(Stroke. 2001;32:553.)
© 2001 American Heart Association, Inc.
Original Contributions |
Human Albumin Therapy of Acute Ischemic Stroke
Marked Neuroprotective Efficacy at Moderate Doses and With a Broad Therapeutic Window
From the Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami School of Medicine, Miami, Fla.
Correspondence to Myron D. Ginsberg, MD, Department of Neurology (D4-5), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101. E-mail mdginsberg{at}stroke.med.miami.edu
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Abstract |
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Background and Purpose—We examined the neuroprotective efficacy of moderate-dose human albumin therapy in acute focal ischemic stroke and defined the therapeutic window after stroke onset, within which this therapy would confer neurobehavioral and histopathological neuroprotection.
Methods—Sprague-Dawley rats were anesthetized with halothane/nitrous oxide and received 2-hour middle cerebral artery occlusion (MCAo) by a poly-L-lysine–coated intraluminal suture. Neurological status was evaluated during occlusion (60 minutes) and daily for 3 days after MCAo. In the dose-response study, human albumin doses of either of 0.63 or 1.25 g/kg or saline vehicle (5 mL/kg) were given intravenously immediately after suture removal. In the therapeutic window study, a human albumin dose of 1.25 g/kg was administered intravenously at 2 hours, 3 hours, 4 hours, or 5 hours after onset of MCAo. Three days after MCAo, brains were perfusion-fixed, and infarct volumes and brain swelling were determined.
Results—Moderate-dose albumin therapy significantly improved the neurological score at 24 hours, 48 hours, and 72 hours and significantly reduced total infarct volume (by 67% and 58%, respectively, at the 1.25- and 0.63-g/kg doses). Cortical and striatal infarct volumes were also significantly reduced by both doses. Brain swelling was virtually eliminated by albumin treatment. Even when albumin therapy (1.25 g/kg) was initiated as late as 4 hours after onset of MCAo, it improved the neurological score and markedly reduced infarct volumes in cortex (by 68%), subcortical regions (by 52%), and total infarct (by 61%).
Conclusions—Moderate-dose albumin therapy markedly improves neurological function and reduces infarction volume and brain swelling, even when treatment is delayed up to 4 hours after onset of ischemia.
Key Words: brain edema • cerebral ischemia, focal • hemodilution • middle cerebral artery occlusion • neuroprotection
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Introduction |
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Ischemic cerebrovascular disease ranks among the leading causes of death and long-term disability throughout developed countries. Preventive measures targeted at major risk factors have reduced stroke incidence and mortality rates.1 Until recently, however, no specific drug therapies have been developed, which, if administered after the onset of acute stroke, would succeed in diminishing the extent of tissue damage and improving functional outcome. The sole exception in current clinical practice is the thrombolytic agent recombinant tissue-type plasminogen activator (tPA), shown in a randomized North American clinical trial to improve functional outcome in ischemic stroke if administered within 3 hours of stroke onset.2 Although some prospective, multicenter surveys of tPA use have subsequently confirmed favorable clinical outcomes and low symptomatic intracerebral hemorrhage rates in clinical practice,3 other community practice surveys have called attention to frequent deviations from national treatment guidelines and high rates of intracerebral hemorrhage and in-hospital death.4 In actual clinical practice, only a very small proportion of patients with acute ischemic stroke actually receive tPA therapy.
