(Stroke. 1999;30:2094-2100.)
© 1999 American Heart Association, Inc.
Original Contributions |
Predictors of Clinical Improvement, Angiographic Recanalization, and Intracranial Hemorrhage After Intra-Arterial Thrombolysis for Acute Ischemic Stroke
Presented in part at the 121st Annual Meeting of the American Neurological Association, Miami, Fla, October 13–16, 1996.
From the Departments of Neurology (J.I.S., O.Z., C.K., D.M.D.L.), Neuroradiology (J.L.S., R.T.), and Neurosurgery (J.I.S., W.R.S.), University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio.
Correspondence to Jose I. Suarez, MD, Department of Neurology, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106. E-mail jis4{at}po.cwru.edu
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Background and Purpose—We sought to evaluate predictors of clinical outcome, angiographic success, and adverse effects after intra-arterial administration of urokinase for acute ischemic stroke.
Methods—We designed a Brain Attack program at University Hospitals of Cleveland for diagnosis and treatment of patients presenting within 6 hours of onset of neurological deficit. Patients with ischemia referable to the carotid circulation were treated with intra-arterial urokinase. Angiographic recanalization was assessed at the end of medication infusion. Intracerebral hemorrhage was investigated immediately after and 24 hours after treatment. Stroke severity was determined, followed by long-term outcome.
Results—Fifty-four patients were treated. There was improvement
of 
4 points on the National Institutes of Health Stroke Scale from
presentation to 24 hours after onset in 43% of the treated
patients, and this was related to the severity of the initial deficit.
Forty-eight percent of patients had a Barthel Index score of 95 to 100
at 90 days, and total mortality was 24%. Cranial CT scans revealed
intracerebral hemorrhage in 17% of patients in
the first 24 hours, and these patients had more severe deficits at
presentation. Eighty-seven percent of patients received
intravenous heparin after thrombolysis, and
9% of them developed a hemorrhage into infarction.
Angiographic recanalization was the rule in
complete occlusions of the horizontal portion of the middle cerebral
artery, but distal carotid occlusions responded less well to
thrombolysis.
Conclusions—The intra-arterial route for thrombolysis allows for greater diagnostic precision and achievement of a higher concentration of the thrombolytic agent in the vicinity of the clot. Disadvantages of this therapy lie in the cost and delay. Severity of stroke and site of angiographic occlusion may be important predictors of successful treatment.
Key Words: hemorrhage • stroke, ischemic • thrombolysis
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Judicious use of thrombolytic agents has greatly improved the care of patients presenting with acute ischemic stroke in the last 5 years.1 2 There are at least 2 major constraints to be considered in planning the timing and technique of thrombolytic therapy. First, it is likely that reperfusion of blocked arteries must be accomplished within 6 to 8 hours of the onset of ischemia if brain tissue is to be rescued.1 2 3 4 5 6 7 8 9 10 11 12 13 14 Second, there is a substantial risk of cerebral hemorrhage when thrombolytic agents are used in the setting of acute cerebral ischemia.1 2 8 9 10 13 If thrombolysis is to emerge as an effective clinical tool, it must be applied early in the ischemic sequence and with care to minimize the risk of hemorrhage.
Several investigations have shown that intra-arterial delivery of thrombolytic agents is effective in lysing angiographically demonstrable occlusions in the cerebral circulation.15 16 17 18 Del Zoppo and colleagues7 further used angiography to show that intravenous delivery of thrombolytic agents can effect lysis of vascular occlusions. Complementary clinical studies of intravenous agents in very early stages of cerebral ischemia provided evidence of clinical efficacy as well.9 10 11 12 13 With this information, we designed and implemented in 1993 a Brain Attack program at University Hospitals of Cleveland, using intravenous and intra-arterial delivery of thrombolytic agents in patients who presented within the first 6 hours after the onset of ischemia. We present here observations based on the treatment with intra-arterial therapy of 54 individuals with ischemia in the carotid circulation.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This report derives from experience with 431 patients seen during the first 6 hours after onset of cerebral ischemia over a 44-month interval ending in August 1997. Fifty-four patients with ischemia referable to the carotid circulation were treated with intra-arterial urokinase.
Patient Selection
All patients were evaluated by a neurologist and/or neurosurgeon
and underwent cranial CT scanning without contrast.
Intra-arterial therapy was considered if it could be
initiated before 6 hours had elapsed from the onset of
ischemia.
