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.

Younger Stroke Patients With Large Pretreatment Diffusion-Weighted Imaging Lesions May Benefit From Endovascular Treatment.

BACKGROUND AND PURPOSE Lesion volume on diffusion-weighted magnetic resonance imaging (DWI) before acute stroke therapy is a predictor of outcome. Therefore, patients with large volumes are often excluded from therapy. The aim of this study was to analyze the impact of endovascular treatment in patients with large DWI lesion volumes (>70 mL). METHODS Three hundred seventy-two patients with middle cerebral or internal carotid artery occlusions examined with magnetic resonance imaging before treatment since 2004 were included. Baseline data and 3 months outcome were recorded prospectively. DWI lesion volumes were measured semiautomatically. RESULTS One hundred five patients had lesions >70 mL. Overall, the volume of DWI lesions was an independent predictor of unfavorable outcome, survival, and symptomatic intracerebral hemorrhage (P<0.001 each). In patients with DWI lesions >70 mL, 11 of 31 (35.5%) reached favorable outcome (modified Rankin scale score, 0-2) after thrombolysis in cerebral infarction 2b-3 reperfusion in contrast to 3 of 35 (8.6%) after thrombolysis in cerebral infarction 0-2a reperfusion (P=0.014). Reperfusion success, patient age, and DWI lesion volume were independent predictors of outcome in patients with DWI lesions >70 mL. Thirteen of 66 (19.7%) patients with lesions >70 mL had symptomatic intracerebral hemorrhage with a trend for reduced risk with avoidance of thrombolytic agents. CONCLUSIONS There was a growing risk for poor outcome and symptomatic intracerebral hemorrhage with increasing pretreatment DWI lesion volumes. Nevertheless, favorable outcome was achieved in every third patient with DWI lesions >70 mL after successful endovascular reperfusion, whereas after poor or failed reperfusion, outcome was favorable in only every 12th patient. Therefore, endovascular treatment might be considered in patients with large DWI lesions, especially in younger patients.

Cerebral Gaseous Microemboli are Detectable During Continuous Venovenous Hemodialysis in Critically Ill Patients: An Observational Pilot Study

BACKGROUND Continuous venovenous hemodialysis (CVVHD) may generate microemboli that cross the pulmonary circulation and reach the brain. The aim of the present study was to quantify (load per time interval) and qualify (gaseous vs. solid) cerebral microemboli (CME), detected as high-intensity transient signals, using transcranial Doppler ultrasound. MATERIALS AND METHODS Twenty intensive care unit (ICU group) patients requiring CVVHD were examined. CME were recorded in both middle cerebral arteries for 30 minutes during CVVHD and a CVVHD-free interval. Twenty additional patients, hospitalized for orthopedic surgery, served as a non-ICU control group. Statistical analyses were performed using the Mann-Whitney U test or the Wilcoxon matched-pairs signed-rank test, followed by Bonferroni corrections for multiple comparisons. RESULTS In the non-ICU group, 48 (14.5-169.5) (median [range]) gaseous CME were detected. In the ICU group, the 67.5 (14.5-588.5) gaseous CME detected during the CVVHD-free interval increased 5-fold to 344.5 (59-1019) during CVVHD (P<0.001). The number of solid CME was low in all groups (non-ICU group: 2 [0-5.5]; ICU group CVVHD-free interval: 1.5 [0-14.25]; ICU group during CVVHD: 7 [3-27.75]). CONCLUSIONS This observational pilot study shows that CVVHD was associated with a higher gaseous but not solid CME burden in critically ill patients. Although the differentiation between gaseous and solid CME remains challenging, our finding may support the hypothesis of microbubble generation in the CVVHD circuit and its transpulmonary translocation toward the intracranial circulation. Importantly, the impact of gaseous and solid CME generated during CVVHD on brain integrity of critically ill patients currently remains unknown and is highly debated.