Rigorous laboratory investigations of cerebral ischemia conducted over the past 2 decades have identified key biochemical and molecular mechanisms that contribute to the death of brain tissue—factors whose prompt antagonism might result in tissue salvage.5 Critical thresholds of ischemic brain injury have been defined,6 and the central roles of excitotoxicity,7 tissue calcium overload,8 oxygen radicals,9 inflammatory mediators,10 and other factors have been established. These insights have stimulated major commercial efforts to develop and test a variety of pharmaceutical antagonists of these processes.11 12 The emergence of vexatious adverse effects in early-phase clinical trials, however, has in many cases thwarted these efforts. To date, no pharmaceutical neuroprotectant has been proven to be efficacious in randomized clinical trials of ischemic stroke.12
Thus, in the therapy of acute ischemic stroke, there is a clear and urgent need for a neuroprotective agent that has proven efficacy, carries minimal risk of side effects or toxicity, is acceptable both to medical personnel and to patients and their families, and can be administered without the need for complicated laboratory studies or sophisticated delivery systems. Human serum albumin (Alb) is a unique multifunctional protein with neuroprotective properties. In recent experimental studies of focal cerebral ischemia, we have shown that high-dose human Alb therapy (2.0 to 2.5 g/kg), if administered promptly (2 hours) after stroke onset, is highly effective in improving neurological status and in reducing infarction volume and extent of brain swelling.13 14 15 These studies were conducted in a widely used, minimally invasive model of middle cerebral artery occlusion (MCAo) in the albino rat that gives rise to a consistent behavioral deficit and a large, highly reproducible cortical and subcortical infarct resembling the lesion of thromboembolic stroke in patients.16 In our previous studies, however, we had not defined the therapeutic window of neuroprotective efficacy for human Alb therapy and we had not assessed the efficacy of lower (clinically more achievable) Alb doses. These goals constituted the objectives of the present study, in which we now demonstrate that human Alb remains highly neuroprotective when administered at moderate doses and that the therapeutic window extends to 4 hours after stroke onset.
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Materials and Methods |
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Animal Preparation
Male Sprague-Dawley rats weighing 270 to 360 g were studied after an overnight fast. Animal protocols were approved by the University of Miami Animal Care and Use Committee. After administration of atropine sulfate (0.5 mg/kg IP), animals were anesthetized with halothane (3.5% for induction, 1% for maintenance), 70% nitrous oxide, and a balance of oxygen; immobilized with pancuronium bromide (0.6 mg/kg IV); and mechanically ventilated. Both rectal and cranial (left temporalis muscle) temperatures were monitored with temperature probes (Omega model CN/76000) and regulated at 37.0° to 37.5°C by separate heating lamps. Femoral catheters were inserted to monitor mean arterial blood pressure (MABP, model RS3200 polygraph, Gould, Inc) and to withdraw samples for measurement of arterial blood gases (model ABL 50, Radiometer America, Inc), hematocrit, plasma glucose (model 2300 Stat, Yellow Springs Instrument Co, Inc), and plasma colloid oncotic pressure (model 5100C osmometer, Wescor, Inc).
Middle Cerebral Artery Occlusion
To occlude the MCA, the right common carotid artery
was first exposed and the occipital branches of the external carotid
artery (ECA) were coagulated. A 3-0 monofilament nylon suture was then
passed through the proximal ECA into the internal carotid artery and
thence into the MCA, a distance of 19 to 20 mm from the carotid
bifurcation according to the weight of the
animal.16 Before use, the
suture was coated with
poly-L-lysine solution as
previously described16 to
enhance its adhesion to the surrounding endothelium and
increase the reproducibility of the resulting infarct. The neck
incision was then closed. Animals were allowed to awaken from
anesthesia and, at 60 minutes of MCAo, were tested on a
standardized neurobehavioral battery (described below) to confirm the
presence of a high-grade neurological deficit. Rats that did not
demonstrate an initial left upper extremity paresis were excluded from
further study. Animals were then reanesthetized for removal of
the intraluminal filament after 2 hours of MCAo. They were then
transferred to a temperature-controlled incubator at 37°C for 24
hours, where they received supplemental oxygen and were observed
carefully for signs of discomfort; no such signs were
observed.
Behavioral Evaluation
A standardized battery of behavioral
tests16 was used to quantify
sensorimotor neurological function at 60 minutes of MCAo (see above)
and daily for 3 days thereafter. The battery, which incorporates
postural reflex and forelimb-placing tests, yields a 12-point score
(normal=0, maximal=12). Tests were conducted by an observer blinded to
the treatment group.
Experimental Groups
Dose-Response Study
Animals were randomly assigned to 1 of 3 treatment
groups (n=5 each): (1) human serum Alb (Alpha Therapeutic Corp, 25%
solution), 0.5% of body weight, for example, 1.25 g/kg; (2) Alb,
0.25% of body weight, for example, 0.63 g/kg; or (3) a similar volume
of sodium chloride (0.9%, 5 mL/kg). The respective agent was infused
intravenously at a constant rate over a period of 3
minutes, commencing just after reversal of MCAo.
