Systemic Administration of Mexiletine for Attenuation of Cerebral Vasospasm Following Experimental Subarachnoid Haemorrhage

Mexiletine is a class Ib drug that is widely used to treat ventricular arrhythmias. This compound is mainly known as a sodium channel blocker, but studies have demonstrated that it can also activate ATP-sensitive K+ channels and block Ca2+ channels. Recent in vitro data from experiments on liposomes indicate that mexiletine is also a potent antioxidant. The unique activity profile of this drug raised the possibility that it might be of benefit in limiting cerebral vasospasm. Our first series of experiments assessed the effects of mexiletine on transclivally exposed rabbit basilar arteries. The arteries were treated with 50-mM KCl, 20-nM endothelin-1 (ET-1), or 100-microM lysophosphatidic acid (LPA) in the presence or absence of 400-mM mexiletine. Vasoconstriction caused by KCl, ET-1, and LPA was inhibited by mexiletine. In a second series of experiments, subarachnoid haemorrhage (SAH) was induced in rabbits by injecting 3-ml of autologous arterial blood into the cisterna magna. Forty-eight hours after SAH induction, transclivally exposed basilar arteries exhibited a spastic constriction that was partially reversed by topical application of 400-microM mexiletine. In a third set of experiments, mexiletine was administered orally at dosages of 80-, 20, and 5-mg/kg/day t.i.d., beginning 3 hours before SAH to study the prevention of vasospasm. In a separate group of animals, 80- and 20-mg/kg/day t.i.d. of mexiletine was administered 21 hours post-SAH induction, to study the reversal of vasoconstriction. Microscopic analysis of vessels from controls (no SAH), SAH-only, and SAH + mexiletine groups indicated there was 71.43% vascular constriction in the SAH-only group compared with controls. Considerable vasorelaxation was seen in the prevention study, in which average arterial cross-sectional areas were reduced by only 17.86% and 39.29% in the mexiletine 80- and 20-mg/kg/day groups, respectively, compared with controls (p < 0.001). Compared with controls, average arterial cross-sectional areas were reduced by 53.58% and 64.29% in the mexiletine 80- and 20-mg/kg/day reversal groups, respectively. Our findings indicate that mexiletine induces potent relaxation in cerebrovascular arteries contracted with various agents, and that it prevents and partially reverses SAH-induced vasoconstriction.     

Reversal of Cerebral Vasospasm by the Nitric Oxide Donor SNAP in an Experimental Model of Subarachnoid Haemorrhage

The constant release of nitric oxide (NO) is essential to maintain basal cerebrovascular tone. Oxyhaemoglobin, liberated by lysis of red blood cells after subarachnoid haemorrhage binds NO and prevents its entry into vascular smooth muscle cells. While endothelium-dependent vasoconstriction is preserved, decreased levels of NO inhibit endothelium-dependent relaxation and may cause vasospasm. S-nitrosothiols are potent vasodilators and precursors of NO. The authors' aim was to determine whether S-nitroso-N-acetylpenicillamine (SNAP), a stable S-nitrosothiol compound, could reverse vasospasm in an experimental vasospasm model in rabbit. Experimental subarachnoid haemorrhage (SAH) was induced in 37 New Zealand white rabbits. The animals were divided into four groups. Control (no SAH), SAH only, SAH plus saline and SAH plus SNAP. SNAP (15 micrograms/kg/min) or 0.09% saline (equal volume) was infused 46 hours after induction of SAH. All animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed, sectioned and their cross sectional areas were evaluated in a blind manner, by light microscopy and by using computer assisted morphometry. Experimental SAH elicited vasospasm in all animals of SAH only and SAH plus saline group. In animals treated with SNAP, arterial narrowing was markedly attenuated without producing systemic hypotension. This widening achieved statistical significance when compared to the arteries of the SAH only and SAH plus saline group (p < 0.01). This study indicates that the NO donor SNAP is a potentially useful drug to reverse cerebral vasospasm due to SAH.     

