With the third generation of hydroxyethyl starches (HES), this product group has again moved into the focus of scientific interest. The pharmacodynamic action of HES as a colloid depends on the number of oncotically active molecules but not directly on the plasma concentration, while effects on blood coagulation, especially on factor VIII and von Willebrand factor, depend on plasma concentration and in vivo molecular weight. HES with a molar substitution above 0.4 tends to accumulate in plasma after repetitive infusion. This effect is most pronounced with hetastarch (e.g. HES 670/0.75) and corresponds to the extent of tissue storage, which is significantly reduced for HES 130/0.4 compared with hetastarch and HES 200/0.5. HES 130/0.4 does not accumulate in plasma after repetitive administration, and plasma clearance of HES 130/0.4 is more than 23 times higher than that of hetastarch. This is beneficial especially in patients with preexisting renal insufficiency, as cumulative urinary excretion, even in the presence of moderate to severe non-anuric renal failure, is higher for HES 130/0.4 than for older HES specifications when given to healthy volunteers. No adverse effects on kidney function have been observed for HES 130/0.4 compared with gelatin in patients with preoperative renal impairment undergoing aortic surgery. Based on recent study results, HES 130/0.4 may be given to patients with renal impairment as long as urine flow is preserved. The volume effect induced by HES does not directly mirror pharmacokinetics. Equivalent volume efficacy has been proven for HES 130/0.4 versus HES 200/0.5 and HES 670/0.75 despite longer intravascular persistence of the less metabolizable HES products. Influence on coagulation is minimal with HES 130/0.4. Recent clinical data showed reduced blood loss and RBC transfusion requirements when comparing HES 130/0.4 (C2/C6 > 8) with hetastarch and pentastarch. HES 130/0.4 combines the advantages of an efficacious volume therapeutic registered for high-dose treatment with a significantly improved safety profile.
Today hydroxyethyl starch (HES) is commonly used worldwide as an efficient colloid for blood volume therapy. There are, however, significant regional differences. In the USA only hetastarch (HES 450/0.7 or HES 670/0.75) is available for volume therapy, while HES 200/0.5 is available for leukapheresis only. In Japan, HES 70/0.5 (Salinhes®, Kyorin Pharmaceutical Co., Tokyo) is used. In contrast, a variety of HES specifications are available in Europe.
When the first-generation HES was introduced back in the 1970s, it was commonly believed that a prolonged intravascular retention time would be preferable with regard to efficacy and safety. This assumption was based, first, on the fact that the intention was to mimic human albumin and, second, that due to the persistence of HES molecules, only a limited dose was believed to be required for efficient stabilization of hemodynamics. Hemodilution effects were erroneously interpreted as persistent volume effects instead of using single- or double-indicator dilution techniques. Only recently could it be shown that some of the assumptions of the early HES development phase were indeed wrong.
HES types are physicochemically characterized by their mean molecular weight, molar substitution and C2/C6 ratio. Molar substitution is defined as the number of hydroxyethyl residues per glucose subunit, while the C2/C6 ratio describes the hydroxyethylation pattern of the carbon atoms in the glucose ring.
This review aims to provide an overview of the pharmacokinetic and pharmacodynamic characteristics of different HES specifications and will discuss these differences with regard to clinical efficacy and safety. HES compounds can be derived from different vegetable sources such as waxy maize and potato. Waxy maize and potato starch-based products are not bioequivalent due to some physicochemical differences (e.g. phosphorylization of potato starch). This review will focus on waxy maize-derived HES products.
