Béla Fülesdi

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Impairment of cerebrovascular reactivity in long-term type 1 diabetes

The early preclinical detection of cerebrovascular complications in individuals with diabetes is one of the goals of care described in the St. Vincent Declaration. In accordance with this goal, the aim of the present work was to investigate whether altered cerebral microvascular function in patients suffering from type 1 diabetes can be detected with a transcranial Doppler probe after the administration of acetazolamide. A total of 72 type 1 diabetic patients and 40 healthy control subjects entered the study. Patients were divided into two groups: those with long-term diabetes (disease duration of >10 years, n = 37) and those with short-term diabetes (disease duration of ≤10 years, n = 35). Mean blood-flow velocity in the middle cerebral artery (MCAV) was measured at rest and at 5, 10, 15, and 20 min after intravenous administration of 1 g acetazolamide with a transcranial Doppler probe and expressed as the percentage change from the pretest measurement. The percentage increase in MCAV (cerebrovascular reactivity) was calculated at each time point and compared between the groups. Cerebrovascular reserve capacity (CRC), expressed as the maximal percentage increase of the MCAV, was compared between the groups. Additionally, a reproducibility study of CRC was performed in 10 patients, using intra-class correlations. Cerebrovascular reactivity in the long-term diabetes group was lower (means ± SD: 5 min, 23.4 ± 15.4%; 10 min, 28.8 ± 17.0%; 15 min, 30.0 ± 15.6%; 20 min, 24.2 ± 17.8%) than that of the control subjects (5 min, 43.5 ± 23.9%; 10 min, 55.3 ± 24.0%; 15 min, 56.7 ± 23.8%; 20 min, 54.8 ± 25.9%) and the short-term diabetic patients (5 min, 43.6 ± 25.9%; 10 min, 52.2 ± 27.7%; 15 min, 55.3 ± 32.2%; 20 min, 45.8 ± 35.8%). CRC was lower in the long-term diabetes group than in the control group or the short-term diabetes group. Impairment of cerebrovascular reactivity was associated with retino- and nephropathy and increased levels of fibrinogen. In contrast, CRC was independent from actual glucose, insulin, glycosylated hemoglobin, von Willebrand factor antigen, and α-2 macroglobulin levels. Transcranial Doppler measurements of the changes in MCAV after stimulation with acetazolamide can detect altered cerebral microvascular function in patients with diabetes. Cerebrovascular reactivity and reserve capacity are reduced in patients with long-term diabetes. Further prospective studies should delineate the clinical significance of our results.

Absent Collateral Function of the Circle of Willis as Risk Factor for Ischemic Stroke

Background: Autopsy studies show a higher prevalence of circle of Willis anomalies in brains with signs of ischemic infarction. Our goal was to examine the collateral function of the circle of Willis in ischemic stroke patients and to assess in a case-control study if a collateral deficient circle of Willis is a risk factor for ischemic stroke in patients with severe internal carotid artery (ICA) occlusive disease. Methods: Our case-control study included 109 patients with an acute ischemic stroke in the anterior circulation and 113 patients with peripheral arterial disease and no known history of cerebral ischemia. The collateral function of the anterior and posterior communicating arteries of the circle of Willis was assessed by means of transcranial color-coded duplex ultrasonography (TCCD) and carotid compression tests. Results: TCCD was successfully performed in 75 case patients (mean age 64 years, range 41–91 years) and in 100 control patients (mean age 61 years, range 35–89 years). In 26 cases and 19 controls, a ≧70% stenosis or occlusion of the ICA was found. A nonfunctional anterior collateral pathway in the circle of Willis was found in 33% of the cases and in 6% of the controls (p < 0.001). The posterior collateral pathway was nonfunctional in 57% of the cases and in 43% of the controls (p = 0.02). In patients with severe ICA occlusive disease, the odds ratios of a nonfunctional anterior and a nonfunctional posterior collateral pathway were 7.33 (95% confidence interval, CI, = 1.19–76.52) and 3.00 (95% CI = 0.77–12.04), respectively. Conclusions: Patients who suffer ischemic stroke in the anterior circulation have a higher incidence of collateral deficient circles of Willis than those with atherosclerotic vascular disease without ischemic cerebrovascular disease. The presence of a nonfunctional anterior collateral pathway in the circle of Willis in patients with severe ICA occlusive disease is strongly associated with ischemic stroke.

