Chih Hung Chen

Get With The Guidelines-Stroke Performance Indicators: Surveillance of Stroke Care in the Taiwan Stroke Registry: Get With The Guidelines-Stroke in Taiwan

Background— Stroke is a leading cause of death around the world. Improving the quality of stroke care is a global priority, despite the diverse healthcare economies across nations. The American Heart Association/American Stroke Association Get With the Guidelines-Stroke program (GWTG-Stroke) has improved the quality of stroke care in 790 US academic and community hospitals, with broad implications for the rest of the country. The generalizability of GWTG-Stroke across national and economic boundaries remains to be tested. The Taiwan Stroke Registry, with 30 599 stroke admissions between 2006 and 2008, was used to assess the applicability of GWTG-Stroke in Taiwan, which spends ≈1/10 of what the United States does in medical costs per new or recurrent stroke. Methods and Results— Taiwan Stroke Registry, sponsored by the Taiwan Department of Health, engages 39 academic and community hospitals and covers the entire country with 4 steps of quality control to ensure the reliability of entered data. Five GWTG-Stroke performance measures and 1 safety indicator are applicable to assess Taiwan Stroke Registry quality of stroke care. Demographic and outcome figures are comparable between GWTG-Stroke and Taiwan Stroke Registry. Two indicators (early and discharge antithrombotics) are close to GWTG-Stroke standards, while 3 other indicators (intravenous tissue plasminogen activator, anticoagulation for atrial fibrillation, lipid-lowering medication) and 1 safety indicator fall behind. Preliminary analysis shows that compliance with selected GWTG-Stroke guidelines is associated with better outcomes. Conclusions— Results suggest that GWTG-Stroke performance measures, with modification for ethnic factors, can become global standards across national and economic boundaries for assessing and improving quality of stroke care and outcomes. GWTG-Stroke can be incorporated into ongoing stroke registries across nations.

Outcomes of Thrombolytic Therapy for Acute Ischemic Stroke in Chinese Patients The Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) Study

Background and Purpose— The safety and efficacy of alteplase for ischemic stroke has not been examined in Chinese patients. We assessed the safety and efficacy of alteplase for acute ischemic stroke in daily clinical practice in Taiwan. Methods— A prospective, multicenter, observational study was conducted in Taiwan from December 2004 to July 2008. Eligible patients (241) receiving alteplase were recruited and divided into 2 groups: standard dose (0.90±0.02 mg/kg, n=125) and lower dose (0.72±0.07 mg/kg, n=116). Primary outcome measures were safety: symptomatic intracerebral hemorrhage and death within 3 months. The secondary outcome measure was efficacy a modified Rankin scale of 0 to 2 after 3 months. Results— The standard-dose group had higher rates of symptomatic intracerebral hemorrhage using National Institute of Neurological Diseases and Stroke, European Cooperative Acute Stroke Study, and Safe Implementation of Thrombolysis in Stroke-Monitoring Study definitions (10.4% versus 5.2%, 8.0% versus 2.6%, and 5.6% versus 1.7%, respectively) and mortality within 3 months (12.8% versus 6.9%), twice that of the lower-dose group. This pattern was more prominent in older patients. Significantly higher rates of symptomatic intracerebral hemorrhage per European Cooperative Acute Stroke Study (15.4% versus 3.3%, P=0.0257) and mortality (21.1% versus 5.0%, P=0.0099) and significantly lower independence rate (32.6% versus 53.6%, P=0.0311) were observed among patients ≥70 years old receiving the standard dose than those receiving the lower dose. Conclusions— This study suggests that the standard dose of 0.9 mg/kg alteplase may not be optimal for treating aged Chinese patients. However, the dose of recombinant tissue plasminogen activator for ischemic stroke in Chinese patients should be based on more broad and convincing evidences and randomized trials of lower versus higher doses are needed.

The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema.