Characterization of the interaction between local cerebral metabolic rate for glucose and acid -base index in ischemic rat brain employing a double-isotope methodology

The association between increases in cerebral glucose metabolism and the development of acidosis is largely inferential, based on reports linking hyperglycemia with poor neurological outcome, lactate accumulation, and the severity of acidosis. We measured local cerebral metabolic rate for glucose (lCMRglc) and an index of brain pH--the acid-base index (ABI)--concurrently and characterized their interaction in a model of focal cerebral ischemia in rats in a double-label autoradiographic study, using ($\sp{14}$C) 2-deoxyglucose and ($\sp{14}$C) dimethyloxazolidinedione. Computer-assisted digitization and analysis permitted the simultaneous quantification of the two variables on a pixel-by-pixel basis in the same brain slices. Hemispheres ipsilateral to tamponade-induced middle cerebral occlusion showed areas of normal, depressed and elevated glucose metabolic rate (as defined by an interhemispheric asymmetry index) after two hours of ischemia. Regions of normal glucose metabolic rate showed normal ABI (pH $\pm$ SD = 6.97 $\pm$ 0.09), regions of depressed lCMRglc showed severe acidosis (6.69 $\pm$ 0.14), and regions of elevated lCMRglc showed moderate acidosis (6.88 $\pm$ 0.10), all significantly different at the.00125 level as shown by analysis of variance. Moderate acidosis in regions of increased lCMRglc suggests that anaerobic glycolysis causes excess protons to be generated by the uncoupling of ATP synthesis and hydrolysis. ^

Contralateral cortical response of a subpopulation of interneurons and the glial glutamate transporter GLT1 to an ischemic core

Introduction: Cerebral ischemia is an important cause of brain lesion in humans. The target in research has been the ischemic core or the penumbra zones; little attention has been given to areas outside the core or the penumbra but connected with the primary site of injury. Objective: Evaluate the laminar response of a subpopulation of gabaergic cells, those that are parvalbumin (PV) positive and the astrocytes through the expression of the glial transporter GLT1 on the contralateral cortex to an ischemic core. Methodology: For this purpose we used the medial cerebral artery occlusion model in rats. The artery was occluded for 90 minutes and the animals were sacrificed at 24 and 72 hours post-ischemia. The brains were removed, cut in a vibratome at 50 microns and incubated with the primary antibodies against PV or GLT1. Sections were developed using the vectastain Kit. In control tissue the primary antibody was omitted. Results: When compared with control animals, treated ones show a decrease in the expression of GLT1, especially in layers III and IV of the contralateral cortex to the ischemic core. PV positive cells increases in layers II and V. Conclusion: Increases in the expression of PV cells could correspond to an adaptation associated with glutamate increases in the synaptic compartment. These increases may be due to decreases in the expression of GLT1 transporter, that could not remove the glutamate present in the synaptic cleft, generating hyperactivity in the contralateral cortex. These changes could represent an example of neuronal and glial plasticity in remote areas to an ischemic core but connected to the primary site of injury.

An evaluation of the time dependence of the anisotropy of the water diffusion tensor in acute human ischemia

We have performed MRI examinations to determine the water diffusion tensor in the brain of six patients who were admitted to the hospital within 12 h after the onset of cerebral ischemic symptoms. The examinations have been carried out immediately after admission, and thereafter at varying intervals up to 90 days post admission. Maps of the trace of the diffusion tensor, the fractional anisotropy and the lattice index, as well as maps of cerebral blood perfusion parameters, were generated to quantitatively assess the character of the water diffusion tensor in the infarcted area. In patients with significant perfusion deficits and substantial lesion volume changes, four of six cases, our measurements show a monotonic and significant decrease in the diffusion anisotropy within the ischemic lesion as a function of time. We propose that retrospective analysis of this quantity, in combination with brain tissue segmentation and cerebral perfusion maps, may be used in future studies to assess the severity of the ischemic event. (C) 1999 Elsevier Science Inc.

Intracranial vascular lesions associated with small epidural hematomas

OBJECTIVE: We studied the angiographic findings in patients with small epidural hematomas and cranial fractures crossing over the trajectory of the middle meningeal artery and its branches. Additionally, the Occurrence of traumatic vascular lesions and their clinical relevance and treatment are discussed. METHODS: A consecutive analysis was performed for 24 patients who harbored small epidural hematomas in middle meningeal artery topography associated with cranial fractures. Computed tomographic scans and plain x-ray studies were used to diagnose linear cranial fractures. Patients with large epidural hematomas or associated traumatic lesions were excluded from the study. Selective ipsilateral external carotid angiograms were obtained, and an endovascular procedure was performed if any vascular injury was evidenced. RESULTS: In all patients with cranial fractures crossing over the middle meningeal artery and its branches, some kind of vascular lesion was seen. Two types of findings were noted: active extravasation of the contrast medium (71%) and pseudoaneurysms (29%). Early filling of diploic vessels was found in 8.3% of fractures concomitantly with active extravasation. Embolization was performed in all patients. No additional enlargement of the epidural hematoma was observed, and the postoperative period was uneventful. CONCLUSION: This study shows that pseudoaneurysms and active extravasation of contrast are common findings in this subset of patients. Although the natural history of these lesions is still poorly understood, additional investigation with ipsilateral external carotid angiography may be recommended, considering the potentially catastrophic consequences of late rupture.

