Does suboccipital decompression and evacuation of intraparenchymal hematoma improve neurological outcome in patients with spontaneous cerebellar hemorrhage?

OBJECTIVE: Spontaneous cerebellar hemorrhages (SCH) can lead to life-threatening complications with high mortality rates of 20-50%. Although complications of SCH can be prevented by surgical therapy, there is a lack of consensus concerning the optimal surgical technique for evacuating SCH. METHODS: In this retrospective study 85 patients with SCH were divided into four treatment groups: (1) Decompression and Hematoma Evacuation via suboccipital craniectomy and removal of the posterior arch of C1 (DHE). (2) Hematoma Evacuation Only via craniotomy (HEO). (3) External Ventricular Drainage (EVD). (4) Conservative treatment (C). To ascertain the level of consciousness, Glasgow Coma Scale (GCS) was calculated. To evaluate the clinical and neurological outcome, modified Rankin Score, Glasgow Outcome Scale and mortality rate were recorded after 6months. RESULTS: The mean volume of hematoma was significant larger in the DHE- and HEO-group compared to the EVD- and C-group before treatment. DHE and HEO could significantly reduce the volume comparing pre- and postoperative measurements. Larger preoperative volume was a strong predictor of worse neurological outcome and high mortality. Overall mortality was 25.9%. After subdivision into the treatment groups, a comparison of the DHE- and HEO-groups showed a trend towards lower mortality and better neurological outcome in the DHE-group. Patients with the worst preoperative GCS scores profited significantly from DHE with respect to regaining consciousness. CONCLUSIONS: Patients with SCH should receive surgical therapy when hemorrhages are space-occupying and when the patient's neurological condition deteriorates. With regards to surgical technique, and limited by the retrospective design of the study, our results indicate that patients might benefit most from DHE.

Is a modification of the radiotherapeutic target volume necessary after resection of glioblastomas with opening of the ventricles?

Extensive surgical resection of centrally localized, newly diagnosed glioblastoma can lead to opening ventricles and therefore carries a potential risk of spreading tumor cells into the cebrospinal fluid. However, whether ventricle opening consequently implies a greater frequency of distant tumor recurrence after radiation therapy-and, therefore, reduced survival-remains unknown. Therefore, is an adaption of target volumes in radiation therapy necessary to account for a potential tumor cell spread into the ventricle system? The present study assessed the resection statuses of 311 primary-glioblastoma patients who underwent radiation therapy. Overall, in 78 cases (25.1 %) the ventricle system was opened during surgical resection. This study assessed the connection between ventricle opening and progression-free survival, overall survival, and distant and multifocal recurrence. OS rates of patients that underwent gross total resection were superior to patients with subtotal resection (p = 0.002). PFS (p = 0.53) and OS (p = 0.18) did not differ due to ventricle opening during surgical resection. However, in a subsample of STR cases increased survival was observed when the ventricle system was opened (16.8 vs. 14.3 months; p = 0.03). The occurrence of distant (p = 0.75) and contralateral recurrence (p = 0.87) was not influenced by ventricle opening. Newly diagnosed glioblastoma patients whose ventricle systems were opened during microsurgical resection did not experience decreased survival or show increased likelihoods of distant and contralateral progressions following radiation therapy. In short, patients profit from surgical resections that are as extensive as reasonably possible, even if this entails ventricle opening. Thus, additional inclusion of the ventricles in the radiation therapy target volume after ventricle opening does not seem to be indicated.

Endogenous nitric-oxide synthase inhibitor ADMA after acute brain injury.

Previous results on nitric oxide (NO) metabolism after traumatic brain injury (TBI) show variations in NO availability and controversial effects of exogenous nitric oxide synthase (NOS)-inhibitors. Furthermore, elevated levels of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) were reported in cerebro-spinal fluid (CSF) after traumatic subarachnoid hemorrhage (SAH). Therefore, we examined whether ADMA and the enzymes involved in NO- and ADMA-metabolism are expressed in brain tissue after TBI and if time-dependent changes occur. TBI was induced by controlled cortical impact injury (CCII) and neurological performance was monitored. Expression of NOS, ADMA, dimethylarginine dimethylaminohydrolases (DDAH) and protein-arginine methyltransferase 1 (PRMT1) was determined by immunostaining in different brain regions and at various time-points after CCII. ADMA and PRMT1 expression decreased in all animals after TBI compared to the control group, while DDAH1 and DDAH2 expression increased in comparison to controls. Furthermore, perilesionally ADMA is positively correlated with neuroscore performance, while DDAH1 and DDAH2 are negatively correlated. ADMA and its metabolizing enzymes show significant temporal changes after TBI and may be new targets in TBI treatment.

