Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke
Andrei V. Alexandrov, M.D., Carlos A. Molina, M.D., James C. Grotta, M.D., Zsolt Garami, M.D., Shiela R. Ford, R.N., Jose Alvarez-Sabin, M.D., Joan Montaner, M.D., Maher Saqqur, M.D., Andrew M. Demchuk, M.D., Lemuel A. Moyé, M.D., Ph.D., Michael D. Hill, M.D., Anne W. Wojner, Ph.D., for the CLOTBUST Investigators
Background Transcranial Doppler ultrasonography that is aimedat residual obstructive intracranial blood flow may help exposethrombi to tissue plasminogen activator (t-PA). Our objectivewas to determine whether ultrasonography can safely enhancethe thrombolytic activity of t-PA.
Half of patients who have had ischemic stroke remain moderatelyor severely disabled despite treatment with intravenous tissueplasminogen activator (t-PA).1 Major reasons for incompleterecovery include a severe initial ischemic insult and slow andincomplete thrombolysis.2,3 Successful thrombolysis dependson the delivery of t-PA to the thrombus through residual bloodflow around the arterial obstruction.4,5
In experimental models, ultrasound has been shown to facilitatethe activity of fibrinolytic agents within minutes of its exposureto a thrombus and to blood that contains t-PA.2,4,5,6,7,8,9The mechanisms of ultrasound-enhanced thrombolysis include improveddrug transport, reversible alteration of the fibrin structure,and increased binding of t-PA to fibrin2,4,5,6,7,8,9 when ultrasoundfrequencies ranging from kilohertz to those used in diagnosticultrasonography are used.10,11 Although kilohertz frequenciespenetrate better with minimal heating,12,13 a combination oft-PA and an experimental kilohertz-delivery system resultedin an excessive risk of intracerebral hemorrhage in patientswith stroke.14,15 Diagnostic 2-MHz transcranial Doppler ultrasonographyis routinely used in patients with stroke to obtain spectralvelocity measurements in intracranial arteries.16,17 TranscranialDoppler can be aimed at the interface between residual flowand the intracranial thrombus by detecting abnormal wave forms.18
In a pilot study, we had found that complete recanalizationcoupled with dramatic clinical recovery from stroke occurredduring transcranial Doppler monitoring of blood flow after t-PAinfusion19 at rates that were higher than expected from studiesof t-PA infusion alone.1 We therefore performed a randomizedtrial with a predetermined sample size to evaluate rates ofrecanalization and clinical recovery with intravenous t-PA administeredwith or without continuous monitoring with transcranial Dopplerultrasonography. Our hypothesis was that continuous exposureto diagnostic ultrasonic waves would not result in an increasedrate of symptomatic intracerebral hemorrhage and that such exposuremight aid recanalization and clinical recovery from ischemicstroke. The purpose of this phase 2 trial was to determine thesafety and biologic activity of this method and to obtain anestimate of the magnitude of the potential clinical benefitin order to plan a subsequent phase 3 efficacy trial.
Methods
Study Design
The Combined Lysis of Thrombus in Brain Ischemia Using TranscranialUltrasound and Systemic t-PA (CLOTBUST) trial was a phase 2,multicenter, randomized clinical trial. Patients received standardintravenous t-PA therapy (i.e., 0.9 mg per kilogram of bodyweight [maximum, 90 mg], with 10 percent given as a bolus and90 percent by continuous infusion). Therapy was initiated withinthree hours of the onset of symptoms of stroke, either withcontinuous monitoring with the use of transcranial Doppler ultrasonography(the target group) or with placebo monitoring (the control group).
The treating physicians administered t-PA (provided by Genentech)according to published criteria,1 irrespective of the ultrasonographicfindings. Patients who were eligible for the CLOTBUST trialalso had evidence of obstructive residual flow in the middlecerebral artery, as observed on transcranial Doppler sonographybefore the t-PA bolus was given. An experienced physician-sonographer,who was not aware of the treatment assignment, diagnosed theseocclusions with the use of previously validated criteria, includingthe Thrombolysis in Brain Ischemia (TIBI) flow-grading system.18,20,21(On the TIBI scale, acute occlusions can present with absent,minimal, blunted, or dampened residual-flow wave forms.) Beforethe initiation of the study at each site, sonographers completeda computerized tutorial and passed (90 percent of the questionsanswered correctly) a validated multiple-choice examinationon the interpretation of TIBI wave forms. In a prospective,multicenter validation study, our criteria for the detectionof occlusions of the middle cerebral artery by transcranialDoppler ultrasonography had a rate of accuracy of greater than90 percent, as compared with the results of invasive angiography.22We used an insonation depth of 45 mm or more with the transcranialDoppler equipment for the identification of presumed proximal(i.e., M1) occlusions of the middle cerebral artery and depthsof 30 to 45 mm for presumed distal (i.e., M2) occlusions. Eligiblepatients had abnormal flow through the middle cerebral artery,with a grade of 0, 1, 2, or 3 on the TIBI scale (a grade of5 indicates complete recanalization), before the administrationof a t-PA bolus.
Study Protocol
Approval was obtained from the institutional review board (IRB)at each clinical site. Written informed consent for participationin the trial was provided by all patients or their legal representatives.In all patients, transducers were positioned over the temporalbone at a constant angle with a standard head frame (Marc series,Spencer Technologies). The depth with the worst residual flowsignal as measured on the TIBI scale was selected for display.All centers had power-motion Doppler units (PMD 100, SpencerTechnologies). The use of other portable transcranial Dopplerunits (EZ-Dop, Multi-Dop T, DWL; 100 M, Multigon; and CompanionIII, Nicolet) was also permitted. All units were equipped with2-MHz pulsed-wave diagnostic transducers approved by the Foodand Drug Administration (FDA).