Ultrasonography in pregnant women with antiphospholipid syndrome using salicylic acid and heparin

The objective of the present study was to evaluate fetal biometry, Doppler values, and perinatal outcomes in pregnant women with antiphospholipid syndrome treated with acetylsalicylic acid and heparin. Twenty-five pregnant women with antiphospholipid syndrome using 100 mg/day acetylsalicylic acid and 5,000 IU heparin every 12 h were evaluated in this prospective observational study. Ultrasonography was performed between 24 and 38 weeks of gestational age to assess estimated fetal weight, placental thickness, amniotic fluid index, fetal biophysical profile and Doppler evaluation of maternal uterine arteries, and fetal middle cerebral and umbilical arteries. Data regarding Apgar score, gender, delivery mode, and birth weight and length were recorded after birth. The observed values for ultrasonographic assessment and perinatal outcomes were not very different from the expected values for normal pregnancies. The birth weight was 2863.3 +/- A 737.7 g (mean +/- A SD) and length was 46.8 +/- A 4.2 cm. Only one newborn (4%) had the 1-min Apgar score < 7 and all had the 5-min Apgar score > 7. Gestational and perinatal evaluation of pregnant women with antiphospholipid syndrome using both acetylsalicylic acid and heparin was reassuring.

Bilateral carotid endarterectomy combined with myocardial revascularization during the same surgical act

The best surgical approach for the treatment of patients with severe cerebral artery disease and simultaneous serious coronary artery disease still remains controversial. In this report we present a case of a 72-year-old female patient admitted to the hospital with unstable angina. Triple coronary artery obstructive disease and severe bilateral carotid artery stenosis were diagnosed. A combined, simultaneous surgical procedure was performed. After total circulatory by-pass with a membrane oxygenator, the patient's body temperature was lowered to 32°C. During the cool-down period, three proximal anastomoses of segments of autologous saphenous veins were performed in the ascending aorta. Immediately afterwards, bilateral carotid endarterectomy was performed, followed by three distal anastomoses to coronary arteries. The patient showed a satisfactory post-operative outcome. It was concluded that the combination of moderate hypothermia, hemodilution with appropriate hemodynamic control, as used in this patient, was an effective method of cerebral protection. The simultaneous approach of carotid endarterectomy and coronary artery by-pass surgery should be seen as a safe option for the treatment of this type of patient.

Aquaporin expression after thrombin preconditioning in ischemic mouse brain

Background: Aquaporin-4 (AQP4), a water channel, is induced early after stroke.The role of AQP4 in the development and resolution of oedema after stroke remainsdebated. The absence of AQP4 in KO-mice reduces the cytotoxic oedema formationbut in contrast aggravates the vasogenic edema. Thrombin at high dose is known toinduce an oedema and at a low dose (thrombin preconditioning, TPC), to inducetolerance to ischemia. We studied the expression of AQPs in ischemic mouse brainsafter TPC and correlation with oedema formation.Methods: For thrombin preconditioning (TPC), mice were injected intracerebroventricularlywith a low dose of thrombin (0.1U in 2?l), followed 24 hours laterby a 30 min transient middle cerebral occlusion (MCAo). AQP4 expression wasevaluated by immunohistochemistry 1h and 48h after ischemia and correlated withoedema formation in vehicle injected and TPC mice.Results: After TPC, oedema formation, assessed by hemispheric enlargement, wassignificantly attenuated at 1h (4.5 ± 2% vs 11.0 ± 5% in CTL, p<0.05, n=8),which was confirmed by wet weight/dry weight ratio (79.6 ± 0.3% vs 80.1 ± 0.1in ctl, p<0.05, n=0.05). At the same time-point, AQP4 expression was significantlyincreased in TPC mice, (148.9% of the control, P<0.05, n=6) in the ischemicstriatum. The oedema was still reduced at 48h after stroke onset in TPC mice. At48h, the level of expression for AQP4 was still higher for TPC animal although notreaching significance (NS). The lesion size was significantly reduced at 48h afterstroke in TPC mice (5.1 ± 1.6 vs 10.6 ± 1.8 mm2 in CTL, n=5).Discussion: The correlation between the early induction of AQP4 and the decreaseof oedema formation in TPC mice suggests that the induction of AQP4 preventsthe development of oedema.Funding: FNS #3100A0-108001, #3200 68306.02 & #3100A0-112484 and Swiss-Heart foundation.

