The Pharmacokinetics and Tolerability of an Intravenous Infusion of the New Hydroxyethyl Starch 130/0.4 (6%, 500 mL) in Mild-to-Severe Renal Impairment

Article (PDF Available)inAnesthesia & Analgesia 95(3):544-51, table of contents · September 2002with65 Reads
DOI: 10.1097/00000539-200209000-00007 · Source: PubMed
Abstract
Unlabelled: Hydroxyethyl starches (HES) are almost exclusively excreted glomerularly, in part after hydrolysis by amylase. HES 130/0.4 (Voluven; Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) was developed to improve pharmacokinetics whereas preserving the efficacy of volume effect. We studied the dependency of pharmacokinetics of HES 130/0.4 on renal function. Nineteen volunteers with stable, non-anuric renal dysfunction, ranging from almost normal creatinine clearance (CL(cr)) to severe renal impairment (mean CL(cr): 50.6 mL. min(-1). 1.73 m(-2)), were given a single infusion of 500 mL 6% HES 130/0.4 over 30 min. HES plasma concentrations were determined until 72 h, urinary excretion until 72-96 h. CL(cr) had been obtained at least twice before and twice after dosing. Standard pharmacokinetic calculations and regression analysis were performed. Area under the time concentration curve (AUC(0-inf)) clearly depended on renal function comparing subjects with CL(cr) < 50 with those with CL(cr) > or =50 (ratio 1.73). Peak concentration (C(max), 4.34 mg/mL) as well as terminal half-life (16.1 h, model independent) were not affected by renal impairment. At CL(cr) > or =30, 59% of the drug could be retrieved in urine, versus 51% at CL(cr) 15-<30. The mean molecular weight of HES in plasma was 62,704 d at 30 min, showing lower values with increased renal impairment (P = 0.04). Pre-dose amylase concentrations inversely correlated with baseline CL(cr). Residual HES plasma concentrations after 24 h were small in all subjects (< or =0.6 mg/mL). We conclude that HES 130/0.4 (500 mL 6%) can be safely administered to patients even with severe renal impairment, as long as urine flow is preserved, without plasma accumulation. Implications: Dependency of the pharmacokinetics of hydroxyethyl starch 130/0.4 on renal function was studied. The area under the time concentration curve increased moderately with more severe renal dysfunction; however, small plasma concentrations were observed after 24 h. Terminal half-life and peak concentration remained unaffected by renal impairment.

Figures

The Pharmacokinetics and Tolerability of an Intravenous
Infusion of the New Hydroxyethyl Starch 130/0.4
(6%, 500 mL) in Mild-to-Severe Renal Impairment
Cornelius Jungheinrich, MD*, Roland Scharpf, PhD*, Manfred Wargenau, PhD†,
Frank Bepperling,
PhD*, and Jean-Franc¸ois Baron, MD, PhD‡
*Clinical Research, Fresenius Kabi, Bad Homburg; †M.A.R.C.O. Biostatistics Institute, Du¨ sseldorf, Germany; and ‡Medical
Department, Fresenius Kabi France, formerly Anesthesia Department, Hoˆpital Pitie´-Salpeˆtrie`re, Paris, France
Hydroxyethyl starches (HES) are almost exclusively ex-
creted glomerularly, in part after hydrolysis by amy-
lase. HES 130/0.4 (Voluven
®
; Fresenius Kabi Deut
-
schland GmbH, Bad Homburg, Germany) was
developed to improve pharmacokinetics whereas pre-
serving the efficacy of volume effect. We studied the
dependency of pharmacokinetics of HES 130/0.4 on re-
nal function. Nineteen volunteers with stable, non-
anuric renal dysfunction, ranging from almost normal
creatinine clearance (CL
cr
) to severe renal impairment
(mean CL
cr
: 50.6 mL · min
1
· 1.73 m
2
), were given a
single infusion of 500 mL 6% HES 130/0.4 over 30 min.
