Arachidonate metabolites and vasospasm after subarachnoid haemorrhage

A wide literature exists about the pathogenesis of cerebral arterial spasm following subarachnoid haemorrhage: several compounds have been identified in human cerebrospinal fluid as possible vasoactive agents involved in the biochemical mechanism of vasospasm onset. Many experimental evidences exist for a major involvement of arachidonate metabolites. The present work represents a review of experimental data supporting the hypothesis of cerebral arterial spasm as a result of an imbalanced vascular regulatory mechanism involving arachidonate metabolites. The authors have also monitored, in 25 cases of aneurysmal subarachnoid haemorrhage, lumbar and cisternal CSF levels of prostacyclin and PGD₂, as representative of vasodilating and, respectively, vasoconstrictor compounds. In all cases CSF arachidonate metabolite levels after SAH were significantly higher than in control cases. Ten patients presented with symptomatic vasospasm: lumbar CSF PGD₂ levels show fluctuations with superimposed peaks related to the neurological deterioration due to vasospasm, while lumbar CSF prostacyclin concentration-trend suggest a decreasing synthesis. In 15 patients presenting without vasospasm, lumbar CSF concentration of arachidonate metabolites are in a 'steady-state'. These data confirm the existence of an imbalanced biochemical situation promoting vasospasrn, markedly in cisterns near to the ruptured aneurysmal wall. The evaluation of cisternal CSF levels of arachidonate metabolites supports the hypothesis of the clotting phenomenon around the ruptured aneurysm as an important predictive pattern of vasospasm, as shown in CT findings.     

Prostacyclin and vasospasm in subarachnoid hemorrhage from ruptured intracranial aneurysm

Experimental and clinical observations suggest the importance of arachidonate metabolites in the genesis of symptomatic cerebral vasospasm after subarachnoid hemorrhage. Prostacyclin (PG12) has a well demonstrated vasodilator action. The authors monitored CSF prostacyclin concentration in 12 consecutive cases of subarachnoid hemorrhage with the purpose of correlating the prostacyclin concentration trend with the clinical course and the risk for vasospasm. In three cases patients presented with clinical and radiological signs of vasospasm. CSF prostacyclin concentration showed a typical decreasing trend, which amounted to a minor form of protection from vasospastic agents. The nine cases which did not develop vasospasm demonstrated no significant changes in the prostacyclin CSF concentration trend. The authors also presented four cases in which cisternal CSF samples were available. In one case of developing vasospasm, the cisternal prostacyclin concentration was seven times lower than the highest lumbar CSF concentration. In three cases without evidence of vasospasm cisternal CSF demonstrated a balanced biochemical situation and a minor risk of vasospasm.     

Effect of Nimodipine on arachidonic acid metabolites after subarachnoid hemorrhage

Arachidonic acid metabolites are under investigation as possible vasoactive agents involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage. Prostaglandins, as well as other vasoactive compounds, activate contractile proteins through utilization of extracellular bound Ca++ to the intracytoplasmic free fraction. Recently, calcium-antagonists, mainly Nimodipine, have been proposed for the prophylaxis and/or reversal of the ischemic damage caused by vasospasm. Nimodipine failed to reduce vasospasm incidence in a series of 30 patients admitted with diagnosis of subarachnoid hemorrhage from ruptured intracranial aneurysm. Nimodipine failed to reduce level of four arachidonate metabolites measured (prostaglandin D2, prostacyclin, thromboxane B2 and leukotriene C4) in lumbar and cisternal CSF. After subarachnoid hemorrhage there is a significant increase of CSF levels of arachidonate metabolites; in perianeurysmic cisterns level of prostaglandin D2, thromboxane B2 and leukotriene C4 are significantly higher than lumbar CSF levels. Moreover, cisternal CSF level of prostaglandin D2 and leukotriene C4 are significantly higher in patients with symptomatic vasospasm. Nimodipine did not significantly modify CFS level of arachidonate metabolites: this suggests that Nimodipine treatment, which definitely improves long-term results of patients for intracranial aneurysms, could exert its pharmacological action reducing Ca++ intake from the extracellular compartment and preventing a direct toxic effect of calcium, without a direct action against the release of vasoactive compounds.     

