(Stroke. 1999;30:787-792.)
© 1999 American Heart Association, Inc.
Original Contributions |
Extracorporeal Rheopheresis in the Treatment of Acute Ischemic Stroke
A Randomized Pilot Study
From the Departments of Neurology (J.B., J.K., A.R., D.S.) and Nuclear Medicine (H.B., S.H.), University of Leipzig, and the Department of Nuclear Medicine, Hannover Medical School (W.H.K.) (Germany).
Correspondence to Jörg Berrouschot, MD, Department of Neurology, University of Leipzig, Liebigstrasse 22a, 04103 Leipzig, Germany. E-mail berj{at}medizin.uni-leipzig.de
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Abstract |
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Background and Purpose—Extracorporeal rheopheresis is a safe method to optimize hemorheology. Our aim was to determine whether treatment with extracorporeal rheopheresis in patients with acute ischemic hemispheric stroke improves cerebral perfusion as assessed with serial 99mTc–ethyl-cysteinate-dimer single-photon emission CT (99mTc-ECD SPECT). We also investigated how clinical outcome is associated with treatment and imaging results.
Methods—Thirty-three patients (mean age, 64±10 years) with acute ischemic hemispheric stroke were included in a prospective, randomized, parallel group pilot study. First treatment with or without extracorporeal rheopheresis took place within 12 hours after the onset of symptoms and was repeated 3 times at intervals of 24 hours. Hemorheological parameters were measured before and after each session. Each patient underwent 99mTc-ECD SPECT immediately before treatment, 6 to 8 hours after treatment, and after 5 days. A semiquantitative SPECT graded scale was used to measure depth and extent of activity deficits and thus to quantify the perfusion deficit.
Results—Seventeen patients were actively treated with extracorporeal rheopheresis, and 16 patients did not receive extracorporeal rheopheresis. After 3 months, no differences were found in the functional or neurological outcome. Despite a rapid, sustained decrease of plasma viscosity and erythrocyte aggregation in the rheopheresis group, there was no significant difference in the SPECT graded scale after therapy between the 2 groups. Patients with early reperfusion (decrease in the SPECT graded scale >25% 6 to 8 hours after therapy compared with the baseline examination) experienced a better functional outcome (Modified Rankin Scale) after 3 months compared with patients without reperfusion (P=0.04).
Conclusions—Since quantitative flow mapping and clinical follow-up did not reveal any differences between patients who were treated with extracorporeal rheopheresis and controls, it appears very unlikely that extracorporeal rheopheresis enhances reperfusion after acute cerebral ischemia.
Key Words: rheology • stroke, ischemic • tomography, emission computed • viscosity
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In a previous study we showed that extracorporeal membrane differential filtration (rheopheresis) is a safe method to optimize hemorheology in patients with acute ischemic stroke.1 Extracorporeal rheopheresis quickly and effectively lowers plasma viscosity and erythrocyte aggregation without affecting the hematocrit, so that the oxygen transport capacity for the ischemic brain remains constant, in contrast to widespread hemodilution.
Single-photon emission CT (SPECT) can be used to assess impaired perfusion in the acute stage of ischemia and during follow-up. The retention of tracer 99mTc–ethyl-cysteinate-dimer (99mTc-ECD), however, not only reflects cerebral perfusion but also intact cerebral metabolism.2 3 The aim of this study was to investigate whether treatment with extracorporeal rheopheresis in patients with acute ischemic hemispheric stroke improves cerebral perfusion as assessed with serial 99mTc-ECD SPECT, and how clinical outcome is associated with treatment and imaging results.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From March 1996 to December 1997, 33 patients (mean age, 64±10 years) at our Neurological Critical Care Unit were included in this prospective, randomized, parallel group pilot study. Inclusion criteria were as follows: age 18 to 80 years, sudden onset of a focal neurological deficit in the territory of the middle cerebral artery (MCA), Scandinavian Stroke Scale score (46 points maximum, without "gait") <40 points, normal CT or slight hypodensity of <33% of the MCA territory, and an activity deficit in the territory of the MCA on the baseline 99mTc-ECD SPECT to rule out transient ischemia or minor stroke.4 Treatment with or without extracorporeal rheopheresis had begun within 12 hours after the onset of symptoms. Exclusion criteria were as follows: coma, previous stroke, severe cardiac insufficiency (New York Heart Association class III or IV), acute infection, and contraindications against therapeutic heparinization.
