The Therapeutic Effect of Continuous Intracisternal L-Arginine Infusion on Experimental Cerebral Vasospasm

Summary  Background. Recent studies on the pathogenesis of cerebral vasospasm following subarachnoid haemorrhage (SAH) suggest a breakdown of the balance between the vasoconstrictor and vasodilator systems. A shortage of a major cerebral vasodilator, nitric oxide (NO), has been accused of causing this breakdown. We investigated the effect of continuous intracisternal infusion of a NO precursor, L-Arginine, in a rabbit SAH model.  Method. Three experimental groups were designated: Group 1 – Cerebral blood flow (CBF) data was obtained via transorbital Doppler ultrasonography (TDU) in 8 normal rabbits. Group 2 – Intracisternal catheter placement and TDU study during saline infusion were performed in 8 animals at the 4^th day of SAH, Group 3 – SAH occurred in 8 animals. 4 days later, L-Arginine was infused intracisternally for 1 hour, while TDU was performed before and during infusion. CBF parameters which were obtained via TDU measurement or calculations, were compared.  Findings. The results of TDU revealed significant vasospasm in all SAH animals, as well as resolution of vasospasm with L-Arginine infusion. After 20 minutes of infusion, a steady and sustained vasodilation was obtained in the third group. The analysis of CBF data revealed a significant difference in SAH values, and no difference in control animals.  Interpretation. Our results support the contribution of the “NO shortage” concept in the pathogenesis of cerebral vasospasm and overconsumption of L-Arginine during the post-SAH period may cause this shortage. L-Arginine treatment may be useful for the prophylaxis and treatment of cerebral vasospasm. The intracisternal infusion method can eliminate the short action time disadvantage of L-Arginine.     

Subarachnoid Heamorrhage-Induced Chronic Cerebral Vasospasm in the Rabbit: IV-DSA Versus IA-DSA

Summary.  Background: Chronic cerebral vasospasm is delayed-onset cerebral arterial narrowing in response to blood clots left in the subarachnoid space after aneurysmal subarachnoid haemorrhage (SAH). Rabbit models of vasospasm have been developed as in vivo experimental pathogenesis and the treatments of cerebral vasospasm using human vessels are not possible. The present study assessed the diagnostic accuracy of the intravenous digital subtraction angiography (IV-DSA) in chronic cerebral arterial spasm following induced SAH in the rabbit.  Method: Ten rabbits' left leg veins catheterised by intravascular access needle and 3F catheters introduced to the right leg arteries probing the proximal of the vertebral arteries. Initially IV-DSA and intra-arterial digital subtraction angiography (IA-DSA) was performed. Three millilitres of fresh autologous arterial blood was injected into the cisterna magna of the ten rabbits' in order to produce in vivo model of chronic SAH. Angiograms were obtained 15 minutes and 72 hours after the SAH.  Findings: Diameters of the basilar arteries were similar to each other in both methods and reduced after the SAH.  Interpretation:The present study shows that IV-DSA is a relatively simple and effective method for demonstrating cerebral vessels, especially the basilar artery. Published online September 2, 2002 Correspondence: Tanzer Sancak M.D., Mesa Camyolu sitesi, B1 Blok A17 Yenikent, Cayyolu, Ankara, Turkey.     

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.     

In vitro therapy with dobutamine, isoprenaline and sodium nitroprusside protects vascular smooth muscle metabolism from subarachnoid haemorrhage induced cerebral vasospasm

