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1 Advanced Research Institute for Science and Engineering, Waseda University, Tokyo 169-8555, Japan; and 2 Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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A phospholipid vesicle encapsulating hemoglobin (Hb vesicle, HbV) has been developed to provide O2-carrying capacity to plasma expanders. Its ability to restore systemic and microcirculatory conditions after hemorrhagic shock was evaluated in the dorsal skinfold window preparation of conscious hamsters. The HbV was suspended in 8% human serum albumin (HSA) at Hb concentrations of 3.8 g/dl [HbV(3.8)/HSA] and 7.6 g/dl [HbV(7.6)/HSA]. Shock was induced by 50% blood withdrawal, and mean arterial pressure (MAP) at 40 mmHg was maintained for 1 h by the additional blood withdrawal. The hamsters receiving either HbV(3.8)/HSA or HbV(7.6)/HSA suspensions restored MAP to 93 ± 14 and 93 ± 10 mmHg, respectively, similar with those receiving the shed blood (98 ± 13 mmHg), which were significantly higher by comparison with resuscitation with HSA alone (62 ± 12 mmHg). Only the HSA group tended to maintain hyperventilation and negative base excess after the resuscitation. Subcutaneous microvascular blood flow reduced to ~10-20% of baseline during shock, and reinfusion of shed blood restored blood flow to ~60-80% of baseline, an effect primarily due to the sustained constriction of small arteries A0 (diameter 143 ± 29 µm). The HbV(3.8)/HSA group had significantly better microvascular blood flow recovery and nonsignificantly better tissue oxygenation than of the HSA group. The recovery of base excess and improved tissue oxygenation appears to be primarily due to the increased oxygen-carrying capacity of HbV fluid resuscitation.
blood substitutes; artificial red blood cells; microcirculation; microhemodynamics; liposome
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PHOSPHOLIPID VESICLES encapsulating concentrated human hemoglobin (Hb) (Hb vesicles, HbV) can serve as blood substitutes of which their O2-carrying capacity can be formulated to be comparable to that of blood (2, 4, 10, 23, 40). They are void of blood-type antigens and infectious viruses and are stable and suitable for long-term storage (26). The cellular structure of HbV (particle diameter ca. 280 nm) has characteristics similar to those of natural red blood cells (RBCs), because both have cell membranes that prevent direct contact of Hb with the components of blood and the endothelial lining. Furthermore, Hb encapsulation in vesicles suppresses hypertension induced by vasoconstriction due to scavenging of the endogenous vasorelaxation factors nitric monoxide (NO) and carbon monoxide (5, 14, 26) consequent to their high affinity with Hb. Once in the circulation, HbV particles are captured by the phagocytes in the reticuloendothelial system (mainly the spleen and liver), and they are metabolized completely within 14 days, with no deposition of iron or lipids (27).
O2-carrying blood replacement fluids using molecular or encapsulated Hb as an O2 carrier have been proposed for volume restoration in hemorrhagic shock (16, 18, 43) and hemodilution being generally assumed that low O2 affinity (high P50) and high Hb concentration should be effective for O2 delivery. However, in previous studies (31) of extreme hemodilution in the hamster dorsal skinfold preparation, we found that the optimal O2 dissociation curve of HbVs is shifted to the left. In this report, we analyze systemic and microvascular responses after resuscitation from hemorrhagic shock by using HbVs with different Hb concentrations to determine the optimal oxygen-carrying capacity, focusing on the responses of small resistance arteries, which were found to be the critical vessels in regulating microvascular blood flow (24-26, 32).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation of HbVs.
HbVs were prepared under sterile conditions as previously reported
(26, 28, 40). Hb was purified from outdated donated blood
provided by the Hokkaido Red Cross Blood Center, Sapporo, Japan. The
encapsulated Hb (38 g/dl) contained 5.9 mM of pyridoxal 5'-phosphate
(PLP, Merck; Darmstadt, Germany) as an allosteric effector at a molar
ratio of PLP/Hb = 2.5. The lipid bilayer was composed of Presome
PPG-I (a mixture of
1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, cholesterol, and
1,5-dipalmitoyl-L-glutamate-N-succinic acid at a
molar ratio of 5:5:1; Nippon Fine Chemical, Osaka, Japan). The surface
of the HbV was modified with polyethylene glycol (mol mass: 5 kDa, 0.3 mol% of the lipids in the outer surface of vesicles) by
using
1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N- polyethylene
glycol (Sunbright DSPE-50H, H-form, NOF; Tokyo, Japan). Carbonylhemoglobin was converted to oxyhemoglobin by exposure to
visible light in an O2 atmosphere. HbVs were suspended in a physiological salt solution and filtered through sterilizable filters
(pore size: 0.45 µm, Dismic, Toyo Roshi; Tokyo, Japan) and
deoxygenated with N2 bubbling for storage
(29). Physicochemical parameters of the HbVs are listed in
Table 1.
