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Vox Sanguinis (2002)82 , 18

REVIEW ARTICLE 2002 Blackwell Science

BlackwellScienceLtd

Resuscitation uidsM. P. W. Grocott & M. A. HamiltonCentre for Anaesthesia, University College London, London, UK

Background and Objectives The aim of this review was to summarize the propertiesof the commonly available resuscitation uids and highlight where knowledge of thecharacteristics of individual uids might guide their use in clinical practice. Some of the current controversies surrounding resuscitation uids are also discussed. Blood or blood products, or strategies of uid administration, are not focused upon.

Conclusions The clinical trial data does not support the concept of a therapeuticadvantage for either crystalloids or colloids, despite claimed theoretical advantagesfor both classes of uid. The available colloid solutions have quite distinct prolesof activity, both in terms of their plasma volume expansion prole and other physio-

logical and pharmacological properties. Recent data suggests that physiologically balanced crystalloid and colloid solutions may improve clinical outcomes whencompared with saline-based uids.

Key words: colloid, crystalloid, dextran, gelatin, hydroxyethyl starch, intravenousuid therapy

Received: 30 July 2001,revised 6 August 2001,accepted 4 September 2001

Introduction

Some uid, any uid ... please!!

The restoration of adequate tissue perfusion by administrationof resuscitation uids to achieve an effective circulating volumeis a fundamental treatment goal in modern medicine. Differentuid types produce varying degrees of magnitude and durationof expansion of the intravascular volume. In addition, admin-istration of a uid into the intravascular space to produce anadmixture with blood can have signicant effects on haema-tological properties. Many resuscitation uids have signicanteffects on haemorrheaology, haemostasis, vascular integrity and inammatory cell function. The aim of this reviewwas to summarize the properties of the commonly availableresuscitation uids and highlight where knowledge of thecharacteristics of individual uids might guide their use inclinical practice. We have also highlighted some of thecurrent controversies surrounding resuscitation uids.

Types of uidThis section will describe the main types of intravenous uidsthat are currently available and used in clinical practice.Transfusion of red cells and other blood products will not bediscussed further in this review. The importance of focusingon and distinguishing between the crystalloid or carrier com-ponent and the colloid component of colloid solutions willbe emphasized.

Crystalloid solutions

Crystalloid is the term commonly used to refer to solutionsin water of inorganic ions and small organic molecules.They are either glucose or sodium chloride based and may beisotonic, hypotonic or hypertonic. In addition, potassium,calcium and lactate are commonly added to make the com-position more similar to that of plasma (see Table 1). To pro-

vide a signicant expansion of the circulating volume, large volumes of crystalloid must be given and this may result inaccumulation of uid in the interstitial compartment. A 1-linfusion of normal (09%) saline will result in an expansionof the circulating volume of less than 250 ml. The increasedextracellular uid may manifest itself as signicant tissueoedema, which could theoretically result in compromised

Correspondence : Mark A. Hamilton, Centre for Anaesthesia, UniversityCollege London, Room 103, The Crosspiece, Middlesex Hospital, MortimerStreet, London, W1T 8AA, UKE-mail: [email protected]


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2 M. P. W. Grocott & M. A. Hamilton

2002 Blackwell Science Ltd. Vox Sanguinis (2002) 82 , 18

end-organ perfusion, both from compression of small vesselsand by increasing diffusion distances within tissues. Large-

volume crystalloid resuscitation does result in signicanttissue oedema, but there is no evidence that this leads toimpaired tissue perfusion or a worse outcome.

Glucose infusions are presented either as an isotonic solu-tion (5% wt/vol containing 50 g of glucose in each litre of water) or as hypertonic solutions (25% and 50% wt/vol). Iso-tonic glucose solution is the appropriate uid to give for puredehydration and water replacement because the glucose con-tent is rapidly metabolized and the water is freely distributedthroughout all body compartments. The hypertonic glucosesolutions are given to provide glucose as a metabolic sub-strate in hypoglycaemia and on occasions with insulin for thecontrol of high potassium levels.

