VA Class:BL800
Hetastarch, a nonprotein synthetic colloid, is a plasma volume expander.100, 106
Hetastarch solutions are used for plasma volume expansion in the treatment of hypovolemia associated with elective surgery; safety of hetastarch in the treatment of hypovolemia in situations other than elective surgery has not been established.100, 106 Hetastarch should not be used as a substitute for whole blood or plasma.100, 106
Plasma volume expansion produced by hetastarch solutions is comparable to that of albumin.100, 106 For additional information on use of colloids in the treatment of hypovolemia, see Uses in Albumin Human 16:00.
Solutions containing 6% hetastarch in 0.9% sodium chloride injection are used as an adjunct in leukapheresis to enhance the yield of granulocytes by centrifugal means.100 The solution containing 6% hetastarch in lactated electrolyte injection, however, is not indicated for such use.106
Hetastarch has been used as a cryoprotective agent for the long-term storage of whole blood†.
Hetastarch solutions are administered by IV infusion.100, 106
When used as an adjunct in leukapheresis, 6% hetastarch in 0.9% sodium chloride injection should be thoroughly mixed with a citrate anticoagulant prior to IV infusion.100 (See Dosage and Administration: Dosage.) Hetastarch volumes of 500-560 mL are compatible with citrate concentrations up to 2.5% for 24 hours at room temperature.100 The safety and compatibility of additives other than citrate have not been established.100
Because 6% hetastarch in lactated electrolyte injection contains calcium, it should not be administered simultaneously with blood through the same administration set due to the potential risk of coagulation.106
Hetastarch solutions contain no preservatives and are intended for single use only; partially used containers of the drug should be discarded.100, 106
Hetastarch solutions should be stored at room temperature (25°C); brief exposure to temperatures up to 40°C does not adversely affect the preparation.100, 106 Hetastarch solutions should not be frozen or exposed to excessive heat.100, 106
When hetastarch is used for the treatment of hypovolemia, total dosage and rate of infusion depend on the amount of blood or plasma lost, the resultant hemoconcentration, and the patient's age, weight, and clinical condition.100, 106 The usual adult dose of hetastarch is 30-60 g (500-1000 mL of 6% hetastarch in 0.9% sodium chloride injection or 6% hetastarch in lactated electrolyte injection).100, 106 Hetastarch doses up to 90 g (1500 mL) have been used during surgery, generally without a need for blood or blood products.106 The manufacturers state that daily dosages exceeding 1.2 g/kg (20 mL/kg) or 90 g (1500 mL) usually are not required; however, such dosages have been used when severe blood loss has occurred (e.g., in postoperative or trauma patients), although generally only in conjunction with the administration of blood and blood products.100, 106
When used as an adjunct in leukapheresis, a citrate anticoagulant should be added to 250-700 mL of 6% hetastarch in 0.9% sodium chloride injection and mixed thoroughly.100 The resultant solution should be aseptically added to the input line of the centrifugation apparatus and infused at a ratio of 1:8 to 1:13 to venous whole blood.100
There are no specific dosage recommendations for geriatric patients; however, because of the greater frequency of decreased renal function in these patients, dosage should be selected with caution.106 (See Geriatric Use and also see Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
Hydroxyethyl starch (HES) preparations, including hetastarch, are contraindicated in critically ill adult patients, including those with sepsis, because of the increased risk of mortality and renal replacement therapy in such patients.100, 106 (See Increased Mortality and Severe Renal Injury under Warnings/Precautions: Warnings, in Cautions.) HES preparations also are contraindicated in patients with severe liver disease, preexisting coagulation or bleeding disorders, and/or clinical conditions that may be exacerbated by volume overload (e.g., congestive heart failure, renal disease with oliguria or anuria not related to hypovolemia).100, 106 The drug also is contraindicated in patients with known hypersensitivity to HES.100, 106
Because 6% hetastarch in lactated electrolyte injection contains lactate, the solution is contraindicated in the treatment of lactic acidosis.106
Increased Mortality and Severe Renal Injury
Increased mortality and/or severe renal injury requiring renal replacement therapy have been reported in critically ill adults, including patients with sepsis, receiving various preparations of HES.100, 104, 106 Data from randomized controlled trials in critically ill adults receiving lower-molecular-weight HES preparations (e.g., 6% hydroxyethyl starch 130/0.4) indicate that increased mortality and/or severe renal injury occurred within the recommended dosage range for HES (30-90 g [500-1500 mL] daily).100, 104, 106 Although the increased risks were reported principally with lower-molecular-weight HES preparations, such safety results may be applicable to higher-molecular-weight HES (e.g., 6% hydroxyethyl starch 450/0.7) because of similarities in chemical structure and mechanism of action, and also because lower- and higher-molecular-weight HES preparations are both metabolized by α-amylase into similar smaller fragments that may be associated with renal toxicity.104, 107 Data from several meta-analyses and observational studies evaluating various preparations of HES confirmed the increased risk of mortality and/or severe renal injury in critically ill adults.104 Based on the reported evidence, the US Food and Drug Administration (FDA) considers the increased risk of mortality and renal injury requiring renal replacement therapy in critically ill adults, including those with sepsis, to be class effects of HES.104
