J StrokeCerebrovasc

D,s 1992,2.22-25

© 1992 National Stroke Associanon

Nimodipine and the Evolution of Hemorheological Variables After Acute Ischemic Stroke Sebastian F. Ameriso, M.D., 'Rosalinda B. Wenby, B.S., IHerbert]. Meiselman, Sc.D., and Mark Fisher, M.D.

We studied the effects of the calcium channel antagonist rumodipine on the evolution of hemorheological variables during the first 3 weeks following ischemic stroke. We studied 13 patients and found that, compared to basehne levels, plasma fibrinogen concentration and low-shear whole-blood viscosity rose sigmficantly In patients receiving placebo but not In those receiving nimodipme. Red blood cell aggregation rose in both groups but less so in nimodiplne-treated patients Hematocrit, high-shear whole-blood viscosity, and red blood cell deformability did not change significantly in either group. In conclusion, the use of nimodipine appears to alter the evolution of some hemorheological vanables following acute ischemic stroke. Key Words: Stroke-Hemorheology-Calcium channel antagonists-Fibrinogen

Hemorheological alterations in cerebral ischemia have been extensively described in the literature. Patients with acute cerebral infarction have elevated whole-blood viscosity, plasma viscosity, and red blood cell (RBC) aggregation compared to controls (1-5). These abnormalities are explained in part by elevated plasma fibrinogen and hematocrit in these patients (1,2,3,5). Hemodilution has been used as acute ischemic stroke therapy, in part to "normalize" hemorheological alterations (6-8). RBC deformability in patients with cerebral infarction may also be abnormal. Sakuta has described decreased RBC deformability in patients with cerebrovascular disease (9); however, other investigators have not confirmed this observation (1,5,10,11). Hemorheological abnormalities are also prominent following subarachnoid hemorrhage (12). From the Departments of Neurology and Iphysiology and Biophysics, University of Southern California, School of Medicine, Los Angeles, CA, U.S A. Address correspondence and reprint requests to Dr M. Fisher at Department of Neurology, USC School of Medicine, 2025 Zonal Avenue, Los Angeles, CA 90033, U S.A 22

/ STROKE CEREBROVASC DIS, VOL 2, NO.1, 1992

The calcium channel antagonist nimodipine reduces the incidence and extent of delayed ischemic injury following aneurysmal subarachnoid hemorrhage (13,14) and has a potential role in the treatment of acute ischemic stroke (15). However, the mechanism for any beneficial effect of nimodipine is unclear at present. In this study, we evaluated the potential effects of nimodipine on the evolution of hemorheological variables in a group of patients with acute ischemic stroke; our goal was thus to determine whether this agent alters the progression of adverse rheological changes consequent to cerebral ischemia.

Subjects and Methods We studied 13 patients hospitalized with diagnosis of acute ischemic stroke and entered into a prospective trial of nimodipine in the treatment of acute brain infarction. This study was performed in accordance with guidelines of the University of Southern Cahfornia Rese arch Committee. Stroke diagnosis was based on clinical features and confirmed by brain computed tomography (CT) performed within 48 h

HEMORHEOLOGYAFTERACUTESTROKE

of the event and repeated within 4 days. Nine patients were treated with oral nimodipine in doses of 60,120, and 240 mg/day (n=3, 2, and 4, respectively) during the 21 days; 4 patients received placebo. Ten-ml blood samples anticoagulated with ethylenediaminetetra-acetic acid (1.5 mg/ml) were taken by venipuncture at admission within 48 h of the stroke (i.e., baseline) and during days 10 and 21 after the event. All rheological analyses were performed within 4 h following venipuncture. We measured hematocrit by the conventional micro hematocrit centrifuge method. Plasma fibrinogen was measured based on the turbidimetric rate of the formation of ftbrin polymer (DuPont ACA, Wllmington, DE). We determined the viscosity, at 25°C, of 40% hematocrit RBC-plasma suspensions at 0.5 S·l (low shear) and 94.5 S·l (high shear) using a small-volume Couette viscometer (Model LS-30, Contraves AG, Zurich, Switzerland). RBCaggregation was measured by zeta sedimentation ratio (ZSR) using the Zetafuge (Coulter Electronics, Hialeah, FL) as follows: after a 3min period of rotation, cell aggregation causes the RBC-suspending medium interface to move toward the tube bottom. This interface determines the "hematocrit" of the suspension and is called the zetacrit. The ZSR is calculated as the ratio of the true hematocrit to the zetacrit, times 100, and increases with increasing RBC aggregation (16,17). We also measured the strength of RBC aggregation (y T-min) using a computerized version (18) of the Myrenne Aggregometer (Model MA-1, Myrenne GmbH, Roetgen, Germany); this technique uses a cone-plate shearing system and is based on the changes in light transmission through a red cell suspension that occurs when RBCs aggregate into rouleaux or when the aggregates are dispersed by shearing forces. For the Myrenne data reported herein, 40% hematocrit RBCplasma suspensions were employed, and the minimum shear rate necessary to induce complete RBC disaggregation (y T-min) was determined by subjecting the suspension to 11 separate levels of shear rate (7.5-500 s-l); the magnitude of y T-min was calculated via a third-order polynomial fit of the resulting light transmission-shear rate data . Note that while the ZSR and y T-min provide different indices of RBC aggregation, both increase for suspensions exhibiting enhanced aggregation (16-18). We used an RBC filtration system, the Cell Transit Time Analyzer, to measure RBC deformability. This instrument measures the mean transit time of 1,000 RBC through 4.5 jim diameter cylindrical micropores at a driving pressure of 6 ern H 2 0 via a computer-based conductometric system. RBC deformability and RBC velocity (i.e., transit time) are highly correlated (19).