HES plasma concentrations were determined until 72 h,
urinary excretion until 72–96 h. CL
cr
had been obtained
at least twice before and twice after dosing. Standard
pharmacokinetic calculations and regression analysis
were performed. Area under the time concentration
curve (AUC
0–inf
) clearly depended on renal function
comparing subjects with CL
cr
50 with those with CL
cr
50 (ratio 1.73). Peak concentration (C
max
, 4.34 mg/
mL) as well as terminal half-life (16.1 h, model indepen-
dent) were not affected by renal impairment. At CL
cr
30, 59% of the drug could be retrieved in urine, versus
51% at CL
cr
15–30. The mean molecular weight of
HES in plasma was 62,704 d at 30 min, showing lower
values with increased renal impairment (P 0.04). Pre-
dose amylase concentrations inversely correlated with
baseline CL
cr
. Residual HES plasma concentrations af
-
ter 24 h were small in all subjects (0.6 mg/mL). We
conclude that HES 130/0.4 (500 mL 6%) can be safely
administered to patients even with severe renal impair-
ment, as long as urine flow is preserved, without
plasma accumulation.
(Anesth Analg 2002;95:544–51)
H
ydroxyethyl starch (HES) solutions are artificial
colloids for intravascular volume replacement
derived from corn starch amylopectin. HES so-
lutions are polydisperse, comprising a distribution of
molecular sizes. The polyglucose chains closely resem-
ble glycogen with predominant
1–4 bindings. The
main characteristics of a HES type are mean molecular
weight (Mw, weight average), molar substitution (MS,
i.e., mol hydroxyethyl residues per mol glucose sub-
units), and C2/C6 ratio (the substitution pattern at the
glucose subunit carbon atoms). There are large re-
gional differences in the use of different HES specifi-
cations. For decades in the United States, only HES
450/0.7 has been available for volume therapy. The
predominant starch in Europe is HES 200/0.5,
whereas in Japan only HES 70/0.5 is available. Safety
issues of a colloid such as HES are related to molecular
properties, resulting in different in vivo Mw, plasma
concentrations over time, and tissue storage. Pharma-
cology, especially regarding half-lives, duration of
volume effect, posology, and possible side effects, sig-
nificantly differs among the different specifications.
However, all HES preparations are excreted renally.
Other ways of excretion are negligible (1). Molecules
above the renal threshold are filtered glomerularly
only after hydrolysis by serum
-amylase to smaller
fragments. A new medium-Mw starch specification,
HES 130/0.4 (6%, Voluven
®
), was developed to im
-
prove pharmacokinetics by more rapid metabolism
whereas preserving the efficacy of volume effect com-
pared with HES 200/0.5 (6%). The pharmacologic
Supported by a grant from Fresenius Kabi Deutschland GmbH,
Bad Homburg, Germany.
Presented in part at the 21st International Symposium on Inten-
sive Care and Emergency Medicine, Brussels, Belgium, March 20
23, 2001.
Accepted for publication May 13, 2002.
Address correspondence and reprint requests to Cornelius Jung-
heinrich, MD, Clinical Research, Fresenius Kabi, 61346 Bad Hom-
burg, Germany. Address e-mail to Cornelius.Jungheinrich@
fresenius-kabi.com.
DOI: 10.1213/01.ANE.0000023340.61499.72
©2002 by the International Anesthesia Research Society
544 Anesth Analg 2002;95:544–51 0003-2999/02
characteristics of HES 130/0.4 are a Mw of 130,000
20,000 d, an MS of 0.4, and a C
2
/C
6
ratio of about 9:1,
leading to a decrease in plasma accumulation (2) and
a smaller tissue storage (3) of HES after repeated ad-
ministration. The Mw distribution was narrowed by
the reduction of the high- and low-Mw fraction, which
led to an increase of the medium-size fraction, with
most of these molecules above the renal threshold. A
low MS results in an increase of metabolic degradation
(4). However, the increased C
2
/C
6
ratio in part coun
-
teracts this effect, because a high C
2
/C
6
ratio decreases
the hydrolysis by
-amylase (5,6). In addition to stud-
ies in patients that demonstrated efficacy and a favor-
able safety profile (713), pharmacokinetic trials in
healthy volunteers showed a rapid elimination from
plasma after both single- (14) and multiple-dose (2)
administration.
According to the European label for HES 130/0.4
and the United States hetastarch label, these can be
used in patients with non-oligoanuric renal impair-
ment. Therefore, information on the dependency of
pharmacokinetics of HES on renal function is a crucial
contribution to increase therapeutic safety, and was
assessed in this study for HES 130/0.4 (6%).