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1).
Animal model and preparation. Experiments were carried out in 26 male Syrian golden hamsters (64 ± 7 g body wt, Charles River; Worcester, MA). All animals were housed in cages and provided with food and water ad libitum in a temperature-controlled room with a 12:12 h dark-light cycle. The dorsal skinfold consisting of two layers of skin and muscle was fitted with two titanium frames with a 15-mm circular opening and surgically installed under intraperitoneal pentobarbital sodium anesthesia (ca. 100 mg/kg body wt, Abbott; North Chicago, IL). A location that included a paired small artery and vein was selected. The resistance artery can be readily identified because a Y-shaped pair of artery and vein can be seen visually when the hamster dorsal skin is extended after removal of the hair (24-26). Layers of skin muscle were separated from the subcutaneous tissue and removed until a thin monolayer of muscle including the small artery and vein and one layer of intact skin remained. A cover glass (diameter 12 mm) held by one frame covered the exposed tissue allowing intravital observation of the small artery (A0, diameter 143 ± 29 µm), the arterial supply of this tissue.
Polyethylene tubes (PE-10, ca. 1 cm, Becton Dickinson; Parsippany, NJ) were connected to PE-50 (ca. 25 cm) via silicone elastomer medical tubes (ca. 4 cm, Technical Products; Decatur, GA) and were implanted in the jugular vein and the carotid artery. They were passed from the ventral to the dorsal side of the neck and exteriorized through the skin at the base of the chamber. Patency of the catheters was ensured by filling them with heparinized saline (40 IU/ml). Microvascular observations of the awake and unanesthetized hamsters were performed 5 days after chamber implantation to mitigate the effects of surgery, after they were placed in a perforated plastic tube from which the window chamber protrudes to minimize animal movement without impeding respiration. All animal studies were approved by the Animal Subject Committee of University of California, San Diego, and performed according to the Guide for the Care and Use of Laboratory Animals Institute of Laboratory Animal Resources Commission on Life Sciences, National Research Council-National Academy of Sciences (Washington, DC: National Academy Press, 1996).Resuscitation from hemorrhagic shock. Hemorrhagic shock was induced by withdrawing 50% of blood in 5 min (10%/min) from the carotid artery. Systemic blood volume was estimated as 7% of the total body weight. Blood was withdrawn into a heparinized syringe and stored for 60 min at room temperature. Mean arterial pressure (MAP) was maintained at ~40 mmHg for 60 min through additional withdrawals in the range of 0.65 ± 0.31 ml. This procedure is based on the Wigger's type constant blood pressure protocol. Hamsters were resuscitated by the infusion of a volume of HbV(7.6)/HSA (n = 6), HbV(3.8)/HSA (n = 6), HSA alone (n = 6), or initially bled shed autologous blood (SAB) (n = 8) in 5 min, which was identical to the shed volume, i.e., 50% of blood volume at baseline.
Measurements of systemic and microhemodynamic parameters. Systemic and microhemodynamic parameters and blood gases were evaluated before hemorrhage (baseline), after 50% hemorrhage, before resuscitation, just after resuscitation, and 0.5, and 1.0 h after resuscitation. The in situ microcirculation of the skinfold chamber was observed using a video microscope system. After 1 h from resuscitation, palladium-porphyrin bound to bovine albumin solution (7.6 wt%, 0.1 ml) was injected intravenously to measure the PO2 in the vessels and interstitium (11, 36).