A study on cisternal CSF levels of arachidonic acid metabolites after aneurysmal subarachnoid hemorrhage

Arachidonic acid (AA) metabolites may play an important role in the pathogenesis of cerebral vasospasm which complicate subarachnoid hemorrhage. Authors have studied levels of 4 major AA metabolites in lumbar CSF samples and in CSF collected from perianeurismatic cisterns of 40 patients admitted with diagnosis of subarachnoid hemorrhage. Lumbar levels of AA metabolites are significantly higher in SAH patients than in control cases; moreover, cisternal CSF levels of PGD2, TxB2 and LTC4 are significantly higher than lumbar levels. Cisternal CSF levels (expressed in pg/ml +/- SEM) are in the "spasm" group: PGD2: 1129.62 +/- 146.33; 6-keto-PGF1 alpha: 214.2 +/- 19.96; TxB2: 4350.25 +/- 656.87; LTC4: 2582.19 +/- 381.83. In the "no spasm" group: PGD2 460.1 +/- 55.89; 6-keto-PGF1 alpha: 306.37 +/- 88.74; TxB2: 5752.5 +/- 899.25; LTC4: 812.92 +/- 142.06. Statistical analysis (paired t-test) shows values significantly higher for cisternal levels of PGD2 (P less than 0.005) and LTC4 (P less than 0.005) in patients presenting vasospasm. This suggests the importance of the subarachnoidal clot as a source of vasoactive compounds. Higher levels of leukotriene C4 in patients presenting vasospasm suggest a role for the compound in the genesis of local inflammatory processes and morphological changes of the arterial wall.     

Effects of subarachnoid haemorrhage on intracranial prostaglandins.

Prostaglandins E2, F2 alpha, 6 oxo F1 alpha and thromboxane B2 increased in cisternal CSF following mock subarachnoid haemorrhage in dogs, particularly PGE2 (X25.5). Concentrations were increased also in lumbar CSF of five patients some 8 days after subarachnoid haemorrhage. Subarachnoid haemorrhage did not alter the production of prostaglandins by dog whole cortex or choroid plexuses in vitro, but production by pooled dissected cerebral arteries of PGE2 was increased and of 6 oxo F1 alpha was decreased. Intravenous indomethacin decreased prostaglandin production by cerebral tissues, and caused a marked decrease in the prostacyclin metabolite in CSF. The implications of our findings for the aetiology of cerebral vasospasm are discussed.     

Prostaglandin D2 monitoring in human CSF after subarachnoid hemorrhage: the possible role of prostaglandin D2 in the genesis of cerebral vasospasm

Experimental and clinical studies indicate that cerebral vasospasm following subarachnoid hemorrhage (SAH) may be caused by changed biochemical properties of the endothelium and vascular smooth muscle cell exposed to vasoactive substances synthetized by cerebral arteries and released in clotted blood. Many compounds have been identified in CSF from SAH patients: Thromboxanes A₂ and B₂, Prostaglandins F₂, E₂ and D₂ are the major prostanoids incriminated in the causation of cerebral arterial spasm. We have monitored the CSF PGD₂ concentrations with serial lumbar punctures at different intervals from the hemorrhage in 16 patients admitted for SAH: PGD₂ was measured with radioimmunoassay as its 9-methoxy derivative. The lumbar CSF PGD₂ concentration ranges from 0,11 to 1.53 ng/ml. In 7 cases vasospasm was angiographically demonstrated. 9 patients presented no clinical or radiological evidence of vasospasm. In 5 cases cisternal CSF samples were available at the operation by cisternal punctures. There was no correlation between CSF PGD₂ concentration and clinical course. In the 7 cases with evidence of vasospasm a significant increase of CSF PGD₂ corresponded to neurological deterioration. In all 9 cases without evidence of vasospasm CSF PGD₂ concentration trend was in a steady-state. The cisternal CSF PGD₂ concentration was higher than lumbar CSF concentration in cases with arterial spasm. This suggests the importance of the clotting phenomenon in vasospasm onset after SAH. PGD₂ is one of the most important spasmogens in clotted blood. Although its role in the genesis of vasospasm onset remains to be defined, its vasospatic action, in addition to that of other analogous compounds, seems to be relevant.

