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The Influence of Two Different Hydroxyethyl Starch Solutions (6% HES 130/0.4 and 200/0.5) on Blood Viscosity

Neff, Thomas A. MD; Fischler, Lukas MD; Mark, Michael MD; Stocker, Reto MD; Reinhart, Walter H. MD

doi: 10.1213/01.ANE.0000149326.45137.9A
Critical Care and Trauma: Research Report

We performed the current study to investigate the influence of 2 different hydroxyethyl starch (HES) solutions, the novel medium molecular weight HES 130/0.4 (6%) and HES 200/0.5 (6%), on plasma and whole blood viscosity in vitro and ex vivo in patients with severe head injury. For the in vitro experiments, blood was incubated with increasing concentrations (0%–50% vol/vol plasma) of either 6% HES 130/0.4 or 6% HES 200/0.5 solution. Plasma viscosity and whole blood viscosity (hematocrit [Hct] 45%) at high (94.5 s−1) and low (0.1 s−1) shear rates were determined. Both HES solutions increased plasma viscosity, but HES 130/0.4 to a lesser extent than HES 200/0.5. Whole blood viscosity was significantly less with HES 130/0.4 than with HES 200/0.5 at concentrations of 37.5% and larger. In the ex vivo study on 31 patients with severe cranio-cerebral trauma treated randomly with either HES 130/0.4 or HES 200/0.5 over several days, frozen plasma samples were thawed and plasma viscosity was determined. Blood was reconstituted with normal erythrocytes (0, Rh neg, Hct 45%) for whole blood viscosity measurements. In both groups plasma and blood viscosity tended to increase over time without statistical significance. Although the prominent effects found in vitro are not in keeping with the ex vivo data, they are likely to reflect the true clinical situation during repetitive, large-dose HES administration. We therefore conclude that HES 130/0.4 may have hemorheological advantages over conventional HES 200/0.5 when used in large quantities.

IMPLICATIONS: As a result of an in vitro trial and a randomized ex vivo study we conclude that hydroxyethyl starch (HES) 130/0.4 has hemorheological advantages over conventional HES 200/0.5 when used in large quantities.

Department of Internal Medicine, Kantonsspital, Chur, Switzerland, and Division of Surgical Intensive Care, University Hospital, Zurich, Switzerland

Supported, in part, by the Bonizzi-Theler Foundation, Switzerland, and by Fresenius Kabi GmbH, Bad Homburg, Germany.

Accepted for publication October 12, 2004.

Address correspondence and reprint requests to W. H. Reinhart, MD, Department of Internal Medicine, Kantonsspital, CH-7000 Chur, Switzerland. Address e-mail to walter.reinhart@scag.gr.ch.

Adequate volume management is pivotal in critically ill patients, especially in those with cranio-cerebral trauma. An aggressive fluid resuscitation strategy is needed to maintain an appropriate cerebral perfusion pressure (CPP) counteracting the increased intracranial pressure (ICP) typical in these patients. A variety of infusion solutions are available, among them blood products (e.g., packed red blood cells [RBC] and plasma products), crystalloids (e.g., lactated Ringer’s solution or normal saline), and colloids (e.g., gelatin, dextran, or hydroxyethyl starch [HES]).

HES is a branched polysaccharide closely resembling glycogen, which is substituted with hydroxyethyl groups at carbons 2, 3, and 6 of the glucose subunits. The chemical and physical characteristics of HES preparations are defined by the mean molecular weight (Mw, weight average), the molar substitution (MS, i.e., mol hydroxyethyl residues per mol glucose subunits), and the C2/C6 ratio (pattern of substitution at the glucose subunit carbon atoms) (1). Concerns have been raised regarding potential side effects of HES solutions, such as impaired blood coagulation and renal function resulting from accumulation of macromolecules in plasma and pruritus because of tissue long-term storage (2–5). These side effects depend on the MS, the C2/C6 ratio, and, to a lesser extent, on the Mw of the specific HES preparation, i.e., they are less pronounced with lower MS, C2/C6 ratio, and average Mw (6,7).