Summary  Background. The cerebrospinal fluid (CSF) from subarachnoid haemorrhage (SAH) patients with cerebral vasospasm stimulates vasoconstriction and oxygen consumption in the porcine carotid artery in vitro. Stimulation of oxygen consumption has been used as an in vitro model of vasospasm to assess the relative benefits of nimodipine, isoprenaline, dobutamine, and sodium nitroprusside (SNP).  Method. Samples of human CSF were obtained from SAH patients and applied to de-endothelialised porcine carotid artery. Stimulation of oxygen consumption (as an in vitro marker for a stimulation of the vessels) was monitored and the effects of SNP, isoprenaline, dobutamine or nimodipine were measured.  Findings. The CSF from SAH patients with evidence of vasospasm stimulated oxygen consumption to 0.91±0.17 (μ M O₂/min/g dry wt, ± SD p≤ 0.01) and CSF from SAH patients without vasospasm did not significantly stimulate oxygen consumption 0.27±0.02, with 0.23±0.03 (μ M O₂/min/g dry wt) being an unstimulated rate of respiration for the porcine carotid artery. SNP, isoprenaline or dobutamine significantly (p≤ 0.01) decreased the stimulation of oxygen consumption of the porcine carotid artery whereas nimodipine did not. In a cohort of 41 SAH patients who received nimodipine alone or nimodipine and dobutamine, the in hospital mortality rate of the patients who received only nimodipine was 42% as compared to an in hospital mortality rate of 17% in the nimodipine plus dobutamine group P≤ 0.076).  Interpretation. The in vivo data on the 41 patients is not statistically significant, so further studies are required to determine if the differences are important. SNP, isoprenaline and dobutamine significantly decreased oxygen consumption of the porcine carotid arteries exposed to CSF from SAH patients who had vasospasm whereas nimodipine did not. Our in vitro results suggest that these compounds require further study in patients with SAH who are at risk for vasospasm because they may have a direct benefit for the vasospastic arteries.     

Nitric oxide metabolites in cisternal CSF correlate with cerebral vasospasm in patients with a subarachnoid haemorrhage

Summary.  Background: The pathogenesis of cerebral vasospasm is likely to be multifactorial. Exposure of the adventitia of large cerebral arteries to blood breakdown products initiates a cascade of changes in both morphology and vasomotor regulation of the exposed vessels. The role of nitric oxide (NO) in development of cerebral vasospasm process is controversial. Basal cerebral vascular tone requires the continuous release of NO, nevertheless NO is involved in free radical mediated injury of endothelial cell membrane. Concentrations of nitrate/nitrite (stabile endproducts of NO metabolism) were studied in cisternal cerebrospinal fluid (cCSF) in patients suffering from aneurysmal subarachnoid haemorrhage (SAH).  Method: 21 patients suffering from aneurysmal SAH were investigated. Treatment included aneurysm clipping, cisternal drainage of CSF and intravenous nimodipine in all patients as well as tripple H therapy when indicated. TCDS was performed on a daily basis. A mean flow velocity of more than 150 cm/sec and the development a delayed neurological deficit was defined as vasospasm. CSF samples were collected on the day of surgery and for the 7 days following. NO-M (nitrite and nitrate) were measured using a commercially available test kit.  Findings: 5 of 21 patients developed clinically symptomatic vasospasm. There was a significant difference in NO levels between the groups. Patients with cerebral vasospasm showed significantly higher levels of NO-M in CSF than patients with a uncomplicated follow-up between day 2 and 8.  Interpretation: Our preliminary results indicate that SAH leads to an increase in NO-M in CSF. This increase of NO-M significantly correlates with the flow velocities in TCDS measurement suggesting that NO plays an important role in the pathogenesis of cerebral vasospasm. Published online April 28, 2003  Correspondence: A. Woszczyk, Department of Neurosurgery, Justus-Liebig University, Klinikstro?e 29, 35292 Giessen, Germany.     

Nitric Oxide Synthase Inhibition Attenuates Vasoactive Response to Spinal Cord Stimulation in an Experimental Cerebral Vasospasm Model

