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8/12/2019 Fluid Therapy 2

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Colloids: Current Recommendations

Daniel L. Chan, DVM, MRCVSDepartment of Veterinary Clinical Sciences, The Royal Veterinary College,University of London, Hawkshead Lane, North Mymms, Hertfordshire, AL9 7TA, UK

F

luid administration remains the cornerstone of critical care medicine andis the standard therapy used to maintain or restore intravascular volume.The optimal choice of fluid for resuscitation likely will remain one of the

most enduring controversies in medicine. Advantages of crystalloid resuscita-tion include the fact that crystalloids replace interstitial and intravascular fluidlosses, minimally impair the coagulation system, do not cause allergic reactions,are inexpensive, and are widely available. Proponents of crystalloid fluid ther-apy also cite the various meta-analyses that suggest that colloid use is associatedwith greater mortality rates, although these studies may have been underpow-ered to truly demonstrate such associations [13]. The main disadvantagesassociated with crystalloid use include limited duration of intravascular volumeexpansion and greater propensity for formation of tissue edema by lowering

plasma colloid osmotic pressure (COP), which may contribute to impairedgas exchange in the lungs, increased bacterial translocation in the gut, and neg-ative impact on wound healing [3]. Advantages of colloid use include longerintravascular effect, smaller volume requirements to achieve comparable intra-vascular expansion, and decreased risk of tissue edema formation by provisionof oncotic support. Disadvantages attributed to colloids that have been welldescribed in people include allergic reactions (particularly with gelatins), possi-

ble renal impairment (dextrans, hetastarches), impairment of coagulation (dex-trans, hetastarches), and substantially higher costs. The purported benefits

colloids have led to widespread use of colloids in critical care patients, however.Concerns over the apparent association between colloid use and increased

risk of morbidity and mortality have prompted researchers to develop newerand better synthetic colloids that produce less serious complications. As thesenewer colloids become more widely available, guidelines for their effectiveuse are needed. Renewed interest in natural colloids, such as concentrated hu-man albumin, has added a new dilemma for practitioners in the selection of themost appropriate fluid type for treatment of various conditions. Recommenda-tions for the use of colloids in veterinary patients must take into consideration

issues such as physiologic rationale, available efficacy data, and patient safety

E-mail address: [email protected]

0195-5616/08/$ see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.cvsm.2008.01.006 vetsmall.theclinics.com

Vet Clin Small Anim 38 (2008) 587593

VETERINARY CLINICSSMALL ANIMAL PRACTICE
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Table 1

Physiochemical properties and recommended dosages of commercially available synthetic colloids

FluidMeanMW (KDa)

Molarsubstitution COP (mm Hg)

Recommendedmaximal dose(mL/kg/d) Ot

Dextran 70 70 N/A 61.7 0.5 20 Impm

4% succinylated fluid gelatin: Gelofusine 30 N/A N/A N/A An

3.5% urea cross-linked gelatin: Haemaccel 35 N/A 15.2 0.3 N/A An6% hetastarch in 0.9% NaCl 600 0.7 32.7 0.2 20 Impm

6% hetastach in balanced electrolytesolution: Hextend

670 0.75 37.9 0.1 20 Impc

10% pentastarch 200 0.5 32.0 1.4 33 Mi6% tetrastarch: Voluven 130 0.4 37.1 0.8 50 Mi

ad

HBOCOxyglobin 200 N/A 43.3 0.1 N/A Va

Abbreviation:HBOC, hemoglobin-based oxygen carrier.

Data from Chan DL, Freeman LM, Rozanski EA, et al. Colloid osmotic pressure of parenteral nutrition components a2001;11(4):26973; and Humm K, Chan DL. Colloid osmotic pressure of synthetic colloids available in veterinary clinica21(3):656.


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or marginal (but statistically significant) abnormalities in clotting times, the ma-jor concern is that critically ill patients generally are at risk for coagulation dis-turbances, and the additional detrimental effects of colloids on coagulation may

become unacceptable [16,24]. With respect to clotting times, activated partialthromboplastin times are more sensitive to the effects of synthetic colloidsthan other coagulation tests [16,24]. Studies demonstrating poorer outcomeswith colloid use suggest that clinically relevant bleeding may have resultedfrom the effects of colloids on coagulation[1,2,23].

DEVELOPMENT OF NEW SYNTHETIC COLLOIDS

The adverse effects of synthetic colloids, including those on the coagulationsystem, are the major driving forces behind development of newer syntheticcolloids. To understand some of the progress in manufacturing newer colloids,a brief overview of their chemical properties may be helpful. Dextrans are com-posed of naturally occurring glucose polymers. Gelatins are derived fromhydrolysis of bovine collagen followed by being either succinylated or linkedto urea. Hemoglobin-based oxygen carriers, such as Oxyglobin, are stroma-free ultrapurified hemoglobin glutamers. Bovine hemoglobin is highly polymer-ized to delay its clearance by the kidneys. Hydroxyethyl starches (HES) aremodified polymers of amylopectin that vary substantially in molecular weight

(MW) and other chemical features that affect their pharmacokinetics andmetabolism. In general, colloids are polydisperse solutions with moleculesthat range in size from a few thousand to several million Daltons. The quotedMW for a specific product represents the weight average MW of the moleculesin that solution. Solutions with high MW have a longer plasma half-life becausethey have delayed renal clearance. The MW of the colloid is particularlyimportant to note because the detrimental effects of colloids on coagulationare partly related to the presence of the higher MW polymers (see Table 1).