Student's t tests (two-tailed) were used for statistical analysis: paired t tests were used to compare individual patient's baseline measurements with those of days 10 and 21; unpaired t tests were used to compare baseline characteristics of patients receiving nimodipine or placebo.

Results Relevant characteristics of the patients studied are shown in Table 1; there were no significant differences in age, stroke risk factors, severity of stroke at admission, or baseline hemorheological variables between the groups (Table 2). All the patients receiving placebo had cortical infarcts on CT. Five patients receiving nimodipine had cortical infarcts, whereas four had subcortical infarcts; the latter group included one patient with pure motor hemiparesis and normal CT. During the 3-week period, hemorheological variables were similar for the three nimodipine-treated groups and did not demonstrate significant dose-related variations (data not shown); the nimodipine-treated patients were thus considered as a single group for further statistical analysis. Fibrinogen and low-shear whole-blood viscosity increased significantly in patients receiving placebo but not in the nimodipinetreated group (Table 2, Fig. 1). The evolution of these variables was similar for nimodipine-treated patients with cortical versus subcortical infarcts (cortical infarcts at baseline-fibrinogen 511 ± 102 mg/dl, blood viscosity 53.7 ± 8.7 cP; at days 10-21-fibrinogen 510 ± 98, blood viscosity 54.2 ± 8.7; subcortical infarcts at baseline-fibrinogen 428 ± 79 mg/dl, blood viscosity 56.0 ± 3.3 cP; at days 10-21-fibrinogen 431 ± 71 mg/dl, blood viscosity 51.6 ± 6.1 cP). Red blood cell aggregation (Le.,ZSR and y T-min) increased in both groups but less in those receiving nimodipine: (a) ZSR increased 4.1% for patients receiving nimodipine versus 7.2% for placebo; (b) y T-min increased

Table 1.

Description of the studypopulation

Number Male/female Age (years) Stroke nsk factors Hypertension Diabetes mellitus Coronary artery disease Toronto Stroke Scale on admission

Nimodipine

Placebo

9 4/5 68 ± 9

4 1/3 67 ± 3

7 (78%) 3 (33%) 4 (44%)

3 (75%) 2 (50%) 0

55

± 32

54

± 36

/ STROKECEREBROVASCDIS, VOL 2, NO 1,1992

23

S F. AMERlSO IT AL.

Table 2. Hemorheological variables at baseline and at days 10 and 21 following ischemic stroke" Nrmodlpine

Hematocrit ('Yo) Fibrinogen (mg/dl) Low-shear viSCOSIty (cP) High-shear viscosity (cP) ZSR YT-min (S-I) Transit time (ms)

Placebo

Baseline

Days 10 and 21

Baseline

Days 10 and 21

42.8 ± 34 470 ± 102 54.8 ± 68 7.0 ± 05 638 ± 4.7 145 ± 22 3.32 ± 0.37

421 ± 31 470 ± 92 53.1 ± 7.6 7.0 ± 0.7 664±6.1 b 162 ± 29' 325 ± 027

420 ± 2.1 445 ± 109 572 ± 74 69 ± 02 635 ± 40 150 ± 38 348 ± 0.19

419 ± 5.0 540 ± 109 b 636 ± 63° 7.3 ± 0.4 681 ± 20.1 181 ± 47.1 340 ± 036

'cP, centiPoise (mPa.s)

"p < 0025.

lP

Nimodipine and the evolution of hemorheological variables after acute ischemic stroke.

We studied the effects of the calcium channel antagonist nimodipine on the evolution of hemorheological variables during the first 3 weeks following i...
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