Initial experiences with Multiplate® for rapid assessment of antiplatelet agent activity in neurosurgical emergencies.

OBJECTIVE: As the population ages, physicians encounter a growing number of patients who are treated with antiplatelet agents and present with severe conditions requiring urgent neurosurgical therapy. Standard laboratory investigations are insufficient to evaluate platelet activity and furthermore, it is difficult to evaluate effects of haemostatic measures on platelet function. In this article we report our initial experiences with the point-of-care device Multiplate® for assessment of platelet activity in neurosurgical emergencies on patients with a reported intake of antiplatelet medication. METHODS: Multiplate® assessment of antiplatelet activity was carried out in 21 non-consecutive patients with a reported intake of antiplatelet medication (aspirin: n=21, clopidogrel: n=3, ticragrelor: n=1) and urgent admission to our hospital because of conditions such as intracranial haemorrhage requiring urgent neurosurgical therapy. Analysis was repeated in order to evaluate the effectiveness of haemostatic drugs and platelet concentrate transfusion on platelet activity in six patients. RESULTS: No technical difficulties occurred and in all cases, results were obtained within 15 min. On admission, patients' arachidonic acid induced platelet activity was reduced by 44.4±33.5% (range: -79.7% to +44.3%) compared to the lower reference limit. Two patients had a normal platelet activity despite a reported intake of aspirin. Haemostatic measures significantly increased arachidonic acid induced platelet activity by 100±66% (p<0.005). CONCLUSION: The Multiplate® device allowed rapid assessment of antiplatelet agent activity and evaluation of haemostatic measures on platelet activity. Further studies with larger patient numbers are needed, but this device may represent a valuable tool to improve treatment modalities in patients treated with antiplatelet medication and conditions requiring urgent neurosurgical therapy.

Role of endogenous monomethylated L-arginine (L-NMMA) after subarachnoid hemorrhage.

OBJECTIVES: Monomethylated L-arginine (L-NMMA) has been proven to be a strong inhibitor of nitric oxide synthase (NOS) and has been used as an exogenous tool in experimental evaluation of cerebrovascular reactivity leading to vasoconstriction. However, L-NMMA is also produced endogenously and belongs, as does asymmetric dimethylated L-arginine (ADMA), to a family of endogenous NOS inhibitors. While ADMA has been associated with cerebral vasospasm (CVS) but not with delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH), no results are available concerning endogenous L-NMMA and SAH. We therefore decided to investigate the role of endogenous L-NMMA with regard to CVS and DCI after SAH. METHODS: Retrospective analysis of cerebro-spinal fluid (CSF) and serum of SAH patients and controls was performed by high performance liquid chromatography (HPLC) and chemiluminescence. Delayed CVS was detected by arteriography and cerebral ischemic events by follow-up computed tomography (CT) scans. RESULTS: Cerebro-spinal fluid and serum L-NMMA concentrations neither correlated with CVS nor with NO2(-) levels (P > 0·05, in both cases). However, endogenous L-NMMA concentrations correlated with cerebral ischemic events and with the size of infarction (cc = 0·459, P = 0·032, 95% CI: 0·046-0·738). CONCLUSIONS: This study shows that endogenous L-NMMA is associated with the occurrence of cerebral ischemic events, but seems not to be involved in CVS after SAH. Therefore, endogenous L-NMMA after SAH features intriguing differences compared with previous reports on exogenous L-NMMA and ADMA after SAH.

CSF and Serum Biomarkers Focusing on Cerebral Vasospasm and Ischemia after Subarachnoid Hemorrhage.

