Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice || Fluid Therapy with...

C H A P T E R • 2 7

Fluid Therapy with MacromolecularPlasma Volume ExpandersDez Hughes and Amanda Boag

“Those who fill our professional ranks are habitually conservative. This salutary mental attitude expresses itselfpeculiarly in our communal relations; namely, when a new idea appears which is more or less subversive to oldnotions and practices, he who originates the idea must strike sledge hammer blows in order to secure even amomentary attention. This must then be followed by a long, patient, propaganda and advertising until in thegrand finale, the public, indifferent at first, is aroused, proceeds to discuss, and finally accepts the iconoclasticproposal as a long-accepted fact of its own invention and asks wonderingly, ‘Why such a bother? What after allis new about this? We knew it long ago!”

Howard A. Kelly, MD. Electrosurgery in gynaecology, Ann Surg 93:323, 1931.

In the late nineteenth century, Ernest Starling proposedthe concept that the balance between hydrostatic andosmotic pressure gradients between the intravascularand interstitial fluid compartments governedtransvascular fluid exchange.151 He postulated that ahydrostatic pressure gradient in excess of the osmotic gra-dient at the arterial end of the capillary bed results in a nettransudation of fluid into the interstitium. At the venousend of the capillary bed, plasma proteins (which do notnormally pass out of the blood vessels) exert an osmoticforce in excess of the hydrostatic gradient, resulting in anet fluid flux into vessels. More than a century of researchhas confirmed that Starling’s hypothesis provides thefoundation for microvascular fluid exchange but alsohas revealed that the anatomy and physiology of themicrovasculature, interstitium, and lymphatic systemare much more complex. Consequently, a much deeperunderstanding of transvascular fluid dynamics is neces-sary for a logical and rational approach to intravenoustherapy with fluids containing macromolecules. Thischapter assumes the reader is familiar with the informa-tion given in Chapter 1 explaining the fluidcompartments of the body and the mechanisms of waterand solute flow among compartments. Although thischapter discusses the anatomy, physiology, and biophysicsof transvascular fluid dynamics in some depth, compre-hensive reviews and texts are available on the subject

for a more complete discussion of solute and solventexchange among the microvasculature, interstitium,and lymphatics.5,127,154 The main aim of this chapteris to objectively address the complexities andcontroversies of colloid therapy while avoiding the ten-dency toward bias apparent in some articles dealing withthe crystalloid-colloid controversy. A deeper appreciationof the relevant issues should ensure a more rationalapproach when deciding whether colloid therapy isappropriate. The present chapter is exhaustive in its deal-ing with some issues but not all-inclusive, and the readeralso is referred to several reviews of colloid fluid therapyavailable in the veterinary31,54,98,135 and human medicalliterature.55,56,103,129,177

THE MICROVASCULARBARRIERIn simple terms, the healthy microvascular barrier is a cap-illary wall that is relatively impermeable to protein.In addition to the endothelial cell and the capillary base-ment membrane, a luminal surface layer (the glycocalyx)and the interstitial matrix also contribute to the selectivepermeability of the microvascular barrier.5,127,180 Theglycocalyx coats the luminal aspect of the endothelial celland is composed of proteins, glycoproteins, andglycolipids that modify the permeability of the

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microvessel by occupying spaces within the wall or viaelectrostatic attraction or repulsion.93 Plasma proteins,especially albumin and orosomucoid, are thought to con-tribute significantly to maintaining the selective perme-ability of the endothelium.45–47,74,102

On a morphologic basis, capillary walls may be contin-uous, fenestrated, or discontinuous.122,158 Continuouscapillaries, which are found in the majority of tissues andorgans of the body, are so called because the wall is com-posedof a continuous endothelial cell andbasementmem-brane.They are freely permeable towater and small solutessuch as sodium but are relatively impermeable tomacromolecules. The passage of smaller plasma proteins,such as albumin (molecular radius of 3.5 nm), is lessrestricted than the passage of larger plasma proteins.Fenestrated capillaries have a continuous basement mem-branewithregionsthatareonlycoveredbythinendothelialdiaphragms or are entirely devoid of endothelium. Theyare found in tissues characterized by large fluxes of waterand small solutes such as the glomerulus and the intestine.Interestingly, the permeability of fenestrated capillaries tomacromolecules is similar to that of continuous capillaries.This feature has been shown to be a result of a net negativecharge of the basement membrane.12,146 Discontinuouscapillaries are found in the liver, spleen, bone marrow,and some glands. They have gaps up to 1 mm betweenendothelial cells with no basement membrane and aretherefore freely permeable to protein.

The permeability of the microvascular barrier has beenexplained by the presence of pores of differing sizes.111

These pore sizes often are extrapolated from experimentaldata regarding fluid and solute fluxes and do not alwayscorrelate with morphologic studies such as electronmicroscopy, implying that they represent functionalrather than anatomic entities. The majority of experimen-tal data suggest there are two effective pore sizes in themicrovascular barrier in most tissues, with a high fre-quency of small pores that restrict efflux ofmacromolecules and a low frequency of large onesthrough which macromolecules can pass freely.127

Rather than being a free fluid space, the interstitiumrepresents a dynamic environment that may contributeto thepermeabilitycharacteristicsof themicrovascularbar-rier andmodify the flowof fluid andmacromolecules fromthe blood vessels to the lymphatics.5,10,11The interstitiumis composed of a collagen framework that contains a gelphase of glycosaminoglycans (of which hyaluronan is themost common), along with protein macromolecules andelectrolytes in solution. The relative proportions of theseconstituents differ widely among organs and tissues,resulting in variations in the permeability and mechanicalproperties of the interstitium. Glycosaminoglycans areextremely long chains of repeating disaccharide subunitswound into random coils and entangled with each otherand the collagen framework. They havemolecular weightsof the order of 107, and each molecule bears many

thousand anionic moieties.5 This interstitial structurehas been suggested to mechanically oppose distention(i.e., edema formation) and resists contraction duringdehydration because of repulsion between the anionicmoieties.71The interstitialmatrix itself isdifferentiallyper-meable tomacromolecules, and a colloid osmotic gradientalso can exist from the perimicrovascular space across theinterstitium to the lymphatics. Although the collagen net-work and many of the glycosaminoglycans are fixed in theinterstitium, hyaluronan may be mobilized and removedvia lymphatic drainage, thereby altering the permeabilityof the interstitium.5 Increasedmicrovascular permeabilitymay occur during inflammatory states therebyexacerbating macromolecule extravasation.

TRANSVASCULAR FLUIDDYNAMICSAlthough not stated implicitly in his seminal article,Starling’s hypothesis was subsequently formalized to statesimply that the hydrostatic pressure gradient between thecapillary and the interstitium (Pc � Pi) is equal to theosmotic pressure gradient between the plasma andthe interstitium (pp� p i). This expression can be expandedto describe fluid flux (Jv) across the microvascular barrier:

Fluid flow ¼ hydrostatic gradient� osmotic gradient

or

Jv ¼ ðPc � PiÞ � ðpp � piÞ

For a solute to exert its full osmotic pressure across amembrane, the membrane must be impermeable to thesolute. If the membrane is partially permeable to the sol-ute molecule, the equilibrium concentration gradient islower, and the solute exerts only part of its potentialosmotic pressure. The realization that the microvascula-ture was only partially impermeable to smallermacromolecules led to the inclusion of the reflectioncoefficient (s) in the fluid flux equation.155

Jv ¼ ðPc � PiÞ � sðpp � piÞ

In descriptive terms, the reflection coefficient is the frac-tion of the total potential osmotic pressure exerted by thesolute in question. Conceptually, one also can consider itas the proportion of the solute molecules reflected fromthe microvascular barrier. If a membrane is completelyimpermeable, no solute molecules pass through, the con-centration gradient is maximal, and the solute exertsits full osmotic pressure (i.e., the reflection coefficient¼ 1). If the membrane is completely permeable to the sol-ute in question, it passes through freely, no concentrationdifference exists, and no osmotic pressure can be exerted(i.e., the reflection coefficient ¼ 0).