PHYSICOCHEMICAL CHARACTERIZATION OF HYDROXYETHYL STARCH
HES represents the latest generation of artificial colloids following gelatin and dextran. The physicochemical properties, metabolic fate and excretion of a HES molecule depend on the actual size of the molecule, but even more on the molecule’s chemical properties that are modified by hydroxyethylation. Hydroxyethylation takes place at the carbon atoms of the glucose subunit of the starch molecule and is predominantly guided to the C2 and C6 carbon atoms. The C3 carbon atom is hydroxyethylated to a lesser degree. The hydroxyethylation process alters the specific physicochemical properties of the starch molecule and thereby influences the properties of the compound in vivo.1
HES solutions are polydisperse, meaning that they contain a distribution of different molecular sizes. After infusion, HES molecules smaller than the renal threshold (45 to 60 kDa) are rapidly excreted. Larger molecules are enzymatically split into smaller ones by plasma α-amylase. Plasma α-amylase is an endo-amylase, indicating that enzymatic breakdown does not start from the ends of the molecule, but cleavage takes place in the middle of the polyglucose chain. This results in smaller HES fragments that will again be excreted by the kidneys when the renal threshold has been reached. A minor proportion of the infused HES is known to be transiently stored in tissues, but is ultimately excreted in urine after redistribution while other forms of excretion, such as in bile, are negligible.2
Pharmacokinetic parameters of a HES type are predominantly determined by its molar substitution and the substitution pattern (C2/C6 ratio). The in vitro mean molecular weight is of minor importance unless a greater proportion of molecules is already initially smaller than the renal threshold. Hydroxyethylation slows down the rate of enzymatic breakdown of HES molecules and thus prolongs the intravascular retention time. A high C2/C6 ratio decreases the hydrolysis of HES by α-amylase and therefore is synergistic to a high molar substitution. Jung et al. investigated the effect of 500 mL of two HES 200/0.5 solutions that differed only with regard to the C2/C6 ratio (5.8 and 10.8).1In vitro molecular weight and molar substitution were similar at study onset. Plasma concentrations and in vivo molecular weight of HES were lower in the group receiving the HES 200/0.5 with the lower C2/C6 ratio as early as 1 hour after infusion end. Correspondingly, the area under the plasma concentration time curve (AUC) was larger in the group with the higher C2/C6 ratio of 10.8; so was the duration of hemodilution.
The importance of molar substitution for HES pharmacokinetics is sometimes underestimated. This is probably due to the fact that in the product description the molecular weight is in the first position, followed by the molar substitution. For example, the HES type used in hetastarch is described as HES 450/0.7, indicating that the molecule has a mean molecular weight of 450 kDa and contains an average of seven hydroxyethyl residues per 10 glucose subunits. The molar substitution, not the molecular weight, is the etymological background for the names hetastarch (MS 0.7), pentastarch (0.5), and tetrastarch (0.4).
HES types are traditionally classified as high (450 to 670 kDa), medium (130 to 200 kDa), and low (≤ 70 kDa) molecular-weight starches. More relevant is the classification according to the molar substitution: a HES type with a molar substitution of 0.62 to 0.75 is considered highly substituted, a molar substitution of around 0.5 is medium, and HES types with a molar substitution at or below 0.4 have a low molar substitution.
IMPACT OF IMPROVED ANALYTICAL METHODS
Analytical methods are important for the characterization of HES both in vitro and in vivo. For the characterization of the HES specification and for continuous verification of product quality, the analysis of both the raw material and the final product is of utmost importance. For the determination of HES plasma concentrations, HES is typically precipitated by acetone and then dissolved and hydrolyzed into isolated glucose units by trifluoroacetic acid which are finally analyzed enzymatically.3,4 State-of-the-art methods for the determination of the in vivo molecular weight of HES comprise low-angle laser light scattering and high-performance liquid chromatography. Refinement regarding the determination of molecular weight revealed that due to prior methodological limitations, the actual molecular weight was systematically underestimated in the past. For example, the HES used for the formulation of hetastarch was initially labeled as HES 450/0.7, but was found to have a true mean molecular weight of 670 kDa. The product label has been corrected accordingly. New HES specifications such as HES 130/0.4 have been developed and validated with state-of-the-art methodologies. For in vivo samples (e.g. plasma or urine), methods validated for the respective body fluid must be used, and careful sampling procedures including amylase inactivation are of importance.