---

Sommario Studi clinici e sperimentali indicano che alla base della genesi del vasospasmo conseguente all'emorragia subaracnoidea starebbe una modificazione delle proprietà biofisiche dell'endotelio e delle cellule muscolari della parete arteriosa in risposta ai composti vasoattivi rilasciati nel coagulo che si forma attorno alla parete dell'aneurisma. Molte sostanze sono state identificate nel liquor di pazienti ricoverati per emorragia subaracnoidea: i Trombossani A2 e B2, la Prostaglandina F2Alfa, E2 e D2 sono i derivati dell'acido arachidonico a dimostrata azione spasmogena. Gli Autori hanno studiato le concentrazioni liquorali di PGD2, in modo sequenziale mediate seriate punture lombari in 16 pazienti ricoverati per emorragia subaracnoidea. La valutazione della concentrazione di PGD2 è stata effettuata mediante dosaggio radioimmunologico. In 7 casi è stato dimostrato angiograficamente il vasospasmo. In 5 casi sono stati effettuati prelievi di liquor cisternale durante l'intervento di esclusione dell'aneurisma. Non è possibile dimostrare una correlazione diretta tra l'andamento della concentrazione liquorale di PGD2 e il decorso clinico; nei 7 casi complicati da vasospasmo si dimostra, comunque, un picco nella concentrazione di PGD2 e il momento del peggioramento delle condizioni neurologiche in relazione all'insorgenza di vasospasmo. Nei 9 casi senza segni clinici e radiologici di vasospasmo la concentrazione liquorale di PGD2 non dimostra variazioni significative. La concentrazione cisternale di PGD2 è nettamente più elevata rispetto a quella lombare nei casi complicati da vasospasmo: questo suggerisce l'importanza della formazione del coagulo e della sua lisi attorno alla parete dell'aneurisma in rapporto alla comparsa di vasospasmo nel segmento arterioso a monte dell'aneurisma.

     

Subarachnoid haemorrhage in the rat: effect on the development of cerebral vasospasm of lesions in the central serotoninergic and dopaminergic systems

In the rat an intracisternal injection of blood induces an angiographically demonstrable biphasic cerebral arterial vasospasm. Chemical destruction of the central serotoninergic and dopaminergic pathways prior to the cisternal blood injection does not affect the spasm pattern after the subarachnoid haemorrhage. It is suggested that neither system plays a role in the development of spasm.     

腰池引流对破裂动脉瘤患者血浆和脑脊液ET浓度及脑血管痉挛的影响

目的探讨腰池持续引流对破裂动脉瘤患者血浆和脑脊液内皮素(ET)浓度及脑血管痉挛的影响。方法将经栓塞治疗后的破裂颅内动脉瘤患者354例分为引流组和对照组。引流组268例,栓塞后行腰池持续引流;对照组86例,每天腰穿放脑脊液一次。用放免法测定栓塞后不同时间血浆和脑脊液中ET浓度,用经颅彩色多普勒超声检测大脑中动脉血流速度。结果引流组血浆和脑脊液中ET浓度轻度增加,对照组ET浓度增加明显,两组差异显著(P<0.01)。引流组大脑中动脉平均血流流速轻度增加,对照组明显增加,两组差异显著(P<0.01)。血浆和脑脊液中ET浓度与脑动脉血流速度呈正相关(r=0.95,P<0.01)。结论蛛网膜下腔出血后脑血管痉挛与血浆和脑脊液中ET浓度异常增加有关,腰池持续引流能够有效地清除引起脑血管痉挛的因子。     

Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage.

