What is Hydroxyethyl Starch?
Hydroxyethyl starches are chemically modified non-ionic polymers. They have been known for many decades. Unlike the equivalent Hydroxyethyl products derived from the polymer analog cellulose, Hydroxyethyl starches (HES) have found relatively few large-scale industrial applications. Their widest use is in medical areas, such as for plasma volume substitutes to treat and prevent hypovolemia (low blood volume) or for blood plasma volume expansion.
Sources of Hydroxyethyl Starch
Hydroxyethyl starches are typically manufactured by hydroxyethylation of starch with ethylene oxide or chlorethanol under alkaline conditions. The modified products are subsequently hydrolyzed under acidic conditions to yield HES.
Hydroxyethyl starches are available with various average molecular weights, molar substitution, solution concentration, and substitution ratios. The number average molecular weights (MW) can range from 69,000 to 670,000 Daltons and the weight average molecular weights are around 450,000 Daltons. The substitution ratios (C2/C6 ratios) reflect the Hydroxyethyl substitution at the C2 and C6 positions of the Glucose repeat units. Molar substitution (MS) is the average number of Hydroxyethyl residues per Glucose subunit.
The first pharmaceutical HES product (Hespan®) was introduced back in the 1970s. Since then, many more HES have been developed with differing molecular weights, molar substitutions, and C2/C6 ratios.
What does Hydroxyethyl Starch do?
Hydroxyethyl starches are plasma volume substitutes used for the treatment and prophylaxis of hypovolemia. Intravenous HES solutions can be used to prevent shock following severe blood loss caused by trauma, surgery, or similar events. HES solutions are often used to restore and maintain intravascular volume, to stabilize hemodynamic conditions (blood flow in blood vessels), and to improve tissue perfusion. Under these clinical indications, HES is used in perioperative situations where there is a high risk of bleeding. Additionally, HES can be used as a macromolecular compound in the medium for sperm isolation, culture and cryopreservation.
Uses of Hydroxyethyl Starch
HES is globally used for fluid replacement in millions of patients in sepsis, trauma, and intensive care. It is one of the most frequently employed therapeutic interventions for surgical patients and in emergency and intensive care units.
In addition to Hespan® there are also some more recent HES-related products, including Hexastarch, Pentastarch, Tetrastarch, and Hextend. They are quite widely used for hypovolemia treatment.
HES preparations which feature on average seven hydroxyethyl residues per 10 Glucose subunits are called Heta starches. Similar names are applied to other levels of substitution: Hexastarch (MS = 0.6), Pentastarch (MS = 0.5), and Tetrastarch (MS = 0.4). Hetastarch (6%) has an average molecular weight of 200 kDa (kilodaltons) and a colloid osmotic pressure (i.e., the physiochemical pressure that develops when two solutions with different colloid concentrations are separated by a semipermeable membrane) of about 30 Pascals. Pentastarch (10%) has an average molecular weight of 200 kDa and a colloid osmotic pressure of 30-60 Pascals. Tetrastarch (VetStarch) 6% has a molecular weight of 130 kDa and a colloid osmotic pressure of 36 Pascals.
Hydroxyethyl starches are typically identified by three parameters, e.g., 10% HES 200/0.5 or 6% HES 130/0.4. The first number indicates the solution concentration or maximum daily dosage, the second represents the mean molecular weight expressed in kilodalton (kDa), and the third, most significant one is MS. Current HES solutions (6% HES 130/0.4 and 130/0.42) are the colloid fluids most often used in intensive care.
Metabolism
Unsubstituted starch anhydroglucose units are prone to α-amylase degradation. However, hydroxyethylation slows down the rate of enzymatic breakdown of the HES molecule and prolongs the intravascular retention time. Hydroxyethyl groups at the Glucose C2 position are known to inhibit α-amylase access to the substrate more effectively than do Hydroxyethyl groups at the C6 position. HES products with high C2/C6 ratios are hence expected to be more slowly metabolized. Older generation HES products with high MS values tend to accumulate in plasma, unlike the latest generation of tetrastarches.