For this reason, new HES preparations with adjusted physicochemical characteristics have been developed. One of them is HES 130/0.4 (6%, Voluven®), which has a smaller and more narrowly distributed Mw, a lower MS, and a larger C2/C6 ratio than the conventionally used HES 200/0.5. It has been evaluated in several clinical trials in recent years. Even at large daily doses, it seems to be at least as safe as gelatin preparations (8,9) or standard dose conventional HES 200/0.5 (3,10,11); it can be infused repetitively in large quantities without relevant accumulation in plasma (12,13); it therefore interferes less with blood coagulation and hemostasis (12,14,15); it diminishes blood loss compared with HES 200/0.5 (15); and it is applicable even in non-anuric patients with severe renal impairment because of its enhanced renal excretion (5).

HES 130/0.4 also improves tissue oxygen tension compared with lactated Ringer’s solution (16) or HES 200/0.5 (17), which is an indicator of improved blood rheology. Infusions affect blood rheology by various mechanisms (18–21), e.g., change of plasma viscosity, decrease of hematocrit (Hct) by plasma volume expansion, and influence on erythrocyte aggregation, which depends primarily on the weight and structure of the macromolecules (22). Blood viscosity is an important determinant of macrocirculatory and microcirculatory blood flow, especially in the critically ill patient.

In the present study the influence of HES 130/0.4 and conventional HES 200/0.5 on blood and plasma viscosity was investigated in vitro and ex vivo as part of a randomized study on patients with severe head injury (12).

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Methods

The test solutions 6% HES 130/0.4 (Voluven®, Mw 130 kDa, MS 0.4, C2/C6 ratio ∼9:1) and 6% HES 200/0.5 (HAES-steril®, Mw 200 kDa, MS 0.5, C2/C6 ratio ∼5:1) were kindly provided by Fresenius Kabi GmbH, Bad Homburg, Germany. Blood was drawn from 11 healthy young volunteers into heparin-containing tubes. For each experiment freshly drawn blood from a single donor was used.

Blood was centrifuged for 10 min at 1500g and plasma was aspirated. Aliquots of 2000, 1900, 1800, 1650, 1500, 1250, 1000, and 0 μl plasma were prepared, to which 0, 100, 200, 350, 500, 750, 1000, and 2000 μl of either 6% HES 130/0.4 or 6% HES 200/0.5 solution were added to obtain a total volume of 2 mL and HES concentrations (% vol/vol plasma) of 0%, 5%, 10%, 17.5%, 25%, 37.5%, 50%, and 100%, respectively. These volume concentrations reflecting absolute HES plasma concentrations of 0%, 0.3%, 0.6%, 1.05%, 1.5%, 2.25%, 3%, and 6% are comparable with clinically relevant HES plasma peak levels reported in the literature (0.8%–1.5%) (23–26). From each of the HES-admixed plasma samples, a portion was incubated for 10 min in a water bath at 37°C and plasma viscosity was measured at the same temperature.

To the remainder of these HES-diluted plasma samples, 1 mL of autologous packed RBCs was added. After mixing, the Hct of each aliquot was determined with an automated quantitative hematology analyzer. Exactly 1.5 mL of each sample was centrifuged for 5 min and a calculated volume of plasma was removed to obtain a Hct of 45%. Blood viscosity of this reconstituted blood was measured as described below.

Viscosity was measured with a Couette viscometer (Contraves, Model LS 30, Mettler-Toledo, Greifensee, Switzerland) at 37°C. Blood is a non-Newtonian fluid i.e., its viscosity depends on the shear rate applied. At high shear rate, corresponding to rapid flow rates, blood viscosity is low because of RBC deformation; at low shear rate, blood viscosity is high because of RBC aggregation (22). We therefore measured whole blood viscosity (Hct 45%) at a high shear rate of 94.5 s−1 and a low shear rate of 0.1 s−1. Plasma and HES solutions are Newtonian fluids, i.e., the viscosity is independent of the shear rate. Their viscosities were measured at shear rates of 37.6 s−1 and 11 s−1, and the arithmetic mean value was calculated.

