Sestre Milosrdnice University hospital and Institute of Clinical Medical Research
Abstract
Spontaneous arterial recanalization occurs at a rate of 6% per hour, and it can be doubled with intravenous tissue plasminogen activator (TPA) therapy since early dramatic clinical improvement, a substitute for early thrombus break-up, occurs in TPA treated patients. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA+TCD compared to 8% of those that received TPA alone (p=0.02). Complete clearance of a thrombus and dramatic recovery of brain function during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the CLOTBUST target group resulted in a trend of 13% more patients achieving favorable outcome at 3 months, thus providing the rationale for a pivotal trial. The ability of TPA to break up thrombi can be further enhanced with harmless diagnostic ultrasound contrast agents. Current ongoing clinical trials include phase II studies of 2 MHz TCD with ultrasound contrast agents, or microbubbles: TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C3F8 ImaRx). Intra-arterial ultrasound-enhanced TPA delivery is tested in the Interventional Management of Stroke (IMS) clinical trial using 1.7-2.1 MHz pulsed wave ultrasound catheter (EKOS). Dose escalation studies of microbubbles, ultrasound exposure and the development of an operator independent ultrasound device are currently underway.Spontana arterijska rekanalizacija odvija se po stopi od 6% na sat, što se može udvostručiti pomoću terapije intravenskim aktivatorom tkivnog plazminogena (TPA), jer u bolesnika liječenih pomoću TPA dolazi do ranog dramatičnog kliničkog poboljšanja kao nadomjestak za rano razbijanje tromba. Aktivnost TPA može se pojačati ultrazvukom uključujući transkranijski Doppler (TCD) od 2 MHz. TCD identificira signale ostatnog krvnog protoka oko trombusa te kroz stvaranje valova mehaničkog tlaka izlaže veću površinu tromba cirkulirajućem TPA. U pokusu CLOTBUST je značajan klinički oporavak od moždanog udara uz potpunu rekanalizaciju unutar 2 sata od davanja bolusa TPA nastupio u 25% bolesnika liječenih pomoću TPA+TCD, u usporedbi s 8% bolesnika koji su primili samo TPA (p=0,02). Potpuno uklanjanje tromba i značajan oporavak moždane funkcije tijekom liječenja izvedivi su ciljevi ultrazvukom pojačane trombolize koji mogu dovesti do održivog oporavka. Kao rezultat ranog stimuliranja moždane perfuzije, zabilježenog u ciljnoj skupini studije CLOTBUST, 13% više bolesnika postiglo je povoljan ishod nakon 3 mjeseca, pruživši time razlog za ključni pokus. Sposobnost TPA da razbije trombe može se dodatno pojačati neškodljivim dijagnostičkim kontrastnim sredstvima za ultrazvuk. Upravo su u tijeku kliničke studije 2. faze s kontrastnim sredstvima za ultrazvuk od 2 MHz ili mikrokuglicama TCD+TPA+Levovist; TCD+TPA+MRX nano-platforma (C3F8 ImaRx). Intraarterijsko davanje TPA pojačano ultrazvukom ispituje se u kliničkom pokusu Interventional Management of Stroke (IMS) uz primjenu ultrazvučnog katetera pulsnih valova od 1,7-2,1 MHz (EKOS). U tijeku su studije pojačavanja mikrokuglica, izlaganja ultrazvuku, kao i razvoj ultrazvučnog uređaja neovisnog o operatoru