ANIMAL DATA ON TISSUE STORAGE AND SAFETY
The amount of HES that is transiently stored in tissues depends on the infused HES dose, intravascular half-life and renal excretion. The absolute amount of HES in tissues of living humans is not directly accessible for obvious reasons. This is the reason why animal studies are required to quantitatively compare HES tissue storage. The available literature regarding animal data on tissue storage has been reviewed by Jungheinrich and Neff.5 The studies on HES 450/0.7 by Hulse and Jacobi6 and on HES 130/0.4 compared with HES 200/0.5 by Leuschner et al.7 are of paramount relevance. Both studies can be combined as both used a multiple dosing regimen and measured the organ-specific tissue storage using 14C radioactive-labeled HES. While data on all three HES types is available for the time periods 8 to 10 days and 24 to 28 days after the last treatment, only data on HES 130/0.4 and HES 200/0.5 is available until 52 days after last treatment. HES plasma residuals were lower for HES 130/0.4 (day 10: 0.0005% of the cumulatively infused dose) than for HES 200/0.5 (0.0021%) showing a further decrease until 52 days after the last treatment. Because the main amount of radioactivity had been excreted earlier, combined renal and bile excretion rates over 24 hours were low for HES 130/0.4 and HES 200/0.5 10 days after the last infusion (0.055% and 0.052%), 24 to 28 days after the last infusion (0.030% and 0.039%) and further decreased until 52 days after the last infusion (0.017% and 0.020%). The corresponding values for HES 450/0.7 were about 1.0% and 0.9% and thus were markedly higher at all available time points. Tissue storage was also markedly higher after HES 450/0.7 (carcass, liver, kidney and spleen) compared with both HES 130/0.4 and HES 200/0.5, and significantly less for HES 130/0.4 compared with HES 200/0.5. Whole-body storage 52 days after the last administration was only about one quarter for HES 130/0.4 compared with HES 200/0.5. This reduction of tissue storage is especially important because both solutions had been given for 18 consecutive days. At 52 days after the last administration, the remaining activity in the kidneys was low for both groups in absolute terms (0.019%), but indicated that continued excretion of residual HES was still occurring even in the case of lower whole-body storage for HES 130/0.4.
PHARMACOKINETICS OF DIFFERENT HYDROXYETHYL STARCHES
In the following the pharmacokinetic properties of the different HES types are reviewed, starting with the first-generation HES, hetastarch.
Hetastarch (e.g. HES 450/0.7, HES 670/0.75)
In a study by Wilkes et al., the pharmacokinetics of hetastarch (HES 670/0.75) after a single infusion were examined in healthy volunteers.8 A first-generation HES in a newly formulated balanced carrier solution (Hextend®, BioTime, Inc., Berkeley, CA, USA) was used, but as expected the composition of the carrier solution had no influence on the pharmacokinetic properties. The authors reported a significant difference between the AUC for the first 24 hours after infusion (AUC24) of 209 mg ⋅ hour/mL and the AUC from zero to infinity (AUC∞) of 926 mg ⋅ hour/mL. This striking difference can be explained by the fact that highly substituted HES types display a total excretion period well beyond 24 hours. This is also reflected by a low plasma clearance of 0.98 mL/min. The mean initial half-life (t1/2α) for the first 8 hours after infusion was 6.3 hours, and the mean half-life for the first 7 days after infusion (t1/2β) was 46.4 hours.
These results confirmed the prior findings by Yacobi et al.9 showing slow elimination characteristics for hetastarch formulated in saline carrier solution. Similar results were reported by Boon et al. when 7 mL/kg of blood were replaced with equivalent volumes of a HES 470/0.7 solution in five volunteers.10 Again, plasma elimination was found to be comparatively slow and plasma concentration after 24 hours (4 mg/mL) was still > 50% of the maximum value (7.4 mg/mL).
Mishler et al. reported the first pharmacokinetic results after repetitive dosing with hetastarch.11 They demonstrated that three infusions with a relatively low HES dose of 30 g led to an accumulation of HES in the plasma with the residual HES plasma concentration 24 hours after the third infusion being higher than the peak HES plasma concentration after the first infusion. The HES plasma concentration measured 20 days after the end of the last infusion was above 2 mg/mL and thus at a comparatively high level. In parallel, the activity of the serum amylase remained at a high level.
The statement of the authors that ‘patients receiving repeated infusions of HES should not be at risk for accumulation of this colloid’ must be viewed in the context of the available knowledge when this study was conducted, but the study results definitely have to be interpreted differently today.
