Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH

Abstract

The safety and efficacy of the thrombolytic agent tissue-type plasminogen activator (tPA) in the elimination of subarachnoid clot and prevention of chronic vasospasm were evaluated in a blind randomized placebo-controlled trial. Twenty-four monkeys were randomly assigned to one of two groups of 12. Each group underwent baseline cerebral angiography and coagulation analysis followed by right-sided craniectomy and experimental subarachnoid hemorrhage (SAH). An Ommaya reservoir was inserted with its catheter placed into the subarachnoid space. Twenty-four hours later one group (the tPA group) received 0.5 mg of tPA in 0.5 ml of buffer injected into the reservoir every 8 hours for three doses, while the second group (the placebo group) received the same volume of normal saline. On Day 7, angiography was repeated and the animals were sacrificed. One animal from the placebo group developed a delayed ischemic neurological deficit on Day 5 after SAH. Moderate to severe vasospasm (greater than 30% reduction in vessel caliber) was present on Day 7 in the internal carotid and middle cerebral arteries of the animals in the placebo group (p less than 0.01), while in the tPA group only mild narrowing of the anterior cerebral artery was seen. No significant change in coagulation status occurred in either group. All animals in the placebo group had a large amount of subarachnoid clot remaining at the time of sacrifice, but 11 of the 12 animals in the tPA group were completely free of clot. The results of electron microscopic studies of the cerebral arteries correlated with angiography, and there was no histological evidence of brain inflammation associated with the intrathecal use of tPA.

Pharmacologic Reduction of Angiographic Vasospasm in Experimental Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis

“…Investigators used monkeys (Macaca species), dogs (mongrel or beagles), rabbits (Japanese or New Zealand species), rats (Sprague Dawley or Wistar species) and mice ( Espinosa et al (1984); Findlay et al (1988Findlay et al ( , 1989Findlay et al ( , 1990; Hariton et al (1993); Hino et al (1995); Kanamaru et al (1990Kanamaru et al ( , 1991; Kim et al (1996); Lewis et al (1988); Macdonald et al (2004); Nosko et al (1985); Steinke et al (1989); Suzuki et al (1998Suzuki et al ( , 1999 Wanebo et al (1997Wanebo et al ( , 1998; Zuccarello et al (1989Zuccarello et al ( , 1996Zuccarello et al ( , 1998 Method of induction of SAH Clot placement 17 (23) Espinosa et al (1984); Findlay et al (1988Findlay et al ( , 1989Findlay et al ( , 1990; Hariton et al (1993); Hino et al (1995); Kanamaru et al (1990Kanamaru et al ( , 1991Kanamaru et al ( , 2000; Kim et al (1996); Lewis et al ( Kanamaru et al (1990Kanamaru et al ( , 1991; Kawada et al (1999); Kawashima et al (2000); Kim et al (1996Kim et al ( , 2000; Kita et al (1998); Kwan et al (1997Kwan et al ( , 2001Kwan et al ( , 2006 Wanebo et al (1997<...>…”

“…Experimental vasospasm models T Zoerle et al Zimmermann et al (1996); Zuccarello et al (1989Zuccarello et al ( , 1996Zuccarello et al ( , 1998 Chung and Lee (1993);Findlay et al (1988Findlay et al ( , 1989Findlay et al ( , 1990 ; Kanamaru et al (1990Kanamaru et al ( , 1991; Kawada et al (1999); Kawashima et al (2000); Kim et al (1996Kim et al ( , 2000; Kita et al (1998); Kwan et al (1997Kwan et al ( , 2001Kwan et al ( , 2006; Experimental vasospasm models T Zoerle et al Zuccarello et al (1998Zuccarello et al ( , 1989Zuccarello et al ( , 1996 Blinding of Zimmermann et al (1996); Zuccarello et al (1998Zuccarello et al ( , 1989Zuccarello et al ( , 1996 Experimental vasospasm models T Zoerle et al into the cisterna magna (rabbit and rat studies) and craniotomy followed by clot placement around the cerebral arteries (all monkey and one dog studies). In the other studies, endovascular perforation (rat and mouse studies), prechiasmatic cistern blood injection (one rat study) (Wang et al, 2010) or modified versions of cisterna magna injection (one rat (Tang et al, 2008) and one dog study) (Zabramski et al, 1986) were used.…”

Prevention of spinal epidural fibrosis by recombinant tissue plasminogen activator in rats

“…3 Thrombolytic drugs have been widely used for thromboembolic disease and preventing vasospasm caused by subarachnoid haemorrhage. 7,8,14 It is stated that fibrinolytic treatment in subarachnoid haemorrhage in man appears effective, and may be associated with acceptable risks. 7,8 Although there was a risk of epidural bleeding with perisurgical epidural use of rt-PA, only one episode of epidural bleeding occurred in rt-PA The rats utilised in this study demonstrate reliable formation of postlaminectomy peridural fibrosis at 6 weeks following laminectomy.…”

“…7,8,14 It is stated that fibrinolytic treatment in subarachnoid haemorrhage in man appears effective, and may be associated with acceptable risks. 7,8 Although there was a risk of epidural bleeding with perisurgical epidural use of rt-PA, only one episode of epidural bleeding occurred in rt-PA The rats utilised in this study demonstrate reliable formation of postlaminectomy peridural fibrosis at 6 weeks following laminectomy. The application of rt-PA demonstrated a clear reduction in the degree of epidural fibrosis when compared with control group in total score (P ¼ 0.001), in intermuscular scar score (P ¼ 0.04), in middle scar score (P ¼ 0.001), in deep scar score (P ¼ 0.001), in dural adhesion score (P ¼ 0.01) and finally in arachnoiditis (P ¼ 0.01).…”

“…The dose of rt-PA chosen for this study was 0.25 mg and was based on the published data in the literature. 7,8 In the second group, all procedures were done in a similar fashion but without the insertion of any medication. The rats were followed-up in a temperaturecontrolled room for 6 weeks.…”