Frank M. Yatsu

Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke Feasibility, Safety, and Efficacy in the First Year of Clinical Practice

BACKGROUND AND PURPOSE The feasibility, safety, and efficacy of intravenous tissue plasminogen activator (t-PA) for patients with acute ischemic stroke in clinical practice need to be assessed. METHODS We initiated a prospective open-label study at a university hospital and two community hospitals in Houston, Tex, immediately after the publication of the National Institute of Neurological Disorders and Stroke (NINDS) t-PA study. A total of 30 patients, age 32 to 90 years, were treated with 0.9 mg/kg of intravenous t-PA (maximum dose, 90 mg) within 3 hours of acute ischemic stroke between December 1995 and December 1996. RESULTS Six percent (6%) of all patients hospitalized with ischemic stroke received intravenous t-PA at the university hospital and 1.1% at the community hospitals. The rates of total, symptomatic, and fatal intracerebral hemorrhage were 10%, 7%, and 3%. Thirty-seven percent (37%) of patients recovered to fully independent function. The average time from stroke onset to emergency department arrival was 57 minutes; emergency department arrival to computed tomography scan 41 minutes; and computed tomography scan to administration of treatment 59 minutes. CONCLUSIONS When treatment guidelines are carefully followed in an urban hospital setting, intravenous t-PA for acute ischemic stroke is feasible and shows safety and efficacy comparable to the results of the NINDS study.

Immediate anticoagulation of embolic stroke: brain hemorrhage and management options

The clinical implications of hemorrhagic transformation of embolic brain infarction were explored by studying 30 patients with cardiogenic brain embolism and either hemorrhagic infarct (HI) or intracerebral hematoma (ICH) on CT. At the time of identification of hemorrhage, 19 patients were receiving anticoagulants and 11 were not. Eight anticoagulated patients and three nonanticoagulated patients developed late HI without attendant worsening after an initial CT was nonhemorrhagic. Hemorrhagic transformation without worsening most often occurred after 12 hours but before 48 hours following stroke onset and was associated with large infarcts (82%) but not with age, blood pressure or embolic source. Seven anticoagulated patients, six with large infarcts, and one nonanticoagulated patient with a small infarct abruptly worsened from eight hours to 11 days after stroke, with CT revealing ICH or severe HI. Excessive anticoagulation or acute hypertension potentially contributed to hemorrhagic transformation in four of five patients who were receiving heparin. Brain hemorrhage in embolic strokes most often occurs with large infarcts. Early CT may not allow the identification of large embolic infarcts that are destined to later undergo spontaneous hemorrhagic transformation. For large embolic infarcts, a delay of several days before anticoagulation and special efforts to avoid excessive anticoagulation and hypertension may be prudent. The initial administration of large, bolus doses of heparin should perhaps be avoided.

Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia

Our understanding of the biochemistry and biologic actions of AA metabolites has been greatly expanded in recent years. The discoveries of TXA2, PGI2, and LTs have fostered new concepts of the pathophysiology of cerebral ischemia. New approaches to treatment of ischemia include seeking an optimal dose of aspirin, developing drugs that selectively inhibit or antagonize TXA2 or LTs, and administering PGI2 or its analogues. Altering the dietary content of essential fatty acids for prophylaxis is also being studied. Though the results of this thrust are still preliminary, the exploration of these therapeutic strategies in cerebrovascular disorders based on further understanding of the pathophysiologic roles of TXA2, PGI2, LTs and probably other AA metabolites is anticipated with some optimism.

Dipyridamole for Preventing Recurrent Ischemic Stroke and Other Vascular Events A Meta-Analysis of Individual Patient Data From Randomized Controlled Trials

Background and Purpose— Results from randomized controlled trials of dipyridamole, given with or without aspirin, for secondary prevention after ischemic stroke or transient ischemic attack (TIA) have given conflicting results. We performed a meta-analysis using individual patient data from relevant randomized controlled trials. Methods— Randomized controlled trials involving dipyridamole in patients with previous ischemic stroke or TIA were sought from searches of the Cochrane Library, other electronic databases, references lists, earlier reviews, and contact with the manufacturer of dipyridamole. Individual patient data were merged from 5 of 7 relevant trials involving 11 459 patients. Results were adjusted for age, gender, qualifying event, and history of previous hypertension. Results— Recurrent stroke was reduced by dipyridamole as compared with control (OR, 0.82; 95% CI, 0.68 to 1.00), and by combined aspirin and dipyridamole versus aspirin alone (OR, 0.78; 95% CI, 0.65 to 0.93), dipyridamole alone (OR, 0.74; 95% CI, 0.60 to 0.90), or control (OR, 0.61; 95% CI, 0.51 to 0.71). The point estimates obtained for the comparisons of aspirin and dipyridamole versus control (OR, 0.63; significant) or versus aspirin (OR, 0.88; nonsignificant) were similar if the data from the largest trial, ESPS II (which provided 57% of data), were excluded. Similar findings were observed for nonfatal stroke. The combination of aspirin and dipyridamole also significantly reduced the composite outcome of nonfatal stroke, nonfatal myocardial infarction, and vascular death as compared with aspirin alone (OR, 0.84; 95% CI, 0.72 to 0.97), dipyridamole alone (OR, 0.76; 95% CI, 0.64 to 0.90), or control (OR, 0.66; 95% CI, 0.57 to 0.75). Vascular death was not altered in any group. Conclusions— Dipyridamole, given alone or with aspirin, reduces stroke recurrence in patients with previous ischemic cerebrovascular disease. The combination of aspirin and dipyridamole also reduces the composite of nonfatal stroke, nonfatal myocardial infarction, and vascular death as compared with aspirin alone.