Basilar Vasospasm Following Spontaneous and Traumatic Subarachnoid Haemorrhage: Clinical Implications

Summary. Summary.   Background: Cerebral vasospasm has been commonly described following subarachnoid haemorrhage (SAH) though its impact on neurological outcome, especially in head trauma, has not been yet elucidated. The purpose of this study was to monitor and correlate neurological condition and flow velocities (FVs) in the arteries of the brain after SAH and more particularly to investigate the influence of basilar artery (BA) vasospasm on neurological outcome.   Methods: Daily transcranial Doppler (TCD) evaluations were conducted in 116 consecutive patients with subarachnoid haemorrhage. SAH was of traumatic origin (tSAH) in 59 patients and spontaneous (sSAH) in 57 patients. Vasospasm in the MCA and ACA was defined by a mean FV exceeding 120 cm/s and three times the mean FV of the ipsilateral ICA. Basilar artery (BA) vasospasm was defined as moderate whenever the FV was higher than 60 cm/s and severe above 85 cm/s.   Findings: Sixty-two patients (53.4%) had elevated FVs in the BA, among these 34 (29.3%) had FVs above 85 cm/s. Basilar vasospasm was significantly more common in tSAH (59.7%) than in sSAH (40.3%, P=0.041). In patients with moderate and severe BA vasospasm, FVs in the BA increased on the third day after admission and remained elevated for a week before returning to normal value by the end of the second week. This elevation in BA FVs in patients with BA vasospasm was followed by a significant and progressive worsening in the neurological condition at the end of the first week. Permanent neurological deficit was associated with elevated BA FVs consistent with moderate BA vasospasm whereas patients who remained in persistent vegetative state, had FVs consistent with severe BA vasospasm (P=0.00019).   Interpretation: The present results further support that BA vasospasm may act as an independent factor of ischaemic brain damage following SAH, especially in head trauma.     

Thrombin Activity in CSF after SAH is Correlated with the Degree of SAH, the Persistence of Subarachnoid Clot and the Development of Vasospasm

Summary  We previously reported that the coagulation system in cerebrospinal fluid (CSF) is strongly activated in the early stage of a subarachnoid haemorrhage (SAH). We evaluated the relationship among thrombin activity, degree of SAH, amount of clearance of SAH, and vasospasm. The CSF levels of fibrinopeptide A (FPA) were measured by radio-immunoassay in 36 SAH patients, who were diagnosed by computerized tomography (CT) within 12 hours and on whom surgery was performed within 48 hours. Clearance of SAH (%) was evaluated as the size of the clot in the basal cistern visualized between the initial and postoperative CT. The mean level of FPA in the patients of Group 3 (Fisher's CT classification) (182.2 ng/ml) was significantly higher than those in the patients of Group 2 (36.2 ng/ml). There was a significant difference in the mean level of FPA between patients with (47.6 ng/ml) and without infarction (408.3 ng/ml). In 18 of the 27 patients of Group 3 for whom the clearance of the SAH was determined, the patients showing a lower clearance rate (<50%) of SAH demonstrated a significantly higher rate of infarction and a significantly higher level of FPA (466.6 ng/ml) than did the patients with a higher clearance rate (>50%) of SAH (79.2 ng/ml). These results suggest that, the thrombin activity in CSF is correlated with the degree of SAH, the persistence of subarachnoid clot and the development of vasospasm.     

Endothelin-1 Initiates the Development of Vasospasm after Subarachnoid Haemorrhage Through Protein Kinase C Activation, but does not Contribute to Prolonged Vasospasm

