(Stroke. 1996;27:882-890.)
© 1996 American Heart Association, Inc.
Articles |
Open Trial of Intravenous Tissue Plasminogen Activator in Acute Carotid Territory Stroke
Correlations of Outcome With Clinical and Radiological Data
From the Cerebrovascular Unit and Ataxia Research Center (P.T., N.N., J.-C.G., G.R., P.N., J.-X.J., L.D., J.X.) and the Department of Neuroradiology (J.-C.F., F.T., Y.B.), Hôpital Neurologique, the Emergency Units of Lyon Hospitals (D.M., G.F.), the Biostatistical Unit of Claude Bernard University (P.A.), and the Hematological and Coagulation Laboratory of Hospices Civils de Lyon (P.F., M.D.), Lyon; and the Emergency Unit of Moutiers Hospital (A.L.G., X.L.), Moutiers, France.
Correspondence to P. Trouillas, Cerebrovascular Unit and Ataxia Research Center, Hôpital Neurologique, 59, boulevard Pinel, 69003 Lyon, France.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Background and Purpose Pilot studies using early thrombolytic therapy in stroke have suggested that recombinant tissue plasminogen activator (rTPA) might be effective. While large, double-blind, randomized studies are needed, open trials could generate hypotheses concerning (1) the clinical correlations of outcome, (2) the significance of CT scan data during the first week, and (3) the use of adjunctive therapies.
Methods We performed an open trial of intravenous rTPA on patients referred to our emergency service with all types of ischemic stroke in the carotid territory. All patients between 20 and 81 years hospitalized during 1994 with completed stroke in the internal carotid artery territory and a baseline Scandinavian Stroke Scale score lower than 48, even with severe disturbances of consciousness, were included. The inclusion time was within 7 hours after stroke onset. A 0.8-mg/kg dose of rTPA was infused for 90 minutes. Intravenous heparin was given either immediately at efficient dosage or after 24 hours. Mannitol was used in patients with severe presentation. The Scandinavian Stroke Scale evaluation was done at baseline, 3 hours, and 1, 7, 30, and 90 days. The CT scan was performed before the treatment and at days 1 (24±6 hours) and 7.
Results Forty-three consecutive patients met the criteria of the protocol. The mean age at inclusion was 65±10.4 years, and the mean interval to treatment was 232±79 minutes. At day 90, 25 patients (58.1%) exhibited a complete regression of symptoms, and 3 had moderate neurological sequelae. Thirteen patients had severe neurological sequelae, 11 with infarcts and 2 with secondary parenchymal hematomas. Two patients died (4.6%), 1 with hematoma. The overall hematoma rate was 6.9%. Excellent outcome at day 90 was significantly correlated with major neurological improvement at day 1. Intravenous immediate heparin versus delayed heparin after 24 hours improved the ischemic outcome but not the overall outcome. Reinfarction syndromes after major neurological improvement, likely to be rethrombosis syndromes, were observed in 3 patients (6.9%). For the day 1 CT scan, poor outcome was associated with the presence of structured and homogeneous hypodensities likely to represent classic infarcts, as confirmed by day 7 CT scan. Conversely, total recovery was significantly associated with the absence of any image or with unstructured hypodensities, a particular type of image characterized by its heterogeneous darkness and often polylobar shape. This type of image disappeared at day 7 in 17.6% of the cases and is likely to represent reperfusion images and/or incomplete ischemic damage.
Conclusions The results obtained in this open, small study suggest safety and effectiveness of rTPA thrombolysis at the dose of 0.8 mg/kg within 7 hours in acute strokes of the carotid territory, including highly serious baseline neurological presentations, until age 81 years and under special therapeutic conditions. Complete recovery is significantly associated with major neurological improvement during the first 24 hours and the presence of a particular type of image at day 1 CT scan characterized by an unstructured hypodensity, often polylobar and heterogeneous, which is likely to correspond to reperfusion images.
Key Words: heparin • mannitol • plasminogen activator, tissue type • thrombolytic therapy • tomography, emission computed
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Open studies with intra-arterial or intravenous administration of a thrombolytic agent after a CT scan, either in the ICA territory or in the vertebrobasilar territory, have shown that both recanalization of the occluded artery and regression of the neurological deficit might be observed.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 rTPA administered by the intravenous route within 6 hours has been shown to be possibly effective and safe in acute MCA strokes, despite the phenomenon of parenchymal hemorrhagic transformation.20 21 22 23 Three double-blind studies concerning limited numbers of patients with acute strokes in the ICA territory have suggested that rTPA may be effective in this indication.24 25 26 Large-scale, multicenter, randomized, double-blind studies are needed to give definite results on the effectiveness and safety of the product, at a given dose and under specific conditions.
However, information is still lacking regarding several problems that have not yet been completely resolved concerning rTPA thrombolysis of acute carotid territory strokes: clinical severity of stroke in patients undergoing therapy, acceptable interval time to treatment, use of an efficient heparin therapy, timing of administration and dose of heparin, existence of early rethrombosis, nature and predictive value of postthrombolytic CT scan images, and causes and possible prevention of hemorrhagic transformation. Therefore, open studies with careful attention to these parameters are still needed to suggest new hypotheses and prepare new multicenter studies.