Inclusion criteria included a National Institutes of Health Stroke Scale (NIHSS)19 of 4, age >18 and <80 years, and no clinical improvement up to the time of evaluation. Patients were excluded from consideration if there was unequivocal evidence of cerebral hemorrhage or definite mass effect on the CT scan. Low density without mass effect, loss of gray/white boundaries, or other evidence of acute ischemia did not exclude the patient. Patients were excluded if the diagnosis could be questioned (history of seizure disorder, preexisting encephalomalacia in the symptomatic arterial territory, cerebral neoplasm, dementia requiring custodial care) and if the patient was at high risk for hemorrhage (prothrombin time >15; platelets <100 000; history of gastrointestinal or genitourinary bleeding in previous 21 days; history of cardiopulmonary resuscitation, trauma, or surgery within 14 days; arterial puncture at a noncompressible site within 7 days; lumbar puncture within 7 days; pregnancy or delivery within 14 days; history of cerebral hemorrhage). No patient received intra-arterial therapy if the diastolic blood pressure was >120 mm Hg despite the use of nitroprusside as acute therapy.
Our Brain Attack program was approved by the Institutional Review Board of the University Hospitals of Cleveland. All patients signed informed written consent before cerebral angiography and intra-arterial urokinase were given.
Technique of Therapy
Cerebral angiography was performed via a femoral artery
approach. Intra-arterial therapy was provided only in the
instances of unequivocal vascular occlusion in intracranial vessels
(top of the carotid, M1 to M3 branches, A1 or A2 branches); we did not
attempt to treat carotid occlusion below the siphon. We used
rapid-transit Prowler-14 catheters (Cordis) and Mach 16 select
and Fast Dasher 14 wires (Target Therapeutics). The initial dose of
urokinase was 250 000 U diluted in 20 mL of a saline solution and
infused over 20 minutes proximal to the clot. A second dose of 250 000
U diluted in 3 mL of a saline solution was administered over 5 minutes
in close proximity to the clot. Repeated doses were given as needed to
achieve recanalization. The total dose of urokinase
was to be limited to 1.4 million U (3 patients actually received
between 1.4 and 1.7 million U). In all instances, mechanical disruption
of clot remnants was attempted after urokinase was infused.
Interpretation of Images
Vascular occlusions visualized during angiography were
categorized as partial or complete.20 Partial occlusion
was defined by passage of contrast material past the area of
obstruction but with a slowed rate of filling of distal vessels and of
clearance of contrast from the distal bed. Complete restoration of flow
was defined as passage of contrast past the previous area of
obstruction, with filling and clearance rates comparable to those of
patent vessels. Partial restoration of flow was defined as passage of
contrast beyond the original area of obstruction but with a rate of
clearance perceptibly slower than that of comparable normal
arteries.
CT scans were categorized as without diagnostic abnormality
(no changes in the arterial territories considered on
clinical grounds to be ischemic), early signs of infarction,
hemorrhagic infarction, or hemorrhage into infarction. Early
signs of infarction included low density and loss of gray-white
junctions, without mass effect (mass effect excluded the patient from
thrombolytic therapy). In CT scans obtained promptly
after intra-arterial thrombolysis,
increased density could reflect contrast enhancement,
hemorrhage, or both. We described areas of increased density in
such scans as hemorrhagic infarction if we could not recognize the
presence of a blood clot. In scans obtained 24 hours after
thrombolysis, hemorrhagic infarction was defined as the
presence of increased density, without apparent clot.
Symptomatic intracranial hemorrhage was defined as
neurological worsening of 4 points on the NIHSS attributable to the
presence of the clot.
Anticoagulation
In the treatment protocol designed for this cohort, all patients
were subsequently anticoagulated with an infusion of heparin unless CT
scanning after thrombolysis revealed hemorrhage
into infarction. In several patients, evidence of clot growth or
reformation during thrombolysis led to the institution
of heparin infusion during thrombolysis, before the CT
scanning performed at the end of the procedure. Heparin was infused at
a rate of 1000 U/h without prior bolus administration. Coagulation
tests were obtained every 4 hours after initiation of anticoagulation
to ensure levels 1.5 to 1.7 times baseline values.
Outcome Measures
The NIHSS was determined within 30 minutes of arrival, 24 hours
after arrival, and 5 days after arrival. Definite neurological
improvement was defined as a 4-point improvement on the NIHSS in the
initial 24 hours after onset of symptoms. Barthel Index21
and Modified Rankin Scale22 scores were obtained 90 days
after the onset of ischemia. Scores of 95 or 100 on the Barthel
Index and scores of 
1 on the Modified Rankin Scale were considered to
indicate a favorable outcome.
