Pharmacological characteristics of artificial colloids
K A R L - E . A R F O R S PhD, Med. Dr.h.c.
Adjunct Professor Department of Surgery, RW Johnson Medical School, New Brunswick, UMDNJ, New Jersey's University ~?f Health Sciences, NJ 08903, USA
P E T E R B. BUCKLEY PhC, MRPhamS Director Medical~Technical Services, Medisan Pharmaceuticals AB, AR4. S-741 74 Uppsala, Sweden
Water binding colloids (albumin, dextrans, synthetically modified starches and gelatins) which are large enough to remain within the intravascular space play a key role in rational fluid therapy, generating sufficient colloid osmotic pressure gradient against the extra- vascular space to restore and/or maintain normal plasma volume. Apart from their value as plasma volume expanders (10% solutions of dextran or hydroxyethyl starch (HES)) or plasma substitutes (3-6% solutions of albumin, dextran, HES or, to a lesser extent, gelatin), some colloids (dextran and, to a lesser extent, HES) specifically improve micro- circulatory perfusion and prevent or attenuate potentially pathological sequelae of cascade activation after surgery, trauma and shock, particularly thromboembolism and ischaemia- reperfusion injury arising from leukocyte-endothelial interaction.
Although all the above colloids are generally well tolerated, high doses of dextran or HES (exceeding 1.5 g/kg) may interfere with haemostasis whilst gelatins may compromise immunodefence (fibronectin opsonizing function). Some protracted storage of persistent residues occurs after HES and rare renal complications have been reported after very high doses of 10% dextran, HES or albumin in dehydrated medical patients. Anaphylactic reactions also occasionally occur with all colloids, particularly after gelatins and dextrans, although hapten inhibition has now virtually eliminated the risk with dextran.
In acute major blood loss, rapid restoration of normal blood volume is a primary objective. In this respect, immediate survival is probably more related to the speed of volume restoration than to the nature of the fluid used.
There is convincing evidence, however, that the choice of fluid, particu- larly the colloid component, is a decisive factor in reducing later mortality and morbidity, not only in the acute, critical care scenario, but also in routine elective surgery (Tonnesen et al, 1977; Shoemaker et al, 1981; Haljam~ie,
1985). This chapter, therefore, reviews the clinical pharmacology of colloidal plasma substitutes, with particular reference to their effects on the pathophysiology of the clinical indications in which they are used.
VOLUME AS A VITAL ORGAN
Over several billion years of evolution, man's struggle for survival has selectively favoured mutants adapted to unexpected injury and moderate blood loss. Although most individuals can survive a 60% loss of red cell mass provided normovolaemia is maintained, relatively few can survive a 30% loss of circulating blood volume if hypovolaemia is not promptly corrected (Messmer, 1987). In acute blood loss, optimal fluid therapy is therefore aimed primarily at restoring intravascular volume. This implies that the ideal initial plasma substitute will contain sufficient osmotically active colloid to bind water within the intravascular space until the body's own resources can re-establish volaemic control.
HYPOVOLEMIA AND CASCADE ACTIVATION
If hypovolaemia is not adequately corrected in time, peripheral ischaemia and hypoxia, aggravated by soft tissue injury, surgical stress, sepsis, etc., will trigger a host of cascades orchestrated by cytokines and other inter- mediates released by activated, degranulating leukocytes, platelets and other cellular elements in the ischaemic microcirculation. Although most cascades are essentially defensive, the raw non-physiological nature of surgical inter- vention tips the delicate balance of homeostasis, generating a devastating pathophysiology of cascades, from complement activation to massive thrombogenesis (Bond et al, 1979; Amundson et al, 1980; Jacob et al, 1980; Barrett et al, 1983; Rowland et al, 1983; Braide et al, 1984; Haljam~ie, 1985a; Messmer and Arfors, 1988). In critical care or prolonged surgery, these events manifest as potentially lethal complications such as dissemi- nated intravascular coagulation (DIC), pulmonary embolism, adult respira- tory distress syndrome (ARDS) and multiorgan failure (Blaisdell et al, 1966; Carlin et al, 1980; Gervin et al, 1975; Risberg et al, 1991). Interaction between blood components and artificial surfaces (bypass circuits, acrylic cements, etc.) can also activate these cascades (Hammerschmidt et al, 1981; Bengtsson et al, 1987). In addition, restoration of blood flow to hypoxic tissues (as after aortic declamping, thrombolysis or organ transplantation) can inflict severe free radical ischaemia-reperfusion injury to cell membranes (Del Maestro et al, 1980; Parks et al, 1983).
OBJECTIVES OF RATIONAL FLUID THERAPY
It is evident from the above that the objectives of rational fluid therapy in both acute traumatic shock and elective surgery will include:
P H A R M A C O L O G Y OF A R T I F I C I A L C O L L O I D S 17
1. Restoring and maintaining intravascular, interstitial and intracellular fluid volumes (by judicious combinations of colloidal plasma sub- stitutes and physiologically balanced crystalloid solutions).
3. Correcting acid-base disturbances (by buffering). 4. Attenuating excessive activation of cascade systems, especially
thrombogenesis (by using dextran). 5. Preventing cell injury on reperfusion after ischaemia (by free radical
scavengers or agents reducing leukocyte-endothelial interaction). 6. Restoring and maintaining optimal oxygen transport capacity (i.e. a
haematocrit of approximately 30% in normovolaemic patients at rest) with packed red cells.
Colloidal plasma substitutes play a significant role in meeting four of the above objectives (numbers 1, 2, 4 and 5). The clinical pharmacology, specific advantages, limitations and safety of colloids are, therefore, discussed below, with particular reference to these specific objectives.
CURRENTLY USED COLLOIDAL PLASMA SUBSTITUTES
The colloids currently used in volume therapy are human albumin, the principal component of plasma proteins, and the artificial (exogenous) colloids dextran, hydroxyethyl starch (HES) and gelatin. Important characteristics of these colloids are presented in Table 1.
Table 1. Artificial colloids for plasma volume substitution.
* For some hydroxyethyl starch preparations with the same degree of substitution, molar and tandem substitution may vary somewhat with possible bearing on safety characteristics. t May be sold under other trade names.
18 K-E. ARFORS AND P. B. BUCKLEY
Both albumin and dextran are unmodified, naturally occurring colloids (dextran is found in some foods, beverages and dental plaque), whereas HES and the gelatins are chemically modified (semi-synthetic) derivatives of amylopectins and polypeptides respectively. HES is synthesized by substituting hydroxyethyl groups into starch, whilst gelatins are generally modified by cross-linking. All four colloids are used extensively in Europe; gelatin, however, was withdrawn by the US FDA in 1978 as unsafe after an extensive review of the modem literature (Federal Register, 1978). Dextran is by far the most documented of artificial colloids (over 13 000 original papers). For this reason, much of the following discussion on artificial colloids is exemplified by reference to research on dextran.
Unlike albumin, which is a monomer (where all molecules have the same size and weight; about 68 kDa), dextran, HES and gelatin are polymers containing mixtures of differently sized molecules, each composed of basic repeating units, which, for the polysaccharides, dextran and HES, are glucose (predominantly 1-6 and 1--4 linked units respectively) and, for gelatin, are peptides (Figure 1). Since any sample of a polymer will contain molecules of different sizes, ranging from very small molecules that may easily leak from the intravascular space to very large molecules that may interfere with coagulation, cross-matching, etc., it is important that the molecular characteristics of polymers, including the degree and pattern of any substitution (Trieb et al, 1995), are well defined and the products are of consistent, reproducible quality.
The relative proportions of differently sized molecules in a polymer can be visualized in molecular weight distribution curves as shown in Figure 2. The horizontal axis is molecular weight and the vertical axis gives the relative proportion of molecules within a given molecular weight interval.
-OH2
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It H
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PHARMACOLOGY OF ARTIFICIAL COLLOIDS 19
CH2- O-CHuCH2-OII
c.~-o. I I cH~ 16 H OH 16
, ,
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H O-CH2-CH2-OH H OH
I c = o Peptide chain c = o I NH O O NH I II II
HC-(CH2)4- NH + CN-R-NC + HN- -CH2-CH I H I II C=O \\ / I N Nil I
Peptide chain
c = o Peptide chain HN OH 0 0
/ tl II HC (CH~)~-CH-CH2- NH~+CN- R- NC + NH2
I C O CHR
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I I C=O C=O I I NH O O NH I I1 II I
HC- CH2)~- N - C - N - R - N - C - N- -CH:~-CH 1 H H H I C=O \\ / C=O I N 1 NH HN OH 0 0
I t II II HC- {CH~)~-CH-CH~-N-C- N- R - N - C - N H
I H H H I C=O CHR 1 I
NH C =O I t
NH I
Figure 1. Chemical structure of dextran, HES and gelatin plasma substitutes.
Such curves are useful because they give much more accurate descriptions of the distribution of molecular sizes in different polymers than, for example, the weight (MW) or number (MN) average molecular weights. They also enable one to estimate what proportion of a given polymer lies under or over certain critical limits (such as the renal filtration threshold; depicted in Figure 2).
2O
I A B C
K-E. ARFORS AND P. B. BUCKLEY
4 ! x Urea-linked gelatin
o Dextran-40
• Dextran-70
Q Hydroxyethyl starch 200/0.5
3 a Hydroxyethyl starch 450/0.7
~ / A l b u m i n
2
1 ,
1 I
0 0 50 100 150 200 250
MW (kDa)
Figure 2. Differential molecular weight distribution of different colloid plasma substitutes. (A) Renal filtration occurs unhindered below indicated molecular weight. (B) Upper renal threshold for dextran. (C) Upper renal threshold for HES 450/0.7. Reproduced from Arfors and Buckley (1989) with kind permission of K. Granath, A. de Belder and W. Zuckswerdt Verlag.
COLLOIDS AND INTRAVASCULAR VOLUME
One of the most important basic requirements of a plasma substitute is the provision of relatively stable volume support to replace lost blood or plasma until the body's own resources can re-establish volaemic control. The ideal plasma substitute will thus contain sufficient colloid to replace the water-binding capacity of lost plasma proteins without unduly dehydrating the extravascular space.
Plasma normally contains about 7.3% protein, mainly albumin (4.5%), which is principally retained within the intravascular space by the confines of semi-permeable glomerular and capillary membranes. The latter separates about 3.5 1 of protein-rich plasma in the intravascular space from some 10.51 of relatively protein-poor fluid in the interstitial space (Figure 3).
