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Stroke. 2004;35:2722-2725
Published online before print September 16, 2004, doi: 10.1161/01.STR.0000143321.37482.b3
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(Stroke. 2004;35:2722.)
© 2004 American Heart Association, Inc.

Articles

Ultrasound Identification and Lysis of Clots

Andrei V. Alexandrov, MD

From the Department of Neurology and Radiology, Cerebrovascular Ultrasound and Center for Noninvasive Brain Perfusion Studies, Stroke Treatment Team, The University of Texas–Houston Medical School, Houston, Texas.

Correspondence to Dr Andrei V. Alexandrov, MSB 7.044 6431, Fannin St, University of Texas, Houston, TX 77030. E-mail avalexandrov{at}att.net


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowReferences
 
Poor recovery after systemic tissue plasminogen activator (tPA) therapy could result from the initial severity of ischemic insult and slow and incomplete thrombolysis. Persisting arterial occlusions can be identified at bedside using portable diagnostic ultrasound by detecting residual flow signals around the thrombus (thrombolysis in brain ischemia [TIBI] flow grades). A narrow pulsed ultrasound beam can be steadily aimed at the thrombus/residual flow interface, exposing more thrombus surface and structures to tPA, and tPA activity can be enhanced with 2 MHz transcranial Doppler (TCD). A randomized, multicenter, clinical trial called CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA) trial showed a 49% rate of complete recanalization or dramatic clinical recovery from stroke within 2 hours after tPA bolus when tPA infusion was continuously monitored with TCD, compared with 30% among patients who received tPA without ultrasound monitoring (P=0.03, number needed to treat, 5). Early complete recanalization was sustained at 2 hours by 38% of monitored patients compared with 12.7% controls. The CLOTBUST Trial showed a trend toward sustaining complete recovery at 3 months (41.5% versus 28%, modified Rankin Scale scores 0 to 1), subject for a pivotal phase III trial. Ultrasound is an inexpensive, noninvasive, real-time monitoring tool to identify nonresponders to systemic tPA and select patients with persisting occlusions for intraarterial interventions. Early brain perfusion augmentation, complete recanalization, and dramatic clinical recovery are feasible goals for ultrasound-enhanced thrombolysis.


Key Words: outcomes • stroke • thrombolysis • tissue plasminogen activator • ultrasonography, Doppler, transcranial


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowReferences
 
Intravenous tissue plasminogen activator (tPA) infusion is the fastest was to initiate thrombolytic therapy; however, poor recovery can expected in up to 50% of patients, likely as a result of the initial severity of ischemic insult and slow and incomplete thrombolysis.1,2 When given intravenously, tPA delivery to the thrombus is dependent on the residual flow to and around the arterial obstruction, and better residual flow signals are associated with higher recanalization rates in stroke patients treated with tPA.3

A 2-MHz pulsed-wave diagnostic ultrasound beam can serve several purposes. First, it can be used to identify the presence of obstructive intracranial thrombus in a vessel. Second, it can provide real-time bedside monitoring of thrombolysis. And finally, it can augment residual flow and speed up thrombolysis, allowing patients to recover from stroke more rapidly and completely.

Diagnosis of an Acute Arterial Occlusion
An acute arterial occlusion is different from chronic because it is often partial and incomplete, being a dynamic process of thrombus propagation, reocclusion, and infrequent spontaneous recanalization with or without pre-existing atheroma. A better term to describe such obstruction is a "lesion amenable to intervention."4 Ultrasound can rapidly identify patients with these lesions regardless of baseline stroke severity. With good temporal windows, an experienced operator can accomplish this in 2 minutes, and in patients with suboptimal windows it takes <15 minutes. Ultrasound testing can be performed at bedside simultaneously with neurological examination, vital signs monitoring, and drawing blood, causing no delay in tPA administration.2,3

The key ultrasound findings for the diagnosis of a lesion amenable for intervention include: (1) 1 of 4 abnormal thrombolysis in brain ischemia (TIBI) waveforms5 in the vessel supplying a territory affected by ischemia; and (2) evidence of flow diversion or collateralization6–10 to compensate for this lesion.

In the absence of flow diversion or collateralization, other findings can point to thrombus presence and location such as stenotic velocities, embolic signals, and flow pulsatility changes in vessels proximal and distal to suspected obstruction.11,12 With these criteria, a non–image-guided Doppler ultrasound can identify thrombus location with accuracy >90% for the middle cerebral artery (MCA) and internal carotid artery (ICA). Once this thrombus/residual flow interface is found, a narrow 3- to 10-mm pulsed-wave ultrasound beam can be steadily aimed at thrombus location (Figure 1) to monitor the effect of a thrombolytic drug.