Summary  Background. The basic mechanism of delayed cerebral vasospasm following subarachnoid haemorrhage (SAH) has been intensively investigated. It is thought that nitric oxide (NO) is a basic mediator of the cerebral vasodilator mechanism. Previous clinical and experimental studies have shown a cerebral vasodilator effect of high cervical spinal cord stimulation (SCS) however, the mechanism of this effect is still controversial. We investigated the contribution of the vasodilator effect of NO to this mechanism in an experimental SAH model using rabbits.  Method. Four experimental groups, were designated: Group 1. Cerebral blood flow (CBF) was evaluated by transcranial Doppler ultrasonography (TDU) in 8 rabbits. Group 2. In 4 animals, intracisternal saline injection and cervical epidural electrode placement without SCS were performed before TDU. Group 3. TDU was performed before and after SCS on the fourth day of SAH in 8 rabbits. Group 4. In 8 animals, N-Nitro-L-Arginine Methyl Esther (L-NAME) was administered intracisternally on the fourth day of SAH, at a dose of 0.6 mg/kg, 45 minutes before SCS. CBF parameters, obtained via measurements or calculations from TDU data, were compared.  Findings. The occurrence of vasospasm after SAH was demonstrated with significant changes in TDU parameters (high peak systolic velocity and positive values of the degree of stenosis). In all SAH animals, SCS resulted in significant vasodilation. Even after the injection of L-NAME, SCS still had a significant vasodilatory effect in SAH animals, but there was also a significant difference in CBF parameters in the SCS-only group when compared with the L-NAME treatment before SCS group.  Interpretation. The mechanism of the cerebral vasodilatory effect of SCS remains controversial. Our results revealed the contribution of a neurohumoral effect which can be partially prevented by use of an NO synthase inhibitor.     

Spinal Cord Stimulation and Early Experimental Cerebral Spasm: The “Functional Monitoring” and the “Preventing Effect”

Summary  Background. Clinical and experimental data on cerebral blood flow (CBF) changes during spinal cord stimulation (SCS) were published since 1986. The aims of the present work are: 1. To find an experimental model of reliable, simple and in vivo monitoring of “early” basilar artery spasm after subarachnoid haemorrhage (SAH) and 2. To investigate the effects of cervical spinal cord stimulation (CSCS) on it. Vasospasm due to SAH is both “acute” and “recurrent”. Early spasm occurs within minutes of the SAH, its duration is approximately 1 hour. The need of different morphological and haemodynamic methods to evaluate experimental early spasm is reported. To overcome intracranial surgical manipulations and biological effects of contrast and fixation media we designed a model that allows “ in vivo” functional monitoring of basilar blood flow far away from the spasm without direct surgical and chemical interference. Subsequently we investigated the effects of CSCS on the new model of “functional monitoring” of the “early” cerebral vasospasm.  Method. 29 adult Burgundy rabbits were studied. Group 1: under homeostatic monitoring, “on-line” carotid blood flow (carotid BF) changes produced by SAH in cisterna magna of 12 (plus 5 sham treated) animals were studied from the common carotid artery after external carotid artery occlusion before, during SAH and up to the end of the experiments. All the animals underwent digital subtraction cerebral panangiography (CPA) after SAH obtaining a significant increase of carotid BF only when basilar vasospasm was shown by CPA. Carotid BF increase during basilar vasospasm was defined “functional monitoring” of early spasm. Group 2: Twelve animals wearing a cervical epidural electrode underwent carotid BF “functional monitoring” of early basilar spasm before and during CSCS.  Findings. Carotid BF changes during CSCS occurred in 10 animals. No carotid BF changes (i.e. no basilar vasospasm) occurred after SAH up to the end of the experiments in all the stimulated animals.  Interpretation. CSCS is able to prevent “early spasm” due to SAH in all the animals studied with the new model of “functional monitoring” described, independently from the occurrence and the sign for stimulation-induced carotid BF variations. The role and the limits of reversible functional sympathectomy in mediating the effect of CSCS on early vasospam are discussed.     

Effects of Intracisternal Methylprednisolone on Lipid Peroxidation in Experimental Subarachnoid Haemorrhage

Summary  The efficacy of intracisternal methylprednisolone was examined on lipid peroxidation in a canine subarachnoid haemorrhage (SAH) model. The concentration of lipid peroxides increased significantly in the cerebrospinal fluid (CSF) supernatant on Day 4, and also in the arterial wall on Day 7. Intracisternal administration of methylprednisolone reduced markedly the products of lipid peroxidation both in CSF and in the arterial wall. The findings suggest that lipid peroxidation might play a significant role in the genesis of vasospasm after SAH, and that direct administration of methylprednisolone into the subarachnoid space might reduce lipid peroxides in the arterial wall and so influence the prevention of vasospasm.     