Elimination of HES from the body also depends essentially on the MS value. HES molecules that are smaller than the renal threshold (60,000-70,000 Daltons) are rapidly excreted in urine when given intravenously, while molecules with higher molecular weights are metabolized by plasma α-amylase before excretion via the renal route. Hetastarch has the highest MS and tends to remain the longest in the vasculature. Hetastarch is cleared much more slowly than Tetrastarch. Hetastarch is prevented from hydrolysis in blood, thereby the prolonging intravascular expansion.
Is Hydroxyethyl Starch safe?
HES was initially not properly evaluated for the long-term mortality and morbidity before it became available in the market. For a long time, there were no reliable clinical data on the safety and clinical benefits of blood volume replacement fluids. The regulatory legislation was changed only in the wake of studies showing renal failure and bleeding, leading to the regulatory requirement of phase 1–3 clinical trials to demonstrate efficacy and safety prior to the approval of new drugs. HES was associated with increased mortality compared with other fluids (e.g., crystalloids, albumin, and gelatin), and increased the risk of requiring renal replacement therapy.
Adverse Effect
The unfavorable interaction of HES with coagulation pathways and the resulting impaired blood clotting were of concern. In addition, adverse effects may also include anaphylactic reactions such as urticaria, wheezing, periorbital edema, mild temperature elevation, chills, headache, flu-like symptoms, pruritus, myalgia, vomiting, peripheral edema, salivary gland enlargement, prolonged bleeding time, and increases in serum amylase levels during infusion.
In 2012, the United States Food and Drug Administration (US FDA) examined the risks and benefits of HES products. Research data showed increased mortality and severe renal injury, when HES was used in critically ill patients, including patients with septicemia. In 2013, the Pharmaco-vigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) concluded that the benefits of HES solutions no longer outweighed their risks and recommended that these fluids be withdrawn. On June 24, 2013, the US FDA recommended that HES products should not be used in critically ill patients or in those with pre-existing renal dysfunction.
Since 2021 the FDA requires safety labeling to warn about the risk of mortality, kidney injury, and excess bleeding. FDA is also requiring related changes to the Indications and Usage, Contraindications, Warnings and Precautions, and Adverse Reactions sections. A Summary of Safety Issues Hydroxyethyl starch (HES) products were approved for the treatment of hypovolemia. Recent data have associated administration of these products with certain serious risks. The FDA has subsequently completed a review of data and information on the safety of HES products, including data from randomized clinical trials, meta-analyses, and observational studies. These data and information reflect the following serious risks associated with use of HES products: mortality, acute kidney injury (AKI) (including need for renal replacement therapy), and excess bleeding in surgical patients who are treated with HES.
The currently FDA-approved HES products include Hespan® (6% Hetastarch in 0.9% sodium chloride injection), Hextend® (6% Hetastarch in Lactated Electrolyte Injection), and Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection). Hespan® and Hextend® are approved for the “treatment of hypovolemia when plasma volume expansion is desired,” and Voluven® is indicated for “treatment and prophylaxis of hypovolemia in adults and children.”
CarboMer, Inc.’s HES Products
CarboMer, Inc.’s HES products stand out due to their high-quality composition. CarboMer, Inc offers a range of HES products for R&D and pharmaceutical applications. They are available as solids and solutions and with different molecular weight ranges, MS and substitution levels.
CarboMer, Inc.’s HES products stand out due to their consistent high-quality. CarboMer, Inc offers several HES products for R&D and pharmaceutical applications.
Composition and Source
CarboMer, Inc.’s offers several high-quality, clinically relevant HES products with different composition and substitution patterns.
CarboMer, Inc. adheres to strict guidelines set by the Food and Drug Administration (FDA), ensuring the safety and quality of its HES products. Additionally, compliance with USP standards and those of other international regulatory bodies reflects CarboMer, Inc.’s commitment to providing the highest-quality HES products. Adherence to these regulatory standards guarantees that clients always receive reliable HES products of excellent quality.
Summary
Hydroxyethyl Starches are important products that offer a wide range of medical benefits. However, it’s essential to be mindful of the potential risks and side effects, and to consult a healthcare provider when HES uses are being considered. By understanding the benefits and safety considerations of HES, you can make informed decisions to enhance their use.