Summary  Endothelium plays a role in the regulation of vascular tone. Endothelin is a family of potent vasoconstrictive peptides, and endothelin-1 (ET-1) produced in the endothelium induces a tonic contraction via specific receptor ETa. ET-1 has been postulated as an important factor in the development of vasospasm after subarachnoid haemorrhage (SAH). We have previously shown that protein kinase C (PKC) of the cerebral artery plays a pivotal role in the pathogenesis of vasospasm. The purpose of this study is to clarify the relationship between ET-1 and PKC in the development and maintenance of vasospasm.  Using a “two-haemorrhage” canine model, chronological changes of angiographic progression of vasospasm, PKC activation, and ET-1 level of the basilar artery were assessed. In an isometric tension study with a control artery, the effects of ETa- and ETa/ETb-antagonists on the tonic contraction induced by ET-1 were examined. The effects of ET-1, ET-1 and an ETa-antagonist, and ET-1 and an ETa/ETb-antagonist on PKC activation were also evaluated.  ET-1 level temporarily increased, then decreased to the control level in a later stage of vasospasm. ET-1 induced a tonic contraction and enhancement of PKC activation, but both were inhibited either by an ETa- or an ETa/ETb-antagonist.  These results indicate that ET-1 initiates the development of vasospasm through PKC activation, but does not contribute to prolonged vasospasm.     

Obligatory Roles of Protein Kinase C and Nitric Oxide in the Regulation of Cerebral Vascular Tone: An Implication of a Pathogenesis of Vasospasm After Subarachnoid Haemorrhage

Summary  We previously showed that a canine basilar artery manifested tonic and potent, protein kinase C (PKC)-dependent contractions when nitric oxide (NO) was inhibited. We also reported a linear correlation between chronological changes in the angiographic severity of vasospasm, enhanced PKC, and attenuated guanosine, 13′,15′-cyclic monophosphate (cGMP) activity in a canine subarachnoid haemorrhage model. The activity of cGMP is an indicator of NO-function. Based on this evidence, we have hypothesized that PKC and NO regulate cerebral vascular tone. We particularly focused on the role of NO in a negative feedback mechanism on PKC activity in the maintenance of vascular tone. To further confirm our hypothesis, we investigated the effect of PKC down-regulation on the tonic vascular contraction induced by NO-inhibition.  Canine basilar artery was used in the experiment. Significant down-regulation of PKC activity in vascular smooth muscle cells was obtained by incubation with 10⁻⁵ mole/L of phorbol 12-myristate 13-acetate (PMA) for 24 hours. The tonic and potent contraction induced by NO-inhibition was completely suppressed in the PKC down-regulated artery, even though the artery manifested a significant contraction in high-K⁺ solutions. These results indicate an obligatory role of PKC activity in tonic contraction when NO is inhibited, and support our previous data. Nitric oxide induces vascular relaxation by inhibiting PKC activity. Subarachnoid haemorrhage impairs this inhibition, resulting in PKC-dependent vascular contraction, such as vasospasm.     

Delayed Administration of the K+ Channel Activator Cromakalim Attenuates Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage

Summary ? Background. Delayed cerebral vasospasm remains an unpredictable and inadequately treated complication of aneurysmal subarachnoid hemorrhage (SAH). Recent evidence indicates that the potassium channel activator cromakalim is capable of limiting cerebral vasospasm in rabbits when administered immediately after experimental SAH (i.e. before spastic constriction has been initiated). However, the ultimate clinical value of cromakalim for treating vasospasm will depend in part on its effectiveness when administered after SAH-induced constriction has already been initiated. The present study examined the effects of cromakalim on vasospasm when treatment was initiated after SAH-induced constriction was underway.  Methods. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. Cromakalim (0.03, 0.1 or 0.3 mg/kg) or vehicle was injected intravenously at 8 hour intervals beginning 24 hours post-SAH. Animals were killed by perfusion fixation 48 hours after SAH. Basilar arteries were removed and sectioned, and cross-sectional area was measured.  Findings. The average cross sectional areas of basilar arteries were reduced by 64% and 68% in the SAH-only and SAH+vehicle groups, respectively. Treatment with cromakalim dose-dependently attenuated SAH-induced constriction. The groups treated with 0.03, 0.1, and 0.3 mg/kg cromakalim exhibited average decreases in cross-sectional area of 57%, 42%, and 19%, respectively.  Interpretation. These findings indicate that cromakalim dose-dependently attenuates cerebral vasospasm when administered 24 hours after experimental SAH in the rabbit. The results suggest K_ATP channel activators, such as cromakalim, could be of benefit for reversing cerebral vasospasm after aneurysmal SAH.     

