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Purpose and Hypothesis: The ability to measure the immediate tissue effects in patients treated with thrombolysis ultra-early relative to their known onset has increased. We hypothesized that shorter onset to treatment times (OTT) would lead to more penumbra saved, calculated using multimodal MRI.Methods: Patients were included in this study if they met the following criteria: (1) were admitted between January 2010 and June 1, 2014 at one of two regional stroke centers, (2) had known last seen normal, acute MRI and IV tPA start times, (3) received an admit diagnosis of ischemic stroke, and (4) were treated with standard IV tPA. Penumbral volumes were calculated using the baseline MRI-defined mismatch regions minus the infarcted regions defined by the co-registered DWI at 24 hours. Patients were categorized to the “early” IV tPA cohort if their OTT was ≤ 120 minutes. Infarct growth was quantitatively defined as lesion volume increase > 5 mL from baseline DWI to 5-day FLAIR. Favorable clinical outcome was defined as discharge or later mRS < 2.Results: Sixty-three patients, 23 early- and 40 late-treated, were included in the study with mean age 75 (±15) years, 48% female, median [IQR]: admit NIHSS 10 [5-19], OTT 139 [109-185] minutes, baseline DWI volume 11.2mL [3.5-39.6], baseline MTT volume 120.9mL [37.8-220.7], and baseline mismatch volume 119.3mL [34.6-200.7]. Aside from time-based variables, only the amount of penumbra infarcted at 24 hours (p=0.015) was significantly different between the early- (9mL [1.7-19.7] and late-treated (2.4mL [0.7-7]) cohorts. The patients with favorable outcome were younger (p=0.012) with less severe admit NIHSS (p=0.026), smaller baseline DWI volume (p=0.017), smaller 24 hour DWI volume (p=0.041), and greater percentage of penumbra saved at 24 hours (p=0.010) but no difference in OTT (p=0.267). Using binomial logistic regression, percentage of penumbra saved at 24 hours (95%CI:0.000-0.011, p=0.010) was the only independent predictor of no infarct growth.Conclusions: This study establishes that significantly larger penumbral tissue saved at 24 hours, not early OTT, is predictive of both favorable clinical outcome and no infarct growth.