Colloid solutions

A colloid is a homogeneous, non-crystalline substance con-sisting of large molecules or ultramicroscopic particles of one

substance dispersed through a second substance the par-ticles do not settle and cannot be separated out by ordinary ltration or centrifugation. There are three principal typesof semisynthetic colloid molecules commonly used in intra-

venous solutions: gelatins; dextrans; and hydroxyethylstarches (see Table 2). In addition, human albumin solutions,plasma-protein fraction, fresh-frozen plasma (FFP) andimmunoglobulin solutions are all human plasma derivativesthat are colloid solutions. All colloids are presented dissolvedin a crystalloid solution. The nature of this carrier solution isoften overlooked as an important element when consideringthe physiological effect of individual solutions. Isotonicsaline is the most commonly used carrier solution, but iso-tonic or hypertonic glucose, hypertonic saline and isotonicbalanced electrolyte solutions are also used.

Colloids often do not consist of molecules of uniform size.Human albumin solution contains more than 95% albuminwith a uniform molecular size. This is described as monodisperse.Conversely, all the semisynthetic colloids have a distributionof molecular sizes and are described as polydisperse.

Table 1 Comparison of contents, osmolarity and pH of crystalloid solutions for intravenous administration

SolutionOsmolarity(mOsmol/l) pH

Na+ (mM)

Cl (mM)

K+ (mM)

Ca2+

(mM)Glucose(mg/l)

HCO3

(mM)Lactate(mM)

Glucose 5% 252 50 Glucose 50% 2520 500

Sodium chloride 09% 300 50 1540 1540 Sodium chloride and glucose 262 300 300 40 Ringers solution 309 1470 1560 40 22 Compound sodium lactate a 278 1310 1110 50 20 290Plasmalyte B 2985 55 140 98 5 50

aCompound sodium lactate = Hartmanns solution or Ringers Lactate solution.

Table 2 Comparison of contents of some UK licensed colloid solutions for intravenous administration

Solution Colloid MW DSNa+ (mmol/ l) Cl (mM) K+ (mM) Ca2+ (mM)

Glucose(mg/l)

Gelofusin (4%) Succinylated gelatin 30 000 150 150 Haemacel (35%) Polygeline 30 000 145 145 51 625 EloHaes 6% Hetastarch 60 000 150 150 HAES-steril 6% or 10% Hetastarch 70 000 05 150 150 Hespan 6% Hetastarch 70 000 07 150 150 Pentaspan 6% or 10% Pentastarch 63 000 045 150 150 Gentran 40 Dextran 40 40 000 150 150 Gentran 40 Dextran 40 40 000 50Gentran 70 Dextran 70 70 000 150 150 Gentran 70 Dextran 70 70 000 50Macrodex Dextran 70 70 000 150 150 Macrodex Dextran 70 70 000 50

DS, degree of substitution; MW, molecular weight.


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Resuscitation uids 3

Gelatins

Gelatins are prepared by hydrolysis of bovine collagen. Thecommonly available preparations are succinylated gelatin(Gelofusin), which is presented in isotonic saline, and urea-linked gelatin polygeline (Haemaccel) which is presentedin isotonic saline with the addition of 51 mmol/l of potas-sium and 625 mmol/l of calcium [1].

Succinylated gelatins are produced by enzymatic altera-tion of the basic gelatin peptide by succinic acid anhydraseto replace NH 3 groups with COO

. This results in a conforma-tional change that increases molecular size without signi-cantly increasing molecular weight (MW) [2]. Urea-linkedgelatins are produced by thermal degradation of the rawmaterial to small peptides (12 00015 000 daltons) followedby urea cross-linking, by means of diisocyanate, resulting inpolymers of 35 000 daltons [3].

A specic safety issue has arisen with bovine-derivedgelatin products since the advent of sporadic cases of new

variant Creutzfeld-Jakob disease (vCJD) associated withexposure to tissue infected with bovine spongiform encepha-litis (BSE). The reported cases implicate bovine-derived foodproducts and there are no cases of transmission involvingpharmaceutical gelatin preparations. The gelatin used incommercially available products in the UK is currently sourced from the US (which is believed to be BSE free) or fromcertied BSE-free herds in Europe. The UK SpongiformEncephalopathy Advisory Committee has concluded thatgelatin is safe to use in this context. Most clinicians continueto use bovine gelatin-based products; however, given theuncertainties concerning the transmission and behaviour of BSE, awareness of this issue is important [46].