Methods
After approval of the study by the local ethics com-
mittee, subjects gave written informed consent for
their participation. All procedures were performed
according to Good Clinical Practice standards. Nine-
teen volunteers (6 women, 13 men) with different
degrees of stable, non-anuric renal dysfunction were
included. Phase I facilities and volunteer database
(Pharm PlanNet Clinical Pharmacology Institute,
Moenchengladbach, Germany) were used. Subject re-
cruitment followed a predefined stratification accord-
ing to the Food and Drug Administration guidance
document (15) to cover a wide range of renal impair-
ment, and to allow for regression analysis rather than
comparing arbitrary renal function groups only. Six
subjects belonged to the group with severe renal
impairment (creatinine clearance [CL
cr
]15
30 mL · min
1
· 1.73 m
2
),4tomoderate (30 50), 5
to mild (5080), and 4 almost normal subjects
showed a CL
cr
in the interval 80 120. Stable renal
function was verified by performing at least 2 separate
measurements of CL
cr
using 24-h urine collection and a
serum sample. Creatinine was measured by the Jaffe´
method. The standard formula was applied for
CL
cr
determination: urine concentration · urine volume ·
body surface area serum concentration
1
· 1.73 m
2
·
1440 min
1
. The mean of both values was taken before
the subjects were assigned to their respective stratum.
Volunteers with unstable renal function, severe hepatic
or cardiac disease, or severe anemia were not included in
the study.
Under supervision of an anesthesiologist, 500 mL of
6% HES 130/0.4 solution (Voluven
®
; Fresenius Kabi
Deutschland GmbH, Bad Homburg, Germany) was
infused over a 30-min period by using an infusion
pump. Venous blood samples were drawn into lith-
ium heparinized tubes before the start of infusion, 5,
10, and 30 min, 1, 2, 4, 6, 8, 24, 48, and 72 h after the
start of infusion. Urine samples were collected quan-
titatively up to 96 h.
The HES either in plasma or urine samples was
precipitated by acetone. After the removal of the su-
pernatant, HES precipitate was dissolved in sodium
azide solution and hydrolyzed into glucose with trif-
luoroacetic acid. After drying and dissolving in buffer
solution, the glucose was determined enzymatically
with a glucose analyzer. The determination of in vivo
mean Mw was performed by using low-angle laser
lights scattering and high-performance liquid chroma-
tography validated for physiologic samples.
The primary objective of this study was to investi-
gate whether renal impairment had an effect on the
pharmacokinetics of HES. Significance tests were ex-
ploratively applied each at nominal
-level of 5% and
referred to the null-hypothesis of zero correlation.
This was statistically addressed by exploring the rela-
tionship between CL
cr
and each of the pharmacokinetic
variables applying correlation and regression analyses.
A subject was judged valid for analysis if CL
cr
was found
stable during the screening phase showing values be-
tween 15 and 120 mL · min
1
· 1.73 m
2
, and if pri
-
mary pharmacokinetic variables (area under the time
concentration curve [AUC
(0inf)
] and peak concentration
[C
max
]) could be derived from the analytic blood sample
profile.
Correlation analyses were also performed to inves-
tigate the relationship between CL
cr
, age, body mass
index, height, weight, and the pharmacokinetic vari-
ables (both model independent and model based) cal-
culating Pearson correlation coefficients. This also in-
cluded consideration of partial correlations that
describe the association between two variables con-
trolling for other potentially confounding variables. In
addition, HES mean Mw, baseline CL
cr
, and serum
amylase were also the subject of partial correlation
analyses.
Descriptive statistics were calculated for each of the
pharmacokinetic variables, including geometric
means and corresponding coefficients of variation.
In addition, two predefined subgroups with CL
cr
50 and 50 mL · min
1
· 1.73 m
2
were compared
with respect to AUC
(0inf)
and C
max
. Log-transformed
variables were submitted to separate analyses of vari-
ance including the fixed effects sex, subgroup, and
interaction sex · subgroup. Point estimates and associ-
ated (explorative) two-sided 95% confidence intervals
were constructed for the ratio of the two subgroups
(50/50 mL · min
1
· 1.73 m
2
). Based on previous
ANESTH ANALG CARDIOVASCULAR ANESTHESIA JUNGHEINRICH ET AL. 545
2002;95:54451 HES 130/0.4 IN RENAL IMPAIRMENT
information, the coefficient of variation (CV) of
AUC
(0inf)
was assumed to be approximately 20%.
This means that a difference of approximately 35%
between two subgroups consisting of 9 subjects each
could be detected with 80% power at an explorative
-level of 5%. In fact, the (pooled within-group) CV
was 19% for AUC
(0inf)
and 22% for C
max
so that this
study was adequately powered to provide valid and
credible results.