Risk Factors Associated with Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage

We studied the risk factors associated with cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). The subjects were 370 patients with ruptured aneurysms who fulfilled all of the following criteria: admission by day 2 after onset, operation performed by day 3 by the same surgeon (T.I.), Hunt-Hess grade I–IV, availability of bilateral carotid angiograms acquired by day 2 and repeated between days 7 and 9. The demographic, clinical, radiographic, surgical, laboratory, and electrocardiographic data were analyzed for angiographic vasospasm (AV), symptomatic vasospasm (SV), and cerebral infarction on computed tomography (CT) scan. Both CT-evident SAH and AV were graded as 0–IV. Among the 370 patients, AV grade III–IV, SV, and cerebral infarction occurred in 26%, 24%, and 20%, respectively. Univariate analysis showed that Hunt-Hess grade III–IV, SAH grade III–IV, intracerebral or/and intraventricular hemorrhage, rebleeding, cigarette smoking, hypertension, alcohol intake, leukocytosis, hyperglycemia, and electrocardiographic QTc prolongation, left ventricular hypertrophy (LVH), and ST depression were significantly related to at least one of AV grade III–IV, SV, or cerebral infarction. Multivariate analysis showed that SAH grade III–IV was the most important risk factor for vasospasm followed by LVH on electrocardiogram, cigarette smoking, and hypertension. AV grade III– IV, SV, and cerebral infarction occurred in 57%, 54%, and 39% of the 46 smokers with LVH, and in 43%, 49%, and 35% of the 68 patients who had both LVH and hypertension, respectively. CT-evident SAH, LVH, cigarette smoking, and hypertension are associated with vasospasm. In smokers or hypertensive patients, premorbid LVH appears to predict much more severe vasospasm.     

Interleukin-6 and Development of Vasospasm after Subarachnoid Haemorrhage

Summary  The authors characterized the role of interleukins in the cerebrospinal fluid (CSF) in the development of vasospasm after subarachnoid haemorrhage (SAH), particularly interleukin-6 (IL-6).  Concentrations of interleukin-1β (IL-1 β), IL-6, and interleukin-8 (IL-8) were measured serially in CSF of 24 patients and in serum of 9 patients with SAH and correlated clinically. Additionally, the effects of the same cytokines on the cerebral arteries of dogs were analyzed on angiograms after intracisternal injection. Changes in levels of eicosanoids, angiogenic factors, and soluble cell adhesion molecules were investigated in the CSF of injected dogs.  CSF concentrations of IL-6 and IL-8 were elevated significantly above control levels from the acute stage of SAH until the chronic stage. Patients with symptomatic vasospasm had significantly higher levels of IL-6 as well as IL-8 in CSF on days 5 and 7. Intracisternal injection of IL-6 induced long-lasting vasoconstriction in five out of eight dogs, while IL-8 did not. The diameter of canine basilar artery after IL-6 was reduced 29±5% from pretreatment diameter at 8 hours. Prostaglandins E₂ and I₂ were elevated in CSF for the first 4.5 hour of this IL-6-induced vasospasm. Neither angioenic factors such as platelet-derived growth factor-AB and vascular endothelial growth factor nor soluble cell adhesion molecules were significantly elevated in CSF.  IL-6, which increases to very high concentrations in CSF after SAH, may be important in inducing vasospasm, as IL-6 produced long-lasting vasoconstriction in the canine cerebral artery, which may be partly related to activation of the prostaglandin cascade.     

Intra-Arterial Infusion of Fasudil Hydrochloride for Treating Vasospasm Following Subarachnoid Haemorrhage

Summary  In this pilot study we treated cerebral vasospasm in patients with subarachnoid haemorrhage to assess intra-arterial fasudil hydrochloride. We analysed effects of intra-arterial infusion on angiographically evident cerebral vasospasm in 10 patients including 3 with symptoms of vasospasm. Over 10 to 30 min 15 to 60 mg was administered via the proximal internal carotid artery or vertebral artery following standard angiography, without superselective techniques. A total of 24 arterial territories (21 internal carotid, 3 vertebral) were treated. Angiographic improvement of vasospasm was demonstrated in 16 arterial territories (local dilation in 2, diffuse dilation in 14) in 9 patients. In 2 symptomatic patients, intra-arterial fasudil hydrochloride was associated with resolution of symptoms without sequelae. In the third symptomatic patient the benefit of fasudil hydrochloride was only temporary, and a large cerebral infarction occurred. All asymptomatic patients showed no progression of angiographic to symptomatic vasospasm after treatment with intra-arterial fasudil hydrochloride. No adverse effect was encountered.     