Statistical Analysis
The Kolmogorov-Smirnov test for normality and the equal variance
test were performed before any statistical procedure was used. A
Wilcoxon signed rank test was used to analyze the
NIHSS. The unpaired t test or the Mann-Whitney rank sum test
was used to evaluate differences between patients with and without
intracerebral hemorrhage. Differences in
angiographic recanalization were measured on a
nominal scale with the Fisher exact test. Simple linear regression
models were calculated to evaluate the associations between NIHSS on
admission, NIHSS at 24 hours, and time to therapy. A value of
P<0.05 was considered significant. All values are expressed
as mean±SD or median.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patient Selection
There were 431 patients evaluated in the first 6 hours after onset of ischemia. We performed angiography in 62 patients with the intention of providing intra-arterial thrombolysis, but only 54 received thrombolytic agent; of the remaining 8, 4 had complete internal carotid artery occlusions, 1 had a calcified vascular occlusion of uncertain nature, 1 had several occlusions in very small arterial branches, and 2 had no demonstrable arterial occlusion.
Time of Therapy
It had been our intention to initiate angiography only when we
thought that intra-arterial therapy could be started before
6 hours had elapsed since the onset of symptoms. However, 10 patients
(19%) received therapy after 6 hours had passed. In 7 instances, this
reflected technical difficulties during the procedure. Two other
patients were younger than 30 years and aphasic; the protocol violation
was predicated on the hope that younger age would support a favorable
outcome despite the delay in therapy. In the final patient, angiography
and therapy were delayed because the patient appeared to be improving
during the initial evaluation and abruptly worsened thereafter.
Initial Outcome
Measures of initial response to therapy are summarized in Table 1
. A histogram of the change in the NIHSS
from presentation to 24 hours after onset (Figure 1) shows that 43% of patients improved
by 4 points. This improvement was statistically significant and was
maintained 5 days after treatment. The likelihood of early improvement
was probably related to the severity of the initial deficit (Figure 2; correlation coefficient, 0.785 at 95%
CI). However, there was not a simple relationship between initial
outcome and the time until the initial delivery of urokinase (Figure 3). Eight patients received urokinase
before 3 hours elapsed, and only 1 worsened in the first 24 hours (this
patient died with an intracerebral hemorrhage).
Ten patients received therapy between 3 and 4 hours after the onset,
and only 1 worsened slightly. Of the 36 patients treated after 4 hours,
9 worsened in the first 24 hours (25%). Interestingly, 10 patients
received therapy after 6 hours, and only 1 worsened; in this cohort,
there was no obvious time after which benefit was not obtained.
|
|
|
|
Twenty-three patients were discharged to home, and an additional 23
patients were transferred for rehabilitation. Eight patients died
during the acute hospitalization, and only 1 of these deaths was not
related to the initial stroke or the complications of therapy. An
additional 5 patients died within 90 days of the onset of symptoms, for
a total mortality of 24% at 90 days. Of patients surviving at 90 days,
26 patients had a Barthel score of 95 to 100 (48%), 13 had Barthel
score of 55 to 90 (24%), and 8 had a score of 0 to 50 (15%).
Twenty-five patients (48%) had a modified Rankin scale score of
1.
Cerebral Hemorrhage
Cranial CT scans were obtained within 1 hour of the
completion of intra-arterial thrombolysis
(Table 2). These are
"contrast-enhanced" scans, and increased density on such scans
might reflect hemorrhage, contrast, or both. Immediately after
angiography and intra-arterial
thrombolysis, 3 scans showed evidence of
hemorrhage into the infarction, and 23 scans were interpreted
as hemorrhagic infarction (increased density but no clot). Of these 23
patients, 5 developed hemorrhage into infarction in the next 24
hours. The outcome of the 8 patients with hemorrhage into
infarction in the first 24 hours was poor: 5 died during the initial
hospitalization (63%).
|
The average time between onset and initial therapy in patients who developed a hemorrhage in the first 24 hours was 4 hours and 53 minutes (for the entire 54-patient cohort, the average time was 4 hours and 45 minutes), and the median NIHSS score at admission was 20. The latter was significantly different from that of the population that did not experience intracerebral hemorrhage (P<0.001). The other factor associated with hemorrhage was higher serum glucose (166±8 compared with 126±6 mg/dL in patients without hemorrhage; P=0.007). There were no statistical associations with serum fibrinogen concentration, recanalization rate, and blood pressure measurements.
