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PubMed1991

Ultrasonic energy. Effects on vascular function and integrity.

BACKGROUND: Ultrasonic energy transmitted via flexible wire probes provides a new means of ablating atherosclerotic plaque. We studied the effects of ultrasonic energy (20 kHz) delivered via a ball-tipped wire probe on arterial vasomotor behavior in rabbit thoracic aortas in a perfused whole-vessel model. METHODS AND RESULTS: After precontraction with phenylephrine (10(-5) M) or KCl (60 mM), the effects of ultrasonic energy (0.7-5.5 W x 60 seconds, 42-330 J) on arterial vasomotor behavior were measured using long-axis ultrasonic vessel imaging of the proximal (ultrasonic probe-treated) and distal (untreated) control segments. The efficacy of plaque ablation at these same probe-tip power outputs was evaluated in atherosclerotic, human cadaver iliofemoral arteries. Ultrasonic energy caused dose (energy)-dependent relaxation in rabbit aortas after precontraction with phenylephrine in arteries with endothelium (n = 8) and without endothelium (n = 8) (p less than 0.001 versus ultrasound treated at power outputs of 2.9 and 5.5 W). There was no difference in the relaxation dose responses between endothelialized and endothelially denuded segments (p = NS). Ultrasonic energy also caused significant relaxation (67 +/- 8%) after voltage-dependent precontraction with 60 mM KCl. Temperature measurements revealed less than 1 degrees C warming of the vessel wall during as long as 2 minutes of treatment at a power output of 5.5 W. Pathological examination showed no smooth muscle injury at (moderate) power outputs that caused arterial relaxation. At probe-tip power outputs of 2.9-5.5 W, ultrasonic energy recanalized two of two totally occluded cadaveric iliofemoral vessel segments. The ultrasonic ablation catheter was also demonstrated to cause arterial relaxation in a recanalized canine femoral artery in vivo. CONCLUSIONS: Ultrasonic energy delivered via a flexible-wire probe produces dose-dependent, endothelium-independent smooth muscle relaxation capable of reversing both receptor-mediated and voltage-dependent vasoconstriction in vitro. At moderate power outputs, this relaxation response does not appear to be due to thermal effects or irreversible smooth muscle cell injury. This vasorelaxant effect of ultrasonic energy is also apparent in vivo, at doses that effectively ablate atherosclerotic plaque, and may improve the safety of arterial recanalization using ultrasonic energy.

Animals↗
PubMed1992

A randomized trial of late reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction-6 Study Group.

BACKGROUND: Experimental and observational clinical studies of acute coronary occlusion have suggested that late reperfusion prevents infarct expansion and facilitates myocardial healing. The purpose of this trial was to assess whether infarct vessel patency could be achieved in late-entry patients and what benefit, if any, can be demonstrated. METHODS AND RESULTS: In a double-blind fashion, 197 patients with 6 to 24 hours of symptoms and ECG ST elevation were randomly assigned to tissue-type plasminogen activator (100 mg over 2 hours) or placebo. Coronary angiography within 24 hours was used to determine infarct vessel patency status. Patients with infarct-related occluded arteries were then eligible for a second randomization to either angioplasty (34 patients) or no angioplasty (37 patients). Ventricular function and cavity size were reassessed at 1 month by gated blood pool scintigraphy and at 6 months by repeat cardiac catheterization. The primary end point, infarct vessel patency, was 65% for plasminogen activator patients compared with 27% in the placebo group (p less than 0.0001). There were no differences between these groups in ejection fraction or infarct zone regional wall motion at 1 or 6 months. At 6 months, infarct vessel patency was 59% in both groups. In the placebo group, there was a significant increase in end-diastolic volume from acute phase of 127 ml to 159 ml at 6-month follow-up (p = 0.006) but no increase in cavity size for the plasminogen activator group patients. Coronary angioplasty was associated with an initial 81% recanalization success and improved ventricular function at 1 month, but by late follow-up no advantage could be demonstrated for this procedure, and there was a 38% spontaneous recanalization rate in the patients assigned to no angioplasty. CONCLUSIONS: The study demonstrates that it is possible to achieve infarct vessel recanalization in the majority of late-entry patients with either thrombolytic therapy or angioplasty. Thrombolytic intervention had a favorable effect on prevention of cavity dilatation and left ventricular remodeling, but there are no late benefits on systolic function after thrombolysis or coronary angioplasty. The conclusions concerning overall potential benefit of applying late reperfusion therapy will require data from large-scale trials designed to assess mortality reduction.