Blood samples were collected in heparinized microtubes (<100 µl, Curtin Matheson Scientific; Norcross, GA) for hematocrit (Hct) and blood gas analyses. A pH/blood gas analyzer (Blood Chemistry Analyzer 248, Bayer Medical; Northwood, MA) was used for analysis of arterial blood O2 tension (PaO2), arterial blood CO2 tension (PaCO2), pH, and base excess (BE). A recording system (MP 150, Biopac System; Santa Barbara, CA) was used for continuous monitoring of MAP and heart rate (HR). Microvessels in the subcutaneous tissue and the skeletal skin muscle were observed by transillumination with an inverted microscope (IMT-2, Olympus; Tokyo, Japan). Microscopic images were video recorded (Cohu 4815-2000; San Diego, CA) and transferred to a TV-VCR (Sony Trinitron PVM-1271Q monitor; Tokyo, Japan) and Panasonic AG-7355 video recorder (Tokyo, Japan). Microvessels were classified according to their position within the microvascular network according to the previously reported scheme (24). Arteriolar microvessels were grouped into small artery (A0, diameter 143 ± 29 µm), large feeding arterioles (A1, 60 ± 12 µm), small arcading arterioles (A2, 27 ± 6 µm), and transverse arterioles (A3, 11 ± 3 µm). Venules were classified as small collecting venules (VC, 31 ± 8 µm), large venules (VL, 89 ± 18 µm), and small veins (V0, 376 ± 95 µm). These microvessels and capillaries were sketched in advance to plan the sequence of measurements. Microvascular diameter and RBC velocity were analyzed online in arterioles and venules (8, 9). Vessel diameter was measured with an image-shearing system (Digital Video Image Shearing Monitor 908, I.P.M.; San Diego, CA), whereas RBC velocity was analyzed by photodiodes and the cross-correlation technique (Velocity Tracker Mod-102 B, I.P.M.). Blood flow rates (Q) were calculated using the equation
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Data analysis. Data are given as means ± SD for the indicated number of animals. Data were analyzed by using analysis of variance, followed by Fisher's protected least-significant difference test between the groups according to the previous studies (11, 12, 24). Student's t-test was used for the comparisons within each group. The level of confidence was placed at 95% for all the experiments.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Systemic responses to the hemorrhagic shock and resuscitation.
MAP of the hamsters before hemorrhage was 105 ± 13 mmHg and
declined to ~40 mmHg during shock, a level maintained for 60 min (Fig. 1). Immediately after
resuscitation, the MAP of the SAB group recovered to 98 ± 13 mmHg, which was maintained for 1 h. MAP of the HbV(7.6)/HSA and
HbV(3.8)/HSA groups recovered on retransfusion to 93 ± 10 and
93 ± 14 mmHg, respectively, values that were maintained for
1 h. The HbV/HSA groups were statistically not different from the
SAB group and showed significantly higher MAP at all time points than
the HSA group, of which its MAP was 62 ± 12 mmHg after resuscitation and remained at this level for 1 h.
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7.6 ± 6.6 mM before infusion. The SAB, HSA(7.6)/HSA, and
HbV(3.8)/HSA groups tended to recover immediately from the
hyperventilation after resuscitation, and there was no significant
differences between the HbV/HSA and SAB groups. Only the HSA group had
significantly higher PaO2 values than the SAB groups
at all the time points. However, all of the groups showed significantly
higher PaO2 values than basal values at all the time
points. All of the groups increased pH and BE after 0.5 h. The HSA
group had the lowest BE values at 0.5 and 1 h after resuscitation.
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Microhemodynamic responses to hemorrhage and resuscitation.
Hemorrhagic shock induced significant constrictions of A0
arterioles to 60 ± 11% of the basal values (P < 0.0001) (Fig. 3). As seen in previous
studies (24), other vessels did not show such significant
changes (data not shown). All groups tended to recover from
A0 constriction after resuscitation to ~80% of the basal
values; however, diameters remained significantly constricted with no
significant difference between groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Our principal findings are that infusion of HbVs suspended in HSA restores blood pressure and blood gas parameters, including BE, after hemorrhagic shock independently of the difference in Hb concentrations (7.6 g/dl vs. 3.8 g/dl) in the HbV suspensions, and that microvascular PO2 were improved in the presence of HbV by comparison with HSA alone. Furthermore, the levels of recovery of blood pressure and blood gas parameters attained with the HbV/HSA suspensions are comparable with that of shed blood and are significantly higher than those attained by treatment with HSA alone.
It has been reported that resuscitation from hemorrhagic shock with acellular Hb modifications such as polymerized or intramolecularly cross-linked Hb causes the elevation of MAP beyond the baseline values (3, 6, 16, 18, 34), presumably because of NO scavenging due to the high affinity for NO of acellular Hbs and their smaller size, which enable NO trapping in the proximity of the endothelium (19, 26); however, MAP did not exceed the baseline values after resuscitation with HbV.