Objective:Osmotherapy with hypertonic saline ameliorates cerebral edema associated with experimental ischemic stroke. We tested the hypothesis that hypertonic saline exerts its antiedema effect by promoting an efflux of water from brain via the perivascular aquaporin-4 pool. We used mice with targeted disruption of the gene encoding &agr;-syntrophin (&agr;-Syn−/−) that lack the perivascular aquaporin-4 pool but retain the endothelial pool of this protein. Design:Prospective laboratory animal study. Setting:Research laboratory in a university teaching hospital. Measurements and Main Results:Halothane-anesthetized adult male wildtype C57B/6 and &agr;-Syn−/− mice were subjected to 90 min of transient middle cerebral artery occlusion and treated with either a continuous intravenous infusion of 0.9% saline or 3% hypertonic saline (1.5 mL/kg/hr) for 48 hr. In the first series of experiments (n = 59), increased brain water content analyzed by wet-to-dry ratios in the ischemic hemisphere of wildtype mice was attenuated after hypertonic saline (79.9% ± 0.5%; mean ± sem) but not after 0.9% saline (82.3% ± 1.0%) treatment. In contrast in &agr;-Syn−/− mice, hypertonic saline had no effect on the postischemic edema (hypertonic saline: 80.3% ± 0.7%; 0.9% saline: 80.3% ± 0.4%). In the second series of experiments (n = 32), treatment with hypertonic saline attenuated postischemic blood-brain barrier disruption at 48 hr in wildtype mice but not in &agr;-Syn−/− mice; &agr;-Syn deletion alone had no effect on blood-brain barrier integrity. In the third series of experiments (n = 34), &agr;-Syn−/− mice treated with either hypertonic saline or 0.9% saline had smaller infarct volume as compared with their wildtype counterparts. Conclusions:These data demonstrate that 1) osmotherapy with hypertonic saline exerts antiedema effects via the perivascular pool of aquaporin-4, 2) hypertonic saline attenuates blood-brain barrier disruption depending on the presence of perivascular aquaporin-4, and 3) deletion of the perivascular pool of aquaporin-4 alleviates tissue damage after stroke, in mice subjected to osmotherapy and in nontreated mice.

Effect of duration of osmotherapy on blood-brain barrier disruption and regional cerebral edema after experimental stroke

Osmotherapy is the cornerstone of medical management for cerebral edema associated with large ischemic strokes. We determined the effect of duration of graded increases in serum osmolality with mannitol and hypertonic saline (HS) on blood-brain barrier (BBB) disruption and regional cerebral edema in a well-characterized rat model of large ischemic stroke. Halothane-anesthetized adult male Wistar rats were subjected to transient (2-h) middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. Beginning at 6 h after MCAO, rats were treated with either no intravenous fluids or a continuous intravenous infusion (0.3 mL/h) of 0.9% saline, 20% mannitol, 3% HS, or 7.5% HS for 24, 48, 72, and 96 h. In the first series of experiments, BBB permeability was quantified by the Evans blue (EB) extravasation method. In the second series of experiments, water content was assessed by comparing wet-to-dry weight ratios in six predetermined brain regions. Blood-brain barrier disruption was maximal in rats treated with 0.9% saline for 48 h, but did not correlate with increases in serum osmolality or treatment duration with osmotic agents. Treatment with 7.5% HS attenuated water content in the periinfarct regions and all subregions of the contralateral nonischemic hemisphere to a greater extent than mannitol did with no adverse effect on survival rates. These data show that (1) BBB integrity is not affected by the duration and degree of serum osmolality with osmotic agents, and (2) attenuation of increases in brain water content with HS to target levels > 350 mOsm/L may have therapeutic implications in the treatment of cerebral edema associated with ischemic stroke.

Functional mutation in the promoter region of thrombomodulin gene in relation to carotid atherosclerosis

Thrombomodulin is an important endothelial anticoagulant protein that decreases thrombin activity and activates protein C. Our recent study has shown that the G-33A promoter mutation of thrombomodulin gene is associated with coronary artery disease. This study was conducted to determine whether the G-33A mutation in the promoter region of thrombomodulin gene is a genetic risk factor for ischemic stroke or carotid atherosclerosis. The functional significance of this mutation was also evaluated. We recruited 333 patients (mean age 64 years, 59% male) with ischemic stroke and 257 age- and sex-matched controls. In all study participants, carotid atherosclerosis was assessed by Duplex scanning, and thrombomodulin G-33A promoter mutation was detected by single-strand conformation polymorphism. Luciferase reporter gene assay was used to assess the influence of this mutation on thrombomodulin promoter activity. There was no significant difference in the thrombomodulin G-33A mutation frequency (GA+AA genotypes) between the stroke and the control groups (18.3 vs. 24. 1%, P=0.105). The G-33A mutation frequency was also similar between the study participants with and without carotid atherosclerosis (22.2 vs. 19.8%, P=0.550). When only younger subjects (age </=60 years) were included in the analysis, however, we found the mutation occurred more frequently in participants with carotid atherosclerosis (33.3 vs. 17.3%, odds ratio [OR]=2.38, 95% confidence interval [CI]=1.16-4.90, P=0.027). Multiple logistic regression analyses showed that only diabetes mellitus (OR=3.11, 95% CI=1.33-7.30, P=0.009) and G-33A mutation (OR=2.46, 95% CI=1.14-5.29, P=0.021) were associated independently with carotid atherosclerosis in younger subjects. As assessed by luciferase reporter gene assays, the contructs bearing the G-33A mutation showed a significant decrease (36+/-12%) in transcriptional activity in comparison with the wild type constructs. Our findings suggest that G-33A mutation reduces the thrombomodulin promoter activity and is associated with carotid atherosclerosis in younger subjects.