For each patient, after the head frame was positioned, sonographersopened a sealed envelope containing the random assignment tothe target group or the control group. Randomization was notstratified by center. Randomization at a 1:1 ratio was performedin blocks of 10 patients at each site. In the target group,ultrasonographic monitoring was initiated before administrationof the t-PA bolus and was continued for two hours. Emitted-poweroutput was set at the maximal achievable level with selectedinsonation depths under the FDA-allowed threshold of 750 mW.Sample volumes, or gates of insonation, were set at 3 to 6 mmfor power-motion Doppler23 units and 10 to 15 mm for all othersingle-channel transcranial Doppler units. For patients in thecontrol group, the probe was replugged into an inactive channelwith no continuous insonation. In both groups, sonographersmuted the volume on transcranial Doppler units and turned thevisual displays away from the treating physicians in order tokeep the physicians blinded to the patients' study-group assignments.Further details of blinding procedures have been published previously.24
In both groups, follow-up measurements were taken 30, 60, 90,and 120 minutes after the t-PA bolus was given. Arterial recanalization,as evident on transcranial Doppler wave forms, was determinedwith the use of the previously validated TIBI system.18,21 Sonographersdetermined that there was complete recanalization of the middlecerebral artery if a flow grade of 5 on the TIBI scale was identified(Figure 1). Concomitant and persisting severe stenosis or occlusionof the proximal internal carotid artery was established by carotidduplex ultrasonography or by angiography. In patients with theseconditions, complete recanalization of the middle cerebral arterywas considered to have been achieved if on transcranial Dopplerultrasonography blunted but low-resistance wave forms were seenover both M1 and M2 segments,21 with an improvement in meanflow velocity to more than 20 cm per second. These criteriapredict grade 3 flow, as measured on the angiographic Thrombolysisin Myocardial Infarction (TIMI) scale,25 in the middle cerebralartery with a rate of accuracy above 90 percent.21 The TIMIscale is an angiographic scale that is applied to coronary andcerebral vessels, with grade 3 indicating unobstructed flowto affected tissues with or without proximal residual narrowingof the artery after thrombolysis. The principal investigatoralso reviewed digitized wave forms to confirm the readings fromeach study site. Partial recanalization was diagnosed if flowimproved by one grade or more from the baseline but not to thelevel of grade 5 on the TIBI scale. Reocclusion was diagnosedif flow worsened by at least one grade.26
Figure 1. Complete Recanalization with the Use of Power-Motion Transcranial Doppler Ultrasonography.
Spectral wave forms from the proximal middle cerebral artery (MCA) were obtained at a depth of 58 to 60 mm (left-hand image, arrow) from the left transtemporal window. A minimal, grade 1, signal as measured on the TIBI scale, with absent diastolic flow is seen on power-motion Doppler images (top) and spectral-transcranial Doppler images (bottom) obtained before the administration of a t-PA bolus. Thirty minutes after the t-PA was given, TIBI grade 3 dampened signals (i.e., cycles with positive end-diastolic flow) indicate the beginning of the recanalization of the proximal middle cerebral artery. TIBI grade 3 signals remain at 60 and 90 minutes. At 120 minutes, embolic tracks are shown by power-motion Doppler display (top, arrows), followed by restoration of low-resistance normal flow in both proximal and distal parts of the middle cerebral artery. Normal flow through the unaffected middle cerebral artery is shown in the far right-hand image for comparison. Corresponding National Institutes of Health Stroke Scale (NIHSS) scores are provided below each frame. (In the general population with stroke, scores range from 0 to 34, with higher scores indicating greater neurologic deficits.) At 24 hours, this patient had an NIHSS score of 4. At three months, he had no residual neurologic deficits, and his modified Rankin score was 0.
The treating physicians assessed neurologic status without knowledgeof random assignment and the results on transcranial Dopplermonitoring at 30, 60, 90, and 120 minutes and at 24 hours withthe use of the National Institutes of Health Stroke Scale (NIHSS).Modified Rankin scores were obtained at three months.
End Points
The prespecified primary-activity end point was the occurrenceof complete recanalization according to TIBI criteria18,21 orearly or dramatic clinical recovery from stroke.24 Early clinicalrecovery was defined as a reduction of 10 or more points onthe NIHSS, and dramatic recovery as a total NIHSS score of 3or less within two hours after administration of the t-PA bolus.
If no early recanalization was observed, the CLOTBUST protocolpermitted, at the discretion of the treating physician, rapidtransport of the patient to the angiography unit for intraarterialintervention. A separate written informed-consent release, approvedby the IRB at each site, was obtained in these circumstances.Participation in other clinical trials was prohibited.
The primary safety end point was intracerebral hemorrhage withclinical worsening (indicated by an NIHSS score of 4) within72 hours of the onset of stroke. Secondary end points were clinicalrecovery at 24 hours, which was defined as a reduction of 10or more on the NIHSS score or a total NIHSS score of 3 or less;a favorable outcome at three months (i.e., a modified Rankinscore of 0 to 1); and death within three months after treatment.
Statistical Analysis
Before the trial began, we determined that a sample of 126 patients,with 63 in each of the two groups, was necessary for the studyto detect a 20 percent absolute benefit in terms of the compositeprimary outcome at two hours after the t-PA bolus,24 assuminga two-sided type I error of 0.05. Missing data on the outcomeduring the two hours of treatment were imputed by carrying forwardthe last available score. TIBI scores at 120 minutes were unavailablefor seven patients (three in the control group and four in thetarget group) because these patients were undergoing cerebralangiography. In these cases, the TIBI scores at 60 minutes (fivepatients) or 90 minutes (two patients) were carried forward.Missing baseline glucose levels were imputed for six patientswith the use of an internal-regression model that was basedon age, sex, presence or absence of diabetes, time from theonset of symptoms to treatment, and the presence or absenceof hypertension. Preplanned interim safety analyses evaluatedthe rate of symptomatic intracerebral hemorrhage after every10 patients enrolled in the trial. Descriptive statistics wereused to summarize the data. The equality of proportions wascompared with the use of Fisher's exact test and the chi-squaretest. Logistic-regression models were used to test for interactionbetween variables and to provide risk estimates adjusted forthe variables of treatment center, age, sex, NIHSS score, timefrom onset of symptoms to the administration of the t-PA bolus,baseline TIBI score, and glucose concentration. Conventionallevels of statistical significance (=0.05) and two-sided testswere used in all analyses.
Results
All 126 patients received treatment with intravenous t-PA: 63were randomly assigned to receive continuous monitoring (thetarget group; median NIHSS score before the t-PA bolus, 16 points;84 percent had scores of 10 or higher) and 63 were assignedto the control group (median NIHSS score, 17; 83 percent hadscores of 10 or higher). The pretreatment characteristics ofthe two groups were similar (Table 1).
Table 1. Pretreatment Characteristics of Patients.