Erythrocyte aggregation was measured with a standardized sedimentation assay (27,28). Citrated blood was drawn, Hct was adjusted to 40%, and an immunoglobulin solution (Redimune®; ZLB Bioplasma, Bern, Switzerland) was added at a volume concentration of 20% plasma. Aliquots of 1150 μL were prepared, to which we added 112, 225, 338, and 450 μL of 6% HES and 338, 225, 112, and 0 μL of 0.9% NaCl, respectively, resulting in 6% HES concentrations (vol/vol plasma) of 9.3%, 18.6%, 28.1%, and 37.5% (or absolute HES concentrations in plasma of 0.56%, 1.125%, 1.69%, and 2.25%) and a constant Hct of 25%. The classical Westergreen method was used to analyze the RBC sedimentation rate as a measure of RBC aggregation.

A prospective, controlled, randomized study investigating repetitive large-dose infusions of HES 130/0.4 and HES 200/0.5 with regard to blood coagulation and renal function was performed at the Division of Surgical Intensive Care of the University Hospital Zurich, Switzerland (12). The ex vivo patient plasma samples for the current investigation on viscosity were derived during that clinical trial, which was conducted in accordance with the principles of Good Clinical Practice and the revised Declaration of Helsinki and was approved by both the institutional and the regional ethics committees. Signed, written informed consent was provided by a close relative of the patient. Patients aged 18–65 yr with severe cranio-cerebral trauma, a pathologic cerebral computed tomography scan, Glasgow Coma Motor Score <5, acute trauma within the previous 24 h, and stabilized hemostasis (international normalized ratio <1.3, platelet count >100/nL, fibrinogen >1 g/L) were eligible. Patients with bilaterally fixed and dilated pupils, history of coagulation disorders, chronic renal insufficiency, severe liver insufficiency, or cardiac insufficiency were excluded. All patients were tracheally intubated and mechanically ventilated. The volume treatment strategy was based on the Guidelines for the Management of Severe Head Injury from the Brain Trauma Foundation and the American Association of Neurological Surgeons (29) targeting a CPP >70 mm Hg (mean arterial blood pressure >90 mm Hg at a given ICP threshold of 20 mm Hg for intracranial hypertension) to counteract the increased ICP typical of these patients. Large infusion volumes were required to meet these criteria.

In one group, HES 130/0.4 (6%, Voluven®) was infused at repetitive large doses of up to 70 mL · kg−1 · d−1 for up to 28 days. The other group received a standard treatment of HES 200/0.5 (6%, HAES-steril®) up to its approved dose limit of 33 mL · kg−1 · d−1, followed by human serum albumin (5%, Baxter, Unterschleissheim, Germany) up to a total dose (HES 200/0.5 + albumin) of 70 mL · kg−1 · d−1 for up to 28 days. For each individual patient, amounts of administered infusion fluids were recorded daily. Serum fibrinogen levels were measured every other day and globulins were calculated from the according serum protein and albumin values (globulins = total protein − albumin).

For the hemorheological part of the study blood samples anticoagulated with EDTA were obtained at patient enrollment (day 0) and every second day until the end of the study. The plasma was separated and frozen at −20°C. Before analyzing, samples were thawed at room temperature and then incubated for 10 min at 37°C in a water bath. Plasma viscosity was measured as described above. RBCs of a single donor (blood group: 0 Rh neg) were used for the reconstitution of whole blood. After washing these RBCs twice in phosphate-buffered saline, 600 μl of donor packed RBC were resuspended in 400 μl of patient plasma. The Hct was measured and a calculated volume of the same plasma sample was added to obtain a Hct of 45%. After incubation for 15 min at 37°C, blood viscosity was measured in the same manner as described above.

To test how freeze-thawing of patient plasma samples would affect viscosity measurements in reconstituted blood, pure plasma as well as plasma with admixed HES 130/0.4 or HES 200/0.5 (16.7% vol/vol plasma) was used fresh and freeze-thawed and was reconstituted with homologous donor RBCs to a Hct of 45%. Blood viscosity was measured at high shear rate (94.5 s−1). To determine the impact of hematocrit on blood viscosity, donor blood anticoagulated with EDTA was drawn. Aliquots with adjusted Hct values of 30%, 35%, 40%, and 45% were prepared. Blood viscosity was measured at high (94.5 s−1) and low (0.1 s−1) shear rate. All experiments were done with blood from four healthy donors.