Leflunomide prevents vasospasm secondary to subarachnoid haemorrhage

Summary Background. Though cerebral vasospasm is one of the most serious complications of subarachnoid haemorrhage (SAH), its complex pathogenesis is poorly understood and available clinical treatment options are unsatisfactory. This study was designed to examine the efficacy of leflunomide, an immunomodulatory agent with inhibitory properties, on vascular smooth muscle cell proliferation and inflammation in a rabbit cerebral vasospasm model. Methods. Twenty-two adult New-Zealand rabbits were assigned to 4 groups: control, SAH, SAH plus vehicle, SAH plus leflunomide. Subarachnoid haemorrhage was induced by administration of 1 ml of fresh unheparinised autologous arterial blood into the cisterna magna. Oral leflunomide (2 mg/kg) or vehicle treatment was started 12 h after the induction of subarachnoid haemorrhage and administered once a day. Three days later, the animals were sacrificed and the basilar artery was examined histologically for the lumen area and the thickness of the vessel wall. Inflammatory reaction was also examined by counting white blood cells within the vessel wall by means of light microscopic examination using haematoxylin and eosin staining. Findings. Severe and moderate vasospasms were detected in the basilar artery of the SAH and SAH plus vehicle treated groups, respectively. Leflunomide effectively reduced the vasospasm of the basilar artery. Compared to the vehicle treated group, leflunomide significantly reduced the lumen area (p < 0.01) and hyperplasia of the vessel wall (p < 0.01). Although inflammatory response within the vessel wall was reduced in the leflunomide treated group, no statistical significance was found between groups (p = 0.07). Conclusion. This study demonstrates for the first time that leflunomide treatment attenuates cerebral vasospasm in a rabbit SAH model while inflammatory reaction in the vessel wall is not affected. Although further studies are needed to reveal its molecular mechanisms in relieving vasospasm, leflunomide may provide a therapeutic potential for human cerebral vasospasm induced by 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.     

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.     

Management-Related Morbidity and Mortality in Unselected Aneurysms of the Basilar Trunk and Vertebrobasilar Junction

Summary  Objects. To analyze the management-related morbidity and mortality in unselected aneurysms of the basilar trunk and vertebrobasilar junction. The secondary objective was to investigate the factors associated with favourable or unfavourable surgical outcome in order to define subgroups for surgical and endovascular treatment.  Methods. 24 consecutive patients with aneurysms of the basilar trunk and vertebrobasilar junction were included in this study. They comprised 2.7% of all aneurysms treated during the study period between 1990 and 1997. 22 patients presented with acute subarachnoid hemorrhage (SAH) and 2 patients with symptoms of brainstem compresssion. All patients were managed using a standard protocol including surgery at the earliest possible moment, aggressive tripe-H therapy in patients with symptomatic vasospasm and mandatory follow-up angiography. 23 patients underwent surgical clipping and one patient endovascular coiling of the aneurysm. 12 patients had an excellent outcome. 6 patients had a good outcome, resulting in a total of satisfactory outcomes in 18 patients (75%). 4 patients (17%) had moderate to severe deficits. Two patients died (8%). Both patients had fusiform basilar trunk aneurysms. Good or excellent outcome was observed in 7 of 8 patients with aneurysms of the vertebrobasilar junction, 13 of 14 patients with moderate or minor SAH or without SAH (Fisher grade 0 to 2) and all patients with small sized aneurysm (n=6). Factors mostly associated with poor outcome or death after surgical treatment were aneurysm location at the basilar trunk, large aneurysm size or fusiforme aneurysm type and severe SAH.  Conclusions. Location, aneurysm size and the severity of SAH may help to predict the subgroup which highly benefits from surgical clipping of these rare vascular lesions.     