Overall, one-hour follow-up was complete for 99 percent of patients,two-hour follow-up for 96 percent, and three-month follow-upfor 97 percent. No patients withdrew from the study. No seriousadverse effects were noted during ultrasonography. Reasons forincomplete follow-up included intubation due to the severityof clinical stroke and transfer to urgent diagnostic angiography.Nine patients in the target group (14 percent) and 11 in thecontrol group (18 percent) underwent additional intraarterialthrombolysis with mechanical manipulation of the thrombus; differencesin outcomes between the groups were not influenced by theseinterventions. All patients whose condition worsened by 4 ormore NIHSS points during the two hours after the bolus was given(five patients in each group [8 percent]) underwent urgent computedtomography (CT) of the head without the use of contrast material.These scans showed no intracerebral hemorrhage during exposureto ultrasonic waves.
Repeated CT scans or magnetic resonance images of the brainwere obtained when clinically indicated between 5 and 72 hoursafter the onset of symptoms. Symptomatic intracerebral hemorrhageoccurred in three patients in the target group and three inthe control group (4.8 percent; difference in risk, 0.0 percent;95 percent confidence interval for the difference in risk, –0.07percent to 0.07 percent). No patient had intracerebral hemorrhagebefore undergoing intraarterial angiography. One symptomaticintracerebral hemorrhage occurred in each group after intraarterialprocedures. When these patients were excluded, symptomatic intracerebralhemorrhage occurred in 2 of 62 patients (3 percent) in bothgroups.
Within two hours of the administration of the t-PA bolus, theprimary combined end point was reached by 31 patients in thetarget group (49 percent) and 19 in the control group (30 percent;P=0.03; relative risk, 1.6; 95 percent confidence interval,1.03 to 2.6). Complete recanalization occurred within two hoursafter the t-PA bolus in 29 patients in the target group (46percent) and 11 in the control group (18 percent; P<0.001)(Table 2). Reocclusion occurred in 11 patients in the targetgroup (18 percent) and 14 in the control group (22 percent).Complete recanalization was sustained at two hours after administrationof the t-PA bolus in 24 patients in the target group (38 percent)and 8 patients in the control group (13 percent; P=0.002) (Figure 2).All on-site readings were confirmed by central reading.The principal investigator reviewed all wave forms, irrespectiveof group assignment, for consistency of on-site interpretationwith the use of TIBI flow-grade definitions. Clinical recoveryoccurred in 18 patients in the target group (29 percent) andin 13 in the control group (21 percent) within two hours ofthe t-PA bolus.
Figure 2. Rate of Sustained Complete Recanalization within Two Hours after Administration of a t-PA Bolus.
A trend toward the achievement of complete recanalization was observed over time with active treatment with the use of transcranial Doppler ultrasonography. Complete recanalization had occurred at 30 minutes after the t-PA bolus in 4 patients in the control group (6 percent; 95 percent confidence interval, 1.8 to 15.5) and in 11 patients in the target group (18 percent; 95 percent confidence interval, 9.0 to 29.1). At 60 minutes, 8 patients in the control group (13 percent; 95 percent confidence interval, 5.6 to 23.5) and 17 in the target group (27 percent; 95 percent confidence interval, 16.6 to 39.7) had complete recanalization. At 90 minutes, 7 patients in the control group (11 percent; 95 percent confidence interval, 4.6 to 21.6) and 16 in the target group (25 percent; 95 percent confidence interval, 15.3 to 27.9) had complete recanalization. At 120 minutes, 8 patients in the control group (13 percent; 95 percent confidence interval, 5.6 to 23.5) and 24 in the target group (38 percent; 95 percent confidence interval, 26.1 to 51.2) had complete recanalization. All 63 patients per group were accounted for at each time point.
Patients who had complete recanalization at 120 minutes weremore likely to have a complete recovery at 90 days (relativerisk, 1.9; 95 percent confidence interval, 1.1 to 3.0), with22 percent more patients recovering completely, as comparedwith patients with partial or no recanalization. Complete recanalizationat 120 minutes was predicted by assignment to active transcranialDoppler monitoring (relative risk, 2.6; 95 percent confidenceinterval, 1.4 to 4.8). In a logistic-regression model, completerecanalization was less likely among patients who had ipsilateralobstruction of the internal carotid artery (odds ratio, 0.35;95 percent confidence interval, 0.14 to 0.90), a higher serumglucose level (odds ratio per additional 50 mg per deciliter,0.57; 95 percent confidence interval, 0.37 to 0.99), and higherNIHSS scores (odds ratio per 5-point increase, 0.60; 95 percentconfidence interval, 0.41 to 0.89). Although 49 percent of patientswere treated and randomly assigned at a single hospital, therewas no evidence of an interaction between site and treatment(P=0.2). Similarly, there was no evidence of an interactionbetween the treatment and the device (five types of transcranialDoppler units were used) (P=0.8).
Ultrasonographic monitoring was interrupted before two hourshad passed after the t-PA bolus in the cases of 4 of the 20patients who underwent intraarterial interventions. The randomizationcode was not broken in these cases, but the patients were excludedfrom secondary analyses. At 24 hours, 24 of 54 patients in thetarget group who were eligible for follow-up analysis (44 percent)and 21 of 52 in the control group (40 percent) had total NIHSSscores of 3 points or lower or had improved by 10 points ormore (P=0.7).
Four patients did not return for the three-month follow-up visit(three patients in the control group, who had 24-hour NIHSSscores of 9, 10, and 15, and one in the target group, who hada 24-hour NIHSS score of 22). Patients who did not return forfollow-up were excluded from the outcome analysis. At threemonths, 22 of the 53 patients eligible for analysis in the targetgroup (42 percent) and 14 of the 49 eligible patients in thecontrol group (29 percent) had modified Rankin scores of 0 or1 (relative risk, 1.45; 95 percent confidence interval, 0.84to 2.51; P=0.2). The mortality rates were 15 percent and 18percent, respectively (P=0.4) (Figure 3).
Favorable outcomes were defined as a score of 0 to 1 on the modified Rankin scale, indicating little or no disability. A total of 42 percent of patients in the target group who were eligible for follow-up and 29 percent of those in the control group met these criteria. Other outcomes included a modified Rankin score of 2 (9 percent in the target group vs. 8 percent in the control group); a score of 3 to 5 (34 percent in the target group vs. 45 percent in the control group); and death (15 percent in the target group vs. 18 percent in the control group).