649Fluid Therapy with Macromolecular Plasma Volume Expanders

Further research showed that fluid flow from vesselsdiffered among tissues depending on the surface area ofthe capillary beds in the organ and the hydraulic conduc-tance (i.e., the ease of fluid flow) through themicrovascu-lar barrier. To account for this variability, the fluid fluxequation ismodifiedby the filtrationcoefficient (Kfc).Thisterm simply implies that fluid flow is equal to a fraction ofthe effective hydrostatic and osmotic pressure gradients.

Jv ¼ Kfc ½ðPc � PiÞ � sðpp � piÞ�

Each different constituent of plasmamay differ in its rate ofefflux from a vessel depending on such factors as its molec-ular radius, shape, and charge, and the permeability of themicrovascular barrier to the constituent in question. Thetwomajorgroupsofmoleculeswith respect to transvascularfluid flux are termed the solvent phase and the solute phase,andexpressionsweredevelopedtopredict theegressofbothmajor groups of molecules from the microvascula-ture.83,92,110,115Thesolventphase includeswaterandthosemolecules that arenot significantly impeded intheir passagethrough the microvascular barrier, whereas the solute fluxequationdescribesthepassageofmolecules thatdonot flowfreely from the vasculature.

The solvent flow equation remains the same as the pre-vious expression of fluid flow except that the filtrationcoefficient is subdivided into the hydraulic conductance(Lp) and the membrane surface area (S), and the hydro-static and osmotic gradients are expressed as DP andDp, respectively:

Jv ¼ LpSðDP � sDpÞ

The two major mechanisms of solute flow through themicrovascular barrier are convection (i.e., carriage in abulk flow of fluid) and diffusion (i.e., random motionresulting in net movement of molecules from an area ofhigh concentration to an area of lower concentration).127

An analogy to illustrate the two mechanisms would be awave breaking on a beach. Some of the sodiummoleculesin the wave will be moving away from the beach by diffu-sion; however, the forward convective flow of the wavecarries them in the opposite direction.

The solute flow equation is the most relevant expres-sion with respect to intravenous therapy with fluidscontaining macromolecules. It states that the rate of sol-ute flux (Js) is equal to the sum of the convective flow andthe diffusional movement.

Solute flowðJsÞ ¼ convective flow þ diffusion

Convective flow is equal to the product of fluid flow (Jv),the fractional permeability of the membrane (1� s ), andthe mean intramembrane solute concentration,C. Diffu-sion is equal to the product of the solute permeability (P),the surface area of the microvascular barrier (S), and the

solute concentration gradient across themembrane (DC).Therefore the expression representing macromolecularflux becomes:

Js ¼ Jvð1� sÞ�C þ PSDC

Solute flow ¼ convective flow þDiffusion

At normal lymph flow rates, convection has beenestimated to account for approximately 30% of the totalflux of albumin into lymph.123 An important point thatwarrants further emphasis is that the rate of solute effluxis dependent on the rate of solvent efflux. Any conditionthat increases the rate of fluid flow across a membrane canincrease the extravasation of macromolecules. Hence,intravenous fluid therapy with crystalloid or colloid canincrease albumin loss into the interstitium.124

These mathematical expressions give the impression ofa constant hydrostatic pressure gradient acting across asingle membrane of static and uniform conductivityand permeability (homoporous), with filtration opposedby an osmotic pressure resulting from a singleimpermeant solute, the plasma “protein.” In fact, thehydrostatic pressure and osmotic pressure gradients varyamong different tissues and at different levels of the cap-illary bed within the same tissue.121,156,159 In diseasestates, the differences among organs may be significantand the clinician must consider the possibility of individ-ual organ edema (e.g., pulmonary, myocardial, or intesti-nal edema) even if there are no overt signs of a systemicedematous state. The total osmotic gradient is a summa-tion of all the impermeant solutes present within plasma,which all have unique reflection coefficients and effluxrates.156 Furthermore, the surface area of the capillarybed may change depending on precapillary sphincteractivity and the permeability of the microvascular barrierand interstitium may also vary physiologically and indisease states.8,71,113,180,181

NORMAL STARLING FORCESAND THE TISSUE SAFETYFACTORS

PLASMA COLLOID OSMOTICPRESSUREAlthough in popular usage colloid is interpreted mostoften as referring to a macromolecule that cannot passthrough a membrane, the strict definition refers to thedispersion in a gas, liquid, or solid medium of atoms ormolecules that resist sedimentation, diffusion, and filtra-tion. This definition is in contradistinction to crystalloids,which are freely diffusible. Oncotic pressure is defined asthe osmotic pressure exerted by colloids in solution(hence it is redundant to use the phrase colloid oncoticpressure). Proteins in plasma are truly in solution, but

TABLE 27-1 Colloid OsmoticPressure in NormalCats and Dogs

Species

Colloid OsmoticPressure

Mean � SD(mm Hg)

ReferenceNumber

Canine (plasma) 20.8 � 1.8 185Canine (plasma) 17.5 � 3.0 108Canine (wholeblood)

19.9 � 2.1 44

Feline (plasma) 19.8 � 2.4 185Feline (wholeblood)

24.7 � 3.7 44

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they closely resemble a colloid solution and thus arereferred to and treated as such. The osmotic pressureexerted by the naturally occurring colloids in plasma ishigher than that calculated for an ideal solution in vitro.One of the main reasons for this discrepancy is that nega-tively charged proteins (such as albumin, which has a netnegative charge of 17 at physiologic pH) retain cationswithin the intravascular space by electrostatic attraction(termed the Donnan effect).71 These cations contributeto the effective plasma protein osmotic pressure becauseosmotic pressure is proportional to the number ofmolecules present rather than their size. Therefore col-loid osmotic pressure (COP) is the most correct termwhen referring to the osmotic pressure exerted by plasmaproteins and their associated electrolyte molecules. Forcomparison, the oncotic pressure exerted by an albuminsolution of 7 g/dL is 19.8 mm Hg, whereas the in vivoCOP is actually 28 mm Hg, and the total osmotic pres-sure of all plasma solutes is 5400 mm Hg.71

By virtue of its relatively high concentration in the vas-cular space, albumin usually accounts for 60% to 70% ofthe plasma COP with globulins making up the remain-der.108,168,176 Interestingly, the variation in COP in dogsmay be because of differences in globulin concentrationthan in albumin concentration.65,108 Red blood cellsand platelets do not contribute significantly to plasmaCOP.118 Serum albumin concentration is determinedby the relative rates of synthesis, degradation, and lossfrom the body and its distribution between the extravas-cular and interstitial spaces. Albumin synthesis, which isunique to the liver, appears to be regulated, at least inpart, by the hepatic plasma COP.53,117,130 Increases ofplasmaCOP independent of albumin concentration, suchas in hyperglobulinemia, are associated with decreasedserum albumin concentration.18,131,132 The main siteof albumin degradation is uncertain, but the reticuloen-dothelial system has been suggested. Equations havebeen derived to estimate plasma COP from plasma pro-tein concentrations,108,160 but direct measurement witha colloid osmometer is more accurate.7,28,160,176