Data were analyzed by using SAS
®
version 6.12
(SAS Institute Inc., Cary, NC). Pharmacokinetic vari-
ables were derived by using WinNonLinversion 3.0
(Pharsight Corp., West El Camino Real, CA) for both
the model independent approach and the two-
compartmental modeling.
Safety was investigated by documentation of ad-
verse events (AE), routine clinical laboratory, physical
examination, blood pressure (BP), pulse rate, and elec-
trocardiogram. Specifically, determination of CL
cr
from 24-h urine (day 3, 4) was performed twice after
drug exposition. Cumulative HES excretion and resid-
ual HES plasma concentrations were regarded as es-
pecially relevant for product safety, in addition to the
primary pharmacokinetic variables AUC
(0inf)
and
C
max
.
Results
All subjects were valid for pharmacokinetic evalua-
tion. Means (sd) of demographic/baseline values
were the following: age 54 (14, range 30 77) yr,
weight 77.3 (15.2) kg, height 172 (10) cm, systolic
BP 144 (19) mm Hg, diastolic BP 83 (10) mm Hg,
heart rate 68 (10) min
1
.CL
cr
at baseline was on
average 50.6 mL · min
1
· 1.73 m
2
ranging between
15.4 and 100.8 mL · min
1
· 1.73 m
2
, with a mean
intraindividual CV of 9% for the baseline measure-
ments done in each subject. Maximal CV was ob-
served in 1 subject in the severe renal group based on
CL
cr
values of 12.2 and 18.6 mL · min
1
· 1.73 m
2
; all
other CVs were less than 17%. Increased restriction of
renal function was associated with older age and
higher baseline systolic BP. For 8 of the 15 subjects
with CL
cr
values 80, the etiology of the impaired
renal function was not known. For two subjects, dia-
betes mellitus was reported as the underlying disease.
Each of the diagnoses, immunoglobulin A (IgA)-
neuropathy, nephrolithiasis, sarcoidosis, suspected
hypertensive nephropathy, and polycystic kidney dis-
ease, was documented once.
HES plasma concentrations were larger in the 10
subjects with CL
cr
50 than in the 9 subjects with CL
cr
50. Figure 1 shows the mean courses of HES concen-
tration up to 72 h after infusion. Table 1 shows the
most relevant pharmacokinetic variables. No differ-
ences were apparent when comparing the two renal
groups (1530) and (30 50). The same is true for a
comparison between the renal groups (5080) and
(80120).
The study showed that AUC
(0inf)
, and conse
-
quently HES total plasma clearance, clearly depended
Figure 1. Mean plasma concentra-
tions (sd) of hydroxyethyl starch
(HES) after infusion of 500 mL of
HES 130/0.4, 6%.
546 CARDIOVASCULAR ANESTHESIA JUNGHEINRICH ET AL. ANESTH ANALG
HES 130/0.4 IN RENAL IMPAIRMENT 2002;95:54451
on renal function (i.e., on CL
cr
).
Figure 2 displays the
correlation between baseline Cl
cr
and AUC
(0inf)
. The
coefficient of correlation was calculated as 0.76 being
significantly different from zero (P 0.001). This re-
lationship seemed even stronger when controlling for
the potentially influencing factors of age, body mass
index, height, and weight: the corresponding partial
correlation coefficient resulted to 0.89.
Subjects with a CL
cr
50 had, on average, a 73%
larger AUC
(0inf)
than subjects with a CL
cr
50. The
95% confidence interval for the mean AUC ratio of
1.73 was 1.44, 2.07, which indicated that a more than
doubled AUC in moderate-to-severe renally impaired
subjects can be excluded.
Inversely, HES total plasma clearance decreased
with decreasing baseline CL
cr
(
Fig. 3); however, the
proportional decrease was less than expected from the
reduction in CL
cr
for a compound such as HES, which
is glomerularly filtered only.
The plasma C
max
was not affected by renal impair
-
ment (r ⫽⫺0.07, P 0.77). Also, renal impairment did
not influence terminal half-life, which was on average
16.1 h and ranged between 14.1 and 18.9 h (r 0.31,
P 0.19).
The cumulative amount of drug excreted into urine
within 72 to 96 h was 59% of the total dose infused in
subjects with a CL
cr
30, whereas it was 51% in the
severely impaired group (1530 mL · min
1
· 1.73
m
2
;
Fig. 4).