Discussion
Our results show that continuous monitoring of intracranialocclusion with the use of 2-MHz, single-element pulsed-waveultrasonography had a positive effect on the primary-activityend point, with no increase in the rate of bleeding. Our findingsindicate a biologic effect of diagnostic ultrasonography thataids systemic thrombolytic therapy in patients with acute ischemicstroke, since the combination of these techniques may facilitateclinical recovery. No patient left the trial despite monitoringwith the head frame tightly fixed and ultrasonic waves deliveredthrough the temporal bone at the full power settings that areallowed for diagnostic Doppler units. A previous study had shownthat transmission of 2-MHz ultrasonic waves through the temporalbone of cadaver skulls caused an energy loss of 65 to 90 percentdue to ultrasound accumulation in the bone.27 Even these lowenergy levels appeared sufficient to enhance t-PA–inducedthrombolysis with transcranial Doppler monitoring in an experimentalskull model.11
In our randomized trial, there was a 38 percent rate of completearterial recanalization that was sustained two hours after theadministration of a t-PA bolus — a finding that is consistentwith observations from the phase 1 trial.19 Previous studiesalso pointed to the possibility that diagnostic ultrasound equipmentsuch as transcranial duplex units may enhance thrombolysis bothwith and without t-PA therapy.28,29 However, the small samplesizes in these studies precluded definitive conclusions frombeing drawn. Recent experimental work using ultrasound in thekilohertz range30 points to a possibility that combined-frequencytransducers may also be developed, although there is concernabout safety with frequencies outside the range used in diagnosticultrasonography.14,15
Our data suggest that continuous monitoring with transcranialDoppler ultrasonography induced a detectable improvement ofresidual flow and probably converted partial recanalizationwith t-PA therapy into more complete early recanalization. Thedetectable flow improvement, in turn, produced a nonsignificanttrend toward faster and near-complete clinical recovery fromstroke within two hours after the administration of a t-PA bolusand complete recovery at three months. The National Instituteof Neurological Disorders and Stroke Recombinant Tissue PlasminogenActivator (NINDS rt-PA) Stroke Study and a subsequent phase4 trial demonstrated a rate of complete recovery from strokeat three months of 31 percent.1,31 In our trial, 29 percentof patients in the target group had early dramatic recoveryshortly after they received the t-PA bolus, an effect not previouslydetected in patients with stroke.32
The relatively low rate of complete recovery at three monthsin our control group may be attributable to the exclusion ofpatients with lacunar strokes and to the presence of more severestroke before treatment, as compared with the severity in patientsin the NINDS rt-PA Stroke Study.1 Also, the rate of completerecanalization in patients in the control group was low andsimilar to that with intravenous treatment with duteplase ina pilot study, involving patients with middle-cerebral-arteryocclusions, in which outcome was measured by angiography.33Furthermore, a trend in baseline characteristics favored thecontrol group, since more patients in that group were treatedwithin two hours of the onset of symptoms and fewer patientshad tandem obstructions of the internal carotid artery.
Previous studies do not provide estimates of the rate of recoveryin patients with occlusions of the middle cerebral artery whowere treated with t-PA within three hours after the onset ofstroke. One objective of this study was to derive estimatesof the sample size for a pivotal efficacy trial. On the basisof the rates of complete recovery at three months (42 percentand 29 percent in this trial), 274 patients per group will beneeded for such a study to be able to demonstrate the effectof thrombolysis enhanced by ultrasonography on the outcome ofstroke, with a two-sided level of 0.05 and 90 percent power.
Supported by grants from the National Institute of NeurologicalDisorders and Stroke (1K23NS02229-01 and 1P50NS044227). Canadiansites were supported by the Canadian Institutes of Health Researchand the Alberta Heritage Foundation for Medical Research. TheCLOTBUST trial is an investigator-sponsored trial (protocolA2207s, Genentech) and is exempted from the InvestigationalNew Drug status by the Food and Drug Administration. SpencerTechnologies, Seattle, provided power-motion Doppler units atno charge and technical support for all participating studysites. DWL, Multigon, and Nicolet also provided portable equipmentto hospitals in Houston at no charge.
Dr. Alexandrov reports having served as a consultant to Sanofi-Synthelaboand Bristol-Myers Squibb and having received lecture fees fromBoehringer Ingelheim and grant support from Genentech. A U.S.patent, "Therapeutic Method and Apparatus for Sonication toEnhance Perfusion Tissue" (no. 6733450), for which Dr. Alexandrovand Dr. Wojner are coinventors, was issued in May 2004; thepatent is owned by the University of Texas. Dr. Grotta reportshaving served as a consultant to Encysive Pharmaceuticals andAlsius and having received lecture fees from ESP Pharma andgrant support from the National Institute of Neurological Disordersand Stroke. A U.S. patent, "A Composition and Method for Treatmentof Cerebral Ischemia" (no. 6500834), for which Dr. Grotta isone of the inventors, was issued in April 2000; the patent isowned by the University of Texas. Dr. Demchuk reports havingserved as a consultant to Sanofi-Synthelabo and having receivedlecture fees from Sanofi-Synthelabo and AstraZeneca and grantsupport from the Canadian Institutes of Health Research, theAlberta Heritage Foundation for Medical Research, the CanadianStroke Network, the Calgary Regional Health Authority, the M.S.I.Foundation, the Canadian Health Region, the Heart and StrokeFoundation of Canada, and NIH NINDS. Dr. Hill reports havingserved as a consultant to Novo Nordisk and having received lecturefees from Sanofi-Synthelabo and grant support from Ono Pharmaceuticals.
* The centers and investigators participating in the CLOTBUSTstudy are listed in the Appendix.
Source Information
From the Stroke Treatment Team, University of Texas–Houston Medical School, Houston (A.V.A., J.C.G., Z.G., S.R.F., A.W.W.); the Neurovascular Unit, Vall d'Hebron Hospital, Barcelona (C.A.M., J.A.-S., J.M.); the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Canada (M.S.); the Department of Clinical Neurosciences (A.M.D., M.D.H.) and the Departments of Community Health Sciences and Medicine (M.D.H.), University of Calgary, Calgary, Alta., Canada; and the Department of Biostatistics, School of Public Health, University of Texas, Houston (L.A.M.).
Address reprint requests to Dr. Alexandrov at MSB 7.044, 6431 Fannin St., University of Texas, Houston, TX 77030, or at avalexandrov{at}att.net.
