Tissue deposits of hydroxyethyl starch (HES): dose-dependent ... - BJA

British Journal of Anaesthesia 82 (4): 510–15 (1999)
Tissue deposits of hydroxyethyl starch (HES): dose-dependent and
time-related
C. Sirtl 1 *, H. Laubenthal 1 , V. Zumtobel 2 , D. Kraft 3 and W. Jurecka 4
1 Department of Anaesthesiology and 2 Department of Surgery, St Josef-Hospital, Ruhr-Universität Bochum,
Gudrunstr. 56, D-44791 Bochum, Germany. 3 Institute of General and Experimental Pathology and
4 Department of Dermatology, Division of General Dermatology, University of Vienna, Vienna, Austria
*To whom correspondence should be addressed
Tissue deposits occur after administration of plasma substitutes. After hydroxyethyl starch
(HES), deposits may last for months, causing pruritus and impairment of function. Because
elimination of HES deposits has not been demonstrated in humans, we studied 26 patients, for
up to 7 yr after HES administration, to assess HES storage. HES dose ranged from 0.34 to
15.00 g kg –1 body weight, and administration intervals from 1 day to 7 yr. Biopsies of the liver,
muscle, spleen, intestine or skin were studied using light and electron microscopy and
immunohistochemistry. HES storage was dose-dependent, decreased in all organs with time
and was greater in patients suffering from pruritus. We conclude that tissue deposition of HES
is transitory and dose-dependent, with differences between subjects in severity and duration.
Br J Anaesth 1999; 82: 510–15
Keywords: blood, substitutes; pharmacology, hydroxyethyl starch; blood, colloids; fluid therapy
Accepted for publication: November 23, 1998
Tissue deposition of hydroxyethyl starch (HES) (used widely
as a plasma substitute) is common, as with other colloidal
plasma substitutes. After HES administration, deposition in
the cells of the monocyte–macrophage system of various
organs in addition to slow elimination of these deposits has
been shown by several indirect techniques. 1–8 HES was
assumed to be present in mainly empty-appearing intracytoplasmic
vacuoles on light and electron microscopy.
Using a polyclonal anti-HES antiserum, these ‘empty’
vacuoles can be shown to contain HES at their margins. 910
In some patients, storage of HES can be shown by immunohistochemistry
and immuno-electron microscopy more than
2 yr after administration, 10 raising the question of whether
deposits may persist.
Severe untreatable pruritus is a major side effect of high
doses of HES. It has been assumed that this itching
phenomenon is caused by large amounts of tissue deposition
of HES. 10–15 At present, it is not known if the duration of
tissue storage of HES is dose-dependent or if elimination
of HES from the tissues occurs. Therefore, we biopsied
tissues from patients after HES administration over a range
of doses, after periods of up to 7 yr, using light and electron
microscopy, and immunohistochemical methods.
Patients and methods
We studied 26 patients retrospectively. They had previously
received HES infusions and were studied during re-admission
© British Journal of Anaesthesia
to hospital. A complete history was obtained, including the
date and duration of HES infusion, dose and preparation
of HES (molecular weight, degree of substitution and
trademark). No other agents had been given. The amount
of HES given varied between 0.34 and 15.00 g kg –1 body
weight, given over several days. According to the dose of
HES, patients were allocated to one of two groups. Patients
in group A (n�16) received a maximum dose of 2 g kg –1 ,
which is often used for volume replacement. Patients in
group B (n�10) received greater doses of HES, ranging
from more than 3 up to 15 g kg –1 , given for microcirculatory
disorders (Table 1).
All 16 patients in group A were undergoing surgery for
malignancy, other surgical indications or for chronic or
bilateral orthopaedic disorders. They received a mean dose
of 0.8 (range 0.3–1.9) g kg –1 within 24 h (Table 1). None
of the patients developed pruritus. Patients were comparable
in blood loss, organ function and clinical laboratory findings.