In this series of 43 consecutive patients with all types of stroke in the carotid artery territory, treated with a classic and slow dose of rTPA (0.8 mg for 90 minutes), we have investigated the preceding problems, with special reference to the correlations between excellent outcome and specific reperfusion images on early CT scan.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patients, Inclusion Criteria, and Clinical Assessment
Between January 1, 1994, and December 31, 1994, we proposed an open protocol of intravenous rTPA to all patients presenting symptoms of acute ICA stroke and meeting specific inclusion criteria. These criteria were as follows: (1) informed consent given by the patient or the patient's relatives; (2) age between 20 and 81 years (2 patients aged 80 years were included); (3) onset of stroke within 7 hours before treatment; (4) absence of hemorrhage at CT scan; (5) presentation with clinical syndromes consistent with occlusions of arteries of the carotid artery territory: MCA (trunk or branch), ACA, and anterior choroidal artery; (6) permanent or ingravescent symptomatology since the onset of stroke; and (7) a baseline neurological presentation with an SSS27 score lower than 48.
The inclusion criteria did not involve a limitation of severity levels. Ten patients had severe disturbances of consciousness, but hemispheric symptoms such as fixed eye deviation and hemiplegia with facial palsy could still be detected. The series included a high proportion of patients with severe deficits, since 34 of 43 patients had a baseline SSS score lower than 30. Inclusion in the trial was also possible for patients with hypodensities on the initial CT scan, which might involve more than one third of the carotid territory and mass effects.
The exclusion criteria included intracranial hemorrhage; systolic hypertension >250 mm Hg; shock; possible pregnancy; critical cardiac, pulmonary, renal, or hepatic condition; and classic contraindications to thrombolysis (surgical operation, recent history of gastrointestinal bleeding, and known coagulopathies).
Treatments
Alteplase, predominantly single-chain rTPA (Actilyse,
Boehringer-Ingelheim), was used. The rTPA infusion was
administered immediately after the CT scan. The drug was given at the
dose of 0.8 mg/kg over 90 minutes at a constant infusion rate, with an
initial bolus of 10% of the dose. Heparin was administered according
to two consecutive protocols: (1) protocol 1, immediate
postthrombolytic efficient intravenous
heparin therapy: the initial dose of 300 U/kg was adjusted according to
the postthrombolytic fibrinogen value and, as soon as
it was normalized, raised to 1.5 times the activated partial
thromboplastin time (10 patients); and (2) protocol 2,
intravenous heparin at 24 hours, according to the same
protocol as in (1) and after the day 1 CT scan (25 patients). Eight
patients had treatments after the 48th hour because of
contraindications to the protocols: 5 had delayed
intravenous heparin because of early various systemic
bleedings, and 3 had low-molecular-weight heparin.
In patients with severe presentations, a complementary treatment of mannitol was given: for highly severe cases with stupor and conjugate eye deviation (SSS <6), a bolus of 100 mL of mannitol 20% was given at the time of thrombolysis and every 2 hours for 8 hours. For cases with complete hemiplegia without stupor (SSS <26), a bolus of 100 mL of 10% mannitol was given with the same pattern. Mannitol was administered to 31 patients (72%).
All patients were treated and monitored in an intensive neurological care unit for a week, with permanent automated control of arterial pressure, pulse rate, respiratory rate, and PaO2 and surveillance of clinical state every hour for at least 3 days. All patients with a clinically and/or echographically identified cardiac source of emboli, with good or bad outcome, had an anti–vitamin K anticoagulant therapy after heparin, with an international normalized ratio of between 2 and 3.
Outcome Assessment
The SSS assessment was done at 3 hours and 1 (24±4 hours), 7,
30, and 90 days. Interobserver reliability controls were done, and the
neurologist evaluation was compared with the nurse neurological
evaluation at days 1 and 7.
Regression of the clinical presentation within 3 hours after the beginning of thrombolysis was documented. Recovery to an SSS score greater than 48 was considered a major neurological improvement and defined "rapid regressors"; the same recovery at 24 hours defined "day 1 major neurological improvement." "Reinfarction syndrome" was defined on the basis of complete regression of the motor and/or aphasic deficit followed by a recurrence of the neurological deficit in the same territory within 48 hours after onset. Outcome was classified into four categories: (1) "total recovery" meant that SSS had returned to normal (score of 58) and that no significant neurological sign was observed, with a thorough neurological examination and higher function analysis; (2) "moderate outcome" corresponded to a presentation with objective neurological sequelae that allowed walking, communicating with speech, and a social life; (3) "poor result" corresponded to persistence of neurological signs or to severe neurological sequelae, with the patient dependent for activities of daily living; and (4) "death" corresponded to neurological death due to the infarct or hemorrhage. No other type of death was observed. The outcome assessment was done at days 30 and 90.
Statistical Analysis
In comparison studies, we made a distinction between overall
poor outcome/death at day 90 (including parenchymal hematomas) and a
specific ischemic poor outcome/death group at day 90,
characterized by the subtraction of the 3 patients with hematomas from
the former group. These groups were compared with the group showing a
complete recovery of symptoms at day 90. For intravenous
heparin, the following groups were considered: patients with immediate
heparin (protocol 1), patients who received heparin at 24 hours
(protocol 2), and the group of all patients who received delayed
intravenous heparin after 24 hours (25 patients of protocol
2 and 5 patients out of the protocol). For statistical
analysis, the values were expressed as mean±SD, and
differences between the groups were examined by two-sided
Student's t test and the exact 
2
two-sided test.
