Professional Documents
Culture Documents
Pharmacological characteristics of
artificial colloids
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
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.
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
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.
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
-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
, ,
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
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.
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.
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)
50
E 4°f
t~
E
t~
2O
~6
I1)
ffl Q
10
¢3
e-
0 I I I I I
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).
.=_ 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
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
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.
100
o
~ 8O
0)
"O
60
O
O
g4o
t-
O
~ 20
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.
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
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.
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
Fibrinogenesis Fibrinolysis
50
32
28
14
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).
100
80
60
o
O
E 40
0~
t-
"O
<
20 ///J
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
Figure 16. The microembolism syndrome. FDP, fibrin degradation products; PAF, platelet-activating
factor.
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
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
'.' .~.,
'
'..'~
' ....... "" " '"~"
,.,. ' "
.- .
- ,-i D¢l e _ j "
~ ~ _~lk:.
'~ ~,']l~-I'm
.... % :
./, , . .:,,
-..,., ' . ' ":"~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
CONCLUSION
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