Platelet-Derived Growth Factor (PDGF-AB) like Immune Reactivity in Serum and in Cerebral Spinal Fluid Following Experimental Subarachnoid Haemorrhage in Dogs

Summary  The aim of this study was to evaluate the following questions: Can the platelet-derived growth factor (PDGF-AB) be identified in the serum and cerebro spinal fluid (CSF) of dogs? Is there an increase in the concentration of PDGF-AB following experimental subarachnoid haemorrhage (SAH)? Is the increase in concentration related to the angiographic cerebral vasospasm of the basilar artery. The “double haemorrhage” model was applied in seven dogs to produce experimental SAH with determination of angiographic vasospasm in the basilar artery. Blood and CSF samples were taken on the first, third and eighth days. The analyses were performed with an ELISA human PDGF-AB antibody kit (quantikine human PDGF-AB, R&D Systems, Minneapolis, USA).  The average PDGF-AB base value in the serum on the day before the SAH was 410.77±177.56 pg/ml, in the CSF it was 6.43±3.19 pg/ml. There was a significant (p=0.05) increase in the concentration of PDGF-AB (third day 717.35 pg/ml, eighth day 918.07 pg/ml) in the serum of all animals. No significant increase was found in the CSF samples of any animal. In summary, a PDGF-AB like immune reactivity was found in the serum of dogs with the human PDGF-AB ELISA kit and the concentration of PDGF-AB in the serum increased after experimental SAH but not in CSF, but there was no relationship between the increase in PDGF-AB serum concentration and angiographic vasospasm.     

Efficacy of Lumbo-Peritoneal Versus Ventriculo-Peritoneal Shunting for Management of Chronic Hydrocephalus Following Aneurysmal Subarachnoid Haemorrhage

Summary ? Background. The clinical usefulness of lumboperitoneal (LP) shunts in selecting patients with communicating hydrocephalus after aneurysmal subarachnoid haemorrhage (SAH) was compared with that of ventriculoperitoneal (VP) shunts.  Method. Chronic hydrocephalus was defined as clinically and radiographically demonstrated hydrocephalus which lasted 3 weeks or longer after the original haemorrhage and which required shunting. Indications for a CSF shunt were assessed on the basis of neurological symptoms and signs, CT findings, and isotope cisternogram findings. The patients were treated with either LP or VP shunts. A significant response to shunting was defined as an improvement of function to a higher grade. The functioning of the shunt was evaluated by the location of the catheter on x-ray studies, CT features, and isotope cisternograms. The operation groups were checked for comparability of demographic and clinical variables including age, Fisher grade, hypertension, vasospasm, shunt interval, preshunt functional grade, and CT findings. A comparative analysis of the outcome was carried out between the two operation groups.  Findings. Fifty-six patients underwent shunt placements (LP shunts: 22, VP shunts with medium pressure valve: 2, VP shunts with high pressure valve: 32). There was no statistically significant difference in patient demographics and clinical characteristics between the patients with LP shunts and those with VP shunts. A follow-up time of 3 months to 8 years revealed clinical improvement in 11 cases (50.0%) of patients with LP shunts and 31 cases (91.1%) in VP shunts was seen (Fisher's exact test, P<0.005).  Interpretation. These findings suggest that VP shunts are a better choice of treatment than LP shunts in treating chronic hydrocephalus after aneurysmal SAH.     