Informed consent was obtained for taking pea-sized tissue
samples from the operating site. Biopsies were obtained
from one or more sites (skin, liver, small intestine, striated
muscle or spleen) between 1 day and 84 months after HES
infusion (Table 1). This procedure was approved by the
Ethics Committee of the Faculty of Medicine at the Ruhr-
Universität Bochum.
Patients in group B received greater amounts of HES,
with a mean dose of 7.8 (3.1–15.0) g kg –1 . Nine patients
(Nos B1–8, B10) received HES infusions for vascular disease,
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Tissue deposits of HES
Table 1 Patient details (dose group, sex, age), type (molecular weight (Mw)/molar substitution (MS)) and amount of HES administered, time interval between
HES infusion and biopsies, organ biopsied (skin, liver, small (S.) intestine, striated (St.) muscle, spleen), and findings regarding HES deposits in organ tissues
(–negative, � weak, �� moderate, ��� marked signs of storage, i.e. vacuoles)
Type of HES infused Amount of HES infused Organ investigated and Time of biopsy after HES administration
Patient No. Sex Age (yr) (Mw/MS) (g kg –1 ) HES storage (d � days, m � months)
A1 F 45 200/0.5 1.69 Skin � 1d
Liver �
S. intestine �
St. muscle �
Spleen �
A2 M 42 200/0.5 0.52 Skin �� 3.5 m
St. muscle �
A3 M 65 200/0.5 1.19 Skin – 3.5 m
S. intestine –
St. muscle –
A4 F 40 200/0.5 1.00 Skin �� 5m
A5 M 62 200/0.5 0.65 Skin � 9m
St. muscle –
A6 M 65 450/0.7 0.34 Skin � 10 m
St. muscle �
S. intestine �
A7 M 54 200/0.5 0.68 Skin � 12 m
St. muscle �
A8 F 61 200/0.5 0.86 Skin � 13 m
A9 F 52 200/0.5 0.53 Skin – 15 m
St. muscle –
A10 F 54 450/0.7 0.50 Skin � 15 m
St. muscle �
S. intestine �
A11 F 63 200/0.5 1.00 Skin � 15 m
Liver �
St. muscle �
A12 M 24 200/0.5 0.69 Skin – 26 m
St. muscle -
A13 M 55 200/0.5 0.60 Skin � 34 m
St. muscle –
A14 F 71 (a) 200/0.5 1.86 Skin � (a) 16 m
(b) 450/0.7 Liver – (b) 48 m
St. muscle –
A15 F 72 450/0.7 0.43 Skin � 53 m
St. muscle –
A16 F 67 450/0.7 0.56 Skin – 84 m
Liver –
St. muscle –
B1 F 26 200/0.5 15.00 Skin ��� 4m
B2 M 50 200/0.5 6.80 Skin ��� 6m
B3 F 68 200/0.5 3.22 Skin ��� 12 m
B4 M 25 200/0.5 4.40 Skin �� 12 m
B5 F 42 200/0.5 6.92 Skin ��� 14 m
St. muscle ���
B6 M 58 200/0.5 7.24 Skin ��(�) 19 m
B7 F 54 200/0.5 8.33 Skin ��(�) 25 m
B8 M 65 200/0.5 13.88 Skin ���/�� 6 m/41 m
B9 M 56 200/0.6 3.10 Skin ���/– 6 m/45 m
B10 M 27 200/0.5 7.80 Skin ���/� 17 m/54 m
one patient (No. B5) to improve tissue perfusion after plastic
surgery and another (No. B9) for treatment of a chronic leg
ulcer. Seven of these patients (Nos B2, B3, B6–10) have
been reported on previously, 10 but biopsy data have not been
published. HES patients B1–8 and B10 developed severe
pruritus, leading to consultation with dermatologists and/or
anaesthetists. After informed consent, one or several diagnostic
and follow-up skin biopsies were performed using
local anaesthesia, between 6 and 25 months after HES infusion.
