From the Division of Neurosurgery (J.G.F., X.L., D.A.H., M.S.S.),
Department of Molecular and Medical Pharmacology (D.A.H.), and Department of
Surgery (L.T.B.), University of California at Los Angeles School of Medicine;
West Los Angeles Veterans Hospital (Calif) (J.G.F.); Department of Pathology,
University of Southern California School of Medicine, Los Angeles (D.S.H.);
and Beijing Neurosurgical Institute (People's Republic of China) (G.L.).
Correspondence to John G. Frazee, MD, Division of Neurosurgery, UCLA School of Medicine, Box 957039, Los Angeles, CA 90095-7039. E-mail frazee{at}surgery.medsch.ucla.edu
Methods—Ten adult male baboons underwent 3.5 hours of reversible
middle cerebral artery occlusion (MCAO) under isoflurane (0.25% to
1.5%) anesthesia. Five randomly chosen animals received
RTN treatment 1 hour after start of MCAO. Somatosensory evoked
potentials were recorded during MCAO. Animals were assigned daily
neurological scores. Animals were killed 6 days after MCAO, and brains
were quantitatively analyzed for infarct volume.
Results—Within 1 hour after RTN was started, treated animals
showed significantly improved somatosensory evoked potentials (103.3%
versus 75% of baseline; P<0.01). Likewise, the
combined neurological score for the RTN-treated group was 99.2, while
the combined mean score for the untreated group was 66.4
(P<0.015). The mean infarction volume was 8.8±3.1%
(of contralateral hemisphere) for the control group and 0.3±0.2% for
the RTN-treated group (P<0.01). No increased
mortality was seen in the RTN-treated group.
Conclusions—We conclude that RTN treatment during MCAO
effectively reverses the pathophysiological
sequelae of ischemia, even when the treatment is initiated 1
hour after the onset of ischemia. Although the infarct volume
in the control group was variable when quantitatively assessed 6
days after 3.5 hours of MCAO, virtually no evidence of infarcts was
seen in the RTN-treated group.
We have refined a technique that addresses the drawbacks of both
the clot lysis and collateral drug delivery approaches to the treatment
of acute stroke. This technique, termed retrograde transvenous
neuroperfusion (RTN), rapidly delivers the patient's own
arterial blood directly to the ischemic brain
through the cerebral venous system, a system that is redundant, is
without valves, and is not affected by
atherosclerosis.9 RTN is an
adaptation of coronary retrograde perfusion used for the
treatment of acute myocardial ischemia.10
We first described the use of RTN in primates in
1990.11 Ueda et al12 have
described a similar technique in rats.
RTN uses an external pump to harvest arterial blood from
the subject's femoral artery and to transport the blood through 2
catheters placed into each of the transverse sinuses near the
torcular.13 The blood is directed
retrograde, opposite to normal venous flow, through the central, deep,
and superficial sinuses and veins to reach the capillary bed. This is
accomplished by pump-controlled flow rates and by partial obstruction
of the venous sinuses using the catheter itself or variably inflatable
balloons at the catheter tips. Pressures only moderately above normal
venous pressures and well within acceptable limits are all that are
necessary to drive the blood toward the ischemic tissue. The
blood presumably traverses the capillary bed to exit through the
redundant venous system.
In this study we hypothesized that RTN treatment, initiated 1 hour
after middle cerbral artery occlusion (MCAO), would reverse the effects
of prolonged ischemia as assessed by somatosensory evoked
potentials (SSEPs), neurological evaluations, and quantitative
neuropathological analysis in baboons.
