Hydroxyethyl Starch Molecules Research Articles

Measurement of solution properties and molecular weight of hydroxyethyl starches using multi-angle laser light scattering: An interlaboratory comparison

The solution properties of hydroxyethyl starch (HES) vary significantly owing to different measurement parameters adopted and sample structures. Here, a round-robin study was conducted to compare inter-laboratory measurements of solution properties, weight-average molecular weight (Mw), and molecular weight distribution of four HES candidates covering the low- and medium-molecular-weight range, and 50 commercially available HES 130/0.4 drug samples. Analysis was performed using size exclusion chromatography (SEC) combined with multi-angle laser light scattering (MALLS) and differential refractive index (dRI) detectors. The results indicate that HES molecules in the Mw range of 17,000–130,000, with varying degrees of substitution (between 0.4 and 0.8), yielded a refractive index increment (dn/dc) value of 0.145 ± 0.003 mL/g (solvent: acetic acid-sodium acetate buffer; wavelength: 658 nm) and that the second virial coefficient (A2) is correlated with Mw. The SEC-MALLS-dRI method for Mw determination of HES demonstrated good inter-laboratory reproducibility; however, the study findings suggest that column specifications should be added for HES quality standards. Comparing Mw results obtained using common and experimentally corrected dn/dc and A2 values revealed an influence of dn/dc and A2 on Mw, indicating that the Mw acceptance criteria of HES quality standards should be adjusted.

Update of use of hydroxyethyl starches in surgery and trauma

Update of use of hydroxyethyl starches in surgery and trauma

Molecular size and origin do not influence the harmful side effects of hydroxyethyl starch on human proximal tubule cells (HK-2) in vitro.

Recently, clinical trials revealed renal impairment induced by hydroxyethyl starch (HES) in septic patients. In prior studies, we managed to demonstrate that HES accumulated in renal proximal tubule cells (PTCs). The related pathomechanism has not yet been discovered. To validate our hypothesis that the HES molecule itself is harmful, regardless of its molecule size or origin, we conducted a comprehensive study to elucidate the influences of different HES preparations on PTC viability in vitro. Cell viability of human PTC was measured with a cytotoxicity assay, quantifying the reduction of tetrazolium salt to colored formazan. Experiments were performed by assessing the influence of different carrier solutions of HES (balanced, nonbalanced, culture medium), different average molecular weights (70, 130, 200 kDa), different origins (potato or corn derived), and various durations of incubation (2-21 hours). Furthermore, HES 130/0.4 was fractionated by ultrafiltration, and the impact on cell viability of average single-size fractions with <3, 3 to 10, 10 to 30, 30 to 50, 50 to 100, and >100 kDa was investigated. We also tested the possible synergistic effects of inflammation induced by tumor necrosis factor-α. All tested HES solutions, regardless of origin or carrier matrix, decreased cell viability in an equivalent, dose-dependent manner. Coincubation with tumor necrosis factor-α did not reduce HES-induced reduction of cell viability. Minor differences were detected comparing 70, 130, and 200 kDa preparations. Analysis of fractionated HES revealed that each fraction decreased cell viability. Even small HES molecules (10-30 kDa) were significantly deleterious. For the first time, we were able to show that only the total mass of HES molecules applied is responsible for the harmful impact on renal PTC in vitro. Neither molecular size nor their origin showed any relevance.

Clinical use of hydroxyethyl starch and serious adverse effects: Need for awareness amongst the medical fraternity

Clinical use of hydroxyethyl starch and serious adverse effects: Need for awareness amongst the medical fraternity

Characterization and compatibility of hydroxyethyl starch–polyethylenimine copolymers for DNA delivery

Hydroxyethyl starch (HES) has been proposed as a biodegradable polymer for shielding of DNA polyplexes, where the feasibility of this approach was shown both in vitro and in vivo. In this study, we report on the physicochemical characterization, the in vitro cytocompatibility and hemotoxicity of HES-decorated polyplexes. For this purpose, various HES molecules were coupled to a 22 kDa linear polyethylenimine (LPEI22) to produce a library of nine different HES–PEI conjugates. Particle analysis using dynamic light scattering showed that, neither the molar mass of HES nor the amount of HES in the polyplexes affected the particle diameter, as it was consistently around 70–80 nm. Imaging using atomic force microscopy and transmission electron microscopy showed that, both naked and HESylated polyplexes were in the same size range and had a spherical morphology. Meanwhile, the HES-mediated particle-shielding effect, manifested as reduction in the surface charge, strongly correlated with the molar mass of HES, where the charge decreased linearly with the increase in molar mass. Ethidium bromide binding assay showed that HES–PEI did not negatively affect DNA condensation at N/P ratios higher than 4. HES conjugation also showed a stabilizing effect against salt-induced particle disassembly, and particle aggregation in protein-containing media. Compatibility tests included cellular viability, as well as erythrocyte aggregation and hemolysis assays. HES–PEI conjugates showed lower cytotoxicity, no aggregation, and much lower hemolysis compared to unmodified PEI. In conclusion, these results show that the HES–PEI conjugates are promising gene delivery polymers with favorable physicochemical properties and compatibility profile.