Despite recent advances in the management of aneurysmal subarachnoid haemorrhage delayed ischaemic deficits from cerebral vasospasm remains a major cause of morbidity and mortality. As magnesium is a potent cerebral vasodilator we have introduced routine supplementation in patients presented with subarachnoid haemorrhage to determine whether there has been a reduction in the incidence of cerebral vasospasm. Method: All patients presented with aneurysmal subarachnoid haemorrhage from February 1997 were included except those who presented after day 5 following bleed. Identical management protocol was used except intravenous magnesium supplementation which was introduced to all patients from May 1999. Incidence of cerebral vasospasm on angiograms among the two groups was analysed. Results: Seven out of 10 patients who did not receive magnesium supplement developed vasospasm requiring intra-arterial papaverine compared with 2 of 13 patients among the treated group (P<0.008). Conclusions: From our pilot study it appears that magnesium supplement has a beneficial role in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. Further studies would seem justified.     

颅内动脉瘤破裂急性期经眉眶上锁孔入路手术治疗

目的探讨颅内动脉瘤破裂急性期经眉眶上锁孔入路手术的可行性及相对适应证。方法对28例颅内动脉瘤破裂急性期经眉眶上锁孔入路手术治疗病人的临床资料进行分析,着重描述该手术方法、注意点、术中动脉瘤破裂及术后脑血管痉挛发生情况。结果28例动脉瘤全部夹闭成功,其中3例术中有动脉瘤破裂出血,术后10例病人有不同程度的脑血管痉挛,其中2例为症状性脑血管痉挛。除1例大脑中动脉瘤有轻偏瘫,1例前交通动脉瘤有单侧下肢轻瘫外,其他病人恢复良好。结论绝大多数颅内动脉瘤破裂病人急性期同样适合锁孔手术,术中动脉瘤破裂和术后脑血管痉挛发生的机会同常规开颅显微手术并无明显差别。     

蛛网膜下腔出血腰池持续引流前后脑脊液中NO浓度的变化

目的 探讨腰池持续引流防治脑血管痉挛的效果及其对脑脊液中一氧化氮（NO）浓度的影响。方法 50例破裂动脉瘤蛛网膜下腔出血患，随机分为引流组25例。对照组25例。引流组在电解可脱弹簧圈（GDC）栓塞术后立即实施腰池持续引流，对照组行间断腰椎穿刺。脑脊液NO浓度采用镉粒子还原法测定。结果 引流组中发生症状性脑血管痉挛2例。对照组7例。血管痉挛患的NO浓度明显降低，引流组脑脊液中NO浓度在出血后第5d起明显高于对照组。结论 腰池持续引流可有效清除蛛网膜下腔积血，提高脑脊液中NO的浓度。     

Subarachnoid haemorrhage in the rat: angiography and fluorescence microscopy of the major cerebral arteries

A subarachnoid haemorrhage (SAH) in the rat was produced by the injection of blood via a previously implanted catheter connected to the cisterna magna. Repeated angiographical examinations of the vertebro-basilar arteries revealed a biphasic vasospasm with a maximal acute spasm at ten minutes and a maximal late spasm at two days after cisternal blood injection. Fluorescence microscopical examination of the major cerebral arteries at day two after the SAH revealed a reduction in the fluorescence intensity and in the number of histochemically visible sympathetic nerve terminals.     