Focal reversible ischemia was induced for 3.5 hours by right
MCAO with a transorbital approach and an aneurysm clip (Figure 1A
Five randomly chosen animals (RTN-treated group) received RTN treatment
beginning 1 hour after the start of ischemia and continued
during the final 2.5 hours of arterial occlusion. The RTN
treatment was initiated 1 hour after MCAO since that was the length of
time typically required to expose the sinus and catheterize the femoral
artery. For RTN treatment, arterial blood was harvested
from a femoral artery by an external bladder pump (Neuroperfusion,
Inc). The blood was passed through the 2 catheters
(Neuroperfusion, Inc) in the transverse sinuses and directed retrograde
by the partial obstruction of the sinuses by the catheter and by the
flow rate. Maximum flow rates were determined by intrasinus pressures
measured at the catheter tips (Neuroperfusion, Inc). Intrasinus
pressures were maintained between 8 and 15 mm Hg. The mean
resting intrasinus pressure during ischemia was 2.8
mm Hg for the RTN-treated group (5.0 mm Hg for the control
group). The mean intrasinus pressure during RTN treatment was 9.8
mm Hg. RTN was continued for the last 2.5 hours of the 3.5 hours of
ischemia. Five additional animals (control group) were
subjected to the same treatments as the RTN-treated group except that
retrograde arterial blood flow was never started. After 3.5
hours, aneurysm clips were removed from all animals in both
groups to permit reperfusion. All surgical sites were closed, and
animals were awakened. Each experiment typically lasted <5 hours.
Animals were observed daily, and neurological examinations were scored
by 2 blinded observers using a system similar to human stroke scores
(Table 1
Grass subdermal needle electrodes were positioned over the median
nerves. For each side, the anode was 1 cm from the wrist crease and the
cathode was 1.5 cm proximal to the anode. The SSEP was elicited by a
0.2-millisecond constant-current square-wave peak given to the left and
right median nerves separately. The stimulus presentation
rate was 4 Hz. Cortical SSEPs were recorded from Grass subdermal
needles placed in the scalp overlying the contralateral (to the evoking
stimulus) somatosensory cortex. Subcortical SSEPs were recorded
with the use of a subdermal electrode placed over the second cervical
vertebra. Bilateral subdermal electrodes were also placed at Erb's
point. The cortical and subcortical electrodes were both referenced to
a subdermal electrode placed over the midline 5 cm behind the orbital
rim. Ground electrodes were placed on both ears and connected together.
SSEP recording was continuously performed by a recorder
(Axon System, Inc) over an analysis time of 40 milliseconds. In
all experiments, a 40% decrease from baseline SSEPs signified the
presence of ischemia.15
Animals were killed on the sixth day after the experiment, and
their brains were removed and immersion fixed in 10% buffered formalin
for 4 weeks. For each case, coronal sections (75 µm) were cut
through the middle cerebral artery (MCA) territory at 1-mm intervals
and stained for hematoxylin and eosin. Each coronal section was
digitized on a high-resolution scanner (Epson 636) and stored on a
CD-ROM. These digitized images were assessed by the neuropathologist
(D.S.H.), who was blinded as to the treatment of each animal. Infarcted
areas were traced with the aid of a computer on the basis of optical
density differences, and volumes were calculated by multiplying infarct
areas of each brain slice by the thickness of each slice. Optical
densities for infarcted areas showed a decrease in optical density of
>40% compared with surrounding tissue. The resulting volumes for all
slices from the right hemisphere were combined and expressed as a
percentage of the contralateral hemisphere volume.
Data Analysis
During each experiment, SSEPs were observed to fall in amplitude after
MCAO. The amplitudes reached a steady depressed state within 30 minutes
and remained depressed in untreated animals until the aneurysm
clips were removed. The RTN-treated animals showed a similar pattern of
depression after arterial occlusion, but within 30 minutes
of the start of RTN they began to show a return toward
preischemic levels. By the end of treatment, the SSEPs were
improved over the baseline levels. The mean potential changes for the
untreated group were -27%, -25%, and -21% at 1, 2, and 3.5 hours
after occlusion, respectively (Table 4
Daily stroke scores were averaged for the 6-day posttreatment
period. Three untreated animals were slow to improve and had
substantially lower scores during their recovery, while 2 showed no
evidence of abnormal behavior. All RTN-treated animals were nearly
normal on the first day after treatment. The combined results of the
untreated group gave a mean stroke score for the 6 days of 66.4, while
the combined mean score for the RTN-treated group was 99.2
(P<0.01) (Table 4
Pathological outcome was consistent with that of the stroke
score results. Major infarctions were present in 4 untreated
animals with lowered neurological scores and were absent or
insignificant in all RTN-treated animals, all of which had stroke
scores of
The infarct size for the control group after 3.5 hours of MCAO
was somewhat variable. In fact, 1 of the 5 untreated control cases
showed only minor signs of an infarction. For the remaining 4
animals, the range of infarct volumes was 5.3% to 17%, which is
consistent with those reported by Young et
al.16 In their investigation, 6-hour MCAO in
anesthetized baboons, with the use of a similar transorbital
approach and microvascular clips, resulted in 3% to 11% infarcted
volume in only 6 of 10 cases. In addition, a recent study by Nehls et
al17 was only able to demonstrate infarcted brain
areas after a similar MCAO in 4 of 6 baboons. These authors and
others14 18 concluded that the infarct size
produced after MCAO is significantly greater and more
consistent when unanesthetized animals are used. Their
assertion is based on the following rationales: (1)
anesthesia offers significant neuroprotection; (2)
anesthesia induces marked recruitment from collateral
vessels; (3) stress from immobilization in unanesthetized
animals results in hypocapnia, which exacerbates the
injury; and (4) long periods of stress induced in
unanesthetized animals may increase blood-brain permeability.