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  		Figure 1. Abnormal thrombolysis in brain ischemia (TIBI) flow grades (upper left images), and acute middle cerebral artery occlusion location on magnetic resonance angiography (white arrows) with relative ultrasound transducer position on the skull (white insert, upper right image). Lower image illustrates residual flow around sausage-like middle cerebral artery thrombus during catheter angiography. Black arrows indicate transcranial Doppler focal zone where TIBI signals are obtained. Black dotted lines demonstrate projected path of a 2 MHz ultrasound beam generated by a single crystal transducer (black inserted object).

Monitoring Thrombolytic Therapy With Ultrasound
Delaying tPA therapy within 3 hours of symptom onset in favor of patient selection with imaging methods that are more time-consuming than a noncontrast CT is unjustified because tPA efficacy decreases with time13 and the first noticeable improvement of flow to the brain occurs at a median time of 17 minutes after tPA bolus.2 Median time to completion of recanalization is 35 minutes after bolus,2 and those patients who complete recanalization before the end of 1 hour of tPA infusion are 3.5x more likely to achieve favorable outcome at 3 months.14

An average rate of spontaneous complete recanalization of the MCA occlusion appears to be about 6% per hour during the first 6 hours after symptom onset.15–17 Systemic tPA increases complete recanalization rate to 12.7% per hour in the control group of the Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA (CLOTBUST) Trial (Figure 2). The likelihood of early recanalization of the M2 MCA occlusion with systemic tPA is 44%; M1 MCA, 22%; and ICA or TICA, <10%.18 Patients with persisting MCA or terminal ICA occlusion have only 10% chance to recover completely at 3 months,19 and we use this information to justify an experimental intraarterial procedure to lyse or remove thrombus even after full-dose intravenous tPA.



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  		Figure 2. Complete early middle cerebral artery recanalization on power-motion transcranial Doppler and serial NIHSS scores (upper row). A graph below shows sustained complete recanalization rates in the target patient group and controls in the CLOTBUST Trial at time intervals after tPA bolus.

Early arterial reocclusion affects up to 25% of tPA-treated patients, more commonly those with partial or incomplete initial recanalization.19,20 Arterial reocclusion accounts for two thirds of patients who experience deterioration following improvement with tPA therapy.19 Intracranial arterial reocclusion occurs at an average time of 65 minutes after bolus.20 After early reocclusion there is a 33% chance of favorable outcome at 3 months, compared to 50% in patients with stable early recanalization.19

Early complete recanalization is closely associated with dramatic clinical recovery,20,21 and the timing of brain reperfusion detected by transcranial Doppler (TCD) and subsequent clinical improvement with reversal of ischemic brain damage show an S-shaped correlation seen in a baboon model of ischemic stroke.22,23 However, one third of early complete recanalizations do not result in immediate clinical improvement. Despite this, one third of patients with silent recanalizations recover completely at 3 months.24

Ultrasound Enhanced Thrombolysis–CLOTBUST Trial
In the past 30 years, numerous scientists showed in experimental models that ultrasound facilitates the activity of fibrinolytic agents within minutes of its exposure to thrombus and blood containing drugs.25–32 The mechanisms of ultrasound-enhanced thrombolysis include improved drug transport, reversible alteration of fibrin structure, and increased tPA binding to fibrin25–34 for frequencies ranging from kHz to those used in diagnostic ultrasound.33,34 Although kHz frequencies penetrate better with less heating, a combination of tPA with an experimental kHz delivery system resulted in excessive risk of intracerebral hemorrhage (ICH) in stroke patients.35

We used diagnostic 2 MHz TCD to evaluate acute stroke patients and reported an unexpectedly high rate of complete recanalization and dramatic clinical recovery when tPA infusion was continuously monitored with TCD for diagnostic purposes.21 The analysis of phase I clinical data36 allowed us to predetermine a sample size of a phase II clinical trial that was powered to demonstrate 20% difference in the primary activity end-point of complete recanalization and dramatic clinical recovery within 2 hours after TPA bolus.37

The CLOTBUST Trial was a phase II, multicenter, randomized, clinical trial (Houston, Texas; Barcelona, Spain; Edmonton and Calgary, Canada). All patients with acute ischemic stroke were treated with 0.9 mg/kg intravenous tPA within 3 hours of symptom onset. All patients had MCA occlusions on pretreatment TCD and were randomized to continuous monitoring with TCD (target group) or placebo monitoring (control). Safety end-point was symptomatic ICH. Primary combined activity end-point was complete recanalization on TCD or dramatic clinical recovery to a total National Institutes of Health Stroke Scale (NIHSS) score ≤3, or improvement by ≥10 NIHSS points within 2 hours after TPA bolus. Secondary end-points included outcomes at 3 months by the modified Rankin Scale (mRS) score.

