Volume replacement with a balanced hydroxyethyl starch (HES) preparation in cardiac surgery patients.

Abstract

Balanced fluids appear to be have advantages over unbalanced fluids for correcting hypovolemia. The effects of a new balanced hydroxyethyl starch (HES) were studied in cardiac surgery patients.
Prospective, randomized, unblinded study.
Clinical study in a single cardiac surgery institution.
Sixty patients undergoing elective cardiac surgery with cardiopulmonary bypass.
Patients received either a balanced 6% HES 130/0.4 plus a balanced crystalloid (n = 30) or an unbalanced HES-in-saline plus saline (n = 30) to keep cardiac index >2.5 L/min/m(2).
Base excess (BE), kidney function, inflammatory response (interleukins-6, -10), endothelial activation (intercellular adhesion molecule-1 [ICAM]), and coagulation (thromboelastometry, whole blood aggregation) were measured after induction of anesthesia, after surgery and 5 hours later, and at the 1st and 2nd postoperative days; 2,950 +/- 530 mL of balanced and 3,050 +/- 560 mL of unbalanced HES were given. BE was reduced significantly in the unbalanced group (from 1.11 +/- 0.71 mmol/L to -5.11 +/- 0.48 mmol/L after surgery) and remained unchanged in the balanced group. Balanced volume replacement resulted in significantly lower IL-6, IL-10, and ICAM plasma concentrations and lower urine concentrations of kidney-specific proteins than in the unbalanced group. After surgery, thromboelastometry data and platelet function were changed significantly in both groups; 5 hours thereafter they were significantly changed only in the unbalanced group.
A plasma-adapted HES preparation in addition to a balanced crystalloid resulted in significantly less decline in BE, less increase in concentrations of kidney-specific proteins, less inflammatory response and endothelial damage, and fewer changes in hemostasis compared with an unbalanced fluid strategy.