COPs measured in normal dogs and cats are given inTable 27-1.44,108,186

INTERSTITIAL COLLOIDOSMOTIC PRESSURECapillaries are permeable to protein, despite the fact thatthe microvascular barrier greatly restricts macromolecularflux. Of the total quantity of albumin present in the body,40% is intravascular and 60% is extravascular.133 Further-more, all of the albumin present in plasma circulatesthrough the interstitium every 24 hours.114 The intersti-tial COP varies from tissue to tissue depending on suchfactors as the permeability of the capillary wall to protein,the rate of transvascular solvent flow, the retention of pro-tein in the interstitial matrix, and the rate of lymphaticclearance of protein. The microvascular barrier of skeletal

muscle or subcutaneous tissue is relatively impermeableto protein, whereas the pulmonary capillary endotheliumis more permeable with a reflection coefficient to albuminof approximately 0.5 to 0.64.113 Consequently, the nor-mal protein concentration in lymph from skin or skeletalmuscle is approximately 50% that of plasma comparedwith 65% in pulmonary lymph.113 Hyaluronan and itsassociated cations also may contribute to interstitialCOP.5 Because of the volume occupied by the interstitialmatrix, interstitial albumin is distributed in a volume thatis less than the total interstitial volume. This phenome-non is called the volume exclusion effect, and the“excluded volume” with respect to albumin may be ashigh as one half to two thirds of the total interstitial vol-ume.13,112,175 Consequently, in a normally hydratedinterstitium, much less protein is required to exert a givenosmotic pressure, and relatively smaller volumes ofextravasated fluid result in greater decrements in intersti-tial COP. This effect maintains the intravascular-to-extra-vascular COP gradient in early edema formation.Conversely, when interstitial volume is overexpanded byfluid in edematous states, a dramatic increase occurs inthe volume available for albumin sequestration.71 Theincrease in interstitial COP that occurs with dehydrationacts to restrict mobilization of interstitial fluid.76

INTRAVASCULARHYDROSTATIC PRESSUREIntravascular hydrostatic pressure is the main force thatdetermines fluid egress from the vasculature. It may varyin different tissues and at different levels within each cap-illary bed. The normal hydrostatic pressure in the capil-lary bed is controlled by local myogenic, neurogenic,and humoral modulation of the arterial and venousresistances. Precapillary arteriolar constriction mayreduce flow, and therefore hydrostatic pressure, througha capillary bed or shunt flow away from that bed, resultingin changes in the total surface area available for


transvascular fluid movement. The hydrostatic pressurewithin a blood vessel at any particular site depends in parton where resistance to flow occurs, with hydrostaticpressures decreasing most across the areas of major resis-tance. In most tissues, the majority of resistance has beenattributed to small arterioles, but experimental studies ofthe lung suggest that a significant pressure decrease mayoccur across the capillary bed itself.15,16,143

INTERSTITIALHYDROSTATIC PRESSUREAs with all the other Starling forces, normal interstitialpressure also varies among tissues. Interestingly, in manytissues the resting pressure is slightly negative (subatmo-spheric), tending to favor rather than oppose fluid filtra-tion from the microvasculature.179 This finding has beenpostulated to be the result of the molecular structure ofthe interstitial matrix, such that with normal hydrationthe biomechanical stresses on the molecules and therepulsion among like electrostatic charges act to expandthe interstitium.5 In encapsulated organs, such as the kid-ney, normal interstitial pressures are positive. Interstitialpressures can also change depending on the functionalstate of the organ. For example, interstitial pressures inthe nonabsorbing intestine are negative to slightly posi-tive, whereas intestinal interstitial pressures are positivein the absorptive state.70 As mentioned before, themolecular structure of the interstitium mechanicallyopposes distention. Conventionally, it is said that onethird of the total body water is found in the extracellularspace and that the interstitium constitutes three fourthsof the extracellular space. These figures are averages forthe whole body, and the relative sizes of the intravascularand interstitial spaces vary among tissues. Tissues vary intheir capacity to accommodate interstitial fluiddepending on the size of the interstitial space relative tothe total volume of the tissue and the nature of the inter-stitial matrix itself, especially its distensibility. Thedistensibility of an organ or tissue is termed its compli-ance, and depending on the nature of the tissue, the com-pliance of the interstitium may vary widely. Extremeexamples would be tendon (which is relatively noncom-pliant) and loose subcutaneous connective tissue (whichis relatively distensible). The accumulation of edema fluidin the peribronchovascular interstitium in canine lungs islikely the result of the higher compliance of this region ofthe pulmonary interstitium.

An extremely important concept related to the intersti-tial hydrostatic pressure is that of stress relaxation. In anormally hydrated animal, the interstitium inmost tissuesis relatively noncompliant. Small increases in volumecaused by increased fluid extravasation result in largechanges in interstitial hydrostatic pressure that act tooppose further extravasation of fluid and increase lym-phatic drainage pressure—two of the tissue safety factorsdescribed later.72,157 As the interstitium becomes

gradually more distended, it continues to oppose disten-tion until a critical point is reached (suggested to corre-spond to the disordering of the interstitial matrix).Abruptly, the resistance to distention decreases (i.e., com-pliance increases), and fluid then can accumulate withouta corresponding protective increase in interstitial pressureand lymph flow. At this point, the distended interstitiumno longer opposes the movement of fluid and protein,resulting in increased extravasation and self-perpetuationof the edemagenic process. Furthermore, the greatlyincreased interstitial space provides a large volume forprotein sequestration.

TISSUE SAFETY FACTORSFrom the previous discussion, it should be apparent thatthere are three main homeostatic mechanisms that pre-vent or limit accumulation of fluid in the interstitium.First, extravasation of fluid into a relatively nondistensibleinterstitium results in an increased interstitial hydrostaticpressure that opposes further extravasation. Second, afterextravasation of low-protein fluid, interstitial COPdecreases because of dilution and washout of protein,therebymaintaining or even enhancing the COP gradientbetween the intravascular space and interstitium. Third,the increased interstitial pressure results in an increaseddriving pressure for lymphatic drainage. These alterationsin Starling forces that act to limit interstitial fluid accumu-lation have been termed the tissue safety factors.72,157

Their relative importance varies depending on thecharacteristics of the tissue.5,33 In a tissue that is relativelynondistensible (e.g., tendon), an increase in interstitialpressure may be the most important means by which tocounteract filtration. In a tissue with moderatedistensibility and with a relatively impermeable microvas-cular barrier (e.g., skin), the decrease in interstitial COPassumes more importance in protecting against intersti-tial fluid accumulation. In a distensible tissue that is quitepermeable to protein (e.g., lungs), increased lymph flowappears to be the most important safeguard against inter-stitial edema.183

PHARMACOKINETICS ANDPHARMACODYNAMICS OFMACROMOLECULAR PLASMAVOLUME EXPANDERSTransvascular fluid dynamics are extremely complex. Thebalance of the hydrostatic and osmotic pressure gradientsbetween the intravascular and interstitial fluidcompartments forms the basis for microvascular fluidexchange. However, this simple concept is belied by thegreat heterogeneity in Starling forces and transvascularfluid dynamics that exists among and within tissues inboth healthy and diseased states. The relative importanceof the different tissue safety factors also varies among

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tissues, and the potential for self-regulation oftransvascular fluid fluxes often is underestimated. Whenconsidering fluid therapy with macromolecular volumeexpanders, a great deal of emphasis has been placed onthe manipulation of individual Starling forces (such asintravascular COP) in isolation rather than addressingthe system in its entirety. Maintenance of intravascularvolume depends on an intricate and dynamic interactionbetween the intravascular and interstitial Starling forcesand the structure and function of the microvascular bar-rier, interstitium, and lymphatic system. Infusion of intra-venous fluids can change all of the Starling forces, modifythe permeability of the microvascular barrier, change thevolume and composition of the interstitium, and increaselymphatic flow. Furthermore, the magnitude and relativesignificance of these changes vary among and withintissues. Consequently, it is a gross and potentially danger-ous oversimplification to view the body as the homoge-nous sum of its individual parts when contemplatingintravenous fluid therapy. From a clinical standpoint,the differences between the lungs and the systemic circu-lation are of the utmost importance. For example, in adog with systemic inflammatory response syndromeand aspiration pneumonia causing pulmonary edema bymeans of increased microvascular permeability, colloidtherapy may be effective in limiting subcutaneous edemaat the expense of worsening pulmonary fluidextravasation.

