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Pharmacological characteristics of
artificial colloids

KARL-E. ARFORS PhD, Med. Dr.h.c.


Adjunct Professor
Department of Surgery, RW Johnson Medical School, New Brunswick, UMDNJ, New Jersey's
University ~?fHealth 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.

Key words: colloid; gelatin; dextran; hydroxyethyl starch; plasma volume; haemostasis;
microcirculation; leukocyte; COR

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,
Baillikre's Clinical Anaesthesiology-- 15
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ISBN 0-7020-2341-8 All rights of reproductionin any form reserved
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16 K - E . A R F O R S A N D P. B. B U C K L E Y

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).
2. Improving microvascular perfusion (by restoring volume and colloid
osmotic pressure).
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.


Wt av. Degree of
MW Polydispersity substitution*
Colloid (kDa) (MW/MN) (average) Colloid content Remarks
Albumin ca 70 1 -- 4, 5, 10 and 20%

Gelatins,
Urea-linked 35 2.3 -- 3.5% Haemaccel/poly-
Modified fluid 35 2.2 -- 4% geline
Oxypolygelatin 30 1.5 -- 5.5% Gelofusine
Dextran 1 1.4 -- 15% (20 ml) Promit®
40 1.6 -- 3, 5 and 10% Macrodex/®
60 1.6 -- 3 and 6% Rheomacrodex®
are leuconostoc
antigen free
70 1.6 -- 6%
Hydroxyethyl 70 2.0 0.5 6 and 10% Expafusin
starch (HES) 120 >2 0.5 3 and 6% Plasmafusin
200 >3 0.5 6 and 10% HES-sterilt
200 >3 0.6 6% Elohes
450 6.3 0.7 6%

* 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

HHc~O
t H3 0
H H
0

HO ~ H
I It H
H

H Hi 0

C ~-"
.~ .6X?" V~o-<?,,

I I H H

"oN~" V ~'-
. &
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 19

CH2-O-CHuCH2-OII

c.~-o. I I cH~
16 H OH 16
, ,

4 ~/~ o~HH H~I 4~/~ H~ 1

H O-CH2-CH2-OH H OH

I
c=o Peptidechain c=o Peptide chain
I
NH O O NH
I II II
HC-(CH2)4- NH + C N - R - N C + H N - - C H 2 - C H
I
C=O
H I
\\ /
II
c=o Peptide chain
I N
Nil HN OH 0 0
I / tl II
HC (CH~)~-CH-CH2- NH~+CN- R- NC + NH2
I
C O CHR
I
NH C=O
I
NH
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 K-E. ARFORS AND P. B. BUCKLEY

I A B C
4 !
x Urea-linked gelatin
o Dextran-40
• Dextran-70
Q Hydroxyethyl starch 200/0.5
3 a Hydroxyethyl starch 450/0.7
~/Albumin

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 [
/
,ov
40% 281
Intracellularwater
I
Extracellularwater [

Plasma Interstitial
volume volume
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- MW 55-69 kDa
~ 100
80
6o
0

0
¢-

in
4o

20
2
E
ffl

.m
,- 5 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.

50

E 4°f
t~
E
t~
2O
~6
I1)
ffl Q
10
¢3
e-

0 I I I I I

0 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.
P H A R M A C O L O G Y OF A R T I F I C I A L COLLOIDS 25

1000

E
=~ 500

1 2 3 4 5

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).

200 - , .... 6% dextran 70


~k k k , - - 10% dextran 40 ,~
o
c
®
.~ 150
x t,

.=_ 100
ID3
C

~ 5o
0 1 2 3 4 5 6
Time (hours)
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 A N D M I C R O V A S C U L A R 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).

6
t-

t-
O
5

E
O9
c-
O
0 4

i i~ i i c
''O ,,._O
3
''3 ,'~
i i I I I ' --I I t I
0
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/100g)
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.

