasospasm with EDH and SDH.  Patients with ICH tend to develop post-trauma vasospasm more often but not statistically significant.

CaptureOnset and Duration:
Onset mean of 5days (2-8d)
Peak at 5-7 days
Tend to be short lasting; prolonged vasospasm correlated closer with SAH on initial CT

*Note that >10% of patients with post-trauma vasospasm have no blood in CSF – there must be a separate pathophysiology for vasospasm in this group.

GCS also correlated with incidence of vasospasm.

PTV

Pathophysiology of Vasospasm
1. strongest correlation is between volume of subarachnoid blood on early CT – blood components (RBC, platelet-rich plasma, oxyHb, thrombin) directly cause vasospasm or induce release of vasoconstrictors from endoth cells (TXA2, endothelin) or hypothalamus
*TXA2 and endothelin are potent, long-lasting vasoconstrictors
2. mechanical stretching and pulling – but based on experiments, spasm only lasts for <1h
3. release of vasoactive substances from parenchyma (endoth cells, blood cells, neurons, glia)

Cerebral Injury:
But not all vasospasm leads to cerebral injury – vasospasm detected in >2/3 of aSAH, but only about half develop ischemic symptoms
1. increased flow
2. extraction of more osygen from blood when flow is reduced
3. ability of collateral vasculature to compensate

Treatment:
Treatments used in aSAH may be deleterious in TBI.  Where aneursyms can be secured in aSAH, source of bleeding in tSAH is oftentimes not correctible by surgery.  Induced hypertension may increase cerebral edema in TBI.  Probably best method is to maintain euvolemia and prevent hypotension.
Nimodipine in preventing post-trauma vasospasm has mixed results, but most studies show a trend towards improvement in vasospasm as well as clinical parameters.

REFERENCE:
Surg Neurol. 2000 Feb;53(2):126-30. Risk factors for the development of post-traumatic cerebral vasospasm. Zubkov AY1, et al.
J Clin Neurosci. 1998 Apr;5(2):146-54.  A review of cerebral vasospasm. Part IV. Post-traumatic vasospasm.  Zurynski YA1, Dorsch NW.
Neurol Res Int. 2013;2013:415813. doi: 10.1155/2013/415813. Epub 2013 Jun 19. Cerebral vasospasm in traumatic brain injury. Kramer DR1, et al.