Twelve patients received heparin during and after
thrombolysis; 11 of these had hemorrhagic infarction on
cranial CT scans immediately after the procedure, and 1 developed
hemorrhage into infarction while on heparin; thus, 8.3% of
these patients treated with heparin during and after
thrombolysis despite hemorrhagic infarction developed
further hemorrhage. An additional 34 patients received heparin
after thrombolysis; 11 had hemorrhagic infarctions
evident immediately after thrombolysis, and 2 of these
developed hemorrhage into infarction (18%). One patient
received heparin only during the intra-arterial infusion of
urokinase; the CT scan after thrombolysis revealed
hemorrhage into infarction, and the heparin was discontinued.
Finally, 1 patient received heparin after thrombolysis
despite equivocal evidence of hemorrhage into infarction; this
patient's hemorrhage enlarged and eventually contributed to
death. In summary, 48 of the 54 patients received heparin after
thrombolysis; 5 of the 48 developed a
hemorrhage into infarction (10%) (Table 2
).
Angiographic Changes During Thrombolysis
The efficacy of thrombolysis, as judged by
dissolution of angiographically demonstrable occlusions, varied with
the location of the occlusion (Table 3).
Distal carotid occlusion responded least well angiographically, despite
the relative accessibility of the clot to mechanical effects of the
selective catheters; in 5 cases, 3 failed to open and 1 opened only the
anterior cerebral artery. There was a 40% mortality, all in patients
in whom recanalization had failed. By contrast,
recanalization was the rule in complete occlusions
of the horizontal portion of the middle cerebral artery. However, there
was a 33% incidence of hemorrhage into infarction in patients
whose complete M1 occlusions had been entirely opened by
thrombolysis. In this cohort, distal (M3) occlusions
were relatively resistant to thrombolysis but
also were not associated with subsequent hemorrhage into
infarction.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
We have used intra-arterial delivery of urokinase to effect thrombolysis of vascular occlusions in the carotid circulation through 8 hours after the onset of symptoms. The angiographic improvement was often accompanied by substantial clinical improvement, even in patients treated from 5 to 8 hours after onset, but there was also a high risk of intracerebral hemorrhage.
Thrombolysis is least dangerous when it can be performed as
early in the disease process as possible.1 2 9 If patients
can be given intravenous tissue plasminogen
activator (tPA) within 3 hours of the onset of symptoms,
approximately 47% have a clinical improvement of 4 points in the
NIHSS in the initial 24 hours, with a risk of symptomatic
intracerebral hemorrhage of approximately 6.4%
and a mortality of approximately 13% in the first month.1
In the 54 patients described here, 43% improved by 4 points in the
first 24 hours, but the risk of intracerebral
hemorrhage was 17% in the first 24 hours, and the mortality
during the initial hospitalization was 15%. By comparison, the risk of
cerebral hemorrhage reported by the European Cooperative Acute
Stroke Study (ECASS) for patients treated with intravenous
tPA in the initial 6 hours after onset is approximately
19.4%.2 If the patients in the 3 groups were entirely
comparable, it would seem that thrombolysis performed
between 6 and 7 hours after the onset of clinical symptoms carries with
it a risk of cerebral hemorrhage 2- or 3-fold greater than that
of intravenous therapy delivered in the first 3 hours. This
was also confirmed by a recent trial reporting on the use of
intra-arterial prourokinase in acute middle cerebral artery
stroke.23 The authors found a 15.4% incidence of
symptomatic intracerebral
hemorrhage and 42.3% incidence of hemorrhagic transformation
within 24 hours of treatment. However, if patients with signs of major
infarction by head CT scanning are excluded, the administration of
intravenous recombinant tPA within 6 hours of symptom onset
may be associated with an 8.8% incidence of symptomatic
hemorrhages.24 This is less than that in the
cohort reported in the present study but more than that in the
National Institute of Neurological Disorders and Stroke (NINDS)
trial.
There are some important differences between the prospective uncontrolled cohort reported here and the populations described in the 3 trials of intravenous tPA. First, we, similar to the prourokinase study, treated only patients with vascular occlusions visible on angiography; therefore, none of the patients reported here had ischemia referable to intrinsic disease of small penetrating vessels. We suspect that the volume of ischemic brain was, on the average, greater in the group described here. The NIHSS score was not very different in the 3 groups. However, we believe that disease in penetrating vessels can cause a deficit with a large NIHSS score because of ischemia in a relatively small volume of myelinated axons, while the volume of cortex that would have to be rendered ischemic to generate a similar score is substantially greater. If the risk of cerebral hemorrhage is proportional to the volume of ischemic tissue and the severity of the ischemia,13 then larger volumes carry a greater risk of hemorrhage.