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.     

Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for long term treatment

Summary.  Background: Magnesium is a neuroprotective agent which might prevent or reverse delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH). Although the dosage for short-term magnesium therapy is well established, there is lack of knowledge on the dosage for extended use of magnesium. Our aim was to find a dosage schedule of magnesium sulphate to maintain a serum magnesium level of 1.0–2.0 mmol/L for 14 days to cover the period of DCI.  Methods: We prospectively studied 14 patients admitted within 48 hours after aneurysmal subarachnoid haemorrhage (SAH) to our hospital. Magnesium sulphate was administrated intravenously for 14 days, using 3 different dosage schedules. Group A (n=3) received a bolus injection of 16 mmol magnesium sulphate followed by a continuous infusion of 16 mmol/dayly; group B (n=6) a continuous infusion of 30 mmol/dayly; and group C (n=5) a continuous infusion of 64 mmol/dayly. Serum magnesium was measured at least every two days and all patients were under continuous observation during magnesium treatment. Renal magnesium excretion was measured only in group C.  Findings: In treatment group A the mean serum magnesium level during treatment was 1.03±0.14 (range 0.82–1.34) mmol/L, in group B 1.10±0.15 (range 0.87–1.43) mmol/L, and in group C 1.38±0.18 (range 1.11–1.98) mmol/L. The renal magnesium excretion in group C was equal to the administrated doses within 48 hours after treatment had started. All patients in group A reported a flushing sensation during the bolus injection; no other side effects were noted.  Interpretation: With a continuous intravenous dosage of 64 mmol/L per day, serum magnesium levels maintained within the range of 1.0–2.0 mmol/L for 14 days. Published online March 3, 2003 Acknowledgments  We gratefully acknowledge the Netherlands Heart Foundation (grant 99.107) and the Schumacher-Kramer Foundation, for financially supporting this study. Dr. Rinkel is clinically established investigator of the Netherlands Heart Foundation (grant D98.014).  Correspondence: W. M. van den Bergh, M.D., Department of Neurosurgery, Room G03.124, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.     

The effect of an adenosine A1 receptor agonist in the treatment of experimental subarachnoid hemorrhage-induced cerebrovasospasm

Summary Background. Adenosine is a potent vasodilator and an important modulator of cardiovascular function. It has been postulated that nitric oxide (NO) is involved in adenosine-induced vasodilation. This study was designed to examine the effect of an adenosine A₁ agonist, N⁶-cyclopentyladenosine (CPA), in the prevention of subarachnoid haemorrhage (SAH)-induced vasospasm. Method. Experimental SAH was induced in Sprague-Dawley rats by injecting 0.3 mL autogenous blood into the cisterna magna. Intraperitoneal injections of CPA (0.003 mg/kg), or vehicle were administered 5 min and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging the cross sectional areas of the basilar artery 2 days after SAH. Expressions of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in basilar artery were evaluated. Findings. There were no significant differences among the control and treated groups in physiological parameters recorded before sacrifice. When compared with animals in the control group, cross-sectional area of basilar arteries areas in the SAH only, SAH plus vehicle and SAH plus CPA groups were reduced by 19% (p < 0.01), 22% (p < 0.01), and 9% (p = 0.133), respectively. The cross-sectional areas of the CPA-treated group differed significantly from those of the SAH only and SAH plus vehicle group (p < 0.05). Induction of iNOS-mRNA and protein in basilar artery by SAH was not significantly diminished by CPA. The SAH-induced suppression of eNOS-mRNA and protein were relieved by CPA treatment. Conclusions. This is the first evidence to show an adenosine A₁ receptor agonist is effective in partially preventing SAH-induced vasospasm without significant cardiovascular complications. The mechanisms of adenosine A₁ receptor agonists in attenuating SAH-induced vasospasm may be, in part, related to preserve the normal eNOS expression after SAH. Inability in reversing the increased iNOS expression after SAH may lead to the incomplete anti-spastic effect of CPA.     