Arteriovenous malformation in meningothelial meningioma: case report.

An unusual association of a meningioma and an arteriovenous malformation is reported. A 68-year-old man developed left homonymous hemianopsia, left hemiparesis, and gaze palsy. Magnetic resonance imaging showed a right occipital mass lesion containing multiple signal-void areas with tubular and honeycomb appearance, suggesting a marked vascular component. An angiogram showed abnormal vasculature in the mass supplied by the posterior cerebral artery and a dural arteriovenous malformation on the tentorium. Neuropathological examination after total removal of the mass revealed a meningothelial meningioma including major portions of an arteriovenous malformation that extended from the dura and leptomeninges, through the meningioma, and into the occipital lobe, where the tumor was located.

Intraarterial nimodipine for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a preliminary study.

OBJECTIVE: Despite dramatic advances in all medical era, cerebral vasospasm is still the major complication in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to assess the influence of intraarterial (IA) nimodipine in the treatment of symptomatic vasospasm and in preventing neurological disabilities. MATERIALS AND METHODS: We retrospectively reviewed 10 patients of SAH who received IA nimodipine in 15 procedures. The decision to perform angiography and endovascular treatment was based on the neurological examination, brain computed tomography (CT) and CT-angiography. The procedure reports, anesthesia records, neurological examination before and after the procedure, brain imaging and short- and long-term outcome were studied. RESULTS: The average dose of nimodipine was 2 mg. The median change in mean arterial pressure at 10 min was -10 mmHg. No significant change of heart rate was observed at 10 min. There was radiological improvement in 80% of the procedures. Neurological improvement was noted after eight out of 12 procedures when nimodipine was used as the sole treatment and after 10 out of 15, overall. Six patients clinically improved after the treatment and had good outcome. In one patient, an embolus caused fatal anterior and middle cerebral arteries infarction. There was no other neurological deficit or radiological abnormality due to the nimodipine treatment itself. CONCLUSION: Low-dose IA nimodipine is a valid adjunct for the endovascular treatment of cerebral vasospasm. Beneficial effects are achieved in some patients, prompting a prospective control study.

Symptomatic intracranial hemorrhage after stroke thrombolysis: comparison of prediction scores.

BACKGROUND AND PURPOSE: Several prognostic scores have been developed to predict the risk of symptomatic intracranial hemorrhage (sICH) after ischemic stroke thrombolysis. We compared the performance of these scores in a multicenter cohort. METHODS: We merged prospectively collected data of patients with consecutive ischemic stroke who received intravenous thrombolysis in 7 stroke centers. We identified and evaluated 6 scores that can provide an estimate of the risk of sICH in hyperacute settings: MSS (Multicenter Stroke Survey); HAT (Hemorrhage After Thrombolysis); SEDAN (blood sugar, early infarct signs, [hyper]dense cerebral artery sign, age, NIH Stroke Scale); GRASPS (glucose at presentation, race [Asian], age, sex [male], systolic blood pressure at presentation, and severity of stroke at presentation [NIH Stroke Scale]); SITS (Safe Implementation of Thrombolysis in Stroke); and SPAN (stroke prognostication using age and NIH Stroke Scale)-100 positive index. We included only patients with available variables for all scores. We calculated the area under the receiver operating characteristic curve (AUC-ROC) and also performed logistic regression and the Hosmer-Lemeshow test. RESULTS: The final cohort comprised 3012 eligible patients, of whom 221 (7.3%) had sICH per National Institute of Neurological Disorders and Stroke, 141 (4.7%) per European Cooperative Acute Stroke Study II, and 86 (2.9%) per Safe Implementation of Thrombolysis in Stroke criteria. The performance of the scores assessed with AUC-ROC for predicting European Cooperative Acute Stroke Study II sICH was: MSS, 0.63 (95% confidence interval, 0.58-0.68); HAT, 0.65 (0.60-0.70); SEDAN, 0.70 (0.66-0.73); GRASPS, 0.67 (0.62-0.72); SITS, 0.64 (0.59-0.69); and SPAN-100 positive index, 0.56 (0.50-0.61). SEDAN had significantly higher AUC-ROC values compared with all other scores, except for GRASPS where the difference was nonsignificant. SPAN-100 performed significantly worse compared with other scores. The discriminative ranking of the scores was the same for the National Institute of Neurological Disorders and Stroke, and Safe Implementation of Thrombolysis in Stroke definitions, with SEDAN performing best, GRASPS second, and SPAN-100 worst. CONCLUSIONS: SPAN-100 had the worst predictive power, and SEDAN constantly the highest predictive power. However, none of the scores had better than moderate performance.