References
The NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587. [Free Full Text]
Francis CW. Ultrasound-enhanced thrombolysis. Echocardiography 2001;18:239-246. [Medline]
Alexandrov AV, Burgin WS, Demchuk AM, El-Mitwalli A, Grotta JC. Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short term improvement. Circulation 2001;103:2897-2902. [Free Full Text]
Francis CW, Blinc A, Lee S, Cox C. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol 1995;21:419-424. [CrossRef][ISI][Medline]
Blinc A, Kennedy SD, Bryant RG, Marder VJ, Francis CW. Flow through clots determines the rate and pattern of fibrinolysis. Thromb Haemost 1994;71:230-235. [Medline]
Trubestein R, Engel C, Etzel F, Sobbe A, Cremer A, Stumpff U. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl 1976;3:697s-698s. [Medline]
Tachibana K, Tachibana S. Ultrasonic vibration for boosting fibrinolytic effects of urokinase in vivo. Thromb Haemost 1981;46:211-211. abstract.
Lauer CG, Burge R, Tang DB, Bass BG, Gomez ER, Alving BM. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation 1992;86:1257-1264. [Free Full Text]
Kimura M, Iijima S, Kobayashi K, Furuhata H. Evaluation of the thrombolytic effect of tissue-type plasminogen activator with ultrasound irradiation: in vitro experiment involving assay of the fibrin degradation products from the clot. Biol Pharm Bull 1994;17:126-130. [Medline]
Blinc A, Francis CW, Trudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood 1993;81:2636-2643. [Free Full Text]
Behrens S, Spengos K, Daffertshofer M, Schroeck H, Dempfle CE, Hennerici M. Transcranial ultrasound-improved thrombolysis: diagnostic vs. therapeutic ultrasound. Ultrasound Med Biol 2001;27:1683-1689. [CrossRef][Medline]
Akiyama M, Ishibashi T, Yamada T, Furuhata H. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Neurosurgery 1998;43:828-832. [CrossRef][ISI][Medline]
Suchkova V, Siddiqi FN, Carstensen EL, Dalecki D, Child S, Francis CW. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998;98:1030-1035. [Free Full Text]
Daffertshofer M, Hennerici M. Ultrasound in the treatment of ischaemic stroke. Lancet Neurol 2003;2:283-290. [CrossRef][Medline]
Daffertshofer M, Hennerici M. TRUMBI trial. Cerebrovasc Dis (in press).
Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982;57:769-774. [ISI][Medline]
Sloan MA, Alexandrov AV, Tegeler CH, et al. Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2004;62:1468-1481. [Free Full Text]
Demchuk AM, Burgin WS, Christou I, et al. Thrombolysis in Brain Ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke 2001;32:89-93. [Free Full Text]
Alexandrov AV, Demchuk AM, Felberg RA, et al. High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored by 2-MHz transcranial Doppler monitoring. Stroke 2000;31:610-614. [Free Full Text]
Demchuk AM, Christou I, Wein TH, et al. Accuracy and criteria for localizing arterial occlusion with transcranial Doppler. J Neuroimaging 2000;10:1-12. [Medline]
Burgin WS, Malkoff M, Felberg RA, et al. Transcranial Doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. Stroke 2000;31:1128-1132. [Free Full Text]
Saqqur M, Alexandrov AV, Hill MD, et al. Transcranial Doppler IMS criteria for rescue intra-arterial thrombolysis: multicenter experience from the Interventional Management Study. Stroke 2003;34:267-267. abstract.
Moehring MA, Spencer MP. Power M-mode Doppler (PMD) for observing cerebral blood flow and tracking emboli. Ultrasound Med Biol 2002;28:49-57. [CrossRef][ISI][Medline]
Alexandrov AV, Wojner AW, Grotta JC. CLOTBUST: design of a randomized trial of ultrasound-enhanced thrombolysis for acute ischemic stroke. J Neuroimaging 2004;14:108-112. [CrossRef][ISI][Medline]
The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings. N Engl J Med 1985;312:932-936. [Medline]
Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002;59:862-867. [Free Full Text]
Grolimund P. Transmission of ultrasound through the temporal bone. In: Aaslid R, ed. Transcranial Doppler sonography. Wien, Germany: Springer-Verlag, 1986:10-21.
Eggers J, Koch B, Meyer K, Konig I, Seidel G. Effect of ultrasound on thrombolysis of middle cerebral artery occlusion. Ann Neurol 2003;53:797-800. [CrossRef][Medline]
Cintas P, Le Traon AP, Larrue V. High rate of recanalization of middle cerebral artery occlusion during 2-MHz transcranial color-coded Doppler continuous monitoring without thrombolytic drug. Stroke 2002;33:626-628. [Free Full Text]
Suchkova VN, Baggs RB, Sahni SK, Francis CW. Ultrasound improves tissue perfusion in ischemic tissue through a nitric oxide dependent mechanism. Thromb Haemost 2002;88:865-870. [ISI][Medline]
Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA 2000;283:1145-1150. [Free Full Text]
Caplan LR, Mohr JP, Kistler JP, Koroshetz W. Should thrombolytic therapy be the first-line treatment for acute ischemic stroke? Thrombolysis -- not a panacea for ischemic stroke. N Engl J Med 1997;337:1309-1310. [Free Full Text]
del Zoppo GJ, Poeck K, Pessin MS, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992;32:78-86. [CrossRef][ISI][Medline]
Appendix
The CLOTBUST Investigators were as follows (numbers of patientsenrolled are given in parentheses): Memorial Hermann Hospital(62) and St. Luke's Episcopal Hospital (8), Houston: F. Al-Senani,S. Burgin, S. Calleja, M. Campbell, C-I. Chen, O. Chernyshev,J. Choi, A. El-Mitwalli, R. Felberg, S. Ford, Z. Garami, W.Irr, J. Grotta, C. Hall, Y. Iguchi, J. Ireland, L. Labiche,M. Malkoff, L. Morgenstern, E. Noser, N. Okon, P. Piriyawat,D. Robinson, H. Shaltoni, S. Shaw, K. Uchino, F. Yatsu; Valld'Hebron Hospital, Barcelona (51): J. Alvarez-Sabín,J.F. Arenillas, R. Huertas, C. Molina, J. Montaner, M. Ribó,M. Rubiera, E. Santamarina; University of Alberta Hospital,Edmonton, Alta., Canada (3): M. Saqqur, N. Akhtar, F. O'Rourke,S. Hussain, A. Shuaib; Calgary Foothills Hospital, Calgary,Alta., Canada (2): E. Abdalla, A. Demchuk, K. Fischer, M.D.Hill, J. Kennedy, J. Roy, K.J. Ryckborst, M. Schebel.