Although the capillary membrane between these two fluid compartments permits free exchange of water, electrolytes, nutrients and smaller macro- molecules up to molecular weights of about 5 kDa (Rutili and Arfors, 1976; Arfors et al, 1979; Haraldsson et al, 1982; Ley and Arfors 1986), it progressively restricts the diffusion of larger macromolecules and is less permeable to those above 25-30 kDa (Grotte, 1956). This upper threshold varies somewhat with the shape, flexibility ('reptation'), and charge of the
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 21
TBV 60% 421
Total body water in 70 kg man
1/3//~2/3
ECV / 20% 141 [
Extracellular water [
Plasma Interstitial volume volume
,ov I 40% 281 Intracellular water
Figure 3. Body water distribution in a 70kg man. After Arfors and Buckley (1989, The Role of Hemodilution in Optimal Patient Care) with permission of W. Zuckswerdt Verlag.
macromolecule (Haraldsson et al, 1982), the location of the capillary bed (Ley and Arfors, 1986) and the extent to which permeability is increased by trauma, shock, local acidosis, inflammation (Arfors et al, 1979) or sepsis (Ellman, 1984). As a rule, neutral colloids such as HES and dextran pass more easily through capillary (and renal glomerular) membranes than do polyanions such as albumin (which are repelled by the negatively charged, endothelial glycocalyx and wall-adsorbed plasma proteins) (Haraldsson et al, 1982).
Normal capillary permselectivity appears to be dependent upon the presence of certain serum constituents, such as orosomucoid, which inter- act with the capillary wall. Albumin clearance, for example, is almost four times higher during perfusion with albumin solutions than during perfusion with serum (Haraldsson, 1986). Some macromolecular flux also occurs by unselected convection through a few very large 'leaks' (or intercellular gaps) whose effective diameter is some 500-1000 A (Haraldsson, 1986; McDonald et al, 1996). In most capillary beds, the fraction of transcapillary filtration that occurs by bulk flow through large pores is only 10-20% (Taylor and Gaar, 1970), but in the lungs it may be at least 30% (McNamee and Staub, 1979; Parker et al, 1981).
Indeed, the lungs exhibit exceptionally high colloid permeability and filtration rates even under normal (non-shock) conditions (a lymph:plasma protein ratio of 0.6-0.8, compared with 0.3 in skin or skeletal muscle) (Taylor and Gaar, 1970). This is generally of no consequence since pulmonary lymph drainage is also exceptionally effective (Zarins et al, 1978). For this reason, shock-induced permeability changes to plasma proteins and other colloids are more critical in the skin and muscle than in the lungs. In the later stage of severe traumatic shock or sepsis, however, massive trapping of activated leukocyte/platelet/fibrin microemboli in the
22 K - E . A R F O R S A N D P. B. B U C K L E Y
lungs inflicts serious free radical injury on the pulmonary microvasculamre. At this stage the colloid leak reaches such proportions that the lymph drainage is overwhelmed and pulmonary interstitial oedema and ARDS develop (Tate and Repine, 1983; Modig, 1986a; Risberg et al, 1991).
As implied above, capillary permeability to colloids can increase considerably in shock, burns, inflammation, etc., often in response to inter- mediates such as histamine, bradykinin or prostaglandins (Arfors et al, 1979). Interestingly, this colloid leak usually first develops in the post- capillary venules (where lower hydrostatic pressure possibly homeo- statically minimizes intravascular colloid losses) (Nakamura and Wayland, 1975; Arfors et al, 1979; Schmidt et al, 1993). Although currently approved intravenous colloids are far too small to seal capillary pores or intercellular gaps, it has been suggested that very large colloid molecules may partially obstruct smaller pores, as implied in some studies on endotoxic shock and other inflammatory models using narrower non-commercial fractions of HES--pentafraction, (molecular weight 100-1000 kDa (Zikria et al, 1989, 1990; Webb et al, 1991; Schnell et al, 1992; Traber et al, 1992; Tanaka et al, 1993) or dextran (molecular weight 150-500kDa (Zikria et al, 1989; Schmidt et al, 1993) when refraction coefficients of 0.82 and 0.85 respectively were reported. It is more likely, however, that this 'sealing' phenomenon can be ascribed to high colloid osmotic pressures generated by the concentrations of the colloids used counteracting leakage from the microcirculation.
Under normal conditions, however, albumin (molecular weight 68 kDa) and other larger colloids are generally retained within the intravascular space where they generate a colloid osmotic (oncotic) pressure (COP) against the adjacent interstitium. The volume of the intravascular space is thus principally maintained by the COP generated within it by the presence of excess non-permeable colloid in accordance with Starling's equilibrium. The magnitude and duration of this volume effect will depend on:
1. how much of the infused colloid stays in the intravascular space; 2. the specific water-binding capacity of the colloid in question.
The former can be roughly estimated from the molecular weight distri- bution curve for the colloid concerned, provided that both capillary and renal thresholds for that colloid are known. For neutral colloids, the glomerular thresholds are very similar (approximately 55 kDa for dextran and approximately 65kDa for HES) (Arturson and Wallenius, 1964; Metcalf et al, 1970; Weidler and Sommermeyer, 1992), and no secretion or reabsorption appears to occur from or into the tubule lumen (Chang et al, 1975). This is illustrated in Figure 4 by plasma persistence studies on a range of narrow fractions of dextran (Arturson and Wallenius, 1964). Dextran 18kDa disappears rapidly (less than 10% is left after 1 hour), whereas most of the 55 kDa fraction remains in circulation for at least 6 hours. It should be borne in mind, however, that in clinical situations involving hypovolaemia or trauma, capillary permeability may be increased while renal losses may be reduced as a result of low renal perfusion, ADH release, etc.
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 23
e -
~ 100 80 6o
0
4o 0 ¢ -
20 i n
E
f f l
. m
,- 5
MW 55-69 kDa
2
MW 28-36 kDa
MW 18-23 kDa I I I I I I
0 1 2 3 4 5 6
Time after dextran injection (hours)
Figure 4. The disappearance of different molecular weight fractions of dextran from serum after intra- venous administration in normal humans. After Arturson and Wallenius (1964).
A glance at the molecular weight distribution curves for dextrans, HES and gelatin (see Figure 2) shows that some 60% of dextran-70 and around 35 % of dextran-40 lie above the upper renal threshold for dextran (approxi- mately 55kDa) (Granath and Str6mberg, 1968; Granath et al, 1969; Nilsson, 1981). These portions will thus remain in the intravascular space until sequestered in the liver and broken down by endogenous dextranase.
Although initially some 80% of HES 450 and 70% of HES 200 lie above the renal threshold for HES (approximately 65 kDa), molecules with a degree of substitution below 0.5-0.6 are fairly rapidly cleaved by circulat- ing amylase so that, in contrast to dextran, the average molecular weight of circulating HES is soon reduced (Weidler and Somermeyer, 1992). Although such cleavage facilitates renal clearance of high molecular weight HES, it can also temporarily increase the number of circulating colloid molecules and thus generate a corresponding increase in COP, which later subsides as further cleavage permits renal clearance (K6hler et al, 1978).
As Figure 2 indicates, some 80% of the molecules in a typical gelatin preparation are smaller than 20 kDa (Granath and Str6mberg, 1968). Since these are rapidly excreted renally, gelatin solutions have an inadequate volume effect. Unfortunately, higher molecular weight gelatins induce pronounced red cell aggregation, which prohibits their clinical use (Scholz et al, 1971).
Intravascular water binding of colloids
Every gram of circulating colloid in the intravascular space holds some 15-25 ml of water in circulation (Hint, 1968). Dextran retains about 20-25 ml per circulating gram, whereas gelatins and albumin hold about 14-15 ml/g. HES holds about 16-17 ml/g (over the first 4 hours), i.e. a
24 K-E. ARFORS AND P. B. BUCKLEY
3.0-3.5% dextran will have approximately the same volume effect as 4% HES (Lamke and Liljedahl, 1976; Arfors and Buckley, 1989; Hiippala et al, 1995). Thus the final volume effect of a given colloid depends upon both the amount of colloid circulating (after transcapillary/glomerular losses) and its specific water-binding capacity, rather than upon the concentration in which it is given. This is illustrated in Figure 5. One gram of dextran was given in two different ways (Hint, 1968): either as 50 ml of a 2% dextran solution, or as 5 ml of a 20% dextran solution. After a period of stabiliza- tion, the increase in plasma volumes was the same in both cases because in both examples the same amount of dextran had been given.
E
t ~
E t ~
~6 I1) f f l
¢3 e -
50
4° f 2O
10
0 0
Q
I I I I I
60 120 180 240 300
Time (minutes)
Figure 5. Changes in plasma volume after infusion of dextran-40 (1 g of substance/kg). Upper curve infused as 50 ml/kg of 2% solution; lower curve infused as 5 ml/kg of 20% solution. After Hint (1968).
These basic principles also hold in clinical practice. Figure 6 shows the effect of infusion of 1000ml of different plasma substitutes in hypo- volaemic post-operative patients (rather than normovolaemic volunteers) (Larnke and Liljedahl, 1976). The volumes illustrated are the plasma volume increases still remaining 1.5 hours after infusion. Both 6% dextran- 70 and 6% HES 450 provide reliable volume support for this period of time. There is, however, no statistical difference between the volume effect of saline and gelatin after 1.5 hours, which makes gelatin a rather expensive saline solution.
In some indications, hypercolloid-osmotic (e.g. 10%) solutions of lower molecular weight colloids, such as HES 70, HES 200 or dextran-40, are preferred. Although 10% solutions contain almost twice as much colloid as 6% solutions, the volume advantage is relatively short lived since they contain greater proportions of small, more rapidly excreted molecules. This is exemplified in Figure 7, comparing volume effects of 10% dextran-40 with 6% dextran-70 over time.
25
E =~ 500
1 2 3 4 5
PHARMACOLOGY OF ARTIFICIAL COLLOIDS
1000
Figure 6. Plasma volume restitution after infusion of 1000 ml of (1) dextran-70 (Macrodex), (2) hydroxyethyl starch (Volex); (3) albumin (Albumin Kabi), (4) polygelatin (Haemaccel), and (5) physiological saline. After Lamke and Liljedahl (1976).
Figure 7. Volume expansion changes following single infusions of 10% dextran-40 or 6% dextran- 60/70 expressed in percentage of given volume as a function of time. The infusion rate was less than 30 minutes. Each symbol represents data obtained from one study. After Arfors and Buckley (1989, The Role of Hemodilution in Optimal Patient Care) with permission of W. Zuckswerdt Verlag.
COLLOIDS AND MICROVASCULAR PERFUSION
Failure to promptly restore adequate nutriative microcirculatory flow to essential organs is the primary lesion in prolonged hypovolaemia and shock and the principal cause of delayed complications. Indeed, hidden perfusion defects in the splanchnic microcirculation during hypovolaemia are probably the primary cause of translocation of endotoxins from the gut, which, in turn, can trigger cascades leading to ARDS and multiple organ failure. Let us therefore examine more closely the effect of plasma sub- stitutes on flow and blood viscosity. First, it is important to bear in mind the basic elements of Poiseuille's law: that the flow of fluid through a tube is directly proportional to the fourth power of the radius and inversely proportional to viscosity. Flow is, of course, also proportional to the driving pressure head P1-P2:
26 K - E . A R F O R S A N D P. B. B U C K L E Y
k r 4 (P~- P2) F=
visc
Thus a doubling of the effective vessel radius will increase blood flow 16-fold whereas halving the blood viscosity will only double the flow.