The patients underwent first extracorporeal rheopheresis within 12 hours after the onset of symptoms, second treatment 12 to 24 hours after first treatment, and third and fourth treatments 24±3 hours after previous treatment. No thrombolytic or neuroprotective drugs, drugs affecting hemorheology, platelet aggregation inhibitors, or antithrombotic drugs (with the exception of heparin) were permitted.
Computed Tomography
Baseline CT was performed before the start of treatment, with
follow-up CTs after the first treatment session and on day 5. For
detection of early infarction signs (parenchymal hypoattenuation or
focal swelling), the baseline CT was used. The size of infarction and
hemorrhagic transformation (according to the European Cooperative Acute
Stroke Study 1 [ECASS-1] classification: hemorrhagic infarction HI 1
or HI 2 and parenchymal hemorrhage PH 1 or PH
25 6 ) were determined on the follow-up CT.
99mTc-ECD SPECT
The 99mTc-ECD studies were performed with
the use of a brain-dedicated SPECT camera (Ceraspect, DSI) with 3
rotating parallel hole collimators. 99mTc-ECD
(400 MBq) was used for the first SPECT examination before therapy
started. Six to 8 hours after the first extracorporeal rheopheresis, a
first SPECT control was performed with 600 MBq
99mTc-ECD, with a second one (600 MBq
99mTc-ECD) after the end of treatment on day 5.
The SPECT examinations for the control group were performed at the same
time as those for the active treatment group. The method and evaluation
technique used have been described in detail in a previous
report.4
For semiquantitative region of interest (ROI) analysis of all 3
SPECT studies, 5 transverse and 3 coronal slices were selected in each
patient at predefined distances from the commissura
anterior–commissura posterior line (transverse slices: Talairach
coordinates=-20 mm, +1 mm, +8 mm, +21 mm, +34
mm) and from the line perpendicular to the commissura
anterior–commissura posterior line cutting the commissura anterior
(coronal slices: Talairach coordinates5 mm, -16 mm,
-37 mm), respectively. In these 8 slices, 88 ROIs were generated
with the use of a commercial program (Ceraspect, DSI) and were assigned
to anatomic structures according to the stereotaxic atlas
of Talairach and Tournoux.7 Count densities of ROIs of the
symptomatic hemisphere were related to those of the
corresponding contralateral regions and classified as abnormal if a
deficit was >10% (ratio 
0.90), in agreement with widely accepted
standards.8 In accordance with Hanson et al,9
we used the SPECT graded scale, a measure of the intensity and spatial
extent of activity deficits (respective ischemia). Each ROI was
given a score of 0 to 9, where 0 indicated a ratio 
0.91, 1 a
ratio of 0.81 to 0.90 (corresponding to 81% to 90% activity compared
with the contralateral side), 2 a ratio of 0.71 to 0.80, etc. The
scores for all the individual ROIs were added to produce the SPECT
graded scale. Early and late reperfusion were defined as a decrease in
the SPECT graded scale >25% between baseline and the first or second
control.10 11 SPECT analysis was performed by
blinded observers with respect to the type of therapy and the clinical
outcome.
Extracorporeal Rheopheresis and Laboratory Investigation
Extracorporeal rheopheresis was performed with a
Hemomat-Plasmomat device (Diamed). The Hemomat-Plasmomat was equipped
with a plasma filter (Plasmaflow OP, Asahi Medical Co) and a rheofilter
(Cascadeflo AC-1760, Asahi Medical Co). After separation of the plasma,
it was pumped through the rheofilter; molecules <900 000 Da were
returned to the patient, whereas the high-molecular-weight components
of the plasma were retained in the hollow fibers of the rheofilter. The
exact procedure is described elsewhere.1
During the entire treatment period, intravenous anticoagulation with heparin (doubling of the partial thromboplastin time) was performed for both patients with extracorporeal rheopheresis and patients of the control group.
The following laboratory parameters were measured before and after each extracorporeal rheopheresis and at parallel times for the patients of the control group: plasma viscosity (capillary tube plasmaviscosimeter, Fresenius; normal range, 1.17 to 1.31 mPa · s), erythrocyte aggregation (Mini-Aggregometer, Myrenne; normal range at 3/s, 16 to 37), hematocrit (Coulter STKS, Coulter; normal range, 0.37 to 0.52), red blood cell count (Coulter STKS, Coulter; normal range, 4.2 to 6.0 1012/L), and fibrinogen (CA 5000, DADE; normal range, 1.5 to 4.5 g/L).
