Continuous intrathecal glyceryl trinitrate prevents delayed cerebral vasospasm in the single-SAH rabbit model in vivo

Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of high morbidity and mortality. The reduced availability of nitric oxide (NO) in blood and cerebrospinal fluid (CSF) is well established as a key mechanism of vasospasm. Systemic administration of glyceryl trinitrate (GTN), an NO donor also known as nitroglycerin, has failed to be established in clinical settings to prevent vasospasm because of its adverse effects, particularly hypotension. The purpose of this study was to analyze the effect of intrathecally administered GTN on vasospasm after experimental SAH in the rabbit basilar artery.

Traumatic subarachnoid hemorrhage, basal ganglia hematoma and ischemic stroke caused by a torn lenticulostriate artery

Subarachnoid hemorrhage (SAH), basal ganglia hematoma (BGH) and ischemic stroke are common diseases with diverging therapies. The simultaneous occurrence of these diseases is rare and complicates the therapy. We report the case of a 30-year-old man with a ruptured lenticulostriate artery after traumatic brain injury that caused the combination of SAH, BGH and ischemic stroke and subsequent cerebral vasospasm. This rupture mimicked the pathophysiology and imaging appearance of aneurysmal SAH. The site of rupture was not secured by any treatment; however, hyperdynamic therapy and percutaneous transluminal angioplasty were feasible in this setting to prevent additional delayed neurological deficit.

Outer skull landmark-based coordinates for measurement of cerebral blood flow and intracranial pressure in rabbits

Despite the increased use of intracranial neuromonitoring during experimental subarachnoid hemorrhage (SAH), coordinates for probe placement in rabbits are lacking. This study evaluates the safety and reliability of using outer skull landmarks to identify locations for placement of cerebral blood flow (CBF) and intraparenchymal intracranial pressure (ICP) probes. Experimental SAH was performed in 17 rabbits using an extracranial-intracranial shunt model. ICP probes were placed in the frontal lobe and compared to measurements recorded from the olfactory bulb. CBF probes were placed in various locations in the frontal cortex anterior to the coronary suture. Insertion depth, relation to the ventricular system, and ideal placement location were determined by post-mortem examination. ICP recordings at the time of SAH from the frontal lobe did not differ significantly from those obtained from the right olfactory bulb. Ideal coordinates for intraparenchymal CBF probes in the left and right frontal lobe were found to be located 4.6±0.9 and 4.5±1.2 anterior to the bregma, 4.7±0.7mm and 4.7±0.5mm parasagittal, and at depths of 4±0.5mm and 3.9±0.5mm, respectively. The results demonstrate that the presented coordinates based on skull landmarks allow reliable placement of intraparenchymal ICP and CBF probes in rabbit brains without the use of a stereotactic frame.

Unsecured intracranial aneurysms and induced hypertension in cerebral vasospasm: is induced hypertension safe?

Induced hypertension is an established therapy to treat cerebral vasospasm (CVS) following subarachnoid hemorrhage (SAH) to prevent delayed ischemic deficits. Currently, there is minimal evidence available assessing the risk of induced hypertension in the presence of unsecured aneurysms. The aim of this study was to investigate the impact of induced hypertension on the rupturing of unsecured aneurysms in treating CVS.

Clazosentan: prevention of cerebral vasospasm and the potential to overcome infarction

Cerebral vasospasm is a common complication occurring after aneurysmal subarachnoid hemorrhage (SAH). It is recognized as a leading preventable cause of morbidity and mortality in this patient group, but its management is challenging, and new treatments are needed. Clazosentan is an endothelin receptor antagonist designed to prevent endothelin-mediated cerebral vasospasm. Vajkoczy et al. (Neurosurg 103:9-17, 2005) initially demonstrated that clazosentan reduced moderate/severe angiographically proven vasospasm by 55% relative to placebo. These findings led to the initiation of the CONSCIOUS trial program to further examine the efficacy and safety of clazosentan in reducing angiographic vasospasm and improving clinical outcome after aneurysmal SAH. In the first of these studies, CONSCIOUS-1, 413 patients were randomized to placebo or clazosentan 1, 5 or 15 mg/h. Clazosentan reduced angiographic vasospasm dose-dependently relative to placebo with a maximum risk reduction of 65% with the highest dose. Despite this, there was no benefit of clazosentan on the secondary protocol-defined morbidity/mortality endpoint; however, additional post-hoc and modified endpoint analyses provided some evidence for a potential clinical benefit. Two additional large-scale studies (CONSCIOUS-2 and CONSCIOUS-3) are now underway to further investigate the potential of clazosentan to improve long-term clinical outcome.

Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a severe, cerebral perfusion pressure (CPP)-independent reduction in cerebral blood flow suggesting alterations on the level of cerebral microvessels. Therefore, we aimed to use in-vivo imaging to investigate the cerebral microcirculation after experimental SAH. Subarachnoid hemorrhage was induced in C57/BL6 mice by endovascular perforation. Pial arterioles and venules (10 to 80 μm diameter) were examined using in-vivo fluorescence microscopy, 3, 6, and 72 hours after SAH. Venular diameter or flow was not affected by SAH, while >70% of arterioles constricted by 22% to 33% up to 3 days after hemorrhage (P<0.05 versus sham). The smaller the investigated arterioles, the more pronounced the constriction (r(2)=0.92, P<0.04). Approximately 30% of constricted arterioles were occluded by microthrombi and the frequency of arteriolar microthrombosis correlated with the degree of constriction (r(2)=0.93, P<0.03). The current study demonstrates that SAH induces microarterial constrictions and microthrombosis in vivo. These findings may explain the early CPP-independent decrease in cerebral blood flow after SAH and may therefore serve as novel targets for the treatment of early perfusion deficits after SAH.

A new rabbit model for the study of early brain injury after subarachnoid hemorrhage.

Pathophysiological disturbances during subarachnoid hemorrhage (SAH) and within the first few days thereafter are responsible for significant brain damage. Early brain injury (EBI) after SAH has become the focus of current research activities. The purpose of the present study was to evaluate whether a novel rabbit SAH model provokes EBI by means of neuronal degeneration, brain tissue death, and apoptosis in cerebral vascular endothelial cells.

Decompressive hemicraniectomy in patients with supratentorial intracerebral hemorrhage

Decompressive craniectomy (DC) lowers intracranial pressure and improves outcome in patients with malignant middle cerebral artery stroke. Its usefulness in intracerebral hemorrhage (ICH) is unclear. The aim of this study was to analyze feasibility and safety of DC without clot evacuation in ICH.

Neuro-imaging of cerebral ischemic stroke

Major progress has recently been made in the neuro-imaging of stroke as a result of improvements in imaging hardware and software. Imaging may be based on either magnetic resonance imaging (MRI) or computed tomography (CT) techniques. Imaging should provide information on the entire vascular cervical and intracranial network, from the aortic arch to the circle of Willis. Equally, it should also give information on the viability of brain tissue and brain hemodynamics. CT has the advantage in the detection of acute hemorrhage whereas MRI offers more accurate pathophysiological information in the follow-up of patients.

Neonatal macrocephaly: cerebral primitive neuroectodermal tumor or neuroblastoma as an infrequent cause--a case report and review of the literature

We report a male term newborn presenting with a congenital macrocephaly 3.5 standard deviations above the median, with a wide and tense anterior fontanel, splayed calvarial sutures, and muscular hypotonia. Antenatal head circumferences were repeatedly below the median. A postnatal head ultrasound showed a large right intracerebral mass with right lateral ventricle compression, right temporal horn dilation, and right frontal horn enlargement with lateral displacement. Additional imaging by computed tomography scan and magnetic resonance imaging was performed. A decompression was performed and histology, immunohistochemistry, and molecular biology supported the diagnosis of a primitive neuroectodermal tumor. A MYCN gene amplification assay remained negative. The incidence of neonatal brain tumors is between 1.4 and 4.1/100,000 live births. Their most common presentation is macrocephaly, hydrocephalus, stillbirth, or diagnosis by pre- or postnatal imaging. Although hydrocephaly and intra- or extracranial hemorrhage are the most frequent causes of congenital macrocephaly, this should be initially investigated by head ultrasound. A suspected malignancy will be confirmed by histopathology, immunohistochemistry, and molecular biology.

Automated, compliant, high-flow common carotid to middle cerebral artery bypass

The authors describe the use of the Cardica C-Port xA Distal Anastomosis System to perform an automated, high-flow extracranial-intracranial bypass. The C-Port system has been developed and tested in coronary artery bypass surgery for rapid distal coronary artery anastomoses. Air-powered, it performs an automated end-to-side anastomosis within seconds by nearly simultaneously making an arteriotomy and inserting 13 microclips into the graft and recipient vessel. Intracranial use of the device was first simulated in a cadaver prepared for microsurgical anatomical dissection. The authors used this system in a 43-year-old man who sustained a subarachnoid hemorrhage after being assaulted and was found to have a traumatic pseudoaneurysm of the proximal intracranial internal carotid artery. The aneurysm appeared to be enlarging on serial imaging studies and it was anticipated that a bypass would probably be needed to treat the lesion. An end-to-side bypass was performed with the C-Port system using a saphenous vein conduit extending from the common carotid artery to the middle cerebral artery. The bypass was demonstrated to be patent on intraoperative and postoperative arteriography. The patient had a temporary hyperperfusion syndrome and subsequently made a good neurological recovery. The C-Port system facilitates the performance of a high-flow extracranial-intracranial bypass with short periods of temporary arterial occlusion. Because of the size and configuration of the device, its use is not feasible in all anatomical situations that require a high-flow bypass; however it is a useful addition to the armamentarium of the neurovascular surgeon.

