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Reperfusion after stroke sonothrombolysis with microbubbles may predict intracranial bleeding

From the Stroke Unit (L.D., M.d.S.), Department of Neurology, University of Genova, San Martino Hospital, Italy; and Unitat Neurovascular (M. Rubiera, M. Ribo, O.M., G.O., J.A.-S., C.A.M.), Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Spain.

Address correspondence and reprint requests to Dr. Carlos A. Molina, Unitat Neurovascular, Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Passeig Vall d’Hebron 119-129, Barcelona, Spain cmolina{at}vhebron.net

Background: Although ultrasound-activated microbubbles (MB) accelerate clot lysis, MB activation has shown to promote blood barrier disruption and bleeding in animal models. We conducted a case–control study aimed to investigate the risk of hemorrhagic transformation (HT) after MB-enhanced sonothrombolysis in acute stroke.

Methods: We evaluated a total of 296 patients with acute stroke treated with IV tissue plasminogen activator (tPA) <3 hours after stroke onset. One hundred eighty-eight patients received continuous 2-hour TCD monitoring plus 3 doses of 2.5 g of MB after tPA bolus (MB group). These patients were compared with 98 historic stroke patients (control group). The presence and extent of HT on 24-hour CT were blindly assessed.

Results: Recanalization rates were higher in the MB compared with the control group at 1, 2, 6, and 12 hours (p < 0.05). MB administration was associated with an increased risk of hemorrhagic infarction (HI)1–HI2 (21% vs 12%, p = 0.026) and a higher degree of clinical improvement at 24 hours (54.9% vs 31.1%, p = 0.004). Parenchymal hematoma (PH)1–PH2 and symptomatic intracranial hemorrhage rates were similar in both groups. Moreover, the extent of bleeding after MB-enhanced sonothrombolysis was correlated with the time to reperfusion. Early (<6 hours) recanalization independently predicted HI in the MB group (odds ratio 6.3, 95% confidence interval 2.3–56) but not in the control group. Delayed (>6 hours) or no recanalization was associated with PH1–PH2 in both the MB group (p = 0.024) and the control group (p = 0.045).

Conclusion: This hypothesis-generating study shows that microbubble administration was associated with early recanalization and a high rate of hemorrhagic transformation but does not seem to increase the risk of symptomatic intracranial hemorrhage. However, definitive conclusions cannot be made based on these data.

Abbreviations: CLOTBUST = Combined Lysis of Thrombus by Ultrasound Trial; BBB = blood–brain barrier; DM = diabetes mellitus; ECASS = European Cooperative Acute Stroke Study; FDA = Food and Drug Administration; HI = hemorrhagic infarction; HT = hemorrhagic transformation; HTN = hypertension; ICA = internal carotid artery; MB = microbubbles; MCA = middle cerebral artery; NIHSS = NIH Stroke Scale; PH = parenchymal hematoma; SBP = systolic blood pressure; SICH = symptomatic intracranial hemorrhage; TCD = transcranial Doppler; TIBI = Thrombolysis in Brain Ischemia; tPA = tissue plasminogen activator; TUCSON = Ultrasound in Clinical Sonothrombolysis; US = ultrasound.

Disclosure: Author disclosures are provided at the end of the article.

Received January 1, 2009. Accepted in final form June 9, 2009.