Nonpharmaceutical Approaches Albumin

Ginsberg's pioneering animal research has shown that albumin infusions enhance red cell perfusion and suppress thrombosis and leukocyte adhesion in the microcirculation, particularly during the early reperfusion phase.54 Albumin also improves microcirculatory flow, plasma viscosity, red cell deformability, and oxygen transport capacity. In addition, albumin has potent antioxidant and antiapoptotic effects. In experimental stroke, albumin has been shown to reduce infarct size, improve neurofunction scores, and reduce brain edema.55 In the Albumin in Acute Stroke (ALIAS) phase II trial, an open-labeled, dose-escalation, nonrandomized pilot clinical trial conducted at two centers in North America, albumin was found to be safe and effective in reducing stroke-related brain injury.56,57 Eighty-two subjects with an NIHSS>6 received 25% albumin within 16hours of stroke onset in two doses, 0.34-1.03 and 1.37-2.05 g/kg. Nearly half of the patients (42) also received rt-PA. The probability of a good clinical outcome at 3 months was greater in the high-dose cohort than in the low-dose cohort (relative risk [RR] 1.81; 95% CI 1.11-2.94), and compared to the NINDS rt-PA Stroke Study cohort (RR 1.95; 95% CI 1.47-2.57). The high-dose albumin cohort members who received concomitant rt-PA were three times more likely to achieve a good outcome than those subjects receiving both lower dose albumin and rt-PA, suggesting a synergistic effect between albumin and rt-PA. Over the course of 3 months after treatment, the NIHSS scores progressively improved in the high-dose albumin group, but did not improve in the low-dose cohort (Fig. 5.3a), achieving statistically significant improvement in the high-dose albumin/rt-PA cohort. Both with and without rt-PA, the distribution of functional outcome scores (mRS scores) in the high- and low-dose albumin groups favored the high-dose albumin cohort (Fig. 5.3b), where 68.2% of patients in the

FIGURE 5.3 The Albumin in Acute Stroke (ALIAS) Phase II Trial. Data represent mean ± SEM. p-Value according to multiple regression analysis. Dead patients have been censored. (a) Mean change in NIH Stroke Scale score over time since treatment in rt-PA and non-rt-PA cohorts receiving the three lowest doses (Tiers I, 0.34 mg/kg; II, 0.68 mg/kg; III, 1.03 mg/kg) and three highest doses of albumin (Tiers IV, 1.37 mg/kg; V, 1.71mg/kg; VI, 2.03mg/kg).

FIGURE 5.3 The Albumin in Acute Stroke (ALIAS) Phase II Trial. Data represent mean ± SEM. p-Value according to multiple regression analysis. Dead patients have been censored. (a) Mean change in NIH Stroke Scale score over time since treatment in rt-PA and non-rt-PA cohorts receiving the three lowest doses (Tiers I, 0.34 mg/kg; II, 0.68 mg/kg; III, 1.03 mg/kg) and three highest doses of albumin (Tiers IV, 1.37 mg/kg; V, 1.71mg/kg; VI, 2.03mg/kg).

high-dose albumin/rt-PA group had a good outcome at 3 months (mRS 0-1). In 13% of the patients who received high-dose albumin, the major side effect was pulmonary edema, which was responsive to diuresis. Based on these encouraging results, the phase III multicenter ALIAS trial has been initiated.

FIGURE 5.3 (Continued) (b) Distribution of modified Rankin Scale (mRS) scores at 3 months in the lower (I—III) and higher (IV-VI) albumin dose tiers for the rt-PA and non-rt-PA cohorts. (Reprinted with permission from reference 57.)
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