Reversal of Radiographically Impending Stroke with Multiple Intraarterial Papaverine Infusions in Severe Diffuse Cerebral Vasospasm Induced by Subarachnoid Hemorrhage

Summary. Background: Selective intraarterial infusion of papaverine is used in the treatment of symptomatic cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage (SAH). Delays in instituting therapy for vasospasm can lead to irreversible cerebral infarction and a devastating outcome. Endovascular papaverine treatment of vasospasm in the presence of low-attenuation lesions on computed tomography (CT) is controversial, because of the fear of reperfusion hemorrhage in completed infarcts. Method: Two patients with aneurysmal SAH who subsequently developed severe diffuse vasospasm were identified. In both patients, large areas of low-attenuation change suggesting impending cerebral infarction were seen on CT scans. The patients received multiple infusions of intraarterial papaverine in an effort to treat vasospasm refractory to medical management. Findings: After multiple intermittent administrations of papaverine, which initially appeared to increase the low-attenuation changes, there was dramatic reversal of the radiographic findings. There was also improvement in circulation time, transcranial Doppler velocities, and clinical outcome. Interpretation: These findings suggest that in some patients, intraarterial infusions of papaverine initiated in the earliest stages of ischemia may exacerbate the radiographic appearance of low-attenuation changes, but may ultimately reverse the evolution of cerebral infarction.     

No Apparent Role for Neutrophils and Neutrophil-Derived Myeloperoxidase in Experimental Subarachnoid Haemorrhage and Vasospasm: A Preliminary Study

Summary ?Objective. The literature contains investigations and discussion of the role of neutrophils and neutrophil-derived myeloperoxidase (MPO) in inflammatory processes, local ischaemia, and ischaemia-reperfusion injury models. Our aim was to determine whether the same roles existed for neutrophils and the system involving neutrophil-derived MPO in experimental subarachnoid haemorrhage (SAH) and associated ischaemia. Material and Method. Forty-eight adult New Zealand white rabbits were divided into six groups of eight. The first SAH model was applied to 16 animals. Eight of these rabbits were sacrificed after 48 hours (Group 1) and the remaining eight were killed after 96 hours (Group 2). The second SAH model applied to another 16 rabbits, which were sacrificed in two groups at the above time periods, forming Groups 3 and 4, respectively. There were two groups of 8 control animals, one group per SAH model, and these rabbits were sacrificed after 48 hours. We carried out histopathological studies using haematoxylin and eosin (H&E) stain, elastin stain, MPO immunohistochemistry, and determination of basilar artery cross-sectional diameter. We also did biochemical analysis of cerebral hemisphere and brainstem specimens, measuring tissue lipid peroxidase and MPO activity. Results were compared between the groups and with their related controls. Results. In contrast to previous experimental findings in local ischaemia and ischaemia-reperfusion models, we found no histopathological or biochemical evidence to suggest a role for neutrophils and neutrophil-derived MPO in relation to subarachnoid haemorrhage and resultant vasospasm. Although we confirmed the successful induction of significant vasospasm and observed the clinical evidences of subsequent ischaemia, there was no notable accumulation of neutrophils or activity of neutrophil-derived MPO in the tissues studied. This suggests that the biological process induced by SAH follows a different pattern from that seen in local ischaemia and ischaemia-reperfusion injury.     

Systemic and Cerebral Haemodynamics During Craniotomy Under Mild Hypothermia in Patients with Acute Subarachnoid Haemorrhage