Intravenous prostacyclin in acute nonhemorrhagic stroke: a placebo-controlled double-blind trial.

The therapeutic efficacy of prostacyclin in nonhemorrhagic cerebral infarction was assessed in a placebo-controlled double-blind trial. A total of 80 patients with stroke onset within 24 hours were randomized into placebo (37 patients) and prostacyclin (43 patients) groups. Demographic data and risk factors were comparable. Patients in the prostacyclin group received a continuous i.v. infusion of prostacyclin at an average rate of 8.5 ng/kg/min for an average of 64 hours. The placebo group received vehicle only in a similar fashion. During treatment hemodynamic changes were more prominent in the patients receiving prostacyclin and included reduction of systolic and diastolic blood pressure and increase in pulse rate. In contrast there was only a slight (but significant) reduction of diastolic blood pressure in the placebo group. Neurologic deficit scores were determined on admission, at Day 3, and at Weeks 1, 2, and 4. Mean neurologic deficit scores upon entry were comparable in the placebo and prostacyclin groups, and a significant improvement in the score for neurologic deficit was noted in both. The placebo group tended to fare better throughout the study, with a significant difference in neurologic deficit score favoring the placebo group at Week 2 (p = 0.0048). Two patients in the placebo and one in the prostacyclin group died. The only difference in adverse reactions was flushing (6 patients in prostacyclin vs. 0 in placebo group, p less than 0.05). The results of this study suggest a lack of therapeutic efficacy of prostacyclin in a defined population of patients with nonhemorrhagic cerebral infarction.

Community Hospital-based Stroke Programs: North Carolina, Oregon, and New York. III. Factors influencing survival after stroke: proportional hazards analysis of 4219 patients.

The possible effect of age, race, sex, consciousness upon admission, geographic location, and history of selected risk factors on the survival after stroke due to infarction or hemorrhage was determined using proportional hazards analysis (Cox regression). For each diagnostic category the most significant prognostic factor was consciousness upon admission. Increasing age, cardiac disease, or previous stroke also decreased the survival time of patients with infarctions. For patients with cerebral hemorrhage, no other variable was significant after control for consciousness level.

Early treatment of ischemic stroke with a calcium antagonist.

We performed a feasibility and safety study (phase II) of nicardipine, a calcium antagonist, in 57 patients. The objectives of the study were to begin therapy as early as possible (less than or equal to 12 hours) after the onset of ischemic stroke and to administer as high a dose as possible. All patients received an intravenous infusion of nicardipine for 72 hours, starting with a dose of 3 mg/hr and increasing to a maximum dose of 7 mg/hr. Upward titration of the dose was limited by a 10% decrease in blood pressure or a 20 beats/min increase in pulse. Intravenous therapy was followed by 30 days of oral therapy. The mean +/- SD interval from onset of stroke to commencement of therapy was 9.1 +/- 5.4 hours. Adverse reactions consisted primarily of hypotension requiring discontinuation of therapy in four patients. Score on a graded neurologic examination increased from 41/100 at baseline to 64/100 at 3 months for the 41 patients completing follow-up. There was no correlation between the dose of nicardipine administered and outcome, but the 11 patients starting therapy less than or equal to 6 hours after onset did better than those starting therapy 6-12 hours after onset. Further study of very early therapy with nicardipine is justified.

Baseline hemodynamic state and response to hemodilution in patients with acute cerebral ischemia.