No evidence of renal injury was noted in a review of randomized controlled trials in which HES preparations were administered in the operating room to adult and pediatric patients who were undergoing surgery and were monitored for a short period of time (less than 7 days).104 Possible explanations for the lack of observed toxicity in these surgical populations include low exposure to HES in a relatively healthier population, requirement for post-administration follow-up monitoring, and/or other unknown factors.104
Because of the increased risk of mortality and severe renal injury, HES solutions are contraindicated in critically ill adults, including those with sepsis.100, 104, 106 HES solutions should be avoided in patients with preexisting renal dysfunction.100, 104, 106 Use of HES should be discontinued at the first sign of renal injury.100, 104, 106 Because the need for renal replacement therapy has been reported up to 90 days after administration of HES, renal function should be monitored for at least 90 days in hospitalized patients receiving HES.100, 104, 106 (See Advice to Patients.)
Life-threatening anaphylactic or anaphylactoid reactions (e.g., rash, erythema multiforme, urticaria, pruritus, angioedema, facial and periorbital edema, chills, flushing, severe hypotension, tachycardia, bradycardia, ventricular fibrillation, cardiac arrest, wheezing, shortness of breath, stridor, tachypnea, cough, chest pain, noncardiac pulmonary edema, laryngeal edema, bronchospasm, restlessness, fever, sneezing) have been reported rarely in patients receiving hetastarch; death has occurred,100, 106 but a causal relationship to the drug has not been established.106 Hypersensitivity reactions can occur after discontinuance of hetastarch.106
Hetastarch is made from corn starch;100 the drug should be used with caution in patients with known allergy to corn because such patients may also exhibit sensitivity to hetastarch.106
If a hypersensitivity reaction occurs, hetastarch should be discontinued immediately and appropriate treatment and supportive measures should be initiated and continued until symptoms have resolved.100, 106
Other Warnings and Precautions
Hemodilution and Circulatory Overload
Substantial hemodilution may occur following administration of hetastarch volumes exceeding 25% of blood volume in less than 24 hours.100, 106 Slight decreases in platelet counts and hemoglobin concentrations have occurred as a result of the volume-expanding effects of hetastarch and the collection of platelets and erythrocytes in donors undergoing repeated leukapheresis procedures.100 Hemoglobin concentration usually returns to normal within 24 hours.100 Hemodilution by hetastarch may also result in 24-hour reductions in concentrations of total protein, albumin, calcium, and fibrinogen; these reductions are not considered clinically relevant.100, 106
The risk of circulatory overload is largely dependent on clinical circumstances; however, use of hetastarch doses exceeding 1.2 g/kg (20 mL/kg) within 24 hours may substantially increase such risk.100
Excessive hemodilution and circulatory overload should be avoided, particularly in patients at risk of congestive heart failure or pulmonary edema.100, 106 If excessive hemodilution occurs,106 administration of blood or blood products (e.g., packed red blood cells, platelets, fresh frozen plasma) should be considered.100, 106
Hematologic Effects and Coagulopathy
Administration of large volumes of hetastarch may transiently alter the coagulation mechanism (due to hemodilution and direct inhibition of factor VIII).100, 106 Transient prolongation of prothrombin time (PT), activated partial thromboplastin time (aPTT), clotting time, and bleeding time may occur.106 Large volumes of hetastarch solution may decrease hematocrit and dilute plasma proteins.100, 106 Bleeding, anemia (secondary to hemodilution and/or factor VIII deficiency), and coagulopathy (including rare cases of disseminated intravascular coagulation and hemolysis) have been reported.100, 106 Increased risk of coagulation abnormalities and bleeding is associated with higher hetastarch doses.100 (See Patient Evaluation and Laboratory Monitoring under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