These studies support the conclusion that anesthetic levels
predominantly influence the variability in infarct size in our
untreated control group.
However, it is important to remember that the variability in infarct
volume within the control group does not invalidate our findings, since
no macroscopic or microscopic evidence of an infarction was seen in 3
of 5 cases after RTN treatment. The 2 remaining cases showed extremely
small infarcts (Table 5
Our data provide indirect evidence that the ischemic
tissue maintained viability as a result of retrograde flow of femoral
arterial blood to the ischemic capillary bed during
the RTN treatment. In support of this hypothesis,
Symon19 measured MCA and middle cerebral vein
pressures in primates before and after MCAO. Before occlusion, pressure
measured in the proximal MCA averaged 94 mm Hg, while middle
cerebral vein pressure averaged 14 mm Hg. Assuming an
The present study was designed to maximize the benefit of RTN
by introducing a short time between the onset of arterial
occlusion and the start of RTN treatment. Previous animal studies by
others have suggested that the therapeutic window for the treatment of
acute stroke may be much longer than 1
hour.21 22 23 This window for reperfusion or
recanalization may be much longer than once
thought. A recent study by Young and coworkers16
compared the infarct volume of 6-hour MCAO with permanent MCAO. They
demonstrated that reperfusion, even after a 6-hour ischemic
insult, can reduce the infarct volume by as much as 85%. Their
findings, as well as those by Ringelstein et
al,24 support the conclusion that early
reperfusion, either by clot lysis or by RTN, leads to better clinical
outcome and smaller infarct size. In fact, when
recanalization took >8 hours, the eventual lesions
invaded cortical MCA territories.24 Our studies
strongly suggest that RTN technique can significantly reduce the time
to reperfusion and thus maintain tissue viability until the
ischemic tissue can be recanalized spontaneously or by tPA.
In future studies, more clinically relevant studies will address the
ability of RTN to reduce or prevent stroke when applied several hours
after the start of an ischemic insult. It is also presumed that
in the future, RTN may be used to deliver important brain-protecting
agents directly to the ischemic vascular bed. The addition of
these agents theoretically could improve outcome and lengthen the
window of opportunity during which a neurological deficit could be
resolved.
Received May 12, 1998;
revision received June 15, 1998;
accepted June 15, 1998.
2.
Kalache A, Aboderin I. Stroke: the global burden.
Health Policy Plan.. 1995;10:1–21.
3.
Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW,
Jacobson MF. Lifetime cost of stroke in the United States.
Stroke. 1996;27:1459–1466.
4.
Sacco RL. Risk factors and outcomes for
ischemic stroke. Neurology. 1995;45(suppl
1):S10–S14.
5.
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.
6.
Grotta JC. Can raising cerebral blood flow improve
outcome after acute cerebral infarction? Stroke. 1987;18:264–267.
7.
Onesti ST, Solomon RA, Quest DO. Cerebral
revascularization: a review.
Neurosurgery. 1989;25:618–628.[Medline]
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8.
Yonas H, Gur D, Claassen D, Wolfson SJ, Moossy, J.