Mortality after intravenous administration of tPA was lower than in the placebo group (17%) at 3 months in the NINDS study,1 whereas in the ECASS trial it was higher (19.4%) in the treated population.2 These mortality rates are smaller than ours (24%). However, the 90-day mortality in the prourokinase trial was slightly higher (26.9%) in the treated population.23 Our cohort may have included sicker patients, as noted by high serum glucose concentrations, which have been associated with greater mortality and poorer survival in patients with intracranial disease.25
The management of arterial hypertension also varied in our group. We used intravenous nitroprusside to control hypertension, and it was not necessary to withhold thrombolytic therapy in any instance because of refractory hypertension. The NINDS study excluded patients refractory to labetalol therapy.1 It is possible, therefore, that our group included a larger proportion of patients with severe hypertension than the NINDS population.
A fourth major difference is the use of heparin anticoagulation after intra-arterial thrombolysis. Both the NINDS and ECASS studies excluded the use of intravenous heparin in the first 24 hours. The design of our protocol was influenced by published experience with thrombolysis for peripheral vascular disease, which pointed out that heparin together with the thrombolytic agent might decrease the risk of clot reformation.26 Forty-four of the 54 patients reported here received intravenous heparin. Of the 8 patients who developed hemorrhage into infarction in the first 24 hours, 2 were receiving heparin after thrombolysis and 1 received heparin during and after thrombolysis. We used heparin during thrombolysis when it appeared that thrombi were enlarging and when extracranial stenosis appeared to limit flow (for example, severe internal carotid stenosis at the bifurcation that was exacerbated by the presence of catheter). At least 2 of the patients reported here developed reocclusion after thrombolysis (1 despite heparin), and a third occlusion in the M1 segment clearly enlarged during thrombolysis without heparin (this enlargement was recognized at the completion of the procedure). At present, there is insufficient information to determine whether the risk of reocclusion justifies the additional risk of cerebral hemorrhage. However, the prourokinase study results suggest that recanalization is enhanced by the addition of heparin, with a higher frequency of intracranial hemorrhages.23
The value of the intra-arterial route for thrombolysis includes the greater precision of diagnosis and the opportunity of using the smallest effective dose of thrombolytic agent. Since we relied on angiographic detection of persisting intravascular occlusion, we did not run the risk of treating individuals in whom spontaneous clot lysis had already occurred. In the group reported here, we performed angiography in 62 patients but found clot in only 54; 8 (13%) were thus spared the risks associated with thrombolysis. Del Zoppo and colleagues7 also failed to detect intravascular clots in 19% of the angiograms they performed to monitor thrombolysis. The frequency of absent occlusions in the carotid territory in the prourokinase study was 23%.23 Because we could image the dissolution of clots, we were able to limit therapy to less than the maximum in 48 patients (89%). It is clear that higher doses of intravenous tPA are associated with increased risk of hemorrhage into clinically normal brain,9 and we infer that smaller doses of intra-arterial urokinase are also likely to decrease the risk of hemorrhage in ischemic brain.
Intra-arterial therapy probably achieves a higher concentration of the thrombolytic agent in the clot, and there may be additional advantages of mechanical disruption of the clot by the catheter.16 17 18 The latter may explain the lower recanalization rate after intra-arterial prourokinase administration (57.7%)23 compared with our cohort in the same vascular territory (100%). We frequently observed that blood in lumen of the middle cerebral artery proximal to an occlusion in the M1 segment was relatively static; the entry of fresh arterial blood into the portion of vessel adjacent to the clot was limited by the rate of runoff in the small penetrating vessels. If thrombolysis depended on diffusion of the thrombolytic agent from arterial blood adjacent to the clot, the availability of the agent to the clot would be limited by the concentration of agent in arterial blood and the turnover of arterial blood adjacent to the clot. Intravenous administration of thrombolytic agent attains a much lower concentration in the arterial blood adjacent to the clot than is accomplished by injection at that site through a catheter. Moreover, injection by catheter into the clot circumvents the limitations of arterial flow proximal to the clot.
The disadvantages of intra-arterial therapy lie in the cost and delay. For intra-arterial therapy to be available for emergency care of ischemic stroke, personnel and equipment must be in constant readiness. Despite our best efforts, the median time from arrival in the emergency department to delivery of urokinase was 130 minutes; the minimal time was 45 minutes, but the median was strongly influenced by several complex procedures. A recent symposium strongly argued for delivery of intravenous agent within 1 hour of presentation27 ; by that standard, intra-arterial therapy in our hands necessitates a median of 70 minutes of undesirable delay.