Therapeutic Window Study
The therapeutic window for Alb was investigated with
a dose of 1.25 g/kg, which was administered at 2 hours (n=9), 3 hours
(n=10), 4 hours (n=10), or 5 hours (n=9) after the onset of MCAo.
Vehicle (0.9% sodium chloride, 5 mL/kg) was administered at 1 hour
after onset of MCAo (n=9).
Histopathological Evaluation
Animals were allowed to survive for 3 days. Brains
were then perfusion-fixed as previously
described16 with a mixture
of 40% formaldehyde, glacial acetic acid, and methanol (1:1:8 by
volume), and brain blocks were embedded in paraffin. Ten-micron-thick
sections were cut in the coronal plane and stained with hematoxylin and
eosin. To quantify infarct volume and depict infarct frequency
distribution, histological sections were digitized at 9
standardized coronal levels (MCID image-analysis system,
Imaging Research Corp), from which data were exported to a UNIX-based
workstation for further processing. An investigator blinded to the
experimental groups outlined the zones of infarction (which were
clearly demarcated) as well as the left- and right-hemisphere contours
at each level. Software developed by us was then used to quantify
infarct size and brain swelling. Infarct volume was corrected for brain
swelling as previously described, and swelling was expressed as the
percentage difference in brain volume between the two
hemispheres.14 16
To facilitate rigorous image-based comparisons of infarction among
treatment groups, we mapped the digitized infarct maps of individual
animals at each coronal level into a common image template derived from
a brain atlas17 and summed
these data to generate computer maps depicting infarct frequency at
each pixel location; these methods have been previously
reported.18
Statistical Analysis
ANOVA with post hoc comparisons was used to compare
infarct areas and brain swelling among treatment groups
(repeated-measures design) and to compare infarct volumes, brain
swelling, neurological score, and physiological
variables among groups. Nonparametric ANOVA on ranks
was used to compare total neurological scores among groups. Pixel-based
intergroup comparison of infarct frequency maps was achieved by
Fisher’s exact test. A probability level of
P<0.05 was regarded as
significant.
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Results |
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Physiological Variables
All animals of this study showed similar values for rectal and cranial temperatures, MABP, arterial blood gases, and plasma glucose (Table 1
). Alb therapy led to the expected moderate
reduction in hematocrit and increase in plasma colloid oncotic pressure
(Table 1).
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Neurobehavioral Assessment
Before MCAo, neurological score was normal (score=0) in
all animals. High-grade behavioral deficits (score=10 to 11) were
present in all animals when tested at 60 minutes of MCAo
(Figure 1); thus, no animals required exclusion on the basis
of an inadequate degree of cerebral ischemia. Saline-treated
animals continued to exhibit severe behavioral impairments throughout
the 3-day survival period. In the dose-response study, the 1.25-g/kg
Alb dose significantly improved the neurological score compared with
vehicle rats at 24 hours, 48 hours, and 72 hours, and the 0.63-g/kg
dose was effective at 72 hours
(Figure 1A). The therapeutic window study revealed that
treatment with moderate-dose Alb (1.25 g/kg), even when initiated as
late as 4 hours after onset of MCAo, significantly improved the
neurological score at 24 hours and 48 hours
(Figure 1B).
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Histopathology
The brains of saline-treated animals with MCAo
exhibited a consistent pannecrotic lesion involving both
cortical and subcortical (mainly striatal) regions of the right
hemisphere, characterized microscopically by destruction of neuronal,
glial, and vascular elements. By contrast, infarct size was
dramatically reduced by Alb therapy in both treatment
groups.
The dose-response study revealed that the extent of
neuroprotection was profound in neocortex (mean tissue salvage, 66%
and 96%, respectively, in the 0.63-g/kg and 1.25-g/kg Alb groups) and
extended across multiple coronal levels
(Figure 2 and
Table 2). The striatum was also significantly protected (by
54% and 52%, respectively;
Figure 2 and
Table 2). Total infarct volume corrected for brain swelling
was reduced by a mean of 58% and 67%, respectively, by treatment with
0.63 g/kg and 1.25 g/kg Alb
(Figure 2). Percentage brain swelling was diminished by 75%
by treatment with 0.63 g/kg Alb and was essentially eliminated in the
1.25-g/kg Alb group
(Figure 2). In the cortical epicenter of the ischemic
lesion—a region protected from pannecrosis in animals treated with
1.25 g/kg Alb—microscopic examination revealed sporadic
ischemic (shrunken, eosinophilic) neurons in several
cases.
