Hetastarch

AHFS Class: Replacement Preparations (40:12)

VA Class: BL800

Hydroxyethyl Starch

HES

View the associated Essentials monograph.

Introduction

Hetastarch, a nonprotein colloid, is a plasma volume expander.

Uses

Shock

Hetastarch is a nonprotein colloid used for early fluid replacement and for plasma volume expansion in the adjunctive treatment of certain types of shock or impending shock when whole blood or blood products are not available or when the need for haste precludes the necessary cross-matching of blood products. Types of shock for which hetastarch may be used include those resulting from burns, hemorrhage, surgery, sepsis, or other trauma in which a circulating volume deficit is present. The use of hetastarch for the treatment of shock not accompanied by hypovolemia may be hazardous because of the danger of volume overloading with its attendant complications. Hetastarch is not a substitute for whole blood or plasma and has no oxygen-carrying capacity. Hetastarch, dextran 70, and dextran 75 have similar properties. Unlike the dextrans, however, hetastarch appears to have little or no antigenic properties, does not generally interfere with blood-typing or cross-matching and is stable even with widely fluctuating temperatures. Hetastarch appears to be comparable with albumin as a plasma volume expander. Further comparative studies with other plasma volume expanders are needed. For additional information, see Uses in Albumin Human 16:00.

Leukapheresis

Hetastarch is also used as an adjunct in leukapheresis to enhance the yield of granulocytes by centrifugal means.

Other Uses

Hetastarch has been used as a cryoprotective agent for the long-term storage of whole blood† and as a priming fluid in pump oxygenators for perfusion during extracorporeal circulation†. The drug has also been used as a plasma volume expander during cardiopulmonary bypass†.

Dosage and Administration

Administration

Hetastarch is administered by IV infusion. Because hetastarch injection does not contain preservatives, partially used containers of the drug should be discarded.

Dosage

When hetastarch is used as an adjunct for the treatment of shock, dosage and the rate of infusion depend on the amount of fluid loss and the resultant hemoconcentration and must be determined by the requirements of the patient. The usual adult dose of hetastarch 6% solution is 30–60 g (500–1000 mL). Total daily dosage of the 6% solution usually should not exceed 1.2 g/kg (20 mL/kg) or 90 g (1500 mL). In patients with acute hemorrhagic shock, hetastarch solution may be administered at a rate approaching 1.2 g/kg per hour (20 mL/kg per hour); slower rates of administration are generally used in patients with burns or septic shock. In patients with severe renal impairment (creatinine clearance less than 10 mL/minute), the usual initial dosage of hetastarch may be administered, but subsequent dosage should be reduced to about 25–50% of the usual dosage.

In continuous-flow centrifugation (CFC) leukapheresis procedures, 250–700 mL of hetastarch 6% solution is usually infused at a constant fixed ratio (usually 1:8) to venous whole blood. When hetastarch is used for multiple CFC leukapheresis procedures, up to 2 procedures per week and a total of 7–10 have been reported to be safe and effective. Sufficient data are not available to establish the safety of more frequent or a greater number of procedures.

Cautions

Adverse Effects

Hetastarch appears to have little or no antigenic properties; however, allergic or sensitivity reactions have been reported. Vomiting, mild temperature elevations, chills, itching, submaxillary and parotid gland enlargement, mild influenza-like symptoms, headache, myalgia, peripheral edema of the lower extremities, and anaphylactoid reactions manifested as periorbital edema, urticaria, and wheezing have occurred in patients receiving the drug. The possibility of severe anaphylactoid reactions should be considered. If allergic or sensitivity reactions occur, hetastarch should be discontinued and the patient given appropriate therapy (e.g., antihistamines, epinephrine, corticosteriods, maintenance of an adequate airway, oxygen) as indicated.

Hetastarch appears to increase the erythrocyte sedimentation rate more than does dextran 75. Hetastarch may interfere with platelet function and administration of the drug may result in transient prolongation of prothrombin, partial thromboplastin, and clotting times. Bleeding time may be temporarily prolonged in patients who receive large doses. In one study, prolongation of bleeding time occurred in patients who received hetastarch 6% solution in a dosage of 1.2–1.8 g/kg (20–30 mL/kg). Large volumes of hetastarch solution may decrease hematocrit and dilute plasma proteins.

Substantial decreases in platelet counts and hemoglobin concentrations have occurred as a result of the volume-expanding effects of hetastarch in donors undergoing repeated leukapheresis procedures. Hemoglobin concentration usually returns to normal within 24 hours. Hemodilution by hetastarch and sodium chloride may also result in 24-hour reductions in serum total protein, albumin, calcium, and fibrinogen.

Elevated indirect serum bilirubin concentrations have been reported in 2 of 20 healthy individuals who received multiple hetastarch infusions; however, total bilirubin and results of other liver function tests remained within normal limits. Indirect bilirubin concentrations returned to normal within 96 hours after the final infusion. Hetastarch has also been reported to increase serum amylase concentrations. It has been suggested that hetastarch may form a complex with amylase which is eliminated more slowly, resulting in an increase in circulating amylase concentration. There is no association of the increased amylase concentration with pancreatitis, but this effect limits the use of serum amylase concentrations as an aid for the diagnosis of pancreatitis for up to 3–5 days after hetastarch administration.

Precautions And Contraindications

Because hetastarch may interfere with platelet function, the drug should be used with caution in patients with thrombocytopenia. Since large volumes of hetastarch solution may cause hemodilution, the patient’s hematocrit should be determined after administration of the drug and care should be taken to avoid depressing it below 30% by volume.