C O L L O I D S 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

0.15

0.10
¢-
03

t..O
,.Q
E
0

I-

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.
4.
5.
Reduced plasma level of factor VIII: RAg
Change in fibrin structure
Potentiated plasminogen activation
/Enhance fibrinolysis

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 l o o d 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

Fibrinogenesis Fibrinolysis
50

32
28

14

Monocyte Ongoing Monocyte


procoagulant coagulation plasminogen
activity (FPA) activator
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).

ARTERIAL ~ i VENOUS
I
I
I
With leukocyte adhesion I
e5 \ I
13_
E
.-_>" 4
O
o
'7

2
O_
<
I No leukocyte adhesion
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
Microvessel luminal diameter (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
o
O

E 40
0~
t-
"O
<
20 ///J

CON HSS HES Dx60 HES* 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

D=5

30 Increase in
lung weight (g)

20

10
D=5
J_

0
PMA-activated PMA-activated
granulocytes 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).

Figure 16. The microembolism syndrome. FDP, fibrin degradation products; PAF, platelet-activating
factor.

LIMITATIONS AND SIDE-EFFECTS OF COLLOIDS

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 A N D 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 o n h a e m o s t a s 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.

I n f l u e n c e on renal f u n c t i o n
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;
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 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

15
10

0,5 50~ ml

0.2

0.1

0.05 IX"
IIIII I I I I I I
0 123 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
PHARMACOLOGY OF ARTIFICIAL COLLOIDS 39

.~..-,a:~.~..~i~,r.. '-'. ".~., ' ,,. ' . -. ' . : ". , ',


:%".-'~.','~]'~r : , v . °
~.~,,~.,,j~.~p-. . ~ - '~b ., ". . . ". ".:. ~ ¥ -~ ~ • . , .:. . . • . . ... ' ,j. • . .• ~..-.
,r-~ ~'. 7- ~ ;." ;'., ". .?.~,. :. • " -" ',
.-. ., , .-~:~, ~ .-~,. , .-;, ~, ..-.,~'-
..- ,.," ~ ~"w ...... .'~., -~,~.- , • , ,, . - .~:,,,'.
,,,, ~ ~ ,,~ .-_-',,~,,- . .. , . . . . ~ . . . . . ,.:.'. .i . % -,~,~,~

,.,: "., .. ;5,,s,b,a,,, - , '.:' :, ... • , • ".- . '. .


I 3.. • "-.-' .,.',.~-." " g" "~. " . . . " .'.' ". ,.. ~-:" .' • :-.'.~_
• .':'... ,',, ~ , i..~ - - .s.%, • . • . .. : ":i. ' NI
"-..- .... ,6x, ,,,',~ . ~;," . . ~ . ") " . . • . ¢:;• ",

,., . .. ~ r'. .: .. .' r ~ . - , ," - "~ .., " . ' ?


;" "; ' • ",,P "- ;";~ . "."~m ...,n,- , ~, ,,,.,. .,, -
," ,' .," ." . " . '.; ."~'-
. ';-,~:.",iP..,.,~ ' - " •'~',.,~' ~/" • " • -", ", "'.i

• .. :;...... ;... ~.~..'.. , :.- _., ,:?.


.. ""." ." .... ' .'." , "":'.-[,.. "" - ~ ' ' , . ' i" .,..
• ._ ,.:., ~ . ~, -~.".~ ~,. ". ,..~.. ~. ~ ", . .. .
• ~, "':.- "~. ' %,. . *" • .. ' " .t .: a:,. ..~ .~

'.' .~.,
'
'..'~
' ....... "" " '"~"
,.,. ' "
.- .
- ,-i D¢l e _ j "
~ ~ _~lk:.
'~ ~,']l~-I'm
.... % :

,..;?.... ,,. , .. ..-. . .,;~, ~',.~.,

~.k... ' ~""!~' ~""

./, , . .:,,
-..,., ' . ' ":"~2..~.•..u%.,]1. •. li~.,~",..
~' .~.:
:, '
..:, , .. .
:. .~,.,~-~..P ~.,
,,,;

Figure 18. Electronmicrograph showing HES deposition in vacuoles of human dermal macrophage.
× 4400 mag. Reproduced with permission of A. Leunig,

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 C O L L O I D H A E M O D I L U E N T

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).

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