Hypovolaemia, surgical stress, ischaemia and reperfusion generally induce tissue oedema and endothelial cell swelling in the micro- circulation, both of which tend to reduce effective vessel radius.
When hypercolloid-osmotic solutions such as 10% dextran or HES are infused, they draw water from peri-capillary tissue, relieving extravascular pressure on the microcirculation and thus improving perfusion. A combi- nation of hypertonic saline and colloid, such as 7.5% NaC1 in 6% dextran- 70, reinforces this effect, preventing or reducing endothelial cell swelling and thus effectively increasing vessel radius and thereby improving flow (Mazzoni et al, 1990). Dextran, and to a lesser extent HES, further promotes microcirculatory perfusion by preventing excessive leukocyte sticking and narrowing of the microvessels (see Figure 15 below). At the same time, colloids improve driving (hydrostatic) pressure by increasing volume and cardiac output (Shoemaker, 1976).
Blood is a non-Newtonian fluid like non-drip paint or tomato ketchup: the slower it flows, the thicker it becomes. In shock and other low flow states, apparent blood viscosity is thus higher than normal, and this raises peripheral resistance to heart work. This is particularly marked at low shear rates, as in the venules and small veins, where some 70% of the circulating blood volume is normally located (Wiedeman, 1963; Intaglietta, 1989).
Another factor that increases blood viscosity is red cell aggregation, a characteristic feature of low-flow states such as in shock and anaesthesia. In vitro aggregation can be induced by most colloids as molecular weight and concentration are increased (Hint, 1968; Arfors and Buckley, 1989). With gelatins, in vitro aggregation begins at molecular weight 25 kDa but does not become a clinical problem until average molecular weight exceeds 40 kDa. This radically restricts the use of this colloid for volume therapy since effective concentrations of molecules large enough to stay in circu- lation cannot be used clinically. For dextrans, in vitro red blood cell aggre- gation begins at around 75 kDa but because weak aggregates are easily disrupted by blood flow (and higher shear rates generated by volume expansion) the effect has little or no clinical significance unless molecular weight exceeds 150kDa. Dextrans below molecular weight 50 kDa have the reverse effect, preventing aggregation and promoting red cell mono- suspension and improving blood flow. The threshold for spherical molecules such as HES is higher than for dextran, which permits the use of higher molecular weight fractions in vivo up to 400 kDa.
Red blood cell aggregation may also be induced by raised concentrations of plasma fibrinogen or other large macromolecules. Although, historically, pseudoagglutination of red cells has sometimes disturbed cross-matching after high doses of colloid, this is no longer a significant problem with modem clinically approved fractions of HES, dextran or gelatin at recom- mended doses.
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 27
TISSUE PERFUSION AND SURVIVAL
In shock, a return to normal tissue perfusion also normalizes total body oxygen consumption. Indeed, oxygen consumption has been shown by Shoemaker and others (Edwards et al, 1988; Shoemaker and Appel, 1988) to correlate well with survival in shock and is therefore a pertinent parameter to follow. Figure 8 summarizes the changes in oxygen con- sumption monitored in a study by Davidson et al (1980) in dogs that were subjected to laparotomy to expose the gut to the air for 3 hours. The gut was then returned and various plasma substitutes were given to treat the hypo- volaemic shock. This model was designed to mimic the kind of soft tissue injury that can occur during volvulus or prolonged surgery under warm theatre lamps. During exteriorization of the gut, capillary permeability changes occur which result in leakage of albumin out of the intravascular space (and possibly mucosal dysfunction with endotoxin translocation). COP falls and hypovolaemia develops, causing shock. Note that all the colloids were given in the same concentration: as a 3.5% solution. As is evident from Figure 8, dextran-40 almost normalized oxygen consumption, as did dog albumin. The control dogs (C) were only anaesthetized. Group N underwent laparotomy and the gut was returned after 3 hours, but no volume substitute was given. The other groups shown received either plasma (P), Ringer's lactate (R) or gelatin (G).
t -
t - O
E O9 c- O 0
7
6
5
4
3
0
i i ~ i i c ' ' O , , . _ O
' ' 3 , ' ~ i i I I I ' - - I I t I
0 I 2 3 4 5 6 7 Time (hours)
Figure 8. Changes in oxygen consumption during 3 hours of shock in 60 dogs and after infusion of different plasma substitutes (mean + SEM). D 40, dextran-40; Alb. (COHN) and (PEG), albumin Cohn and PEG; C, non-shocked control; D 70, dextran-70, E ACD plasma; R, Ringer's lactate; G, gelatin; N, shocked but non-treated. Reproduced from Davidson et al (1980, Critical Care Medicine 8: 75-82) with permission.
28 K-E. ARFORS AND P. B. BUCKLEY
Figure 9 is from the same study. The horizontal axis reflects skeletal muscle capillary flow measured with xenon-133, the other axis oxygen tension in the skeletal muscle. Values for the control animals and the shocked animals were first shown to lie within the ringed areas marked control and shock respectively. The shocked animals were then infused with the same plasma expanders prepared as 3.5% solutions. Only two solutions, dextran-70 (D) and dextran-40 (M), restored values to control levels.
80
-1-~m 60 ~ C E E ontrol g4o c~ A ~ ' - ~ - " ' ~
a. 20 Shock
0 i f ,
0 10 20 30 40 Qxe (ml/min/100 g)
Figure 9. Skeletal muscle oxygen tension (PmO2) in relation to skeletal muscle capillary flow measured with xenon 133 (Q~o) 1 hour after the start of therapy. The letters indicate the mean effect in the different groups. D, dextran-40; M, dextran-70; E, albumin PEG; A, albumin Cohn.; P, plasma; G, gelatin; R, Ringer's lactate; N, shocked non-treated. Reproduced from Davidson et al (1980, Critical Care Medicine 8: 75-82) with permission.
The effects of various plasma substitutes on microcirculatory flow can also be compared by measuring the improvement in collateral flow around an arterial occlusion. This was performed in dogs by Moraes et al (1967), who clamped the iliac and sacral arteries after measuring aortic flow with an electromagnetic flowmeter. The increase in collateral flow to the lower extremities after 100 ml of different plasma substitutes is presented in Figure 10. This increase was only highly significant for 10% dextran-40, which practically restored normal perfusion to distal tissue as a result of the dramatic increase in collateral flow.
Paradoxically, prolonged therapy with high doses of dextran and some variants of HES may increase in vitro plasma viscosity as lower molecular weight fractions are selectively excreted renally, leaving the larger molecules in circulation. Plasma viscosity, however, is a relatively minor component of in vitro whole blood viscosity and has been shown in in vivo animal studies to have no significant effect on perfusion or tissue oxygenation of vital organs (Bruckner and Messmer, 1991; Krieter et al, 1995). This is partly due to colloid-induced haemodilution, which reduces haematocrit, thereby reducing whole blood viscosity. Dextrans also prevent leukocyte sticking, one of the most important components in in vivo apparent viscosity (see Figures 14 and 15 below). Interestingly, substantial
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 29
100
o ~ 8O
0) "O
60 O O
g4o t -
O
~ 20
Blood Plasma Dextran-75 Heparin Saline Dextran-40
Figure 10. Increase in collateral flow around an acute arterial occlusion following infusion of differ- ent plasma volume expanders or heparin. Reproduced from Moraes et al (1967, Archives of Surgery 95: 49-53) with permission.
increases in plasma viscosity also occur in natural pregnancy, which implies that such changes are not physiologically detrimental.
COLLOIDS AND CASCADE SYSTEM ACTIVATION
Untreated hypovolaemic shock, acute trauma, and sepsis trigger a complex series of defensive cascades that have developed during evolution to maintain homeostasis and optimize survival. Although these cascades are invaluable in a primitive and hostile environment to minimize blood loss or fight infection, for example, their excessive activation in the controlled environment of intentional trauma (elective surgery) can induce un- desirable and potentially life-threatening complications.
The hypercoagulable state is one such homeostatic response to shock, trauma and surgical stress, which is associated with fatal complications such as pulmonary thromboembolism, shock lung (ARDS) or multiple organ failure (MOF). Complement activation in bypass circuits or occlusion of vascular grafts or stents are similar pathological extensions of the natural processes of defence and repair. Although colloids are often considered pharmacologically inert, dextran (and to a lesser extent HES) attenuates excessive activation of some of these cascades, and this property has been exploited clinically.
Thrombogenesis Dextran, for example, counteracts the hypercoagulable state induced by surgery and other trauma (Rosberg et al, 1977) and, in this connection, is the only plasma substitute shown to reduce the risk of post-operative
30 K - E . A R F O R S A N D P. B. B U C K L E Y
pulmonary embolism significantly (Bergqvist, 1983; National Institutes of Health, 1986; Clagett and Reisch, 1988) and ARDS (Modig, 1986b). Dextran is particularly effective in high-risk surgery and trauma, such as fractures, total hip replacement and re-operations (Agolini et al, 1978; Bergqvist, 1983; Ljungstr6m, 1983a; National Institutes of Health, 1986; Clagett and Reisch, 1988). Since dextran counteracts the initial phase of thrombus formation (the 'white' mural platelet thrombus), whereas heparins primarily prevent its extension as a 'red' floating ribbon, a judicious combination of both agents may optimise protection (Bergqvist, 1992; Matthiasson, 1994). Recent studies indicate that combination of subcutaneous low molecular weight heparin with intravenous dextran at recommended doses does not significantly increase the risk of bleeding (Matthiasson, 1994; Matthiasson et al, 1994; Hjertberg et al, 1995).
The ability of dextran to both attenuate excessive platelet adhesiveness and improve macro- and microcirculatory flow has also been shown in a major l 1-centre controlled trial to provide significant protection against early graft occlusion in difficult vascular reconstruction (Rutherford et al, 1984; Rutherford and Jones, 1988). This same combination of properties appears to account for its protective value in a range of indications from microvascular/plastic (flap) surgery (Wolfert et al, 1992; Rothkopf et al, 1993) to cerebral embolism (Laha et al, 1980), and in preventing excessive platelet adhesion (and risk of microembolism) in balloon angioplasty (Pasternak et al, 1980) and stent implantation (Palmaz, 1989; Fernandez- Aviles et al, 1996). Interestingly, the ability of dextran to suppress thrombo- genesis appears to be independent of the effects on haemodilution and improved haemodynamics, since comparative doses of albumin or crystalloid have little or no effect in reducing thrombus weight in a rabbit aorta model (Figure 11) (Frost-Arner and Bergqvist, 1995) or in preventing platelet deposition on to Dacron or PTFE graft surfaces (Shoenfeld et al, 1987). This anti-platelet effect also makes dextran the drug of choice in treating heparin-induced platelet aggregation and thrombocytopenia (Sobel et al, 1986; Bell, 1988).