Schellinger, P. D., Kohrmann, M.
(2008). MRA/DWI Mismatch: A Novel Concept or Something One Could Get Easier and Cheaper?. Stroke
39: 2423-2424
[Full Text]
Olivot, J.-M., Mlynash, M., Thijs, V. N., Kemp, S., Lansberg, M. G., Wechsler, L., Schlaug, G., Bammer, R., Marks, M. P., Albers, G. W.
(2008). Relationships Between Infarct Growth, Clinical Outcome, and Early Recanalization in Diffusion and Perfusion Imaging for Understanding Stroke Evolution (DEFUSE). Stroke
39: 2257-2263
[Abstract][Full Text]
Albers, G. W., Amarenco, P., Easton, J. D., Sacco, R. L., Teal, P.
(2008). Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
133: 630S-669S
[Abstract][Full Text]
Eggers, J., Konig, I. R., Koch, B., Handler, G., Seidel, G.
(2008). Sonothrombolysis With Transcranial Color-Coded Sonography and Recombinant Tissue-Type Plasminogen Activator in Acute Middle Cerebral Artery Main Stem Occlusion: Results From a Randomized Study. Stroke
39: 1470-1475
[Abstract][Full Text]
Tsivgoulis, G., Alexandrov, A.
(2008). Ultrasound-Enhanced Thrombolysis: From Bedside to Bench. Stroke
39: 1404-1405
[Full Text]
Sharma, V. K., Tsivgoulis, G., Lao, A. Y., Malkoff, M. D., Alexandrov, A. W., Alexandrov, A. V.
(2008). Quantification of Microspheres Appearance in Brain Vessels: Implications for Residual Flow Velocity Measurements, Dose Calculations, and Potential Drug Delivery. Stroke
39: 1476-1481
[Abstract][Full Text]
Alexandrov, A. V., Mikulik, R., Ribo, M., Sharma, V. K., Lao, A. Y., Tsivgoulis, G., Sugg, R. M., Barreto, A., Sierzenski, P., Malkoff, M. D., Grotta, J. C.
(2008). A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke. Stroke
39: 1464-1469
[Abstract][Full Text]
Nichols, C., Khatri, P., Tomsick, T., Broderick, J.
(2008). Advantages of a Combined Approach to Recanalization Therapy. Stroke
39: e71-e71
[Full Text]
Saguchi, T., Onoue, H., Urashima, M., Ishibashi, T., Abe, T., Furuhata, H.
(2008). Effective and Safe Conditions of Low-Frequency Transcranial Ultrasonic Thrombolysis for Acute Ischemic Stroke: Neurologic and Histologic Evaluation in a Rat Middle Cerebral Artery Stroke Model. Stroke
39: 1007-1011
[Abstract][Full Text]
Pagola, J., Ribo, M., Alvarez-Sabin, J., Lange, M., Rubiera, M., Molina, C. A.
(2007). Timing of Recanalization After Microbubble-Enhanced Intravenous Thrombolysis in Basilar Artery Occlusion. Stroke
38: 2931-2934
[Abstract][Full Text]
Goldstein, L. B.
(2007). Acute Ischemic Stroke Treatment in 2007. Circulation
116: 1504-1514
[Full Text]
Foerch, C., Wunderlich, M. T., Dvorak, F., Humpich, M., Kahles, T., Goertler, M., Alvarez-Sabin, J., Wallesch, C. W., Molina, C. A., Steinmetz, H., Sitzer, M., Montaner, J.
(2007). Elevated Serum S100B Levels Indicate a Higher Risk of Hemorrhagic Transformation After Thrombolytic Therapy in Acute Stroke. Stroke
38: 2491-2495
[Abstract][Full Text]
van der Worp, H. B., van Gijn, J.
(2007). Acute Ischemic Stroke. NEJM
357: 572-579
[Full Text]
Kollmar, R., Schwab, S.
(2007). Ischaemic stroke: acute management, intensive care, and future perspectives. Br J Anaesth
99: 95-101
[Abstract][Full Text]
The IMS II Trial Investigators,
(2007). The Interventional Management of Stroke (IMS) II Study. Stroke
38: 2127-2135
[Abstract][Full Text]
Adams, H. P. Jr, del Zoppo, G., Alberts, M. J., Bhatt, D. L., Brass, L., Furlan, A., Grubb, R. L., Higashida, R. T., Jauch, E. C., Kidwell, C., Lyden, P. D., Morgenstern, L. B., Qureshi, A. I., Rosenwasser, R. H., Scott, P. A., Wijdicks, E. F.M.
(2007). Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.. Circulation
115: e478-e534
[Abstract][Full Text]
Mikulik, R., Ribo, M., Hill, M. D., Grotta, J. C., Malkoff, M., Molina, C., Rubiera, M., Delgado-Mederos, R., Alvarez-Sabin, J., Alexandrov, A. V., for the CLOTBUST Investigators,
(2007). Accuracy of Serial National Institutes of Health Stroke Scale Scores to Identify Artery Status in Acute Ischemic Stroke. Circulation
115: 2660-2665
[Abstract][Full Text]
Alonso, A., Della Martina, A., Stroick, M., Fatar, M., Griebe, M., Pochon, S., Schneider, M., Hennerici, M., Allemann, E., Meairs, S.
(2007). Molecular Imaging of Human Thrombus With Novel Abciximab Immunobubbles and Ultrasound. Stroke
38: 1508-1514
[Abstract][Full Text]
Adams, H. P. Jr, del Zoppo, G., Alberts, M. J., Bhatt, D. L., Brass, L., Furlan, A., Grubb, R. L., Higashida, R. T., Jauch, E. C., Kidwell, C., Lyden, P. D., Morgenstern, L. B., Qureshi, A. I., Rosenwasser, R. H., Scott, P. A., Wijdicks, E. F.M.
(2007). Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke
38: 1655-1711
[Abstract][Full Text]
Tsivgoulis, G., Sharma, V. K., Lao, A. Y., Malkoff, M. D., Alexandrov, A. V.
