Plasma volume expansion by medium molecular weight
hydroxyethyl starch in neonates: A pilot study*
Jean-Michel Liet, MD, MSc; Anne-Sophie Bellouin, MD; Cécile Boscher, MD; Corinne Lejus, MD;
Jean-Christophe Rozé, MD.
Objective: To study the renal effects (measured by creatininemia) of plasma volume expansion with a medium molecular
weight hydroxyethyl starch in the newborn.
Design: A prospective, randomized, double-blinded, pilot study.
Patients: The study included 26 neonates weighing 690 – 4030
g (gestational age, 26 – 40 wks), without cardiac or renal failure or
major hemostasis abnormalities and requiring a peripherally inserted central catheter for parenteral nutrition.
Setting: Pediatric and neonatal intensive care unit of a university-affiliated hospital.
Interventions: Plasma volume expansion was performed to
facilitate insertion of the central catheter. After parental consent,
neonates were randomly allocated to receive intravenous infu-
A
systematic review found insufficient evidence to determine
what type of early volume expansion should be used in preterm infants (1). The international guidelines 2000 conference for neonatal
resuscitation recommended that emergency volume expansion be accomplished
with an isotonic crystalloid solution or
O-negative red blood cells (2).
In adults, hydroxyethyl starch (HES)
has replaced albumin as the colloid administered for intravascular volume expansion in many indications (3). Albumin
is a blood product with a possible infectious risk, which costs substantially more
than starch and has no proven benefit
with respect to final outcome.
The various HES solutions on the
market differ greatly in their pharmacologic properties and are available in two
concentrations (high, 10%; and low, 6%).
*See also p. 388.
From the Pediatric and Neonatal Critical Care Unit
(JML, ASB, CB, JCR), University Hospital of Nantes,
Nantes, France; and the Department of Anesthesiology
(CL), University Hospital of Nantes, Nantes, France.
Copyright © 2003 by the Society of Critical Care
Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/01.PCC.0000074262.84240.1E
Pediatr Crit Care Med 2003 Vol. 4, No. 3
sions at 10 mL·kgⴚ1 of 5% albumin or 6% hydroxyethyl starch
200/0.5. Sample size was calculated to detect an increase in
mean creatininemia of >20 ␮mol·Lⴚ1 (with ␣ ⴝ 0.05, ␤ ⴝ 0.80).
Measurements and Main Results: No clinically or statistically
significant differences were found between the two groups 6 hrs,
24 hrs, 48 hrs, and 7 days after plasma volume expansion. The
study could detect an increase in creatininemia >20 ␮mol·Lⴚ1
with a power of 80%.
Conclusions: In 13 healthy neonates, plasma volume expansion with 10 mL·kgⴚ1 of 6% hydroxyethyl starch 200/0.5 does not
increase creatininemia. (Pediatr Crit Care Med 2003; 4:305–307)
KEY WORDS: hydroxyethyl starch; newborn; premature; renal
effects; blood coagulation; plasma volume expanders.
The initial molecular weight of these solutions can be high (⬎400 kDa), medium
(130 –200), or low (40 –70). The degree of
hydroxyethyl substitution may be high
(0.6 – 0.7) or low (0.4 – 0.5), and the same
is true for the C2/C6 ratio (high, ⬎8; low,
⬍8) (3). Molecular weight determines
colloidal activity, and the degree of substitution is the major determinant of circulating half-life. Hydrolysis is rapid with
minimal substitution, and starch metabolism increases as the C2/C6 ratio decreases. Medium or low molecular weight
HES are quickly split in vivo into smaller,
more favorable, molecule sizes that result
in faster renal elimination and fewer adverse effects on coagulation (3). Although
medium molecular weight (mmw) HES
can prolong activated partial thromboplastin time (aPTT) and induce a moderate decrease in plasma concentrations of
von Willebrand factor, clinical studies
have found no increased bleeding tendency after administration of mmw HES
(4). The rate of anaphylactoid reactions is
0.058% for HES and 0.099% for albumin
(5). Some reports have suggested that
HES could lead to adverse renal effects
(6), and the use of a slowly degradable
mmw HES was found to be an independent risk factor for acute renal failure in
severe sepsis (7).
No HES side effects were reported in
the three controlled trials performed to
date in pediatrics (8 –10), and a search
procedure in Pubmed failed to turn up
any data for newborns. Our assumption
was that HES could replace human albumin in neonates. The renal function
of newborns is remarkably immature.