Delayed cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) remain severe complications after subarachnoid hemorrhage (SAH). Although focal changes in cerebral metabolism indicating ischemia are detectable by microdialysis, routinely used biomarkers are missing. We therefore sought to evaluate a panel of possible global markers in serum and cerebrospinal fluid (CSF) of patients after SAH. CSF and serum of SAH patients were analyzed retrospectively. In CSF, levels of inhibitory, excitatory, and structural amino acids were detected by high-performance liquid chromatography (HPLC). In serum, neuron-specific enolase (NSE) and S100B level were measured and examined in conjunction with CVS and DCI. CVS was detected by arteriography, and ischemic lesions were assessed by computed tomography (CT) scans. All CSF amino acids were altered after SAH. CSF glutamate, glutamine, glycine, and histidine were significantly correlated with arteriographic CVS. CSF glutamate and serum S100B were significantly correlated with ischemic events after SAH; however, NSE did not correlate neither with ischemia nor with vasospasm. Glutamate, glutamine, glycine, and histidine might be used in CSF as markers for CVS. Glutamate also indicates ischemia. Serum S100B, but not NSE, is a suitable marker for ischemia. These results need to be validated in larger prospective cohorts.

European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage.

BACKGROUND: Intracranial aneurysm with and without subarachnoid haemorrhage (SAH) is a relevant health problem: The overall incidence is about 9 per 100,000 with a wide range, in some countries up to 20 per 100,000. Mortality rate with conservative treatment within the first months is 50-60%. About one third of patients left with an untreated aneurysm will die from recurrent bleeding within 6 months after recovering from the first bleeding. The prognosis is further influenced by vasospasm, hydrocephalus, delayed ischaemic deficit and other complications. The aim of these guidelines is to provide comprehensive recommendations on the management of SAH with and without aneurysm as well as on unruptured intracranial aneurysm. METHODS: We performed an extensive literature search from 1960 to 2011 using Medline and Embase. Members of the writing group met in person and by teleconferences to discuss recommendations. Search results were graded according to the criteria of the European Federation of Neurological Societies. Members of the Guidelines Committee of the European Stroke Organization reviewed the guidelines. RESULTS: These guidelines provide evidence-based information on epidemiology, risk factors and prognosis of SAH and recommendations on diagnostic and therapeutic methods of both ruptured and unruptured intracranial aneurysms. Several risk factors of aneurysm growth and rupture have been identified. We provide recommendations on diagnostic work up, monitoring and general management (blood pressure, blood glucose, temperature, thromboprophylaxis, antiepileptic treatment, use of steroids). Specific therapeutic interventions consider timing of procedures, clipping and coiling. Complications such as hydrocephalus, vasospasm and delayed ischaemic deficit were covered. We also thought to add recommendations on SAH without aneurysm and on unruptured aneurysms. CONCLUSION: Ruptured intracranial aneurysm with a high rate of subsequent complications is a serious disease needing prompt treatment in centres having high quality of experience of treatment for these patients. These guidelines provide practical, evidence-based advice for the management of patients with intracranial aneurysm with or without rupture. Applying these measures can improve the prognosis of SAH.

The CSF concentration of ADMA, but not of ET-1, is correlated with the occurrence and severity of cerebral vasospasm after subarachnoid hemorrhage.

Under physiological conditions, vasoconstrictors and vasodilators are counterbalanced. After aneurysmal subarachnoid hemorrhage (SAH) disturbance of this equilibrium may evoke delayed cerebral vasospasm (CVS) leading to delayed cerebral ischemia (DCI). Most studies examined either the vasoconstrictor endothelin-1 (ET-1) or the vasodilative pathway of nitric oxide (NO) and did not include investigations regarding the relationship between vasospasm and ischemia. Asymmetric dimethyl-L-arginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), decreases the concentration of NO. Studies have correlated increasing concentrations of ADMA with the course and degree of CVS after SAH. We sought to determine, if ADMA and endothelin-1 (ET-1) are associated with CVS and/or DCI after SAH. CSF concentrations of ADMA and ET-1 were retrospectively determined in 30 patients after SAH and in controls. CVS was detected clinically and by arteriogaphy. DCI was monitored by follow-up CT scans. 17 patients developed arteriographic CVS and 4 patients developed DCI. ADMA but not ET-1 concentrations were correlated with occurrence and degree of CVS. However, ET-1 concentrations were correlated with WFNS grade on admission. Neither ADMA nor ET-1 correlated with DCI in this cohort. ET-1 concentrations seem to be associated with the impact of the SAH bleed. ADMA may be directly involved in the development and resolution of CVS after SAH via inhibition of NOS disturbing the balance of vasodilative and -constrictive components.