Radiological Assessment
CT scans were obtained before treatment, at 24±6 hours, and at
day 7 and were reviewed independently by a neuroradiologist and a
neurologist, without knowledge of treatment assignment and clinical
data. The images observed at days 1 and 7 were studied in terms of
morphology, with particular attention focused on the structured or
unstructured aspect of the hypodensities. An agreement on the
structuration of the images was found between the two observers on the
basis of the presented descriptions. Fig 1
shows
characteristic structured hypodensities (A and B) and unstructured
hypodensities (C and D). The topography of the images was studied
according to the following classification: (1) MCA territory, including
"basal ganglia" (including centrum semiovale);
"localized superficial," including limited
cortical-subcortical localization; "total superficial MCA,"
including lobular superficial MCA territory cortical-subcortical
localization, without lenticulostriate involvement; and "total
MCA," including superficial and basal ganglia territory, with
hemispheric involvement; (2) ACA territory; (3) MCA and ACA territory;
and (4) anterior choroidal artery territory. This classification allows
comparisons with classic MCA series.28 29 30 The CT template
used for vascular territories of the MCA and ACA was that of
Damasio31 and for the anterior choroidal artery that of
Hupperts et al.32 Parenchymal hematomas were defined
according to Pessin.33
|
Etiologic Data
All surviving patients (n=41) had an echo-Doppler
exploration and cardiac echography, either transthoracic or
transesophageal.
Biological Data
Coagulation tests were obtained before treatment and 2 and 24
hours after thrombolysis. They included fibrinogen,
FDP, activated partial thromboplastin time, euglobulin lysis
time, and prothrombin time. Blood count was done at days 1 and 2.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Outcome
Forty-three consecutive patients presented with an acute ischemic stroke of the carotid artery territory and met with the inclusion criteria of the protocol. The mean age at inclusion was 65±10.4 years, and the mean interval to treatment was 232±79 minutes. Table 1
presents the overall outcome
observed in these 43 patients. Twenty-four patients (55.8%) were
free of any neurological symptom at day 30 and 25 (58.1%) at day 90.
Twenty-four of these had had continuous improvement. One patient
who had a primary total recovery of his right hemiplegia showed signs
of recurrence at the 25th hour but totally recovered again
within 30 minutes with an increase in the dose of continuously infused
heparin. This case might be classified as transitory, or even
"controlled," early reinfarction syndrome. Three patients (6.9%)
had sequelae at day 90 after a slow improvement and were classified as
moderate. Thirteen patients (30.2%) had severe neurological sequelae,
with persisting hemiplegia and/or severe aphasia. Of these, 2 patients
who had a primary complete recovery experienced a secondary
recurrence of deficit: 1 at the 12th hour (early reinfarction)
and the other at the 48th hour; 9 patients had a progressive
aggravation or a stable deficit, without significant regression; and 2
patients had parenchymal hematoma with clinical deterioration. Two
patients died (4.6%), one of an ischemic evolution and the
other of a parenchymal hematoma.
|
Fourteen patients experienced major neurological improvement at 3 hours and 20 at 24 hours.
The overall parenchymal hematoma rate of this series was 6.9%. The 3 patients with these hematomas had had a major neurological improvement within 3 hours. In 2 patients the onset of deterioration took place before 24 hours, while they received early heparin according to protocol 1.
The overall early reinfarct rate was 6.9%; interestingly, 2 of 3 patients with early reinfarct syndrome had strokes in the territory of the anterior choroidal artery.
Table 1
also shows the outcome of patients with isolated MCA stroke on
the basis of days 1 and 7 CT scans (n=37). The total recovery rate at
day 90 was 62.1%. The 3 cases with MCA plus ACA strokes were in the
poor outcome group. In anterior choroidal artery stroke (3 cases), 2
patients had a total recovery.
Outcome Comparison Studies
The total recovery group (Group C) was compared with the
overall poor outcome/death group (Group A, including the 3 hematomas)
and the ischemic poor outcome/death group (Group B, without the
3 hematomas) (Table 2). The total recovery group was
significantly different from both poor outcome groups by several
characteristics: (1) increased proportion of 24-hour regressors; (2)
improved neurological score (SSS) at day 1; (3) lower proportion of
patients who had mannitol treatment; and (4) increased proportion
of patients showing "unstructured hypodensities" compared with
structured hypodensities at day 1 CT scan. There was also a trend
toward a higher baseline SSS score (less grave) in the total recovery
group (22.4 versus 15.1 and 14.2), but it did not reach statistical
significance. Conversely, no difference could be detected in this group
for age, time interval to treatment, proportion of 3-hour regressors,
proportion of isolated cardiac embolic sources, proportion of patients
with atrial fibrillation, and coagulation parameters.
|
Immediate heparin (protocol 1) versus heparin at 24 hours (protocol 2) resulted in no definite distinction between the outcome groups. The ischemic poor outcome/death group included a significantly lower proportion of patients with immediate heparin versus delayed heparin (at 24 and after 48 hours) compared with the total recovery group (P=.04), while the overall poor outcome/death group did not.
Etiologic Data
The causes of the artery occlusion could be deduced from
echo-Doppler and cardiac echography performed in the 41 survivors.
Nineteen isolated cardiac causes (44.1%) were detected. Eleven
isolated carotid atherothrombotic causes (25.6%) were found. Of the 5
patients with ICA thrombosis, 3 had a total recovery despite a
bilateral ICA thrombosis in 1 case. In the latter, 133Xe
measurement of the hemispheric blood flow showed no deficit in the
carotid territories. Six patients had ICA stenosis greater than
70%: 3 had a poor outcome and 3 had a total recovery. These 3 patients
had subsequent endarterectomy, with excellent
results.
Radiological Data
Baseline CT scan provided the following data: the images could be
considered normal in 18 cases; in 18 cases there was an effacement of
the sulci and the sylvian valley. A hypodensity less than one third of
the MCA territory was present in 5 patients and exceeding one third
of the MCA territory in 2. A hyperdense MCA sign was observed in 3
patients.