Angioplasty, Balloon, Coronary↗
PubMed1992

Thrombus regression in deep venous thrombosis. Quantification of spontaneous thrombolysis with duplex scanning.

BACKGROUND: Thrombus regression in heparin-treated, acute deep venous thrombosis of the lower extremity is poorly documented in the literature; different rates of thrombus resolution and recanalization are reported. METHODS AND RESULTS: In a prospective follow-up study, duplex scanning was used to evaluate the thrombus regression in patients with documented acute femoropopliteal thrombosis. Eighty vein segments in 20 legs of 18 patients were subjected to repeat duplex scans at 1, 3, 6, 12, and 26 weeks after diagnosis; 49 segments showed thrombus at diagnosis. The popliteal vein showed the highest thrombus load at diagnosis, followed in descending order by the superficial femoral, profunda femoris, and common femoral vein segments (p less than 0.001). Thrombus regression was significant (p less than 0.001) in all segments and proceeded at an exponential rate that was equal in the different vein segments of the upper leg. Both thrombus resolution and recanalization appeared to be a function of the initial thrombus load and could not be related to individual vein segments. Recanalization was seen in 23 of 31 initially occluded segments and occurred within the first 6 weeks after diagnosis in 20 of 23 segments. Extension of thrombus despite anticoagulant therapy was observed in 15 vein segments and was not related to the initial thrombosis score (p = 0.1) or individual vein segments (p = 0.23). Thrombus extension in seven patients with prethrombotic conditions was not different (p = 0.9) from the other patients. CONCLUSIONS: Duplex scanning is an important noninvasive tool to quantify thrombus regression in acute deep venous thrombosis in detail without unnecessary discomfort to the patient.

Female↗
PubMed1992

Induction of endothelial cell expression of the plasminogen activator inhibitor type 1 gene by thrombosis in vivo.

BACKGROUND: We have shown previously that products from activated platelets can augment synthesis of plasminogen activator inhibitor type 1 (PAI-1) in cultured endothelial and hepatoma (Hep G2) cells in vitro and increase plasma PAI-1 activity in vivo in rabbits. Accordingly, the effects of activation of platelets associated with thrombosis and thrombolysis in vivo on plasma PAI-1 activity and expression of the PAI-1 gene in endothelium, liver, and other organs were characterized. METHODS AND RESULTS: Endothelial injury giving rise to platelet-rich thrombi was induced with electrical stimulation in carotid arteries in rabbits. Clot lysis and recanalization were induced subsequently with intravenous tissue-type plasminogen activator (t-PA) and verified with Doppler flow probes. Plasma PAI-1 activity (mean +/- SD) increased from 6 +/- 2 arbitrary units (AU)/ml to 129 +/- 48 AU/ml (n = 15) within several hours after recanalization. When t-PA had failed to induce recanalization, the increase was much less (from 7 +/- 2 to 42 +/- 23 AU/ml, n = 11). To define mechanisms responsible for these changes, PAI-1 messenger RNA (mRNA) was evaluated by Northern blot analysis and localized in tissues by in situ hybridization. Strong and consistent induction of PAI-1 mRNA was evident in aorta, heart, and liver of animals subjected to thrombosis (twofold to threefold increases compared with values in controls), particularly in those in which thrombolysis had been induced (fourfold to sixfold). After thrombolysis, an intense, PAI-1 mRNA-specific signal was detected in endothelium of aorta, liver, and heart, with less intense signals in endothelium of lung, adrenals, and kidneys. CONCLUSIONS: The increases in plasma PAI-1 activity follow a preceding increase in endothelial cell expression of the PAI-1 gene as reflected by PAI-1 mRNA levels. Thus, increased synthesis of endothelial cell PAI-1 after thrombosis and thrombolysis may attenuate endogenous fibrinolysis early after coronary thrombolysis, thereby potentiating early, thrombotic reocclusion.

Animals↗
PubMed1995

Cardiac release of cytokines and inflammatory responses in acute myocardial infarction.