The possibility of circulatory overload should be considered in patients receiving hetastarch. Overexpansion of blood volume may be best detected by monitoring central venous pressure. Hetastarch should be used with caution in very young or aged patients, those with pulmonary edema and/or congestive heart failure, and those with impaired renal function since these patients are particularly susceptible to circulatory overload. In those patients for whom restriction of sodium is indicated, it must be noted that 500 mL of 6% hetastarch in 0.9% sodium chloride injection contains 77 mEq of sodium and chloride. Urinary volume is a useful guide in the treatment of hypovolemic shock; however, persistence of oliguria after the patient has recovered from shock indicates possible renal insufficiency, and hetastarch therapy should be discontinued in these patients.

Although the importance of a reported hetastarch-induced elevation of indirect serum bilirubin concentration is not known, the drug should be used with caution in patients with a history of liver disease.

Regular and frequent clinical evaluation of the patient and laboratory determinations are necessary for monitoring hetastarch use during leukapheresis. Laboratory determinations should include complete blood cell count, total leukocyte and platelet counts, leukocyte differential count, hemoglobin, hematocrit, prothrombin time, and partial thromboplastin time.

The safety of hetastarch in situations other than leukapheresis that require frequent use of the drug for extended periods of time has not been fully evaluated to date, and certain conditions appear to have been associated with substantial risk during chronic use of hetastarch.^{100 102} For example, 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} Coagulopathy, local bleeding, and intracranial bleeding have been reported in hetastarch-treated patients undergoing surgery for cerebral aneurysm and in patients with subarachnoid hemorrhage receiving the drug for the prevention of cerebral vasospasm;^{101 102 103} severe intracranial bleeding resulting in cerebral herniation and death has been reported in at least one patient.¹⁰¹ 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

Hetastarch is contraindicated in patients with severe bleeding disorders, severe congestive heart failure, or renal failure with oliguria or anuria.

Pediatric Precautions

Safety and efficacy of hetastarch in children have not been determined.

Pregnancy

Pregnancy

There are no adequate and controlled studies to date using hetastarch in pregnant women. Reproduction studies in mice receiving hetastarch have not revealed evidence of harm to the fetus. The drug should not be used in pregnant women, especially during early pregnancy, unless the potential benefits to the mother outweigh the potential risks to the fetus.

Pharmacology

The colloidal properties of 6% hetastarch solution resemble those of human albumin. The principal effect of hetastarch following IV administration is plasma volume expansion, resulting from the drug’s colloidal osmotic effect. Hetastarch produces a plasma volume expansion slightly in excess of the volume of hetastarch solution infused. 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; effective plasma volume expansion may persist for 24 hours or longer. 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, hetastarch increases the erythrocyte sedimentation rate.  

Pharmacokinetics

Hetastarch molecules with a molecular weight of less than 50,000 are rapidly excreted by the kidneys, presumably via glomerular filtration. About 40% of a dose of hetastarch is excreted in urine within 24 hours in patients with normal renal function. The large unexcreted molecules with a molecular weight of 50,000 or greater are slowly degraded enzymatically to molecules small enough to be excreted. Hydroxyethylated glucose units are excreted intact. Starch molecules that are not hydroxyethylated are slowly degraded enzymatically to glucose. Generally, by 2 weeks after administration of hetastarch, intravascular concentration of the drug is less than 1% of the total dose administered; however, some clinicians have reported that it may take 4–17 weeks to reach 1%.

Chemistry and Stability

Chemistry

Hetastarch is a synthetic polymer derived from a waxy starch composed mainly of amylopectin. Hydroxyethyl ether groups are introduced into glucose units of the starch to retard degradation by serum amylase; about 70% of the glucose units in hetastarch are hydroxyethylated. Glucose units in the hetastarch polymer are joined by α-1-4-glycosidic linkages. Hetastarch closely resembles glycogen and has an average molecular weight of approximately 450,000 and a molecular weight range of approximately 10,000 to 1,000,000.

Hetastarch occurs as a white powder and is very soluble in water and insoluble in alcohol. The commercially available colloidal solution of the drug occurs as a clear, pale yellow to amber solution. Each 500 mL of the commercially available solution, containing 6% hetastarch and 0.9% sodium chloride, provides 77 mEq each of sodium and chloride. The commercially available solution has a pH of approximately 5.5 and a calculated osmolarity of approximately 310 mOsm/L.

Stability

The commercially available hetastarch solution should be stored at ambient temperatures less than 40°C; freezing should be avoided. Prolonged exposure of the solution to temperatures above 40°C or below freezing may result in a change to a turbid deep brown color or formation of a crystalline precipitate; if these changes are present, the solution should not be used.

Preparations

Hetastarch in Sodium Chloride

Routes	Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV infusion only	6% Hetastarch in 0.9% Sodium Chloride*	Hespan®	Braun
			6% Hetastarch in 0.9% Sodium Chloride Injection	Baxter, Hospira

* available by nonproprietary name

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Selected Revisions January 2004, © Copyright, July 1973, American Society of Health-System Pharmacists, Inc. 7272 Wisconsin Avenue, Bethesda, MD 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Du Pont Pharmaceuticals. Hespan^® (6% hetastarch in 0.9% sodium chloride injection) prescribing information. In: Huff BB, ed. Physicians’ desk reference. 43rd ed. Oradell, NJ: Medical Economics Company Inc; 1989:904-5.

101. Damon L, Adams M, Stricker RB et al. Intracranial bleeding during treatment with hydroxyethyl starch. N Engl J Med. 1987; 317:964-5.

102. Bianchine JR. Intracranial bleeding during treatment with hydroxyethyl starch. N Engl J Med. 1987; 317:965.

103. Symington BE. Hetastarch and bleeding complications. Ann Intern Med. 1986; 105:627-8.