The topography of the ischemic process could only be deduced
from the day 1 CT scan and is presented in Table 3. Only 3 cases could be classified as anterior
choroidal artery strokes, 2 of them with a good evolution. The other
cases were in the territory of the MCA, 3 of them with hypodensities in
the ACA territory as well. The structure of the CT images is also shown
in Table 3. Review of the CT scans disclosed that there were actually
two types of hypodensity, according to the conformation and homogeneity
of density. Structured hypodensities were rather
homogeneous and could be clearly related to the classic
shape of infarcts of a specific arterial territory (Fig 1A and 1B). Unstructured hypodensities exhibited a round shape when they
were small and a polylobar and heterogeneous look when they
were larger, lacking the classic shape of the arterial
territory (Fig 1C and 1D). Their density was generally less
marked (Fig 1C). A trend toward local swelling, particularly affecting
the caudate nucleus (Fig 3A, J1), was observed. Table 3 shows that in
the poor outcome group, the day 1 scan always revealed a hypodensity,
structured in 9 cases and unstructured in 2. In the group with total
recovery, the day 1 CT scan was often normal (7 cases) and showed
hypodensities in 17 cases, exclusively of the unstructured type. We
observed only 1 case of unequivocal petechial hemorrhagic
transformation. The 3 parenchymal hematomas were located in the basal
ganglia region.
|
|
The data of the day 7 CT scan disclosed that in the ischemic
poor outcome/death group, all the hypodensities had transformed into
classic structured and dense hypodensities (Fig 2).
Conversely, in the total recovery group, only 1 unstructured
hypodensity had transformed into a structured infarct, while 3 (17.6%)
had disappeared, showing that these images might be transitory (Fig 3A). Moreover, a qualitative assessment of day 7 CT
scans showed that the remaining images tended to remain unstructured
and highly atypical (Fig 3B) or to clearly diminish in size (Fig 3C).
|
Coagulation Data
Table 2 presents the mean±SD of the coagulation
parameter values according to outcome. No significant
differences could be detected between the outcome groups, although
there was a trend toward higher postthrombolytic FDP
values in the poor outcome groups. In the subgroup with parenchymal
hematomas, 2 patients presented high
postthrombolytic FDP values (600 and 500 mg/L) and
rather low fibrinogen values (1.9 and 2.8 g/L).
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Clinical, Therapeutic, and Biological Data
In this small, open study of thrombolysis with rTPA in acute carotid artery territory strokes, the safety and efficacy of the method can only be suggested. The mortality at days 30 and 90 was 4.6%, and the parenchymal hematoma rate was 6.9%. This hemorrhagic complication is associated with a poor outcome, either severe neurological sequelae (2 cases) or death (1 case). This major drawback is compensated for by a large proportion of definitely improved cases, even with highly severe presentations: 25 of 43 patients (58.1%) showed a total recovery at day 90. Thus, in this study the risk-benefit ratio is fairly good. These results have been obtained with a medium dose of rTPA.
In MCA distribution strokes, the complete recovery at day 90 was 62.1%. Although an MCA occlusion was not angiographically proven in this series, the outcome is much better than that observed in the historical MCA occlusion series of Saito et al28 and Yoshimoto et al.29 The 3 patients with MCA and ACA distribution strokes all had poor prognoses. Anterior choroidal artery strokes showed a reinfarction syndrome in 2 of 3 patients but finally had an excellent prognosis in 2 patients with immediate post-rTPA heparin therapy.
The reinfarction phenomenon was observed in 3 patients (6.9%). It had been observed in 1 patient by Brott et al21 and documented in 1 patient by postmortem study by Von Kummer and Hacke.20 Although its frequency seems less than in myocardial infarction,34 the phenomenon might be underestimated and could occur in patients with poor prognosis.
Clinically, our 3 patients with parenchymal hematomas had primary excellent outcomes, and all 3 belonged to the subgroup of rapid regressors (within 3 hours). Clinical deterioration due to the hematoma was thus an extreme disappointment. To our knowledge, the link between complete rapid recovery and hematoma has not been reported; it should be studied in future series. In these patients, abnormalities of systolic and diastolic tension were not found,35 and primary recanalization was probable. Conversely, 2 patients had high postthrombolytic FDP values. These data suggest that in the mechanism of parenchymal hematomas, at least two factors might be combined: (1) a particularly strong and sudden reperfusion after recanalization, which might sollicitate the lenticulostriate arteries in particular, and (2) a particularly strong fibrinolytic syndrome.
The outcome comparison studies showed that there was a strong correlation between major neurological improvement at day 1 and excellent outcome. It is highly probable that this primary reactivity is the clinical translation of early recanalization of the occluded vessel, as suggested by several authors in studies with angiography.5 6 7 9 10 11 12 20 23 25 Moreover, at day 1, 2 of 3 hematomas had already occurred. Conversely, major neurological improvement within the first 3 hours is not a significant predictor of overall outcome, as shown by our comparison data.
A clear trend toward a higher baseline SSS score (less grave) in the total recovery group was observed. The lack of statistical significance might be due to the small size of our series. Thus, it seems probable that patients with intermediate and minor clinical symptoms have a better chance of total recovery than those with grave presentations. The mannitol data provide further information on this subject, since the total recovery group was characterized by a significantly lower proportion of patients who had received mannitol. However, 13 of 25 patients received the drug in this group, ie, those with a baseline SSS score lower than 26, which indicates that 13 patients classified as severe had a final total recovery. Thus, there may be no a priori invalidity score limitation to be used in the indication of the method.