BACKGROUND: In animal models of myocardial infarction (MI), inflammatory responses compromise microcirculation during reperfusion and restrict functional recovery. To investigate cardiac inflammatory responses in patients with acute MI, we examined the cardiac release of cytokines, the expression on neutrophils of the beta 2-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L), and the cardiac release of thrombomodulin as a marker of endothelial injury. METHODS AND RESULTS: In 12 patients with acute anterior MI, blood samples were obtained from the coronary sinus and from the aorta immediately before and after recanalization of the coronary occlusion by balloon angioplasty. Twelve patients undergoing elective balloon angioplasty served as control subjects. Plasma concentrations of interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor-alpha, and thrombomodulin were determined by immunoassay, and surface expression of CD11b and CD62L was assessed by flow cytometry. Differences in coronary sinus and arterial blood were found in IL-6 before (median, 6.3 ng/L, P = .01) and after (13.4 ng/L, P = .002) recanalization and in IL-8 after recanalization (10.7 ng/L, P = .02). The cardiac release of both cytokines significantly (P < or = .03) increased with reperfusion. Cytokine release after reperfusion was associated with significant transcardiac gradients in surface expression on neutrophils of CD11b (10.1 mean channel of fluorescence intensity [mean fl], P = .01) and CD62L (-87 mean fl, P = .007) and with a thrombomodulin release (4.5 micrograms/L, P = .004). Transcardiac gradients in IL-1 beta and tumor necrosis factor-alpha were not found. None of the changes found in MI were detectable in the control group. CONCLUSIONS: As evidence of cardiac inflammatory responses in reperfused acute MI, the study demonstrates cardiac neutrophil activation with signs of endothelial injury and a release of the proinflammatory cytokines IL-8 and IL-6. These findings may assist in the design of pharmacological interventions aimed at reducing microvascular reperfusion injury.

Adult↗
PubMed1996

Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction.

BACKGROUND: Epicardial coronary flow is occasionally reduced even after coronary intervention despite the absence of vessel obstruction in patients with acute myocardial infarction. Our aim was to clarify the cause and outcomes of radiocontrast slow filling in patients with reperfused acute anterior myocardial infarction by assessing microvascular damage with the use of myocardial contrast echocardiography (MCE) and functional outcomes. METHODS AND RESULTS: We carefully reviewed the cineangiograms of 86 patients who achieved coronary revascularization within 12 hours of the onset and underwent MCE before and soon after recanalization with the intracoronary injection of sonicated microbubbles. Antegrade coronary flow after recanalization was graded by two observers based on Thrombolysis in Myocardial Infarction (TIMI) trial flow grades. Left ventricular ejection fraction was measured on the day of infarction and 1 month later. TIMI grade 2 was observed in 18 patients (21%), and the other 68 patients manifested TIMI grade 3 after recanalization. All patients with TIMI 2 showed substantial MCE no reflow, whereas only 11 patients (16%) with TIMI 3 showed MCE no reflow. Functional improvement was worse in patients with TIMI 2 than in those with TIMI 3 (TIMI 2, 38 +/- 8% versus 40 +/- 8%, P = NS [acute versus late]; TIMI 3, 44 +/- 13% versus 55 +/- 13%, P < .001). Among patients with TIMI 3, significant functional improvement was observed only in patients with MCE reflow (MCE reflow, 46 +/- 13% versus 57 +/- 12%, P < .001; MCE no reflow, 35 +/- 11% versus 45 +/- 12%, P = NS). CONCLUSIONS: Despite no obstructive lesion of the vessel, TIMI 2 is caused by advanced microvascular damage and is a highly specific, although not sensitive, predictor of poor functional outcomes in patients with acute myocardial infarction. TIMI 3 does not necessarily indicate myocardial salvage, and detection of MCE no reflow in these patients is particularly useful for the prediction of functional outcome.

Adult↗
PubMed2002

Acute basilar artery occlusion treated with combined intravenous Abciximab and intra-arterial tissue plasminogen activator: report of 3 cases.