Results are presented as mean ± sd. Changes in viscosity, cumulative amounts of administered HES, erythrocyte sedimentation rate, fibrinogen, and globulins over time within each group were analyzed with two-way analysis of variance followed by Dunnett’s posttest to allow multiple comparisons to baseline. Differences between groups were analyzed by analysis of variance with Bonferroni’s posttest. The null hypothesis was rejected at P ≤ 0.05.

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Results

Both HES 130/0.4 and HES 200/0.5 increased in vitro plasma viscosity with increasing concentrations (P < 0.0001; two-way analysis of variance) (Fig. 1). At HES volume concentrations (vol/vol plasma) of 25% and larger plasma viscosity was significantly higher compared with 0% HES (baseline) in both groups (P < 0.05; Dunnett’s posttest). HES 200/0.5, which was significantly more viscous than HES 130/0.4 (100% vol/vol plasma) tended to increase plasma viscosity to a larger extent than HES 130/0.4, with a statistically significant difference at 50% (P < 0.05) and more (P < 0.001; Bonferroni’s posttest).

Figure 1

Figure 1

In vitro whole blood viscosity at high shear rate (94.5 s−1) did not differ between the two HES preparations and did not change compared to baseline (Fig. 2). At low shear rate (0.1 s−1), HES 130/0.4 concentrations of 25% and 50% showed a significant decrease in whole blood viscosity compared with 0% HES (P < 0.05 and P < 0.001), whereas HES 200/0.5 at 37.5% and larger caused a viscosity increase (P < 0.05). Group comparison revealed a significantly lower viscosity with HES 130/0.5 at concentrations of 37.5% and larger (P < 0.001). This change in viscosity (HES 200/0.5 versus HES 130/0.4) was more pronounced than what was seen with a 5% change in Hct (Table 1).

Figure 2

Figure 2

Table 1

Table 1

Erythrocyte aggregation as assessed with the standardized sedimentation rate was dose-dependently increased by HES 200/0.5 compared with HES 130/0.4 (P < 0.001 at 28.1% and 37.5%) (Fig. 3).

Figure 3

Figure 3

Thirty-one patients were included in the ex vivo study, 16 treated with HES 130/0.4 and 15 with HES 200/0.5. As expected from the dose regimen planned in the protocol, the cumulative amount of administered HES 130/0.4 was significantly larger than of HES 200/0.5 at all time points (P < 0.05) (Fig. 4).

Figure 4

Figure 4

Plasma viscosity tended to increase over time in both groups (Fig. 5). With HES 130/0.4 no significant increase compared to baseline (day 0) was observed. HES 200/0.5 demonstrated a statistically detectable increase at days 10 and 12 when compared with baseline (P < 0.05). However, the significance of this observation given that no differences between the two HES groups at these time points were statistically detectable is uncertain.

Figure 5

Figure 5

Suspensions of normal RBCs from a healthy, universal donor in the patient plasmas were done to reconstitute whole blood with standardized RBCs (Fig. 6). In general, blood viscosity at standardized Hct tended to increase over time in both treatment groups. This was not significant at high shear rate (94.5 s−1) for any of the groups. At low shear rate (0.1 s−1), a statistically detectable increase compared with baseline was observed with HES 200/0.5, but not with HES 130/0.4, at days 4 to 8 (P < 0.05). Given that no group differences were detectable at any of these time points, the significance of this observation is uncertain.

Figure 6

Figure 6

The use of freeze-thawed plasma samples for the reconstitution of whole blood with fresh RBCs had no influence on viscosity measurements (Table 2). This was true for plasma alone as well as plasma with admixed HES 130/0.4 or HES 200/0.5.

Table 2

Table 2

Serum fibrinogen increased over time in both groups above baseline and above upper normal (normal range, 1.7–4.0 g/L) (Fig. 7). This increase was statistically significant with both HES solutions for all time points (P < 0.001). No differences were detected between the two treatment groups. Globulins did not change over time relative to baseline values and did not reveal any group differences.

Figure 7

Figure 7

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Discussion

The current study was conducted to investigate the influence of two different HES preparations (6% HES 130/0.4 and HES 200/0.5) on blood and plasma viscosity in vitro and ex vivo in patients with severe head injury.