Unlike heparin, dextran is not an anticoagulant. Its ability to suppress thrombogenesis is principally related to its moderating effect on platelet hyperactivity and factor VIII (Bergentz, 1978), both of which rise character- istically in the hypercoagulable state associated with surgery and trauma. The mechanism by which dextran suppresses thrombogenesis is summarized in Table 2. Dextran seems to be more effective in preventing pulmonary embolism than deep vein thrombosis (National Institutes of Health, 1986; Clagett and Reisch, 1988), which may be partly explained by its effect on the fibrin structure. Electron micrographs of fibrin formed in the presence of dextran (Tangen et al, 1972) reveal that the fibrin fibres are coarser and more easily lysed than normal. The clot is thus more fragile and probably disinte- grates into small microemboli before it reaches the lungs. Apart from modifying fibrin structure, dextran also increases fibrinolysis (which is often impaired after trauma) by potentiating plasminogen activation (Carlin et al, 1980; Miller and Lira, 1985; Eriksson and Saldeen, 1995). This activation of tissue plasminogen activator may also partly account for the protective effect
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 31
¢-
0 3
t..O
,.Q
E 0
I -
0.15
0.10
0.05
-r"
I I Control Dextran Albumin
Figure 11. Effects of treatment with crystalloid (control), dextran, and albumin on thrombus weight in a rabbit aorta model. Reproduced from Frost-Arner and Bergqvist (1991) with permission.
Table 2. Factors contributing to prevention of thromboembolism by dextran.
1. Reduced blood viscosity--haemodilution increases blood flow, especially in veins 2. Reduced platelet activity 3. Reduced plasma level of factor VIII: RAg / 4. Change in fibrin structure Enhance fibrinolysis
5. Potentiated plasminogen activation 6. Reduction in plasma fibrinogen levels 7. Coating of vascular endothelium and blood cells
of dextran against shock lung or ARDS (Modig, 1986b). Since most surgical patients require both volume support and thrombosis prophylaxis, dextran is a rational fluid choice in many fields of surgery.
Although HES also alters fibrin morphology and reduces factor VIII and platelet activation to some extent, particularly variant 200/0.62 (Stump et al, 1985; Haas, 1992; Kuitunen et al, 1993), there is no convincing clinical evidence that it reduces post-operative thrombo-embolism (Arrants et al, 1969).
32 K-E. ARFORS AND P. B. BUCKLEY
Gelatins have also been reported to disturb fibrin polymerization but provide no known protection against thromboembolism (Mardel et al, 1996).
Effects on white b lood cells
Some elements of the hypercoagulable state are partially regulated by monocytes, which are crucial to the balance between fibrinolysis and coagulation (Craddock et al, 1977; Chapman et al, 1983; Sch6tt et al, 1987). Apart from their established role in phagocytosis, they also play a key role in maintaining the balance between generation of regulatory (i.e. suppression) immune function and helper immune function (Miller, 1981; Unanue, 1981; Webb and Nowowiejski, 1981). After severe injury and burns, a number of monocyte dysfunctions have been identified which appear to precede and predict both infectious episodes and coagulopathy (Miller et al, 1981, 1982). Interesting findings from a comparative clinical trauma study in San Francisco suggest that in this scenario, too, early addition of dextran to the fluid regime counteracts monocyte dysfunction and the related imbalance between coagulation and fibrinolysis (Figure 12) (Miller and Lim, 1985).
In poorly perfused tissue, secondary to hypovolaemia or arterial stenosis (as in shock, peripheral vascular disease or stroke), hypoxia triggers other
Figure 12. Effects of moderate trauma and resuscitation with ~ or without ~ dextran on the monocyte-regulated balance between control thrombogenesis and thrombolysis [-~], Control. After Miller and Lim (1985).
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 33
cascades that increase the adhesiveness and rigidity of circulating leuko- cytes. These hyperadhesive leukocytes impair flow in post-capillary venules and play a far greater role in further reducing microvascular flow than do concomitant changes in plasma viscosity or red cell flexibility (Chien, 1987), virtually dOubling the resistance to microcirculatory flow despite the fact that leukocytes comprise far less than 1% of all blood cells. (Figure 13).
e5 13_ E
.-_>" 4 O o '7
2 O_
<
ARTERIAL ~ i VENOUS I I I
With leukocyte adhesion I \ I
I No leukocyte adhes ion I
0 I I t i t i | t i t I I I 70 60 50 40 30 20 10 20 30 40 50 60 70
Microvesse l luminal d iameter (IJm)
Figure 13. Arteriovenous distribution of apparent viscosity as a function of microvessel diameter with and without leukocyte adhesion to vascular endothelium. After Chien (1987).
Elegant intravital studies on haemodilution in controlled ischaemia (Thierjung et al, 1988) have shown that both dextran and HES reduce leukocyte sticking under ischaemic conditions and that this effect is statistically more pronounced with dextran than with HES (Figure 14) (Menger et al, 1989, 1993; Nolte et al, 1991, 1992; Menger, 1995; Steinbauer et al, 1996; Werner et al, 1996). These new findings could explain the well-established protective value of dextran in a wide range of ischaemic states, from threatening gangrene (Bergan and DeBoer, 1970), aortal clamping (Ekl6f et al, 1981) or acute pancreatis (Werner et al, 1976) to acute acoustic trauma (loss of hearing) (Kellerhals et al, 1971). They also support other evidence indicating that dextran prevents trauma/sepsis- induced pulmonary colloid leak (and ARDS) by reducing the 'rolling' and 'sticking' of hyperactive granulocytes onto the pulmonary endothelium (Figure 15) (Shasby et al, 1983; Fox, 1985; Modig, 1988).
Several groups have shown that this 'margination' is a pre-condition for granulocyte-mediated free radical injury to endothelial cells (Curtis et al, 1993). The injured cells appear to contract and open intracellular gaps that permit the massive colloid 'leak' characteristic of ARDS (Figure 16) (Martin, 1984). Although free radicals seem to play a key role in the patho-
34 K-E. ARFORS AND P. B. BUCKLEY
100
80
60
40
20
CON HSS HES Dx60
o O
E
0~ t -
"O <
HES*
/ / / J
Dx70*
Figure 14. Summary of data from the literature reporting leukocyte adhesion in the post-capillary venules of striated muscle (in percent of non-treated controls). CON, control following 4 hours of ischaemia and 30 minutes of reperfusion. HSS, as CON + 4 ml/kg body weight 7.2% hypertonic saline (haematocrit 31%). HES, as CON + isovolaemic haemodilution with 6% HES 200/0.62 to a haemato- crit of 30%. Dx60, as CON + isovolaemic haemodilution with 6% dextran-60 to a haematocrit of 30%. HES* and Dx70*, as CON + non-dilutional microdose (3 mg/kg body weight) of 6% HES 200/062 or 6% dextran 70 respectively. After Menger (1995).
40
30
20
D = 5
10
0 PMA-activated granulocytes
Increase in lung weight (g)
J_ D = 5
PMA-activated granulocytes
+ dextran
Figure 15. Role of granulocyte activation on albumin leak in isolated lung. PMA: phorbol myfistate acetate. After Shasby et al 0983).
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 35
genesis of ARDS, most direct evidence of their harmful effects on cell membranes is associated with ischaemia-reperfusion injury, where oxygen- rich blood flow is suddenly restored to hypoxic tissue as, for example, after cardiac arrest and resuscitation, or after organ transplantation, thrombolysis or aortic declamping. Such reperfusion injury can be prevented by a wide range of free radical scavengers, including mono- and oligosaccharides such as glucose and mannitol. Some evidence indicates that dextran, also a polysaccharide, provides some protection against reperfusion injury in the brain (Safar et al, 1976; Lin et al, 1979) and in radiation injury (Bicher et al, 1977), which is also mediated by free radicals. No protection, however, was provided by HES (a substituted polysaccharide) in a similar cerebral reperfusion model (Ruiz et al, 1986). Dextran also appears to protect against the cardiotoxic effects of hypertonic saline (Brown et al, 1990; Weber and Bruch, 1993), whereas HES does not (Prien et al, 1993). These differences may be related to free radical scavenging by dextran (Weber and Bruch, 1993) or the converse--free radical generation by HES (Ruiz et al, 1986).
Important limitations and adverse effects directly related to the structural and pharmacological characteristics of colloids are briefly discussed below.
Anaphylaxis and antigenicity All intravenous colloids, including human albumin, can induce anaphyl- actoid reactions, the 'incidence' varying widely from region to region depending on local reporting rates and true local variations in pre- disposition or endemic antibody titres (Ring and Messmer, 1977; Messmer
36 K - E . A R F O R S AND P. B. B U C K L E Y
et al, 1980; West, 1980; Schoning et al, 1982; Renck et al, 1983; Ljungstr6m et al, 1988; Ljungstr6m, 1993; Laxenaire et al, 1994; Lorenz et al, 1994; Kreimeier et al, 1995). Most prospective studies suggest that the true incidence is highest with gelatins, particularly urea-linked gelatin, which in one recent limited series was associated with a 2% incidence of life-threatening histamine release despite pre-medication with anti- histamines (Lorenz et al, 1994). Other studies, however, suggest a some- what lower risk (about 1 in 500 patients), whereas for modified fluid gelatins the risk is about 1 in 1600 (Ring and Messmer, 1977; Schoning et al, 1982; Ljungstr6m, 1993; Laxenaire et al, 1994). The corresponding risk for dextrans without hapten inhibition is about 1 in 2500, but the intro- duction of hapten inhibition to block circulating antibodies to dextran has dramatically reduced the risk to less than 1 in 70 000 patients (Renck et al, 1983; Ljungstr6m et al, 1988; Ljungstr6m, 1993), which is less than that with human albumin (Ring and Messmer, 1977). The incidence of severe reactions to HES is of the same order of magnitude as for dextran with hapten when allowance is made for far lower reporting rates in Germany than Sweden (Ljungstr6m, 1983b).
Gelatin reactions have been associated with both histamine release (Lorenz et al, 1994) and circulating antibodies (Laxenaire et al, 1994), and most can be prevented by pre-injection of histamine receptor antagonists (Schoning et al, 1982; Lorenz et al, 1994).
The aetiology of HES reactions, however, is not yet established although antibodies have been reported in one case (Kreimeier et al, 1995). No effective prophylaxis is available.