Summary ? Background. Mild hypothermia provides cerebral protection against ischaemic insults in various animal models. We compared systemic and cerebral oxygenation between mild hypothermic and normothermic management in 60 patients with acute subarachnoid haemorrhage who underwent clipping of cerebral aneurysms.  Method. The temperature in the pulmonary artery was maintained at 36°C in 28 patients and was reduced to 34°C in 32 patients. Parameters in the systemic and cerebral haemodynamics from pulmonary artery and internal jugular vein catheters were compared between the two groups immediately after the induction of anaesthesia (T1), and just before temporary occlusion or aneurysm clipping (T2).  Findings. Cardiac index, oxygen delivery index, oxygen consumption index, and oxygen saturation of the jugular bulb were significantly lower at T2 in hypothermic group (H) (2.9±0.6 L/min/m², 400.8±106.3 ml/min·m², 87.0±14.8 ml/min·m², 55.2±6.6%, respectively) than in normothermic group (N) (3.7±0.6, 521.0±105.5, 109.9±21.7, 60.9±6.6) (p<0.05). The arterial lactate and arteriojugular difference in oxygen content were significantly higher in H (2.3±1.3 mmol/L, 6.5±1.5 ml/dl, respectively) than in N (1.7±1.0, 5.6±1.2) (p<0.05). Arteriojugular differences in carbon dioxide tension and hydrogen ion content were significantly lower at T2 in H (−10.8±2.1 mm Hg, −6.4±1.3 nmol/L, respectively) than in N (−8.9±2.8, −5.3±1.0) (p<0.05).  Interpretation. The balance between oxygen supply and demand systemically and in the brain may worsen during aneurysm surgery for patients with acute subarachnoid haemorrhage under mild hypothermia. Oxygenation of the brain and the whole body should be monitored closely during this surgery, and adequate circulatory assistance is recommended under mild hypothermia.     

Cerebral Blood Flow and Oxygen Metabolism During Mild Hypothermia in Patients with Subarachnoid Haemorrhage

Cerebral blood flow and O2 metabolism during hypothermia (33-34 degrees C) was evaluated in 5 patients with aneurysmal subarachnoid haemorrhage by positron emission tomography (PET). Their preoperative clinical condition was WFNS scale IV or V. The patients received surface cooling postoperatively, and were maintained in a hypothermic state during transfer for radiological examination. Positron emission tomography revealed a decrease in cerebral blood flow and O2 metabolic rate. Cerebral blood flow was 34.8+/-15.1 ml/100 ml/min and the O2 metabolic rate was 1.85+/-0.61 ml/100 ml/min in areas of the middle cerebral artery ipsilateral to the ruptured aneurysms, whereas these values were 30.8+/-7.1 and 2.21+/-0.45 ml/100 ml/min, respectively, on the contralateral side. This represents a decrease of 37+/-27% compared to normal cerebral blood flow and 52+/-16% compared to normal O2 metabolic rate (p < 0.02) in the ipsilateral areas, and decreases of 44+/-13% and 43+/-12%, respectively, on the contralateral side. The present results reflected the luxury perfusion state in almost all cases and provide the first PET evidence of decreased cerebral blood flow and metabolic rate of O2 during hypothermia in humans.     

Toll-like Receptor 4 (TLR4) is Associated with Cerebral Vasospasm and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

In the present prospective study, the Toll-like receptor 4 (TLR4) levels on peripheral blood mononuclear cells (PBMCs) were investigated in 30 patients with aneurysmal subarachnoid hemorrhage (aSAH) and in 20 healthy controls (HCs). The relationship between TLR4 levels and the occurrence of cerebral vasospasm (CVS) was also analyzed. TLR4 expression level on cell surface of PBMCs on days 1, 3, and 7 after admission was determined by flow cytometry. Results showed that patients with aSAH presented a significantly higher TLR4 levels. For patients with Hunt-Hess grades IV–V, higher TLR4 levels were also observed; higher TLR4 levels have already been seen in patients developing CVS and/or delayed cerebral ischemia (DCI). Higher TLR4 levels were also associated with modified Fisher score, occurrence of dCVS, DCI, cerebral infarction (CT), and poor neurological functional recovery. Binary logistic regression analysis indicated that high TLR4 expression on blood monocytes was an independent predictive factor of the occurrence of dCVS, DCI, and poor neurological functional recovery. Taken together, TLR4 levels on PBMCs is significantly altered in the early stage of aSAH, especially in those patients experiencing CVS and DCI. Furthermore, higher TLR4 levels in the early stage of aSAH is also associated with the neurological function outcome. As far as we know, this is the first clinical study about TLR4''s significance for patients with aSAH.     