Hexastarch and pentastarch (HES 200/0.62 and 200/0.5)
Pharmacokinetics of HES 200/0.62 (6%) and HES 200/0.5 (10%) were compared in a randomized study in healthy volunteers by Weidler et al.12 Because of the different HES doses, the maximum plasma concentration was expectedly higher after the infusion of 500 mL of HES 200/0.5 (10%) than after infusion of 500 mL of HES 200/0.62 (6%), 8.0 mg/mL and 5.2 mg/mL, respectively. Plasma half-lives estimated by a two-compartment model were shorter for the more rapidly metabolizable HES 200/0.5: t1/2α was 5.08 hours for HES 200/0.62 and 3.35 hours for HES 200/0.5. Similarly the terminal half-life (t1/2β) was 69.69 hours for HES 200/0.62 and 30.61 hours for HES 200/0.5. Clearance of HES 200/0.62 was 1.23 mL/min and thus slightly higher than that of hetastarch8 but markedly lower than the clearance found for HES 200/0.5 (9.24 mL/min).12 These results are in line with studies on HES 200/0.513 and HES 450/0.7.8
The study by Asskali and Förster compared the pharmacokinetic profiles of HES 200/0.62 and HES 200/0.5 after daily administration of 500 mL over five consecutive days.14 Significant plasma accumulation was found for both HES types from day 2 onwards. HES 200/0.62 clearly showed higher plasma accumulation than HES 200/0.5. Plasma concentration 24 hours after the end of the last HES 200/0.62 infusion was 7.8 mg/mL compared with a maximum concentration of 7.0 mg/mL directly after the end of the first infusion. A lesser degree of plasma accumulation was reported for HES 200/0.5. While plasma concentrations of HES 200/0.5 decreased below 0.5 mg/mL for 20 days after the end of the last infusion, there was still a considerable plasma concentration of 1.3 mg/mL for HES 200/0.62 30 days after the end of the last infusion. This finding is of special interest as the infused HES 200/0.5 dose (250 g) was higher than the HES 200/0.62 dose (150 g) due to different product concentrations (10%vs. 6%). Another important finding of this study was that the elimination half-lives of HES 200/0.62 significantly increased over time for HES 200/0.62 from 8.58 hours on day 1 to 28.48 hours on day 5, while the repetitive infusion of HES 200/0.5 did not lead to an increase of the elimination half-life. Using a three-compartment model, terminal half-lives of HES 200/0.62 and HES 200/0.5 were 211 and 113 hours, respectively.
Low-molecular-weight pentastarch (HES 70/0.5)
Lehmann et al. investigated the plasma concentration time course and the renal elimination of HES 70/0.5 after five consecutive infusions of 835 mL per day.15 Plasma accumulation was much lower compared with HES 450/0.7, for example, but still detectable. Elimination half-lives increased in the course of the study and reached 90 hours for the first 10 days after completion of the last infusion. This study again showed the importance of molar substitution, showing similar accumulation after repetitive use of HES 70/0.5 compared with prior results for HES 200/0.5.
Tetrastarch (HES 130/0.4)
Low-substituted HES 130/0.4 is the most recently developed HES type. Single-dose pharmacokinetics were studied by Waitzinger et al.16 Plasma clearances were 31.4 mL/min for the 6% solution and 26.0 mL/min for the 10% solution, the highest values reported so far for any HES type. Between 62% and 68% of the administered HES could be found in the urine during the first 72 hours, which is again higher than values reported for other HES types. Initial elimination half-lives were 1.39 hours for the 6% solution and 1.54 hours for the 10% solution using a model-independent approach. Terminal half-lives were 12.1 hours for HES 130/0.4 (6%) and 12.8 hours for HES 130/0.4 (10%). As expected, maximum plasma concentrations were higher after the infusion of the 10% product (6.5 vs. 3.7 mg/mL) but 24 hours after the end of the infusion, plasma concentrations were below 0.5 mg/mL for both concentration groups.