Cerebral metabolism after early decompression craniotomy following controlled cortical impact injury in rats.

After traumatic brain injury, a cascade of metabolic changes promotes the development of secondary brain damage. In this study, we examined metabolic changes in rats in the acute stage after trauma. Furthermore, we investigated the effect of a very early decompression craniotomy on intracranial pressure (ICP) and on metabolic parameters. For this study, a moderate controlled cortical impact injury (CCII) on rats was performed. The observation time was 180 minutes after trauma. ICP was measured continuously and microdialysate samples were collected every 30 minutes from the peri-contusional region. As representative metabolic parameters, glutamate, lactate, lactate/pyruvate ratio (L/P ratio), and glucose concentrations were measured. Compared to sham-operated animals, a significant, sustained decrease in glucose concentration and increase in L/P ratio occurred immediately after CCII. Additionally, delayed increase in lactate and glutamate concentrations occurred 60 minutes after trauma. After this initial peak, glutamate concentrations declined continuously via the observation time and reached levels comparable to sham-operated animals. In our model, thus we could detect a very early deterioration of glucose utilization and energy supply after trauma that recovered, due to the moderate intensity of the trauma, within 60 minutes without leading to ischemia in the peri-contusional region. Following decompression craniotomy, the increase of intracranial pressure could be reduced significantly. Any significant beneficial effects on metabolic changes, however, could not be proven in this very early stage after moderate CCII.

Helmet use in winter sport activities--attitude and opinion of neurosurgeons and non-traumatic-brain-injury-educated persons.

PURPOSE: During the last winter season, some fatal sport injuries with severe traumatic brain injury (TBI) prompted major discussions about protective helmet use. Although ski helmets reportedly lead to a 60% decrease of risk to incur TBI, little is known about the distribution of helmet users and which factors are crucial for the decision to wear a helmet. Especially, it is unknown whether knowledge or experience concerning TBI in winter sports influences the use of helmets, as well as the attitude and opinion of people. METHODS: Since treatment of TBI is a major field in neurosurgery, 55 neurosurgical departments (NS) in Germany, Switzerland and Austria were addressed and asked to answer anonymous questionnaires. A "non-trauma-educated" control cohort (NTP) was interviewed in ski resorts in Austria as well as sports equipment stores in Germany. RESULTS: Questionnaires were returned by 465 NS and 546 NTP. Half of NS and NTP wore helmets in winter sports. Although some interviewees showed cognitive dissonant behaviour, experience in TBI after ski or snowboard accidents significantly affected the decision to wear helmets. After the fatal ski accidents, and increased media coverage 15.4% NS and 13.2% NTP bought their helmet. Furthermore, incidence of helmet use in children was correlated with the actual use and disposition of their parents to make the use of helmet compulsory. CONCLUSIONS: This study indicates that brain-trauma education affects ones attitude and opinion concerning protective helmet use in winter sports. However, without neglecting educational measures, emotional arguments should be added in the promotion of helmets to make them a popular integral part of winter sport outfits.

Attitude and opinion of neurosurgeons concerning protective bicycle-helmet use.

Wearing protective helmets decreases the risk of incurring traumatic brain injury (TBI) in bicycle accidents. In 2007, the German Neurosurgical Society advocated compulsory use of bicycle helmets. Although neurosurgeons are the specialists who primarily treat patients with TBI in Europe, the distribution of helmet users among neurosurgeons (NS), as well as factors that influence the decision to wear helmets and whether professional knowledge or experience in TBI influences the use or attitude concerning bicycle helmets, remains unclear. A total of 55 neurosurgical departments in Germany, Austria, and Switzerland were contacted and asked to answer anonymous questionnaires concerning helmet use and TBI experience. To compare the neurosurgical attitude with that of a "non-neurosurgical, non-TBI-educated" control group, people of the general public (PUB) were interviewed. A total of 465 NS and 546 PUB returned questionnaires, with 49.7% of the NS and 44.5% of PUB indicated that they wear helmets while bicycling. Trauma experience did effect the personal decision of whether to wear bicycle helmets. Support of compulsory use was influenced by TBI experience. Furthermore, the incidence of helmet use in children was correlated to actual helmet use and disposition of their parents to make helmet use compulsory. NS and PUB behaved in similar ways. Only half wear protective helmets, while the others show cognitive dissonant behavior. With respect to compulsory helmet use, NS are also split in half. Experience with TBI and trauma education has effects. However, education alone does not suffice in promoting the use of bicycle helmets.