Dextran reactions do not involve direct histamine release in man (Messmer et al, 1980), but this does occur in mice and rats, which (apart from NR Whistar rats) exhibit specific hypersensitivity to dextran and may thus invalidate experimental work on small rodents (West, 1980).
Effects on haemostas i s
Within their recommended dose ranges (10-20 ml/kg body weight), which permit haemodilution down to the normal operating range (27-33% haematocrit), modem dextrans and HES do not significantly interfere with normal haemostasis or normal platelet function (Atik and Broghammer, 1979; Stump et al, 1985; Hahn, 1996). At doses exceeding 1.5 g/kg body weight (20 ml/kg body weight), however, both dextran and HES may increase bleeding by depressing factor VIII and platelet activity (Damon et al, 1987; Iacono and Linford, 1987; Abramson, 1988; Warren and Durieux, 1977). Gelatins on the other hand have relatively little effect on haemo- stasis apart from dilution of clotting factors.
Inf luence on renal funct ion
Although very rare cases of acute renal failure have been reported in non- surgical dehydrated patients with latent renal failure following repeated high doses of hyperoncotic (10%) dextran-40 or HES (Matheson, 1976;
P H A R M A C O L O G Y O F A R T I F I C I A L C O L L O I D S 37
Moran and Kapsner, 1987; Haskell and Tannenberg, 1988; German Medical Association, 1992), there is no convincing evidence that colloids induce renal problems in normally hydrated surgical patients (Matheson, 1976). A recent drug alert from Germany, however, called attention to an increased risk of renal injury and reduced organ survival among recipients of kidneys whose donors had received HES prior to explantation (German Health Authority, 1993).
Colloid metabolism, retention, and organ function
Mounting concern that homologous (bank) plasma and blood may promote tumour growth (Blumberg et al, 1994) or infection (Jensen et al, 1996) has focused renewed attention on fluid therapy and host defence, particularly the effect of persistent colloids on RES function. Isotope studies indicate that both dextran and gelatin are fully metabolized to carbon dioxide and water (Terry et al, 1953; Zekom, 1969; Dubick et al, 1992) and can thus be eliminated via the lungs even in renal failure. HES, on the other hand, is not completely degraded or metabolized (Bogan et al, 1969). Although most large molecules are eventually cleaved by serum amylase to residues small enough to permit renal excretion, each dose of HES inevitably contains a minority of molecules whose degree of sub- stitution (DS) is so uniformly high (DS >0.7) that it sterically hinders amylase cleavage. The proportion of such non-degradable, non-excretable material depends upon the distribution of DS values within the dose (and not the average DS, which is normally quoted). This is particularly emphasized in a recent drug alert from the German Medical Association (1993), which stresses that all preparations of HES contain some persist- ent material since DS is always an average value with a standard Gaussian distribution. Although this problem is greater with older high DS variants of HES such as 450/0.7 (Metcalf et al, 1970; Boon et al, 1976), intravascular and organ persistence studies on modem HES variants do not indicate that reduction of average DS to 0.5 or less has produced any major improvement. K6hler et al (1982), for example, compared serum levels of a 'modem' HES (200/0.5) with dextran-40 and clearly showed intravascular retention of very persistent DS components (Figure 17). Dextran levels were zero at 8 days, whereas HES levels were still detectable at 35 days.
Similar patterns are seen with organ persistence, animal studies indi- cating that liver levels only peak when plasma levels are zero (Lindblad, 1970; Jesch et al, 1979). Liver half-life for HES in rats (which have serum amylase levels 30 times higher than man) is approximately 132 days (Thompson et al, 1970). Other evidence indicates that HES accumulates in man, too (Sirtl et al, 1988) and may disturb liver function and induce persistent itching (Pfeifer et al, 1984; Dienes et al, 1986; Spittal and Findlay, 1995). Sirtl et al (1988) for example, showed that 'modem' HES 200/0.5 persisted in human lymph nodes and muscle biopsies for at least 10 months after a dose of only 1 g/kg body weight, and HES residues were still found in human skin macrophages 19 months
38 K-E. ARFORS AND P. B. BUCKLEY
1
0,5
0.2
0.1
0.05
15
10
5
50~ ml
IX" I I I I I I I I I I I
0 1 2 3 4 7 9 14 21 28 35
Time (days)
Figure 17. Colloid concentration in serum after infusion of 500ml 10% HES 200/0.5 and 10% dextran-60 in man over 35 days. After K6hler et al (1982).
after HES had been administered. This has been related to intense persistent itching in both medical and surgical patients who have received HES, one group (Spittal and Findlay, 1995) reporting that 'the nature of its delayed onset has hidden its true incidence, which may approach 30%'. Many others (Gall et al, 1993; Jurecka et al, 1993; Schneeberger, 1993; Leunig et al, 1995) have reported similar findings and demonstrated histological evidence of persistent residue storage in macrophages long after HES was given (Figure 18). Apart from the molar and mean degrees of substitution, the pattern of substitution of HES (i.e. the C2/C6 ratio) is also important in regulating persistence, higher C2/C6 ratios slowing down enzyme degradation (Yoshida et al, 1984; Trieb et al, 1995) and increasing coagulation complications (Heilmann et al, 1991; Trieb et al, 1995).
Hydroxyethylation of starch can also generate low levels of multiple substitution at the same C site (Sommermeyer et al, 1992), which can impart a varying degree of weak lipophilicity to HES molecules. Such 'tandem substitution' may explain some evidence of lipid leaching from cell membranes and associated disturbances in Na+/K + pump mechanisms in bypass patients on HES (Mannoji et al, 1983; Schmidt and Sesin, 1987).
Naturally, some concern has arisen that HES residues may irreversibly block the reticulo-endothelial system, but no concrete evidence of severe immunosuppression has emerged to date, although most studies have been performed on rodents, which generally have serum amylase levels 30 times
P H A R M A C O L O G Y O F A R T I F I C I A L C O L L O I D S 39
F i g u r e 1 8 . E l e c t r o n m i c r o g r a p h s h o w i n g H E S d e p o s i t i o n i n v a c u o l e s o f h u m a n d e r m a l m a c r o p h a g e .
× 4 4 0 0 m a g . R e p r o d u c e d w i t h p e r m i s s i o n o f A . L e u n i g ,
higher than those in man. Since the rate at which HES is partially degraded is related to environmental amylase concentration, work on rodents may be misleading.
The effect of gelatins on the RES and immunocompetence is also controversial. Comparative clinical evidence indicates that one unit of gelatin reduces the opsonizing function of fibronectin (essential for phago- cytosis), to half the normal level, whereas dextran has no effect (Brodin et al, 1984). Other workers have confirmed that gelatin impairs plasma opsonizing activity both in vitro and in vivo in man (Imawari et al, 1985; Biel et al, 1993), and carbonyl iron phagocytosis in animals (Woltjes et al, 1979). Recent work suggests HES also reduces fibronectin (Trieb et al, 1996).
C H O I C E OF COLLOID HAEMODILUENT
Maintenance of normal blood volume to prime the compensatory increase in cardiac output is an absolute pre-condition for safe surgery at low haematocrits. For this reason, a reliable long-acting colloid is required to fully sustain normovolaemia for the duration of surgery and the immediate post-operative period (Zetterstrom and Wiklund, 1986; Martin et al, 1987; Messmer, 1987; Fujii, 1988)•
40 K-E. ARFORS AND P. B. BUCKLEY
As evident from comparative volume studies (see Figures 5 and 6 above), crystalloids and rapidly excreted colloids such as gelatin are unable to maintain normovolaemia over 1.5 hours. In this respect, gelatin offers no statistical advantage over saline and carries an unacceptable risk of severe reactions.
Although albumin, HES and dextran are effective volume substitutes, none is entirely perfect. Albumin is prohibitively expensive for routine use, HES is not completely metabolized (Bogan et al, 1969) and exhibits un- acceptable plasma and organ persistence (Boon et al, 1976; Sirtl et al, 1988), and dextran requires monovalent dextran prophylaxis (at least in elective indications) to prevent rare reactions. On the other hand, dextran does have the added clinical advantage over other colloids of providing significant protection against fatal post-operative thromboembolism (Bergqvist, 1983; National Institutes of Health, 1986) and ARDS (Modig, 1986), and of attenuating other undesirable cascades such as excessive platelet and leukocyte activation.
Should haemodiluent requirements exceed the recommended doses of 6% dextran or HES (20 ml/kg body weight), combination with albumin is preferable.
CONCLUSION
There is now considerable scope for more universal acceptance of artificial colloids in peri-operative fluid therapy. Growing awareness of the risks of homologous blood transfusion and a distinct trend towards lower operating haematocrits implies greater future dependence on reliable intravenous colloids. Although human albumin is an ideal colloid in many respects, its limited supply and prohibitive cost restrict its routine use in an increasingly cost-conscious society. A switch to the cheapest fully approved colloid on the US market for indications in which albumin is not necessary has been calculated to save the community some US $300 million annually in the USA alone, taking into account all incidental costs to society of any morbidity or mortality related to the use of albumin, or the artificial colloids HES and dextran (Munoz, 1987).
REFERENCES
Abramson N (1988) Plasma expanders and bleeding. Annals of Internal Medicine 108: 307. Agolini G, Buckley P, Quaini Let al (1978) Dextran or LD heparin in the prevention of postoperative
thromboembolism. Minerva Anestasiologica 44: 789-802. Altman LC, Furukawa CT & Klebanoff G (1977) Depressed mononuclear leukocyte chemotaxis in
thermally injured patients. Journal ()flmmunology 119: 119-205. Amundson B, Jennische H & Haljamae H (1980) Correlative analysis of microcirculatory and cellular
metabolic events in skeletal muscle during hemorrhagic shock. Acta Physiologica Scandinavica 108: 147-158.
Arfors K-E & Buckley PB (1989) Role of artificial colloids in rational fluid therapy. In Tuma RF, White JV & Messmer K (eds) The Role of Hemodilution in Optimal Patient Care. Munchen: W Zuckschwerdt.
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 41
Arfors K-E, Rutili G & Svensj6 E (1979) Microvascular transport of macromolecules in normal and inflammatory conditions. Acta Physiologica Scandinavica 463 (supplement): 93-103.
Arrants JE, Cooper N & Lee WH (1969) Effects of a new plasma expander (HES) on intravascuiar clot formation. American Surgeon 35: 465.
Arturson G & Wallenius G (1964) The intravascular persistence of dextran of different molecular sizes in normal humans. Scandinavian Journal of Clinical and Laboratory Investigation I: 76-80.
Atik M & Broghammer W (1979) The impact of prophylactic measures on fatal pulmonary embolism. Archives of Surgery 114: 366-369.
Barrett J, Sheaff C, Smith S & Jonasson O (1983) Correlation of spontaneous microaggregate formation with the severity of trauma in man. Journal of Trauma 23: 388-392.