Our experience with this uncontrolled population thus far indicates that the administration of intra-arterial urokinase may improve outcome in patients with acute ischemic stroke. Severity of stroke, not timing, as well as site of angiographic occlusion may be important predictors of successful treatment.
|
Acknowledgments |
|---|
The authors thank the neurology and neurosurgery residents and the nursing, neuroradiology, and emergency department staff of the University Hospitals of Cleveland for helping in the care of these patients.
Received May 21, 1999; revision received June 30, 1999; accepted June 30, 1999.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-
The National Institute of Neurological Disorders
and Stroke rt-PA Stroke Study Group. Tissue plasminogen
activator for acute ischemic stroke. N
Engl J Med. 1995;333:1581–1587.
[Abstract/Free Full Text] - Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne M-H, Hennerici M, for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017–1025.[Abstract]
- Heiss WD, Rosner G. Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol. 1983;14:294–301.[Medline] [Order article via Infotrieve]
-
Bednar MM, McAuliffe T, Raymond S, Gross CE. Tissue
plasminogen activator reduces brain injury in a
rabbit model of thromboembolic stroke. Stroke. 1990;21:1705–1709.
[Abstract/Free Full Text] -
del Zoppo GJ, Zeumer H, Harker LA.
Thrombolytic therapy in acute stroke: possibilities and
hazards. Stroke. 1986;17:595–607.
[Free Full Text] - Fieschi C, Argentino C, Lenzi GL, Sacchetti ML, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci. 1989;91:311–322.[Medline] [Order article via Infotrieve]
- del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, Alberts MJ, Zivin JA, Wechsler L, Busse O, Greenlee R, Brass L, Mohr JP, Feldman E, Hacke W, Kase CS, Biller J, Gress D, Otis SM. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992;32:78–86.[Medline] [Order article via Infotrieve]
-
Fletcher AP, Alkjaersig N, Lewis M, Tulevski V, Davies
A, Brooks JE, Hardin WB, Landau WM, Raichle ME. A pilot study of
urokinase therapy in cerebral stroke. Stroke. 1976;7:135–142.
[Abstract/Free Full Text] -
Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J,
Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R, Marler JR.
Urgent therapy for stroke, I: pilot study of tissue
plasminogen activator administered within 90
minutes. Stroke. 1992;23:632–640.
[Abstract/Free Full Text] -
Haley EC Jr, Levy DE, Brott TG, Sheppard GL, Wong MCW,
Kongable GL, Torner SC, Marler JR. Urgent therapy for stroke, II: pilot
study of tissue plasminogen activator
administered 91–180 minutes from onset. Stroke. 1992;23:641–645.
[Abstract/Free Full Text] -
Haley EC Jr, Brott TG, Sheppard GL, Barsan W, Broderick
J, Marler JR, Kongable GL, Spilker J, Massey S, Hansen CA, Torner JC,
for the TPA Bridging Study Group. Pilot randomized trial of tissue
plasminogen activator in acute ischemic
stroke. Stroke. 1993;24:1000–1004.
[Abstract/Free Full Text] -
Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S,
Ohsumi Y, Kitano K, Tsutsumi A, Yamadori A. Intravenous
recombinant tissue plasminogen activator in
acute ischemic stroke. Neurology. 1992;42:976–982.
[Abstract/Free Full Text] -
von Kummer R, Hacke W. Safety and efficacy of
intravenous tissue plasminogen
activator and heparin in acute middle cerebral artery
stroke. Stroke. 1992;23:646–652.
[Abstract/Free Full Text] - Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, del Zoppo GJ. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. AJNR Am J Neuroradiol. 1993;14:3–13.[Abstract]
-
Hacke W, Zeumer H, Ferbert A, Bruckman H, del Zoppo
GJ. Intra-arterial thrombolytic
therapy improves outcome in patients with acute vertebrobasilar
occlusive disease. Stroke. 1988;19:1216–1222.
[Abstract/Free Full Text] -
Mori E, Tabuchi M, Yoshida T, Yamadori A.
Intracarotid urokinase with thromboembolic occlusion of the middle
cerebral artery. Stroke. 1988;19:802–812.
[Abstract/Free Full Text] -
del Zoppo GJ, Ferbert A, Otis S, Bruckmann H, Hacke W,
Zyroff J, Harker LA, Zeumer H. Local intra-arterial
fibrinolytic therapy in acute carotid territory stroke: a pilot study.