Stable xenon-enhanced CT measurement of cerebral blood flow in
reversible focal ischemia in baboons. J
Neurosurg. 1990;73:266–273.[Medline]
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Bousser MG, Barnett HJM. Stroke:
Pathophysiology, Diagnosis, and Management. New York, NY:
Churchill Livingstone; 1992:517–537.
10.
Corday E, Haendchen RV. Seminar on coronary
venous delivery systems for support and salvage of jeopardized
ischemic myocardium, I: introduction. J
Am Coll Cardiol. 1991;18:253–256.[Medline]
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11.
Frazee JG, Jordan SE, Dion JE, Kar S, Vinuela F, Rand
RW, Corday E. Ischemic brain rescue by transvenous perfusion in
baboons with venous sinus occlusion. Stroke. 1990;21:87–93.
12.
Ueda T, Yamamoto YL, Takara E, Diksic M. Tolerance of
the cerebral venous system to retrograde perfusion pressure in focal
cerebral ischemia in rats. Stroke. 1989;20:378–385.
13.
Hudgins WR, Garcia JH. Transorbital approach to the
middle cerebral artery of the squirrel monkey: a technique for
experimental cerebral infarction applicable to ultrastructural studies.
Stroke. 1970;1:107–111.
14.
Spetzler RF, Selman WR, Weinstein P, Townsend J,
Mehdorn M, Telles D, Crumrine RC, Macko R. Chronic reversible cerebral
ischemia: evaluation of a new baboon model.
Neurosurgery. 1980;7:257–261.[Medline]
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15.
Nuwer MR. Evoked Potential Monitoring in the
Operating Room. New York, NY: Raven Press; 1986.
16.
Young AR, Touzani O, Derlon J-M, Sette G, MacKenzie ET,
Baron J-C. Early reperfusion in the anesthetized baboon reduces
brain damage following middle cerebral artery occlusion.
Stroke. 1997;28:632–638.
17.
Nehls DG, Todd MM, Spetzler RF, Drummond JC, Thompson
RA, Johnson PC. A comparison of the cerebral protective effects of
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primates. Anesthesiology. 1987;66:453–464.[Medline]
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18.
Jones TH, Morawetz RB, Crowell RM, Marcoux FW,
FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral
ischemia in awake monkeys. J Neurosurg. 1981;54:773–782.[Medline]
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Symon L. Regional vascular reactivity in the middle
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Fagrell B, Intaglietta M. Microcirculation: its
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Del Zoppo GJ, Copeland BR, Waltz TA, Zyroff J, Plow EF,
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22.
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FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral
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24.
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PN, Thron A. Type and extent of hemispheric brain infarctions and
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Associate Editor for Basic Science,
Virginia Commonwealth University,
Medical College of Virginia,
Richmond, Virginia
Clearly, additional work would be necessary before deciding that this
technique is a useful addition to our armamentarium for treatment of
human stroke.
Received May 12, 1998;
revision received June 15, 1998;
accepted June 15, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Retrograde Transvenous Neuroperfusion: A Back Door Treatment for Stroke
Abstract
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
Background and Purpose—Stroke is
the third leading cause of death and the leading cause of adult
disability in the United States. The clot-lysis drug tissue
plasminogen activator is the only treatment
that has been effective for acute stroke patients, yet there are
significant limitations to its use and effectiveness. In this study
retrograde transvenous neuroperfusion (RTN) was evaluated for its
efficacy in reversing acute ischemia, preventing paralysis, and
limiting pathological evidence of infarction in baboons.
Key Words: cerebral ischemia • middle cerebral artery occlusion • perfusion • stroke, experimental • baboons
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
For decades, investigators have unsuccessfully sought an
effective early treatment for stroke.1 Stroke is
the third leading cause of death in the United States, affecting
>500 000 people each year. It is the leading cause of adult
disability, with costs reaching >$30 billion
annually.2 3 4 Eighty percent of strokes are
ischemic, resulting from an arterial obstruction.