In patients B8, B9 and B10, additional follow-up
biopsies were obtained approximately 3 yr later (Table 1).
511
Tissue processing
All biopsies, regardless of tissue source, were processed
similarly. Biopsies were divided into several pieces and
fixed in 7% buffered paraformaldehyde or Karnovsky’s
fixative. Some were post-fixed in osmium tetroxide
and embedded in paraplast, Epon 812 or LR White.
Haematoxylin–eosin (HE) or periodic acid–Schiff (PAS)
stained paraffin sections, or semi-thin toluidine blue
stained Epon sections were used for light microscopy,
and unstained paraffin sections for immunohistochemistry.
Ultra-thin uranyl acetate and lead citrate stained Epon
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sections and ultra-thin LR White sections were used for
electron microscopy or immuno-electron microscopy,
respectively.
Immunohistochemistry
For light microscopy, after blocking endogenous peroxidases,
paraffin sections were incubated with a well defined
polyclonal rabbit antiserum against HES (kindly given by
Dr Richter, Helsingborg, Sweden), 16 followed by swine antirabbit
immunoglobulin, horseradish peroxidase conjugated
with rabbit anti-peroxidase (peroxidase anti-peroxidase
(PAP) technique) and 3-amino-9-ethyl-carbazol. Sections
were counterstained with haematoxylin. For immunoelectron
microscopy, ultra-thin LR White sections were
incubated with the anti-HES antiserum followed by protein
A gold using 15-nm gold particles and counterstained with
uranyl acetate.
Controls included dilution series, omission of primary
antibody, replacement of the primary antibody by a nonimmune
serum or an unrelated antibody, incubation with
protein A gold alone or incubation with non-labelled protein
A before protein A gold application.
Quantification
The amount of HES deposition in each biopsy was quantified
by combining the results of all staining procedures. Results
were categorized as follows: ����a large number of
storage vacuoles present on light microscopy (semi-thin
section, paraffin section) confirmed by immunohistochemistry
or immuno-electron microscopy; ���moderate
numbers of storage vacuoles present on light microscopy
(mainly semi-thin section) confirmed by immunohistochemistry
or immuno-electron microscopy; ��scanty storage
vacuoles either in semi-thin sections or immunohistochemistry;
and – �no evidence of deposition with any
method used.
The methods of tissue processing, staining, immunohistochemistry
and controls for light and electron microscopy
have been described previously. 10
Results
We considered either a positive immunohistochemistry/
immuno-electron microscopy or a definite vacuolization of
cells to indicate HES deposition. Paraffin section vacuolated
cells, which were partly PAS-positive, could only weakly
be seen in the skin of patients in group B. However, in
toluidine blue stained semi-thin sections, apparently empty
intra-cytoplasmic vacuoles could be detected easily in
various cells of positive organs. In addition to vascular
endothelial cells, HES deposition occurred mainly in cells of
the monocyte–macrophage system. In the liver, parenchymal
cells or sinusoidal spindle-shaped cells showed vacuolization.
In striated muscle, muscle cells showed no signs
of HES deposition, but interstitial histiocytes or macrophages
had intra-cytoplasmic vacuoles. In the spleen,
Sirtl et al.
512
Fig 1 Positivity or negativity of biopsies of several organs for HES
deposition at different time intervals after HES infusion (Note HES persists
longest in skin).
vacuoli were prominent in reticular cells in the red pulp
and at the border between red and white pulp. In the
intestine, mucosal epithelium did not have HES deposition,
but vascular endothelial cells and stromal macrophages had
some vacuoli. In the skin, vascular endothelial cells and
dermal macrophages had vacuoli. In patients in group B,
perineural cells, endoneural connective tissue cells and
Langerhans’ cells also had vacuoli. Light microscopy findings
were confirmed by electron microscopy, showing intracytoplasmic
empty membrane-bound vacuoles with some
electron-dense material at their margins. In each patient,
HES deposition was also shown either by positive immunohistochemical
or immuno-electron microscopy staining of
vacuolated cells with the anti-HES antiserum. Control
stainings were negative.