Association of an endogenous inhibitor of nitric oxide synthase with cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage.

OBJECT: Delayed cerebral vasospasm after subarachnoid hemorrhage (SAH) may be evoked by the decreased availability of nitric oxide (NO). Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl-L-arginine (ADMA), an endogenous inhibitor of NO synthase (NOS), have been associated with the course and degree of cerebral vasospasm in a primate model of SAH. In this study, the authors sought to determine if similar changes in CSF ADMA levels are observed in patients with SAH, and whether these changes are associated with NO and NOS metabolite levels in the CSF and the presence of cerebral vasospasm. METHODS: Asymmetric dimethyl-L-arginine, L-arginine, L-citrulline, and nitrite levels were measured in CSF and serum samples collected during the 21-day period after a single aneurysmal SAH in 18 consecutive patients. Samples were also obtained in a control group consisting of seven patients with Chiari malformation Type I and five patients with spontaneous intracerebral hemorrhage without SAH. Vasospasm, defined as a greater than 11% reduction in the anterior circulation vessel diameter ratio compared with the ratio calculated from the initial arteriogram, was assessed on cerebral arteriography performed around Day 7. RESULTS: In 13 patients with SAH, arteriographic cerebral vasospasm developed. Cerebrospinal fluid ADMA levels in patients with SAH were higher than in those in the control group (p < 0.001). The CSF ADMA level remained unchanged in the five patients with SAH without vasospasm, but was significantly increased in patients with vasospasm after Day 3 (6.2 +/- 1.7 microM) peaking during Days 7 through 9 (13.3 +/- 6.7 microM; p < 0.001) and then gradually decreasing between Days 12 and 21 (8.8 +/- 3.2 microM; p < 0.05). Nitrite levels in the CSF were lower in patients with vasospasm compared to patients without vasospasm (p < 0.03). Cerebrospinal fluid ADMA levels positively correlated with the degree of vasospasm (correlation coefficient [CC] = 0.88, p = 0.0001; 95% confidence interval [CI] 0.74-0.95) and negatively correlated with CSF nitrite levels (CC = -0.55; p = 0.017; 95% CI -0.81 to -0.12). CONCLUSIONS: These results support the hypothesis that ADMA is involved in the progression of cerebral vasospasm. Asymmetric dimethyl-L-arginine and its metabolizing enzymes may be a future target for treatment of cerebral vasospasm after SAH.

In vitro and in vivo effects of probucol on hydrolysis of asymmetric dimethyl L-arginine and vasospasm in primates.

OBJECT: Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl L-arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), are associated with delayed vasospasm after subarachnoid hemorrhage (SAH); however, the source, cellular mechanisms, and pharmacological inhibition of ADMA production following SAH are unknown. METHODS: In an in vitro experiment involving human umbilical vein endothelial cells (HUVECs), the authors examined mechanisms potentially responsible for increased ADMA levels during vasospasm and investigated whether this increase can be inhibited pharmacologically. In a second study, an in vivo experiment, the authors used probucol, which effectively inhibited ADMA increase in HUVEC cultures in vitro, in a randomized double-blind placebo-controlled experiment in a primate model of delayed cerebral vasospasm after SAH. Oxidized low-density lipids (OxLDLs; positive control; p < 0.02) and bilirubin oxidation products (BOXes; p < 0.01), but not oxyhemoglobin (p = 0.74), increased ADMA levels in HUVECs. Probucol inhibited changes in ADMA levels evoked by either OxLDLs (p < 0.001) or BOXes (p < 0.01). Comparable changes were observed in cell lysates. In vivo probucol (100 mg/kg by mouth daily) did not alter serum ADMA levels on Days 7, 14, and 21 after SAH compared with levels before SAH, and these levels were not different from those observed in the placebo group (p = 0.3). Despite achieving therapeutic levels in plasma and measurable levels in CSF, probucol neither prevented increased CSF ADMA levels nor the development of vasospasm after SAH. Increased CSF ADMA and decreased nitrite levels in both groups were strongly associated with the degree of delayed vasospasm after SAH (correlation coefficient [CC] 0.5, 95% confidence interval [CI] 0.19-0.72, p < 0.002 and CC -0.43, 95% CI -0.7 to -0.05, p < 0.03, respectively). CONCLUSIONS: Bilirubin oxidation products, but not oxyhemoglobin, increased ADMA levels in the HUVEC. Despite its in vitro ability to lower ADMA levels, probucol failed to inhibit increased CSF ADMA and decreased nitrite levels, and it did not prevent delayed vasospasm in a primate SAH model.