Full text

Page 1

Volume Replacement With a Balanced Hydroxyethyl Starch (HES) Preparation
in Cardiac Surgery Patients
Joachim Boldt, MD, PhD, Jochen Mayer, MD, Christian Brosch, MD, Andreas Lehmann, MD, and
Andinet Mengistu, MD
Objective: Balanced fluids appear to be have advantages
over unbalanced fluids for correcting hypovolemia. The ef-
fects of a new balanced hydroxyethyl starch (HES) were
studied in cardiac surgery patients.
Design: Prospective, randomized, unblinded study.
Setting: Clinical study in a single cardiac surgery institu-
tion.
Participants: Sixty patients undergoing elective cardiac
surgery with cardiopulmonary bypass.
Intervention: Patients received either a balanced 6% HES
130/0.4 plus a balanced crystalloid (n ? 30) or an unbalanced
HES-in-saline plus saline (n ? 30) to keep cardiac index >2.5
L/min/m2.
Measurements and Main Results: Base excess (BE), kidney
function, inflammatory response (interleukins-6, -10), endo-
thelial activation (intercellular adhesion molecule-1 [ICAM]),
and coagulation (thromboelastometry, whole blood aggre-
gation) were measured after induction of anesthesia, after
surgery and 5 hours later, and at the 1st and 2nd postoper-
ative days; 2,950 ? 530 mL of balanced and 3,050 ? 560 mL
of unbalanced HES were given. BE was reduced significantly
A
in cardiac surgery generally is accepted to be of funda-
mental importance because intravascular volume deficits may
result in inadequate cardiac output, microcirculation, and tissue
oxygenation.1,2Several mediators are released and an inflam-
matory process is generated by cardiopulmonary bypass (CPB),
leading to altered endothelial integrity with leakage of fluids
from the intravascular to the interstitial compartment, resulting
in hypovolemia without obvious fluid loss.3
There is still controversy regarding the ideal volume replace-
ment strategy in cardiac surgery patients.4-6There is not only a
debate whether colloids have advantages for volume replace-
ment compared with crystalloids, it is also a matter of discus-
sion what colloid is best to treat the hypovolemic patient.4-6
Most colloids (including human albumin [HA]) are dissolved in
saline consisting of unphysiologic high concentration of so-
dium (154 mmol/L) and chloride (154 mmol/L).7-9Use of
considerable amounts of these colloids may be associated with
development of metabolic (hyperchloremic) acidosis. The first
colloid prepared in a plasma-adapted (“balanced”) solution was
a first-generation balanced hydroxyethyl starch (HES) prepara-
tion with a high mean molecular weight (Mw ? 550 kD) and
a high molar substitution (MS ?0.7) (Hextend, BioTime, Berk-
ley, CA).10,11This type of HES, however, is associated with
unwanted side effects including accumulation and impaired
coagulation including platelet dysfunction.12Consequently,
HES preparations with a lower mean molecular weight (Mw:
130 kD) with a lower molar substitution (MS: ? 0.5) showing
favorable physicochemical characteristics compared to the
first-generation HES have been developed.13Dissolving this
type of HES in a balanced solution appears to be promising
because unwanted alterations in acid-base status can be
avoided, especially when higher doses are needed. As cardiac
surgery patients undergoing CPB are at risk of an increased
in the unbalanced group (from 1.11 ? 0.71 mmol/L to
?5.11 ? 0.48 mmol/L after surgery) and remained un-
changed in the balanced group. Balanced volume replace-
ment resulted in significantly lower IL-6, IL-10, and ICAM
plasma concentrations and lower urine concentrations of
kidney-specific proteins than in the unbalanced group. After
surgery, thromboelastometry data and platelet function
were changed significantly in both groups; 5 hours thereaf-
ter they were significantly changed only in the unbalanced
group.
Conclusion: A plasma-adapted HES preparation in addi-
tion to a balanced crystalloid resulted in significantly less
decline in BE, less increase in concentrations of kidney-
specific proteins, less inflammatory response and endothe-
lial damage, and fewer changes in hemostasis compared
with an unbalanced fluid strategy.
© 2010 Elsevier Inc. All rights reserved.
KEY WORDS: cardiac surgery, balanced volume replace-
ment, hydroxyethyl starch, kidney function, hemostasis, in-
flammatory response
PPROPRIATE VOLUME REPLACEMENT THERAPY
inflammatory response, altered endothelial integrity, decreased
kidney function, and altered hemostasis, the present study was
designed to assess the effects of a new balanced HES prepara-
tion on kidney integrity, inflammatory response, and hemosta-
sis in comparison to a conventional unbalanced HES in patients
undergoing cardiac surgery.
MATERIALS AND METHODS
Following approval of the Institutional Review Board (IRB) and
patients’ informed consent were taken, 60 patients undergoing first-
time elective cardiac surgery were included. Patients with preoperative
serum creatinine concentration (sCr) of ?2.0 g/dL or chronic oliguric/
anuric kidney dysfunction requiring dialysis were not included as it has
been suggested to avoid starches in patients with established dysfunc-
tion whenever possible. Patients with liver insufficiency (aspartate
aminotransferase ?40 U/L and alanine aminotransferase ?40 U/L)
also were excluded because inflammatory response in these patients is
modified by the malfunctioning liver. Use of diuretics also was defined
as an exclusion criterion as they modify urine concentrations of kidney-
specific proteins. Patients using platelet-receptor antagonists until the
day of surgery were excluded because the risk of bleeding is increased
in these patients and the specific influence of HES on blood loss cannot
be assessed clearly.
From the Department of Anesthesiology and Intensive Care Medi-
cine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany.
This study was not supported by a pharmaceutical company, but by
a hospital grant.
Address reprint requests to Joachim Boldt, MD, PhD, Department of
Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Lud-
wigshafen, Bremserstr 79, D-67063 Ludwigshafen, Germany. E-mail:
BoldtJ@gmx.net
© 2010 Elsevier Inc. All rights reserved.
1053-0770/2403-0003$36.00/0
doi:10.1053/j.jvca.2010.03.001
399Journal of Cardiothoracic and Vascular Anesthesia, Vol 24, No 3 (June), 2010: pp 399-407