HES deposits were found in all biopsied organs (liver,
muscle, spleen, intestine, skin) on the first day after HES
infusion. The amount of HES found in all patients at
different times after HES administration is shown in Table 1.
In group A (low dose group, 0.3–1.9 g kg –1 ), in liver,
muscle and skin biopsies, HES deposits decreased with
time, and organs became negative for HES. In the spleen
and intestine, not enough patients were studied to show the
time course. In liver and muscle, deposits were found up
to 15 months, and in skin up to 54 months, after HES
infusion (Table 1, Fig. 1).
In all 10 patients in group B (high dose group, 3.1–15.00
gkg –1 ) massive deposits of HES were demonstrated in the
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Fig 2 Skin biopsies of patient No. B8, who received HES 200/0.5
13.88 g kg –1 . (A) Six months after infusion, numerous large ‘empty’
vacuoles can be seen in the dermis in cells of the monocyte–macrophage
system; (B) 45 months after infusion only few small vacuoles can be seen
in a macrophage (Y) and endothelial cell (I) Toluidine blue stained semithin
sections; A�420, B�340.
skin and in one patient in muscle at 4–25 months after HES
administration (Table 1). Nine of 10 patients (Nos B1–4,
B6–8, B10) had severe pruritus at the time of the first
biopsy. In three patients, biopsies repeated approximately
3 yr later showed remarkable reduction of HES deposition
in the skin (Fig. 2A, B) and one patient (No. B9) was
Tissue deposits of HES
513
completely negative by that time (Table 1). Pruritus had
resolved in two of these patients (Nos B8, B10).
Discussion
Our results showed clearly that tissue deposition of HES
was dose- and time-dependent. In particular, patients in
group B who received 3.1–15.00 g kg –1 within a few days,
showed massive tissue deposition of HES. In the low dose
group (0.3–1.9 g kg –1 ) only moderate or slight tissue
deposits were found. With greater time between HES
administration and biopsy, a decrease in HES deposits
occurred in both groups, with complete loss of HES deposits
in some patients in group A and in one patient in group B.
Tissue deposition occurs with all colloidal plasma substitutes.
For gelatins and albumin there is only indirect
evidence of delayed elimination from the circulation and
of some deposits in the cells of the monocyte–macrophage
system in vitro. 17–20 For dextrans, storage has been described
in the monocyte–macrophage system in vivo and in vitro, 21
which may be important in patients undergoing chronic
haemodialysis. 522HES has been demonstrated mainly in
the cells of the monocyte–macrophage system of various
tissues by indirect methods (i.e. empty vacuoles2 4–8 ),
14C-HES uptake, 3 7 photometric measurements3 7 and
specifically by immunohistochemical and immuno-electron
microscopy techniques in several rat tissues and in human
skin by our group. 910Using the same techniques, we have
shown HES deposits in human liver, striated muscle, spleen
and intestine. We also showed that HES deposits in skin
increased with the amount of HES administered and
decreased with time after HES administration.
Until now, complete elimination of HES deposits from
human tissue was uncertain. We found no HES in all organs
investigated, including skin, in five of our 26 patients (Nos
A3, A9, A12, A16, B9) and a decrease (i.e. negative
findings) in some organs, except skin, in four other patients
(Nos A5, A13, A14, A15) over several years. This loss of
deposits may reflect the different specific kinetics of HES
in human organs, as is the case for animal organs, except
skin. 23 Hitherto, slow elimination of HES from plasma and
tissues has been inferred from indirect investigations in
animals and humans1 3–6 8 24over relatively short time
intervals, but complete elimination has never been demonstrated.