动脉瘤性蛛网膜下腔出血并发脑血管痉挛患者血清血管内皮生长因子表达的变化

目的:探讨动脉瘤性蛛网膜下腔出血(SAH)并发脑血管痉挛(CVS)与血清血管内皮生长因子(VEGF)表达的关系.方法:27例动脉瘤性SAH患者为试验组(SAH组),再依据是否并发不同程度CVS分为:无CVS亚组(11例),轻度CVS亚组(9例)、中度CVS亚组(4例)和重度CVS亚组(3例);另设10名健康体检者为对照组.采用ELISA法检测血清VEGF水平.结果:SAH各时间点各组血清VEGF水平为①SAH组发病第1天起即明显高于对照组;②无CVS组不增高.SAH后第1、3、5、7天时血清VEGF水平为①轻度CVS组与中度CVS组相同时间点比较,差异无统计学意义;②重度CVS组明显高于轻度和中度CVS组.SAH后出现脑梗死患者血清VEGF水平明显高于未出现脑梗死患者.结论:SAH后出现CVS患者和出现脑梗死的患者血清VEGF水平明显增高,血清VEGF水平能反映脑血管痉挛的程度.     

Endothelin and aneurysmal subarachnoid haemorrhage: a study of subarachnoid cisternal cerebrospinal fluid.

Endothelin (ET) is considered one of the most potent vasoconstrictor polypeptides; several experimental studies have suggested its possible role in the pathogenesis of arterial vasospasm after subarachnoid haemorrhage (SAH). Previously reported data on plasma and CSF levels of endothelin in patients with a diagnosis of SAH have been controversial. Cisternal endothelin CSF levels and the possibility that they could be related to vasospasm and other clinical patterns of SAH were investigated. CSF samples were obtained from 55 patients admitted after angiographic diagnosis of intracranial aneurysm. Levels of ET-1 and ET-3 were measured through radio-immunoassay technique. Twelve patients who had operations for unruptured aneurysms were considered control cases; 43 patients with SAH were classified according to: Hunt and Hess grading at admission, vasospasm grading, CT classification and timing of surgery. In all 55 patients ET-1 was measured, while positive levels of ET-3 were found only in 17 cases of 48. No linear correlation was found between cisternal CSF ET-1 levels when considering time of surgery, CT classification, Hunt and Hess grading at admission, and vasospasm grading. The results of ET-3 assay should be considered with great caution because of the low percentage of positive cases. Cisternal CSF levels of ET-1 and ET-3 are not directly related to the occurrence of arterial vasospasm after the aneurysm rupture, or to other major clinical patterns of SAH; however, ET-1 expression occurs either in paraphysiological (unruptured aneurysm) or in pathological conditions (SAH). It is suggested that ET may potentiate, or may be potentiated by, other factors playing a consistent pathophysiological role in the development of vasospasm.     

Prostaglandin D2 in subarachnoid hemorrhage. Biological and diagnostic implications

The concentration of PG D2 (a prostanoid with demonstrated vasoconstrictor activity on human cerebral arteries was studied in the cerebrospinal fluid of 7 patients admitted for subarachnoid aneurysmal hemorrhage. CSF samples were sequentially obtained at different intervals following the hemorrhage and the PG D2 concentration was detected with radioimmunological assay. Four patients developed vasospasm leading to neurological deterioration. PG D2 concentrations varied from 0.21 to 1.09 mg/ml. The highest CSF PG D2 concentrations were seen 24-48 hours after the hemorrhage in three patients, who subsequently died due to resumption of bleeding. In the four cases with angiographically demonstrated vasospasm a peak in PG D2 concentration could be observed corresponding to the clinical appearance of neurological deterioration. In the three cases without a neurological finding of vasospasm, PG D2 concentrations tended to be stable. Serial monitoring of arachidonic acid metabolites having different vasoactive actions on the cerebral arterial wall could be of great interest as a clinical and biological marker useful in the management of subarachnoid hemorrhage.     