All 126 projected patients received tPA and were randomized 1:1 to continuous monitoring (median NIHSS 16) or control (median NIHSS 17). Age, occlusion location (M1-MCA or M2-MCA) on TCD, and time to tPA bolus were similar. Symptomatic ICH occurred in 3 target patients (4.8%, CI95 1.0 to 13.3) and 3 controls (4.8%, CI95 1.0 to 13.3). Complete recanalization or dramatic clinical recovery within 2 hours after tPA bolus (primary end-point) were observed in 31 (49%, target) versus 19 patients (30%, control), P=0.03, number needed to treat, 5. At 3 months, 22 (41.5%, target) and 14 patients (28%, control) achieved favorable outcomes (mRS 0 to 1).

In stroke patients treated with intravenous tPA, continuous TCD monitoring of intracranial occlusion safely augments tPA-induced arterial recanalization, producing a trend toward sustained improvement at 3 months, subject to a properly powered phase III trial. The phase II CLOTBUST Trial provides clinical evidence for existence of ultrasound-enhanced thrombolysis in humans that can amplify the existing therapy for ischemic stroke. Early brain perfusion augmentation, complete recanalization, and dramatic clinical recovery are feasible goals for ultrasound-enhanced thrombolysis.


*    Acknowledgments
 
CLOTBUST is an Investigator Sponsored Trial (A2207s; Genentech, Inc). Study sites and onsite principal investigators include Houston, Texas (James Grotta); Barcelona, Spain (Carlos Molina); and Edmonton (Maher Saqqur) and Calgary (Andrew Demchuk), Canada. A.V.A., Principal Investigator, is supported by the National Institutes of Health Career Development Award (1 K23 NS-02229–01).

Received June 9, 2004; accepted August 5, 2004.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *References
 