Comparison of Risk-scoring Systems in Predicting Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis

Background and Purpose— Various risk score models have been developed to predict symptomatic intracerebral hemorrhage (SICH) after intravenous thrombolysis for acute ischemic stroke. In this study, we aimed to determine the prediction performance of these risk scores in a Taiwanese population Methods— Prospectively collected data from 4 hospitals were used to calculate probability of SICH with the scores developed by Cucchiara et al, the Hemorrhage After Thrombolysis (HAT) score, the Safe Implementation of Thrombolysis in Stroke-SICH risk score, the Glucose Race Age Sex Pressure Stroke Severity score, and the Stroke Prognostication using Age and National Institutes of Health Stroke Scale-100 index. We used logistic regression to evaluate the effectiveness of each risk model in predicting SICH and the c statistic to assess performance. Results— A total of 548 patients were included. The rates of SICH were 7.3% by the National Institute of Neurological Diseases and Stroke definition, 5.3% by the European-Australasian Cooperative Acute Stroke Study II definition, and 3.5% by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study definition. The Cucchiara score, the HAT score, and the Safe Implementation of Thrombolysis in Stroke-SICH risk score were significant predictors of SICH for all 3 definitions, whereas the Glucose Race Age Sex Pressure Stroke Severity score and the Stroke Prognostication using Age and National Institutes of Health Stroke Scale-100 index predicted well only for 1 or 2 definitions of SICH. The c statistic was highest for the HAT score (range, 0.69–0.73) across the definitions of SICH. Conclusions— The Cucchiara score, the HAT score, and the Safe Implementation of Thrombolysis in Stroke-SICH risk score predicted SICH reasonably well regardless of which SICH definition was used. However, only the HAT score had an acceptable discriminatory ability.

Developing a stroke severity index based on administrative data was feasible using data mining techniques

OBJECTIVES Case-mix adjustment is difficult for stroke outcome studies using administrative data. However, relevant prescription, laboratory, procedure, and service claims might be surrogates for stroke severity. This study proposes a method for developing a stroke severity index (SSI) by using administrative data. STUDY DESIGN AND SETTING We identified 3,577 patients with acute ischemic stroke from a hospital-based registry and analyzed claims data with plenty of features. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). We used two data mining methods and conventional multiple linear regression (MLR) to develop prediction models, comparing the model performance according to the Pearson correlation coefficient between the SSI and the NIHSS. We validated these models in four independent cohorts by using hospital-based registry data linked to a nationwide administrative database. RESULTS We identified seven predictive features and developed three models. The k-nearest neighbor model (correlation coefficient, 0.743; 95% confidence interval: 0.737, 0.749) performed slightly better than the MLR model (0.742; 0.736, 0.747), followed by the regression tree model (0.737; 0.731, 0.742). In the validation cohorts, the correlation coefficients were between 0.677 and 0.725 for all three models. CONCLUSION The claims-based SSI enables adjusting for disease severity in stroke studies using administrative data.

4G/5G promoter polymorphism of plasminogen activator inhibitor-1, lipid profiles, and ischemic stroke.

The 4G allele of common 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with increased PAI-1 transcription and has been proposed as a candidate genetic risk factor for thrombotic diseases. We investigated the relationship between this polymorphism and lipid profiles and stroke risk. One hundred patients with ischemic stroke and 150 age- and sex-matched control subjects were enrolled. PAI-1 genotype was determined with the use of polymerase chain reaction and restriction-length analysis. Genotype distribution in the stroke group was 40% 4G/4G, 46% 4G/5G, and 14% 5G/5G; in the control group it was 38.7% 4G/4G, 45.3% 4G/5G, and 16% 5G/5G. The allele and genotype frequencies of 4G/5G polymorphism were not different between the stroke and control groups. Control subjects who were homozygous for the 4G allele had significantly lower high-density lipoprotein (HDL) cholesterol levels than did those carrying the 5G allele (51.2 +/- 11.8 vs 58.4 +/- 15.8 mg/dL; P =.002). In the control group, regression analysis revealed a significant contribution of 4G/4G genotype to increased triglyceride (P =.042) and to decreased HDL cholesterol (P <.001) levels. Our findings suggest that PAI-1 4G/5G promoter polymorphism alone is not associated with ischemic stroke. However, this polymorphism influences lipid levels, and the underlying mechanism must be determined.