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In the therapeutic window study, treatment with Alb (1.25
g/kg) reduced total infarct volume (corrected for brain swelling) by a
mean of 58% when administered at 2 hours; by 66% at 3 hours; and by
61% at 4 hours
(Figures 3 and 4). Cortical infarct areas were significantly
reduced by the administration of Alb compared with vehicle (mean tissue
salvage, 62%, 83%, and 68%, respectively, in the 2-hour, 3-hour, and
4-hour Alb-treated groups) and extended across multiple coronal levels
(Figures 3 and 4). In addition, the subcortical region was
also significantly protected (by 52%, 44%, and 52%, respectively, in
the 2-hour, 3-hour, and 4-hour Alb-treated groups), with the
neuroprotection again extending across multiple coronal levels
(Figures 3 and 4). When Alb therapy was delayed to 5 hours
after the onset of MCAo, the neuroprotective effect was
lost.
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Treatment with Alb also significantly reduced brain swelling
compared with vehicle-treated rats, even when initiated as late as 4
hours after onset of MCAo
(Figure 5).
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Discussion |
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In the first part of this study, we have shown that human Alb therapy substantially improves neurological function, markedly reduces the volume of cerebral infarction, and nearly eliminates brain swelling in animals with acute ischemic stroke when administered promptly at doses of 0.63 or 1.25 g/kg—a dose range potentially amenable to clinical application in patients. In the second portion of the study, we have demonstrated the existence of a broad therapeutic window of neuroprotective efficacy with moderate-dose (1.25 g/kg) human Alb therapy, such that treatment initiated even 4 hours after stroke onset of ischemia is highly effective.
The present study was prompted by our earlier findings demonstrating the neuroprotective efficacy of considerably higher doses of human Alb (2.0 to 2.5 g/kg) administered at earlier times after ischemic or traumatic injury. In focal ischemic stroke, high-dose Alb therapy diminished the volumes of brain infarction and swelling,13 14 ameliorated behavioral function, and improved local perfusion to zones of critical blood flow reduction.15 Focal ischemia-induced blood-brain barrier dysfunction permitted Alb to penetrate into the brain parenchyma, where it was taken up by cortical neurons with normal morphological features, suggesting that Alb may have protected these neurons from ischemic injury.19 Alb also mitigated pannecrotic histopathology in tissue zones of residual ischemic injury by fostering the partial preservation of glial and endothelial elements, and it normalized the apparent diffusion coefficient of water on diffusion-weighted magnetic resonance images, even in zones of residual histological injury.14 Taken together, these observations bespeak a direct protective effect exerted by Alb on both parenchymal and vascular elements of the brain.
High-dose Alb therapy was also neuroprotective in experimental models of both transient global ischemia20 and fluid-percussion traumatic brain injury.21 In the former, Alb partially protected vulnerable neurons of the hippocampus from injury; in the latter, it diminished contusion volume.
Alb molecules have a prolonged circulating half-life (
20
days), and, because they do not easily leave the intravascular space,
they are capable of increasing plasma oncotic pressure over prolonged
periods of time.22 Indeed,
Alb is responsible for 80% of the plasma colloid oncotic
pressure.23 In the
present study, Alb therapy (1.25 g/kg dose) increased plasma
oncotic pressure acutely by 20%
(Table 1
), consistent with its effect in our
previous reports.14 By
contrast, plasma osmolality is not affected by Alb
administration.14 23
This is not surprising in view of the high molecular weight of Alb
(69 000); exogenous Alb (1.25 g/kg dose) would therefore contribute
<0.001 mOsm/mL to plasma osmolality.
