Page 666 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

Fluid Therapy with Macromolecular Plasma Volume Expanders 653

To reiterate, the osmotic effect of macromolecules is (-OH) groups on the glucose units with hydroxyethyl
because of their number rather than their size. Conse- (-OCH 2 CH 2 OH) groups.
quently, if more than 50% of the molecules leak into The terms “hetastarch,” “pentastarch,” and
the interstitium, a net reduction in intravascular volume “tetrastarch” are nonspecific terms used to describe dif-
is likely as water leaves the intravascular space by osmosis ferent preparations of hydroxyethyl starches. The term
along with the colloid. Therefore the difficulty is how “hetastarch” and the abbreviation “HES” are sometimes
to determine the magnitude of increase in permeability used interchangeably, but this should be avoided;
(i.e., the size of the “gaps” in the microvascular barrier). hetastarch is just one of the hydroxyethyl starches. The
Although experimental techniques exist to detect an abbreviation, HES, may be correctly used as an umbrella
increase in microvascular permeability, 14,25 they are not term for all hydroxyethyl starches, which are then
currently applicable in a clinical setting. A growing body subclassified on the basis of their molecular structure.
of evidence suggests that hydroxyethyl starches can miti- The HES family is most precisely described by reference
gate increases of microvascular permeability in several to their molecular weight and their degree of substitution
capillary leak states. 34,97,109,184 The optimal molecular (e.g., HES 450/0.7 or HES 130/0.4). These
weight for this effect seems to be between 100 and 300 characteristics are described more fully later. The C2/
kDa. 185 Unfortunately, relatively few products with C6 hydroxyethylation ratio is another important pharma-
molecules in this size range are available in the United cologic characteristic that may be used as a descriptor but
States. Only 35% of the molecules in one preparation of it is not routinely included in product descriptions at this
hetastarch fall within this optimal size range. 184 European time. 177
formulations of hydroxyethyl starch (e.g., Haes-steril,
Fresenius Kabi, Bad Homburg, Germany) contain more Molecular Weight (MW)
molecules in the optimal molecular size range. In general, the molecules in HES preparations show great
polydispersity. The molecules can range in size from a few
COLLOID PREPARATIONS thousand to a few million Daltons and in any one solution
The artificial colloids used most commonly worldwide fall will generally follow a bell-shaped distribution.
into three major groups: the hydroxyethyl starch Hydroxyethyl starches have been arbitrarily divided into
derivatives, the dextrans, and the gelatins. Availability high molecular weight (>400 kDa), medium MW (200
varies among countries. The hydroxyethyl starches are to 400 kDa) and low MW (<200 kDa) preparations.
synthesized by partial hydrolysis of amylopectin (the The quoted MW represents the weight average molecular
branched form of plant starch), the dextrans from a mac- weight (e.g., 480 kDa for Hespan, 130 kDa for Voluven)
romolecular polysaccharide produced from bacterial fer- but the actual range of sizes is wide. For example, the
mentation of sucrose, and the gelatins from hydrolysis package insert for Hextend (Hospira, Lake Forest, Ill.)
of bovine collagen followed either by succinylation or states that 80% of molecules fall between 2 and 2500
linkage to urea. The preparations used most commonly kDa, which means that 20% fall outside of this range.
in the United States are hydroxyethyl starch preparations An independent analysis found that 85% of Hespan (Teva,
and dextran 70, both of which are available as 6% (6 g/ Irvine, Calif.) consisted of molecules smaller than 300
dL) solutions in 0.9% saline. Several gelatin-based kDa, 50% consisted of molecules smaller than 100 kDa,
products are available in Europe and Australia and molecular masses ranged up to 5000 kDa. 184
(Haemaccel, Intervet/Schering Plough Animal Health, It should also be remembered that the quoted MW only
Milton Keynes, UK; Gelofusine, Dechra Veterinary applies to the solution in vitro; as soon as the product is
Products, Shrewsbury, UK). administered to a patient, the average MW will change as
Hydroxyethyl starches are manufactured by a complex the product is subjected to excretion and hydrolysis. Mea-
process and are described using standardized pharmaco- surement and interpretation of MW is further compli-
logic terminology. An understanding of this terminology cated as the quoted weight average molecular weight is
gives the clinician information about their molecular only one way of calculating the “average” weight of a
structure and allows estimation of their likely pharmaco- polydisperse polymer, the other method being the num-
kinetics and pharmacodynamics. Amylopectin is a poly- ber average molecular weight. The number average
saccharide, which along with amylose, forms the plant molecular weight simply represents the total weight of
structural polysaccharide, starch. Amylopectin is very polymer in solution divided by the number of molecules,
similar in structure to glycogen and contains short chains whereas the weight average takes into account that the
of a-1,4-linked glucose units linked to other chains by polymers are of different sizes and is exaggerated by larger
a-1,6-links. Solutions of native starch would be unstable particles in the mixture. As the detrimental effects of the
if injected as they are rapidly hydrolyzed by plasma colloids have been considered to be related to the pres-
amylases. Chemical modification is required to resist ence of the higher molecular weight polymers, the weight
degradation and thereby increase intravascular persis- average may be the more appropriate measure. The
tence. This is achieved by substitution of the hydroxyl weight average MW is calculated from light scattering