Dextrans

Dextrans are high-MW D-glucose polymers joined largely by -1,6 bonds into linear-branched macromolecules. They arebiosynthesized commercially from sucrose by the B512 strainof Leuconostoc mesenteroides , using the enzyme dextransucrase [3]. This produces a high-MW dextran that is thencleaved by acid hydrolysis and separated by repeated ethanolfractionation to produce a nal product with a relatively narrowMW range. The products in current clinical use are describedby their number-averaged MW, Dextran 40 and Dextran 70

having MWs of 40 000 and 70 000, respectively [2]Dextrans, like all the other semisynthetic colloids, are poly-

disperse, with 90% of the molecules of Dextran 40 havingMWs of between 10 000 and 80 000. The renal thresholdfor dextrans is quoted to be between 50 000 and 55 000.Molecules with a MW less than this threshold are freely lteredat the glomerulus and molecules with a MW less than 15 000have a clearance similar to creatinine. Approximately 70% of an administered dose of Dextran 40 will be excreted into the

urine within 24 h. Larger molecules are excreted throughthe gut or phagocytosed by cells of the reticuloendothelialsystem, where they are either metabolized by endogenousdextranases or recirculated into the systemic circulation [7].

Hydroxyethyl starches

Hydroxyethyl starches (HES) are synthesized from amylo-pectin, a waxy starch derived from maize or sorghum. Amylo-pectin is a D-glucose polymer with a branching structure.Reaction with ethylene oxide in the presence of an alkalinecatalyst results in hydroxyethyl substitution. The majority of these substitutions occur at Carbon (C)2 in the glucose ring,with the rest occurring at C3 and C6. An increased C2/C6substitution ratio results in slower enzymatic degradation [8].The unsubstituted starch is rapidly hydrolysed by non-specic -amylases in the bloodstream and substitutionwith hydroxyethyl groups substantially slows this process.The degree of substitution (DS) indicates the proportion of

glucose moieties that have been substituted and can beexpressed as a number from 0 to 1. Starches with a DS closeto 1 have a greater resistance to hydrolysis than those with alower DS. The substituted starch is then rened into the nalproduct by hydrolysis to the required MW, purication and(for certain products) a fractionation process to produce speci-ed MW bands. All HES products are polydisperse and theMW prole and degree of substitution dene the individualproducts.

Key characteristics of articial colloidsThe key characteristics of articial colloids are as follows:(1) magnitude and duration of plasma volume expansion;(2) haemorrheological characteristics;(3) haemostatic effects;(4) interaction with endothelial and inammatory cells;(5) adverse drug reactions; and(6) cost.These characteristics are discussed in detail below.

Magnitude and duration of plasma volumeexpansion

The essential characteristic of colloid solutions is that they persist in the intravascular space. Duration of intravascular persistence is governed by the rate of loss of colloid mole-cules from the circulation and by their metabolism. Colloidmolecular size and surface charge characteristics determinethe rate of loss through the capillary endothelial barrier intothe interstitial compartment and the rate of glomerular ltra-tion, and hence loss into the urine. The extent and rate of intra- and extravascular metabolism is determined predom-inantly by the individual chemical properties of the colloid


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molecule. Although their specic physicochemical propertiesdictate their rate of disappearance after infusion into thecirculation, the most useful descriptors of intravascular per-sistence are intravascular half-life and the fraction of admin-

istered volume retained within the circulation after a specictime (see Table 3) [9,10]. Intravascular persistence is reducedin clinical conditions where integrity of the endothelial barrier is compromised (e.g. sepsis, systemic inammatory responsesyndrome [SIRS]), where there will be an increased ux of colloid molecules into the extravascular compartment.

Haemorrheological characteristics

All colloid solutions alter whole-blood rheology (the physicsof ow and deformation of matter). By simple haemodilutionthey reduce whole-blood viscosity, resulting in improvedow. This dilutional decrease in viscosity is clearly propor-tional to the magnitude of intravascular expansion for agiven infused volume and is therefore greater initially for thelower MW (30 00040 000) HES and Dextran products. Thehigher MW colloids, particularly dextrans and hydroxyethylstarches, have been shown to increase plasma viscosity, butthis phenomenon does not result in compromised perfusionbecause the whole-blood viscosity is decreased by the domin-ant effect of dilution of the normal blood constituents.