Because A0 vessels constricted to the same extent in all
the groups, the changes in peripheral resistance and therefore recovery of MAP, could be expected to follow a similar pattern. However, peripheral resistance is also a function of the viscosity of the circulating blood. The viscosity of the HSA solution was significantly lower than that of the HbVs solutions. Because the volume taken out and
replaced was 50% of the total blood volume, we may assume that the
replaced volume was 50% diluted with the remaining blood before volume
restitution, which had an approximately uniform Hct of 25% in all
groups. Baseline blood and plasma viscosity of hamsters are 4.47 ± 0.59 and 1.20 ± 0.04 cP, respectively, at Hct 45% and 37°C.
Volume restitution with HSA reduced this Hct to 12%, and the viscosity
achieved in restituting blood volume with HSA whose viscosity is 1 cP
should be slightly lower than the viscosity of blood diluted to 12%
with plasma, which is ~1.2 cP (shear rate, 250 s1).
Conversely, restitution of volume with blood or HbVs, of which their
minimum viscosity was 1.8 cP, probably restored viscosity of the
circulating blood to ~1.5 cP, a 25% higher viscosity than HSA and
therefore correspondingly higher peripheral vascular resistance, presumably causing the observed higher MAP. An additional contributing factor may be the slightly lower HR found for HSA resuscitation suggesting a slightly lower cardiac output.
Hb-based O2-carrying resuscitation fluids tend to be formulated with a Hb concentration close to that of normal blood. However, normal blood has a surplus O2-carrying capacity, and hemodilution up to 30% may improve O2 delivery and maintain the O2 consumption. Moreover, molecular O2 carriers and HbV, being much smaller than RBCs, release O2 in closer proximity to the arteriolar wall (17, 31), significantly augmenting the flux O2 to the arteriolar walls inducing vascular autoregulatory responses aimed at maintaining tissue oxygenation constant through vasoconstriction and the reduction of blood flow (7, 41). When these two factors are taken into consideration, Hb concentration can be adjusted to be ~5 g/dl provided that the level of blood exchange does not exceed 80%, in which case the tissue can become hypoxic (30). Lower Hb concentrations such as 3.8 g/dl may still be useful but only applicable to a 50-60% level of blood exchange.
Another parameter that regulates the O2 release is O2 affinity. A right-shifted O2 equilibrium curve for RBCs has been reported to be effective for tissue oxygenation; however, contradictory results are reported for the Hb-based O2 carriers (1, 42). In our previous report (31), reducing P50 from 30 to 16 mmHg resulted in increased FCD. Thus conventional concepts for RBCs may not be applicable to Hb-based O2 carriers, and lower Hb concentration and lower P50 may be advantageous when using Hb-based O2 carriers. However, further study is necessary to confirm this concept with systemic O2 consumption, peripheral resistance, etc.
Microvascular blood flow dropped significantly during hemorrhagic shock to nearly 10% of the baseline values as a consequence of the lowered blood pressure and the significant vasoconstriction of the resistance artery A0 as previously reported (24). Other vessels did not show such significant changes. In terms of Poiseuille's law, blood flow in a tube is proportional to the fourth power of the radius, the pressure gradient, and inversely proportional to fluid viscosity. If we assume that the A0 vessels are the primary determinants of microvascular blood flow, application of Poiseuille's law for a diameter of 80% of baseline value and a reduced blood viscosity due to hemodilution (due to the reduction of Hct from ca. 50% to ca.40% for the SAB group) and the reduced MAP affecting the regional arteriovenous pressure difference (ca. 90%) shows that blood flow rate is reduced to (0.8)4 × 50/40 × 0.9 × 100 = 46% of the basal value. This calculation is speculative but corresponds to our finding on the incomplete recovery of blood flow rates of the SAB group and suggests that the reactivity of the A0 small arteries is crucial in determining microvascular flow.
Cardiac output is reported to fall as much as 50% during hemorrhage (13, 22, 33), and although not measured in the present study because of the small size of the hamsters (60 g), it is unlikely that it would be reduced to nearly 10% of baseline, which is the level of skin microvascular blood flow during hemorrhagic shock. The decrease in flow seen in our experiments is probabaly due to a significant redistribution of vascular resistance concomitant with the "centralization" of blood flow in hemorrhage, controlled by these resistance vessels. Because the sympathetically driven A0 constriction is a normal physiological response required for blood centralization, the early reversal of this phenomenon in resuscitation may not be beneficial; however, the constriction should eventually be reverted to restore normal tissue conditions. It should be noted, however, that the changes in microvascular flow were not consistent.