(2007). Validation of Transcranial Doppler With Computed Tomography Angiography in Acute Cerebral Ischemia. Stroke
38: 1245-1249
[Abstract][Full Text]
Tsivgoulis, G., Saqqur, M., Sharma, V. K., Lao, A. Y., Hill, M. D., Alexandrov, A. V., for the CLOTBUST Investigators,
(2007). Association of Pretreatment Blood Pressure With Tissue Plasminogen Activator-Induced Arterial Recanalization in Acute Ischemic Stroke. Stroke
38: 961-966
[Abstract][Full Text]
Rha, J.-H., Saver, J. L.
(2007). The Impact of Recanalization on Ischemic Stroke Outcome: A Meta-Analysis. Stroke
38: 967-973
[Abstract][Full Text]
Wilhelm-Schwenkmezger, T., Pittermann, P., Zajonz, K., Kempski, O., Dieterich, M., Nedelmann, M.
(2007). Therapeutic Application of 20-kHz Transcranial Ultrasound in an Embolic Middle Cerebral Artery Occlusion Model in Rats: Safety Concerns. Stroke
38: 1031-1035
[Abstract][Full Text]
Reinhard, M., Els, T., Hetzel, A.
(2007). Response to Letter by Gerriets et al. Stroke
38: 252-252
[Full Text]
Khatri, P., Wechsler, L. R., Broderick, J. P.
(2007). Intracranial Hemorrhage Associated With Revascularization Therapies. Stroke
38: 431-440
[Abstract][Full Text]
Zangerle, A., Kiechl, S., Spiegel, M., Furtner, M., Knoflach, M., Werner, P., Mair, A., Wille, G., Schmidauer, C., Gautsch, K., Gotwald, T., Felber, S., Poewe, W., Willeit, J.
(2007). Recanalization after thrombolysis in stroke patients: Predictors and prognostic implications. Neurology
68: 39-44
[Abstract][Full Text]
Jovin, T.G., Gupta, R., Horowitz, M.B., Grahovac, S.Z., Jungreis, C.A., Wechsler, L., Gebel, J.M., Yonas, H.
(2007). Pretreatment Ipsilateral Regional Cortical Blood Flow Influences Vessel Recanalization in Intra-Arterial Thrombolysis for MCA Occlusion. Am. J. Neuroradiol.
28: 164-167
[Abstract][Full Text]
Shaltoni, H. M., Albright, K. C., Gonzales, N. R., Weir, R. U., Khaja, A. M., Sugg, R. M., Campbell, M. S. III, Cacayorin, E. D., Grotta, J. C., Noser, E. A.
(2007). Is Intra-Arterial Thrombolysis Safe After Full-Dose Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke?. Stroke
38: 80-84
[Abstract][Full Text]
Saqqur, M., Molina, C. A., Salam, A., Siddiqui, M., Ribo, M., Uchino, K., Calleja, S., Garami, Z., Khan, K., Akhtar, N., O'Rourke, F., Shuaib, A., Demchuk, A. M., Alexandrov, A. V., for the CLOTBUST Investigators,
(2007). Clinical Deterioration After Intravenous Recombinant Tissue Plasminogen Activator Treatment: A Multicenter Transcranial Doppler Study. Stroke
38: 69-74
[Abstract][Full Text]
Lee, K.-Y., Han, S. W., Kim, S. H., Nam, H. S., Ahn, S. W., Kim, D. J., Seo, S. H., Kim, D. I., Heo, J. H.
(2007). Early Recanalization After Intravenous Administration of Recombinant Tissue Plasminogen Activator as Assessed by Pre- and Post-Thrombolytic Angiography in Acute Ischemic Stroke Patients. Stroke
38: 192-193
[Abstract][Full Text]
Buchan, A. M
(2006). Acute stroke treatment: the end of the first decade. PN
6: 338-340
[Full Text]
Gonzalez-Conejero, R., Fernandez-Cadenas, I., Iniesta, J. A., Marti-Fabregas, J., Obach, V., Alvarez-Sabin, J., Vicente, V., Corral, J., Montaner, J., for the Proyecto Ictus Research Group,
(2006). Role of Fibrinogen Levels and Factor XIII V34L Polymorphism in Thrombolytic Therapy in Stroke Patients. Stroke
37: 2288-2293
[Abstract][Full Text]
Martini, S. R., Hill, M. D., Alexandrov, A. V., Molina, C. A., Kent, T. A.
(2006). Outcome in hyperglycemic stroke with ultrasound-augmented thrombolytic therapy.. Neurology
67: 700-702
[Abstract][Full Text]
Sugg, R. M., Pary, J. K., Uchino, K., Baraniuk, S., Shaltoni, H. M., Gonzales, N. R., Mikulik, R., Garami, Z., Shaw, S. G., Matherne, D. E., Moye, L. A., Alexandrov, A. V., Grotta, J. C.
(2006). Argatroban tPA Stroke Study: Study Design and Results in the First Treated Cohort.. Arch Neurol
63: 1057-1062
[Abstract][Full Text]
Fatar, M., Stroick, M., Griebe, M., Alonso, A., Hennerici, M. G., Daffertshofer, M.
(2006). Brain Temperature During 340-kHz Pulsed Ultrasound Insonation: A Safety Study for Sonothrombolysis. Stroke
37: 1883-1887
[Abstract][Full Text]
Sekoranja, L., Loulidi, J., Yilmaz, H., Lovblad, K., Temperli, P., Comelli, M., Sztajzel, R. F.
(2006). Intravenous Versus Combined (Intravenous and Intra-Arterial) Thrombolysis in Acute Ischemic Stroke: A Transcranial Color-Coded Duplex Sonography-Guided Pilot Study. Stroke
37: 1805-1809
[Abstract][Full Text]
Reinhard, M., Hetzel, A., Kruger, S., Kretzer, S., Talazko, J., Ziyeh, S., Weber, J., Els, T.
(2006). Blood-Brain Barrier Disruption By Low-Frequency Ultrasound. Stroke
37: 1546-1548
[Abstract][Full Text]
Schneider, F., Gerriets, T., Walberer, M., Mueller, C., Rolke, R., Eicke, B. M., Bohl, J., Kempski, O., Kaps, M., Bachmann, G., Dieterich, M., Nedelmann, M.
