title: Potentiating intra-arterial sonothrombolysis for acute ischemic stroke by the addition of the ultrasound contrast agents (Optison™ & SonoVue(®)).
abstract: Transcranial ultrasound in combination with intravenously administered ultrasound contrast agents (UCA) in the presence or absence of recombinant tissue plasminogen activator (rt-PA) has been widely evaluated as a new modality for treatment of ischemic stroke. Despite the successful demonstration of accelerated clot lysis there are inherent limitations associated with this modality such as inconsistency in temporal window thickness and/or potential serious cardiopulmonary reactions to intravenous administration of UCA that prevent broad application to ischemic stroke populations. As a complementary modality, we evaluated potential lysis enhancement by intra-arterial ultrasound with concurrent intra-clot delivery of UCA and rt-PA. To this end, clots were formed with average pore diameter similar to clinically retracted clots by adjusting the thrombin concentration. Physical characteristic and retention of UCA after delivery through the catheter as a function of clinically relevant flow rates of 6, 12, 18 ml/h were determined using a microscopic method. The ability of the UCA employed in this study, Optison and SonoVue, to penetrate into the clot was verified using ultrasound B-mode imaging. Clot lysis as a function of rt-PA concentration, 0.009 through 0.5 mg/ml, in the presence and absence of UCA diluted to 1:10, 1:100, and 1:200 v/v at two Peak rarefaction acoustic pressures of 1.3 and 2.1 MPa were evaluated using a weighing method. The study results suggest the addition of only 0.02 ml of 1:100 diluted UCA to rt-PA of 0.009, 0.05, 0.3, and 0.5 mg/ml can enhance the lysis rate by 3.9, 2.6, 1.9 and 1.8 fold in the presence of peak rarefaction acoustic pressure of 1.3 MPa and by 5.1, 3.4, 2.6, 3.1 in the presence of peak rarefaction acoustic pressure of 2.1 MPa, respectively. In addition, Optison and SonoVue demonstrated comparable effectiveness in enhancing the clot lysis rate. Addition of UCA to intra-arterial sonothrombolysis could be considered as a viable treatment option for ischemic stroke patients.
authors.affiliation: Research and Development Department, EKOS Corporation, 11911 North Creek Parkway South, Bothell, WA 98011, USA. asoltani@ekoscorp.com
authors.forename: Azita
authors.initials: A
authors.lastname: Soltani
authors.forename: Ruchi
authors.initials: R
authors.lastname: Singhal
authors.forename: Melissa
authors.initials: M
authors.lastname: Obtera
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Roy
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Clark
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Hansmann
mesh_terms: D000418:Albumins / Q000494:pharmacology*; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000628:therapy; D003287:Contrast Media / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005466:Fluorocarbons / Q000494:pharmacology*; D006801:Humans; D045423:Microbubbles; D008955:Models, Cardiovascular; D010743:Phospholipids / Q000494:pharmacology*; D020521:Stroke / Q000000981:diagnostic imaging / Q000628:therapy; D013459:Sulfur Hexafluoride / Q000494:pharmacology*; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D017585:Ultrasonography, Doppler, Transcranial / Q000295:instrumentation / Q000379:methods*
chemical_list: D000418:Albumins; D003287:Contrast Media; C099458:FS 069; D005343:Fibrinolytic Agents; D005466:Fluorocarbons; D010743:Phospholipids; C420843:contrast agent BR1; D010959:Tissue Plasminogen Activator; D013459:Sulfur Hexafluoride
references.citation: Phys Med Biol. 2008 Dec 7;53(23):6837-47
references.pmid: 19001697
references.citation: J Neuroimaging. 2004 Apr;14(2):113-7
references.pmid: 15095555
references.citation: Circulation. 2001 Jun 19;103(24):2897-902
references.pmid: 11413077
references.citation: Stroke. 2009 Aug;40(8):2945-8
references.pmid: 19478221
references.citation: Ultrasound Med Biol. 2002 Oct;28(10):1349-64
references.pmid: 12467862
references.citation: J Clin Invest. 1992 Nov;90(5):2063-8
references.pmid: 1430229
references.citation: J Acoust Soc Am. 1996 Apr;99(4 Pt 1):2403-8
references.pmid: 8730086
references.citation: Stroke. 2005 Nov;36(11):2400-3
references.pmid: 16224088
references.citation: J Thromb Thrombolysis. 2005 Aug;20(1):27-32
references.pmid: 16133892
references.citation: Stroke. 1998 Jan;29(1):4-11
references.pmid: 9445320
references.citation: Int J Stroke. 2008 Feb;3(1):66-72
references.pmid: 18705918
references.citation: AJNR Am J Neuroradiol. 2003 Mar;24(3):534-8
references.pmid: 12637311
references.citation: Ultrasonics. 2008 Apr;48(2):109-16
references.pmid: 18067940
references.citation: Invest Radiol. 1998 Dec;33(12):880-5
references.pmid: 9851822
references.citation: Ultrasound Med Biol. 2008 Oct;34(10):1573-7
references.pmid: 18450360
references.citation: Curr Neurol Neurosci Rep. 2009 Jan;9(1):46-54
references.pmid: 19080753
references.citation: Ultrasound Med Biol. 2006 Dec;32(12):1931-41
references.pmid: 17169705
references.citation: Vet Radiol Ultrasound. 1998 Jul-Aug;39(4):349-53
references.pmid: 9710140
references.citation: Ultrasound Med Biol. 2007 Jun;33(6):924-33
references.pmid: 17434661
references.citation: Int J Hyperthermia. 2007 Mar;23(2):105-20
references.pmid: 17578336
references.citation: J Am Soc Echocardiogr. 1994 Jul-Aug;7(4):347-54
references.pmid: 7917342
references.citation: Blood. 1993 May 15;81(10):2636-43
references.pmid: 8490172
references.citation: Stroke. 2007 Jul;38(7):2127-35
references.pmid: 17525387
references.citation: J Am Coll Cardiol. 1993 May;21(6):1507-11
references.pmid: 8473663
references.citation: JAMA. 1999 Dec 1;282(21):2019-26
references.pmid: 10591384
references.citation: Stroke. 2010 Feb;41(2):280-7
references.pmid: 20044531
references.citation: N Engl J Med. 1995 Dec 14;333(24):1581-7
references.pmid: 7477192
references.citation: Stroke. 2007 Mar;38(3):967-73
references.pmid: 17272772
references.citation: Ultrason Sonochem. 1998 Nov;5(3):113-8
references.pmid: 11270344
references.citation: Blood. 1998 Mar 15;91(6):2019-25
references.pmid: 9490686
references.citation: Stroke. 2007 May;38(5):1655-711
references.pmid: 17431204
references.citation: Thromb Res. 2000 Nov 15;100(4):333-40
references.pmid: 11113277
references.citation: Ultrasound Med Biol. 1996;22(7):939-48
references.pmid: 8923712
references.citation: Med Res Rev. 2002 Mar;22(2):204-23
references.pmid: 11857639
references.citation: Stroke. 2006 Feb;37(2):425-9
references.pmid: 16373632
references.citation: Ultrasound Med Biol. 2000 Sep;26(7):1153-60
references.pmid: 11053750
references.citation: Am J Physiol. 1987 Nov;253(5 Pt 2):H1069-73
references.pmid: 3688251