Waitzinger et al. also studied the pharmacokinetics of HES 130/0.4 (10%, C2/C6 > 8) after ten consecutive daily infusions of 500 mL.17 Plasma concentration measurements over 24 hours for the first and the last infusion day showed virtually identical elimination curves. Additionally, the derived pharmacokinetic parameters such as the maximum plasma concentration (7.8 vs. 7.3 mg/mL), AUC (32.8 mg ⋅ hour/mL vs. 35.7 mg ⋅ hour/mL) and clearance (23.7 mL/min vs. 21.8 mL/min) were almost identical after the first and after the last infusion. Urinary excretion was stable over time without signs of saturation. Despite the high cumulative doses that were infused (5 L, equivalent to 500 g HES raw material), in this study no relevant plasma accumulation was found for HES 130/0.4.
Figure 1 shows the plasma concentrations of different HES types over the first 24 hours after infusion in percentages of the observed maximum plasma concentration within each study. Plasma accumulation at 24 hours can be observed for molar substitution ≥ 0.5, the highest being for hetastarch. Table 1 presents the clearances of four different HES types (hetastarch, hexastarch, pentastarch and tetrastarch) after repetitive dosing. Clearance of HES 130/0.4 was at least 23 times higher than for HES 200/0.62 or 450/0.7, and almost five times higher than for HES 200/0.5.
Table 1. Plasma clearance after multiple infusions of different hydroxyethyl starch (HES) types in healthy volunteers
Hydroxyethyl starch plasma concentration in patients
HES plasma concentrations measured in patients in clinical studies generally confirmed the findings in healthy volunteers after repeated administrations. In a study in patients with peripheral artery disease, Költringer et al. reported a rise in the HES plasma concentration until the end of the 12-day treatment period during which the patients received a daily dose of 500 mL HES 200/0.62 (6%).18 Maximum plasma concentration was 8.3 mg/mL. In a study in patients with cerebrovascular disease, patients were treated with a daily infusion of HES 200/0.62 (6%), HES 200/0.5 (10%) and HES 40/0.5 (former label for HES 70/0.5; 6%).19 Cumulative infused doses were 7.5 L. HES serum concentrations were measured prior to start of the last HES infusion and were 18 mg/mL, 12 mg/mL and 3 mg/mL for HES 200/0.62, HES 200/0.5 and HES 40/0.5, respectively, indicating an intravascular accumulation of all examined HES types (molar substitution ≥ 0.5). Krömer et al. also reported accumulation of HES 200/0.5 after repeated infusions in stroke patients.20 The cumulative dose was 7 L. Maximum HES plasma concentration was 11.7 mg/mL after the first infusion and increased to 12.4 mg/mL on treatment day 5 prior to the fifth infusion. Despite the reduction of the daily dose from day 5 onwards, the maximum HES plasma concentration remained stable until the end of the treatment period (day 10). These results are consistent with the data from volunteer studies showing that HES types with a molar substitution higher than 0.4 cause accumulation in the plasma.
The study by Treib et al. compared two different HES 200/0.5 (10%) solutions with C2/C6 ratios of 5.7 and 13.7 in patients with cerebrovascular disease.21 Patients were treated with cumulative doses of 7.5 L. While the in vivo molecular weight in plasma decreased in both groups, the decrease was significantly more pronounced and the HES plasma concentration was lower from day 3 onwards in the group with the lower C2/C6 ratio (P < 0.01 each). The authors did not observe a greater degree of hemodilution, but reported a prolonged hemodilution effect in the group with the higher C2/C6 ratio. The results of this study and the study by Jung et al.1 clearly demonstrate the influence of the C2/C6 ratio on the pharmacokinetics of HES.
In contrast to the studies with HES 200/0.62, 200/0.5 and 70/0.5, no plasma accumulation was reported for HES 130/0.4 in volunteers after repetitive dosing.17 These results were recently confirmed in a clinical study in orthopedic surgery patients comparing plasma concentrations after the infusion of equivalent doses of HES 130/0.4 versus HES 200/0.5.22 Plasma concentrations were significantly different starting 5 hours post surgery and remained significantly different until the first postoperative day (2.6 mg/mL for HES 200/0.5 and 1.0 mg/mL for HES 130/0.4, P < 0.01).