Stroke. 1988;19:307–313.
[Abstract/Free Full Text] - Zeumer H, Freitag H-J, Zanella F, Thie A, Arning C. Local intra-arterial fibrinolytic therapy in patients with stroke: urokinase versus recombinant tissue plasminogen activator (r-TPA). Neuroradiology. 1993;35:159–162.[Medline] [Order article via Infotrieve]
- Lyden P, Brott T, Tilley B, Welch KMA, Mascha EJ, Levine S, Haley EC, Grotta J, Marler J, and the NINDS TPA Stroke Study Group. Improved reliability of the NIH Stroke Scale using video training. Stroke. 1994;25:2220–2226.[Abstract]
- Gorup TS. Special report: the Thrombolysis in Myocardial Infarction (TIMI) trial. N Engl J Med. 1985;312:932–936.[Medline] [Order article via Infotrieve]
- Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J. 1965;14:61–65.[Medline] [Order article via Infotrieve]
- Rankin J. Cerebral vascular accidents in patients over the age of 60, II: prognosis. Scott Med J. 1957;2:200–215.[Medline] [Order article via Infotrieve]
-
del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS,
Rowley HA, Gent M, and the PROACT Investigators. PROACT: a phase II
randomized trial of recombinant pro-urokinase by direct
arterial delivery in acute middle cerebral artery stroke.
Stroke. 1998;29:4–11.
[Abstract/Free Full Text] - Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P, for the Second Europena-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Lancet.. 1998;352:1245–1251.[Medline] [Order article via Infotrieve]
- Spitzer K, Thie A, Kunze K. Haufigkeit und Prognose internistischer Komplikationen bei spontanen Intrakraniellen Hamotomen. Nervenarzt. 1988;11:647–653.
- McNamara TO, Bomberger RA, Merchant RF. Intra-arterial urokinase as the initial therapy for acutely ischemic lower limbs. Circulation. 1991;83:I-106–I-119.
- Bock BF. Response system for patients presenting with acute stroke. In: Marler JR, Jones PW, Emr M, eds. Rapid Identification and Treatment of Acute Stroke. Bethesda, Md: National Institute of Neurological Disorders and Stroke; 1997.
This article has been cited by other articles:
 |
|
 |
|
  G. W. Albers, P. Amarenco, J. D. Easton, R. L. Sacco, and P. Teal Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 630S - 669S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Mandava and T. A. Kent Intra-arterial therapies for acute ischemic stroke Neurology, June 12, 2007; 68(24): 2132 - 2139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Christoforidis, A. Slivka, Y. Mohammad, C. Karakasis, B. Avutu, and M. Yang Size Matters: Hemorrhage Volume as an Objective Measure to Define Significant Intracranial Hemorrhage Associated With Thrombolysis Stroke, June 1, 2007; 38(6): 1799 - 1804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ikushima, H. Ohta, T. Hirai, K. Yokogami, D. Miyahara, N. Maeda, and Y. Yamashita Balloon Catheter Disruption of Middle Cerebral Artery Thrombus in Conjunction with Thrombolysis for the Treatment of Acute Middle Cerebral Artery Embolism AJNR Am. J. Neuroradiol., March 1, 2007; 28(3): 513 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Khatri, L. R. Wechsler, and J. P. Broderick Intracranial Hemorrhage Associated With Revascularization Therapies Stroke, February 1, 2007; 38(2): 431 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.G. Jovin, R. Gupta, M.B. Horowitz, S.Z. Grahovac, C.A. Jungreis, L. Wechsler, J.M. Gebel, and H. Yonas Pretreatment Ipsilateral Regional Cortical Blood Flow Influences Vessel Recanalization in Intra-Arterial Thrombolysis for MCA Occlusion AJNR Am. J. Neuroradiol., January 1, 2007; 28(1): 164 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Shaltoni, K. C. Albright, N. R. Gonzales, R. U. Weir, A. M. Khaja, R. M. Sugg, M. S. Campbell III, E. D. Cacayorin, J. C. Grotta, and E. A. Noser Is Intra-Arterial Thrombolysis Safe After Full-Dose Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke? Stroke, January 1, 2007; 38(1): 80 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Imai, T. Mori, H. Izumoto, N. Takabatake, T. Kunieda, H. Shimizu, and M. Watanabe Clot Removal Therapy by Aspiration and Extraction for Acute Embolic Carotid Occlusion AJNR Am. J. Neuroradiol., August 1, 2006; 27(7): 1521 - 1527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.A. Christoforidis, Y. Mohammad, B. Avutu, A. Tejada, and A.P. Slivka Arteriographic Demonstration of Slow Antegrade Opacification Distal to a Cerebrovascular Thromboembolic Occlusion Site As a Favorable Indicator for Intra-Arterial Thrombolysis AJNR Am. J. Neuroradiol., August 1, 2006; 27(7): 1528 - 1531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