Our results showed a lack of significant correlation between the time interval to treatment and the total recovery rate, within 7 hours. These data indicate that in the therapeutic window proposed, the inclusion time might not be the main issue for outcome. Experiments of reperfusion after complete MCA occlusion in the baboon have recently shown that a definite benefit concerning final ischemic damage could still be obtained at the 6th hour.36
Comparison studies showed that the effect of immediate heparin versus delayed heparin was ambiguous. From an ischemic point of view, there was a trend toward an increased proportion of patients with such a regimen in the total recovery group compared with the ischemic poor outcome group. This positive role might be due to the prevention or control of early reinfarction, a fact verified in one case of anterior choroidal artery stroke. However, immediate heparin versus delayed heparin had no influence on the overall outcome (with hematomas), since 2 patients with protocol 1 had this hemorrhagic complication.
In our series, the better prognosis of strokes of cardiac origin was not observed. Conversely, good clinical results were observed in patients with thrombosis of the ICA (3 total recoveries of 5), despite the rarer recanalization of the artery.20 23 37 In ICA thrombosis, thrombolysis might be useful by directly dissolving the downstream MCA or MCA and ACA emboli or by the recanalization of an occluded artery that has strategic importance for the hemodynamic compensation of the occlusion. This mechanism is highly probable in 1 patient with bilateral carotid thrombosis, who presented with a completed MCA stroke with complete recovery, normal CT scan at day 7, and an excellent cerebral blood flow demonstrated with 133Xe single-photon emission CT. As reported by Von Kummer and Hacke,20 both recanalization and collateral reperfusion are involved in good results of rTPA.
In high-grade ICA stenosis, our study shows that good clinical results were obtained as well (3 total recoveries of 6). Thrombolysis might work by dissolving the downstream emboli but also by impeding the complete local thrombosis of the prethrombotic process, a mechanism documented by angiography in 1 of these patients. The complete regression of symptoms transformed these three strokes into transient ischemic attacks. All 3 patients had endarterectomy, just as with transient ischemic attacks, with an excellent result.
The efficacy of rTPA (alteplase) thrombolysis in acute ischemic stroke, suggested in the present small study, has recently been demonstrated by the National Institutes of Health large, double-blind, randomized study on functional outcome at 3 months of patients with all types of strokes, without baseline clinical or CT scan limitations and with treatment within 3 hours.38 No excess mortality was observed. Another large, double-blind, randomized study, the European Cooperative Acute Stroke Study,39 has also shown the efficacy of the drug for this end point when administered within 6 hours, but in a selected population of patients with hemispheric acute strokes with clinical and CT scan gravity restrictions and only in the target population.
Given this general efficacy, the published open and double-blind
rTPA trials can be reviewed (Table 4), so that several
parameters of the rTPA technique can be evaluated. The dose
of rTPA is the main parameter to be discussed. Our dose of
0.8 mg/kg seems to be related to a low hematoma rate and a high
complete recovery rate. It is close to that of the early inclusion
double-blind series of Haley et al,26 in which 0.85
mg/kg was administered for 60 minutes within 180 minutes after stroke
onset, with various protocols of heparin administration: the mortality
rate in the informative group was also low (8.3%), the hematoma rate
was 0%, and the excellent outcome rate (no limitations) was 41.6%. In
the NINDS study,38 with another comparable dose of 0.9 mg,
the outcome parameters also included a low hematoma rate
(7%) and a high excellent outcome rate at day 90 (39%), despite
probable inclusion of grave vertebrobasilar strokes. The problem of
higher doses of alteplase has been posed by the open study of Von
Kummer and Hacke,20 who used 100 mg (
1.6 mg/kg) during
60 minutes in all MCA stroke patients. Compared with the preceding
low-dose series, this study might indicate that a high dose of
alteplase does not provoke a definite increase of the excellent outcome
rate, while it might increase the mortality rate. This might be due to
the possible increase of the hematoma rate with the increase of the
rTPA dose21 37 but also to other factors that remain to be
determined, such as sudden postthrombolytic reperfusion edema with
mass effect.40 In the European Cooperative Acute Stroke
Study,39 with a dose of 1.1 mg/kg administered in a
clinically and radiologically selected population, even in the target
population the hematoma rate remained fairly high (19.4%), while the
excellent outcome rate at day 90 was 40.9%. Thus, a dose in the range
of 0.8 to 0.9 mg/kg of alteplase with a 10% bolus might be a
reasonable compromise between efficacy and safety, even when applied to
series of patients that include severe cases.
|
Other factors might play a role in the satisfactory outcome rates of our series: the longer time of rTPA infusion (90 minutes), the use of intravenous heparin in most of the patients, and the use of mannitol in the acute phase in gravely ill patients. Mannitol has never been shown in a controlled trial to improve stroke outcome. However, this antiedematous agent might contribute to the control of postthrombolytic brain edema40 and the final recovery of a subgroup of patients in grave condition at risk of herniation.
Concerning the role of postthrombolytic heparin,
administered immediately or with delay, the data of the literature as
reviewed in Table 4 do not allow clear correlations. The study of Von
Kummer and Hacke,20 in which heparin was immediately
given, suggested that this procedure might not actually be a factor in
increasing the parenchymal hematoma rate. Similarly, according to the
data of the literature it is not yet possible to assess (1) the role of
an initial bolus of rTPA, (2) the duration of administration of the
drug, (3) the time interval to treatment, (4) the monitoring of
arterial tension, and (5) the use of antiedematous
adjunctive drugs. Large-scale, double-blind, randomized trials
with several arms are needed to address these issues.