Bell WR (1988) Heparin-associated thrombocytopenia and thrombosis. Journal of Laboratory and Clinical Medicine 111: 600-605.
B engtsson A, Larsson M, Gammer W & Heidemann M (1987) Anaphylatoxin release in association with methyl methacrylate fixation in hip prosthesis. Journal of" Bone and Joint Surgery 69: 46-49.
Bergan JJ & DeBoer A (1970) Venous thrombosis and pulmonary embolism: total care. Surgical Clinics of North America 50: 173-192.
Bergentz S-E (1978) Dextran in the prophylaxis of pulmonary embolism. Worm Journal of Surgery 2: 19-25.
Bergqvist D (1983) Postoperative thromboembolism: frequency, etiology, prophylaxis. Berlin: Springer.
Bergqvist D (1992) Dextran. In Goldhaber SZ (ed~) Prevention of Venous Thromboembolism, pp. 167-215. New York: Marcel Dekker.
Bicher H, D'Angostino L, Doss LL et al (1977) Prevention of ionizing radiation-induced liver micro- circulation changes by flow improvers. Advances in Experimental and Medical Biology 94: 383-389.
Biel S, Seifert J, Sass W & Eldfelt R (1993) The influence of gelatin plasma substitute on the fibronectin concentration and migration of neurophil granulocytes. XXIII Congress of the European Society of Surgical Research, Turku, Finland. p. 12.
Blaisdell RW, Lim RC, Amberg JR et al (1966) Pulmonary microembolism: a cause of morbidity and death after major vascular surgery. Archives of Surgery 93: 776-786.
Blumberg N & Heal JM (1994) Effects of transfusion on immune functions, cancer recurrence and infection. Archives of Pathology and Laboratory Medicine 118: 371-379.
Bogan RK, Gale GR & Walton RP (1969) Fate of 14C-labelled HES in animals. Toxicology and Applied Pharmacology 15:206-211.
Bond RE Manning ES & Peissner LC (1979) Correlation between skeletal muscle vascular decompensation and survival: roles of tissue ischemia and innervation. Circulatory Shock 6: 43-54.
Boon J, Jesch F, Ring J & Messmer K (1976) lntravascular persistence of HES in man. European Surgical Research 8: 497-503.
B raide M, Amundson B, Chien S & Bagge U (1984) Quantitative studies on influence of leukocytes on vascular resistance in a skeletal muscle preparation. Microvascular Research 27:331-352.
Brodin B, Hesselvik F & v o n Schenck H (1984) Decrease of plasma fibronectin concentration following infusion of a gelatin-based plasma substitute in man. Scandinavian Journal of Clinical and Laboratory Investigation 44: 529-533.
Brown JM, Grosso MA & Moore E (1990) Hypertonic saline and dextran: impact on cardiac function in the isolated rat heart. Journal of Trauma 30:6646-6651.
Bruckner UB & Messmer K (1991) Organ perfusion and tissue oxygenation after moderate isovolemic hemodilution with HES 200/0.62 and dextran 70. Anaesthesist 40: 434-440.
Buckley P (ed.) (1995) Colloid Safety in Surgery and Critical Care. pp 1-49. Medisan. Carlin G, Karlstrom G, Modig J & Saldeen T (1980) Effect of dextran on fibrinolysis inhibition
activity in the blood after major surgery. Acta Anaesthesiologica Scandinavica 24: 375-378. Chang RLS, Ueki IF, Troy JL et al (1975) Permselectivity of the glomerular capillary wall to macro-
molecules. Biophysics Journal 15: 887-895. Chapman HA, Vavrin Z & Hibbs JB (1983) Coordinate expression of macrophage procoagulant and
fibrinolytic activity in vitro and in vivo. Journal of Immunology 130: 261-266. Chien S (1987) Physiological and pathophysiological significance of hemorheology. In Chien S,
Dormandy J, Ernst E & Matrai A (eds) ClinicalHemorheology, pp. 125-163. Boston: Nijhoff.
42 K-E. ARFORS AND P. B. BUCKLEY
Clagett GP & Reisch JS (1988) Prevention of venous thromboembolism in general surgery patients: results of meta analysis. Annals of Surgery 208: 227-240.
Craddock PR, Fehr J, Brigham KL et al (1977) Complement and leukocyte-mediated pulmonary dys- function in hemodialysis. New England Journal of Medicine 296: 769-774.
Curtis WE, Gillinov AM, Wilson IC, et al (1993) Inhibition of neutrophil adhesion reduces myo- cardial infarct size. Annals of Thoracic Surgery 56:1069-1073.
Damon L, Adams M, Stricker R & Ries C (1987) Intracranial bleeding during treatment with HES. New England Journal of Medicine 317: 964-965.
'Davidson I, Gelin L-E & Haglind E (1980) Plasma volume, intravascular protein content, hemo- dynamic and oxygen transport changes during intestinal shock in dogs. Critical Care Medicine 8: 75-82.
Del Maestro R, Thaw H, Bj6rk J e t al (1980) Free radicals as mediators of tissue injury. Acta Physiologica Scandinavica 492 (supplement): 43-57.
Dienes HE Gerharz C-D, Wagner R et al (1986) Accumulation of HES in the liver of patients with renal failure and portal hypertension. Journal of Hepatology 3: 223-227.
Dubick MA, Ryan BA, Summary JJ et al (1992) Dextran metabolism following infusion of 7.5% NaC1 / 6% dextran 70 to euvolumic and hemorrhaged rabbits. Drug Development and Research 25: 29-38.
Edwards JD, Redmond AD, Nightingale P & Wilkins RG (1988) Oxygen consumption following trauma: a reappraisal in severely injured patients requiring mechanical ventilation. British Journal of Surgery 75: 690-692.
Ellman H (1984) Capillary permeability in septic patients. Critical Care Medicine 12: 629-633. Eriksson M & Saldeen T (1995) Effect of dextran on plasma tissue plasminogen activator (t-PA) and
Ekl6f B, Neglen P & Thomson D (1981 ) Temporary incomplete ischemia of the legs caused by aortic damping in man. Improvement of skeletal muscle metabolism by LMW dextran. Annals of Surgery 193: 99-104.
Federal Register (1/4/1978) 43,68: 14743-14744. Fernandez-Aviles F, Jesus Alonso J, Manuel Duran J e t al (1996) Subacute occlusion, bleeding
complications, hospital stay and restenosis after Palmaz-Schatz coronary stenting under a new antithrombotic regimen. Journal of the American College of Cardiology 27: 22-29.
Fox RB (1985) Prevention of free radical induced permeability pulmonary edema by HMW dextran. Federation Proceedings 44: 1909.
Frost-Arner L, Bergqvist D (1995) Effect of isovolemic hemodilution with dextran and albumin on thrombus formation in artificial vessel grafts inserted into the abdominal aorta of the rabbit, Microsurgery 16: 357-361.
Fujii H (1988) Plasma exchange using dextran 40 electrolyte solution as sole replacement fluid in malignant paraproteinemia. TransJusion 28: 42-45.
Gall H, Kaufmann R, van Ehr M e t al (1993) Persistent pruritus after HES infusions. Retrospective long term study of 266 cases. Hautarzt 44(1): 713-716.
German Health Authority Drug Alert (1993). Injury to donor kidneys by HES? Deutsche Arzteblad 90, Heft 48: B-2393.
German Medical Association Drug Alert (1992) Acute renal failure following infusion of HES during hemodilution therapy. Deutsche Arzteblad 89, Heft 50: B-2745.
German Medical Association (1993) Once again: caution in hemodilution therapy with HES. Deutsche fi~rzteblad 90: B-2454.
Gervin AS, Mason KG & Wright GB (1975) Microaggregate formation during regional hypo- perfusion. Surgery, Gynecology and Obstetrics 141: 719-723.
Granath K & Str6mberg R (1968) Physikalisch-chemische Daten fiber einige in der Infusion Therapie verwendete Polymere. Anaesthesist 17: 224--230.
Granath K, Str6mberg R & de Belder AN (1969) Studies on hydroxyethyl starch. Stgirke 10: 251- 256.
Grotte G (1956) Passage of dextran molecules across the blood-lymph barrier. Acta Chirurgica Scandinavica 211 (supplement): 1-84.
Haas A (1992) Hemodilution with medium mol wt starch in the therapy of ischemic insult, sub- arachnoid hemorrhage and intracerebral hemorrhage: hemorheological and physiological coagu- lation considerations. In Lawin P, Zander J & Weidler B (eds). HES--A Current Ovelwiew. New York: G Thieme.
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 43
Hahn RG (1996) Dextran 70 and blood loss during transurethral resection of the prostate. Acta Anaesthesiologica Scandinavica 40: 820-823.
Haljam~ie H (1985a) Pathophysiology of shock-induced disturbances in tissue homeostasis. Acta Anaesthesiologica Scandinavica 29: 38-44.
* Haljam~ie H (1985b) Rationale for the use of colloids in the treatment of shock and hypovolemia. Acta Anaesthesiologica Scandinavica 29: 48-54.
Hammerschmidt DE, Weaver L J, Hudson LD et al (1981) Complement activation and neutropenia occurring during CPB. Journal of Thoracic and Cardiovascular Surgery 81: 370-377.
Haraldsson B (1986) Physiological studies of macromolecular transport across capillary walls. Acta Physiologica Scandinavica 128 (supplement 553): 1-40.
Haraldsson B, Moxham BJ & Rippe B (1982) Capillary permeability to sulphate substituted and neutral dextran fractions in the rat hindquarter vascular bed. Acta Physiologica Scandinavica 115: 397-404.
Haskell LP & Tannenberg AM (1988) Elevated urinary specific gravity in acute oliguric renal failure due to HES. New York State Journal of Medicine 88: 387-388.
Heilmann L, Lorch E, Hojnacki Bet al (1991) Accumulation of two different HES preparations in the placenta after hemodilution in patients with fetal intrauterine growth retardation or pregnancy hypertension, lnfusionstherapie 18: 236-243.
Hiippala S, Linko K, Myllyl6 G e t al (1995) Replacement of major surgical blood loss by hypo- oncotic or conventional plasma substitutes. Acta Anaesthesiologica Scandinavica 39: 228-235.
Hint H (1968) Pharmacology of dextran and the physiological background for the clinical use of Rheomacrodex and Macrodex. Acta Anaesthesiologica Belgica 2:119-138.
Hjertberg H, Olsson J, Ekstr6m T et al (1995) Combining dalteparin and dextran does not increase the blood loss in transurethral resection of the prostate. Acta Anaesthesiologica Scandinavica (supplement 105): 39.
Iacono RP & Linford 1 (1987) Use of hetastarch for volume expansion. Journal of Neurosurgery 66: 635-636.