Acetazolamide as a vasodilatory stimulus in cerebrovascular diseases and in conditions affecting the cerebral vasculature

Pathologic processes affecting the brain vessels may damage cerebral vasodilatory capacity. Early detection of cerebral dysfunction plays an important role in the prevention of cerebrovascular diseases. In recent decades acetazolamide (AZ) has frequently been used for this purpose. In the present work the mechanism of action and the previous studies are reviewed. The authors conclude that AZ tests are useful in cerebrovascular research. Further investigations are recommended to prove how impaired reserve capacity and reactivity influence the stroke risk in patients and whether these tests may indicate therapeutic interventions.

Nitrous oxide and risk of surgical wound infection: A randomised trial

BACKGROUND Nitrous oxide inactivates vitamin B12 and methionine synthase, thereby impairing DNA formation and, consequently, new cell formation. The gas also inhibits methionine production, which can reduce scar formation and depresses chemotactic migration by monocytes. Therefore, we assessed whether nitrous oxide increases the incidence of surgical wound infection. METHODS We recruited 418 patients aged 18-80 years, scheduled for colon resection that was expected to last more than 2 h, at three hospitals in Austria and Hungary. Patients were randomly assigned 65% intraoperative nitrous oxide (n=208) or nitrogen (n=206), with remifentanil and isoflurane. The primary outcome was the incidence of clinical postoperative wound infection, analysed by intention to treat. FINDINGS 206 patients in the nitrous oxide group and 202 in the nitrogen group were included in the final analysis. Duration of surgery was longer in the nitrogen group (3.4 h [1.5]) than in the nitrous oxide group (3.0 h [SD 1.3]) and arterial pressure (84 mm Hg [10] vs 81 mm Hg [9]), bispectral index values (53 [9] vs 44 [8]), and end-tidal isoflurane concentration (0.64% [0.14] vs 0.56% [0.13]) were greater in patients given nitrogen than in those given nitrous oxide. Infection rate was 15% (31/206) in patients given nitrous oxide and 20% (40/202) in those given nitrogen (p=0.205). Additionally, the ASEPSIS wound healing score, wound collagen deposition, number of patients admitted to critical care unit, time to first food ingestion, duration of hospital stay, and mortality did not differ between treatment groups. INTERPRETATION Nitrous oxide does not increase the incidence of surgical wound infection.

Cerebrovascular Reactivity and Reserve Capacity in Type II Diabetes Mellitus

The aim of the study was to test the hypothesis that cerebrovascular reserve capacity and cerebrovascular reactivity are impaired in patients suffering from non insulin-dependent diabetes mellitus. We also intended to investigate factors which may influence resting cerebral blood flow velocity and cerebrovascular reserve capacity. A total of 28 patients suffering from type II diabetes mellitus and 20 healthy control subjects were studied. Based on diabetes duration patients were divided into two groups: subjects with > 10 years and those with < or = 10 years disease duration. Middle cerebral artery mean blood flow velocities were measured at rest and after intravenous administration of 1g acetazolamide. Cerebrovascular reactivity and reserve capacity were calculated. Blood glucose, insulin, glycosylated hemoglobin, hemostatic factors (fibrinogen, alpha-2 macroglobulin and von Willebrand factor antigen) were determined. Cerebrovascular reactivity and reserve capacity values were compared between the two diabetic subgroups and controls. Correlations between laboratory parameters and cerebrovascular reserve were investigated by linear regression analysis. Resting cerebral blood flow velocity was similar in controls and in the two diabetic subgroups. Cerebrovascular reactivity was elevated for a shorter time in patients with > 10 years disease duration than in controls and short-term diabetic patients. Cerebrovascular reserve capacity was lower in the long-term diabetes group (means +/- SD: 39.6 +/- 20.7%) than in patients with < or = 10 years disease duration (63.3 +/- 17.4%, p < 0.02 after Bonferroni correction). Cerebrovascular reserve capacity was inversely related to the duration of the disease (R = 0.53, p < 0.003). None of the determined laboratory factors had any relation with resting cerebral blood flow and cerebrovascular reserve capacity. The vasodilatory ability of cerebral arterioles is diminished in long-standing type II diabetes mellitus.