The safety of prolonged use (i.e., over several days) of hetastarch has not been established in situations other than leukapheresis.100 Prolonged use of the drug has been associated with coagulation abnormalities in conjunction with an acquired, reversible von Willebrand-like syndrome and/or factor VIII deficiency.100, 106 Replacement therapy should be considered if severe factor VIII deficiency or von Willebrand disease occurs.100, 106 Coagulopathy may take several days to resolve.100, 106 Certain conditions appear to be associated with substantial risk during chronic use of hetastarch.100, 102 Clinically important bleeding may occur in patients with subarachnoid hemorrhage receiving hetastarch repeatedly over a number of days for the prevention of cerebral vasospasm;100, 102 severe intracranial bleeding resulting in cerebral herniation and death has been reported in at least one patient receiving 6% hetastarch in 0.9% sodium chloride injection.100, 101, 106 Therefore, it currently is recommended that hetastarch not be used for the management of cerebral vasospasm associated with subarachnoid hemorrhage or for conditions other than leukapheresis that necessitate repeated use of the drug over several days.102 In addition, some clinicians suggest that use of hetastarch be avoided in all neurosurgical patients, since prevention of intracranial hemorrhage in such patients is critical.101
Increased bleeding has been reported in patients undergoing open heart surgery in association with cardiopulmonary bypass receiving HES solutions;104, 106 such excess bleeding occurred irrespective of the molecular weight or molar substitution of the HES preparation and, therefore, is considered by FDA to be a class effect of HES.104 The coagulation status of patients undergoing open heart surgery in association with cardiopulmonary bypass should be monitored.104, 106 6% Hetastarch in 0.9% sodium chloride injection should not be used as a cardiac bypass pump prime, during cardiopulmonary bypass, or in the immediate period after discontinuance of the pump.100, 104 Use of HES should be discontinued at the first sign of coagulopathy.100, 104, 106
Elevated indirect serum bilirubin concentrations have been reported in 2 of 20 healthy individuals who received multiple infusions of 6% hetastarch in 0.9% sodium chloride injection; however, total bilirubin concentrations remained within normal limits.100, 106 Indirect bilirubin concentrations returned to normal within 96 hours after the final infusion.100, 106 The importance of these elevations is not known; however, hetastarch should be used with caution in patients with a history of liver disease.100, 106
Liver function should be monitored in patients receiving HES preparations, including hetastarch.100, 104, 106
Hetastarch and other HES preparations are contraindicated in patients with severe liver disease.100, 106
Transient increases in amylase concentrations may occur following administration of hetastarch; elevated serum amylase concentrations may persist for longer periods in patients with renal impairment.100, 106 There is no association of the increased amylase concentration with pancreatitis, but this effect limits the use of serum amylase concentrations as an aid in the diagnosis of pancreatitis for up to 3-5 days after hetastarch administration.100, 106
Hetastarch has not been shown to increase serum lipase concentrations.100, 106
Electrolyte and Other Components of Hetastarch Preparations
Solutions containing 6% hetastarch in 0.9% sodium chloride injection contain sodium;100 at least one manufacturer states that preparations containing sodium should be used with caution in patients receiving concomitant therapy with drugs affecting electrolyte balance (e.g., corticosteroids, corticotropin).106 Such preparations should be used with extreme caution, if at all, in patients with edema with sodium retention.106
The solution containing 6% hetastarch in lactated electrolyte injection contains dextrose and various electrolytes (e.g., lactate, potassium, sodium).106 Therefore, the preparation should be used with caution in patients with known subclinical or overt diabetes mellitus, patients with cardiac disease (particularly those receiving digoxin), and patients receiving concomitant therapy with drugs affecting electrolyte balance (e.g., corticosteroids, corticotropin).106 The preparation should be used with extreme caution in patients with metabolic or respiratory alkalosis and in patients with conditions that result in increased concentrations or impaired utilization of lactate ions (e.g., severe hepatic impairment).106 The solution containing 6% hetastarch in lactated electrolyte injection also should be used with extreme caution, if at all, in patients with hyperkalemia, potassium retention, or edema with sodium retention.106
Patient Evaluation and Laboratory Monitoring
When used for treatment of hypovolemia, the patient's vital signs, fluid balance, electrolyte concentrations, acid-base balance, hemoglobin, hematocrit, platelet count, PT, and aPTT should be closely monitored.100, 106
When used as an adjunct in leukapheresis, regular and frequent clinical evaluation and complete blood cell counts (CBCs) are necessary.100 Additional laboratory determinations (i.e., total leukocyte and platelet counts, leukocyte differential count, hemoglobin, hematocrit, PT, and aPTT) should be considered if the frequency of leukapheresis exceeds the guidelines for whole blood donation.100
Category C.100, 106 (See Users Guide.)