Page 2

A sealed envelope system was used to randomize patients preoper-
atively. Patients received either a balanced 6% HES 130/0.4 containing
Na?137 mmol/L, Cl?110 mmol/L, K?4 mmol/L, Mg??1.5 mmol/L,
acetate?34 mmol/L (Volulyte; Fresenius Kabi, Bad Homburg, Ger-
many) plus balanced crystalloid containing Na?140 mmol/L, Cl?127
mmol/L, K?4 mmol/L, Ca?2.5 mmol/L, Mg2?1 mmol/L, acetate?24
mmol/L, and malate2?5 mmol/L, (Sterofundin Iso; B. Braun, Melsun-
gen, Germany) or a conventional 6% HES 130/0.4 in saline (containing
Cl?154 mmol/L, Na?154 mmol/L; Voluven; Fresenius Kabi, Bad
Homburg, Germany) plus saline solution as an unbalanced crystalloid.
Volume was administered perioperatively and until the morning of
the 2nd postoperative day (POD) to keep cardiac index (CI) measured
by thermodilution using a pulmonary artery catheter (PAC) ?2.5
L/min/m2. CI was measured every 1/2 hour in the OR, hourly during
the first 5 hours and every 3 hours during the night. During surgery, 250
mL/h of crystalloids according to the grouping were administered
routinely in both groups.
Weight-related doses of sufentanil, midazolam, and pancuronium
bromide were used for induction and maintenance of anesthesia. A
nonpulsatile pump and a membrane oxygenator were used for cardio-
pulmonary bypass. The circuit was primed either with 500 mL of the
balanced 6% HES 130/0.4 plus 1,000 mL of the balanced crystalloid
(balanced group) or 500 mL of the conventional 6% HES 130/0.4 plus
1,000 mL of saline solution (unbalanced group). Tranexamic acid (2 g
as a bolus after induction of anesthesia followed by a continuous
infusion of 6 mg/kg/h, 1 g added to the priming) was used in all
patients. Temperature was kept at mild hypothermia (bladder temper-
ature ?33°C) and a flow rate of 2.5 L/min/m2was used. Mean arterial
blood pressure (MAP) was kept between 50 and 70 mmHg by adding
norepinephrine when necessary. To maintain filling volume of the
circuit, HES corresponding to the grouping was added. When hemo-
globin (hgb) was ?7g/dL, packed red blood cells (PRBC) were given.
After termination of CPB, the blood from the CPB circuit was collected
and retransfused unprepared before the patients were transferred to the
intensive care unit. Shed mediastinal blood was not retransfused.
All patients were transferred to the intensive care unit and controlled
mechanical ventilation was continued. Tracheal extubation was per-
formed when hemodynamics were stable, temperature was ?36°C, and
the patient breathed spontaneously with adequate blood gases. Bal-
anced or unbalanced HES was given to keep CI ?2.5 L/min/m2.
Epinephrine or dobutamine was used when MAP was ?60 mmHg and
CI was ?2.5 L/min/m2in spite of sufficient volume infusion (target for
CI: 2.5 to 3.0 L/min/m2). Norepinephrine was administered when
systemic vascular resistance (SVR) was ?600 dynes · s · cm?5and
MAP was ?60 mmHg (target for SVR: 600 to 800 dynes · s · cm?5).
PRBC were given when hemoglobin was ?9 g/dL, fresh frozen plasma
(FFP) was given only when bleeding occurred (250 mL/h of blood loss
over 3 hours) with activated partial thromboplastin time (aPTT) ?60 s
in spite of a normal activated coagulation time. The patients’ postop-
erative management was carried out by physicians who were not
involved in the study and did not know about the purpose of the study.
Heart rate (HR), MAP, pulmonary capillary wedge pressure
(PCWP), central venous pressure (CVP), and cardiac output (CO, using
a PAC) were monitored and derived hemodynamic parameters (SVR,
CI) were calculated using standard formulae.
Glutathione transferase-alpha (?-GST) were analyzed by enzyme
immunoassay with Nephkit-Alpha (Biotrin International, Sinsheim-
Reihen, Germany), normal values in healthy volunteers: ?11 ?g/L and
neutrophil gelatinase-associated lipocalin (NGAL) were analyzed by
sandwich enzyme-linked immunosorbent assay using microwells
coated with monoclonal antibody against human NGAL (Kit 0236),
Antibody Shop, Grusbakken, Denmark; and normal values in healthy
volunteers (5.3 ng/mL [range 0.7-9.8 ng/mL]) were measured from
urine specimen. Interleukin-6 (IL-6) and interleukin 10 (IL-10) plasma