Physical plugging does not account for attenuation of capillary leakage by hydroxyethyl starch 130/0.4: A synthetic gel layer model

Hydroxyethyl starch (HES) solutions, widely used plasma substitutes, reportedly attenuate capillary leakage via physical plugging of capillary defects. We investigated how 2% HES solutions of different molecular weights (HES(70): 70 kDa, HES(130): 130 kDa, HES(200): 200 kDa, and HES(670): 670 kDa) affect dye release from polyacrylamide gels (PAGs) as a model of endothelial glycocalyx. We assessed dye release from 4% PAG with varying concentrations of albumin [0, 1, 2, 4, and 8% (w/v)] by measuring the change in dye absorbance (ΔAbs) at 5 h for each HES solution. For PAG containing no albumin, ΔAbs for HES(130) was 30% lower than that for HES(70) and HES(200), and 50% lower than that for HES(670). At concentrations of 1-8% albumin, ΔAbs at 5 h with HES(70), HES(130), and HES(200) solutions were almost half that with the HES(670) solution, but no significant differences were noted in ΔAbs at 5 h among HES(70), HES(130), and HES(200) solutions. The inhibition of dye release by HES(670) is likely due to the hindering effect of HES molecules partitioned into gel pores. However, a unique property of HES(130) , including the heavy hydroxyethylation at the C(2) position, may promote specific interactions with PAG and thereby inhibit solute release.

Molecular weight of Hydroxyethyl Starch Molecules influences Coagulation Profile measured by thrombelastography

The consensus about the ideal intravenous fluid in trauma patients remains open. However, hypertonic saline and hydroxyethyl starch (HES) seems to have advantages in terms of immuno-modulatory and haemodynamic effects. Nevertheless clotting abnormalities are frequently reported in association with the use of HES. We investigated the influence of light, medium and heavy molecular weight (MW) hydroxyethyl starch (HES) on coagulation in 29 healthy subjects. Ringer's lactate (RL) served as a control solution. Thrombelastography using Haemoscope's Thrombelastograph (TEG) hemostasis system was used to assess the effect of HES polymers and RL. TEG analysis was performed using recalcified native whole blood both with and without the addition of platelet activating factor IV (PAF IV) before and immediately after infusion of one of the solutions. Infusion of RL or one of the three HES solutions exerts an anticoagulant effect as demonstrated by a increase in clot formation time (R) and a decrease in maximum amplitude (MA), and the angle. The addition of PAF IV reversed these changes. This data indicate clear evidence of platelet activity per se or platelet interaction with the plasmatic coagulation system.

Fibrinogen Concentrate Reverses Dilutional Coagulopathy Induced In Vitro by Saline but Not by Hydroxyethyl Starch 6%

Severe bleeding often induces coagulopathy via loss, consumption, and dilution of clotting factors and platelets. The aims of our in vitro study were to characterize the influence of progressive hemodilution with either NaCl 0.9% or hydroxyethyl starch (HES) 6% on blood clot formation and to analyze the effect of substitution of fibrinogen and platelets on dilutional coagulopathy. Whole blood samples drawn from 8 volunteers were diluted from 20% to 80% of the sample volume with both diluents separately. Clot formation was measured by thrombelastography. At a 60% dilution, either fibrinogen and/or platelets were added to the samples. Clot firmness became critical after 40% dilution with HES 6% but not until 60% dilution with NaCl 0.9%. When platelet function was blocked, fibrin polymerization was severely impaired after 20% dilution with HES 6%, whereas such an effect was only seen after 80% dilution with NaCl 0.9%. The addition of fibrinogen reconstituted the clot firmness in the presence of NaCl 0.9%, but this had only a minor effect after dilution with HES 6%. Platelets alone or in addition were not able to improve clot firmness to a clinically relevant extent. Dilutional coagulopathy induced by crystalloids can, in vitro, be effectively reversed by supplementation of fibrinogen. In contrast, HES molecules interfere with fibrin polymerization and, thus, administration of fibrinogen after dilution with HES 6% failed to significantly improve clot firmness.