Constrictive structural elements in human cerebral arteries following aneurysmal subarachnoid haemorrhage

Histoimmunological, histochemical, and histological studies were conducted on cerebral arteries from four living patients with a recent aneurysmal subarachnoid haemorrhage. There appeared to be a correlation between the severity of vasospasm and the magnitude of pathological findings. Large myofibroblast cells and type V collagen within the medial layer were abundant in arteries showing marked vasospasm, but were less conspicuous in those showing milder involvement. Intracranial arteries from patients who died from non-cerebral causes did not demonstrate these changes. In ruptured vessels, there was also a positive fluorescence for actin-myosin filaments in layers of the arterial wall other than the media. It is postulated that the intimal and adventitial actin-myosin, myofibroblasts and type V collagen may contribute to cerebral vasospasm by holding the damaged vessel in a contracted phase during the healing period.     

The 5-hydroxytryptamine antagonist ketanserin inhibits the vasoconstrictor activity of per-operative CSF, from subarachnoid haemorrhage patients, on isolated tissues.

Peri-aneurysmal CSF was obtained at operation from 13 patients with subarachnoid haemorrhage from ruptured intracranial aneurysms. The 5-hydroxytryptamine antagonist ketanserin inhibited contractions of isolated human intracranial arteries, elicited by this CSF. The presence of 5-HT in CSF was confirmed by high performance liquid chromatography. The use of ketanserin in the therapy of postoperative cerebral vasospasm is discussed.     

Constrictive structural elements in human cerebral arteries following aneurysmal subarachnoid haemorrhage

Histoimmunological, histochemical, and histological studies were conducted on cerebral arteries from four living patients with a recent aneurysmal subarachnoid haemorrhage. There appeared to be a correlation between the severity of vasospasm and the magnitude of pathological findings. Large myofibroblast cells and type V collagen within the medial layer were abundant in arteries showing marked vasospasm, but were less conspicuous in those showing milder involvement. Intracranial arteries from patients who died from non-cerebral causes did not demonstrate these changes. In ruptured vessels, there was also a positive fluorescence for actin-myosin filaments in layers of the arterial wall other than the media. It is postulated that the intimal and adventitial actin-myosin, myofibroblasts and type V collagen may contribute to cerebral vasospasm by holding the damaged vessel in a contracted phase during the healing period.     

Spasm index in subarachnoid haemorrhage: consequences of vasospasm upon cerebral blood flow and oxygen extraction

A spasm index, defined as transcranial Doppler detected flow velocity in the middle cerebral artery divided by regional cortical cerebral blood flow (CBF), was used on 24 patients with subarachnoid haemorrhage (SAH). The aim was to estimate degree and time course of vasospasm, even in cases with great day-to-day variation in CBF, and correlate to CBF and oxygen extraction. All patients showed increase in spasm indices with peak index in the second or third week. The index seemed stable in spite of day-to-day fluctuations in CBF. Severe vasospasm were associated with poor clinical condition, reduced CBF (less than 30) and high AVDO2. The same picture could be seen with minor degree of vasospasm, probably, in some cases, due to high intracranial pressure. The results suggest that the spasm index is useful in monitoring patients with subarachnoid haemorrhage, and that severe vasospasm has a negative influence on clinical condition, CBF and oxygen extraction.     

Endothelin-1 levels in plasma and cerebrospinal fluidfollowing subarachnoid haemorrhage

A serial measurement of endothelin-1(ET-1) levels in plasma, cisternal and ventricular cerebrospinal fluid(CSF) was performed in 16 patients with subarachnoid haemorrhage (SAH). The patients were classified as grade III or IV according to the clinical grade of Hunt and Hess, and computerised tomography(CT) was classified as Fisher's CT group 3. Cisternal and ventricular CSF and plasma were obtained from the patients on the day of operation days 0-3, days 5-8 and days 14-18 after SAH. ET-I concentration in each sample was quantified by sandwich-enzyme immunoassay. ET-I levels in plasma and CSF were the highest between days 0-3 and then decreased. The ET-I levels in the cisternal CSF were significantly higher during days 0-3(p<0. 01) and days 5-8(p<0. 01) than those in the ventricular CSF It is suggested that ET-I could play an important role in the early stages of the cerebral vasospasm.