Dextrans above 60 000 MW (e.g. Dextran 70) tend to causeaggregation of red cells. Conversely, the lower MW dextrans(e.g. Dextran 40) tend to cause reduced red blood cell aggrega-tion, which results in improved blood ow, particularly in the

venous system.

Haemostatic effects

All the semisynthetic colloid solutions produce a degree of impairment of haemostasis. The predominant mechanism issimple haemodilution of clotting factors, but the differentcolloid molecules also have specic effects on componentsof the haemostatic mechanism.

The gelatins appear to have the least impact on haemos-tasis and it is not clear whether they have any impact over and above simple haemodilution of clotting factors. Recentwork using the thromboelastograph (TEG) suggests that clotstrength may be reduced after large-volume gelatin infusions[11,12].

The dextrans are associated with more signicant haemo-static derangements [13]. In addition to simple haemodilutionof clotting factors, low-MW dextrans increase microvascular ow and have specic effects on several components of thehaemostatic system. Factor VIII activity is reduced [14], plas-minogen activation and brinolysis are increased [15], clotstrength is reduced [16] and there is impairment of plateletfunction. Red cell aggregation is also reduced with the lower-MWdextrans. In patients whose haemostatic function is normalprior to infusion, a maximum dose of 15 g/kg is oftenrecommended to avoid the risk of bleeding complications.

HES solutions have varying effects on haemostasis, whichare dependent on the MW of the HES molecule [17]. Although

conventional clotting indices are unaffected, high-MW HESproducts in particular have been reported to produce a coagulo-pathy and to be associated with increased blood loss. Impairedplatelet function and a von Willebrand-like syndrome havebeen reported and may explain these clinical ndings [18,19].Low-MW HES products have been shown to produce similar,but lesser, effects than the higher-MW products.

Interaction with endothelial and inammatory cells

Both HES and dextran solutions are recognized to interact withboth endothelial and inammatory cells. Dextran moleculesreduce postischaemic leucocyteendothelial cell interactionsand platelet adhesiveness. HES molecules have a similar,but less marked, effect. Pentastarch (HES pentafraction) isthought to exert more pronounced inhibition of endothelialcell activation and neutrophil adhesion [7]. Pentafraction is alsobelieved to have specic benets in retaining uid within thecapillaries, probably by physically plugging endothelialpores, in situations where capillary leak occurs [20]. Whether these pathophysiological phenomena have clinical impact isunknown at present.

Adverse drug reactions

All colloidal plasma expanders, including human albuminsolution and plasma protein fraction, are associated with asmall, but signicant, incidence of anaphylactic or anaphy-lactoid reactions. The colloid-specic incidence rates foundin two prospective studies [21,22] are reported in Table 4.

In these studies a severe reaction was a life-threateningevent, e.g. shock, life-threatening smooth muscle spasm, or cardiac or respiratory arrest. Only human serum albumin andthe two dextran products were associated with cardiac or

Table 3 Magnitude of plasma expansion of some commonly used colloids

Colloid solution

Plasma volumeexpansion of1 l at 90 min

COP50:COP10a

ratio

35% Haemaccel 02 l 018

6% Dextran 70 0708 l 025Hespan 0708 l 058

aThe molecular size distribution of a colloid in solution can be described as aratio of the measured colloid osmotic pressure (COP) across two membraneswith different pore sizes, e.g. the pressure across a membrane with a nominal50-kDa pore size compared with the pressure across a membrane with anominal pore size of 10 kDa: the COP50:COP10 ratio.


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respiratory arrest [21]. Fatal cardiorespiratory arrest has alsobeen reported with urea-linked gelatin (Haemaccel) [23].