Hemodynamic data were obtained in 9 patients (mean age 65 yrs) with carotid territory cerebral infarct within the preceding 24 hours (mean 14 +/- 8) as part of a pilot study testing the feasibility and safety of hypervolemic hemodilution. Pulmonary arterial catheters (PACs) were placed without complication in all patients, and after baseline measurements were obtained, up to 1500 cc of 6% hetastarch in 0.9% sodium chloride was administered the first day and up to 1000 cc per day the second and third days. Pulmonary wedge pressure (PWP) rose from 6.3 +/- 3.5 to 14.4 +/- 3.4 mm Hg (p less than 0.001) without development of congestive heart failure in any patient. This was accompanied by a drop in hematocrit (Hct) from 40.3 +/- 3.4 to 32.9 +/- 2.0 (p less than 0.001) and rise in cardiac output (CO) from 4.3 +/- 1.0 to 5.3 +/- 0.6 (p less than 0.05). Phlebotomy of 250 cc was performed in 2 patients and 500 cc in one in order to reduce Hct to desired levels. The volume of fluid needed to raise PWP to 15 was unpredictable (2361 +/- 1106 cc) and therefore PACs were necessary to monitor the rate and volume of fluid administration. The data show that PWP is sufficiently low and Hct sufficiently high following stroke in most patients that hemodilution by volume expansion with phlebotomy added if necessary can be undertaken safely with appropriate monitoring of hemodynamic function, and that this therapy results in optimal reduction of Hct and increased CO without risk of hypotension.

Herpes zoster ophthalmicus and delayed ipsilateral cerebral infarction

We studied five patients who had acute cerebral infarctions 5 weeks to 6 months after herpes zoster ophthalmicus (HZO). All had infarcts of the cerebral hemisphere ipsilateral to the HZO, and one also had a cerebellar infarct. Cerebral arteriography in one patient disclosed narrowing of the middle cerebral artery, occlusion of the anterior cerebral artery ipsilateral to the HZO and narrowing of the opposite anterior cerebral artery. In another case, arteriography revealed occlusion of the distal internal carotid artery on the side of the HZO.

Acrolein activates mitogen-activated protein kinase signal transduction pathways in rat vascular smooth muscle cells.

Acrolein, a major component of cigarette smoke, an environmental pollutant and an endogenous lipid peroxidation product, has been implicated in the development of atherosclerosis. Although a link between vascular injury and acrolein has been indicated, the exact molecular mechanism of acrolein-induced toxicity to vasculature is unknown. In an effort to elucidate the molecular basis of acrolein-induced vascular toxicity, the possibility of the intracellular signaling system as one of the targets of acrolein-induced toxicity is investigated in the present study. Exposure of cultured rat vascular smooth muscle cells (VSMCs) to different doses of acrolein not only causes cytotoxicity but also alters cellular morphology in a concentration and time-dependent manner. VSMCs exhibit cytotoxicity to a narrow concentration range of 5–10 μg/ml and display no toxicity to 2 μg/ml acrolein even after 24 h of exposure. Furthermore, exposure to acrolein results in activation of members of the mitogen-activated protein kinase (MAPK) family and protein tyrosine kinases. The extracellular signal-regulated kinases 1 and 2 (ERK1/2), stress-activated protein kinases/c-jun NH2-terminal kinases (SAPK/JNK) and p38MAPK are effectively and transiently activated by acrolein in a concentration and time-dependent fashion. While all three MAPKs exhibit significant activation within 5 min of exposure to acrolein, maximum activation (ERK1/2 and p38MAPK) or close to maximum activation (SAPK/JNK) occurs on exposure to 5 μg/ml acrolein for 2 h. Acrolein-induced activation of MAPKs is further substantiated by the activation of transcription factors, c-jun and activator transcription factor-2 (ATF-2), by acrolein-activated SAPK/JNK and p38MAPK, respectively. Additionally several cellular proteins exhibit spectacular protein tyrosine phosphorylation, particularly in response to 2 and 5 μg/ml of acrolein. Interestingly, the acrolein-induced activation of MAPKs precedes acrolein-stimulated protein tyrosine phosphorylation, which occurs after 2 h of exposure to acrolein. However, the time course of maximum protein tyrosine phosphorylation profile corresponds to the peak activation profile of MAPKs. The activation of MAPKs and protein tyrosine phosphorylation by acrolein appears to be independent of acrolein-induced toxicity. VSMCs exposed to 2 μg/ml acrolein exhibit no toxicity but stimulates significant activation of MAPKs and protein tyrosine phosphorylation. Although acrolein-induced VSMC toxicity is not blocked by MAPK inhibitors, PD98059, an inhibitor of MAPK kinase and SB203580, an inhibitor of p38MAPK, either alone or in combination, each MAPK responds differently to the inhibitors. Most prominently, although SB203580, an inhibitor of both SAPK/JNK and p38MAPK, significantly inhibited acrolein-induced activation of p38MAPK, it also stimulated SAPK/JNK activation by acrolein alone and in combination with PD98059. These results provide the first evidence that the activation of both growth-regulated (ERK1/2) and stress-regulated (SAPK/JNK and p38MAPK) MAPKs as well as tyrosine kinases are involved in the mediation of acrolein-induced effects on VSMC, which may play a crucial role in vascular pathogenesis due to environmentally and endogenously produced acrolein.