Condiloma acuminado em cicatriz cirúrgica de amputação abdômino-perineal do reto: relato de caso / Condyloma acuminata in surgery scar of abdominal amputation of rectum: case story

Os autores relatam um caso de condiloma acuminado em cicatriz cirúrgica abdominal, perineal e pericolostômica, em uma mulher submetida a amputação abdômino-perineal do reto por adenocarcinoma de reto inferior. O tratamento inicial consistiu em exérese das lesões e posterior tratamento químico das recidivas.

Association between cerebrospinal fluid levels of asymmetric dimethyl-L-arginine, an endogenous inhibitor of endothelial nitric oxide synthase, and cerebral vasospasm in a primate model of subarachnoid hemorrhage.

OBJECT: Decreased availability of nitric oxide (NO) has been proposed to evoke delayed cerebral vasospasm after sub-arachnoid hemorrhage (SAH). Asymmetric dimethyl-L-arginine (ADMA) inhibits endothelial NO synthase (eNOS) and, therefore, may be responsible for decreased NO availability in cases of cerebral vasospasm. The goal of this study was to determine whether ADMA levels are associated with cerebral vasospasm in a primate model of SAH. METHODS: Twenty-two cynomolgus monkeys (six control animals and 16 with SAH) were used in this study. The levels of ADMA, L-arginine, L-citrulline, nitrites, and nitrates in cerebrospinal fluid (CSF) and serum were determined on Days 0, 7, 14, and 21 following onset of SAH. Cerebral arteriography was performed to assess the degree of vasospasm. Western blot analyses of the right and left middle cerebral arteries (MCAs) were performed to assess the expression of eNOS, type I protein-arginine methyl transferase (PRMT1) and dimethylarginine dimethylaminohydrolase (DDAH2). Cerebrospinal fluid levels of ADMA remained unchanged in the control group (six animals) and in animals with SAH that did not have vasospasm (five animals; p = 0.17), but the levels increased in animals with vasospasm (11 animals) on Day 7 post-SAH (p < 0.01) and decreased on Days 14 through 21 (p < 0.05). Cerebrospinal fluid levels of ADMA correlated directly with the degree of vasospasm (correlation coefficient = 0.7, p = 0.0001; 95% confidence interval: 0.43-0.83). Levels of nitrite and nitrate as well as those of L-citrulline in CSF were decreased in animals with vasospasm. Furthermore, DDAH2 expression was attenuated in the right spastic MCA on Day 7 post-SAH, whereas eNOS and PRMT1 expression remained unchanged. CONCLUSIONS: Changes in the CSF levels of ADMA are associated with the development and resolution of vasospasm found on arteriograms after SAH. The results indicate that endogenous inhibition of eNOS by ADMA may be involved in the development of delayed cerebral vasospasm. Inhibition of ADMA production may provide a new therapeutic approach for cerebral vasospasm after SAH.

Endothelial dysfunction in a primate model of cerebral vasospasm.