The mechanisms of reaction vary. Preformed antidextranantibodies are present as a result of synthesis of dextransby Lactobacilli , which occur naturally as gut commensals.Dextrans can precipitate true anaphylactic reactions, the risk of which can be decreased 10-fold by pretreatment withmonovalent haptendextran. Indeed, the advent of Dextran1-hapten pretreatment has reduced the risk of anaphylacticevents with the dextrans to 00014200005% [24]. Whenused with hapten premedication, dextrans probably nowhave the best safety prole of all the colloid solutions.Dextran infusion, particularly of the high-MW products withmultiple branches, can also precipitate anaphylactoid-typereactions, but this is independent of their capacity to causehistamine release [25]. Histamine release is a predictableresponse to gelatin infusions and appears to be related to theanaphylactoid reactions that occur [26]. Urea-linked gelatin(Haemaccel) has been associated with a greater number of anaphylactoid reactions than the succinylated product. Since

1981, the cross-linking agent has been reduced subsequentto the polymerization step in an attempt to reduce the incid-ence of this problem [1]. The clinical impact of this change isas yet unclear. Anaphylactoid reactions occurring with HESinfusions are believed to be complement-mediated hypersen-sitivity [27].

Cost

See Table 5 for a summary of cost of the standard colloids.

Current uid controversies

The crystalloidcolloid controversy

Arguments over the best type of uid for volume resuscita-tion have raged for more than 30 years. While all sides agreethat uid resuscitation is fundamental in the management of hypovolaemia, there is disagreement as to which solutions

to use. Those who favour crystalloid uids, highlight thehaemostatic derangement, the signicant incidence of adversedrug reactions and the greater risk of intravascular volumeoverload that occurs with colloidal uids. Colloid enthusiastsfocus on the large volumes of crystalloid required to achieveadequate resuscitation and on the resultant tissue oedemaand reduction in tissue oxygen delivery. Numerous rand-omized controlled trials (RCTs) have attempted to address thisquestion in a variety of clinical settings, although none havebeen sufciently powered to consider mortality as an end-point. There have been three meta-analyses reviewing thisliterature with mortality as an end-point [2830]. The mostrecent of these focused on 19 RCTs, comprising a total of 1315 patients, and suggested an increased absolute risk of mortality of 4% with use of colloid for volume replacement(95% condence interval: 08%). However, these meta-analyses have been widely criticised for pulling together a largenumber of studies comparing a number of different solutionsamongst diverse patient populations, for varying indications.None of the original studies used mortality as a primary end-point; the vast majority of studies included were of albuminor dextran solutions and these two colloids contributed all of the excess mortality. In current UK practise, gelatin and HESproducts are the commonly used colloid solutions. At presentthere is a lack of adequate studies upon which to base a

judgement on this question and many clinicians continue touse colloids in combination with crystalloids.

Balanced versus unbalanced intravenous uids

A number of crystalloid and colloid solutions are availablethat, in an attempt to approximate the composition of thesolution to plasma, contain a number of components addi-tional to that of normal saline. These components include

Table 4 Incidence of anaphylactoid and anaphylactic reactions tocommonly used intravenous colloid solutions in two prospective studies[21,22]

ColloidRing & Messmer [21]Severe reactions (%)

Laxenaire et al . [22]Severe reactions (%)

Human albumin solution 00033 0099Dextran 60/75 a 00173 0273Dextran 40 00019 0273Haemaccel 00488 0345Gelofusin 00166 0345Hydroxyethyl starch 00061 0058

aFive different products of varying weights.NB: Rate of serious reaction to penicillin = 001005%.

Table 5 Cost of commonly available colloid plasma expanders andcrystalloids

Colloid solution Volume (ml) Cost ()

Haemaccel 500 371Gelofusin 500 463Dextran 40 in saline 500 478Pentaspan 500 1125Hespan 500 1630Elo-Haes 500 1250Human albumin solution 45% 500 4644Human albumin solution 20% 100 412809% Saline 1000 0465% Glucose 1000 046Lactated ringers 1000 056


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inorganic ions such as calcium, potassium or magnesium,molecular glucose and buffer components commonly bicarbonate or lactate. The theoretical advantages of balanced solutions are the prevention of dilutional reduction of normal plasma components, such as calcium and potassium,and the avoidance of a hyperchloraemic acidosis. High-

volume administration of sodium chloride has been demon-strated to produce a hyperchloraemic acidosis relative to agroup receiving Plasmalyte 148 an isotonic balanced crys-talloid solution containing potassium, magnesium and bicar-bonate in the form of acetate and gluconate [31].

Balanced crystalloids, such as compound sodium lactate(Hartmanns solution), have been in clinical use for many

years but there is little literature comparing them with 09%saline solution. Colloids presented in balanced solutions haveonly recently been developed and trials are currently under-way to examine whether clinical benet can be demonstratedwith their use. Early work suggests that the haemostaticimpairment associated with HES infusion may be lessened

when the starch is presented in a glucose-containing, lactate-buffered balanced solute [32].