BACKGROUND: Acute vertebrobasilar occlusion remains a disease with a high mortality even after treatment by local intra-arterial fibrinolysis. Adjunctive treatment with platelet glycoprotein IIb/IIIa receptor inhibitors such as abciximab may facilitate recanalization and improve the neurological outcome. Results after treatment of 3 patients by combined intravenous abciximab and local intra-arterial tissue plasminogen activator (tPA) are reported. CASE DESCRIPTIONS: Treatment was performed within 6 hours of stroke onset. Angiography revealed embolic occlusion of the basilar artery in 2 patients and atherothrombotic occlusion at the vertebrobasilar junction in 1 patient. Therapy consisted of intravenous abciximab bolus administration (0.25 mg/kg) followed by 12-hour infusion therapy (0.125 microg/kg per minute) and local intra-arterial thrombolysis with tPA (10 mg/h). Heparin was only applied for catheter flushing (500 IU/h). The patient with the atherothrombotic occlusion was treated with additional percutaneous transluminal angioplasty and stenting. Complete recanalization of the basilar artery occurred in 2 patients, whose conditions improved clinically to functional independence. In the third patient only partial recanalization was seen, with only slight clinical improvement. This patient died of cardiac failure 2 months later. Besides a subtle subarachnoid hemorrhage (n=1), no intracranial or extracranial bleeding complication was observed. CONCLUSIONS: The combination of glycoprotein IIb/IIIa receptor inhibitor with local intra-arterial tPA might be a promising therapy for patients with acute vertebrobasilar occlusion. Further studies are necessary to define the clinical benefit and the bleeding rate of this new pharmacological approach.

Abciximab↗
PubMed2002

Response to intra-arterial and combined intravenous and intra-arterial thrombolytic therapy in patients with distal internal carotid artery occlusion.

BACKGROUND AND PURPOSE: The objective of this study was to determine the clinical features, angiographic findings, and response to treatment with thrombolytic therapy in patients with ischemic stroke caused by acute occlusion of the distal internal carotid artery. METHODS: This is a retrospective case series from a prospectively collected stroke database for patients with acute internal carotid occlusion presenting within 6 hours of stroke onset to evaluate safety, feasibility, and response to thrombolytic therapy. The University Hospital-based brain attack database was reviewed over a 5-year period. Demographics, clinical features, stroke mechanisms, severity, imaging findings, type of thrombolysis, treatment responses, mortality, and long-term outcome using modified Rankin Scale and Barthel Index were determined. The short-term outcome was assessed using the National Institutes of Health Stroke Scale (NIHSS). Acute thrombolytic therapy was administered using recombinant tissue plasminogen activator or urokinase given intra-arterially or in combination with intravenous (IV) routes. RESULTS: Two hundred seven patients treated with thrombolysis between 1995 and 2000 were reviewed, and of these, 101 were studied with cerebral angiography. Eighteen patients were identified with acute ischemic stroke and ipsilateral occlusion of the distal internal carotid artery. Time to treatment was the most powerful predictor of response to thrombolytic therapy (P<0.001). The response to therapy also correlated well with the severity of the initial clinical deficit as judged by the NIHSS (P<0.001). There was no difference in recanalization rate, symptomatic hemorrhage, and NIHSS for IV/intra-arterial (IA) versus IA alone (P=NS). Complete angiographic recanalization was accomplished in 80% of those who received combined IV/IA thrombolysis and in 62% of those who received IA therapy (P=NS). Those with distal occlusions extending to the middle and anterior cerebral arteries were the least likely to respond to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 20% of the patients receiving IV/IA therapy, and in 15% of the IA only (P=NS). At 24 hours, the NIHSS dropped by 3 points in the IA group and 4 points in the IV/IA group (P=NS). Mild disability with independence was found in 77% of the survivors at 3-month follow-up. The mortality rate was 50% in this group despite thrombolysis. CONCLUSIONS: Thrombolytic therapy using a combination of IV and IA routes and using the IA-only route may be effective in improving outcome for the patients suffering from occlusion of the distal internal carotid artery. Shorter intervals between onset and treatment seem to be correlated with higher rate of recanalization and improved outcome.

Aged↗
PubMed2003

Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator--treated patients.