It is not known whether hetastarch is distributed into milk in humans.100, 106 Caution is advised if the drug is administered to nursing women.100, 106
Safety and efficacy of hetastarch have not been established in pediatric patients.100, 106 However, in a small double-blind study in which a limited number of pediatric patients (1-15.5 years of age) were randomized to receive either hetastarch (i.e., 6% hetastarch in 0.9% sodium chloride injection) or albumin as a postoperative volume expander during the first 24 hours after surgery for repair of congenital heart disease, no differences in coagulation parameters or amount of required replacement fluids were found between pediatric patients receiving 1.2 g/kg (20 mL/kg) or less of hetastarch compared with those receiving albumin.100, 106 However, an increase in PT was observed among patients receiving more than 1.2 g/kg of hetastarch.100, 106
In clinical trials of 6% hetastarch in lactated electrolyte injection, 30% of patients were 65 years of age or older, and 12% were 70 years of age or older.106 Experience with 6% hetastarch in 0.9% sodium chloride injection has not revealed overall differences in response relative to younger adults, but increased sensitivity in some older individuals cannot be ruled out.106
Because hetastarch is primarily excreted by the kidneys and geriatric patients are more likely to have decreased renal function, caution should be exercised in dosage selection,106 and renal function should be monitored for at least 90 days in hospitalized patients receiving HES.100, 104, 106 (See Increased Mortality and Severe Renal Injury under Warnings/Precautions: Warnings and also see Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
Hetastarch should be used with caution in patients with a history of liver disease.100, 106 (See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) Liver function should be monitored in patients receiving HES preparations, including hetastarch.100, 104, 106 (See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Hetastarch and other HES preparations are contraindicated in patients with severe liver disease.100, 106
Because of the lactate component in 6% hetastarch in lactated electrolyte injection, the preparation should be used with extreme caution in patients with severe hepatic impairment.106 (See Electrolyte and Other Components of Hetastarch Preparations under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
The manufacturers and FDA state that HES solutions, including hetastarch, should be avoided in patients with preexisting renal impairment.100, 104, 106 (See Increased Mortality and Severe Renal Injury under Warnings/Precautions: Warnings, in Cautions.) Hetastarch is contraindicated in patients with renal disease with oliguria or anuria not related to hypovolemia.100, 106 (See Cautions: Contraindications.)
Limited data suggest that in the presence of renal glomerular damage, larger molecules of hetastarch can leak into urine and elevate the specific gravity, which can obscure the diagnosis of renal failure.106
Adverse effects reported in patients receiving hetastarch include hypersensitivity reactions, coagulopathy, hemodilution, circulatory overload, metabolic acidosis, congestive heart failure, pulmonary edema, bleeding, vomiting, peripheral edema, submaxillary and parotid glandular enlargement, mild influenza-like symptoms, headache, and muscle pain.100, 106
Because hetastarch may alter the coagulation mechanism, the drug should be used with caution in patients receiving drugs that affect the coagulation system.100, 106
Drugs Affecting Electrolyte Balance
Because of the electrolyte components in hetastarch preparations, at least one manufacturer states that hetastarch should be used with caution in patients receiving concomitant therapy with drugs that affect electrolyte balance (e.g., corticosteroids, corticotropin).106
Hetastarch, a hydroxyethyl starch (HES), is a synthetic colloid derived from a waxy starch composed mainly of amylopectin.100, 106 Hydroxyethyl ether groups are introduced into glucose units of the starch, and the resultant material is hydrolyzed to yield a product with a molecular weight suitable for use as a plasma volume expander and for use in leukapheresis to promote erythrocyte sedimentation and thereby enhance granulocyte yield.100, 106 Hetastarch resembles glycogen, and the polymerized d-glucose units in the hetastarch polymer are primarily joined by α-1-4-glycosidic linkages with occasional α-1-6 linkages.100, 106 Hetastarch is characterized by its molecular weight and molar substitution.100, 106 The average molecular weight of hetastarch is approximately 600 (6% hetastarch in 0.9% sodium chloride injection [Hespan®]) or 670 (6% hetastarch in lactated electrolyte injection [Hextend®]); while the average molecular weight of hetastarch ranges from 450-800, at least 80% of the polymers have molecular weights ranging from 200-2600.100, 106 The molar substitution of hetastarch is approximately 0.75 (i.e., there are 75 hydroxyethyl groups per 100 glucose units).100, 106 Hetastarch is commercially available as premixed solutions containing 6 g of hetastarch per 100 mL of 0.9% sodium chloride injection (e.g., Hespan®) or lactated electrolyte injection (Hextend®).100, 106 Hespan® and Hextend® are designated as 6% HES 450/0.7.104