Transdermal nitroglycerin in patients with subarachnoid hemorrhage

Delayed ischemic neurological deficit (DIND) following cerebral vasospasm remains a cause for high morbidity and mortality in patients with subarachnoid hemorrhage (SAH). There is experimental and clinical evidence of positive effects of nitric oxide (NO) donors on cerebral vasospasm. We therefore analysed the effect of transdermal nitroglycerin in patients with SAH measuring transcranial Doppler velocities (TCD), cerebral blood flow (CBF) and DIND. Nitroglycerin was used in a target dose of 14 microg/kg/h. TCD assessment was performed daily. CBF measurements were done using the perfusion CT-technique. Blood pressure, volume intake and vasopressor administration, were registered. Nine patients were randomly assigned either to the nitroglycerin group (N-group) and eight patients in the control group (C-group). Mean TCD values in the extracranial portion of the internal carotid artery (ICA) were lower in the N-group (p<0.005). Mean TCD in the middle cerebral arteries (MCA) showed no difference. The Lindegaard ratio was higher in the N-group (p<0.04). CBF in the N-group was higher than in the C-group (p<0.03). Even though nitroglycerin reduces blood pressure and lowers ICA TCD-values and increases the Lindegaard ratio, a higher CBF was measured in the N-group. Thus, nitroglycerin influences the cerebral vascular tone and increases CBF. SAH therapy with nitroglycerin is possible without increasing the risk of DIND. The exact timing of onset, duration and reduction of nitroglycerin administration in respect to the appearance of vasospasm may have a strong impact on the success of such a therapy.

Measurement of nitric oxide and brain tissue oxygen tension in patients after severe subarachnoid hemorrhage

OBJECTIVE: Nitric oxide (NO), one of the most powerful endogenous vasodilators, is thought to play a major role in the development of delayed vasospasm in patients with subarachnoid hemorrhage (SAH). However, the role of the production of cerebral NO in patients with SAH is not known. In other SAH studies, NO metabolites such as nitrite and nitrate have been demonstrated to be decreased in cerebrospinal fluid and in plasma. METHODS: In this study, a microdialysis probe was used, along with a multiparameter sensor, to measure NO metabolites, brain tissue oxygen tension, brain tissue carbon dioxide tension, and pH in the cortex of patients with severe SAH who were at risk for developing secondary brain damage and vasospasm. NO metabolites, glucose, and lactate were analyzed in the dialysates to determine the time course of NO metabolite changes and to test the interrelationship between the analytes and clinical variables. RESULTS: Brain tissue oxygen tension was strongly correlated to dialysate nitrate and nitrite (r2 = 0.326; P < 0.001); however, no correlation was noted between brain tissue oxygen tension and NO metabolites in cerebrospinal fluid (r2 = 0.018; P = 0.734). No significant correlation between NO production, brain tissue carbon dioxide tension, and dialysate glucose and lactate was observed. CONCLUSION: Cerebral ischemia and compromised substrate delivery are often responsible for high morbidity rates and poor outcomes after SAH. The relationship between brain tissue oxygen and cerebral NO metabolites that we demonstrate suggests that substrate delivery and NO are linked in the pathophysiology of vasospasm after SAH.

Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo

OBJECTIVE: Intrathecal bolus administration of nitric oxide donors and calcium channel antagonists has been proposed to reduce cerebral vasospasm (CVS) in animal subarachnoid hemorrhage (SAH) models. Intrathecal continuous administration of these substances for CVS prevention has not been extensively evaluated. This study compared the efficacy of continuous intrathecal infusions of the NO donor glyceroltrinitrate and nimodipine in preventing delayed CVS associated with SAH in an animal model in vivo. METHODS: New Zealand White rabbits were randomly assigned to six groups: no SAH/NaCl, no SAH/NO, no SAH/nimodipine, SAH/NaCl, SAH/NO, or SAH/nimodipine. Glyceroltrinitrate (GTN) at 0.5 microg/microl (0.5 microl/h) or nimodipine at 0.2 microg/microl (10 microl/h) or NaCl was continuously infused into the cisterna magna via an Alzet osmotic pump from day 0 to day 5 after injection of 1.0 ml autologous blood. The magnitude of spasm in the basilar artery was determined by comparison of pre- and posttreatment angiography and was calculated as proportional change in intraluminal diameter based on automatic measurements. RESULTS: A total of 55 experiments and 110 angiograms were performed. SAH was associated with vasoconstriction of the basilar artery (SAH/NaCl group 19.85+/-2.94%). Continuous intrathecal injection of GTN and nimodipine prevented SAH-induced CVS. There was significant prevention of CVS in animals treated with GTN (SAH/NO group 5.93+/-5.2%, n=11) and nimodipine (SAH/nimodipine group: 0.55+/-2.66%, n=9). There was no significant difference between the treatment groups and controls in prevention of CVS. CONCLUSIONS: This study demonstrates that prophylactic continuous intrathecal administration of either GTN or nimodipine equally prevents SAH-associated CVS in an animal model.

Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2)

We report here results of a randomized, double-blind, placebo-controlled study ( http://www.ClinicalTrials.gov , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.