Despite this great heterogeneity, the concept that netfluid extravasation depends on the balance between intra-vascular COP and capillary hydrostatic pressure forms thebasis for intravenous colloid therapy.64,73,90,174 By virtueof their larger molecular size, and in the absence of anincrease in microvascular permeability, colloid moleculesare retained within the vasculature to a greater degreethan are crystalloids. Consequently, smaller volumes ofcolloid result in greater plasma volume expansion com-pared with crystalloid,51,144,145 and crystalloid isexpected to leak into the interstitium to a greater degreethan colloid and cause more interstitial expansion oredema.27 This may be beneficial if the animal has an inter-stitial fluid deficit or deleterious if there is interstitialedema. One hour after infusion of a crystalloid solution,as little as 10% of the infused volume may remain in theintravascular space.145 Some evidence indicates that tissueperfusion is better after volume expansion with colloidsthan with crystalloids, even when resuscitation is titratedto physiologic endpoints.63 Unfortunately larger colloidsmay reduce tissue perfusion by increasing plasma viscos-ity.22 Many factors influence the volume and duration ofintravascular expansion associated with artificial colloids,including the species of animal, dose, specific colloid for-mulation, preinfusion intravascular volume status, andthe microvascular permeability. These factors likelyexplain the great variability in intravascular persistenceand volume expansion in published studies.

Artificial colloids are polydisperse; that is, they containmolecules of different molecular weight. In contrast, in amonodisperse colloid such as albumin, molecules are allthe same size. The artificial colloids have extremely com-plex pharmacokinetics in part because of this large rangeof molecular sizes.84 The smaller molecules pass rapidlyinto the urine and interstitium, whereas the largermolecules remain in circulation and gradually arehydrolyzed by amylase or removed by the monocytephagocytic system.161 This initial rapid excretion of small,osmotically active molecules followed by gradual elimina-tion of large molecules results in an exponential decline inintravascular expansion. Manufacturer data sheets can bemisleading because they may imply that a major propor-tion of the volume expansion lasts for 24 to 36 hours.Estimates of the degree of initial plasma volume expan-sion for hetastarch and dextran 70 vary from 70% to170% of the infused volume.67,77,87,91,124 This decreasesto approximately 50% of the infused volume after 6 hours.Volume expansion with hydroxyethyl starch then declinesgradually from 60% to 40% of the infused volume duringthe next 12 to 18 hours, whereas with dextran 70 itdecreases gradually from 40% to 20% of the infused vol-ume.161 In experimental dogs, blood volume wasincreased by approximately 25% both immediately and4 hours following infusion of 20mL/kg of both dextran70 and hetastarch.147 In dogs with hypoalbuminemia ofvarious causes receiving hydroxyethyl starch, COP wasnot significantly different from baseline 12 hours afterinfusion.106 In the authors’ experience, the duration ofvolume expansion with artificial colloids can be evenshorter, especially with capillary leak syndromes. This rel-atively short duration of action and the high cost of arti-ficial colloids have led some authors to question the cost-effectiveness of colloid infusions in veterinary patients.173

The duration of action of colloids may be expressed interms of plasma colloid concentrations, plasma COPmeasurements, or degree of volume expansion. The initialvolume of intravascular expansion is the result of the COPof the infused colloid, which is determined by the numberof molecules, not their size. This concept is extremelyimportant because the distribution of molecular weightsis narrowed after intravenous infusion.57,58 The smallermolecules that are responsible for a large part of theCOP and intravascular volume expansion are extravasatedorexcretedwithinhours.The intravascularcolloidconcen-tration (i.e., mass per unit volume) is still high due to thelarge molecules, but the COP is relatively low. COP anddegree of volume expansion tend to decrease faster thandoes the plasma concentration of colloid. Data from anexperimental study of euvolemic human volunteers giventwice the usual dose of a high molecular weight form ofhydroxyethyl starch may therefore have little bearing onthe effects of commercially available hydroxyethylstarchin a dog with systemic inflammatory response syndromein hypodynamic, septic shock.


To reiterate, the osmotic effect of macromolecules isbecause of their number rather than their size. Conse-quently, if more than 50% of the molecules leak intothe interstitium, a net reduction in intravascular volumeis likely as water leaves the intravascular space by osmosisalong with the colloid. Therefore the difficulty is howto determine the magnitude of increase in permeability(i.e., the size of the “gaps” in the microvascular barrier).Although experimental techniques exist to detect anincrease in microvascular permeability,14,25 they are notcurrently applicable in a clinical setting. A growing bodyof evidence suggests that hydroxyethyl starches can miti-gate increases of microvascular permeability in severalcapillary leak states.34,97,109,184 The optimal molecularweight for this effect seems to be between 100 and 300kDa.185 Unfortunately, relatively few products withmolecules in this size range are available in the UnitedStates. Only 35% of the molecules in one preparation ofhetastarch fall within this optimal size range.184 Europeanformulations of hydroxyethyl starch (e.g., Haes-steril,Fresenius Kabi, Bad Homburg, Germany) contain moremolecules in the optimal molecular size range.

COLLOID PREPARATIONSThe artificial colloids usedmost commonly worldwide fallinto three major groups: the hydroxyethyl starchderivatives, the dextrans, and the gelatins. Availabilityvaries among countries. The hydroxyethyl starches aresynthesized by partial hydrolysis of amylopectin (thebranched form of plant starch), the dextrans from a mac-romolecular polysaccharide produced from bacterial fer-mentation of sucrose, and the gelatins from hydrolysisof bovine collagen followed either by succinylation orlinkage to urea. The preparations used most commonlyin the United States are hydroxyethyl starch preparationsand dextran 70, both of which are available as 6% (6 g/dL) solutions in 0.9% saline. Several gelatin-basedproducts are available in Europe and Australia(Haemaccel, Intervet/Schering Plough Animal Health,Milton Keynes, UK; Gelofusine, Dechra VeterinaryProducts, Shrewsbury, UK).

Hydroxyethyl starches are manufactured by a complexprocess and are described using standardized pharmaco-logic terminology. An understanding of this terminologygives the clinician information about their molecularstructure and allows estimation of their likely pharmaco-kinetics and pharmacodynamics. Amylopectin is a poly-saccharide, which along with amylose, forms the plantstructural polysaccharide, starch. Amylopectin is verysimilar in structure to glycogen and contains short chainsof a-1,4-linked glucose units linked to other chains bya-1,6-links. Solutions of native starch would be unstableif injected as they are rapidly hydrolyzed by plasmaamylases. Chemical modification is required to resistdegradation and thereby increase intravascular persis-tence. This is achieved by substitution of the hydroxyl

(-OH) groups on the glucose units with hydroxyethyl(-OCH2CH2OH) groups.