Hetastarch exhibits colloidal oncotic effects.106 The drug retains intravascular fluid,106 resulting in plasma volume expansion.100, 106 The degree of plasma volume expansion and improvement in hemodynamic state depend on the intravascular status of the patient.100, 106 Plasma volume expansion produced by hetastarch is comparable to that of albumin human 5% solution.100, 106 Maximum plasma volume expansion in hypovolemic patients is reached within a few minutes after the end of infusion; the extent and duration of the expansion in plasma volume vary with the volume of solution infused and depend on the preadministration plasma volume, the distribution of hetastarch through body water, and the rate of renal clearance of the drug. Following IV infusion, plasma volume expansion diminishes over 24-36 hours.100, 106 In hypovolemic patients, hetastarch causes a temporary increase in arterial and venous pressures, cardiac index, stroke work index, and pulmonary wedge pressure. When added to whole blood, 6% hetastarch in 0.9% sodium chloride injection increases the erythrocyte sedimentation rate.100
Hetastarch is not completely metabolized.100, 106 The hydroxyethyl group is not cleaved during metabolism but remains intact and attached to glucose units when excreted; therefore, metabolism of hetastarch does not produce substantial amounts of glucose.100, 106 Hetastarch is primarily excreted by the kidneys; molecules with a molecular weight of less than 50 are rapidly excreted,100, 106 while larger molecules are retained for varying periods depending on their size and ease of breakdown.107 Following IV infusion of a single 30-g (500-mL) dose of 6% hetastarch in 0.9% sodium chloride injection, about 33% of the dose is excreted in urine within 24 hours.100, 106 Although excretion of hetastarch is variable, intravascular concentration of the drug decreases to less than 10% of the total administered dose within 2 weeks following IV infusion.100, 106 Biliary excretion of hetastarch accounts for less than 1% of the dose.100, 106 Hetastarch is not removed by hemodialysis; it is not known whether hetastarch is removed by other extracorporeal elimination techniques.100, 106
Each liter of 6% hetastarch in 0.9% sodium chloride injection provides 154 mEq each of sodium and chloride.100 Each liter of 6% hetastarch in lactated electrolyte injection provides 143 mEq of sodium, 124 mEq of chloride, 28 mEq of lactate, 5 mEq of calcium, 3 mEq of potassium, and 0.9 mEq of magnesium; the electrolyte content of 6% hetastarch in lactated electrolyte injection resembles that of the principal ionic constituents of normal plasma.106 Commercially available hetastarch solutions have a pH of approximately 5.9 and a calculated osmolarity of approximately 307-309 mOsm/L.100, 106
Risk of severe kidney damage.104 Importance of immediately reporting signs and symptoms suggestive of kidney damage (e.g., change in frequency, volume, or color of urine; blood in urine; difficulty in urinating; swelling of the legs, ankles, feet, face, or hands; unusual weakness or fatigue; nausea and vomiting; shortness of breath).104
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., congestive heart failure, liver disease, renal impairment).100, 106
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.100, 106
Importance of informing patients of other important precautionary information.100, 106 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion only | 6% Hetastarch in 0.9% Sodium Chloride* | ||
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. B. Braun Medical Inc. Hespan® (6% hetastarch in 0.9% sodium chloride injection) prescribing information. Bethlehem, PA; 2013 Oct.
101. Damon L, Adams M, Stricker RB et al. Intracranial bleeding during treatment with hydroxyethyl starch. N Engl J Med . 1987; 317:964-5. [PubMed 2442613]
102. Bianchine JR. Intracranial bleeding during treatment with hydroxyethyl starch. N Engl J Med . 1987; 317:965.
104. Food and Drug Administration. FDA Drug Safety Communication: Boxed warning on increased mortality and severe renal injury, and additional warning on risk of bleeding, for use of hydroxyethyl starch solutions in some settings. 2013 Nov 25. From FDA website. Accessed 2014 Jan 8. [Web]
106. Hospira, Inc. Hextend® (6% hetastarch in lactated electrolyte injection) prescribing information. Lake Forest, IL; 2013 Oct.
107. Westphal M, James MF, Kozek-Langenecker S et al. Hydroxyethyl starches: different products--different effects. Anesthesiology . 2009; 111:187-202. [PubMed 19512862]