Hemodilution Effects
In this study, Alb therapy reduced the hematocrit
acutely by 25% to 30%. This is similar to our previous results, in
which Alb therapy produced an acute reduction in hematocrit from 40%
to 42% to 23% to 28% that recovered to normal levels by 1
day.14 A traditional view of
therapeutically administered Alb is that it acts solely by its
hemodiluting action. We consider it very unlikely, however, that the
marked neuroprotective efficacy of moderate- to high-dose human Alb in
our studies is mediated solely by hemodilution because both
experimental and clinical studies that used other hemodiluents have, in
general, been disappointing. Interpretation of the experimental
hemodilution literature is difficult, however, because of the large
variety of hemodiluents used (human Alb, low-molecular-weight dextran,
hydroxyethyl starch, di-aspirin cross-linked hemoglobin, and
hetastarch) that were obtained from various sources and administered at
differing times and in diverse concentrations to differing species
(dog, cat, rat) and ischemia models (permanent versus temporary
MCAo, embolism) and resulting in differing degrees of hematocrit
reduction. Another confounding factor is the use of both isovolemic
protocols (in which the animal’s blood is partially exchanged for the
hemodiluent) and hypervolemic protocols (in which a net excess of
colloid is administered, with or without partial exchange).
Some hemodilution studies have supported a beneficial effect, particularly in temporary rather than permanent vascular occlusion models and with colloid agents administered in high concentrations close to the onset of the ischemic event (for example, see References 24 through 2724 25 26 27 ).24 25 26 27 Alb has been specifically assessed as a hemodiluent in occasional experimental ischemia reports, which have varied considerably in both the dose and timing of Alb administration, concurrent therapies, and outcome assessment. In general, these studies have not rigorously tested Alb when administered at higher doses and at early times after stroke. In one study, however, Alb administered at a 2-g/kg dose to rats shortly after permanent MCAo significantly reduced infarction size and attenuated brain swelling.28
Other Mechanisms of Alb Action
Several other mechanisms by which Alb therapy may
have induced neuroprotection must also be considered. As the major
protein of blood plasma, Alb is in fact a unique and complex molecule
with a variety of physiochemical properties. It is a principal
transporter of plasma fatty acids: Most circulating long-chain fatty
acids exist as Alb
complexes.29 Alb also
accounts for the majority of drug binding in the
plasma.30
Antioxidant Effects
Importantly, Alb constitutes the plasma’s
primary oxygen radical trapping and antioxidant defense, exceeding that
of vitamin E, for example, by 10- to
20-fold.31 As such, it
functions as a major plasma antioxidant defense, both against oxidizing
agents generated endogenously (eg, neutrophil
myeloperoxidase) as well as against exogenous substances (eg, phenolic
dietary compounds).22 By
avidly binding to copper ions, Alb inhibits copper ion–dependent lipid
peroxidation and retards the formation of the highly reactive hydroxyl
radical species.
Endothelial Effects
Alb also exerts direct effects on vascular
endothelium by binding to the
endothelial glycocalyx, functioning to maintain normal
microvascular permeability, and serving, through its transcytosis
across endothelium, as a carrier for various small
molecules.32 Perfusion of
vessels with protein-free solution dramatically increases hydraulic
permeability in various vascular beds—an effect that is prevented by
adding serum Alb to the perfusate at low
concentrations.33
Microvascular endothelial cells express specific Alb
binding sites on their surface that mediate its transcytosis or
endocytosis.34 Alb
influences erythrocyte aggregation in a complex manner, increasing
low-shear viscosity but decreasing erythrocyte sedimentation under
no-flow conditions.35 In
addition, Alb is a specific inhibitor of
endothelial cell
apoptosis.36
Anti-Edema Effects
Alb has several characteristics that suggest its
theoretical usefulness for cerebral dehydration: It does not
equilibrate across the normal blood-brain barrier (BBB) into the
interstitial space; it has a long half-life; and it is not
excreted in the urine. A large body of literature suggests that Alb
would cross the damaged BBB in ischemic regions, bringing with
it a certain amount of fluid, and might hold the fluid within the
ischemic
area.37 38 Evans
blue dye, bound to Alb, certainly crosses the damaged BBB, but evidence
is lacking that increasing the serum Alb concentration and oncotic
pressure would significantly increase the oncotic pressure of edema
fluid or worsen edema.23 The
oncotic pressure of the edema fluid does not equilibrate with that of
circulating plasma.39 In
previous studies, Alb administration either has not
changed39 or has decreased
dramatically23 28 40
the brain water content, as estimated by the wet weight/dry weight
method after cerebral injury. In the present experiment and in our
previous studies of Alb therapy of focal
ischemia,13 14
treatment with Alb significantly reduced brain swelling compared with
vehicle-treated rats as measured by volumetric comparison of
ipsilateral versus contralateral hemispheres.