levels were measured using solid-phase 2-site chemiluminescent en-
zyme immunometric assays (Diagnostic Product Corporation [DPC],
Los Angeles, CA). Normal values for IL-6 are ?5 pg/dL and for IL-10
2-24 pg/mL. Plasma levels of soluble intercellular adhesion molecule-1
(sICAM-1; normal range: 200 to 300 ng/mL) were measured using
enzyme-linked immunosorbent assays (ELISA; British Bio-Technol-
ogy Products, Abington, UK).
Rotation thromboelastometry (ROTEM, Pentapharm, Munich, Ger-
many) was used to assess changes in coagulation. ROTEM allows
measurement of the onset of coagulation (coagulation time [CT], con-
ventional thromboelastography (TEG): reaction time [r]), kinetics of
clot formation (clot formation time [CFT], conventional TEG: coagu-
lation time [k]), maximum clot firmness [MCF], conventional TEG:
maximum amplitude [MA]).14300 ?L of whole blood were mixed with
thromboplastin-phospholipid (20 ?L) to monitor the intrinsic system
clot formation (IntrinsicROTEM). Clot formation also was monitored
after addition of liquid stable thromboplastin reagent derived from
rabbit brain (ie, tissue factor plus phospholipids [20 ?L]) for monitor-
ing the extrinsic coagulation system (ExtrinsicROTEM).
Platelet function was assessed by whole blood aggregometry (WBA)
using a whole blood platelet function analyzer (Multiplate; Dynabyte
Medical, Munich, Germany).15WBA is based on impedance aggre-
gometry and WBA measures electrical impedance between electrodes
immersed in whole blood. The attachment of platelet aggregates on the
electrodes increases the impedance between them. The change of
impedance is transformed to arbitrary aggregation units (AU) and
plotted against time. WBA assesses platelet function under more phys-
iologic conditions than platelet aggregometry using platelet-rich
plasma because centrifugation is not needed. Platelet function was mea-
sured after activation by adenosine diphosphate (ADPTest 2 mM/mL),
thrombin-receptor-activating protein (TRAPTest 1 mM/mL, and colla-
gen (COLTest 100 ?g/mL) (all tests Instrumentation Laboratory, IL,
Munich, Germany). Blood was incubated at 37°C for 3 minutes and
was stirred using an electromagnetic stirrer at 800 rpm. Twenty ?L of
the activating substrate were added to the probe and activated platelet
function was recorded for 6 minutes and the computer analyzed the
area under the curve (AUC) of the clotting procedure of each measure-
ment and calculates the mean value. Measurements were done after
induction of anesthesia (before volume was administered), at the end of
surgery, 5 hours after surgery (on the ICU), and at the morning of the
1st and 2nd postoperative day (POD).
A MedCalc 4.30 (MedCalc Software, Mariakerke, Belgium) soft-
ware package was used for statistical analyses. Data are expressed as
mean and standard deviation (SD) unless otherwise indicated. The
unbalanced volume replacement was expected to result in difference in
base excess (BE) after surgery of 3 mmol/L compared to the balanced
group. A preoperative sample size calculation was based on the results
of the study from Wilkes et al11and led to a minimum of sample size
of n ? 15 (2-sided question using the U-test [rank sum test according
to Wilcoxon-Mann-Whitney]). The sample size calculation was based
upon the primary endpoint (BE difference) with a level of significance
of 5% and a power of at least 99%. The authors included a total of 30
patients in each group to compensate for possible dropouts and because
the authors expected larger variations than in the study of Wilkes et al.
Chi-square test was used to analyze categoric data. Normally distrib-
uted data (tested by Kolmogorov-Smirnov test) were analyzed using
Student t test. Two-way analysis of variance (ANOVA) with repeated
measures and post hoc Scheffé test were used to determine the effects
of group, time, and group-time interaction for all laboratory analyses
and all hemodynamic measurements. When multiple comparisons were
made, Bonferroni correction was done for serially measured data; eg,
for hemodynamics, biochemical data. Mann-Whitney U test or the
Kruskal-Wallis H test also was used when appropriate. A p value
?0.05 was considered significant.
400BOLDT ET AL