The terms “hetastarch,” “pentastarch,” and“tetrastarch” are nonspecific terms used to describe dif-ferent preparations of hydroxyethyl starches. The term“hetastarch” and the abbreviation “HES” are sometimesused interchangeably, but this should be avoided;hetastarch is just one of the hydroxyethyl starches. Theabbreviation, HES, may be correctly used as an umbrellaterm for all hydroxyethyl starches, which are thensubclassified on the basis of their molecular structure.The HES family is most precisely described by referenceto their molecular weight and their degree of substitution(e.g., HES 450/0.7 or HES 130/0.4). Thesecharacteristics are described more fully later. The C2/C6 hydroxyethylation ratio is another important pharma-cologic characteristic that may be used as a descriptor butit is not routinely included in product descriptions at thistime.177

Molecular Weight (MW)In general, the molecules in HES preparations show greatpolydispersity. The molecules can range in size from a fewthousand to a fewmillion Daltons and in any one solutionwill generally follow a bell-shaped distribution.Hydroxyethyl starches have been arbitrarily divided intohigh molecular weight (>400 kDa), medium MW (200to 400 kDa) and low MW (<200 kDa) preparations.The quotedMWrepresents the weight average molecularweight (e.g., 480 kDa for Hespan, 130 kDa for Voluven)but the actual range of sizes is wide. For example, thepackage insert for Hextend (Hospira, Lake Forest, Ill.)states that 80% of molecules fall between 2 and 2500kDa, which means that 20% fall outside of this range.An independent analysis found that 85% ofHespan (Teva,Irvine, Calif.) consisted of molecules smaller than 300kDa, 50% consisted of molecules smaller than 100 kDa,and molecular masses ranged up to 5000 kDa.184

It should also be remembered that the quoted MW onlyapplies to the solution in vitro; as soon as the product isadministered to a patient, the average MW will change asthe product is subjected to excretion and hydrolysis. Mea-surement and interpretation of MW is further compli-cated as the quoted weight average molecular weight isonly one way of calculating the “average” weight of apolydisperse polymer, the other method being the num-ber average molecular weight. The number averagemolecular weight simply represents the total weight ofpolymer in solution divided by the number of molecules,whereas the weight average takes into account that thepolymers are of different sizes and is exaggerated by largerparticles in the mixture. As the detrimental effects of thecolloids have been considered to be related to the pres-ence of the higher molecular weight polymers, the weightaverage may be the more appropriate measure. Theweight average MW is calculated from light scattering

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of the solution. The polydispersity index can be calculatedfrom the ratio of the weight average to the number aver-age for that solution. Hydroxyethyl starch with a weightaverage molecular mass of 100 to 300 kDa seems to pro-vide the best compromise between colloid osmotic vol-ume expansion and duration of action.40 Furthermore,this size distribution has less effect on coagulation164

and is the best size for reducing the increases in perme-ability present in patients with vascular leaks.184

Degree of Substitution and MolarSubstitution RatioThe amylopectin may be hydroxyethylated at carbons 2,3, or 6 of the constituent glucose molecules. The degree ofsubstitution is determined by measuring the number ofsubstituted glucose molecules and dividing this by thetotal number of glucose molecules present. In contradis-tinction, the term substitution ratio or more correctly“molar substitution ratio” may also be used and refersto the total number of hydroxyethyl groups presentdivided by the quantity of glucose molecules. Althoughnot identical, the terms are often used interchangeablywith the degree of substitution being used most com-monly in product descriptions. A higher degree of substi-tution prolongs intravascular persistence by slowingdown the rate of hydrolysis (i.e., those products with ahigh degree of substitution will have longer persistencein the body). “Hetastarches” have the mosthydroxyethylation (between 0.6 and 0.7),“pentastarches” a degree of substitution of 0.5, and“tetrastarches” a degree of substitution of 0.4.

C2/C6 RatioThe hydroxyethylation can occur at carbons in position 2,3, or 6 of the glucose unit. Individual glucose moleculescan have from zero to three hydroxyethyl groups. Hydro-lysis by amylase is slowed more by substitution at C2 asopposed to C6,166 thus those products with a highC2/C6 ratio will be metabolized more slowly and intra-vascular volume expansion will be expected to be longer.Hydroxyethylation at the C2 position confers greaterresistance to degradation than the C6 position.

Hydroxyethyl starches are thus generally characterizedby their weight average molecular weight, substitutionratio, and C2/C6 hydroxyethylation ratio.163 Hespan,for example, has an average molecular weight of 450kDa and a substitution ratio of 0.7 and therefore isreferred to as HES 450/0.7. Two forms of high molecu-lar weight hydroxyethyl starch are available in the UnitedStates, HES 450/0.7 (Hespan, Teva, Irvine, Calif.) andHextend (Hospira, Lake Forest, Ill.), which have a weightaverage molecular weight of 670 kDa, a molar substitu-tion of 0.75, and a high C2/C6 ratio. In many Europeancountries and Australia, the high molecular weightstarches are no longer available. Several hydroxyethylstarch products are available in these countries with

smaller average molecular weights, including pentastarch(HES 200/0.5) and HES 130/0.4 (Voluven, FreseniusKabi). These lower molecular weight products have beendeveloped to maximize volume expansion effects whileminimizing the risk of adverse effects on the hemostaticsystem by reducing the number of large molecules. TheFDA recently approved Voluven for use in the UnitedStates.

Albumin, obtained from purified human plasma, hasbeen used to provide colloid support in human medicinefor many years. Albuminmost commonly is given to smallanimal patients as stored or fresh frozen plasma, storedwhole blood, or fresh whole blood. Human serum albu-min has been used in small animal patients and a canineserum albumin preparation has recently become available.Albumin has a molecular weight of approximately 69 kDaand a molecular radius of 3.5 nm. It is a monodispersecolloid (i.e., all albumin molecules are the same size).In addition to its role in maintaining plasma COP, it car-ries a wide range of substances such as bilirubin, fattyacids, metals and other ions, hormones, and drugs.134

Albumin equilibrates with the interstitial space more rap-idly and to a greater extent than artificial colloids, and rel-atively large volumes must be given to achieve a sustainedincrease in plasma COP. In human medicine, a large trialcomparing fluid resuscitation of critical patients witheither saline or albumin found no significant differencesbetween the groups in a number of variables, including28-day outcome.60 The authors of the study concludedthat decisions about which fluid to use should be basedon clinician preference, possible adverse effects, and cost.Although administration of human albumin solutions tocritically ill dogs has been associated with effectiveincreases in serum albumin concentration, refractometrictotal solids, and COP with relatively few adverseeffects,32,167 administration to healthy animals has beenassociated with serious adverse outcomes.36,61

When considering chronic albumin supplementation,as opposed to acute volume expansion, the amount ofalbumin required can be estimated using an equation thatcorrects for the expected volume of distribution acrossthe intravascular and interstitial spaces75:

Albumin deficit ðgÞ ¼ 10� ½desired albuminðg=dLÞ�patient albuminðg=dLÞ� � body weightðkgÞ � 0:3

To increase the serum albumin concentration from1.5 g/dL to 2.5 g/dL in a 20-kg dog:

Albumin deficit ¼ 10� ð2:5� 1:5Þ � 20� 0:3 ¼ 60 g

This amount is equivalent to 2 L of plasma or 4 L of freshwhole blood and does not take into account ongoinglosses. Hence, administration of albumin in plasma isan inefficient means of providing colloid support.