BACKGROUND AND PURPOSE: We sought to investigate the impact of hyperglycemia before reperfusion on long-term outcome in patients treated with intravenous tissue plasminogen activator (tPA). METHODS: Of 268 consecutive patients with a nonlacunar middle cerebral artery (MCA) stroke evaluated at <3 hours after onset, 73 (27.2%) received intravenous tPA. Serum glucose was determined at baseline before tPA administration. Hyperglycemia was defined as a glucose level >140 mg/dL. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours. Transcranial Doppler monitoring of recanalization and reocclusion was conducted during the first 24 hours. Total infarct volume was measured on CT at day 5 to 7. Modified Rankin Scale was used to assess outcome at 3 months. RESULTS: Median NIHSS score was 17. At baseline, 31 patients (42.5%) were hyperglycemic and 42 (57.5%) normoglycemic. Early reperfusion (<6 hours) occurred in 43 patients (58.9%). Admission blood glucose correlated negatively with the degree of neurological improvement at 24 hours in reperfused (r=-0.43; P=0.019) but not in nonreperfused (r=-0.20; P=0.21) tPA-treated patients. Increased age (P=0.014), history of diabetes mellitus (P=0.043), admission glucose >140 mg/dL (P=0.002), and early reocclusion (P=0.004) were factors associated with poor outcome among reperfused patients. A logistic regression modeling revealed that only admission glucose value >140 mg/dL (odds ratio, 8.4; 95% CI, 1.76 to 40.02; P=0.005) emerged as an independent predictor of poor outcome despite tPA-induced recanalization. In patients with 6-hour persistent MCA occlusion, baseline NIHSS score >15 points (P=0.011) and proximal MCA occlusion (P=0.039) were variables associated with poor outcome on univariate analysis. In a logistic regression model, only NIHSS score >15 points (odds ratio, 11.9; 95% CI, 1.48 to 97.1; P=0.032) remained as an independent predictor of poor outcome and functional dependence at 3 months in nonreperfused tPA-treated patients. CONCLUSIONS: Hyperglycemia before reperfusion may in part counterbalance the beneficial effect of early restoration of blood flow, which translates into a worse outcome in hyperglycemic patients despite tPA-induced recanalization.

Adult↗
PubMed2003

Perfusion-weighted magnetic resonance imaging thresholds identifying core, irreversibly infarcted tissue.

BACKGROUND AND PURPOSE: Identifying core, irreversibly infarcted tissue and salvageable penumbral tissue is crucial to informed, physiologically guided decision making regarding thrombolytic and other interventional therapies in acute ischemic stroke. Pretreatment perfusion MRI offers promise as a means to differentiate core from penumbral tissues. METHODS: Diffusion-perfusion MRIs were performed before treatment and on day 7 in patients undergoing successful vessel recanalization with intra-arterial thrombolytic therapy. Perfusion maps of the time to peak of the residue function (Tmax) were generated after deconvolution of an arterial input function. Initial perfusion abnormalities and final infarct regions were outlined by hand. Posttreatment images were coregistered to the pretreatment study. Voxel-by-voxel and volume analyses were performed to identify thresholds of perfusion abnormalities that best predict core, irreversibly infarcted tissue. RESULTS: Fourteen patients (4 men, 10 women) with vessel recanalization were studied. Mean age was 73 years, and median entry National Institutes of Health Stroke Scale score was 12. Mean time from symptom onset to start of intra-arterial infusion was 245 minutes and to recanalization was 338 minutes. With a voxel-by-voxel analysis, Tmax > or =6 and > or =8 seconds (sensitivity, 71% and 53%; specificity, 63% and 80%) correlated most highly with day 7 final infarct. With a volume analysis, Tmax > or =6 and > or =8 seconds (r2=0.704 and r2=0.705) correlated most highly with day 7 final infarct. CONCLUSIONS: Perfusion-weighted imaging measures of ischemia severity accurately differentiate irreversibly injured core from penumbral, salvageable tissue. The best threshold for identifying core infarcted tissue is adjusted Tmax of > or =6 to 8 seconds.

Acute Disease↗
PubMed2003

Local intra-arterial fibrinolysis of thromboemboli occurring during neuroendovascular procedures with recombinant tissue plasminogen activator.

BACKGROUND AND PURPOSE: There is a lack of systematic data regarding local intra-arterial fibrinolysis (LIF) of thromboemboli occurring during neuroendovascular procedures with the use of recombinant tissue plasminogen activator (rtPA). We report our technique for treating LIF of intracerebral thromboemboli occurring during neuroendovascular procedures. METHODS: Nine of 723 patients (1.2%) who underwent neuroendovascular procedures during the period from January 1997 to September 2002 suffered thromboembolic complications. These patients were treated by LIF with a maximum dose of 0.9 mg rtPA per kilogram body weight. Recanalization was categorized as successful (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3) versus unsuccessful (TIMI grade 0 or 1), and clinical outcome was categorized as independent (Rankin Scale score 0 to 2) versus dependent or dead (Rankin Scale score 3 to 6). RESULTS: The minimum time between thrombus detection and beginning of LIF was 10 minutes, and the maximum time was 90 minutes. Successful recanalization was achieved in 4 of 9 patients (44%). All 9 patients suffered cerebral ischemic infarctions, and none of the patients sustained intracerebral hemorrhage. Two patients (22%) died from malignant brain infarctions. Four patients (44%) remained moderately disabled, and 3 patients (33%) were severely disabled 3 months after LIF. CONCLUSIONS: Although we used relatively high doses of rtPA, the recanalization rates and clinical outcome of LIF in our patients were not satisfactory. Strategies for the prevention of thromboemboli during neuroendovascular procedures must be improved, and novel fibrinolytic or thrombolytic techniques should be developed.