Clinical Investigations and Follow-Up
Scores on the Scandinavian Stroke Scale were determined before
the start of therapy, on day 5, and after 90±14 days. Patients who
died received 0 points. On day 90±14, scores on the Barthel Index and
the Modified Rankin Scale were determined by one of the examiners
(A.R.), who was not aware of the kind of treatment the patients
received.
Statistical Analysis
Clinical data, SPECT, and CT findings between the 2 groups were
compared with the Mann-Whitney U test, the Student's
t test for unpaired data, and the 
2
test. For paired samples the Wilcoxon test was used. For
laboratory values a level of significance of 0.01 was selected; a level
of 0.05 was selected for all other values.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Demographic and Clinical Findings
Seventeen of 33 patients were treated with and 16 without rheopheresis. The 2 groups did not differ in terms of demographic findings, vital parameters, or the severity of neurological deficit on admission (Table 1
). Therapy
was commenced on average 6.5 hours after the onset of symptoms (range,
4 to 9 hours).
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There were no statistical differences in neurological or functional
outcome between the 2 groups after 5 days or after 3 months (Table 1
). Three patients in each group died. Four patients (2 in each
group) died of space-occupying brain edema caused by the
ischemic infarction between day 5 and 10. The other 2 patients
died of pneumonia after 46 and 74 days.
Hemorheological Findings
Treatment with extracorporeal rheopheresis produced an immediate
reduction of plasma viscosity (18% reduction), red blood cell
aggregation (55% reduction), and fibrinogen (58% reduction) sustained
throughout the entire period of treatment. Red blood cell counts and
hematocrit did not change. In the control group, the rheological
parameters remained constant throughout the entire
treatment period (Table 2).
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CT Findings
Twenty patients (61%) (12 rheopheresis, 8 controls) had early
infarct signs in the baseline CT. In the follow-up CT after 5 days, no
infarct signs were found in 3 patients, 11 patients had infarcts <33%
of the MCA territory, 8 patients had infarcts 33% to 66% of the MCA
territory, and 11 patients had infarcts >66% of the MCA territory.
There was no statistical difference between actively treated patients
and controls with respect to infarct size (Table 3).
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Twelve patients (36%), 6 in each group, had a hemorrhagic transformation, including 1 patient in the control group with PH 2 and clinical deterioration.
Semiquantitative 99mTc-ECD SPECT Findings
There was no difference in the SPECT graded scale changes between
patients treated with extracorporeal rheopheresis and patients of the
control group. Although patients in the control group experienced on
average a greater improvement of the SPECT graded scale, the difference
was not statistically significant (Table 3).
Patients with early reperfusion (6 to 8 hours after therapy) had a
better functional outcome after 3 months than patients without (Table 4). Of the 6 patients with early
reperfusion who had a good functional outcome (Modified Rankin Scale 0
to 1), 3 patients were actively treated and 3 were controls.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results of this study do not lend support to the hypothesis that optimization of hemorheology (namely of plasma viscosity and red blood cell aggregation) leads to an improvement of cerebral blood flow and cerebral metabolism in patients with hemispheric ischemic stroke. To date, a large number of studies on the effectiveness of hemodilution in acute ischemic stroke have been performed. None of these studies has demonstrated the efficacy of this therapy principle.12 13 14 15 One possible reason is the time window, which may still be too large. Indeed, in a study based on animal experiments in which hemodilution was started within 3 hours after the onset of symptoms, the size of infarct was shown to have been reduced and the neurological outcome improved.16 Another possible reason is that pure rehydration alone in the placebo group obviously had a beneficial effect, and, particularly in patients with hematocrit
45%, seems to
have a better effect than hemodilution.17 Furthermore,
blame has been placed on the limited reduction of hematocrit, although
the optimum hematocrit (ie, that which facilitates the best possible
flow properties of the blood and sufficient oxygen transport capacity)
for humans with ischemic stroke is not known.18 An
increase in cerebral blood flow is not a result of the improved
rheological properties of blood but rather of vasodilatation owing to
the lower oxygen supply and the shift of the oxygen dissociation
curve.19 20 21 In the ischemic tissue, where the
vessels undergo maximum dilatation as a result of acidosis, an
additional increase in blood flow is not possible, and the reduction of
oxygen transport capacity tends to lead to a further drop in oxygen
tension in the cerebral tissue.22
The main target of a rheological therapy approach should therefore not
be the hematocrit (whole blood viscosity, more influence on
macrocirculation23 24 ) but rather plasma viscosity and
erythrocyte aggregation (more influence on
microcirculation).23 25 Reduced plasma viscosity lowers
vessel resistance (Hagen-Poiseuille's law) and thus raises cerebral
blood flow (Ohm's law). Using extracorporeal rheopheresis, we
were able to quickly and lastingly reduce plasma viscosity and
erythrocyte aggregation by the selective elimination of
high-molecular-weight proteins (fibrinogen,
2-macroglobulin),1 26
lipoproteins,27 28 and
cholesterol.29 This approach is designed to
improve not only the flow characteristics in microcirculation but also
the disrupted erythrocyte-endothelium
interaction.24 29 30 There are currently no comparable
studies in the literature.31 Rubba et al29
demonstrated an increase in blood flow velocities in
transcranial Doppler after LDL apheresis in patients
with familial hypercholesterolemia that they
attributed to the restoration of endothelium-mediated
vasodilation, which is inhibited by a high concentration of LDLs.