  1. The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.[Abstract/Free Full Text]
  2. Alexandrov AV, Burgin WS, Demchuk AM, El-Mitwalli A, Grotta JC. Speed of intracranial clot lysis with intravenous tPA therapy: sonographic classification and short-term improvement. Circulation. 2001; 103: 2897–2902.[Abstract/Free Full Text]
  3. Labiche LA, Malkoff M, Alexandrov AV. Residual flow signals predict complete recanalization in stroke patients treated with tPA. J Neuroimaging. 2003; 13: 28–33.[CrossRef][Medline] [Order article via Infotrieve]
  4. The IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: The Interventional Management of Stroke Study. Stroke. 2004; 35: 904–912.[Abstract/Free Full Text]
  5. Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD, Alexandrov AV. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery and mortality in intravenous TPA treated patients. Stroke. 2001; 32: 89–93.[Abstract/Free Full Text]
  6. Schneider PA, Rossman ME, Bernstein EF, Torem S, Ringelstein EB, Otis SM. Effect of internal carotid artery occlusion on intracranial hemodynamics. Transcranial Doppler evaluation and clinical correlation. Stroke. 1988; 19: 589–593.[Abstract/Free Full Text]
  7. Zanette EM, Fieschi C, Bozzao L, Roberti C, Toni D, Argentino C, Lenzi GL. Comparison of cerebral angiography and transcranial Doppler sonography in acute stroke. Stroke. 1989; 20: 899–903.[Abstract/Free Full Text]
  8. Brass LM, Duterte DL, Mohr JP. Anterior cerebral artery velocity changes in disease of the middle cerebral artery stem. Stroke. 1989; 20: 1737–1740.[Abstract/Free Full Text]
  9. Kaps M, Damian MS, Teschendorf U, Dorndorf W. Transcranial Doppler ultrasound findings in the middle cerebral artery occlusion. Stroke. 1990; 21: 532–537.[Abstract/Free Full Text]
  10. Ley-Pozo J, Ringelstein EB. Noninvasive detection of occlusive disease of the carotid siphon and middle cerebral artery. Ann Neurol. 1990; 28: 640–647.[CrossRef][Medline] [Order article via Infotrieve]
  11. Alexandrov AV, Demchuk AM, Felberg RA, Grotta JC, Krieger D. Intracranial clot dissolution is associated with embolic signals on transcranial Doppler. J Neuroimaging. 2000; 10: 27–32.[Medline] [Order article via Infotrieve]
  12. Demchuk AM, Christou I, Wein TH, Felberg RA, Malkoff M, Grotta JC, Alexandrov AV. Specific transcranial Doppler flow findings related to the presence and site of arterial occlusion with transcranial Doppler. Stroke. 2000; 31: 140–146.[Abstract/Free Full Text]
  13. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768–774.[CrossRef][Medline] [Order article via Infotrieve]
  14. Alexandrov AV, Labiche LA, Wojner AW. Ultra-early prediction of stroke outcome in patients treated with 0.9 mg/kg IV tPA. Stroke. 2002; 33: 342. Abstract.
  15. Alexandrov AV, Bladin CF, Norris JW. Intracranial blood flow velocities in acute ischemic stroke. Stroke. 1994; 25: 1378–1383.[Abstract]
  16. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. PROlyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282: 2003–2011.[Abstract/Free Full Text]
  17. Molina CA, Montaner J, Abilleira S, Ibarra B, Romero F, Arenillas JF, Alvarez-Sabin J. Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke. 2001; 32: 1079–1084.[Abstract/Free Full Text]
  18. Uchino K, Molina C, Saqqur M, Demchuk AM, Felberg RA, Calleja S, Wojner AW, Alexandrov AV. Likelihood of early arterial recanalization with intravenous tPA and its predictors: a multicenter transcranial Doppler study. Stroke. 2003; 34: 247. Abstract.
  19. Alexandrov AV, Grotta JC. Arterial re-occlusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology. 2002; 59: 862–867.[Abstract/Free Full Text]
  20. Molina CA, Ribo M, Rubiera M, Montaner J, Arenillas JF, Santamarina E, Alvarez-Sabin J. Predictors of early arterial reocclusion after tPA-induced recanalization. Stroke. 2004; 35: 250. Abstract.
  21. Alexandrov AV, Demchuk AM, Felberg RA, Christou I, Barber PA, Burgin WS, Malkoff M, Wojner AW, Grotta JC. 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.[Abstract/Free Full Text]
  22. Felberg RA, Okon NJ, El-Mitwalli A, Burgin WS, Grotta JC, Alexandrov AV. Early dramatic recovery during IV-tPA infusion: clinical pattern and outcome in acute MCA stroke. Stroke. 2002; 33: 1301–1307.[Abstract/Free Full Text]
  23. Christou I, Alexandrov AV, Burgin WS, Wojner AW, Felberg RA, Malkoff M, Grotta JC. Timing of recnalization after tPA therapy determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000; 31: 1812–1816.[Abstract/Free Full Text]
  24. Alexandrov AV, Hall CE, Labiche LA, Wojner AW, Grotta JC. Ischemic stunning of the brain: early recanalization without immediate clinical improvement in acute ischemic stroke. Stroke. 2004; 35: 449–452.[Abstract/Free Full Text]
  25. Trubestein R, Bernard HR, Etzel F, Sobbe A, Cremer A, Stumpff U. Thrombolysis by ultrasound. Clin Sci Mol Med. 1976; 51: 697–698.
  26. Tachibana K, Tachibana S. Ultrasonic vibration for boosting fibrinolytic effects of urokinase in vivo. Thromb Haemost. 1981; 46: 211. Abstract.
  27. 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.[Abstract/Free Full Text]
  28. Blinc A, Francis CW, Trudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood. 1993; 81: 2636–2643.[Abstract/Free Full Text]
  29. 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] [Order article via Infotrieve]
  30. 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][Medline] [Order article via Infotrieve]
  31. Suchkova V, Siddiqi FN, Carstensen EL, Dalecki D, Child S, Francis CW. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation. 1998; 98: 1030–1035.[Abstract/Free Full Text]
  32. Behrens S, Daffertshoffer M, Spiegel D, Hennerici M. Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull. Ultrasound Med Biol. 1999; 25: 269–273.[CrossRef][Medline] [Order article via Infotrieve]
  33. Spengos K, Behrens S, Daffertshofer M, Dempfle CE, Hennerici M. Acceleration of thrombolysis with ultrasound through the cranium in a flow model. Ultrasound Med Biol. 2000; 26: 889–895.[CrossRef][Medline] [Order article via Infotrieve]
  34. 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] [Order article via Infotrieve]
  35. Daffertshoffer M, Hennerici M. Ultrasound in the treatment of ischaemic stroke. Lancet Neurol. 2003; 2: 283–290.[CrossRef][Medline] [Order article via Infotrieve]
  36. Alexandrov AV, Demchuk AM, Burgin WS, Robinson DJ, Grotta JC. Ultrasound enhanced thrombolysis for acute ischemic stroke: phase I findings of the CLOTBUST trial. J Neuroimaging. 2004; 14: 113–117.[CrossRef][Medline] [Order article via Infotrieve]
  37. 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][Medline] [Order article via Infotrieve]




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