Cerebral Blood Flow Velocities After Subarachnoid Haemorrhage in Relation to the Amount of Blood Clots in the Initial Computed Tomography

Summary  In 72 patients with acute subarachnoid haemorrhage (SAH) the relationship between the amount of subarachnoid blood clots detected by initial cranial computed tomography (CCT) up to 48 hours after bleeding and the later development of vasospasm, established by blood flow velocity measurement with transcranial Doppler ultrasound (TCD) was investigated. The serial Doppler examinations started within the first 72 hours after SAH and were carried out every second day up to three weeks. Each Doppler recording was accompanied by a neurological examination. Patients classified as Hunt and Hess grade V were excluded from the study. All patients with remarkable brain oedema in CCT or with intracranial pressure above 25 mmHg were also excluded. Because of the well known age-dependence of vasospasm after SAH, two age groups were formed.  A statistically significant correlation (p>0.05) between blood flow velocities and blood load after SAH was not found. The mean age of the investigated 72 individuals was 48.9 years (14 up to 76 years). 47 patients were younger than 56 years. Linear regression analysis indicated a correlation with a quite low significance level (r=0.350, p<0.025) between TCD blood flow velocities and blood load in CCT in these younger subjects. No significant correlation (p>0.05) between these two variables could be established in the 25 patients older than 55 years. In a second step an intra-individual comparison of side-to-side differences in TCD and CCT was made. There were no significant differences in blood flow velocities between subjects with or without side-to-side differences in cisternal blood load.  It is concluded that the amount of blood visible on initial CCT after SAH is not a powerful predictor of cerebral blood flow velocities measured by TCD.     

The Stimulation of Vascular Smooth Muscle Oxidative Metabolism by CSF from Subarachnoid Haemorrhage Patients Increases with Fisher and WFNS Grades

Summary  The purpose of this paper is to present an in vitro method for examining cerebral vasospasm after subarachnoid haemorrhage (SAH) which correlates to the patients' condition. The O₂ consumption of the porcine carotid artery was monitored, using an oxygen electrode, after exposure to cerebrospinal fluid (CSF) from patients who had a SAH. The vessels were exposed to CSF from SAH patients at a 1 in 30 dilution. Force measurements were carried out using freeze-dried CSF, reconstituted in the organ bath equivalent to undiluted CSF. These observations were then compared to the patients' condition.  We divided the patient CSF samples into those that stimulated oxygen consumption above 0.4 μM/min/g dry wt, and those that did not. It was found that there was a correlation between the stimulation of oxygen consumption and the Fisher grade as well as the World Federation of Neurosurgeons Grading System (WFNS) for the patients. Of the CSF tested, 24 stimulated oxygen consumption above our cut off, and 8 did not (0.84±0.34, n=24 compared with the rate of 0.27±0.1 μmol/min/g dry wt, respectively; SD n=8) at 180 minutes. We then examined the Fisher Grades of these two groups, the results were 3.21±0.88 vs 2.25±0.83 respectively (SD p≤0.01). When examining the WFNS System we found a similar difference between the groups that stimulated respiration and those who did not (WFNS Grades of 2.64±1.1 vs. 1.43±0.53; p≤0.01). The observed stimulation of oxygen consumption also correlated with tension generation in vitro.  The CSF from subarachnoid haemorrhage patients stimulates the oxygen consumption of the porcine carotid artery. This stimulation correlated to the WFNS and Fisher Grades of the patients and can be performed using 1:30 dilution of CSF. We conclude that the metabolic changes that occur in the vessels during vasospasm are important parameters for assessing cerebral vasospasm.     