HES pharmacokinetics are often described using a
two-compartmental model (14). The two-compartmental
model also provided a valid fit to the individual HES
plasma concentration-versus-time curves in this study.
The
half-life (t1/2
) was prolonged by impaired
renal function. In subjects with a CL
cr
between 80 and
120, mean t1/2
was calculated as 0.6 h compared
with1hinthegroup with CL
cr
between 50 and 80,
and to approximately 1.5 h in subjects with a CL
cr
50
(mL · min
1
· 1.73 m
2
). A linear relationship between
t1/2
and CL
cr
could be assumed, showing a correla
-
tion coefficient of r ⫽⫺0.55 (P 0.02). Corresponding
results were obtained for drug elimination half-life
from the central compartment: means of 2 h for (80
120), 3 h for (50 80), and approximately 5 h for
CL
cr
50. Half-life (central compartment) linearly in
-
creased with decreasing CL
cr
, showing an r ⫽⫺0.73
(P 0.001). Mean t1/2
resulted in 9.7 h. An influence
of renal impairment on t1/2
was not detected
(r ⫽⫺0.37, P 0.12).
The mean Mw of the original 6% solution was ana-
lyzed as 130,652 d. In the first sample taken (after
0.5 h), mean Mw was 62,704 d, and in the second
Table 1. HES Pharmacokinetic Variables, Model Independent
Variable
Renal
group
a
Mean (CV %) (geometric) 95% CI
AUC
(0inf)
(mg h/mL)
15 30 41.1 (19.9) (33.4, 50.6)
30 50 35.1 (13.9) (28.1, 43.8)
50 80 20.0 (6.8) (18.4, 21.8)
80 120 25.5 (21.3) (18.3, 35.4)
All subjects 29.8 (34.4) (25.3, 35.0)
C
max
(mg/mL)
15 30 4.68 (17.4) (3.90, 5.62)
30 50 4.37 (14.1) (3.50, 5.46)
50 80 3.48 (12.5) (2.99, 4.05)
80 120 5.11 (25.4) (3.45, 7.57)
All subjects 4.34 (21.9) (3.91, 4.81)
Total plasma clearance (L/h) 1530 0.73 (20.3) (0.59, 0.90)
30 50 0.85 (12.8) (0.69, 1.05)
50 80 1.52 (6.9) (1.40, 1.65)
80 120 1.19 (21.3) (0.86, 1.65)
All subjects 1.02 (34.9) (0.87, 1.20)
Volume of distribution at steady state (L) 15 30 14.2 (18.4) (11.7, 17.2)
30 50 15.4 (12.7) (12.7, 18.7)
50 80 27.1 (6.6) (24.9, 29.5)
80 120 19.9 (23.1) (13.8, 28.7)
All subjects 18.4 (31.2) (15.9, 21.3)
Terminal half-life (h) 15 30 15.9 (8.8) (14.5, 17.4)
30 50 15.5 (9.6) (13.3, 18.0)
50 80 15.9 (5.4) (14.8, 17.1)
80 120 17.2 (6.8) (15.4, 19.2)
All subjects 16.1 (8.1) (15.5, 16.7)
HES hydroxyethyl starch, CV coefficient of variation, CI confidence interval, AUC area under the time concentration curve, C
max
peak
concentration.
a
Defined according to measurements of creatinine clearance (mL/min/1.73 m
2
).
ANESTH ANALG CARDIOVASCULAR ANESTHESIA JUNGHEINRICH ET AL.
547
2002;95:54451 HES 130/0.4 IN RENAL IMPAIRMENT
sample (after 1 h), the mean value was 59,117 d. How-
ever, the Mw tended to decrease with decreasing base-
line CL
cr
(r 0.63, P 0.04 after 0.5 h). Baseline serum
amylase was inversely correlated with CL
cr
(r
0.72, P 0.001), and Mw in plasma after1hwasalso
inversely correlated with baseline amylase (r ⫽⫺0.76,
P 0.001) (Fig. 5). In subjects with higher baseline
amylase, lower HES Mw after 1 h can be regarded as
an indicator of accelerated intravascular breakdown,
because there was no indication that the lower plasma
Mw was caused by a selective retention of smaller
HES molecules in these subjects. In fact, partial corre-
lation analysis provided evidence for an association
between baseline amylase activity in the metabolism
of HES independent of CL
cr
.
There was no deterioration in renal function after
dosing, as determined by repetitive CL
cr
measure
-
ments in the individual subjects. On average, CL
cr
Figure 2. Regression plot of creati-
nine clearance versus area under the
time concentration curve (AUC
(0inf)
).