In the normal tissue, intravascular PO2 decreases from 54 ± 3 mmHg in the A0 vessels to 40 ± 8 mmHg in the A3. This reduction is due to O2 diffusion from arterioles and consumption by the vascular wall (7, 38). In the present experiments normal interstitial PO2 was 22 ± 6 mmHg, and blood PO2 increased after passing through the capillaries being 27 ± 10 mmHg in VC and 30 ± 7 mmHg in V0 due to the presence of diffusive and convective shunts between arterioles and venules (7). The two HbV/HSA groups and the SAB group tended to show similar or slightly higher PO2 in A0 compared with the baseline value probably because of the higher central PO2 after resuscitation due to hyperventilation. However, intravascular PO2 in A1, A2, and A3 and interstitial PO2 for the HbV/HSA groups were significantly lower than the baseline and higher than the HSA group. Because the recovery of FCD was similar for all groups (but significantly lower than for SAB), the higher tissue PO2 values are due to the increased O2-carrying capacity by the addition of HbV to HSA.
The improved microvascular recovery found for SAB by comparison with
HbV/HSAs may be due to the different viscosities of the fluids. The
viscosities of HbV(3.8)/HSA and HbV(7.6)/HSA at 150 s1
are 1.8 and 3.0 cP, respectively, being lower than the viscosity of
blood (4.5 cP) and that of previously reported HbV(10)/HSA (4 cP) (30). Higher viscosities should lead to higher
shear stress, the consequent release of vasorelaxation factors, and higher FCD, even though we did not find a related response of microvascular diameters. Lowered blood viscosity and blood flow does
not transmit adequate pressure to the capillaries, causing the decrease
of FCD (37, 39). The significant decrease in Hct could
also be a contributing factor to decrease FCD because the reduction of
Hct increases the plasma layer and the resulting plasma skimming,
leading to an underestimation of the number of perfused capillaries
(30). Semitransparent elements presumed to be HbV
particles were visible in the capillaries of the HbV/HSA groups, and
because FCD was estimated on the basis of number of capillaries through
which RBCs were flowing, FCD values might have underestimated the total
number of functioning capillaries for the HbV/HSA groups.
In summary, this study shows that resuscitation from hemorrhage with HbVs suspended in HSA restore systemic parameters to the same level as shed blood, whereas subcutaneous microvascular function and tissue oxygenation return to a level that is intermediate between that attained with whole blood and HSA. The degree of systemic restoration does not appear to be dependant on Hb concentration within the range of 3.8-7.6 g/dl, indicating that low concentrations of Hb are effective and that there may be a plateau in effectiveness that can be achieved with HbVs in this model of resuscitation from hemorrhagic shock. Our results indicate that HbVs are not vasoactive (26) and that the sustained constriction of resistance arteries during the resuscitation period is a physiological response probably related to the maintenance of blood pressure and blood flow to vital organs. Thus complete microvascular recovery in our model during the observation period of this study may be related to the time needed for the relaxation of the resistance arteries of this tissue and not dependent on the specific formulation of the HbVs within the range of Hb concentrations tested.
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ACKNOWLEDGEMENTS |
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The authors greatly acknowledge A. Barra and C. Walser (University of California, San Diego) for technical assistance, Dr. K. Sou, I. Fukutomi, Y. Masada, and N. Naito (Waseda University) for the preparation of the HbV suspension, and Prof. M. Takaori (Kawasaki Medical University) for the discussion of the experimental procedure.
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FOOTNOTES |
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This work was supported in part by Health Sciences Research Grants (Research on Advanced Medical Technology, Artificial Blood Project), the Ministry of Health, Labour and Welfare, Japan (12090101), and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (B12480268, B12558112). This work has also been supported by the National Heart, Lung, and Blood Institute Bioengineering Partnership Grant R24 HL-64395 and Grants R01 HL-40696 and R01 HL-62354. H. Sakai was a research fellow of the Japan Health Sciences Foundation (2001).
Address for reprint requests and other correspondence: E. Tsuchida, Advanced Research Institute for Science and Engineering, Waseda Univ., Tokyo 169-8555, Japan (E-mail: eishun{at}mn.waseda.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 16, 2002;10.1152/ajpheart.00080.2002
Received 30 January 2002; accepted in final form 6 May 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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significantly different from "before infusion"
(P < 0.05).
significantly
different from the HSA group (P < 0.05).