513. rt-PA plus hypothermia reduces complications of rt-PA treatment
X. Tang1, L. Liu1,2, M. Koike1 and M. Yenari1
1Neurology, UCSF SF VAMC, San Francisco, California, USA; 2Tiantan Hospital, Beijing, China
Both mild hypothermia and recombinant tissue plasminogen activator (rt-PA) have been shown to have beneficial effects in outcome from clinical brain ischemia. However, the benefits of rt-PA treatment are tempered by cerebral hemorrhage and blood brain barrier (BBB) disruption. Since coagulation and fibrinolytic pathways can be affected by temperature, the safety of hypothermia in combination with rt-PA is unknown. This study explored whether mild hypothermia plus rt-PA treatment is feasible in a model of focal cerebral ischemia. Male C57/BL6 mice were subjected to transient middle cerebral artery occlusion (MCAO) for 1 or 2 h using an intraluminal suture, followed by 24 h reperfusion. In the first study, mice were cooled to 33°C immediately after occlusion for 2 h followed by rt-PA treatment (10 mg/kg, IV: 10% bolus, and the remainder over 30 mins) begun 3 h post occlusion (TH, n = 12), and compared to rt-PA treatment at normothermia (TN, n = 14) and no treatment (NN, n = 6). Because brain hemorrhage is thought to occur during the reperfusion phase, we conducted a second study where both interventions were started upon reperfusion. TH (n = 6): rt-PA plus hypothermia (33°C), TN (n = 5): rt-PA treatment at normothermia (37°C), NN (n = 6): MCAO at normothermia and no rt-PA, NH (n = 8): hypothermia but no rt-PA. Infarct volumes were measured, and the extent of cerebral hemorrhage was evaluated by counting the number of faces from 5 sequential blocks with any visible hemorrhage (maximum # of faces = 5). Ischemic brain samples were also assessed for endogenous tPA and PAI-1 levels using immunohistochemistry and Western blot. rt-PA treatment itself did not affect infarct size in this model (Exp. 1 and Exp. 2: TN versus NN, N.S.), but hypothermia did (Exp. 2: NH (78.1±8.9 mm3) versus NN (152.1±8.6 mm3), P<0.05), even with the addition of rt-PA (Exp. 1: infarct volume was reduced by 34% in TH versus TN, P<0.05; Exp. 2: infarct volume was reduced by 48.9% in TH versus TN, P<0.05). Hemorrhage patterns were similar in both experiments; thus, the data for Exp. 2 are presented. Administration of rt-PA at normothermia increased the amount of cerebral hemorrhage (TN: 4.7±0.3 faces, NN: 1.2±0.6, TH: 1.4±0.4, P<0.001), while hypothermia reduced it to levels similar to that seen in MCAO without rt-PA treatment. Furthermore, the combination of hypothermia and rt-PA treatment did not increase brain hemorrhage compared to hypothermia alone (TH: 1.4±0.4 versus NH: 0.7±0.3, NS). Both Western blots and immunohistochemistry showed that endogenous tPA expression was reduced in hypothermic mice, whereas PAI-1 was not changed by temperature. Combination therapy with mild hypothermia and rt-PA, whether administered sequentially or simultaneously, should be safe, and may even reduce complications of rt-PA treatment.
570. Significance of clinical-diffusion mismatch in hyperacute cerebral infarction
I. Deguchi, H. Takeda, D. Furuya, K. Hattori, H. Nagoya, Y. Kato, T. Fukuoka and N. Tanahashi
Neurology, Saitama Medical University Internatinal Medical Center, Saitama, Japan
Background and aims: In recent years, patient selection for intravenous tissue plasminogen activator (t-PA) based on clinical-diffusion mismatch (CDM) has been closely examined. Here, we investigated the relationship between prognosis and CDM in patients with hyperacute cerebral infarction within three hours of onset and compared CDM to diffusion-perfusion mismatch (DPM).
Methods: Of 122 patients with hyperacute cerebral infarction who visited the hospital within three hours of onset from April 2007 to November 2008, subjects were 85 patients with cerebral infarction in the anterior circulation who underwent head MRI diffusion weighted image (DWI)/magnetic resonance angiography (MRA) (51 men and 34 women with an average age of 74±10 years). Of these, CT perfusion (CT-P) was performed in 17 patients. CDM-positive cases were subdivided into ⩾8 National Institute of Health Stroke (NIHSS) and ⩾8 Alberta Stroke Program Early CT Score-DWI (ASPECTS-DWI) groups. CDM-negative cases were subdivided into ⩾8 NIHSS and <8 ASPECTS-DWI groups. Other patients were classified as belonging to the <8 NIHSS group.
Results: Of the 35 CDM-positive cases, t-PA infusion was performed in 11 patients, and the modified Rankin Scale (mRS) score at 90 days after onset for these patients was clearly better when compared to the 24 patients who did not receive t-PA infusion. Of the nine CDM-positive cases, there were five DPM(+) cases and four DPM(−) cases, and a discrepancy was confirmed between CDM and DPM. In all DPM(+) cases, MRA confirmed lesions in major intracranial arteries.
Conclusions: In hyperacute cerebral infarction, CDM was useful for predicting the enlargement and progression of infarcts and determining whether to perform t-PA. By combining CDM and MRA findings (presence or absence of lesions in major intracranial arteries), it is also possible to more accurately ascertain the indications for t-PA in hyperacute phase cerebral infarction, and this may be used instead of DPM.
934. Changes in arrival time to hospital from onset of cerebral infarction in the t-PA era
S. Takagi, S. Takizawa, F. Yoshii, H. Takahashi, W. Takahashi, E. Nagata, Y. Ohnuki, T. Ishikawa, Y. Ohnuki, R. Kumazawa, S. Kontani, Y. Tsukamoto, Y. Moriya, E. Sakabe and A. Mizuma
Neurology, Tokai University School of Medicine, Isehara-shi, Kanagawa-ken, Japan
Background: Tissue plasminogen activator (t-PA) has been used to treat acute cerebral infarction for more than 10 years. In order to increase the number of patients who benefit from t-PA, early arrival of patients to the hospital is essential. Efforts to facilitate early arrival include:
giving appropriate information to public, physician, and ambulance, and
medical control over an ambulance department.
Purpose: The purpose of this presentation is to find out whether the arrival of stroke patients to the hospital after onset is getting earlier or not in the t-PA era.
Subjects and method: The subjects included 71 and 62 patients with acute cerebral embolism admitted to the Neurological and Cerebrovascular Center of Tokai University Hospital in the first year (from November 2005 to October 2006) and the second year (from November 2006 to October 2007), respectively. The age was 72±11, and 73±14, respectively. We evaluated medical records and calculated arrival time of these patients.
Results: In the first year, 36 of 71 (50.7%) patients came to hospital within 2 h after onset. t-PA was used in 13 of these 36 (37.1%) patients. In the second year, 35 of 62 (56.5%) patients came to hospital within 2 hours after onset. t-PA was used in 15 of these 35 (42.9%) patients. In total, 13 of 71 (18.3%) patients with cerebral embolism were treated using t-PA in the first year, and this rate was increased to 15 of 62 (24.2%) in the second year.
Discussion and conclusion: Our data showed that patients come to hospital earlier in the second year, and that the frequency of using t-PA in the early-arrived patients is also getting higher in the second year. In order to increase the number of patients who benefit from t-PA, firstly, continuous effort is necessary to facilitate further the early arrival of patients. Secondly, enough human power and inter- and intra-department collaboration is necessary. Thirdly, the indication of t-PA should be re-evaluated, from the aspect of time window, age, severity, and so on.