No. individual.
Figure 3. Regression plot of creati-
nine clearance versus hydroxyethyl
starch (HES) clearance.
548 CARDIOVASCULAR ANESTHESIA JUNGHEINRICH ET AL. ANESTH ANALG
HES 130/0.4 IN RENAL IMPAIRMENT 2002;95:54451
even increased by 7.8 mL · min
1
· 1.73 m
2
(sd
16.6, P 0.054) from prestudy to poststudy. All AE
had been recorded throughout the study, whether or
not causally related. There was no drop-out. Eight of
19 subjects experienced 17 AE, none of them serious or
otherwise important, all lasting 24 h, except for uri-
nary infection. Headache, nausea, transient vision dis-
turbances, and precordial pressure (all rated as
mild) were classified as possibly related to the study
medication, but could alternatively be explained by
the volunteer setting. The other AE had an unlikely
relationship to the study drug. Interestingly, there was
no AE at all in the worst renal function group (CL
cr
1530).
Amylase increased postdose, which however was
judged as clinically irrelevant (predose mean: 62.5; 8 h:
96.9; 24 h: 75.4; 48 h: 65.4 U/L), because this is a well
known effect for HES based on the formation of
macro-amylase (16), which is excreted more slowly
and not related to pancreatic dysfunction. The tran-
sient, induced amylase increase did not correlate with
in vivo Mw (data not shown), as opposed to the cor-
relation of baseline amylase and Mw described above.
Overall, no clinically relevant laboratory changes oc-
curred. Also, the coagulation variables studied were
unremarkable: partial thromboplastin time 35 6sat
8 h (baseline 33 6 s), thrombin time 16 1sat8h
(16 1 s), and platelets 237 49/nL (238 54/nL).
Discussion
The pharmacokinetics of HES 130/0.4 were evaluated
in subjects with stable renal insufficiency. HES 130/0.4
was developed to improve pharmacokinetics of cur-
rent medium Mw HES whereas maintaining efficacy.
Studies in healthy volunteers after single (14) and
multiple administration of 500 mL for 10 days (2)
showed rapid renal excretion and no plasma accumu-
lation. In contrast, older starches, such as HES 450/0.7
accumulate in plasma after multiple infusions (17,18).
This has been known since the 1970s, but is often not
acknowledged. Large residual concentrations of col-
loid after 24 hours should be avoided, because they
are not expected to exert a relevant therapeutic effect,
but could be related to potential side effects.
In this study, we found residual concentrations
24 hours after 500 mL HES 130/0.4 to be small, even in
subjects with severe renal dysfunction. In the worst
renal function group (CL
cr
1530), the mean HES
plasma concentration at 24 hours was 0.5 mg/mL.
Persisting large plasma concentrations beyond the du-
ration of volume effect (which lasts 4 6 hours in the
case of HES 130/0.4) (19) should be avoided, because
potential harm will not be balanced by the benefit. As
a comparison, 24 hours after the same amount of
Figure 4. Urinary excretion of hy-
droxyethyl starch (HES) after infu-
sion of 500 mL, 6% HES 130/0.4.
Figure 5. Regression plot baseline amylase versus hydroxyethyl
starch (HES) molecular weight at 60 min after start.
ANESTH ANALG CARDIOVASCULAR ANESTHESIA JUNGHEINRICH ET AL. 549
2002;95:54451 HES 130/0.4 IN RENAL IMPAIRMENT
hetastarch (450/0.7, 6%) was given to volunteers with
normal renal function, the concentration was 4 mg/dL
(17). In a recent study with pentastarch (200/0.5,
500 mL, 10%), approximately 1.5 mg/dL HES was
found in plasma after 24 hours, again in normal vol-
unteers (20). Hence, residual plasma concentrations
after 24 hours in our subjects with mild-to-severe renal
impairment were smaller than those in normal volun-
teers after hetastarch or pentastarch in the cited
studies.
In a pilot study, Gassmayr et al. (21) revealed no
clinically relevant differences in half-time and plasma
HES concentrations using a single HES 200/0.5 (10%)
infusion in patients with renal impairment compared
with healthy subjects; therefore, no undue risks with
an improved HES specification were to be expected.