In vitro, HES 130/0.4 increased plasma viscosity to a lesser degree than conventional HES 200/0.5 at comparable volume concentrations. Plasma viscosity is determined by the number and physical properties of dissolved macromolecules, such as fibrinogen and globulins (22) or infused colloids (19,21). The lower Mw of HES 130/0.4 explains the lower plasma viscosity with this compound compared with the medium Mw HES 200/0.5 (Fig. 1). Our results are in agreement with earlier investigations on HES solutions with a higher Mw (30,31). The in vivo Mw of HES solutions may vary with time because HES molecules are hydrolyzed by plasma amylase. The speed of this hydrolyzation is inversely related to the degree of MS and the C2/C6 ratio of the HES molecules (2,4). This enzymatic hydrolyzation is probably negligible in our in vitro study because of the short incubation time. In addition, the concentration of HES is not expected to change during the incubation period, as cleaved products are not removed from the in vitro system (viscometer). This is in contrast to an in vivo situation, where continuous renal filtration of the low molecular cleavage products would continuously maintain the enzymatic breakdown.

Whole blood viscosity at high (94.5 s−1) and low (0.1 s−1) shear rates tended to increase in vitro with larger concentrations of conventional HES 200/0.5. With HES 130/0.4, however, whole blood viscosity at high shear rate was at least as low as baseline values (0% HES). Whole blood viscosity at high shear rate is in part determined by plasma viscosity (22). Because plasma viscosity was higher with HES 200/0.5 than with HES 130/0.4 (Fig. 1), it may explain the tendency to a higher whole blood viscosity at high shear rate with HES 200/0.5 (Fig. 2). Low shear viscosity is primarily determined by erythrocyte aggregation (22). The concentration-dependent decrease of whole blood viscosity with HES 130/0.4 at 0.1 s−1 therefore suggests that HES 130/0.4 decreased erythrocyte aggregation, which is caused by macromolecular bridging of neighboring erythrocytes thus overcoming the repulsive forces of the negatively charged cell surfaces. Large macromolecules have a larger bridging capacity than smaller molecules. Smaller molecules, e.g., albumin, are adsorbed to the surface and may interfere with the binding of bridging molecules (28). Our data suggest that HES 200/0.5 is large enough to contribute to intercellular bridging and thus increases aggregation. HES 130/0.4, on the other hand, is too small for bridging RBCs, interferes with the physiological bridging of fibrinogen and globulins, and thus decreases erythrocyte aggregation. This hypothesis is supported by the HES-specific differences we found in erythrocyte aggregation (Fig. 3).

The ex vivo viscosity measurements during repetitive large-dose infusion of either HES 130/0.4 or HES 200/0.5 in. patients with severe head injury tended to increase over time (Figs. 4 and 5). Although differences in plasma as well as low shear blood viscosity were statistically detectable in the HES 200/0.5 group at some single time points, significance is uncertain because no group differences (HES 200/0.5 versus HES 130/0.4) were present at those time points. The ex vivo experiments are hence not in keeping with the prominent effects found in vitro. Explanations for this discrepancy may be the following study limitations: first, the decreasing sample size at later time points because of completion of the study treatment by an increasing number of patients. This caused a substantial loss of statistical power in the ex vivo part of the study. Second, each plasma sample collected for the viscosity measurements represents only one single time point not necessarily reflecting the true course of viscosity between the consecutive sampling time points. Significant changes in viscosity, e.g., as expected after repetitive HES administration with short infusion intervals, and differences between the two treatment groups may therefore not have been detectable with the sampling interval that was chosen in our study. Third, albumin was administered as an add-on colloid in the HES 200/0.5 group. It has been attributed to interfere with erythrocyte aggregation as it is adsorbed to the RBC surface (19,28), thus attenuating a potential HES-induced viscosity increase in comparison with HES 200/0.5 alone (28).

The acute phase reactants fibrinogen and globulins show typically increased serum levels in response to acute inflammation and trauma, and are major contributors to plasma viscosity. Fibrinogen significantly increased in both groups up to day 6 after trauma almost identically (Fig. 7). It may explain the overall tendency towards higher plasma viscosity seen over time with both treatment regimens (Fig. 5).