Radiological Data
The specific imaging referred to as unstructured
hypodensities, observed at day 1 on the CT scan, was significantly
related to total recovery of neurological symptoms. To our knowledge,
the characteristics and outcome associated with the structure of the
day 1 images have not been described before this report. A relationship
between the small size of the infarct on the day 1 CT scan and
recanalization of the occluded artery had been
described.41 Indeed, the unstructured hypodensities
observed here are very different from documented conventional
ischemic hypodensities, mainly by their polylobar and round
shape, with a lack of the precise structure related to the territory of
a specific branch. The density at day 1 is already different from that
of preinfarction hypodensities. A swelling of deep structures is often
associated: a typical aspect of basal ganglia unstructured
hypodensities is the swelling of the caudate nucleus in the lateral
ventricle (Fig 3A [day 1] and 3B [day 1]). Brott et
al21 had reported that mass effects on CT scan might be
associated with neurological improvement. The disappearance of this
type of image at day 7 in 3 of 17 cases in our experience indicates
that it is different from the classic ischemic process and may
have a benign significance. The coexistence of this type of image with
total recovery or rapidly improving deficit at day 1 also shows that a
massive parenchymal lesion does not take place. The most probable
origin of these images is a transitory edema associated with
reperfusion and rupture of the hematocerebral barrier. In the
reperfusion of large areas associated with complete MCA or ACA-MCA
occlusion, however, this edema might be harmful.
In conclusion, these results support the potential efficacy and safety of intravenous rTPA in carotid artery strokes, even in late treatments and in severe presentations with disturbances of consciousness, with a dose of 0.8 mg/kg given for 90 minutes after a bolus. The intervention of adjunctive treatments, particularly mannitol in the acute phase, possibly explains our total recovery rate at day 90. Unstructured hypodensities on the day 1 CT scan, which were sometimes impressive in our study, may coexist with return of neurological function and are likely to be reperfusion images.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
The authors wish to express their gratitude to the rescue squads of SAMU, the emergency personnel (Services of Professors Malicier and Fournier), and the personnel of the Cerebrovascular Unit of Hôpital Neurologique, Lyon (Sylvie Baillart, chief nurse), without whose courage and dedicated efforts this work would not have been possible.
Received August 14, 1995; revision received January 22, 1996; accepted January 22, 1996.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. Zeumer H, Freitag HJ, Brzyska U, Nunzig HP. Local intraarterial fibrinolysis in acute vertebrobasilar occlusion: technical developments and recent results. Neuroradiology. 1989;3:336-340.
2. Miyakawa T, Sakuragawa N. The cerebral vessels and thrombosis. Rinsho Ketsueki. 1984;2:1001-1026.
3. Zeumer H. Vascular recanalising techniques in interventional neuroradiology. J Neurol. 1985;231:287-294. [Medline] [Order article via Infotrieve]
4. Maiza D, Theron J, Pelouze GA, Casasco A, Courtheoux P, Derlon JM, Mercier V, Petetin L, Everard C. Local fibrinolytic therapy in ischemic carotid pathology. Ann Vasc Surg. 1988;2:205-214. [Medline] [Order article via Infotrieve]
5.
del Zoppo GJ, Ferbert A, Otis S, Bruckmann H, Hacke W,
Zyroff J, Harker L, Zeumer H. Local
intraarterial fibrinolytic therapy in acute carotid
territory stroke: a pilot study. Stroke. 1988;19:307-313.
6.
Hacke W, Zeumer H, Ferbert A, Bruckmann H, del
Zoppo GJ. Intra-arterial
thrombolytic therapy improves outcome in patients with
acute vertebrobasilar occlusive disease. Stroke. 1988;19:1216-1222.
7. Theron J, Courtheoux P, Casasco A, Alachkar F, Notari F, Ganem F, Maiza D. Local intraarterial fibrinolysis in the carotid territory. AJNR Am J Neuroradiol. 1989;10:753-765. [Abstract]
8. Lehmann R, Zschenderllein R, Gromnica-Ihle E, Ziemer S. Lokale intravasale Fibrinolyse (LIF) bei akuten zerebrovascularen Vershlussen. Radio Diagn. 1989;30:481-488.
9.
Mori E, Tabuchi M, Yoshida T, Yamadori A.
Intracarotid urokinase with thromboembolic occlusion of the middle
cerebral artery. Stroke. 1988;19:802-812.
10. Mori E, Tabuchi M, Yoshida T, Yamadori A. Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery. Stroke. 1988;19:802-812.
11. Mori E, Tabuchi M, Ohsumi Y, Yoshida T, Ohkawa S, Yoneda Y, Yamadori A. Intraarterial urokinase infusion therapy in acute thromboembolic stroke. Stroke. 1990;21(suppl I):I-74. Abstract.
12. Mori E. Fibrinolytic recanalization therapy in acute cerebrovascular thromboembolism. In: Hacke W, del Zoppo GJ, Hirschberg M, eds. Thrombolytic Therapy in Acute Ischemic Stroke. New York, NY: Springer-Verlag; 1991:207-212.
13. Ikeda S, Muraishi K. Intracranial major artery occlusion. Stroke. 1990;21(suppl I):I-95-I-96.
14. Berg-Dammer E, Topper R, Mobius E, Nahser HC, Kuhne D. Local thrombolytic therapy of thromboembolic occlusion of the middle cerebral artery. In: Proceedings of the Second International Conference on Acute Stroke; June 1-2, 1991; Geneva, Switzerland; 62.