Intra-Aortic Balloon Counterpulsation: Augmentation of Cerebral Blood Flow after Aneurysmal Subarachnoid Haemorrhage

 Objective. To measure cerebral blood flow before and after intra-aortic balloon counterpulsation (IABC) in patients at high risk of developing delayed cerebral ischaemia after aneurysm surgery following subarachnoid haemorrhage.  Methods. Six prospectively selected patients at high risk of developing delayed ischaemia had elective IABC after clipping of their cerebral aneurysm(s). The IAB inflates in early diastole and deflates at the end of diastole to increase cardiac perfusion and decrease afterload. This results in enhanced cardiac efficiency. It also augments cerebral blood flow (CBF).  Results. We demonstrated a significant increase in the mean hemispheric CBF from the preoperative (preIABC) value of 35.6 mls/100 g/min to 50.9±12.3 mls/100 g/min (p=0.0042) as a result of balloon augmentation. Each patient developed a neurological deficit as a result of delayed cerebral ischaemia. These were reversed in 5 patients with increased CBF. There were minimal balloon related complications.  Conclusion. IABC consistently enhanced CBF in these patients and resulted in stable cardiovascular parameters. This represents a possible new technique in the management of cerebral ischaemia following subarachnoid haemorrhage and needs further assessment to ascertain its role.     

The Effect of Tizanidine on Chronic Vasospasm in Rats

Summary ? Background. Cerebral vasospasm after subarachnoid hemorrhage (SAH) has remained a major cause of morbidity and mortality in patients with SAH. Excitatory neurotransmitters are gathered in the extracellular space during ischemia due to cerebral vasospasm and initiate or stimulate a series of pathophysiological biochemical processes which consequently lead to neuronal death. Tizanidine (Sandoz compound DS 103–282, 5-chloro-4,2 (2-imidazolin-2-yl-amino)-2,1,3-benzothiazol hydrochloride) is a centrally-acting muscle relaxant and a selective α 2 adrenoreceptor agonist which shows its effect by stimulating presynaptic α 2 adrenoreceptors in central ASPergic and GLUergic system by inhibiting aspartic acid and glutamic acid release. In this study, the effect of Tizanidine on vasospasm was evaluated.  Methods. We used a femoral artery vasospasm model in rats which has been described by Okada et al. 60 rats were examined in three groups. The first group was used as control group (Control) (n=20), in the second group subarachnoid hemorrhage was performed (SAH) (n=20), in the third group Tizanidine was administered in addition to SAH (SAH+Tizanidine administration) (n=20). Animals in SAH+Tizanidine administration group received 0,3 mg/kg/day intraperitoneally for 7 days. Seven days after the experiment, after perfusion-fixation, 10 mm segments of both femoral arteries were removed and the femoral artery was prepared for light microscope examination, scanning and transmission electron microscopy and for morphometric analysis.  Results. There was a statistically significant difference between the electron, scanning and light microscopic observations and morphometric analysis of SAH+Tizanidine administration group and SAH group, and no statistically significant difference between SAH+Tizanidine administration group and control group.  Conclusion. This study has disclosed that Tizanidine administration before the vasospasm reduces ultrastructural and morphometric vasospastic insult significantly. However, the clinical application of Tizanidine as a protective and therapeutic agent in cerebral vasospasm needs further studies including the employment of clinically more relevant SAH models.     

Comparison of computerized tomography angiography and digital subtraction angiography in ruptured cerebral aneurysm surgery

Objective: The aim of the present study was to review the efficacy of 16‐row multislice computerized tomography angiography (CTA) in ruptured cerebral aneurysm surgery by comparison with conventional digital subtraction angiography (DSA). Methods: A systemic review of patients suffering from ruptured cerebral aneurysm was performed. We report the results obtained during the 19‐month period from April 2003 to October 2004. In total, 32 patients had undergone aneurysm surgeries, in which 11 patients had both DSA and CTA performed. Results: Among the 11 patients with both DSA and CTA performed, two aneurysms were missed in DSA in two patients. The sensitivity and specificity of CTA were 100%. The correlation of CTA with DSA in operative findings was 100%. Our CTA could detect the aneurysm size down to 2 mm in diameter. Conclusion: The diagnostic accuracy of 16‐row multislice CTA is promising and it compares well with DSA for detection and evaluation of ruptured cerebral aneurysms. It is safe and effective to establish treatment decision on the basis of CTA alone in the majority of cases.