OBJECT: Although abnormalities in the control of endothelial vasomotility have been reported in both experimental and clinical studies, the mechanism of the endothelial dysfunction that occurs following subarachnoid hemorrhage (SAH) remains unclear. Because of the absence of previous in vivo studies of endothelial function in cerebral vessels in response to SAH or cerebral vasospasm, the authors investigated endothelium-dependent responses in an established primate model of vasospasm after SAH. Endothelial function was assessed by examining vascular responses to intracarotid injections of various drugs known to act via the endothelium. Drugs that have a rapid total body clearance were selected so that their pharmacological effects would be limited to the cerebral circulation after an intracarotid infusion. METHODS: Seventeen adult male cynomolgus monkeys were used. Cerebrovascular endothelium-dependent responses were examined in control animals and in animals with SAH 7, 14, and 21 days after placement of a subarachnoid clot around the right middle cerebral artery. Cortical cerebral blood flow (CBF) and cerebrovascular resistance (CVR) were recorded continuously during 5-minute intracarotid infusions of 5% dextrose vehicle, acetylcholine, histamine, bradykinin, or Calcimycin. In control animals the intracarotid infusion of acetylcholine produced a significant (7.8 +/- 9.5%) increase in CBF and a 9.3 +/- 8.7% reduction in CVR in comparison with a control infusion of dextrose vehicle. The responses to acetylcholine disappeared in animals 7 days post-SAH, specifically in the subset of animals in which arteriography confirmed the presence of vasospasm. Infusion of Calcimycin produced no significant changes in CBF or CVR in control animals, but resulted in a significant reduction in CBF and increase in CVR in animals 7 days after SAH and in animals with vasospasm. An infusion of histamine or bradykinin had no significant effect on CBF or CVR. CONCLUSIONS: An intracarotid infusion of acetylcholine, but not one of histamine, bradykinin, or Calcimycin, produced a measurable physiological response in the normal primate cerebrovasculature. Cerebral vasospasm that occurred after SAH produced a pathophysiological effect similar to the endothelial denudation shown in the in vitro experiments of Furchgott and Zawadzki, in which acetylcholine constricted the vessels via activation of receptors on smooth-muscle cells. Changes in vascular responses to acetylcholine and Calcimycin in animals with vasospasm, compared with control animals, provide evidence that endothelial dysfunction plays a key role in the development and/or sustenance of vasospasm after SAH.

[D-Val22]big ET-1[16-38] inhibits endothelin-converting enzyme activity: a promising concept in the prevention of cerebral vasospasm.

The aim of this study was to investigate whether the blocking of endothelin-converting enzyme (ECE) activity offers a new approach to inhibiting the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) by preventing transformation of big endothelin-1 (big ET-1) to vasoactive endothelin-1 (ET-1). The effect of potential ECE inhibitors was determined in vitro by measurement of isometric contractions, induced by big ET-1, in isolated rat basilar arteries. Intact and de-endothelialized endothelium (E+ and E-, respectively) segments were examined after preincubation with the putative ECE inhibitors: phosphoramidon (10(-4) M), and [22D-Val]big ET-1 [16-38] (10(-5) M and 10(-6) M). Additionally, the effect of [D-Val22]big ET-1 [16-38] was investigated in rabbits after intracisternal application in order to inhibit the contraction of the basilar artery induced by (2x10(-6) M) big ET-1. Application of 10(-4)-M phosphoramidon resulted in a statistically significant decrease in big ET-1-induced contraction in E+ and E- segments; 10(-5)-M and 10(-6)-M [22D-Val]big ET-1 [16-38] in E- segments produced no statistically significant effect. The application of 10(-6)-M [22D-Val]big ET-1 [16-38] in E+ segments caused increased contractions, as shown by the shift to the left of the concentration-effect curve (CEC). In the rabbit group pretreated with [D-Val22]big ET-1 [16-38] (2x10(-5) M) (n=8), the angiographically measured diameter of the basilar artery increased from 0.63+/-0.12 mm to 0.66+/-0.12 mm. In the control group (n=8), this diameter decreased from 0.71+/-0.13 mm to 0.57+/-0.15 mm. This corresponded to an increase in vessel diameter of 5.24+/-9.89% in the treatment group and a decrease of 19.54+/-15.81% in the control group (P=0.002). The present study indicates the existence of functional ECE activity in rat basilar artery, which differs in the endothelium and the smooth muscle layer. These results demonstrate that [D-Val22]big ET-1 [16-38] has a potent ECE-inhibitory effect, preventing cerebral vasospasm in rabbit basilar artery by inhibiting the transformation of big ET-1 to vasoactive ET-1 after intracisternal application in vivo, whereas no inhibitory effect was detectable in rat basilar artery in vitro. Therefore, further studies of the biochemical nature of cerebrovascular ECE activity are required.