13. Siepmann G, Muller-Jensen M, Gossens H, Lachenmeyer L, Zeumer H. Local intraarterial fibrinolysis in acute middle cerebral artery occlusion. Neuroradiology. 1991;33(suppl):69-71.
14. Möbius E, Berg-Dammer E, Kuhne D, Nahser HC. Local thrombolytic therapy in acute basilar artery occlusion: experience with 18 patients. In: Hacke W, del Zoppo GJ, Hirschberg M, eds. Thrombolytic Therapy in Acute Ischemic Stroke. New York, NY: Springer-Verlag; 1991:213-215.
15. Seikmann R, Wakhloo AK, Schumacher M. Local intraarterial thrombolysis in old patients. In: Proceedings of the Second International Conference on Acute Stroke; June 1-2, 1991; Geneva, Switzerland.
16. Matsumoto K, Satoh K. Topical intraarterial urokinase infusion for acute stroke. In: Hacke W, del Zoppo GJ, Herschberg M, eds. Thrombolytic Therapy in Acute Ischemic Stroke. New York, NY: Springer-Verlag; 1991:207-212.
17. Yamaguchi T, Hayakawa T, Kikuchi H, Abe T. Thrombolytic therapy in embolic and thrombotic cerebral infarction: a cooperative study. In: Hacke W, del Zoppo GJ, Hirschberg M, eds. Thrombolytic Therapy in Acute Ischemic Stroke. New York, NY: Springer-Verlag; 1991:168-174.
18. Baird AE, Donnan GA, Austin MC, Fitt GJ, McKay WJ. HMPAO SPECT measures reperfusion after thrombolytic therapy in acute stroke. In: del Zoppo GJ, Mori E, Hacke W, eds. Thrombolytic Therapy in Acute Ischemic Stroke II. New York, NY: Springer-Verlag; 1993:301-303.
19. Williams MA, Razumovshy AY, Diringer MN, Monsein LH, Debrun GM, Bryan RN, Hanley DF. Transcranial Doppler sonographic (TCD) monitoring of basilar artery thrombolysis. In: del Zoppo GJ, Mori E, Hacke W. Thrombolytic Therapy in Acute Ischemic Stroke II. New York, NY: Springer-Verlag; 1993:298-300.
20.
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.
21.
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, part I: pilot study for tissue
plasminogen activator administered within 90
minutes. Stroke. 1992;23:632-640.
22.
Haley EC Jr, Levy DE, Brott TG, Sheppard GL, Wong MCW,
Kongable GL, Torner JC, Marler JR. Urgent therapy for stroke,
part II: pilot study of tissue plasminogen
activator administered 91-180 minutes from onset.
Stroke. 1992;23:641-645.
23. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Greenlee R Jr, Brass L, Mohr JP, Feldmann 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]
24. Yamaguchi T, Hayakawa T, Kikuchi H. Intravenous tissue plasminogen activator in acute thromboembolic stroke: a placebo-controlled, double blind trial. In: del Zoppo GJ, Mori E, Hacke W, eds. Thrombolytic Therapy in Acute Ischemic Stroke II. New York, NY: Springer-Verlag; 1993:59-65.
25.
Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S,
Oshumi Y, Kitano K, Tsutsumi A, Yamadori A.
Intravenous recombinant tissue plasminogen
activator in acute carotid artery territory stroke.
Neurology. 1992;42:976-982.
26.
Haley EC Jr, Brott TG, Sheppard GL, Barsan W, Broderick
J, Marler JR, Kongable GL, Spilker J, Massey S, Hansen CA, Torner
JC. Pilot randomized trial of tissue plasminogen in
acute ischemic stroke. Stroke. 1993;24:1000-1004.
27. Lindenstrom E, Boysen G, Christiansen LW, Hansen BR, Nielsen PW. Reliability of Scandinavian Neurological Stroke Scale. Cerebrovasc Dis. 1991;23:646-652.
28.
Saito I, Segawa H, Shikawa Y, Taniguchi M, Tsutsumi
K. Middle cerebral artery occlusion: correlation of computed
tomography and angiography with clinical outcome.
Stroke. 1987;18:863-868.
29. Yoshimoto T, Ogawa A, Seki H, Kogure T, Suzuki J. Clinical course of acute middle cerebral artery occlusion. J Neurosurg. 1986;65:326-330. [Medline] [Order article via Infotrieve]
30.
Ueda S, Fujitsu K, Inomori S, Kuwabara T.
Thrombotic occlusion of the middle cerebral artery.
Stroke. 1992;23:1761-1766.
31.
Damasio H. A computed tomographic guide to the
identification of cerebral vascular territories. Arch
Neurol. 1983;40:138-142.
32.
Hupperts RMM, Lodder J, Heuts-van Raak EM, Kessels
F. Infarcts in the anterior choroidal artery territory:
anatomical distribution, clinical syndromes, presumed pathogenesis and
early outcome. Brain. 1994;117:825-834.
33. Pessin MS. Hemorrhagic transformation in the natural history of acute embolic stroke. In: Hacke W, del Zoppo GJ, Hirschberg M, eds. Thrombolytic Therapy in Acute Ischemic Stroke. New York, NY: Springer-Verlag; 1991:67-74.