Trends in Subarachnoid Haemorrhage in Elderly Persons from Nagasaki, Japan: Analysis of the Nagasaki SAH Data Bank for Cerebral Aneurysm, 1989–1998

Summary.  Background: Many industrialized countries are facing a volumetric growth of the senior population. We studied the trends in the incidence and outcome of subarachnoid haemorrhage (SAH) in patients aged ≥70 years.  Method: We retrospectively reviewed the cases of 1030 patients registered in the Nagasaki SAH Data Bank from 1989 to 1993 and 1274 patients registered from 1994 to 1998.  Findings: The annual age-adjusted incidence of SAH per 100,000 increased only in women, from 15.4 in the 1989–1993 period to 19.7 in the 1994–1998 period. The average annual incidence of SAH per 100,000 women in the elderly aged ≥70 years increased significantly from 44.3 in the first period to 58.2 in the second period. In patients aged ≥70 years, the proportion of high-grade SAH (Hunt & Kosnik Grade IV and V) significantly increased from 27.2% in the first 5 years to 38.2% in the second 5 years. In patients aged<70 years, it increased slightly from 23.4% to 26.7%. The rate of favorable outcomes significantly fell from 43.9% (first period) to 30.9% (second period) in patients aged ≥70 years but was stable in patients aged<70 years.  Interpretation: Although the incidence of elderly patients with SAH in our study is compatible with or higher than that of other reports, we believe that elderly patients (especially women) with high-grade SAH may not have all been identified. When we discuss the management of ruptured and unruptured aneurysms in the elderly, we should bear these trends of SAH in mind. Published online October 31, 2002 Correspondence: Makio Kaminogo, M.D., Department of Neurosurgery, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.     

Nitric oxide in subarachnoid haemorrhage and its therapeutics implications

Summary Background. After the discovery that nitric oxide (NO) plays a major role in the regulation of vascular tone, this substance moved into the focus of interest with regard to vasospasm after subarachnoid haemorrhage (SAH). A multitude of interactions were discovered and some concepts of therapeutic intervention were developed. Method. The present review is based on a Medline search with the terms “nitric oxide” and “subarachnoid haemorrhage”. Findings. SAH and particularly liberated oxyhaemoglobin sequestrate the physiologically produced NO. Reactivity to NO appears to be principally preserved. As other types of injury, SAH leads to induction of inducible NO synthase (iNOS). The NO produced by this pathway cannot compensate for the lack of the physiological NO and may even lead to tissue damage by oxidative stress. Experimental therapeutic attempts use stimulation of NO production and delivery of NO donors. NO donors were also used in some small clinical trials. A final assessment of efficacy and safety is not yet possible. Conclusion. NO physiology and pathophysiology are important in the genesis of vasospasm after subarachnoid haemorrhage. NO directed therapeutic strategies enlarge the spectrum of available instruments, but complete elimination of the problem of vasospasm cannot be expected.     

Decrease in Intraoperative Brain Surface Temperature in Patients with Subarachnoid Haemorrhage

Summary  Background. Recent experimental and clinical evidence of hypothermic protection against neuronal injury creates new interests regarding human brain temperature. However, very little information is available for the brain temperature under certain pathological conditions. In this study, intra-operative brain temperature in patients with subarachnoid haemorrhage (SAH) is particularly addressed.  Methods. Brain surface temperature and oxygen saturation of jugular bulb (SjO₂) were monitored during early surgery undergone within 48 hours after the onset in patients with SAH (n=16). Those were also measured in patients with unruptured aneurysms during elective surgery as control (n=15).  Findings. The brain surface temperature was significantly lower in SAH than control (35.3±0.8 vs. 36.1±0.5°C, P<0.01). The reduction in brain surface temperature was correlated with the severity of the Hunt and Kosnik's aneurysmal grade (r=0.837, P<0.01). SjO₂ was significantly lower in SAH than control (51.5±7.3 vs. 68.5±7.6%, P<0.01), and was positively correlated with brain surface temperature (r=0.642, P<0.01).  Interpretation. These results suggest that the brain temperature and/or the temperature gradient within the brain may be altered in an early period after SAH. Since brain temperature is determined by cerebral blood flow (CBF), metabolism, temperature of both circulating blood and surrounding environment, the brain surface temperature reduction may be explained by depressed CBF and metabolism in SAH.