Imawari M, Hughes R, Gove C & Williams R (1985) Fibronectin and Kupffer cell function in fulminafit hepatic failure. Digestive Disease Science 30: 1028-1033.
Intaglietta M (1989) Microcirculatory effects of hemodilution: Background and Analysis. In Tuma RE White JV & Messmer K (eds) The Role of Hemodilution in Optimal Patient Care, pp. 21-40. Mtinchen: W Zuckschwerdt.
Jacob HS, Craddock PR, Hammerschmidt DE & Muldow CF (1980) Complement-induced granulo- cyte aggregation. New England Journal of Medicine 302: 789-793.
Jensen LS, Kissmeyer-Nielsen P, Wolffe B & Qvist N (1996) Randomised comparison of leucocyte depleted versus buffy coat poor blood transfusion and complications and complications after colorectal surgery. Lancet 348: 841-845.
Jesch F, Htibner G, Zumtobel Vet al (1979) lIES 450/0.7 in plasma and liver. Concentration kinetics and histological changes in man. lnfusionstherapie 6:112-117.
Jurecka W, Szepfalusi Z, Parth E et al (1993) HES deposits in human skin--a model for pruritus? Archives of Dermatological Research 285(1-2): 13-19.
Kellerhals B, Hippert F & Pfattz CR (1971) Treatment of acute acoustic trauma with LMW dextran. Practical Otology Rhinology Laryngology 33: 260-264.
K6hler H, Kirch W, Klein H & Distler A (1978)Effects of 6% HIES 450/0.7, 10% dextran 40 and 3.5% gelatin on plasma volume in patients with terminal renal failure. Anaesthesist 27:421-426.
* K6hler H, Zschiedrich H, Linfante Ae t al (1982) The elimination of HES 200/0,5, dextran 40 and Oxypolygelatine. Klinisehe Wochenschrifte 60: 293-301.
Kreimeier U, Christ E Kraft D et al (1995) Anaphylaxis due to HES reactive antibodies. Lancet 346: 49-50.
Krieter H, Brtickner UB, Kefalianakis F & Messmer K (1995) Does colloid-induced plasma hyper- viscosity in haemodilution jeopardize perfusion and oxygenation of vital organs. Acta Anaesthesiologica Scandinavica 39: 236-244.
Kuitunen A, Hynynen M, Salmenper~i M et al (1993) HES as a prime for cardiopulmonary bypass: effects of two different solutions on haemostasis. Acta Anaesthesiologica Scandinavica 37: 652-658.
Laha R, Israeli J, Dujovny M e t al (1980) Low molecular weight dextran in experimental embolectomy. Stroke 11: 59-63.
* Lamke L-O, Liljedahl S-O (1976) Plasma volume changes after infusion of various plasma expanders. Resuscitation 5: 93-102.
44 K-E. ARFORS AND P. B. BUCKLEY
Laxenaire MC, Charpentier C & Feldman L (1994) Anaphylactoid reactions to colloid plasma substitutes: frequency, risk factors, mechanisms. A French prospective multicentre inquiry. Annales Francais d'Anesthesie et de Reanimation 13: 301-310.
Leunig A, Szeimies RM, Wilmes E et al (1995) Clinical and elecronmicroscopic study for evaluation of sudden hearing loss therapy using a combination of 10% HES 200/0,5 and Pentoxifyllin. Laryngology-Rhinology-Otology 74: 135-140.
Ley K & Arfors K-E (1986) Segmental differences of microvascular permeability for FITC-dextrans measured in the hamster cheek pouch. Microvascular Research 31: 84-99.
Lin S-R, O'Connor M, King Aet al (1979) Effect of dextran on cerebral function and blood flow after cardiac arrest. Stroke 10: 13-20.
Lindblad G (1970) The toxicity of HES in investigation in mice, rabbits and dogs. Excerpta Medica International Congress Series 198" 128-144.
Ljungstrrm K-G (1983a) Dextran prophylaxis of fatal pulmonary embolism. World Journal of Surgery 7: 767-772.
Ljungstrrm K-G (1983b) Prophylaxis of post-op, thromboembolism with dextran 70. Improvements of efficacy and safety. Thesis, Karolinska Institute, Stockholm.
*Ljungstr/3m K-G (1993) Safety of dextran in relation to other colloids--ten years experience with hapten inhibition, lnfusionsther. Transfitsionsmedicine 20: 206-210.
Ljungstrrm K-G, Renck H, Hedin H et al (1988) Hapten inhibition and dextran anaphylaxis. Anaesthesia 43: 729-732.
Lorenz W, Duda D, Dick Wet al (1994) Incidence and clinical importance of perioperative histamine release: randomised study of volume loading and antihistamines after induction of anaesthesia. Lancet 343" 933-940.
McDonald DM, Baluk E Hirata A & Thurston G (1996) Endothelial gaps revealed in inflamed venules by silver staining, scanning EM & lectin binding. International Journal of the Miclvcirculation 16 (supplement 1): 66, S164.
McNamee JE & Stanb NC (1979) Pore models of sheep lung microvascular barrier using new data on protein tracers. Microvascular Research 18: 229-244.
Mannoji M, Sugihara T, Koresawa S & Yawata Y (1983) Abnormal heinz body formation test due to red cell membrane damage induced by HES. Acta Haematologica Japan 46: 1023-1028.
Mardel SN, Saunders F, Ollerenshaw Le t al (1996) Reduced quality of in vitro clot formation with gelatin based plasma substitutes. Lancet 347:825 (letter).
Martin E, Hansen E & Peter K (1987) Acute limited hormovolemic hemodilution. A method for avoiding homogenous transfusion. Worm Journal of Surgery 11: 53-59.
Martin WJ (1984) Neutrophils kill pulmonary endothelial cells by a H202 dependent pathway. American Review of Respiratory Disease 130:209-213.
Matheson NA (1976) Macromolecules and the kidney. Anesthesia Analgesia Reanimation 33: 445-456.
Matthiasson SE (1994) LMW heparin and dextran in thromboprophylaxis. Thesis, Department of Surgery, Land University, Malmr, Sweden.
Matthiasson SE, Lindblad B, Mfitzsch T et al (1994) Study of the interaction of dextran and enoxaparin on haemostasis in humans. Thrombosis and Haemostasis 72: 722-727.
Mazzoni MC, Borgstrrm P, Intaglietta M & Arfors K-E (1990) Capillary narrowing in hemorrhagic shock is rectified by hyperosmotic saline-dextran reinfusion. Circulatory Shock 31:407M,18.
Menger M, Thierjung C, Hammersen F & Messmer K (1989) Influence of isovolaemic haemodilution with dextran and HAES on the PMN-endothelium interaction in postischaemic skeletal muscle. European Surgical Research 21 (supplement 2): 74.
Menger MD, Thierjung C, Hammersen F & Messmer K (1993) Dextran versus HES in inhibition of post-ischemic leucocyte adherence in striated muscle. Circulatory Shock 41: 248.
Messmer KFW (1987) Acceptable hematocrit levels in surgical patients. Worm Journal of Surgery 11: 41-46.
Messmer K & Arfors K-E (1988) Can primary resuscitation therapy be improved? In Vincent JL (ed.) Update in Intensive Care, pp. 13-18. Berlin: Springer-Verlag.
Messmer K, Seeman C, Hedin H et al (1980) Anaphylactoid reactions after dextran. II. Allergologie 3: 1724.
Metcalf W, Papadopoulos A, Tufaro I & Batth A (1970) A clinical physiologic study on hydroxyethyl starch. Surgery Gynecology and Obstetrics 131: 255-267.
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 45
Miller CL (1981) Secondary immunodeflciency in bums and trauma. Clinics in Immunology and Allergy 1: 641~567.
* Miller CL & Lim R (1985) Dextran as a modulator of immune and coagulation activities in trauma patients. Journal of Surgical Research 39: 183-191.
Miller CL, Graziano CJ & Lim RC (1982) Monocyte plasminogen activator production. Correlation to immune function. Journal oflmmunology 128: 2194-2200.
Miller CL, Graziano C J, Lim RC & Chin M (1981) Production of tissue procoagulant factor by patient monocytes. Correlation to thromboembolic complications. Thrombosis and Haemostasis 46: 489-495.
* Modig J (1986b) Effectiveness of dextran 70 vs Ringer's in traumatic shock and ARDS. Critical Care Medicine 14: 454-457.
Modig J (1988) Comparison of dextran 70 and Ringer's on pulmonary function, hemodynamics, and survival in experimental septic shock. Critical Care Medicine 16: 266-271.
Moraes I, Teixeira E, Arbit J & Bergan JJ (1967) Augmentation of arterial collateral blood flow. Archives of Surgery 95: 49-53.
Moran M & Kapsner C (1987) Acute renal failure associated with elevated plasma oncotic pressure. New England Journal of Medicine 317: 150-153.
Munoz E (1987) Costs of altemative colloid solutions. Infection in Surgery 634-638. Nakamura Y & Wayland H (1975) Macromolecular transport in the cat mesentery. Microvascular
Research 9: 1-21. National Institutes of Health (1986) Consensus statement. Prevention of thromboembolism. Journal
of the American Medical Association 256: 744-749. Nilsson K (1981) Measurement and control of quality determining properties of clinical dextrans.
Joint WHO/lABS Symposium, Geneva. Development of Biological Standards 48: 169-177. Nolte D, Lehr H-A & Messmer K (1991) Dextran and adenosine-coupled dextran reduce post-
ischemic leucocyte adherence in postcapillary venules of the hamster. Progress in Applied Microcirculation 18: 103.
Nolte D, Illner A, Menger MD & Messmer K (1992) Reduction of post-ischemic leucocyte- endothelial interaction by dextran 70, but not by HES 200/06. International Journal of the Microcirculation 11: 210.
Palmaz JC, Garcia O, Kopp DT et al (1989) Balloon-expandable intrarterial stents: effect of antithrombotic medication on thrombus formation. In Zeitler E, Seyferth W (eds) Pros and Cons in PTA and Auxilliary Methods. pp. 170-178. Berlin: Springer-Verlag.
Parker JC, Parker RE, Granger DN & Taylor AE (1981 ) Vascular permeability and transvascular fluid and protein transport in the dog lung. Circulation Research 48:549-561.
Parks DA, Bulkley GB & Granger DN (1983) Role of oxygen-free radicals in shock, ischemia, and organ preservation. Surgery 94: 428.
Pastemak R, Baughman K, Fallon J & Block P (1980) Scanning electron microscopy after coronary transluminal angioplasty of normal canine arteries. American Journal of Cardiology 45:591.
Pfeifer U, Kult J & Forster H (1984) Ascites as a complication of hepatic storage of HES in dialysis patients. Klinische Wochenschrifte 62: 862-866.