34. Marder VJ, Sherry S. Thrombolytic therapy: current status. N Engl J Med. 1988;318:1585-1595. [Medline] [Order article via Infotrieve]
35. Levy DE, Brott TG, Haley EC, Marler JR, Sheppard GL, Barsan W, Broderick P. Factors related to intracranial hematoma formation in patients receiving tissue-type plasminogen activator for acute ischemic stroke. Stroke. 1994;25:291-297. [Abstract]
36. Touzani O, Young AR, Derlon JM, Baron JC, MacKenzie ET. Reversible middle cerebral artery occlusion (MCAO) in anesthetized baboons: serial metabolic studies with PET. Cerebrovasc Dis. 1995;5:230. Abstract.
37.
Overgaard K, Sperling B, Boysen G, Pedersen H, Gam J,
Ellemann K, Karle A, Arlien-Soborg P, Olsen TS, Videbaek Ch, Knudsen
JB. Thrombolytic therapy in acute ischemic
stroke: a Danish pilot study. Stroke. 1993;24:1439-1446.
38.
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.
39.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, Von
Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerici M,
for the ECASS Study Group. Intravenous
thrombolysis with recombinant tissue
plasminogen activator for acute hemispheric
stroke. JAMA. 1995;274:1017-1025.
40. Koudstaal PJ, Stibbe J, Vermeulen M. Fatal ischaemic brain oedema after early thrombolysis with tissue plasminogen activator in acute stroke. Br Med J. 1988;297:1571-1574.
41. Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, Gregory J, del Zoppo GJ, and the rt-PA Acute Stroke Study Group. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. AJNR Am J Neuroradiol. 1993;14:32-43.
This article has been cited by other articles:
 |
|
 |
|
  H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.M. Sugg, E.A. Noser, H.M. Shaltoni, N.R. Gonzales, M.S. Campbell, R. Weir, E.D. Cacayorin, and J.C. Grotta Intra-arterial reteplase compared to urokinase for thrombolytic recanalization in acute ischemic stroke. AJNR Am. J. Neuroradiol., April 1, 2006; 27(4): 769 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mangiafico, M. Cellerini, P. Nencini, G. Gensini, and D. Inzitari Intravenous Tirofiban With Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke: Preliminary Experience in 11 Cases Stroke, October 1, 2005; 36(10): 2154 - 2158. [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]
|
|
|
|
 |
|
 J M Wardlaw, T M West, P A G Sandercock, S C Lewis, and O Mielke Visible infarction on computed tomography is an independent predictor of poor functional outcome after stroke, and not of haemorrhagic transformation J. Neurol. Neurosurg. Psychiatry, April 1, 2003; 74(4): 452 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A C Pereira, P J Martin, and E A Warburton Thrombolysis in acute ischaemic stroke Postgrad. Med. J., March 1, 2001; 77(905): 166 - 171. [Full Text]
|
|
|
|
|
|
H. Yanamoto, I. Nagata, Y. Niitsu, Z. Zhang, J.-H. Xue, N. Sakai, H. Kikuchi, and C. Iadecola Prolonged Mild Hypothermia Therapy Protects the Brain Against Permanent Focal Ischemia Editorial Comment Stroke, January 1, 2001; 32(1): 232 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Brott and J. Bogousslavsky Treatment of Acute Ischemic Stroke N. Engl. J. Med., September 7, 2000; 343(10): 710 - 722. [Full Text] [PDF]
|
|
|
|
 |
|
 K. H. Lee, S. J. Lee, S.-J. Cho, D. G. Na, H. S. Byun, Y.-B. Kim, H.-J. Song, I.-S. Jin, and C.-S. Chung Usefulness of Triphasic Perfusion Computed Tomography for Intravenous Thrombolysis With Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Arch Neurol, July 1, 2000; 57(7): 1000 - 1008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Trouillas, L. Derex, N. Nighoghossian, J. Honnorat, W. Li, P. Neuschwander, G. Riche, J. C. Getenet, Y. Berthezene, F. Turjman, et al. rtPA intravenous thrombolysis in anterior choroidal artery territory stroke Neurology, February 8, 2000; 54(3): 666 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Thulborn, T. S. Gindin, D. Davis, and P. Erb Comprehensive MR Imaging Protocol for Stroke Management: Tissue Sodium Concentration as a Measure of Tissue Viability in Nonhuman Primate Studies and in Clinical Studies Radiology, October 1, 1999; 213(1): 156 - 166. [Abstract] [Full Text]
|
|
|
|
|
|
P. Trouillas, N. Nighoghossian, L. Derex, P. Adeleine, J. Honnorat, P. Neuschwander, G. Riche, J.-C. Getenet, W. Li, J.-C. Froment, et al. Thrombolysis With Intravenous rtPA in a Series of 100 Cases of Acute Carotid Territory Stroke : Determination of Etiological, Topographic, and Radiological Outcome Factors Stroke, December 1, 1998; 29(12): 2529 - 2540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gonner, L. Remonda, H. Mattle, M. Sturzenegger, C. Ozdoba, K.-O. Lovblad, R. Baumgartner, C. Bassetti, and G. Schroth Local Intra-Arterial Thrombolysis in Acute Ischemic Stroke Stroke, September 1, 1998; 29(9): 1894 - 1900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Grond, C. Stenzel, S. Schmulling, J. Rudolf, M. Neveling, A. Lechleuthner, S. Schneweis, and W.-D. Heiss Early Intravenous Thrombolysis for Acute Ischemic Stroke in a Community-Based Approach Stroke, August 1, 1998; 29(8): 1544 - 1549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. Choudhri, B. L. Hoh, R. A. Solomon, E. S. Connolly Jr, and D. J. Pinsky Use of a Spectrophotometric Hemoglobin Assay to Objectively Quantify Intracerebral Hemorrhage in Mice Stroke, November 1, 1997; 28(11): 2296 - 2302. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||