Albumin, hetastarch, and pentastarch

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Albumin, hetastarch, and pentastarch

Edwin H. Rho, MD

The colloid controversy

For decades, medical debate has continued over the value of colloid infusion in the perioperative setting. It is important to note, however, that in patients who are bleeding and who require intravascular volume expansion—especially patients with trauma—first-line therapy is the use of blood products. Early colloid advocates argued that it was important to maintain normal colloid osmotic pressure to keep intravascular fluid from passing into the tissues and thereby contributing to pulmonary, cerebral, subcutaneous edema or ascites. Albumin was the most widely used colloid until hydroxyethyl starch, and pentastarch were developed, and it still is commonly used.

Albumin

Albumin is available in 5% and 25% concentrations, the latter being most useful in patients who are unable to tolerate large volumes of fluid. Albumin is a heat-stable tightly wound protein molecule derived from human whole blood. It is heated to 60°C for 10 h to eradicate infectious organisms (both bacterial and viral). Transmission of Creutzfeldt-Jakob disease has not been reported with the use of albumin.

Hetastarch and pentastarch

Both hetastarch and pentastarch are composed of chains of glucose molecules to which hydroxyethyl ether groups have been added to retard degradation. The glucose chains are highly branched, being derived from the starch amylopectin. One in twenty glucose monomers branches. Starch chains of various lengths are present in hetastarch, giving it an average molecular weight of 450 kD. Its number-average molecular weight is 69 kD; this term describes a simple average of the individual molecular weights and is more closely related to oncotic pressure. About 80% of hetastarch polymers have molecular weights in the range of 30 to 2400 kD. Hetastarch is available as a 6% solution in 0.9% sodium chloride or a lactated electrolyte solution. The chemical and pharmacokinetic properties of hetastarch and pentastarch are listed in Table 100-1.

Table 100-1

Chemical and Pharmacokinetic Properties of Hetastarch * and Pentastarch

Property	6% Hetastarch	10% Pentastarch
pH	5.5	5.0
MW_W (kDa)	450 (range, 10-1000)	264 (range, 150-350)
MW_N (kDa)	69	63
Calculated osmolar concentration (mosmol/L)	310	326
Molar substitution ratio	0.7	0.45
Intravascular half-life (h)	25.5	2.5
Renal elimination	Molecules smaller than 50 kDa are rapidly excreted; <10% detected intravascularly at 2 weeks	Molecules smaller than 50 kDa are rapidly excreted; undetectable intravascularly at 1 week
Coagulation effects	↑ in PT, aPTT, and clotting time; may interfere with platelet function	↑ in PT, aPTT, and clotting time; may interfere with platelet function
Other miscellaneous effects	↑ in indirect serum bilirubin levels; temporary ↑ in serum amylase concentration	Temporary ↑ in serum amylase concentration

aPTT, Activated partial thromboplastin time; MW_N, number-average molecular weight; MW_W, weight-average molecular weight; PT, prothrombin time.

^*In 2010-2011, several medical journals retracted articles describing studies examining the use of hetastarch. However, the data presented here are accurate.

Hetastarch and pentastarch do not interfere with blood typing or crossmatching, are stable with fluctuating temperatures, and rarely cause allergic reactions. Both have been used successfully as an adjunct in leukapheresis by increasing the erythrocyte sedimentation rate to enhance granulocyte yield.

Pharmacokinetics and pharmacodynamics of hetastarch and pentastarch

The colloidal properties of both hetastarch and pentastarch resemble those of 5% human albumin. Distribution is throughout the intravascular space. The principal effect following intravenous administration of any colloidal solution is plasma volume expansion secondary to the colloidal osmotic effect. In hypovolemic patients, the prolonged plasma volume expansion causes a temporary increase in arterial and venous pressures, cardiac index, left ventricular stroke work index, and pulmonary artery occlusion pressure. The effective intravascular half-life is 25.5 h for 6% hetastarch and 2.5 h for 10% pentastarch. Both substances are eliminated by the kidney. The hydroxyethyl group is not cleared but remains attached to glucose units when excreted. Hetastarch and pentastarch molecules less than 50,000 Da are rapidly eliminated by the kidneys. However, only 33% of an initial dose of hetastarch is eliminated within 24 h of administration, compared with approximately 70% of an initial dose of pentastarch. Up to 10% of administered hetastarch can be detected intravascularly after 2 weeks. Pentastarch is undetectable intravascularly 1 week after administration.

As a result of a lower molar substitution ratio (i.e., the number of hydroxyethyl groups per glucose unit), pentastarch is more rapidly and completely degraded by circulating amylase than is hetastarch. Hetastarch has a very long tissue-retention time (a half-life of 10 to 15 days) because the larger molecules are stored in the liver and spleen, where they are slowly degraded enzymatically by amylase. There is a theoretical concern of impaired reticuloendothelial function caused by hetastarch. Accordingly, a lower molecular weight pentastarch was developed to minimize this theoretical risk.

Adverse effects of hetastarch and pentastarch

Both hetastarch and pentastarch prolong prothrombin time, partial thromboplastin time, and bleeding times when given in large doses, most likely secondary to hemodilution. There is some evidence to suggest that platelet function may also be altered by both products. For this reason, the maximum recommended dose is 15 to 20 mL/kg. Although there are case reports of neurosurgical patients developing coagulopathies after large (2 L) doses of hetastarch, the effects of hetastarch on the coagulation system seem clinically insignificant when maximum dose recommendations are not exceeded. More recently, tetrastarches have been developed to enhance degradation and minimize retention in the blood and tissues. This may be beneficial, as the effects on coagulation and platelets may be decreased.

Both hetastarch and pentastarch have been reported to produce rare hypersensitivity reactions, such as wheezing and urticaria. However, neither substance has been shown to stimulate antibody formation.

Transient increases in serum amylase and indirect bilirubin levels have occurred following hetastarch and pentastarch administration. However, no association with pancreatitis or biliary injury has been reported.

Clinical usefulness of colloids

Multiple authors have studied the importance of colloids in perioperative fluid therapy and tried to determine the value of colloid solutions in comparison with inexpensive crystalloid solutions. The theory that albumin and other colloids would enable the body to keep more fluid in the intravascular space has never held water, figuratively speaking. Colloids have not been proved to prevent the extravascular accumulations that lead to edema in the lungs, pleura, brain, abdomen, and soft tissues of critically injured and ill patients. In the past, clinical trials failed to show a difference in outcome for patients receiving colloid versus crystalloid solutions. More recent studies have suggested that hetastarch and pentastarch may be associated with an increased risk of mortality, acute kidney injury, renal replacement therapy or a combination, compared with crystalloid solutions. Nonetheless, colloids may be useful in patients who are intolerant of receiving large volumes of intravenous fluids yet are in need of preload expansion.

Contraindications to the use of colloid solutions

Hetastarch and pentastarch are contraindicated in patients with known hypersensitivity to hydroxyethyl starch, coagulopathy, congestive heart failure in which volume overload may pose a problem, or renal disease associated with oliguria or anuria.

Acknowledgment

The author and editors would like to thank Ronald J. Faust, MD, for his work on this chapter in previous editions.

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