Adult↗
PubMed2003

Matrix and bioabsorbable polymeric coils accelerate healing of intracranial aneurysms: long-term experimental study.

BACKGROUND AND PURPOSE: Acceleration of intra-aneurysmal clot organization and fibrosis may be a solution to preventing aneurysm recanalization after endovascular treatment. The purpose of this study was to evaluate the short-term efficacy and long-term safety of the new Matrix coil system. METHODS: Matrix coils consist of thin platinum coils covered with a bioabsorbable, polymeric material (polyglycolic acid/lactide). Fifty-two experimental aneurysms were created in 26 swine. All of the aneurysms were tightly packed with Matrix or Guglielmi detachable coils (GDC). Comparative angiographic and histopathologic data were analyzed at 2 weeks (n=14), 3 months (n=6), and 6 months (n=6) after embolization. RESULTS: Three aneurysms treated with GDC ruptured despite tight packing. No recanalization or rupturing was observed in the aneurysms embolized with Matrix coils. At 14 days after embolization, the aneurysms treated with Matrix coils exhibited a more extensive area of organized thrombus when compared with the aneurysms treated with GDC (87% versus 75%, P=0.008, n=11). At 3 months, both Matrix and GDC-treated aneurysms demonstrated complete clot organization. Neck tissue thickness was higher in Matrix-treated aneurysms at 14 days and 3 months, but not at 6 months. No untoward parent artery stenosis was observed in aneurysms treated with Matrix during follow-up. The angiographic cross-sectional area of the Matrix-treated aneurysms was smaller than those treated with GDC at the 3 months. CONCLUSIONS: Matrix accelerated aneurysm fibrosis and neointima formation without parent artery stenosis. The Matrix system might prevent aneurysmal recanalization after endovascular treatment of cerebral aneurysms.

Absorbable Implants↗
PubMed2004

Ultrasound identification and lysis of clots.

Poor recovery after systemic tissue plasminogen activator (tPA) therapy could result from the initial severity of ischemic insult and slow and incomplete thrombolysis. Persisting arterial occlusions can be identified at bedside using portable diagnostic ultrasound by detecting residual flow signals around the thrombus (thrombolysis in brain ischemia [TIBI] flow grades). A narrow pulsed ultrasound beam can be steadily aimed at the thrombus/residual flow interface, exposing more thrombus surface and structures to tPA, and tPA activity can be enhanced with 2 MHz transcranial Doppler (TCD). A randomized, multicenter, clinical trial called CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA) trial showed a 49% rate of complete recanalization or dramatic clinical recovery from stroke within 2 hours after tPA bolus when tPA infusion was continuously monitored with TCD, compared with 30% among patients who received tPA without ultrasound monitoring (P=0.03, number needed to treat, 5). Early complete recanalization was sustained at 2 hours by 38% of monitored patients compared with 12.7% controls. The CLOTBUST Trial showed a trend toward sustaining complete recovery at 3 months (41.5% versus 28%, modified Rankin Scale scores 0 to 1), subject for a pivotal phase III trial. Ultrasound is an inexpensive, noninvasive, real-time monitoring tool to identify nonresponders to systemic tPA and select patients with persisting occlusions for intraarterial interventions. Early brain perfusion augmentation, complete recanalization, and dramatic clinical recovery are feasible goals for ultrasound-enhanced thrombolysis.

Humans↗
PubMed2004

MERCI 1: a phase 1 study of Mechanical Embolus Removal in Cerebral Ischemia.