Prien Th, Thulig B, Wusten R et al (1993) Effects of hypertonic saline-hyperoncotic HES infusion prior to coronary artery bypass grafting (CABG). Zentralbladfiir Chirurgie 118: 257-263.
Renck H, Ljungstr6m K-G, Hedin H & Richter W (1983) Prevention of dextran-induced anaphylactic reactions by hapten inhibition. Ill. Acta Chirurgica Scandinavica 149: 355-360.
Ring J & Messmer K (1977) Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet i: 466-469.
Risberg B, Smith L & Ortenwall P (1991) Oxygen radicals and lung injury, Acta Anaesthesiologica Scandinavica 35 (supplement 95): 106-118.
Rosberg B, Ahlberg/~, Nillius A & Uden A (1977) Hemodilution in total hip replacement surgery. In Lewis DH (ed.) Dextran, 30 Years, pp. 111-121. Uppsala: Almqvist & Wiksell.
Rothkopf DM, Chu B, Bern S, May JW (1993) The effect of dextran on microvascular thrombosis in an experimental rabbit model. Plastic and Reconstructive Surgery 92:511-515.
Rowland RR, Carmona R, Miller S e t al (1983) Effects of low molecular weight dextran on the coagulation activity of trauma patients. Journal of Trauma 23: 659.
Ruiz E, Brunette D, Robinson E et al (1986) Cerebral resuscitation after cardiac arrest using HES hemodilution, hyperbaric 02 and Mg-ion. Resuscitation 14: 213-223.
46 K-E. ARFORS AND P. B. BUCKLEY
* Rutherford RB, Jones DN (1988) Does dextran improve graft patency? In Greenhalgh RM, Jamieson CW & Nicolaides AN (eds) Limb Salvage and Amputation for Vascular Disease, pp. 287-294. Philadelphia: WB Saunders.
Rutherford R, Jones D, Bergentz S-E et al (1984) The efficacy of dextran 40 in preventing early post- operative thrombosis following difficult lower extremity bypass. Journal of Vascular Surgery 1: 765.
Rutili G & Arfors KE (1976) Fluorescein-labelled dextran measurement in interstitial fluid in studies of macromolecular permeability. Microvascular Research 12: 221-230.
Safar P, Stezoski W & Nemoto M (1976) Amelioration of brain damage after 12 minutes' cardiac arrest in dogs. Archives of Neurology 33" 91-95.
Schrnidt J, Fernandez d Castillo C, Rattner D et al (1993) Hyperoncotic ultrahigh mol wt dextran solutions reduce trypsinogen activation, prevent acinar necrosis and lower mortality in rodent pancreatitis. American Journal of Surgery 165: 40~-5.
Schmidt RE & Sesin GP (1987) Hetastarch-induced hyperkalemia. Drug Intelligence in Clinical Pharmacology 21:922 (letter).
Schneeberger R (1993) Occurence of itching as side effect of high dosage hemodilution therapy with HES. Aktnel Erngihr Medicine 1993 18: 263-265.
Schnell RM, Cole DJ, Schultz RL & Osborne TN (1992) Temporary cerebral ischemia---effects of Pentastarch or albumin on reperfusion injury. Anesthesiology 77: 86-92.
Scholz PM, Engeset J, Matheson NA & Gruber UF (1971) Red cell aggregation induced by a high molecular weight gelatin plasma substitute. European Surgical Research 3: 428-435.
Schoning B, Lorenz W & Doenicke A (1982) Prophylaxis of anaphylactoid reactions to a polypeptidal plasma substitute by H~ plus H2 receptor antagonists: synopsis of three randomized trials. Klinische Wochenschr~ft 60: 1048-1055.
Sch0tt U, Berseus O & Jaremo P (1987) Blood substitution and complement activation. Acta Anaesthesiologica Scandinavica 31: 559-566.
Shasby DM, Shasby SS & Peach MJ (1983) Granulocytes and PMA increase permeability to albumin of cultured endothelial monolayers and isolated perfused lungs. American Review of Respiratory Disease 127: 72-76.
Shoenfeld NA, Eldrup-Jorgensen J, Connolly R et al (1987) The effect of LMW dextran on platelet deposition onto prosthetic materials. Journal of Vascular Surgery 5: 76-82.
* Shoemaker WC (1976) Comparison of the relative effectiveness of whole blood transfusions and various types of fluid therapy in resuscitation. Critical Care Medicine 4: 71-78.
Shoemaker WC & Appel PL (1988) Tissue oxygen debt as a determinant of lethal and non-lethal post- op. organ failure. Critical Care Medicine 16: 1117-1127.
Shoemaker WC, Schuluchter M, Hopkins JA et al (1981) Comparison of the relative effectiveness of colloids and crystalloids in emergency resuscitation. American Journal of Surgery 142: 73-81.
*Sirtl C, Hiibner G & Jesch F (1988) Zur Speicherung von hoch- und mittelmolekularer Hydroxy~ithylstfirke (HAS) im menschlichen Gewebe. Beitrage zur Anaesthesiologie lntensiv- medicine 26: 74-97.
Sobel M, Adelman B & Greenfield LJ (1986) Dextran 40 reduces heparin-mediated platelet aggre- gation. Journal of Surgical Research 40: 382-387.
Sommermeyer K, Hildebrand U, Cech F et al (1992) Fine and hyperfine structure of clinically utilized HES. Starch/Stgirke 44: 173-179.
Spittal MJ & Findlay GP (1995) The seven year itch. Anaesthesia 50: 913-914. Steinbauer M, Harris A, Hoffman T & Messmer K (1996) Pharmacological effects of dextrans on the
postischemic leucocyte-endothelial interaction. In Messmer K (ed.) Compromised Perfusion. Progress in Applied Microcirculation 22:114-125.
Stump DC, Strauss RG, Henricksen RA & Saunders R (1985) Effect of HES on blood coagulation, particularly factor VIII. TransJksion 25: 349.
Tanaka H, Dahms TE, Bell E et al (1993) Effect of HES on alveolar flooding in acute lung injury in dogs. American Review of Respiratory Diseases 148: 852-859.
Tangen O, Wik KO, Almquist IAM et al (1972) Effects of dextran on the structure and plasmin- induced lysis of human fibrin. Thrombosis Research 1: 487.
Tate RM & Repine JE (1983) Neutrophils and the adult respiratory distress syndrome. American Review of Respiratory Disease 128: 552-559.
Taylor AE & Gaar KE (1970) Estimation of equivalent pore radii of pulmonary capillary and alveolar membranes. American Journal of Physiology 218: 1133-1140.
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 47
Terry R, Uile C, Golodetz A et al (1953 ) Metabolism of dextran--a plasma volume expander. Journal of Laboratory and Clinical Medicine 42: 6-15.
Thierjung C, Menger M, Sack FU et al (1988) The effect of prophylactic isovolemic hemodilution on the PMN-endothelium interaction in postischemic skeletal muscle. International Journal of Microcirculation: Clinical and Experimental (special issue): 69.
Thompson WL, Fukushima T, Rutherford R & Walton R (1970) Intravascular persistence, tissue storage, and excretion of lIES. Surgery Gynecology and Obstetrics 131: 965-972.
Tonnesen AS, Gabel JC & McLeavey CA (1977) Relation between lowered colloid osmotic pressure, respiratory failure, and death. Critical Care Medicine 5: 239-240.
Traber LD, Brazeal BA & Schmitz M (1992) Pentafraction reduces the lymph response after endo- toxin administration in the ovine model. Circulatory Shock 36: 93-103.
Trieb J, Haas A, Pindur G e t al (1995) HES 200/0.5 is not always HES 200/0.5. Thrombosis and Haemostasis 74(6): 1452-1456.
Trieb J, Haas A, Pindur Get al (1996) Decrease of fibronectin following repeated infusion of highly substituted HES. Infusionstherapie Transfusionmedicine 23: 71-75.
Unanue ER (1981) Regulatory role of macrophages in antigenic stimulation. II. Symbiotic relation- ships between lymphocytes and macrophages. Advances in Immunology 31: 1-136.
Warren BB & Durieux ME (1977) Hydroxethyl starch: safe or not? Anesthesia and Analgesia 84: 206-212.
Webb AR, Tighe D, Moss RF et al (1991) Advantages of a narrow range, medium mol. wt. starch for volume maintenance in a porcine model of fecal perotonitis. Critical Care Medicine 19(3): 409-416.
Webb DR & Nowowiejski 1 (1981) Control of suppressor cell activation via endogenous prostaglandin synthesis: role of T cells and macrophages. Celhdar Immunology 63: 321-328.
Weber GF & Bruch HP (1993) HES and diseases mediated by free-radicals. Free Radicals in Biology and Medicine 14:96-97 (letter).
Weidler B & Sommermeyer K (1992) HES kinetics in studies with test subjects: influence of molecular weight, substitution and substitution position. In Lawin P e t al (eds) 'Hydroxyethyl Starch' New York: G Thieme.
:Werner J, Schmidt J, Gebhard MM et al (1996) Superiority of dextran compared to other colloids and crystalloids in inhibiting the leucocyte--endothelium interaction in experimental necrotizing pancreatitis. Langenbecks Archives of Surgery (supplement 1): 467-470.
West GB (1980) Dextran intolerance in rats. In Pseudo-allergy Reactions. Involvement of Drugs and Chemicals, vol 1, pp. 108-124. Basel: Karger.
Wiedeman MP (1963) Dimensions of blood vessels from distributing artery to collecting vein. Circulatory Research 12: 375-378.
Wolfert SF, Angel MF, Knight KR et al (1992) The beneficial effect of dextran on anastomotic patency and flap survival in a strongly thrombogenic model. Journal of Reconstructive Microsurgery 8(5): 375-378.
Woltes J, De Jong J, Ten Duis H et al (1979) Priming extracovporeal circuits. Transfusion 19: 552- 557.
Yoshida M, Minami Y & Kishikawa T (1984) A study of HES. IIl. Comparison of metabolic fates between 2-0-hydroxyethyl and 6-0-hydroxyethyl starch in rabbits. Starch/StiT"rke 36: 209-212.
Zarins CK, Rice CL, Peters RM & Virgilio RW (1978) Lymph and pulmonary response to isobaric reduction in plasma oncotic pressure in baboons. Circulatory Research 43: 925-930.
Zekorn D (1969) Intravascular retention, dispersal, excretion and breakdown of gelatin plasma substitutes. Bibliotheca Haematologica 33: 131-140.
Zetterstrom H & Wiklund L (1986) A new nomogram facilitating adequate haemodilution. Acta Anaesthesiologica Scandinavica 30: 300-304.
Zikria BA, King TC, Stanford J & Freeman HP (1989) A biophysical approach to capillary permeability: Surgery 105:625-631.
Zikria BA, Subbarao C, Oz MC et al (1990) HES macromolecules reduce myocardial reperfusion injury. Archives of Surgery 125: 930-934.