The current study with HES 130/0.4 for the first
time gives extensive pharmacokinetic data of a HES in
dependency of well defined, stable, non-anuric renal
dysfunction. C
max
and terminal half-life were not de
-
pendent on renal function, whereas AUC increased
moderately. HES total plasma clearance in renal dys-
function decreased less than expected from the reduc-
tion in CL
cr
. This might be attributed to the higher
baseline amylase levels in subjects with renal dysfunc-
tion, because higher baseline amylase levels were also
associated with lower in vivo Mw, indicating increased
HES metabolism. Data analysis showed that the effect
of amylase can be postulated as independent of base-
line renal function although both amylase and Mw
were closely related with baseline renal function ex-
pressed as CL
cr
. Thus, the results suggest that the
increased baseline amylase levels (caused by the renal
insufficiency itself) in part compensated for the re-
duced glomerular filtration rate, explaining the higher
than expected HES clearance. The infusion volume
was fixed to 500 mL in all subjects to allow compara-
bility to the previous data generated in normal volun-
teers (14). Because the four groups were comparable
with regard to body weight, the individual differences
concerning the dose per kilogram of body weight did
not affect the study results and conclusions presented
in this report. A limitation of all pharmacokinetic
studies with colloidal infusion solutions is that they
influence their own volume of distribution (which was
not a primary variable of this study) because of their
volume-expanding effect. Overall, HES 130/0.4 in
subjects with mild-to-severe renal impairment
showed excellent urinary excretion compared with
HES 130/0.4 in healthy volunteers (14), and small
residual plasma concentrations after 24 h when com-
pared with other HES preparations in healthy
volunteers.
After our single-dose application, we found no de-
terioration in renal function, as measured by CL
cr
determination in duplicate after exposition. Dehne et
al. (22) did not find an effect of HES on renal function
or sensitive tubular markers in surgical patients with-
out prior renal impairment. Kumle et al. (23) studied
the influence of 3 different intravascular volume re-
placement regimens (HES 70/0.5, HES 200/0.5, and
gelatin) on renal function in elderly patients without
prior renal dysfunction undergoing major abdominal
surgery. As assessed by sensitive markers of renal
function, all three regimens could be used safely for
volume replacement without renal dysfunction.
Schortgen et al. (24) compared HES 200/0.62 (6%) to a
3% gelatin solution in patients with severe sepsis, and
described HES 200/0.62 to be a risk factor for deteri-
oration of renal function. However, as noted in several
letters (25), the conclusions of that study should not be
generalized. Baseline renal function is a known major
risk factor for the development of postoperative renal
dysfunction, as determined in many other studies
(2628).
Among the HES solutions, it is important to differ-
entiate between those with a longer-lasting volume
effect accompanied by plasma accumulation after re-
petitive use (high Mw and/or highly substituted, HES
450/0.7 or 200/0.62), and medium Mw starches (HES
200/0.5, HES 130/0.4), which are more easily excreted
renally, as shown for HES 130/0.4 in this study.
Residual HES plasma concentrations after 24 hours
were small. Considering these and the pharmacoki-
netic results of this study, we conclude that HES 130/
0.4 (500 mL 6%) can be administered to patients even
with severe renal impairment, as long as urine flow is
preserved, without the risk of plasma accumulation.
Further studies in renally impaired patients in the
perioperative setting and in intensive care are
justified.
References
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ANESTH ANALG CARDIOVASCULAR ANESTHESIA JUNGHEINRICH ET AL. 551
2002;95:54451 HES 130/0.4 IN RENAL IMPAIRMENT
    • "even though net cystC serum content rises, leads to a dilution of serum cystC concentration early after the infusion [23] . However , as 6 % HES 130/0.4 has a terminal half-life of 16.1 h independent of the degree of pre-existing renal impairment [24], in theory, postoperatively rather than intraoperatively infused fluids may have caused such an effect on cystC on day 3 or 5 postoperatively. Moreover, it has been shown that an increase in extracellular fluid volume leads to increased GFR above baseline values in patients without renal impairment, partly compensating for the extracellular fluid increase, as long as the patients do not exhibit increased extracellular volume at baseline due to fluid overload caused by pre-existing chronic kidney disease [25]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Hydroxyethyl starch (HES) is used for repletion of acute intravasal volume loss in surgical patients. However, in critically ill patients, HES is associated with acute kidney injury. We aimed to evaluate the effect of HES on perioperative cystatin C (cystC)-derived estimated glomerular filtration rates (eGFRcystC) in patients undergoing open and robot-assisted radical prostatectomy. Methods In this retrospective study we included 179 patients who underwent general anaesthesia for radical prostatectomy received HES perioperatively, and had complete cystC and fluid therapy data available. CystC and corresponding eGFRcystC at postoperative days 1, 3, and 5 were compared with preoperative baseline using Wilcox rank-sum test. ResultsIn 179 eligible patients, 6 % HES 130/0.4 was administered in a median (25th to 75th percentile) dose of 1000 mL (1000 to 1000 mL). Baseline eGFRcystC was 109.4 mL/min (100.3 to 118.7 mL/min). eGFRcystC on postoperative days 1, 3, and 5 was 120.4 mL/min (109.4 to 134.0 mL/min), 120.4 mL/min (109.4 to 132.9 mL/min), and 117.9 mL/min (106.6 to 129.8 mL/min), respectively (p < 0.001 compared with baseline, each). No patient had an eGFRcystC-decrease of ≥25 % from baseline. Conclusions The results indicate that the administration of a median dose of 1000 mL of 6 % HES 130/0.4 is not associated with a postoperative deterioration of renal function in patients with normal to near-normal baseline renal function undergoing radical prostatectomy.