Reconstituted blood instead of freshly drawn whole blood was used for the ex vivo study. Immediate sample analysis after blood withdrawal, as required for the whole blood viscosity experiments, was not possible for logistic reasons. However, the comparative reconstitution experiments done with fresh and freeze-thawed plasma samples showed no influence of freeze-thawing on viscosity measurements, which was true for pure plasma as well as plasma with admixed HES. The question may also arise if a possible group difference in the amount of administered mannitol to decrease ICP was a confounding variable in the viscosity analysis. This is unlikely, as the infusion trigger for mannitol was very stringent, and total amounts of administered mannitol among patients who had received this treatment and calculated for all patients were small and did not differ between the groups (data not shown).

Based on the pertinent literature (23–26), the HES concentrations that could be expected in our patient plasma samples were comparable to the concentrations that were set up in the in vitro part of the study. During hemodilution therapy with HES 200/0.5 (10%), Kroemer et al. (23) and Treib et al. (24) reported mean HES plasma peak concentrations of 1.2% and 1.5%, respectively, after 5 days of treatment. Asskali and Forster (25) showed in healthy volunteers HES plasma concentration profiles of 500 mL of HES 200/0.5 (10%) during repetitive daily infusions. Mean plasma peak concentrations amounted to about 0.8% at day 5. With regard to HES 130/0.4 (6%), Jungheinrich et al. (26) reported from patients undergoing orthopedic surgery mean plasma concentrations of approximately 0.9% at end of surgery. Considering that our infusion regimen allowed up to 5 times larger daily HES 200/0.5 doses (2500 mL) and up to 5000 mL of HES 130/0.4 per day over several days (12), substantially larger HES plasma peak concentrations than found in the above-mentioned trials can be extrapolated for our study at least with HES 200/0.5. Therefore, the in vitro data we present are likely to reflect a true clinical situation during repetitive large-dose HES administration.

Microcirculation in general is determined by a variety of factors such as perfusion pressure, vascular resistance, Hct, and the viscous properties of the perfusate. With regard to cerebral perfusion, a viscosity-mediated form of autoregulation similar to pressure autoregulation has been suggested (32). In areas with normal autoregulation, a decrease in blood viscosity and hence a decrease in resistance to flow as a result of decreased blood viscosity is balanced by compensatory vasoconstriction. The net cerebral blood flow (CBF) would remain the same. In areas with impaired autoregulation (e.g., in traumatic brain injury), a decrease in viscosity would not lead to reflex vasoconstriction. CBF would consequently remain increased in these vascular beds of injured tissue that are probably more dependent on oxygen. An improved microcirculation may be the mechanism behind the better tissue oxygenation described with HES 130/0.4 (16,17). In the current study the overall significantly lower plasma viscosity and the pronounced decrease in low shear blood viscosity seen with HES 130/0.4 in vitro (Figs. 1 and 2) suggest therefore potential advantages of HES 130/0.4 over HES 200/0.5.

As previously reported from our randomized, clinical trial in patients with severe head injury (12), patients treated with HES 130/0.4 had less ventilation days, colloid treatment days and intensive care unit days. Furthermore, the number of patients with ICP peaks and mean cumulative hours of increased ICP was significantly less in the HES 130/0.4 group. The reason for these findings was not clear. Based on evidence about albumin extravasation into the cerebrospinal fluid in areas with regionally disrupted blood-brain barrier and blood-cerebrospinal fluid barrier, we hypothesized that albumin used as an add-on colloid in the HES 200/0.5 group might have caused the group differences. The presented data from this current study, in addition, suggest that lower viscosity and consequently improved microcirculation after HES 130/0.4 administration might have at least in part contributed to the overall more favorable course in this treatment group.

In summary, our data provide compelling evidence that HES 130/0.4 has better rheological properties than conventional HES 200/0.5 at least with larger dosages, and suggest a critical role of the physicochemical characteristics of HES solutions regarding hemorheology. Even small differences in viscosity may be relevant under low flow conditions typical in shock or in areas with critical perfusion. Under these circumstances HES 130/0.4 may be the colloid of choice.

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