CLINICAL USESSupport Of Intravascular VolumeThe principle use of colloids is for intravascular volumeexpansion in patients with hypovolemic or distributiveshock. Colloids are generally considered to bemore effec-tive for this purpose on a mL/kg basis than isotoniccrystalloids. However, given the many factors involvedin the efficacy and persistence of colloid therapy andthe heterogeneous nature of the patient population inwhich they are used, it is crucial to carefully assess theneed for colloidal therapy and the clinical response ofthe patient. Colloid therapy is not a panacea; rather itrepresents one more group of drugs with specificindications, contraindications, benefits, and risks. Thetreatment of critically ill human patients with colloidsolutions recently has been questioned in several meta-analyses of randomized clinical trials in human patients.17,35,116,139,171 Despite the limitations of randomizedclinical trials and meta-analyses,128 all showed a trendtoward increased mortality when colloids were used toresuscitate human trauma patients. Subdivision of thepatients in one study171 demonstrated that in traumapatients there was a 12.3% difference in mortality ratein favor of crystalloid therapy, and when data from studiesthat used nontrauma patients were pooled, there was a7.8% difference in mortality rate in favor of colloid treat-ment. The authors concluded:

“in patients with trauma who are septic and in whom thecapillary leak syndrome leads to adult respiratory distresssyndrome, it may be assumed that colloid resuscitationwould be no better than crystalloid resuscitation.In this study the meta-analysis of published data showedthat this form of treatment is deleterious. In patients whoare nonseptic or having elective surgery, however, thebasement membrane is intact, and meta-analysis of datain this setting showed that treatment with colloids wouldbe efficacious.”

The likely explanation of these results is that if vascularleak is sufficiently severe to allow significant colloidextravasation then colloids may worsen outcome com-pared with crystalloids. A meta-analysis that was designeda priori to investigate resuscitation after trauma showed alower mortality rate associated with the use of crystalloidfluids.35

Similar large scale studies do not yet exist within theveterinary field. In experimental dogs given standardboluses of isotonic saline (80 mL/kg) or hetastarch(20 mL/kg), volume expansion was initially significantlygreater with isotonic saline, was not significantly different30 minutes following administration, and was greater,although not significantly so, in the hetastarch groupafter 4 hours.147 Hetastarch was more effective than crys-talloid in reversing isoflurane-induced hypotension inhealthy experimental beagles.1 Two small clinical studies

comparing dextran/hypertonic saline with isotonic salinefor fluid resuscitation of dogs suffering from gastric dila-tation-volvulus syndrome137 and trauma138 did notreveal a consistent benefit with either approach.

Recommended DoseThe recommended dosage for the high molecular weighthydroxyethyl starches, the gelatins, and the dextrans is20 mL/kg/day. Dependent on the patient’s status, thismay be administered as one or more boluses with thespeed of bolus administration being dependent on theclinical status of the patient. Although higher dosageshave been used without apparent adverse effects,106,150

deleterious effects on coagulation (see later discussion)occur more commonly at and above this dosage. Thenewer low molecular weight hydroxyethyl starches avail-able in Europe may be used at higher doses of up to50 mL/kg/day.89 A dosage of 20 mL/kg representsone quarter of a dog’s blood volume, and if repeateddoses are required to maintain perfusion, the underlyingreason should be pursued aggressively. Cats seem to bemuch more likely to develop volume overload than dogs,at least in part due to their smaller blood volume as a per-centage of body weight. The suggested dose in cats is5 mL/kg. Lastly, colloid solutions may not contain a bac-teriostat and such formulations are therefore intended forsingle-dose usage.

COLLOID THERAPY INPULMONARY DISEASEMany pulmonary diseases result in accumulation of excessfluid in the interstitium alone or in the interstitium andalveoli. This increase in so-called extravascular lungwater is synonymous with pulmonary edema. The lungis relatively resistant to the edemagenic effects ofhypoproteinemia,182 and the two most importantmechanisms by which pulmonary edema occurs are anincrease in pulmonary hydrostatic pressure and an increasein pulmonary microvascular permeability.153 High-pres-sure edemamay occur secondary to left-sided heart failureor volume overload, whereas increased permeabilityedema may be caused by conditions such as pneumonia,toxic lung injury, and systemic inflammatory responsesyndrome. In some clinical settings, the pathogenesis ofpulmonary edema may be unclear or include bothcomponents (e.g., neurogenic and reexpansion edema).

The pulmonary endothelium is relatively permeable toprotein compared with other tissues, and albumin170 andHES86 equilibrate more rapidly with the interstitial spaceeven in a normal lung. Consequently, the effective COPgradient that can be generated between the intravascularspace and the pulmonary interstitium is lower than inother tissues. Therefore the lung must rely more onincreased lymph flow than interstitial COP dilution to

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protect against pulmonary edema.153 Certain types oflung injury, such as pneumonia or chemical injury, furtherincrease the permeability of the capillary endothelium toprotein. When one considers the Starling equation, itbecomes obvious that the capillary hydrostatic pressurebecomes the major determinant of edema formation.Smaller increases in capillary hydrostatic pressure resultin much greater fluid extravasation than occurs whenthe endothelium remains intact. This finding clearlyexplains clinical and experimental studies that show thatcolloid therapy significantly worsens pulmonary edemacaused by increased microvascular permeability.78 If thealveolar epithelium is also damaged, interstitial edemacan rapidly progress to alveolar flooding because thereis, in effect, a direct conduit from the vasculature to thealveolar space.

Absorption of water, solutes, and protein occurs viadifferent mechanisms and at vastly different rates.Resorption of sodium-containing alveolar fluid occursmainly via active transport by the alveolar epithelium,most likely via a sodium-potassium pump with glucosecotransport, which b-adrenergic agonists stimu-late.100,136 Fluid absorption occurs against the colloidosmotic gradient, which increases as fluid is reabsorbedand protein remains behind. Protein is cleared from thealveoli at a very slow rate,99 which is one of the reasonsfor the protracted resolution often seen with edemacaused by increased permeability.

Colloid therapy may worsen pulmonary edema if theincrease in endothelial permeability is such that themajority of colloid molecules can pass through the pul-monary capillary endothelium.79 This is particularly trueif a significant increase in pulmonary capillary pressureoccurs simultaneously, as is more likely with colloid infu-sion. Considering the extremely slow clearance ofmacromolecules from the alveolar space, this increase inedema may be life threatening. Conversely, if the increasein permeability is insufficient to allow loss of colloid intothe interstitium, prudent colloid therapy can reduceextravascular lung water. Therefore it is important to crit-ically evaluate the patient’s response to a test infusion ofcolloid. An increase in COP should be titrated to preventan increase in respiratory rate and effort, or, at worst, adecrease in arterial oxygen concentration. In moreadvanced critical care settings, pulmonary capillary wedgepressure or even measurement of extravascular lung watermay be used to guide fluid therapy. When using colloidsin the patient with a systemic vascular leak state, and in theabsence of hemorrhage, failure to retain colloid in theintravascular space for an appropriate time periodsuggests that extravascular leakage of colloid could beworsening, not helping, hypovolemia and edema. If arte-rial oxygenation worsens after colloid therapy in an ani-mal with pulmonary edema caused by alteredpermeability, one must consider the possibility that thecolloid is contributing to the pulmonary edema.

