gms | German Medical Science

Objective: Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as a therapy for spontaneous intracerebral hemorrhage (ICH). Optimal dose and treatment schedule are still unknown. Our earlier studies showed a 50% increase of clot thrombolysis using low dose rtPA in combination with endosonography. The aim of the current study was to establish a reduced rtPA dose and exposure time in a in vitro clot model. Ultrasound energy, thermal and irrigation effects of .9% NaCl solution were investigated.

Method: In vitro blood clots were produced 25 ml and 50 ml of human blood by incubation 1.5 h at 37°C. Ventricular drainage (EVD) was placed into all clots, mimicking the intracranial situation. A dose-response relationship was evaluated in 6 groups each consisting of 50 ml blood clots (3 rtPA, 3 placebo, 1 control) with 6 different doses of rtPA (0.5-5 mg). Clots were weighed before and after treatment. Similar to this, 5 different doses of rtPA were applied in 25 ml clots (0.5-3 mg). Each rtPA treated clot was compared to a placebo (5 ml NaCl) treated clot and to an untreated control (only EVD). Additionally 25 ml clots were treated with rtPA by different time schedules. For ultrasound investigation we used a 3.52 l agar-agar gel mimicking brain tissue. Ultrasound was applied by a 10 F endosonography catheter in B-mode (10 mHz) and Doppler-mode (7 mHz). Temperature and ultrasound energy by acoustic peak rarefaction pressure were measured. For statistical analyses a three-parameter logistic model was used.

Results: In our dose response analysis of 25 and 50 ml clots an optimal dose of 1mg rtPA was found. Placebo treated and untreated clots showed no significant difference (p=0.12). The average relative clot lysis of 80% could be achieved after 15 min with 1 mg rtPA. In ultrasound measurements we determined an increase of temperature by 0.5°C within a radius of 3 cm. There was a logarithmic decrease of acoustic peak rarefaction pressure in a distance of 0-8 cm from the endosonography catheter from 36.8 to 2.48 kPa.

Conclusions: Dose-response relationship of rtPA showed a surprisingly low optimal dose of 1 mg rtPA independent of clot size. Our results showing a maximum lysis rate of 80% after 15 min correspond well with the known half-life of rtPA. Compared to literature, energy delivery is within the range of effective thrombolysis within a radius of 3cm. Based on our findings we suggest combined rtPA endosonography lysis for further in vivo experimental investigations.