(2006). Brain Edema and Intracerebral Necrosis Caused by Transcranial Low-Frequency 20-kHz Ultrasound: A Safety Study in Rats. Stroke
37: 1301-1306
[Abstract][Full Text]
Sugg, R.M., Noser, E.A., Shaltoni, H.M., Gonzales, N.R., Campbell, M.S., Weir, R., Cacayorin, E.D., Grotta, J.C.
(2006). Intra-arterial reteplase compared to urokinase for thrombolytic recanalization in acute ischemic stroke.. Am. J. Neuroradiol.
27: 769-773
[Abstract][Full Text]
Frenkel, V., Oberoi, J., Stone, M. J., Park, M., Deng, C., Wood, B. J., Neeman, Z., Horne, M. III, Li, K. C. P.
(2006). Pulsed High-Intensity Focused Ultrasound Enhances Thrombolysis in an in Vitro Model. Radiology
239: 86-93
[Abstract][Full Text]
Ribo, M., Alvarez-Sabin, J., Montaner, J., Romero, F., Delgado, P., Rubiera, M., Delgado-Mederos, R., Molina, C. A.
(2006). Temporal Profile of Recanalization After Intravenous Tissue Plasminogen Activator: Selecting Patients for Rescue Reperfusion Techniques. Stroke
37: 1000-1004
[Abstract][Full Text]
Meschia, J. F., Kissela, B. M., Brott, T. G., Brown, R. D. Jr, Worrall, B. B., Beck, J., Skarp, A. N.
(2006). The Siblings With Ischemic Stroke Study (SWISS): A Progress Report.. Clin Med Res
4: 12-21
[Abstract][Full Text]
Molina, C. A., Ribo, M., Rubiera, M., Montaner, J., Santamarina, E., Delgado-Mederos, R., Arenillas, J. F., Huertas, R., Purroy, F., Delgado, P., Alvarez-Sabin, J.
(2006). Microbubble Administration Accelerates Clot Lysis During Continuous 2-MHz Ultrasound Monitoring in Stroke Patients Treated With Intravenous Tissue Plasminogen Activator. Stroke
37: 425-429
[Abstract][Full Text]
Alexandrov, A. V., Bornstein, N. M.
(2006). Advances in Neurosonology 2005. Stroke
37: 299-300
[Full Text]
Krejza, J., Weigele, J. B., Alokaili, R., Arkuszewski, M., Hurst, R. W., Gunter, S., Eggers, J.
(2006). Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology
66: 154-155
[Full Text]
Mikulik, R., Alexandrov, A. V., Ribo, M., Garami, Z., Porche, N. A., Fulep, E., Grotta, J. C., Wojner-Alexandrov, A. W., Choi, J. Y.
(2006). Telemedicine-Guided Carotid and Transcranial Ultrasound: A Pilot Feasibility Study. Stroke
37: 229-230
[Abstract][Full Text]
Lansberg, M. G., Fields, J. D., Albers, G. W., Jayaraman, M. V., Do, H. M., Marks, M. P.
(2005). Mechanical Thrombectomy Following Intravenous Thrombolysis in the Treatment of Acute Stroke. Arch Neurol
62: 1763-1765
[Abstract][Full Text]
Molina, C. A., Saver, J. L.
(2005). Extending Reperfusion Therapy for Acute Ischemic Stroke: Emerging Pharmacological, Mechanical, and Imaging Strategies. Stroke
36: 2311-2320
[Abstract][Full Text]
Smith, W. S., Sung, G., Starkman, S., Saver, J. L., Kidwell, C. S., Gobin, Y.P., Lutsep, H. L., Nesbit, G. M., Grobelny, T., Rymer, M. M., Silverman, I. E., Higashida, R. T., Budzik, R. F., Marks, M. P., for the MERCI Trial Investigators,
(2005). Safety and Efficacy of Mechanical Embolectomy in Acute Ischemic Stroke: Results of the MERCI Trial. Stroke
36: 1432-1438
[Abstract][Full Text]
Daffertshofer, M., Gass, A., Ringleb, P., Sitzer, M., Sliwka, U., Els, T., Sedlaczek, O., Koroshetz, W. J., Hennerici, M. G.
(2005). Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia: Increased Risk of Hemorrhage With Combined Ultrasound and Tissue Plasminogen Activator: Results of a Phase II Clinical Trial. Stroke
36: 1441-1446
[Abstract][Full Text]
Meairs, S., Dempfle, C.-E., Pfaffenberger, S., Speidl, W. S., Wojta, J., Gottsauner-Wolf, M.
(2005). In Vitro Models for Assessing Transcranial Ultrasound-Enhanced Thrombolysis * Response:. Stroke
36: 929-931
[Full Text]
Ogata, T., Kitazono, T., Kuroda, J., Kamei, K., Kamouchi, M., Ooboshi, H., Ibayashi, S., Iida, M.
(2005). A Case of Recanalized Cardioembolic Stroke: Possible Effect of Transcranial Color-Coded Real-time Sonography on Thrombolytic Therapy. J Ultrasound Med
24: 561-565
[Full Text]
Kim, Y. S., Garami, Z., Mikulik, R., Molina, C. A., Alexandrov, A. V., for the CLOTBUST Collaborators,
(2005). Early Recanalization Rates and Clinical Outcomes in Patients With Tandem Internal Carotid Artery/Middle Cerebral Artery Occlusion and Isolated Middle Cerebral Artery Occlusion. Stroke
36: 869-871
[Abstract][Full Text]
Francis, C.
(2005). March 22 Highlight and Commentary: Therapeutic effects of ultrasound. Neurology
64: 935-935
[Full Text]
90 percent of the questions answered correctly) a validated multiple-choice examination on the interpretation of TIBI wave forms. In a prospective, multicenter validation study, our criteria for the detection of occlusions of the middle cerebral artery by transcranial Doppler ultrasonography had a rate of accuracy of greater than 90 percent, as compared with the results of invasive angiography.22 We used an insonation depth of 45 mm or more with the transcranial Doppler equipment for the identification of presumed proximal (i.e., M1) occlusions of the middle cerebral artery and depths of 30 to 45 mm for presumed distal (i.e., M2) occlusions. Eligible patients had abnormal flow through the middle cerebral artery, with a grade of 0, 1, 2, or 3 on the TIBI scale (a grade of 5 indicates complete recanalization), before the administration of a t-PA bolus. 
=0.05) and two-sided tests were used in all analyses. 
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