The use of colloids in patients with high-pressure pul-monary edema is controversial because of their greaterpropensity for volume overload and because existingtherapies for heart failure are so effective. Therefore col-loid therapy should be used with extreme caution to pre-vent increases in pulmonary capillary hydrostaticpressure. Colloid support in the patient with left-sidedheart failure should only be used in a critical care environ-ment with invasive monitoring capabilities. Increased leftatrial pressure secondary to left-sided heart failure resultsin increased pulmonary capillary pressure and increasedfluid extravasation into the pulmonary interstitium.73

Lymph flow in the lung increases to protect against inter-stitial fluid accumulation,182 but as extravasationincreases, fluid begins to accumulate in the interstitium.In the alveoli, where gas exchange occurs, the capillaryendothelial cell is closely apposed to the alveolar epithelialcell, and the perimicrovascular interstitium is relativelynoncompliant. In contrast, the peribronchovascularinterstitial tissue is more compliant, and fluid tends toaccumulate as peribronchovascular edema cuffs, therebyprotecting gas exchange.38,39 Eventually, edema fluiddistends all parts of the pulmonary interstitium and ulti-mately fills the airspaces of the lung. Current theorysuggests that because the alveolar membrane is so imper-meable to solutes, alveolar filling does not occur by fluidflow through the epithelium, but rather fluid spills intothe airspaces at the junction of the alveolar and airwayepithelia.152 In the absence of increases in permeability,maintenance of intravascular COP via colloid administra-tion can be protective against cardiogenic pulmonaryedema.174 Furosemide also increases COP, and, contraryto popular belief, it does not appear to reduce plasma vol-ume.48,142 Because of the opposing effects of intravascu-lar hydrostatic pressure and COP, monitoring thegradient between pulmonary artery occlusion pressureand COP has been suggested in the management of pul-monary edema.48,119,120

CHRONIC HYPOPROTEINEMIAThe effective COP acting to retain fluid within the intra-vascular space is the net difference between the intravas-cular COP and interstitial COP. As intravascular COPdecreases, fluid with a lower COP passes from the vascu-lature and dilutes the interstitial protein concentrationsuch that interstitial COP also decreases. Consequently,the gradient between intravascular and interstitial COPis preserved. In addition, increased lymphatic drainagewill also protect against edema formation. Hence, a lowplasma COP per se does not necessitate colloid therapyin the absence of clinical signs such as hypovolemia oredema. Indeed, people with an hereditary form of com-plete albumin deficiency have plasma COP that still is halfof normal because of increased globulin concentrations,and affected individuals exhibit minimal peripheraledema.9,49 There also appear to be no serious clinical


signs in an autosomal recessive hereditary albumin defi-ciency in rats.107 Interestingly, affected rats have markedhypercholesterolemia.

In our clinical experience and in experimental stud-ies,182 animals with severe hypoproteinemia (COP,<11 mm Hg) may exhibit peripheral edema but rarelydevelop pulmonary edema. In dogs withhypoalbuminemia, hydroxyethyl starch has been shownto result in clinical improvement of peripheral edema orascites.150 The role of macromolecules in maintainingthe selective permeability of the microvascular bar-rier46,102 provides a rationale for the prophylactic use ofalbumin or artificial colloid. It is, however, most impor-tant to diagnose and treat the underlying cause of thehypoproteinemia rather than administer palliative colloidtherapy. Furthermore, if large ongoing losses are present,as can be the case with protein losing nephropathies andenteropathies, colloid support may not be effective.106

TREATMENTCOMPLICATIONS ANDADVERSE EFFECTS

EFFECTS ON HEMOSTASISThe debate about whether artificial colloids causeabnormalities in coagulation is largely redundant becauseall of the older, higher molecular weight artificial colloidscan cause abnormalities of primary and secondary hemo-stasis. The more important question is whether thesecoagulopathies are clinically relevant. Despite many stud-ies supporting a lack of clinically relevant bleeding, therealso is a large amount of clinical and experimental evi-dence documenting serious, potentially life-threateningbleeding after administration of hydroxyethyl starchesand dextran.6,21,42,162,172 This apparently conflicting evi-dence implies that coagulation abnormalities are clinicallyrelevant only in some cases. The effects on coagulationappear to be directly related to the intravascular concen-tration of artificial colloid.172 Higher plasmaconcentrations of colloid may occur after larger doses,repeated administration, or reduced intravascular degra-dation. However, although high molecular weight hasbeen considered to be one of the key factors in determin-ing coagulation effects of HES products,164 in general areduction in molecular weight has also been associatedwith a reduction in degree of substitution. Recentintriguing work evaluating the coagulation effects ofproducts with differing MW but the same low degreeof substitution (HES 130/0.42, HES 500/0.42, andHES 900/0.42) that demonstrated similar effects oncoagulation for all three preparations suggests thatmolecular weight has less effect than the degree of substi-tution.95 A further study evaluating HES 700 with vary-ing degrees of substitution and C2/C6 ratios suggeststhat effects on coagulation are minimized when there is

a low degree of substitution and a low C2/C6 ratio.169

This opens up the possibility for development of HESproducts with higher MW (and thus potentially betterintravascular persistence) but minimal effects on coagula-tion. With repeated administration, the small colloidmolecules are constantly excreted, and the relative con-centration of larger molecules increases. This fact explainswhy many studies reporting clinically relevant bleedingrefer to patients who received repeated doses of colloidover a period of days.

The exact mechanism of action by which coagulation isaffected still is not fully understood; however, great prog-ress has been made over recent years. Older studiesreported reductions in factor VIII and von Willebrand’sfactor (greater than those expected by dilution) andweakened clot formation.2–4,68,69,82 Colloid moleculesmay impair the action of endothelial adhesion molecules,thereby reducing endothelial release of von Willebrand’sfactor.37 Decreases in vWF and factor VIII may also occurdue to binding with HESmolecules and accelerated elim-ination of the complex.88 In essence, colloids can cause anacquired type 1 form of Von Willebrand disease (VWD).Dogs that already have mild tomoderate VWDmay expe-rience severe reductions in VWF and factor VIII follow-ing colloid infusion. Colloids should be avoided inknown cases of VWD. Platelet dysfunction independentof von Willebrand factor is also present; its mechanismhas not been fully elucidated but is at least in part dueto the ability of HES molecules to coat the surface ofplatelets and interfere with ligand binding.52

The reductions in factor VIII (FVIII), which isstabilized by vWF in circulation, accounts for the mildlyprolonged activated partial thromboplastin times thathave been observed in people afterHES administration.81

Hydroxyethylstarches decrease agonist-induced expres-sion and activation of platelet integrin aIIbß3 (formerlyknown as GPIIb/IIIa).62 Integrin aIIbß3 on the surfaceof the platelet binds fibrinogen, and therefore plays a vitalrole in platelet aggregation and formation of a plateletplug. It has also been shown that HES molecules coatthe surface of the platelet, limiting binding of ligandsto cell surface receptors, which may decrease functionof platelets independent of the integrin aIIbß3blockade.52

The clinical relevance of platelet dysfunction afterHESadministration has been manifest in people as increasedpostoperative blood loss or increased transfusionrequirements in some patient populations.20 Neverthe-less, some studies in surgical patients have also shownno significant increase in blood loss.80,94 Trials in postop-erative patients that have used rapidly degradable HESsolutions found no difference in rates of blood loss andtransfusion requirements when compared to albumin orgelatin.88 A recent pooled analysis of studies in major sur-gery comparing HES 130/0.4 (Voluven) and HES 200/0.5 (Starquin) found that estimated blood loss and

658 SPECIAL THERAPY

transfusion requirements were significantly reduced inthe group receiving HES 130/0.4.89

In veterinary medicine, administration of hetastarch670/0.75 as compared with 0.9%NaCl has been shownto affect canine platelet function both in vitro178 and invivo148 in clinically healthy dogs. A single dose of HES670/0.75 at 20 mL/kg IV causes platelet dysfunctionin dogs for at least 5 hours after injection. The clinicalimpact of platelet dysfunction induced by HES solutionsin veterinary medicine remains to be established but it isreasonable to assume that it could be of clinical signifi-cance. Assessing platelet function by performing a buccalmucosal bleeding time (or other platelet function analysisif available) following colloid infusion would seem pru-dent in select at-risk patients.