CLINICAL EFFICACY OF HYDROXYETHYL STARCHES
Important effects of prophylactic or therapeutic administration of HES colloids are the maintenance and rapid restoration of intravascular volume. Besides these effects on macrocirculation, effects on microcirculation and tissue oxygenation are important for the preservation of organ function. HES 130/0.4 (6%) was found superior regarding tissue oxygenation when compared with crystalloids in major abdominal surgery,23 and provided a larger and faster increase of tissue oxygen tension when compared with other HES solutions after infusion in volunteers.24 One likely explanation besides macrohemodynamic effects is the lower whole-blood viscosity after HES 130/0.4 administration compared with older starch preparations.25
HES differs from other pharmaceutical active ingredients like small molecules or albumin because of its polydispersity and because of changes in molecular weight from in vitro to in vivo situations. Pharmacokinetic parameters such as half-lives cannot be defined rigorously. HES clearances and residual HES concentrations after 24 hours, however, clearly depend on the molar substitution and the C2/C6 ratio, whereas the initial mean molecular weight in the bottle is of secondary importance. In the case of HES products, plasma concentration half-lives should not erroneously be interpreted as efficacy half-lives. Intravascular volume is known to be regulated by a number of mechanisms including the colloid osmotic pressure which is raised by infusion of colloid solutions. Counter-regulatory mechanisms after plasma volume expansion have to be taken into account. Therefore, the extent and duration of the volume effects induced by the infusion solution, besides the type of infusion, also highly depend on the individual patient’s condition, blood loss status, infusion dose and speed. A longer plasma persistence of HES was initially regarded as favorable as this was thought to result in a prolonged volume effect. The retrospective view on the results of a study published by Köhler et al. in the 1970s demonstrates that this belief was not justified.26 Despite the slow elimination of HES 450/0.7, no relevant volume effect could be detected after 24 hours both in patients with normal renal function and in dialysis patients. This finding is supported by other studies where despite significant residual HES concentrations in plasma,8,9 no volume effects lasting longer than 24 hours after the last HES infusion were found.11,27
The extent and duration of the volume effect of 500 mL HES 130/0.4 (6%) was studied by Waitzinger et al. in healthy volunteers using chromium (51Cr) marked erythrocytes.28 The authors reported a measurable increase of the plasma volume for a period of 4–6 hours. Initial absolute increase was 380 mL and the plasma volume returned to baseline 8 to 24 hours after the infusion. The observed volume effects were not inferior to results previously reported by Köhler et al. for HES 200/0.5.13 A volume effect of about 100% in acute normovolemic hemodilution for HES 130/0.4 (6%) was confirmed by a recent study using double indicator labeling.29 James et al. compared the extent and duration of the volume effects of HES 130/0.4 and HES 670/0.7 (6% solutions) in healthy volunteers that were bled of 10% of their calculated blood volume.30 In this setting, HES 670/0.7 led to a less sustained volume effect compared with HES 130/0.4 after hemorrhage. Several other studies have compared HES 130/0.4 and HES 200/0.5 with regard to their pharmacodynamic profile31–33 showing comparable efficacy in the setting of preoperative autologous blood donation,31 same responses to hypervolemic infusion prior to cardiac surgery,32 and in patients with major surgery using acute normovolemic hemodilution.33
Several double-blind studies compared the colloid volume of HES 130/0.4 and HES 200/0.5 necessary for hemodynamic stabilization during and after surgery.22,34,35 Gallandat Huet et al. reported that comparable HES volumes (2550 ± 561 mL vs. 2466 ± 516 mL) were required in 59 cardiac surgery patients for hemodynamic stabilization until 16 hours after end of surgery.34 These results were confirmed by Langeron et al. in a different surgical setting. For 100 patients undergoing orthopedic surgery, 1662 ± 641 mL versus 1696 ± 675 mL were required for hemodynamic stabilization until 5 hours after end of surgery.35 A second study in orthopedic surgery patients yielded comparable results showing that 2035 ± 446 mL versus 2000 ± 424 mL of colloid solutions were used for hemodynamic stabilization until the first postoperative day.22 The same study showed that colloid osmotic pressure could be similarly maintained in both groups. These results can be explained by the fact that colloid osmotic pressure does not directly depend on HES concentration, but on the number of oncotically active particles. As HES 130/0.4 was more rapidly excreted and the in vivo molecular weight of HES 130/0.4 was found to be significantly lower compared with HES 200/0.5, more macromolecules per gram were available for HES 130/0.4, thus compensating for the more rapid excretion.