Albumin and plasma-protein fraction

Human albumin is a naturally occurring monodisperse col-loid. The various preparations of plasma proteins in solution(FFP, plasma-protein fraction, etc.) are a more polydispersehuman-derived colloidal solution with signicant amountsof higher-MW proteins the globulins. Human-derivedcolloid has a number of signicant disadvantages. These areexpensive products and concerns have been raised abouttransmission of infectious agents such as vCJD disease asso-ciated with BSE. A recent meta-analysis suggested thatadministration of human albumin in the critically ill may increase mortality [33]. However, this analysis includedstudies looking at albumin use for both hypoalbuminaemia(which is not common current clinical practice in the perio-perative setting) and hypovolaemia. Use of albumin in themanagement of hypovolaemia is also relatively uncommonowing to the high cost and because the semisynthetic colloidsare believed to be at least as effective. This analysis looked ata number of studies, half of which showed benet for thisindication, in widely divergent populations, and does notprovide a clear message to inuence clinical practice. Rather,it suggests the need for a well-designed RCT with appropriateoutcome goals.

The role of hypertonic solutions

In recent years, hypertonic (6001800 mosml 1) crystalloidand colloid solutions have been introduced for certain clin-ical indications. The theoretical advantage of these solutionsis that a small volume of administered uid will provide a

signicant plasma volume expansion. The high osmolarity of these solutions draws tissue uid into the intravascular spaceand thus should minimize tissue oedema for a given plasma

volume increment. In the perioperative setting, literature onuse in humans is limited [34]. Hypertonic crystalloids andcolloids presented in a hypertonic saline carrier have beenshown to achieve adequate resuscitation in a number of clin-ical settings. A smaller volume of hypertonic solution is norm-ally required to achieve similar plasma volume expansion.In particular, these solutions are thought to result in reducedcerebral oedema in those patients at risk of this complicationand indeed these solutions may have a place in treatingrefractory cerebral oedema. Outside the perioperative arenathey are nding use in the management of patients with burnsinjuries and in prehospital resuscitation of trauma victims [35].They are limited, at present, to single-dose administrations.

Blood

Transfusion policies have become more restrictive over thelast few years. The results of a large clinical trial in criticalcare patients seem to back up this restrictive approach [36].

As a result, the use of blood as a resuscitation uid hasdeclined. There are many other reasons for this decline, suchas increased cost, especially with the advent of leucodeple-tion, concerns over immunosuppression and increased ratesof infection and malignancy following transfusion.

Blood substitutes: haemoglobin solutions

Blood substitutes as resuscitation uids are at an early stageof development and probably some way from routine clinicaluse. Early trial results are mixed and predominantly based ondiaspirin cross-linked haemoglobin (DCLHb). They rangefrom a reduction of erythrocyte transfusion in cardiac sur-gery patients, but with little measurable clinical benet [37],to less favourable results in trauma and ischaemic strokepatients [38,39]. Indeed, the development of DCLHb has beenstopped based on two unsuccessful trials in trauma patients.In the future, however, it is probable that the use of articialor semisynthetic oxygen-carrying solutions will becomeincreasingly common. A number of products are currently under development, including modied human Hb, modiedbovine Hb, recombinant Hb solutions and the perouro-carbons [40,41]. These products not only function as oxygencarriers but are also capable of sustained plasma volumeexpansion. Unlike Hb present in intact red cells, these prod-ucts often have a linear O 2Hb dissociation prole and theeffects of this on O 2 uptake in the lungs and release in thetissues have not yet been clearly dened. Additionally, they may have specic pharmacological effects nitric oxidescavenging resulting in vasoconstriction is a well-recognizedexample.


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ConclusionThe clinical trial data does not support the concept of atherapeutic advantage for either crystalloids or colloids, despiteclaimed theoretical advantages for both classes of uid. Thecolloid solutions currently available have quite distinctproles of activity, both in terms of their plasma volumeexpansion prole and other physiological and pharmacologicalproperties. Recent data suggests that physiologically balancedcrystalloid and colloid solutions may improve clinical outcomeswhen compared with saline-based uids.

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