The glomerular filtration rate doubles
from birth to 2 wks of life (from 5 to 10
mL·min⫺1·m⫺2) and reaches adult values only at about 2 yrs of life (70
mL·min⫺1·m⫺2) (11). The main objective of our pilot study was to estimate
the renal effects of HES in healthy newborns.
MATERIALS AND METHODS
A randomized, blinded study was designed
to compare the effects of HES and albumin on
creatininemia in neonates. Approval was obtained from the Ethics Committee of Nantes
University Hospital, and both parents of each
child gave their informed consent.
Infants eligible for inclusion were ⬍28
days old (regardless of gestational age), without cardiac failure and in need of a central
catheter for prolonged parenteral nutrition. In
our unit, a plasma volume expander often is
infused into these infants to facilitate peripheral insertion of a central catheter by filling up
the peripheral veins. The criteria contraindi-
305
cating vascular expansion were cardiomegaly,
hepatomegaly, or patent ductus arteriosus.
Other exclusion criteria were renal failure defined as creatininemia of ⬎150 ␮mol·L⫺1, hemostasis factors (II, V, VII⫹X) of ⬍40%, and
thrombopenia (platelet count of ⬍100,000
mL⫺1).
After parental consent, the neonates were
allocated randomly to receive intravenous infusion at 10 mL·kg⫺1 of 5% albumin (Albumine20%-LFB; Laboratoire Français du Fractionnement et des Biotechnologies,
Courtaboeuf, France) diluted with 5% glucose
or 6% HES 200/0.5 (Hesteril; Fresenius
France Pharma, Louviers, France), a rapidly
degradable mmw HES with a circulating halftime of 4 hrs in adults. Syringes were prepared
outside the unit by pharmacist and covered
with aluminum paper to preserve the doubleblind conditions of the study. Vascular expansion was done for 30 mins just before catheter
insertion.
Creatininemia was measured before infusion (H0) and 6 hrs, 24 hrs, 48 hrs, and 7 days
after infusion, with monitoring of diuresis.
This dosage was performed by the rateblanked creatinine/Jaffe method (variance ⫽
0.95 ␮mol·L⫺1), which eliminates bilirubin
interference (12) in nonhemolyzed blood samples (hemolysis of fetal hemoglobin could lead
to underestimation of creatininemia value).
Coagulation was explored by measuring aPTT
before and 6 hrs after infusion. The anaphylactoid reactions searched for during 6 hrs in
both groups were respiratory disturbance, hypotension, and rash. Measurements of systemic pressure and heart rate were performed
every 5 mins by using an automated oscillometric device (Critikon; Johnson & Johnson,
Arlington, TX).
Statistical Analysis. The primary outcome
measure under study was creatininemia. Our
hypothesis was that HES should definitely not
be used as a plasma expander in newborns if
the increase in mean creatininemia exceeded
20 ␮mol·L⫺1. Thus, sample size was calculated to detect an increase in median creatininemia of ⬎20 ␮mol·L⫺1 between the two
groups (with ␣ ⫽ 0.05, ␤ ⫽ 0.80, a unilateral
formula, and with expected variance ⫽ 420).
Thirteen newborns were required in each
group. The characteristics of the two groups
were studied by using the Mann-Whitney test
for unpaired nonparametric data. Creatininemia and mean arterial pressure were compared by using analysis for repeated measurements with group as one factor and time as
second factor (general linear model procedure
with analysis of variance). Data were analyzed
with SPSS 10.0 computer software (SPSS,
Chicago, IL). Values are presented as median
(25th and 75th percentiles). The significance
level was set at p ⬍ .05.
306
Table 1. Baseline data
n
Gestational age, wks
Weight, g
Postnatal age, days
MAP, mm Hg
Heart rate, bpm
Creatinine, ␮mol䡠L⫺1
aPTT, secs
HES Group
Albumin Group
p
13
30 (29, 33)
1265 (945, 1585)
3 (3, 6)
46 (42, 54)
145 (140, 166)
64 (39, 80)
50 (41, 60)
13
30 (29, 34)
1330 (915, 1780)
5 (4, 6)
53 (47, 59)
139 (129, 157)
55 (43, 67)
47 (44, 52)
.8
.7
.2
.1
.2
.5
.4
HES, hydroxyethyl starch; MAP, mean arterial pressure; aPTT, activated partial thromboplastin
time.