A recent double-blind study by Gandhi et al. performed in the USA investigated the efficacy and safety of HES 130/0.4 and HES 670/0.75 in patients undergoing major orthopedic surgery.36 Infusion of the colloids was guided by a predefined algorithm taking central venous pressure and arterial blood pressure into account. The required total volume of colloids for intraoperative volume replacement was 1613 ± 778 mL for HES 130/0.4 and 1584 ± 958 mL for HES 670/0.7, showing that both colloids were equally effective in the stabilization of hemodynamics. Volume of infused crystalloids was similar in both groups.
CLINICAL SAFETY OF HYDROXYETHYL STARCHES
Differences in pharmacokinetics of HES products may have direct consequences regarding maximum daily doses and safety profile of the finished products. HES types reportedly show differences regarding effects on coagulation,36–43 tissue storage,6,7 and potential effects on renal function.4,44–55
Safety with regard to coagulation and tissue storage
In the study by Gandhi et al.,36 after exposure to equivalent HES volumes, nadir factor VIII activity within 2 hours of end of surgery was significantly lower for HES 670/0.7 than for HES 130/0.4. The transfused erythrocyte volume as a surrogate for blood loss was significantly higher for hetastarch compared with HES 130/0.4 (13.8 vs. 8.0 mL/kg). The authors concluded that HES 130/0.4 was equivalent regarding the volume effect, but was found to have a lesser effect on coagulation.
HES macromolecules are known to interact with platelets and plasma coagulation factors such as factor VIII and von Willebrand factor, causing a decrease in the plasma levels of these factors, and ultimately might lead to coagulation impairment in case of high doses of slowly metabolizable HES types.19,40,41 Recent studies in cardiac, urologic, aortic and orthopedic surgery and in patients with craniocerebral trauma showed that the effect of HES 130/0.4 in doses up to 50 to 70 mL/kg on coagulation was not negative or even smaller compared with different controls.22,53,55–57 Importantly, blood loss was similar in cardiac surgery when compared with gelatin, which is generally regarded to exert minimal effect on coagulation.42 In a pooled analysis of 449 surgical patients comparing blood loss and transfusion requirements after HES 130/0.4 and HES 200/0.5, Kozek-Langenecker et al. found significantly lower losses of red blood cells (difference: −149 mL) and less red blood cell transfusions (−137 mL) after HES 130/0.4. Activated partial thromboplastin time and von Willebrand factor were significantly less influenced by HES 130/0.4 compared with HES 200/0.5.
The positive safety results for HES 130/0.4 in adults have also led to first studies in the pediatric population. Lochbühler et al. studied the effects of HES 130/0.4 compared with human albumin in children aged less than 24 months in elective surgery.58 No differences were observed with regard to the infusion volumes required for hemodynamic stabilization (HES 130/0.4: 16 mL/kg; human albumin: 17 mL/kg). The authors concluded that HES 130/0.4 was well tolerated and as safe as albumin in the studied population, especially regarding coagulation.
Tissue storage of HES depends on cumulative dose and exposure time,59 and importantly on the HES type used.6,7 Both tissue storage and plasma persistence should be minimized. Rapidly degradable HES 130/0.4 has the lowest tissue and plasma persistence of all known HES types. Recent data from high-dose surgical studies (50 mL/kg) support prior results of animal studies concerning reduced tissue storage (although not directly measurable in living humans) and a reduced influence on coagulation.56,57
The authors of these high-dose studies56,57 as well as Neff et al. (up to 70 mL/kg/day HES 130/0.4 for several days)53 did not report metabolic acidosis as a relevant problem, despite the saline carrier solution used in all three studies. The concomitant infusion of balanced crystalloid solutions was not artificially prohibited in either of these studies. Figure 2 shows that the use of about 2 L of saline-based HES 130/0.4 in orthopedic surgery did not cause a relevant fall in pH or base excess (previously unpublished data from the Jungheinrich et al. trial22).
