Intracerebral Hemorrhage After Experimental Embolic Infarction

Background and Purpose-Transcranial near-infrared laser therapy (TLT) is currently under investigation in a pivotal clinical trial that excludes thrombolytic therapy. To determine if combining tissue plasminogen activator (tPA; Alteplase) and TLT is safe, this study assessed the safety profile of TLT administered alone and in combination with Alteplase. The purpose for this study is to determine if the combination of TLT and thrombolysis should be investigated further in a human clinical trial. Methods-We determined whether postembolization treatment with TLT in the absence or presence of tPA would affect measures of hemorrhage or survival after large clot embolism-induced strokes in New Zealand white rabbits. Results-TLT did not significantly alter hemorrhage incidence after embolization, but there was a trend for a modest reduction of hemorrhage volume (by 65%) in the TLT-treated group compared with controls. Intravenous administration of tPA, using an optimized dosing regimen, significantly increased hemorrhage incidence by 160%. The tPA-induced increase in hemorrhage incidence was not significantly affected by TLT, although there was a 30% decrease in hemorrhage incidence in combination-treated rabbits. There was no effect of TLT on hemorrhage volume measured in tPA-treated rabbits and no effect of any treatment on 24-hour survival rate. Conclusion-In the embolism model, TLT administration did not affect the tPA-induced increase in hemorrhage incidence.TLT may be administered safely either alone or in combination with tPA because neither treatment affected hemorrhage incidence or volume. Our results support the study of TLT in combination with Alteplase in patients with stroke.

Section: Discussionmentioning

confidence: 80%

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confidence: 99%

Safety Profile of Transcranial Near-Infrared Laser Therapy Administered in Combination With Thrombolytic Therapy to Embolized Rabbits

Lapchak

Han

Salgado

et al. 2008

“…Previous experimental work using animal models of stroke has similarly suggested that anticoagulant therapy promotes brain hemorrhage, 1819 although one more recent study reported no increase in brain hemorrhage in animals acutely treated with therapeutic or excessive doses of heparin. 20 In the only randomized clinical trial of anticoagulant therapy for acute cardioembolic stroke to date, the Cerebral Embolism Study Group 16 reported no significant hemorrhagic complications and a trend toward reduction of recurrent embolization in their treated patients. Unfortunately, that study was terminated before statistically significant evidence of benefit from early anticoagulant therapy could be established.…”

Section: Discussionmentioning

confidence: 99%

Acute anticoagulation following cardioembolic stroke.

Rothrock

Dittrich

McAllen

et al. 1989

Whether acute anticoagulation after cardioembolic stroke affords substantial protection against early recurrent emboli or an unacceptable risk of hemorrhage remains controversial. To assess this further, we evaluated 121 consecutive patients with acute cardioembolic stroke. Forty-nine were therapeutically anticoagulated within 96 hours of stroke onset, and 41 received no anticoagulants within the first 2 weeks after stroke. These two groups did not differ significantly with regard to age, sex, severity of acute neurologic deficit, or spectrum of underlying cardiac disease. The incidences of clinically significant brain hemorrhage (2%) and early recurrent embolization (2%) were equally low in both groups. Our data suggest that acute anticoagulation may be employed safely in most patients with cardioembolic stroke but that such treatment does not clearly benefit this population as a whole. (Stroke 1989;20:730-734)

“…We have found this to be a sensitive and reproducible method of quantifying cerebral hemorrhage. 56 ' 20 This technique identifies visible cerebral hemorrhage but does not differentiate between intracerebral hematomas and hemorrhagic infarction.…”

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confidence: 99%

“…These hemorrhage incidence results are similar to our previous study, which also did not detect an increased incidence of hemorrhage using various heparin doses in this model (an approximate 37% hemorrhage rate). 20 Caution is needed when generalizing the results from young, previously healthy, ischemic animals to the clinical situation. However, the combined results from our two heparin experimental embolic stroke studies, representing 69 heparin-treated animals, did not show an increased cerebral hemorrhage rate or size with heparin anticoagulation, even when used concurrently with t-PA thrombolysis.…”

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confidence: 99%

Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits.

Clark

Madden

Lyden

et al. 1991

We studied the incidence of cerebral hemorrhage in an animal model of embolic stroke to determine the safety of aspirin, heparin, and tissue plasminogen activator therapies. We occluded the middle cerebral arteries of rabbits with labeled blood clots and administered either tissue plasminogen activator, heparin, aspirin, tissue plasminogen activator plus aspirin, tissue plasminogen activator plus heparin, or saline at various times after stroke. Compared to saline controls, both the aspirin-only and the tissue plasminogen activator-plus-aspirin groups had a significantly higher incidence of cerebral hemorrhage, whereas the heparin and tissue plasminogen activator combination groups did not. We conclude that aspirin antiplatelet therapy alone may increase the risk of hemorrhagic infarction, whereas heparin or tissue plasminogen activator therapy appears to be relatively safe. (Stroke 1991;22:872-876) T he recent availability of pharmacologic quantities of the thrombolytic agent tissue plasminogen activator (t-PA) has stimulated renewed clinical interest in thrombolytic therapy for stroke. Tissue plasminogen activator acts on plasminogen predominantly in the presence of fibrin, thus limiting its activity to the accessible surface of the clot. 1 -2 By producing less systemic depletion of fibrinogen and other clotting factors than other thrombolytic agents, t-PA may confer less risk of cerebral hemorrhage.We previously have used large and small clot experimental embolic stroke models to demonstrate efficacy of t-PA therapy without finding a significant increase in cerebral hemorrhage rate or severity. -6Animal studies by other investigators using t-PA have produced similar results.7 " 11 However, the risk of cerebral hemorrhage associated with clinical t-PA thrombolysis remains a concern. Data from the Received December 14, 1990; accepted March 28, 1991. Thrombolysis in Myocardial Infarction Trial and other cardiac thrombolysis studies indicate a 0-5% incidence of "spontaneous" cerebral hemorrhage. 12" 16 Initial results from two multicenter acute t-PA stroke trials recently completed also show a 40% (Acute Stroke Study Group Trial-Burroughs Wellcome) rate of cerebral hemorrhagic infarction and a 5% (National Institutes of Health Trial) rate of intracerebral hematoma. 1718A potential explanation for the difference in cerebral hemorrhage rates between the experimental and clinical studies is the concurrent use of anticoagulant or antiplatelet therapies in the clinical populations. Because the concurrent use of heparin or aspirin may be indicated to prevent vessel reocclusion after thrombolysis, and given that the majority of high-risk patients may be on aspirin before their stroke, an understanding of the risk of their concurrent use with t-PA is critical. To assess the cerebral hemorrhagic potential of t-PA with aspirin or heparin, we undertook the present study using an animal model of embolic occlusion of the middle cerebral artery.