AltitudeOmics : Resetting of Cerebrovascular CO2 Reactivity Following Acclimatization to High Altitude.

Previous studies reported enhanced cerebrovascular CO2 reactivity upon ascent to high altitude using linear models. However, there is evidence that this response may be sigmoidal in nature. Moreover, it was speculated that these changes at high altitude are mediated by alterations in acid-base buffering. Accordingly, we reanalyzed previously published data to assess middle cerebral blood flow velocity (MCAv) responses to modified rebreathing at sea level (SL), upon ascent (ALT1) and following 16 days of acclimatization (ALT16) to 5260 m in 21 lowlanders. Using sigmoid curve fitting of the MCAv responses to CO2, we found the amplitude (95 vs. 129%, SL vs. ALT1, 95% confidence intervals (CI) [77, 112], [111, 145], respectively, P = 0.024) and the slope of the sigmoid response (4.5 vs. 7.5%/mmHg, SL vs. ALT1, 95% CIs [3.1, 5.9], [6.0, 9.0], respectively, P = 0.026) to be enhanced at ALT1, which persisted with acclimatization at ALT16 (amplitude: 177, 95% CI [139, 215], P < 0.001; slope: 10.3%/mmHg, 95% CI [8.2, 12.5], P = 0.003) compared to SL. Meanwhile, the sigmoidal response midpoint was unchanged at ALT1 (SL: 36.5 mmHg; ALT1: 35.4 mmHg, 95% CIs [34.0, 39.0], [33.1, 37.7], respectively, P = 0.982), while it was reduced by ~7 mmHg at ALT16 (28.6 mmHg, 95% CI [26.4, 30.8], P = 0.001 vs. SL), indicating leftward shift of the cerebrovascular CO2 response to a lower arterial partial pressure of CO2 (PaCO2) following acclimatization to altitude. Sigmoid fitting revealed a leftward shift in the midpoint of the cerebrovascular response curve which could not be observed with linear fitting. These findings demonstrate that there is resetting of the cerebrovascular CO2 reactivity operating point to a lower PaCO2 following acclimatization to high altitude. This cerebrovascular resetting is likely the result of an altered acid-base buffer status resulting from prolonged exposure to the severe hypocapnia associated with ventilatory acclimatization to high altitude.

Atropine and ODQ antagonize tetanic fade induced by L-arginine in cats

Although it has been demonstrated that nitric oxide (NO) released from sodium nitrite induces tetanic fade in the cat neuromuscular preparations, the effect of L-arginine on tetanic fade and its origin induced by NO have not been studied in these preparations. Furthermore, atropine reduces tetanic fade induced by several cholinergic and anticholinergic drugs in these preparations, whose mechanism is suggested to be mediated by the interaction of acetylcholine with inhibitory presynaptic muscarinic receptors. The present study was conducted in cats to determine the effects of L-arginine alone or after pretreatment with atropine or 1H-[1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ) on neuromuscular preparations indirectly stimulated at high frequency. Drugs were injected into the middle genicular artery. L-arginine (2 mg/kg) and S-nitroso-N-acetylpenicillamine (SNAP; 16 µg/kg) induced tetanic fade. The Nw-nitro-L-arginine (L-NOARG; 2 mg/kg) alone did not produce any effect, but reduced the tetanic fade induced by L-arginine. D-arginine (2 mg/kg) did not induce changes in tetanic fade. The tetanic fade induced by L-arginine or SNAP was reduced by previous injection of atropine (1.0 µg/kg) or ODQ (15 µg/kg). ODQ alone did not change tetanic fade. The data suggest that the NO-synthase-GC pathway participates in the L-arginine-induced tetanic fade in cat neuromuscular preparations. The tetanic fade induced by L-arginine probably depends on the action of NO at the presynaptic level. NO may stimulate guanylate cyclase increasing acetylcholine release and thereby stimulating presynaptic muscarinic receptors.