Brain tissue oxygenation monitoring supplementary to somatosensory evoked potential monitoring for aneurysm surgery. Initial clinical experience.

The object of the study was to evaluate brain tissue oxygenation (p(ti)O2) for intra-operative monitoring of critical ischemic events during early cerebral aneurysm surgery of the anterior circulation supplementary to somatosensory evoked potentials (SEPs). P(ti)O2 was continuously evaluated during surgery for an intracranial aneurysm in 28 patients. Standard cortical SEP monitoring was simultaneously performed. The two monitoring methods were compared by evaluating their respective responses to intra-operative events (particularly temporary vessel occlusion), clinical and neuroradiological outcome. P(ti)O2 and SEPs were reliably used for monitoring in 16 patients. Seven patients were excluded due to too high or too low p(ti)O2 readings or initial absence of SEPs (six patients). Of 64 intra-operative events 19 events (eight patients) were associated with a significant decrease in p(ti)O2 (below 10 mmHg), 22 events (13 patients) were associated with a significant change in SEP amplitude (< 50% decrease related to baseline). Temporary vessel occlusion (six SEP andp(ti)O2 changes each in eightpatients) and surgical dissection were most likely to be followed by significant changes in a monitoring method. Intra-operative p(ti)O2 was found to be a safe, rapid method for documenting ischemic events. P(ti)O2 was found to supplement SEP monitoring. The use of p(ti)O2 measurement as a routine monitoring method in aneurysm surgery is limited by its focal spatial resolution. Nevertheless, it might be helpful as an adjunct in situations when SEPs are absent at baseline, in aneurysms when parent vessel anatomy is complex or if temporary vessel occlusion is planned.

Effect of the novel endothelin(A) receptor antagonist LU 208075 on contraction and relaxation of isolated rat basilar artery.

Increased levels of endothelin (ET)-1 and bigET-1 may be responsible for enhanced cerebroarterial resistance under pathologic conditions. Therefore, the effect of LU 208075, a novel ET(A)-selective receptor antagonist was determined. The aim of the study was to investigate in vitro the inhibitory effect of LU 208075 on ET-1 and bigET-1 induced contraction and relaxation in rat basilar artery segments. Segments with (E+) and without (E-) endothelium were prepared for the measurement of isometric force. Concentration-effect curves (CECs) were constructed by cumulative application of ET-1 or bigET-1. The shift of the CECs in the presence of LU 208075 against the control curve was determined. Relaxation was investigated on precontracted segments, calculated in percentage decrease of precontraction and compared by the pD(2) and E(max). ET-1 and bigET-1 induced contraction was dose dependently inhibited by LU 208075. Shifts of the CECs in the presence of LU 208075 (10(-6) M and 10(-5) M) were for ET-1 (1) in E+: 4.4 and 19.7; (2) in E-: 8.1 and 60.4 and for bigET-1 (3) in E+: 10.8 and (4) in E-: 26.0 respectively. LU 208075 (10(-5) M) completely inhibited bigET-1-induced contraction. Relaxation by ET-1 or bigE-1 was only observed in the presence of LU 208075. CECs were shifted to the right by LU 208075 (10(-5) M) by a factor of 24 (ET-1) and 4.5 (bigET-1). E(max) values were 45+/-18% and 51+/-15% (ET-1; in the presence of 10(-5) and 10(-6) M LU 208075 respectively), and 56+/-20% and 49+/-17% (bigET-1; in the presence of 10(-5) and 10(-6) M LU 208075 respectively). The data suggests a competitive ET(A)-receptor inhibition by LU 208075. The enhanced inhibitory effect on bigET-1-induced contraction could indicate an additional inhibitory effect on endothelin-converting enzyme activity. The pronounced effect on E-vessels and the inhibition of relaxation may suggest an ET(B) receptor affinity.