Instructions for Obtaining Journal CME Credit

Anesthesiology’s journal-based CME program is open to all readers. Members of the American Society of Anesthesiologists participate at a preferred rate, but you need not be an ASA member or a journal subscriber to take part in this CME activity. Please complete the following steps:The American Society of Anesthesiologists is approved by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians.The American Society of Anesthesiologists designates this continuing medical education program for a maximum of 1 hour of Category 1 credit toward the AMA’s Physician Recognition Award. Each physician should claim only those hours of credit actually spent in the activity.Purpose: The focus of the journal-based CME program, and the articles chosen for the program, is to educate readers on current developments in the science and clinical practice of the specialty of Anesthesiology.Target Audience: Physicians and other medical professionals whose medical specialty is the practice of anesthesia.Learning Objectives: After reading this article, participants should have a better understanding of the pharmacology, use, and limitations of hydroxyethyl starch solutions.Authors –Sibylle A. Kozek-Langenecker, M.D.Grants or research support: NoneConsultantships or honoraria: NoneThe article authored by Dr. Kozek-Langenecker was supported solely from institutional and/or departmental sources.Question Writer –Peter L. Bailey, M.D.Dr. Bailey has no grants, research support, or consultant positions, nor does he receive any honoraria from outside sources, which may create conflicts of interest concerning this CME program.Based on the article by Kozek-Langenecker entitled “Effects of hydroxyethyl starch solutions on hemostasis”http://content.wkhealth.com/linkback/openurl/trusted?issn=0003-3022&amp;volume=103&amp;issue=3&amp;spage=654&amp;part=fulltextin the September issue of Anesthesiology, choose the one correct answer for each question:Which of the following statements concerning hydroxyethyl starch (HES) solutions is most likely true?A. Each HES product has one particular molecular weight.B. The number of hydroxyl-ethyl residues does not influence HES physicochemical characteristics.C. The pattern of hydroxyethylation (e.g. , C2 carbon in a glucose subunit) does not influence HES physicochemical characteristics.D. Larger HES molecules are hydrolyzed by serum α-amylase.Which of the following statements concerning the adverse or side effects of HES solutions is most likely true?A. Hemostasis is not affected.B. Allergic reactions are more common compared to other colloid volume expanders.C. Long-term infusions can cause pruritus.D. There is no risk of renal dysfunction.Which of the following statements concerning coagulopathic bleeding associated with the administration of HES solutions in surgery patients is most likely true?A. It is less likely to occur with the use of slowly degradable HES solutions.B. It is not associated with an increased activated partial thromboplastin time.C. It is related to a factor VIII deficiency.D. It is not associated with a von Willebrand factor–type deficiency.Factors that can contribute to bleeding associated with perioperative HES solution administration include all of the following except A. The decrease in factor VIII which is part of postoperative acute phase reactionsB. Decreased platelet functionC. HemodilutionD. The solvent composition of HES solutionsWhich of the following statements concerning volume expanders is most likely true?A. The duration of the expansion effects of HES solutions is predicted by the pharmacokinetics of the particular HES molecule.B. Restricted use of slowly degradable HES solutions is recommended when hemostatic competence is critical.C. Most HES solutions produce considerable volume expansion effects beyond the 24 hours after their administration.D. Compared to albumin-based or gelatin volume expanders, only HES solutions induce platelet dysfunction.

Volume replacement with hydroxyethyl starch: is there an influence on kidney function?

Hydroxyethyl starch (HES) solutions are synthetic colloids with the pharmacological properties that are closest to natural colloids. In Germany, numerous types of HES preparations with different combinations of concentration, weight-averaged mean molecular weight (Mw), and hydroxyethylation pattern are available. They differ with regard to their volume-supporting capacity, intravascular half-life, and side effect profile. The elimination of HES molecules varies with the Mw and degree of substitution (DS). Large HES molecules undergo hydrolytic cleavage by alpha-amylase and are excreted in the urine, or they are phagocytosed by the reticuloendothelial system. The smaller HES molecules are eliminated by glomerular filtration. The higher the DS, the slower the metabolism and elimination of the molecule. Although HES can be used safely even in large doses in patients without altered kidney function, renal dysfunction and acute renal failure after HES infusion have been reported in patients who share several risk factors, such as preexisting renal disease, advanced age in combination with dehydration, or treatment with high doses of slow degradable HES solutions. Since there is no direct chemical toxicity of HES, the most likely mechanism for HES-induced renal dysfunction may be swelling and vacuolization of tubular cells ("osmotic nephrosis-like lesions") and tubular obstruction due to the production of hyperviscous urine. Considering this pathogenesis, it can be hypothesized that all hyperoncotic colloid solutions can induce renal impairment. In the case of HES, the risk of high plasma colloid osmotic pressure and thus the risk of acute renal failure are probably increased by high concentrations of the colloid or repeated administration of slowly degradable HES with a high Mw and DS. With adequate hydration, using sufficient amounts of crystalloids, HES has little if any adverse effects on renal function. Furthermore, modern -rapidly degradable HES solutions with a low Mw and DS, such as HES 130/0.4, do not increase the risk for renal dysfunction even when used in large amounts perioperatively.