The IMS Study Investigators Hemorrhage in the Interventional Management of Stroke Study Stroke, March 1, 2006; 37(3): 847 - 851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Choi, B. T. Bateman, S. Mangla, R. S. Marshall, S. Prabhakaran, J. Chong, J. P. Mohr, H. Mast, and J. Pile-Spellman Endovascular Recanalization Therapy in Acute Ischemic Stroke Stroke, February 1, 2006; 37(2): 419 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Part 9: Adult Stroke Circulation, December 13, 2005; 112(24_suppl): IV-111 - IV-120. [Full Text] [PDF]
|
|
|
|
|
|
Part 9: Stroke Circulation, November 29, 2005; 112(22_suppl): III-110 - III-104. [Full Text] [PDF]
|
|
|
|
|
|
G. A. Christoforidis, Y. Mohammad, D. Kehagias, B. Avutu, and A. P. Slivka Angiographic Assessment of Pial Collaterals as a Prognostic Indicator Following Intra-arterial Thrombolysis for Acute Ischemic Stroke AJNR Am. J. Neuroradiol., August 1, 2005; 26(7): 1789 - 1797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Smith, G. Sung, S. Starkman, J. L. Saver, C. S. Kidwell, Y.P. Gobin, H. L. Lutsep, G. M. Nesbit, T. Grobelny, M. M. Rymer, et al. Safety and Efficacy of Mechanical Embolectomy in Acute Ischemic Stroke: Results of the MERCI Trial Stroke, July 1, 2005; 36(7): 1432 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Wardlaw and O. Mielke Early Signs of Brain Infarction at CT: Observer Reliability and Outcome after Thrombolytic Treatment--Systematic Review Radiology, May 1, 2005; 235(2): 444 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Saqqur, A. Shuaib, A. V. Alexandrov, M. D. Hill, S. Calleja, T. Tomsick, J. Broderick, and A. M. Demchuk Derivation of Transcranial Doppler Criteria for Rescue Intra-arterial Thrombolysis: Multicenter Experience From the Interventional Management of Stroke Study Stroke, April 1, 2005; 36(4): 865 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Kwon, S. U. Kwon, J. H. Lee, C. G. Choi, D. C. Suh, and J. S. Kim Factors Affecting the Angiographic Recanalization and Early Clinical Improvement in Middle Cerebral Artery Territory Infarction After Thrombolysis Arch Neurol, November 1, 2004; 61(11): 1682 - 1686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sorimachi, Y. Fujii, N. Tsuchiya, T. Nashimoto, A. Harada, Y. Ito, and R. Tanaka Recanalization by Mechanical Embolus Disruption during Intra-Arterial Thrombolysis in the Carotid Territory AJNR Am. J. Neuroradiol., September 1, 2004; 25(8): 1391 - 1402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Albers, P. Amarenco, J. D. Easton, R. L. Sacco, and P. Teal Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 483S - 512S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pedraza, Y. Silva, J. Mendez, L. Inaraja, J. Vera, J. Serena, and A. Davalos Comparison of Preperfusion and Postperfusion Magnetic Resonance Angiography in Acute Stroke Stroke, September 1, 2004; 35(9): 2105 - 2110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Leigh, O. O. Zaidat, M. F. Suri, G. Lynch, S. Sundararajan, J. L. Sunshine, R. Tarr, W. Selman, D. M.D. Landis, and J. I. Suarez Predictors of Hyperacute Clinical Worsening in Ischemic Stroke Patients Receiving Thrombolytic Therapy Stroke, August 1, 2004; 35(8): 1903 - 1907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Greer, W. J. Koroshetz, S. Cullen, R. G. Gonzalez, and M. H. Lev Magnetic Resonance Imaging Improves Detection of Intracerebral Hemorrhage Over Computed Tomography After Intra-Arterial Thrombolysis Stroke, February 1, 2004; 35(2): 491 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Provenzale, R. Jahan, T. P. Naidich, and A. J. Fox Assessment of the Patient with Hyperacute Stroke: Imaging and Therapy Radiology, November 1, 2003; 229(2): 347 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|