Regarding the influence of HES on monocyte function, the study by Dieterich et al. is of special relevance as the authors demonstrated that HES 200/0.5 plasma concentrations of < 30 mg/mL did not decrease the phagocytic capacity of monocytes.60 In the clinical setting, plasma concentrations exceeding 25 mg/mL are unlikely to occur even after repetitive administration of large doses of pentastarch or tetrastarch.14,22
Safety with regard to renal function
There are some studies indicating that HES administration might lead to the deterioration of renal function or cause morphological changes in the kidneys.44,47,49 These reports should not be uncritically generalized to other HES types or other patient populations.51 Other studies did not show adverse effects on kidney function.45,46,52 For the third-generation HES 130/0.4, which is rapidly metabolized and excreted, studies on patients at risk for renal dysfunction (prior mild to severe renal dysfunction, elderly, high-dose therapy in craniocerebral trauma) showed favorable results.4,48,53 In an observational study [data from the prospective Sepsis Occurence in Acutely ill Patients (SOAP) study], Sakr et al. investigated the effect of HES administration on renal function in 1057 critically ill patients.54,61 The need for renal replacement therapy was influenced by independent risk factors such as hematological cancer, sepsis, cardiovascular failure and baseline renal function. HES administration was found to have no influence on renal function and the subsequent need for renal replacement therapy.
A recent study by Godet et al. studied HES 130/0.4 (6%, C2/C6 > 8) versus 3% gelatin in abdominal aortic surgery patients with prior renal dysfunction.55 The study showed that HES 130/0.4 and gelatin were equally safe regarding renal function and that the perioperative administration of HES 130/0.4 did not cause deterioration of renal function in patients with preexisting renal impairment in comparison to gelatin.
There are several reasons why some studies with less metabolizable HES products (molar substitution ≥ 0.5) have yielded different results. First, dose limitations and product specific contraindications have to be observed. HES products should not be given in anuria not related to hypovolemia, as the kidneys are the only relevant excretion organ for HES. Second, hyperoncotic states, especially use of hyperoncotic products without sufficient concomitant crystalloids, have to be avoided. Hyperoncotic states – even when induced by products like dextran or 20% albumin – reportedly can result in renal failure. Glomerular filtration ceases when the hydrostatic pressure gradient is equal to or lower than the oncotic pressure gradient. Early treatment of this condition might reverse renal failure.62 Third, pharmacokinetic differences of HES types have to be taken into account. The amount of tissue storage and plasma persistence are not class effects, but greatly differ between first, second and third-generation HES.
SUMMARY AND CONCLUSIONS
HES types differ significantly with regard to pharmacokinetics, maximum daily doses and safety profile. The development of new HES molecules was guided towards faster and more complete elimination. For the latest-generation HES (molar substitution 0.4), clearances more than 23 times higher than for first-generation hetastarch and almost five times higher than for second-generation pentastarch have been shown. Consequently, tissue storage could be greatly reduced, and plasma accumulation is virtually absent after multiple dosing. Nevertheless, as proven by several well-designed double-blind trials, volume efficacy of HES 130/0.4 is equivalent to HES 200/0.5 as well as to HES 670/0.75. The prior belief that prolonged intravascular retention is associated with a prolonged volume effect was not justified, as even slowly metabolizable HES types do not cause considerable volume effects 24 hours after the last administration.
The scientific discussion on the possible side effects of HES on renal function is still controversial. However, pharmacological differences between HES types, especially a markedly more rapid metabolism and renal excretion of HES 130/0.4 compared with HES 200/0.5 and older HES types, as well as recent clinical data indicate that the latest HES generation is superior with regard to renal safety compared with older HES types, as long as treatment recommendations are observed. Regarding coagulation, recent clinical data clearly showed the reduced influence of HES 130/0.4 (C2/C6 > 8, 6%) on coagulation compared with hetastarch and HES 200/0.5, leading to significantly reduced red blood cell transfusion requirements. The increased safety margin of HES 130/0.4 was recognized by European regulatory authorities63 when the maximum daily dose was increased to 50 mL/kg which is the highest dose limit for any HES type approved for human use so far.