BACKGROUND AND PURPOSE: To report the result of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) 1 study, a phase 1 trial to evaluate the safety and efficacy of mechanical embolectomy in the cerebral vasculature. METHODS: MERCI 1 enrolled 30 patients in 7 US centers. Main inclusion criteria were: National Institutes of Health Stroke Scale score (NIHSS) > or =10; treatment performed within 8 hours from symptoms onset and contra-indication to intravenous thrombolysis; no large hypodensity on computed tomography; and occlusion of a major cerebral artery on the angiogram. Safety was defined by the absence of vascular injury or symptomatic intracranial hemorrhage. Efficacy was assessed by recanalization rate and clinical outcome at 1 month. Significant recovery was defined as 30-day modified Rankin of 0 to 2 in patients with baseline NIHSS 10 to 20 and 30-day modified Rankin of 0 to 3 in patients with baseline NIHSS >20. The procedures were performed with the Merci Retrieval System, a system specially designed for intracranial embolectomy. RESULTS: Twenty-eight patients were treated. Median NIHSS was 22. Median time from onset to completion of treatment was 6 hours and 15 minutes. Successful recanalization with mechanical embolectomy only was achieved in 12 (43%) patients, and with additional intra-arterial tissue plasminogen activator in 18 (64%) patients. There was one procedure related technical complication, with no clinical consequence. Twelve asymptomatic and no symptomatic intracranial hemorrhages occurred. At 1 month, 9 of 8 revascularized patients and 0 of 10 nonrevascularized patients had achieved significant recovery. CONCLUSIONS: This phase 1 study shows that cerebral embolectomy with the Merci Retriever was safe and that successful recanalization could benefit a significant number of patients, even when performed in an extended 8-hour time window.

Adult↗
PubMed2006

Identification of penumbra and infarct in acute ischemic stroke using computed tomography perfusion-derived blood flow and blood volume measurements.

BACKGROUND AND PURPOSE: We investigated whether computed tomography (CT) perfusion-derived cerebral blood flow (CBF) and cerebral blood volume (CBV) could be used to differentiate between penumbra and infarcted gray matter in a limited, exploratory sample of acute stroke patients. METHODS: Thirty patients underwent a noncontrast CT (NCCT), CT angiography (CTA), and CT perfusion (CTP) scan within 7 hours of stroke onset, NCCT and CTA at 24 hours, and NCCT at 5 to 7 days. Twenty-five patients met the criteria for inclusion and were subsequently divided into 2 groups: those with recanalization at 24 hours (n=16) and those without (n=9). Penumbra was operationally defined as tissue with an admission CBF <25 mL x 100 g(-1) x min(-1) that was not infarcted on the 5- to 7-day NCCT. Logistic regression was applied to differentiate between infarct and penumbra data points. RESULTS: For recanalized patients, CBF was significantly lower (P<0.05) for infarct (13.3+/-3.75 mL x 100 g(-1) x min(-1)) than penumbra (25.0+/-3.82 mL x 100 g(-1) x min(-1)). CBV in the penumbra (2.15+/-0.43 mL x 100 g(-1)) was significantly higher than contralateral (1.78+/-0.30 mL x 100 g(-1)) and infarcted tissue (1.12+/-0.37 mL x 100 g(-1)). Logistic regression using an interaction term (CBFxCBV) resulted in sensitivity, specificity, and accuracy of 97.0%, 97.2%, and 97.1%, respectively. The interaction term resulted in a significantly better (P<0.05) fit than CBF or CBV alone, suggesting that the CBV threshold for infarction varies with CBF. For patients without recanalization, CBF and CBV for infarcted regions were 15.1+/-5.67 mL x 100 g(-1) x min(-1) and 1.17+/-0.41 mL x 100 g(-1), respectively. CONCLUSIONS: We have shown in a limited sample of patients that CBF and CBV obtained from CTP can be sensitive and specific for infarction and should be investigated further in a prospective trial to assess their utility for differentiating between infarct and penumbra.

Acute Disease↗
PubMed2006

Is intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue plasminogen activator for acute ischemic stroke?