Data are presented as median (percentiles: 25th, 75th).
Figure 1. After colloid infusion, no significant differences between the hydroxyethyl starch (HES) and
albumin groups were observed for mean arterial pressure (p ⫽ .8), creatininemia (p ⫽ .7), or hourly
diuresis during a 24-hr period (p ⫽ .6). Data of hourly diuresis and mean arterial pressure (MAP) are
presented as the median (25th and 75th percentiles).
RESULTS
Twenty-six neonates (11 girls) were
administered a 30-min infusion of 10
mL·kg⫺1 of a plasma volume expander
and then equipped with a peripherally
inserted central catheter for prolonged
parenteral nutrition. Thirteen received
6% HES (HES group) and 13 others 5%
albumin (albumin group). No catheter
insertion failures occurred in either
group.
Weight, gestational age, and postnatal
age were similar in both groups (Table 1),
each of which included 11 preterm infants. Mean arterial pressure, heart rate,
creatininemia, and aPTT were comparable before colloid infusion (Table 1).
No differences were observed in creatininemia between the two groups at 6
hrs, 24 hrs, 48 hrs, and 7 days after
plasma volume expansion (Fig. 1). On the
7th day, creatininemia was 41 ␮mol·L⫺1
(25th and 75th percentiles, 33 and 59) in
the HES group vs. 43 (36 and 69) in the
albumin group. As the observed variance
of creatininemia was 420, the study detected an increase in creatininemia ⱖ20
␮mol·L⫺1 with a power of 80% and p ⬍
.05. Hourly diuresis in both groups
showed a comparable course throughout
a 24-hr period (Fig. 1).
No differences in mean arterial pressure were observed between the two
groups at H0, 30 mins, and 1 hr after
plasma volume expansion (Fig. 1). No
bleeding duration of ⬎3 mins occurred in
either group after venous prick for catheter insertion. At 6 hrs, aPTT was 47 secs
(42 and 59) in the HES group and 45 secs
(42 and 58) in the albumin group (p ⫽
.3). No anaphylactoid reactions occurred.
DISCUSSION
Plasma volume expansion with 10
mL·kg⫺1 of 6% HES 200/0.5 did not increase creatininemia in neonates without
initial renal failure.
In newborns, plasma creatinine concentrations vary according to maternal
creatinine concentration and gestational
age and postnatal age (13). The plasma
creatinine concentration is elevated at
birth (almost identical to maternal concentration) and decreases concomitantly
Pediatr Crit Care Med 2003 Vol. 4, No. 3
I
mL·kg
n 13 healthy neonates, plasma volume
expansion with 10
⫺1
of 6% hydroxyethyl
starch 200/0.5 does not increase creatininemia.
with the rapid increase in glomerular filtration rate during the first postnatal
weeks. In preterm infant, plasma creatinine concentrations remain high because
of backflow of creatinine across leaky immature tubular and vascular structures.
Paradoxically, concentrations are higher
for a long time as the infant is more
premature. In this study, both groups had
comparable baseline creatininemia, gestational age, and postnatal age. Creatininemia developed similarly in both
groups, with no differences in diuresis.
Therefore, renal effects were no more severe with the HES we infused than with
albumin.
Our study did not explore coagulation
patterns extensively, and factor VIII was
not measured in order to save neonate
blood. However, no differences in aPTT
and no tendency to increased bleeding
were observed. The fact that newborns
and preterms have increased von Willebrand factor concentration may be an important consideration (14).
Pediatr Crit Care Med 2003 Vol. 4, No. 3
Six percent HES 200/0.5, a lowconcentration (6%), medium molecular
weight (200 kDa) HES, was chosen to
treat newborn and premature infants because it is iso-oncotic for plasma and has
a low degree of hydroxyethyl substitution
(0.5), thereby allowing faster metabolism.
Rapidly degradable mmw HES also has
fewer adverse effects on coagulation than
high molecular weight HES or slowly degradable mmw HES (3).
This study has several limitations: A
single dose of HES was considered in
healthy newborns, and too few infants
were investigated to detect anaphylactoid
reactions. However, the data reported
suggest that 10 mL·kg⫺1 of HES, administered to facilitate intravenous insertion,
has no apparent deleterious effects on
newborns.
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