This obstruction is most commonly caused by a blood clot, which has led
to the use of clot-lysis drugs such as tissue plasminogen
activator (tPA).5 However, tPA use
has important limitations, including a potentially significant time to
achieve clot lysis, 3-hour treatment window from the onset of symptoms,
and nearly 6% occurrence of cerebral
hemorrhage.5 Another approach to stroke
treatment has been the reliance on collateral circulation for the
delivery of drugs that may reduce or prevent cellular
injury.6 7 The use of the collateral circulation
depends on an indirect pathway for delivery of these drugs, a pathway
that is neither efficient nor completely
effective.8
Materials and Methods
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
Ten adult male baboons (Papio ursinus) weighing 20 to
30 kg were studied. Their care and treatment were in accordance with
institutional guidelines. All animals were premedicated with
ketamine (7.5 mg/kg IM) and atropine (0.04 mg/kg IM), then
intubated, paralyzed with pancuronium bromide (Pavulon, 0.1 mg/kg IV),
and placed on a respirator delivering a tidal volume of 10 mL/kg.
Isoflurane (0.25% to 1.5%) and nitrous oxide (60%) were used for
continuous anesthesia. Animals were monitored for ECG,
blood pressure, end-tidal CO2, oxygen saturation,
electroencephalography, and SSEPs. 
). All animals had catheters placed in
1 femoral artery as a source for arterial blood. Two
catheters were surgically placed in the right and left transverse
sinuses adjacent to the torcular (Figure 1B). All animals were fully
anticoagulated (heparin, 100 U/kg) and periodically supplemented with
one third of the original dose of heparin as needed to maintain the
activated clotting time at >300 seconds.
View larger version (23K):
[in a new window]
Figure 1. The baboon anterior cerebral arterial
(ACA) system is shown with a single aneurysm clip occluding the
right MCA. Major venous sinuses (sagittal and transverse) are shown
with RTN catheters in place. Arterial blood is harvested
from a femoral artery by an external pump and passed through the 2
catheters. Blood is directed retrograde through the sagittal as well as
other sinuses (not shown). ICA indicates internal carotid artery; A-1
segments, the right and left anterior cerebral arteries before becoming
a single A-2 segment. ). The scores between the
2 observers, which did not deviate by >5 to 15 points (out of 100),
were averaged for each day.
View this table:
[in a new window]
Table 1. Scoring System for Neurological
Evaluations
All values are expressed as mean±SEM. Statistical
analysis for SSEPs was conducted with one-way ANOVA by group
and time, with percent change from baseline levels as within-subject
variable. Neurological evaluations (stroke scores) between treated
and untreated groups over 6 days were compared with the Kruskal-Wallis
test. Comparisons of vital signs and infarct size for treated and
nontreated control groups were made with the 2-tailed Student's
t test. Values of P<0.05 were considered
significant.
Results
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
Vital signs remained stable throughout all experiments, except
that systolic and mean arterial blood pressures
began to rise in each animal after MCAO (Table 2). Nitroprusside (1 to 5 µg/kg per
minute) was intravenously infused to maintain a mean
systolic pressure of 170 mm Hg and a mean
arterial pressure of 115 mm Hg. Ventilation was
adjusted during the experiment to maintain normal blood chemistry
values (Table 3). The start of RTN, by
design, raised intrasinus pressures to higher than resting levels but
no greater than 20 mm Hg. Intracranial pressures followed the
intrasinus pressures in a delayed fashion, and values for both
pressures were similar. After the termination of RTN, intrasinus and
intracranial pressures returned to baseline levels.
View this table:
[in a new window]
Table 2. Physiological Values From Control (n=5) and
RTN-Treated (n=5) Animals During
Treatment
View this table:
[in a new window]
Table 3. Blood Chemistry Values From Control (n=5) and
RTN-Treated (n=5) Animals During
MCAO ).
The values for the same time periods in the RTN-treated group were
-13%, 3.3%, and 72%.
View this table:
[in a new window]
Table 4. Results From Control (n=5) and RTN-Treated
(n=5) Animals 
). 
98. The worst untreated animal had a 17% infarction
(volume of infarction expressed as a percentage of the contralateral
hemisphere) (Table 5). The 1 remaining
untreated animal also had a detectable infarct localized to the right
MCA territory, but it constituted only 2.5% of the contralateral
hemisphere. For the RTN-treated group, only 2 animals showed any
indications of infarction, but even in these cases, the infarct sizes
(0.5% to 0.8%) were 3 to 4 times smaller than the most minor infarct
seen without RTN treatment (Table 5; Figure 2). The mean infarction volume of the
right hemisphere was 8.8±3.1% for the control group and 0.3±0.2%
for the RTN-treated group (P<0.01).