It seems prudent to supplement clotting factors inanimals at risk by use of fresh frozen plasma. In addition,desmopressin has been shown to increase factor VIII:Cactivity after hydroxyethyl starch infusion and should beconsidered as adjunctive therapy along with fresh frozenplasma administration.41

The observation that colloids impair the action ofendothelial adhesion molecules also raises the possibilitythat colloids may reduce neutrophil adhesion in sepsis37

and explain the higher neutrophil counts observed afterdextran 70 infusion in endotoxic shock.105

INTRAVASCULAR VOLUMEOVERLOADBecause colloids are retained within the vascular system toa greater extent than are crystalloids, there is a greaterlikelihood of volume overload with injudicious adminis-tration of colloids. Most clinicians are more familiar withcrystalloid than with colloid infusion rates, and a helpfulmethod to ensure a safe colloid infusion rate is to estimatethe equivalent crystalloid infusion rate. Approximately20% to 25% of crystalloid remains within the intravascularspace 1 hour after infusion compared with 100% of thevolume of infused colloid. Therefore multiplying the col-loid infusion rate by four allows one to conceptualize thevolume expansion effects of the colloid in terms of anequivalent crystalloid volume: 20 mL/kg/hr of colloidis equivalent to 80 mL/kg/hr of crystalloid. Animalswith heart, lung, or brain disease or oliguria/anuriashould be closely monitored during colloid administra-tion, ideally by direct monitoring of central venous pres-sure. Cats are more likely to develop volume overloadthan dogs. This is due in part to their smaller blood vol-ume as a percentage of body weight, but also to inadver-tently administering the canine dose to a cat.

EFFECTS ON THE KIDNEYThelowmolecularweightdextrans suchasdextran40havebeen reported to cause acute renal failure.59,96 Renal dys-function has also been associated with HES solutionsalthough recent reports suggest that concerns regarding

renal function related to the older high MWHES shouldnot be extrapolated to the new low MW products.19,177

In people, there is growing evidence that there is a dose-related association between the use of slowly degradablehydroxyethyl starch solutions and acute kidney injury incertain subsets of patients, such as in sepsis.29,141 Glomer-ular filtration of a high concentration of small colloidmolecules is postulated to cause obstruction of the renaltubules or osmotic nephrosis.59,96 Another concern inpatients with oliguric or anuric renal failure is that thekidneys are the major route of excretion for all artificialcolloids; a situation analogous to the pharmacokineticsof mannitol. There is no other rapid excretion route forcolloids, so animals with renal failure and reduced glomer-ular filtration rate will be at much greater risk of volumeoverload. Although published evidence is lacking in veter-inary medicine, it is prudent to limit or avoid artificial col-loid therapy in patients with documented renal failure andin those at high risk of renal tubular injury/renal failure. Ifuse of colloids is deemed necessary in these patients, urineoutput andrenal functionshouldbemonitoredclosely andthe dose of colloid (both total cumulative and duration)should be minimized.

ANAPHYLAXISAnaphylactic or anaphylactoid reactions have beenreported in people following the administration ofdextrans, hydroxyethyl starches, and gelatins,125 butthe incidence of serious complications is extremelylow.126 Hydroxyethyl starch was associated with pruritusin up to 33% of patients treated with long-terminfusions.66 Deposits of hydroxyethyl starch in cutaneousnerves101 and histiocytic skin infiltrates43 were thoughtto be responsible. Interestingly, pruritus also has beenreported after infusion of lactated Ringers solution.24

Several studies have raised concerns about the potentialeffects of plasma substitutes on reticuloendothelial func-tion.140 Decreased concentrations of the opsonic plasmafactor, fibronectin, have been reported with use ofhydroxyethyl starch165 and gelatins.26

LABORATORY TESTS ANDINTERPRETATION, CLINICALEVALUATION, ANDMONITORINGRefractometry does not accurately reflect the concentra-tion or the osmotic effect of synthetic colloids.30 Theolder forms of hydroxyethyl starch and dextran 70 avail-able in the United States both yield refractometric totalsolids (RTS) readings of 4.5 g/dL. As plasma volume isreplaced by artificial colloid, the measured RTS shouldapproach that of the artificial colloid. Theoretically,administering artificial colloid to an animal with an initialRTS concentration greater than 4.5 g/dL will reduce the


measured RTS, whereas administering artificial colloidsto an animal with an initial RTS concentration less than4.5 g/dL should increase the measured RTS toward4.5 g/dL. However, in vitro addition of either of thesecolloid preparations (in an amount corresponding to a22-mL/kg dose in a patient) to a 2.5% solution of humanserum albumin (initial RTS concentration, <2.5 g/dL)led to minimal increases in the RTS concentration despitean increase in measured COP.30 As more artificial colloidwas added to the albumin solution, the RTS concentra-tion did increase, but the amount of colloid necessaryto cause this change was greater than the volume likelyto be used in clinical patients.

The in vivo situation is more complicated because ofother effects such as extravasation, excretion of colloid,and osmotic fluid shifts into the vascular space afteradministration. In the authors’ experience, most patientswith preinfusion RTS concentration of 5 g/dL have adecrease in RTS concentration after colloid administra-tion. Conversely, increases in RTS after colloid adminis-tration seem to be uncommon, regardless of the initialRTS. The clinician should anticipate the dilutional effectcaused by intravascular volume expansion that occurswith colloid infusion.

Hematologic and biochemical parameters maydecrease due to simple dilution. Objective measures ofhemodilution (e.g., serum albumin concentration andPCV) almost invariably decrease after colloid infusion.Platelet count and serum potassium concentration alsoseem to be reliably decreased. Failure to recognize thedilutional decrease in RTS or albumin concentrationscould cause the clinician to misinterpret the decrease asan indication for more colloid and increase the likelihoodof volume overload. In contrast, administration of HESmay result in increased serum amylase activity (200% to250% of normal) because of its binding to HES anddecreased excretion.23,85,104

Unfortunately, assays for the quantitative determina-tion of serum colloid concentrations are not readily avail-able. Therapy with artificial colloids would ideally bemonitored by measurement of plasma COP using a col-loid osmometer but this is rarely possible. In most clinicalpractice, the response to colloids is assessed indirectly bymonitoring the cardiovascular response to infusion.Because artificial colloids are excreted primarily by thekidneys, the presence of colloidmolecules in the urine willtypically lead to an increase in urine specific gravity (USG)measured after administration.149 Urine specific gravitiesin excess of 1.080 may occur. Changes are somewhat var-iable and depend upon the excretion rate of colloid andthe volume of urine being produced. The increase inUSG due to colloids means that it can no longer be usedas an indicator of renal concentrating ability followingcolloid administration.

As mentioned previously (see TreatmentComplications and Adverse Effects section), tests of

primary and secondary hemostasis may be affected by col-loid administration. For primary hemostasis, plateletfunction defects have been documented in dogs178 so itis likely that buccal mucosal bleeding times may also beprolonged. Increases in partial thromboplastin timemay also be seen, presumably due to colloid-inducedreductions in factor VIII and direct interference in clotformation. Finally, colloids have been reported toincrease plasma viscosity,22 and hydroxyethyl starch canproduce predictable but potentially misleading resultsin blood typing and crossmatching.50

ACKNOWLEDGMENTSThe authors gratefully acknowledgeDr. Lisa Smart BVSc,DACVECC for her assistance with the sections ontreatment complications and adverse effects and labora-tory tests and interpretation, clinical evaluation, andmonitoring.

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