    Full-text · Article · Dec 2015
    • "Accordingly, efforts were then directed toward the creation of a ''third generation'' product, which resulted in two tetrastarch formulations: Voluven (6 % HES 130/0.4 in 0.9 % saline) and Tetraspan (6 % HES 130/0.42 in Ringer's lactate). After their release, a commercial marketing push was followed by papers espousing a similar efficacy profile to prior HES generations with a reduced likelihood of adverse effects424344. Joachim Boldt, a German anesthesiologist with a long track record of prolific HES research and industry ties, was quick to espouse the benefits of these new products. "
    [Show abstract] [Hide abstract] ABSTRACT: Controversy regarding the role of colloids in the resuscitation of trauma patients has persisted for the past century without a clear resolution. Recently, the early treatment goals of traumatic hypovolemic shock have changed with an emphasis on minimal intravenous fluid administration and the avoidance of over-resuscitation. While some clinicians see a role for colloids in this model, others have become wary as evidence mounts against the efficacy and safety of hydroxyethyl starch and human albumin in critically ill patients. We reviewed the history and fundamentals of the crystalloid versus colloid debate and explored the relevant findings from the prominent non-trauma literature with attention to their applicability in the trauma population. Critical appraisal of the trauma-specific colloid literature is offered with a focus on study design and practical utility. Finally, we offer recommendations about the rational selection of fluids for clinicians who treat these challenging patients.
    Article · Sep 2014
    • "It has been suggested that the initial rescue crystalloid be kept at 20ml/kg, and the subsequent fluid should be colloid, especially hydroxyethly starch [11]. Some data indicated that hydroxyethyl starch has a suitable molecular shape and size to reduce the vascular leakage, and to inhibit the expression of proinflammatory mediators11121314. However, a recent meta-analysis showed that hydroxyethyl starch was associated with an increased risk of mortality and acute kidney injury [15], suggesting clinical use of hydroxyethyl starch for acute volume resuscitation needs further investigation. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to describe the clinical features, management strategies and outcomes of 31 infants with systemic capillary leak syndrome (SCLS) secondary to sepsis or systemic inflammatory response syndrome. There were 23 boys and 8 girls, with an average age 9.6 +/- 2.1 days (range, 3.1 to 20 days). The primary disease was pneumonia in 11 patients and sepsis in other 20. Within 72 hrs of admission, all had progressive skin and mucosal edema, septic shock, respiratory distress, oliguria and severe hypoalbuminemia (10-20g/L). Other complications were pulmonary edema or hemorrhage, disseminated intravascular coagulopathy, heart failure, renal or liver dysfunction. All patients were treated with mechanical ventilation with a mean mechanical ventilation time of 19.7 +/- 3.5 days. Intravenous hydroxyethyl starch was also applied at an early stage for 4-12 days, together with broad spectrum antibiotics, plasma and albumin infusion. Twenty one patients (67.0%) were discharged from the neonatal intensive care unit after a median stay of 29 days, and 7 died (37.0%) in the hospital. During a 6.3-month follow-up, 4 patients had hydrocephalus and another 4 had muscle spasm or rigidity in the lower-limbs. We conclude that SCLS is a serious complication of neonatal sepsis with a high rate of in-hospital mortality and post-discharge disability.
    Full-text · Article · Jun 2014
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