This article focuses primarily on HES because they are the most commonly

used colloids in practice. A key modification in the molecular structure of theamylopectin molecule is the substitution of some hydroxyl groups on the glu-cose units with hydroxyethyl groups, which stabilize the polymer and interferewith plasma amylase activity, thereby prolonging the colloids effect. A higherdegree of hydroxyethylation (ie, molar substitution) correlates with slower deg-radation of HES by amylase and longer persistence in plasma. Unfortunately,higher degrees of molar substitution also impact coagulation. There are severaltypes of HES, which are grouped by their degree of substitution. The term he-tastarch should not be considered synonymous with HES but rather is used

to describe a type of HES with a high degree of substitution (between 0.6 and0.7). Pentastarches and tetrastarches have degrees of substitution of 0.5and 0.4, respectively. Hydroxyethyl groups usually are added at the C2, C3,and C6 carbon positions of the constituent glucose molecules. The degree ofsubstitution is not the only way to prolong persistence in plasma, however.Higher substitution on position C2 in relation to C6 (expressed as the

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C2:C6 ratio) also imparts greater resistance to amylase degradation withoutcompromising coagulation.

Newer HES solutions have been developed to address the problems associ-ated with coagulation. These colloids are widely available in Europe and gen-erally have smaller mean MW and are hydroxyethylated to a lesser degree. Tocompensate for the reduction in plasma half-life incurred by these alterations,there is an increase in C2:C6 ratio, which improves amylase resistance. Bymanipulation of these characteristics, these newer colloids can be administeredat higher dosages without affecting clotting times. For example, the maximaldosage of HES 130/0.4 (mean MW of 130 kDa and molar ratio of 0.4) is50 mL/kg as compared with the typical dosage of 20 mL/kg forHES 450/0.7, which is more commonly found in the United States.

Because most colloids are suspended in sodium chloride solutions, an addi-tional complication associated with their use is development of hyperchloremicmetabolic acidosis [25]. This effect has been a particular problem in peopletreated with saline-based colloids, but there is limited information about thisproblem in animals. Newer HES solutions suspended in balanced electrolytesolutions (eg, Hextend) have been developed to decrease the risk of this com-plication. The inclusion of calcium in such solutions has been proposed to ame-liorate some of the effects of the colloid on coagulation, particularly effects onplatelet function[22,26]. The effects on coagulation, however, cannot be cor-

rected completely by calcium supplementation alone, which suggests that otherfeatures of the balanced electrolyte colloid solutions may confer these benefits[27,28]. Recent studies also have yielded conflicting results with regard to dif-ferences in coagulation parameters between sodium-based and balancedelectrolyte colloid solutions, emphasizing the need for additional studies[22,23,2628].

Another intriguing effect of synthetic colloids, which is only beginning to beexploited, is their potential to modulate inflammation[2933]. Although someauthors originally hypothesized that colloids acted by physically sealing the

barrier defects created by injury[34], only recently have the actual mechanismsfor attenuation of capillary leakage and the anti-inflammatory effects of colloidsbeen more clearly understood[30,32,33,35]. It is becoming increasingly clearthat certain colloids can decrease capillary permeability, down-regulate theexpression of adhesion molecules, inhibit neutrophil recruitment, and decreasecytokine production[30,32,33,35]. Colloids with lower MW (< 200 kDa) andmolar substitution (< 0.4) seem to be superior in this respect. In the setting ofcritical illness, in which inflammation is a major component of most disorders,colloids with lower MW and lower degree of substitution may be the preferred

type of colloid. As these newer colloids become more widely available, futurestudies evaluating their efficacy in clinical patients are warranted.

SUMMARY

Colloids are increasingly becoming considered indispensable in the manage-ment of critically ill patients, especially patients that require administration of

591COLLOIDS: CURRENT RECOMMENDATIONS
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large quantities of fluid and demonstrate signs of tissue edema. Current guide-lines for the use of colloids in veterinary patients balance the benefits of superiorand longer-lasting volume expansion with the risks of developing complications,such as volume overload and coagulation disturbances. Recent studies substan-tiate the negative effects of the most commonly available HES preparations(450/0.7 and 670/0.75) on the coagulation system, and maximum safe dosagesfor these products are approximately 20 mL/kg/d, although dosages of 30 to40 mL/kg/d have been used in clinical patients. In animals with pre-existing coa-gulopathies, lower dosages should be used, and such patients may require freshfrozen plasma transfusions if synthetic colloid therapy is necessary. Newer prep-arations of synthetic colloids with decreased impact on the coagulation systemmay have maximal safe dosages approaching 50 mL/kg/d. Other advantages

of these newer colloids include anti-inflammatory properties, which could proveto be particularly useful in the management of critically ill patients. Although thedebate over which fluid type is optimal for fluid resuscitation will continue,acquiring a better understanding of how different fluids influence the hostresponse may enable us to target disturbances other than volume deficits.

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593COLLOIDS: CURRENT RECOMMENDATIONS

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