Normally, persistent tissue deposits of HES do not
appear to be clinically relevant to the function of organs or
of the monocyte–macrophage system. 810252627However, in patients with renal failure started on chronic dialysis,
even small quantities of pentastarch, such as HES 200/0.5
or HES 70/0.55, may cause hepatosplenomegaly, portal
hypertension and ascites. This is thought to be caused
by hepatocytes ballooning with HES vacuoli and thus
narrowing hepatic sinusoids. This can resolve after months
or years. 228
In our 26 patients, in addition to the amount of HES
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administered, other factors appeared to be responsible for
the duration of HES deposition. It is not surprising that
patients who received the largest amounts of HES had
persistence of this substance in their tissues. However,
patient No. A3, who received a relatively large amount of
HES (1.19 g kg –1 ) over a short time showed no tissue
deposits in skin, intestine and muscle after 3.5 months.
Comparing patients A9 and A10, who received two different
types (A9 pentastarch-like vs A10 hetastarch-like with a
different degree of substitution) but comparable amounts
of HES, patient No. A9 had no deposits in skin and muscle
while patient A10 had deposits in skin, muscle and intestine
after 15 months. Comparing patients A12 and A13, who
received HES 200/0.5 in comparable quantities, patient
No. A12 had no deposits in skin and muscle at 26 months
while patient No. A13 had none in muscle but still had
deposits in skin 34 months after HES administration. This
could be caused by differences in patient hydration status
(amount of fluid ingested by or crystalloid infusions given
to patients during or shortly after HES administration) or
kidney function, resulting in differences in elimination
of HES from the circulation in the early phase after
administration.
2 28–31
Another explanation is that increased blood loss may
eliminate HES, as shown in patient No. A3. Finally,
metabolic differences may exist. HES is metabolized by
hydrolysis of glycosidic bonds within the glucose chains
by various plasma and lysosomal glycosidases. Differences
in metabolic capacity could be responsible for the development
of pruritus, 32 which could also explain differences in
duration of HES deposits in patients receiving similar
amounts of the same substance.
HES deposits have been described in several organs, and
probably all organs except the central nervous system are
involved. In 16 patients in group A it is obvious that the
skin was the organ most involved, retaining HES deposits
longer than other organs (Fig. 1), but the number of patients
investigated was small. No clear explanation can be given
for this phenomenon. Differences in the density of cells of
the monocyte–macrophage system and/or differences in
their mobility, or metabolic capacity in various organs could
be responsible.
Deposits may not be found if they are in very coarsely
or inhomogeneously distributed vacuoles. Previous investigations,
taking parallel biopsies at different sites in the
same organ, did not find inhomogeneity of the deposits in
various tissues. 8 Very isolated vacuoles (e.g. 1 cm –3 ) may
be of no clinical importance.
Hepatosplenomegaly in chronic terminal renal failure and
persistent pruritus are the only major side effects attributed
to tissue deposition after HES infusion. Even after large
doses during prolonged ICU therapy, patients do not complain
of pruritus. Previous studies concluded that tissue
deposition in general and pruritus in particular are dosedependent
and time-limited phenomena. 10–13 15 33 Our study
supports this. Only patients in the high dose group (except
Sirtl et al.
514
patient No. B9) suffered from pruritus, although the latter
received comparable amounts of HES and showed similar
massive deposition of HES in the skin. At follow-up
approximately 3 yr later, patients B8 and B10 had recovered
from pruritus, and their skin biopsies still had HES deposits,
but to a lesser content. This supports the belief that HES
deposits and pruritus are dose-dependent and transitory.
Previous recommendations to reduce the dose of HES,
especially for long-term treatment, reduced the frequency
of HES-induced pruritus.
In summary, tissue deposition of HES and its major
clinical effect (pruritus) are mainly dose-dependent transitory
phenomena. Complete elimination of HES deposits
occurs over different times after administration.
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