BACKGROUND AND PURPOSE: The optimal approach for acute ischemic stroke patients who do not respond to intravenous recombinant tissue plasminogen activator (IV rt-PA) is uncertain. This study evaluated the safety and response to intra-arterial thrombolytics (IATs) in patients unresponsive to full-dose IV rt-PA. METHODS: A case series from a prospectively collected database on consecutive acute ischemic stroke patients treated with IATs after 0.9 mg/kg IV rt-PA during a 7-year interval was collected. Primary outcome measures included symptomatic intracranial hemorrhage and mortality. As indicators of response, secondary outcome measures were recanalization and discharge disposition. RESULTS: Sixty-nine patients (mean+/-SD age, 60+/-13 years; range, 26 to 85 years; 55% male) with a median pretreatment National Institutes of Health Stroke Scale score of 18 (range, 6 to 39) were included. IV rt-PA was started at 124+/-32 minutes (median, 120 minutes) and IAT, at 288+/-57 minutes (median, 285 minutes). IATs consisted of reteplase (n=56), alteplase (n=7), and urokinase (n=6), with an average total dosage of 2.8 U, 8.6 mg, and 700 000 U, respectively. Symptomatic intracranial hemorrhage occurred in 4 of 69 (5.8%) patients; 3 cases were fatal. Recanalization was achieved in 50 (72.5%) and a favorable outcome (home or inpatient rehabilitation) in 38 (55%). CONCLUSIONS: IAT therapy after full-dose IV rt-PA in patients with persisting occlusion and/or lack of clinical improvement appears safe compared with IV rt-PA alone or low-dose IV rt-PA followed by IAT. A high rate of recanalization and favorable outcome can be achieved.

Acute Disease↗
PubMed2006

Clinical deterioration after intravenous recombinant tissue plasminogen activator treatment: a multicenter transcranial Doppler study.

BACKGROUND AND PURPOSE: Patients may experience clinical deterioration (CD) after treatment with intravenous recombinant tissue plasminogen activator (rt-PA). We evaluated the ability of flow findings on transcranial Doppler to predict CD and outcomes on modified Rankin Scale. METHODS: Patients with acute stroke received intravenous rt-PA within 3 hours of symptom onset at four academic centers. CD was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score by 4 points or more within 24 hours. Poor long-term outcome was defined by modified Rankin Scale > or =2 at 3 months. Transcranial Doppler findings were interpreted using the Thrombolysis in Brain Ischemia flow grading system as persistent arterial occlusion, reocclusion, or complete recanalization. Multiple regression analysis was used to identify transcranial Doppler flow as a predictor for CD after controlling for age, sex, baseline NIHSS, hypertension, and glucose. RESULTS: A total of 374 patients received intravenous rt-PA at 142+/-60 minutes (median pretreatment NIHSS score 16 points). At the end of intravenous rt-PA infusion, transcranial Doppler showed persistent arterial occlusion in 219 patients (59%), arterial reocclusion in 54 patients (14%), and complete recanalization in 101 patients (27%). CD occurred in 44 patients: 36 had persistent arterial occlusion or reocclusion (82%), 13 symptomatic intracerebral hemorrhage (29%), and both persistent occlusion/reocclusion and symptomatic intracerebral hemorrhage in 10 patients (23%). After adjustment, patient risk for CD with persistent occlusion was OR 1.7 (95% CI: 0.7 to 4) and with arterial reocclusion 4.9 (95% CI: 1.7 to 13) (P=0.002). Patient risk for poor long-term outcomes with persistent occlusion, partial recanalization, or reocclusion was OR 5.2 (95% CI: 2.7 to 9, P=0.001). CONCLUSIONS: Inability to achieve or sustain vessel patency at the end of rt-PA infusion correlates with the likelihood of clinical deterioration and poor long-term outcome. Early arterial reocclusion on transcranial Doppler is highly predictive of CD and poor outcome.

Adult↗
PubMed1988

Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery.

Intracarotid urokinase infusion therapy was performed on 22 patients with evolving cerebral infarction due to acute thromboembolic occlusion of the middle cerebral artery. Mean time from onset of symptoms to start of infusion and mean dosage of urokinase were 4.5 hours and 927,000 units, respectively. Immediate recanalization was achieved in 10 patients (45%) after urokinase therapy. In patients with successful recanalization, rapid amelioration of symptoms followed the restoration of blood flow. Thrombolytic recanalization was associated with reduction of neurologic deficits and of computed tomography-demonstrable infarction volume. The reduction of infarction volume and functional outcome correlated highly with the degree of reflow. Hemorrhagic transformation of infarction occurred in four patients and controllable extracranial bleeding in three patients. These results support the safety and efficacy of urokinase therapy for acute thromboembolic occlusion of the middle cerebral artery.

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