Collateral Configuration of the Circle of Willis Transcranial Color-Coded Duplex Ultrasonography and Comparison With Postmortem Anatomy

BACKGROUND AND PURPOSE The anterior communicating artery (AcoA) and posterior communicating arteries (PcoA) of the circle of Willis provide the main route for collateral blood flow in cases of carotid artery obstruction. Transcranial color-coded duplex ultrasonography (TCCD) allows real-time measurement of the collateral function of the AcoA and PcoA. The primary objective of this study was to determine the collateral artery threshold diameters for supplying collateral flow. METHODS In 12 acute stroke patients with a median age of 75 years (51 to 91 years), the collateral integrity of the circle of Willis as assessed by TCCD and carotid compression tests was compared with their postmortem anatomy. The lengths and diameters of the collateral arteries were measured. RESULTS TCCD demonstrated absent anterior collateral flow in 3 patients. In 1 of these patients, absence of anterior cross-flow was due to an occluded anterior cerebral artery, which was revealed at autopsy. Absent posterior collateral flow was found in 14 hemispheres. In 2 of these hemispheres, autopsy revealed a fetal configuration of the posterior cerebral artery hampering posterior collateral flow. The median (range) diameters as found at autopsy of the functional (n=19) and nonfunctional (n=16) collateral arteries of the circle of Willis were 1.1 (0.4 to 2.0) and 0.5 (0.3 to 0.7) mm, respectively (P=0.003). PcoA diameters were found to correlate negatively (rho=-0. 50, P=0.01) to the diameters of their accessory P1 segments. CONCLUSIONS The threshold diameter allowing for cross-flow through the primary collateral arteries of the circle of Willis is between 0. 4 and 0.6 mm.

Cerebrovascular reactivity in hypertensive patients: A transcranial Doppler study

We studied the usefulness of transcranial Doppler sonography for assessing changes in vasoreactivity in patients with hypertension and the hemodynamic consequences of hypertension.

Mannitol Use in Acute Stroke Case Fatality at 30 Days and 1 Year

Background and Purpose— Mannitol is used worldwide to treat acute stroke, although its efficacy and safety have not been proven by randomized trials. Methods— In a tricenter, prospective study, we analyzed the 30-day and 1-year case fatality with respect to mannitol treatment status in 805 patients consecutively admitted within 72 hours of stroke onset. Confounding factors were compared between treated and nontreated patients. Results— Two thirds of the patients received intravenous mannitol as part of their routine treatment (mean dose, 47±22 g/d; mean duration, 6±3 days). The case fatality was 25% versus 16% (P =0.006) at 30 days and 38% versus 25% (P <0.001) at 1 year in the-mannitol treated and nontreated groups, respectively. Mannitol treatment effect was adjusted for age, stroke severity, fever in the first 3 days, and aspirin treatment (for ischemic strokes) in logistic regression models. Depending on the factors entered into the model, either no effect or harm could be attributed to mannitol. When the analysis was restricted to those admitted within 24 hours (n=568), case fatality differed significantly only at 1 year (35% in treated and 26% in nontreated patients, P =0.044). Although the prognostic scores of the Scandinavian Neurological Stroke Scale were similar in treated and nontreated patients, both in ischemic and hemorrhagic strokes, the patient groups differed in several factors that might also have influenced survival. Conclusions— Based on the results of this study, no recommendations can be made on the use of mannitol in acute stroke, and properly randomized, controlled trials should be performed to come to a final conclusion.

Transcranial Doppler Study of the Cerebral Hemodynamic Changes During Breath-Holding and Hyperventilation Tests

Background and purpose. The aim of the present study was to assess the time course of hyperventilation (HV) and breath‐holding (BH) tests in healthy volunteers. Subjects and Methods. Young healthy volunteers (n= 29) underwent continuous registration of the middle cerebral artery mean blood flow velocity (MCAV) during and after 30 seconds of BH and 60 seconds of HV. Absolute values as well as percentage changes of the MCAV are reported. In 13 subjects, determination of capillary blood gas parameters (pH, pCO2, pO2, and O2 saturation) was performed before tests, after BH and after HV. Results. MCAV during 30 seconds of breath‐holding starts to increase after 10 seconds and reaches its highest level at 30 seconds. After breathing normally, MCAV normalizes within 30 seconds. Hyper‐ ventilation results in a decrease in MCAV, which reaches a plateau at 20 to 30 seconds after starting to hyperventilate, and blood flow velocity did not change significantly any further until the end of the procedure. The normalization of the MCAV is incomplete at 30 seconds after finishing hyperventilation. None of the capillary blood gases changed significantly after breathholding, whereas capillary pH, pO2, and oxygen saturation increased and pCO2 decreased after hyperventilation. No relationship was found between capillary blood gas parameters and MCAV values. Conclusions. The authors concluded that breathholding and hyperventilation tests seem to be a practical alternative to acetazolamide and the CO2 inhalation method in the assessment of cerebral hemodynamics.