Osmotherapy with hypertonic saline attenuates water content in brain and extracerebral organs

Objective:Because of their beneficial effects in patients with hemorrhagic shock and multiple-system trauma, hypertonic saline solutions are increasingly being used perioperatively for volume resuscitation. Although the anti-edema effects of hypertonic saline on brain are well documented in a variety of brain injury paradigms, its effects on the water content on other organs has not been studied rigorously. In this study, we tested the hypothesis that a) hypertonic saline when given as an intravenous bolus and continuous infusion attenuates water content of small bowel, lung, and brain in rats without neuro-injury; and b) attenuation of stroke-associated increases in lung water is dependent on achieving a target serum osmolality. Design:Prospective laboratory animal study. Setting:Research laboratory in a teaching hospital. Subjects:Adult male Wistar rats. Interventions:In the first series of experiments, under controlled conditions of normoxia, normocarbia, and normothermia, spontaneously breathing, halothane-anesthetized (1.0–1.5%) adult male Wistar rats (280–320 g) were treated in a blinded randomized fashion with 7.5% hypertonic saline or 0.9% normal saline in a 8-mL/kg intravenous infusion for 3 hrs followed by a continuous intravenous infusion (1 mL/kg/hr) of 5% hypertonic saline or normal saline, respectively (n = 10 each), for 48 hrs. A second group of rats were treated with continuous infusion only for 48 hrs of either 7.5% hypertonic saline or normal saline (1 mL/kg/hr) (n = 10 each) without an intravenous bolus. Naïve rats served as controls (n = 10). Tissue water content of small bowel, lung, and brain was determined by comparing the wet-to-dry ratios at the end of the experiment. In a second series of experiments, rats (n = 94) were subjected to 2 hrs of transient middle cerebral artery occlusion by the intraluminal occlusion technique. At 6 hrs following middle cerebral artery occlusion, rats were treated in a blinded randomized fashion with a continuous intravenous infusion of normal saline, 3% hypertonic saline, or 7.5% hypertonic saline for 24, 48, 72, and 96 hrs. Surgical shams served as controls (n = 7). Hypertonic saline was instituted as chloride/acetate mixture (50:50) in all experiments. Serum osmolality was determined at the end of the experiment in all animals. Measurements and Main Results:In rats without neuro-injury that received intravenous bolus followed by a continuous infusion, lung water content was significantly reduced with hypertonic saline (73.9 ± 1.1%; 359 ± 10 mOsm/L) (mean ± sd) compared with normal saline treatment (76.1 ± 0.53%; 298 ± 4 mOsm/L) as was water content of small bowel (hypertonic saline, 69.1 ± 5.8%; normal saline, 74.7 ± 0.71%) and brain (hypertonic saline, 78.1 ± 0.87%; normal saline, 79.2 ± 0.38%) at 48 hrs. Stroke-associated increases in lung water content were attenuated with 7.5% hypertonic saline at all time points. There was a strong correlation between serum osmolality and attenuation of stroke-associated increases in lung water content (r = −.647) Conclusions:Bowel, lung, and brain water content is attenuated with hypertonic saline when serum osmolality is >350 mOsm/L without adverse effect on mortality in animals with and without neuro-injury. Attenuation of water content of extracerebral organs with hypertonic saline treatment may have therapeutic implications in perioperative fluid management in patients with and without brain injury.

Association of CD14 Promoter Gene Polymorphism and Chlamydia pneumoniae Infection

Recent studies have suggested that Chlamydia pneumoniae infection is an important factor in the development of atherosclerosis. The C(-260)-->T polymorphism in the CD14 promoter gene has been reported to regulate the density of CD14 expression on monocytes for the activation of monocytes to secrete inflammatory cytokines by lipopolysaccharide. We investigated this genetic marker and its association with C. pneumoniae infection. Among 315 healthy subjects, the distribution of the C(-260)-->T polymorphism in the CD14 promoter gene was 14.9% for the CC genotype, 54.3% for the CT genotype, and 30.8% for the TT genotype. Among subjects with the 3 CD14 genotypes, 59.5%, 64.9%, and 78.3%, respectively, were seropositive for C. pneumoniae. With multiple logistic regression analysis, the odds ratio of C. pneumoniae infection was 2.08 for CD14 TT genotype (95% confidence interval, 1.18-3.69; P=.016). A significant association between the CD14 TT genotype and C. pneumoniae infection was found.