View this table:
[in a new window]
Table 5. Quantitative Measurements of Infarct Size From
Control (n=5) and RTN-Treated (n=5)
Animals
View larger version (94K):
[in a new window]
Figure 2. A, Macroscopic coronal views used to determine
infarct boundaries by the neuropathologist (D.S.H.) blinded to
treatment protocol. Coronal sections from an unstained control
(untreated) case. IC indicates internal capsule; C, caudate; P,
putamen; and GP, globus pallidus. B, Sections similar to those in A
except from a representative RTN-treated case. Note the
absence of necrosis and edema within the basal ganglia (arrows). C,
Histological section showing the edge of cerebral
infarct in the region of the extreme capsule and claustrum (denoted by
asterisks in A and B) from a representative control
animal stained with hematoxylin and eosin. Note the macrophage
infiltration within the infarct. D, Histological
section showing region similar to that presented in C for a
representative RTN-treated animal. Bar=1 cm for A and B
and 0.2 mm for C and D.
Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
In this study the results from SSEPs, stroke scores, and
infarct size consistently demonstrated a positive effect from
RTN treatment. After 1 hour of ischemia, RTN treatment was
begun and was able to produce recovery from ongoing ischemia as
measured by SSEPs. Stroke scores used to monitor the recovery of these
animals over the next 6 days demonstrated a rapid and nearly full (mean
stroke score, 99.2) recovery for the treated animals. The untreated
animals incompletely recovered (mean stroke score, 66.4). Finally, the
volume of injured brain was greater for the untreated animals in which
it was found and occurred in more animals than for the RTN-treated
group. ; Figure 1B), which were 3 to 21 times smaller
than any infarct seen in the control group. 
80%
drop in pressure between arterial and capillary pressures,
it would be predicted that pressures in the nonischemic
capillary bed would range between 18 and 28 mm Hg. This is in
keeping with actual capillary bed measurements of 18 to 22 mm Hg
in more accessible tissue of the finger.20 We
predicted, therefore, that when RTN reached a pressure near 20
mm Hg, blood would flow retrograde to normal brain perfusion. When
Symon19 measured pressures during
ischemia, he found that arterial pressures fell to
a mean of 20.6 mm Hg and venous pressures fell to a mean of
9.4 mm Hg. The pressure in the ischemic capillary bed of
a primate must therefore be intermediate between measured
arterial and venous pressures, ie, 9.4 to 20.6 mm Hg.
Thus, it would only be necessary to generate pressures slightly higher
than that of the ischemic capillary bed to produce retrograde
flow that would pass preferentially to the ischemic bed. The
pressures measured in the transverse sinuses during experiments
reported here averaged 10 mm Hg, which agrees well with our
theoretical prediction.
Acknowledgments
We thank Gena Behnke for her excellent photographic work and
Heather Carter for her assistance in preparing this manuscript. We
acknowledge the generous use of the retroperfusion system from
Neuroperfusion, Inc, Irvine, Calif.
References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
1.
Barinaga M. Finding new drugs to treat stroke.
Science. 1996;272:664–666.
Editorial Comment
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
In the accompanying article, Frazee and colleagues showed that
application of RTN baboons subjected to MCAO resulted in improved
functional and pathological outcomes. Clearly, this technique supplies
enough blood to the ischemic brain to prevent permanent neurological
damage. It is important to consider what might be the potential
clinical application of this technique in human stroke. Since the
technique of necessity can be applied for only relatively short periods
of time, it will be necessary to couple it with a more definitive
treatment for the arterial obstruction, such as thrombolytic therapy.
This raises 2 questions. First, assuming the patient arrives at a
medical facility within the appropriate therapeutic window, would the
combined application of RTN and thrombolytic therapy be more beneficial
than thrombolytic therapy alone? A second important question is whether
the application of RTN is safe under conditions of thrombolysis.
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