Klinische und elektronenmikroskopische Untersuchung zur Hörsturztherapie mit der Kombination 10% HES 200/0,5 und Pentoxifyllin

The incidence of sudden hearing loss has increased. The pathogenetic mechanisms are still unknown, but viral infections and vascular phenomena with acute impairment of microvascular perfusion are thought to play a major role. Infusion of hydroxyethyl starch (HES) is used as a regimen to treat sudden hearing loss. In our clinic, anaphylactic reactions due to HES have not been observed so far. However, the use of HES is still discussed controversially due to long-term storage of HES molecules in tissue and due to high incidence of long-lasting pruritus. In a retrospective analysis of 118 patients treated with HES for sudden hearing loss, we observed pruritus starting in 64% of patients one to three weeks after therapy. This symptom with a duration between two weeks and four months was refractory to medical interventions. During therapy with HES improvement of hearing was observed in 75% of patients, in 62% improvement of hearing persisted still at the end of the observation period (7 months post infusionem). Light and electron microscopic assessment of human skin biopsies of one patient after treatment with HES showed storage of HES especially within dermal macrophages. Pathogenetically a pathway independent of histamin seems responsible for the induction of pruritus. Accordingly, classic antihistaminic drugs had no therapeutic effect in our patients. Dextran is used as an alternative to hydroxyethyl starch. In contrast to HES, the often mentioned higher incidence of severe anaphylactic reactions due to dextran has dramatically decreased with hapten inhibition (after preinjection of monovalent haptendextran Promit).(ABSTRACT TRUNCATED AT 250 WORDS)

Ingestion of hydroxyethyl starch by human leukocytes

Following infusion into animals, hydroxyethyl starch (HES) can be found in nearly all tissues, including phagocytic leukocytes (WBCs) of the reticuloendothelial system (RES). Conceivably, the ingestion of HES molecules by these cells might lead to RES blockade. We studied the ability of WBCs obtained from human blood (neutrophils, mononuclear leukocytes, and mixtures of these cells) and from the RES (alveolar macrophages) to interact with radioactive HES in vitro in the presence of normal serum. In general, 14C-HES failed to associate with blood WBCs (i.e., the cells did not acquire significant amounts of radioactivity). Generally, less than 0.1 percent of radioactivity available in the reaction mixtures became cell associated. Moreover, when used as a phagocytic stimulus, HES elicited practically no superoxide anion production from blood WBCs. Alveolar macrophages acquired significant amounts of 14C-HES (presumably by ingestion). However, only tiny quantities (0.09%) of the total amount of radioactivity available in the reaction mixture became cell associated. Despite this slight interaction with alveolar macrophages, it seems unlikely that the internalization of HES by WBCs will lead to phagocytic dysfunction (such as RES blockade) in humans since human WBCs seem quite limited in their ability to interact with this drug.

Changes in the molecular composition of circulating hydroxyethyl starch following consecutive daily infusions in man.

1 Changes in the circulating molecular composition of hydroxyethyl starch (HES) were determined in four normal men following three consecutive daily 500 ml infusions (total 1,500 ml), by passage of trichloroacetic acid filtrates of plasma through a Sepharose CL4B gel filtration column. 2 The HES recovered from the intravascular space 10 min following the injection on Days 1, 2 and 3, was of a narrower molecular size distribution than the injected material, with a noticeable shift to molecules of a low molecular weight (LMW) size. 3 The HES in the sampled plasma 24 h post-injection on Days 1, 2 and 3 consisted of molecules possessing a LMW distribution, concomitantly with a slight shift to molecules of a larger molecule size. 4 The HES recovered from the bloodstream 480 h after the third and final injection consisted of molecules possessing an intermediate size distribution, between LMW and high molecular weight (HMW) size material. 5 The results indicate that large HES molecules contained in the injected material are eliminated from the bloodstream; the HMW fraction at least partially by a alpha-amylase mediated catabolism, and the resulting LMW fraction by excretion.