Metabolic Effects
Alb exerts major effects on brain astrocytes,
eliciting intercellular calcium waves and functioning as a
mitogen.41 As such, it may
stimulate glial scar formation in pathological states in which it is
able to cross a permeable BBB into the brain. Alb also appears to be a
major regulator of the enzyme pyruvate dehydrogenase in astrocytes,
capable of more than doubling the flux of glucose and
lactate.42 This property
takes on relevance in that pyruvate dehydrogenase is inhibited by
cerebral ischemia, and this leads to substrate limitation and
decreased electron flow into the mitochondrial electron-transport
chain.43 As plasma Alb
enters the brain under pathological conditions, it may help to sustain
neuronal metabolism under pathological conditions by
increasing the export of pyruvate to
neurons.
Clinical Applications
Several large, randomized, multicenter trials of
non-Alb hemodilution have either failed to show improved neurological
outcome,44 45
were inconclusive,46 or were
terminated prematurely.47
Alb therapy for stroke has, to date, been assessed in only a single,
small, prospective clinical study in which it was administered in an
individually customized
fashion48 (the study was
methodologically flawed but suggested a treatment-associated reduction
in mortality rate of 
10%).
In current clinical practice, human Alb is being commonly
prescribed for a variety of indications. Thus, Alb is administered in
large quantities over prolonged time periods to patients with
aneurysmal subarachnoid hemorrhage after
surgical clipping of the aneurysm, in an effort to prevent
delayed ischemia secondary to
vasospasm.49 In a recent
report describing 82 patients with subarachnoid
hemorrhage who were receiving crystalloids plus Alb infusions
under normovolemic or hypervolemic
conditions,50 the daily Alb
dose amounted to 2 g/kg body wt. In that study, Alb infusions
produced no elevation of pulmonary artery diastolic
pressure or central venous pressure, and congestive heart failure
occurred in only 1 patient. In another study, 25% Alb was administered
in moderate to high doses over a 2-week period to elevate plasma
oncotic pressure in patients with brain contusion; this therapy safely
and effectively reduced contusional
edema.51 Similarly, patients
with putaminal hemorrhage treated with 12.5 to 25 g per
day of Alb for 2 weeks showed reductions of cerebral edema and improved
outcome.52 In another study,
patients with cirrhosis and spontaneous bacterial peritonitis were
treated with intravenous Alb at an initial dose of 1.5
g/kg, followed by 1 g/kg on day 3; this treatment was tolerated and led
to reduced renal impairment and lowered mortality
rates.53 It is of relevance
that the per-kilogram Alb dose ranges administered in the above-cited
studies overlaps with the per-kilogram doses shown in our experimental
studies to be highly neuroprotective when administered within the first
4 hours after stroke onset. Taken together, these findings support the
potential clinical feasibility of administering human Alb in moderate
doses to patients with acute ischemic stroke.
In summary, the present study has shown that human Alb therapy, in moderate doses, is strongly neuroprotective in focal ischemia; has a broad therapeutic window extending to 4 hours after stroke onset; and produces no observable adverse effects in young adult experimental animals. This 4-hour time frame is clinically relevant in that it is logistically difficult to institute therapy in many patients with acute stroke at earlier times. We therefore suggest that this agent offers great promise in the therapy of cerebral ischemia and we propose that it may now be appropriate to consider the initiation of early-phase clinical trials in patients with acute ischemic stroke.
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Acknowledgments |
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These studies were supported by Program Project Grant NS 05820 of the National Institutes of Health (Dr Ginsberg) and by an American Heart Association Initial Investigatorship Award (No. 9930263V) (Dr Belayev). The authors thank Guillermo Fernandez for expert technical assistance.
Received July 27, 2000; revision received September 19, 2000; accepted October 3, 2000.
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