To examine the effect of the hemorheological treatment approach on cerebral blood flow and ultimately on cerebral metabolism, we chose 99mTc-ECD SPECT examinations. SPECT can be performed easily and in a well-reproducible manner in the acute setting of ischemic stroke patients. In a number of studies, semiquantitative SPECT analyses were used for interindividual and intraindividual follow-up studies in ischemic stroke patients.32 33 34 35 36 In contrast to 99mTc–hexamethlypropyleneamine oxime, 99mTc-ECD is not purely a perfusion marker but also seems to depend on the intact cerebral metabolism.2 3 37 Consequently, use of the term "reperfusion" here is somewhat problematical; on the other hand, without reperfusion (spontaneous or therapeutically induced) of parts of the ischemic brain tissue, the brain metabolism will not be improved, and the ultimate objective of our therapeutic efforts is not improved cerebral blood flow (luxury perfusion, nonnutritional flow) but rather improved brain metabolism. Despite sufficient optimization of the rheological properties in the treatment group compared with the control group, we were unable to demonstrate any effect on cerebral blood flow or metabolism on 99mTc-ECD SPECT. There were no differences between the 2 groups either in the acute phase 6 to 8 hours after therapy or after the end of treatment on day 5. This cannot be due to a lack of sensitivity on the part of SPECT because we have distinctly shown that even with small numbers of patients, those with early reperfusion (within 6 to 8 hours after therapy) had a better functional 3-month outcome than patients without reperfusion. Hence, 99mTc-ECD SPECT appears to be a good indicator of clinical improvement in patients with ischemic stroke.
The main reason for extracorporeal rheopheresis failing to benefit cerebral blood flow and metabolism could be the large time window between the onset of symptoms and the start of treatment. The manner in which we provided extracorporeal rheopheresis was correct (rapid and sustained optimization of the hemorheology), and at the present time extracorporeal rheopheresis is one of the most or perhaps the most effective method to improve hemorheology.26 However, the therapeutic time window in patients with ischemic stroke is unknown.38 39 40 Key animal experiment studies argue that after ischemia lasting >6 hours in conscious monkeys, there is no brain tissue left that can be saved.41 42 This hypothesis is also supported by the fact that all studies with neuroprotective drugs,43 44 45 thrombolysis,5 46 47 and hemodilution15 in the 6-hour time window had negative results in humans. This does not mean that individual patients may have a longer time window,48 although this appears to be the exception rather than the rule. It is probably no coincidence that the only positive stroke trial performed thus far had a 3-hour time window.49
In summary, extracorporeal rheopheresis resulted in a rapid and sustained optimization of hemorheology in patients with acute ischemic stroke. However, within a therapeutic time window of 12 hours after the start of symptoms, this treatment did not produce an improvement in neurological or functional outcome in comparison to the control patients. On 99mTc-ECD SPECT, a positive effect on cerebral blood flow and metabolism could not be ascertained either in the acute phase (6 to 8 hours after first rheopheresis) or after the end of the 4 extracorporeal rheopheresis sessions. The chief reason for this may have been that the therapeutic time window was too large. Patients with early reperfusion (6 to 8 hours after therapy) on 99mTc-ECD SPECT had a better functional 3-month outcome than patients without reperfusion.99mTc-ECD SPECT could be a useful tool for monitoring therapeutic interventions in patients with acute ischemic stroke.
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Acknowledgments |
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This study was sponsored by Diamed (Cologne, Germany) and Hoechst-Germany.
Received November 26, 1998; revision received January 22, 1999; accepted January 22, 1999.
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