Page 3

RESULTS
The patients did not statistically differ with regard to co-
morbidities, preoperative medication, and type of surgery
(Table 1). No patient was excluded during the study. Duration
of surgery, cross-clamping, CPB, anesthesia, stay in the ICU and
in the hospital did also not differ between the 2 groups (Table 1).
One patient of each group died in the ICU secondary to mul-
tiorgan failure. None of the survivors needed renal replacement
therapy through discharge from the hospital.
HES, 2,950 ? 530 mL of balanced and 3,050 ? 560 mL of
unbalanced, was administered until the 2nd POD (Table 2).
Urine output, use of crystalloids, as well as use of blood/blood
products also were similar in the 2 groups (Table 2). Hemody-
namics were without group differences at each data point in
both groups (Table 3). Need for inotropic support and use of
vasopressors also did not differ between the groups within the
entire study period (Table 4).
BE decreased significantly in the unbalanced group (from
1.11 ? 0.71 mmol/L at baseline to ?5.11 ? 0.48 mmol/L
immediately after surgery) and remained unchanged in the
balanced group (Fig 1).
Serum creatinine level remained unchanged within the study
period including the day of discharge from the hospital and it
did not differ between the 2 groups during the entire study
period. Alpha-GST (representing distal tubular damage) and
NGAL (representing proximal tubular damage) increased sig-
nificantly in both groups after CPB. Both ?-GST and NGAL
increased significantly more after surgery in the unbalanced
than the balanced group of patients and both remained signif-
icantly higher at the 2nd POD in the unbalanced group (Fig 2).
Interleukin-6 increased in both groups after CPB with a
significantly higher increase in the unbalanced (from 2.8 ? 0.9
to 220 ? 33 pg/dL 5 hours after surgery) than in the balanced
group (from 3.0 ? 1.1 to 110 ? 30 pg/dL 5 hours after
surgery). After surgery until POD 1, interleukin-10 plasma
levels were significantly higher in the balanced than in the
unbalanced group. Plasma levels of soluble intercellular adhe-
sion molecule-1 increased significantly only in the unbalanced
group and did not change significantly in the balanced group
(Fig 3).
In both groups, CT-Int and CFT-Int were significantly higher
immediately after surgery compared to baseline data by throm-
Table 1. Demographic Data and Data from the Perioperative Period
HES-Balanced (n ? 30) HES-Unbalanced (n ? 30)p Value
Demographics
Age (years) (range)
Weight (kg)
Height (cm)
Sex (M/F)
Type of surgery
CABG
AVR
CABG?AVR
Preoperative cardiac function
LVEF (%)
LVEDP (mmHg)
Chronic preoperative medication
Beta-blockers
ACE inhibitors
Nitrates
AT1-inhibitors
Oral antidiabetics
Other antihypertonic drugs
Statins
Time of (min)
Anesthesia (range)
CPB (range)
Cross-clamp (range)
Patients requiring renal replacement therapy
During ICU stay
During hospital stay
30 days after surgery
60 days after surgery
Death
During ICU stay
During hospital stay
30 days after discharge
60 days after discharge
68 ? 8 (54-83)
79 ? 13
169 ? 7
20/10
70 ? 10 (55-85)
77 ? 13
168 ? 10
21/9
0.44
0.53
0.55
0.44
20
7
3
18
6
6
0.44
0.33
0.49
50 ? 12
26 ? 11
54 ? 15
24 ? 12
0.44
0.33
19
13
12
10
20
13
11
12
0.41
0.56
0.32
0.65
0.40
0.43
0.34
7
5
9
6
7
10
171 ? 46 (133-301)
67 ? 22 (40-93)
44 ? 17 (29-86)
185 ? 45 (111-299)
71 ? 21 (43-99)
49 ? 19 (33-97)
0.39
0.56
0.43
11
—
—
—
—
—
—
1 (MOF)
—
—
—
1 (MOF)
—
—
—
Abbreviations: CABG, coronary artery bypass grafting; AVR, aortic valve replacement; f, female; m, male; CPB, cardiopulmonary bypass; LVEF,
left ventricular ejection fraction; LVDP, left ventricular end-diastolic pressure; 1st POD, first postoperative day; ICU, intensive care unit; ACE,
angiotensin-converting enzyme; AT, angiotensin; MOF, multiorgan failure; HES, hydroxyethyl starch; mean ? standard deviation (SD).
401BALANCED HES IN CARDIAC SURGERY

Page 4

boelastometry (Figs 4 and 5). Only in the unbalanced group,
both also were significantly increased 5 hours after surgery;
however, without reaching statistical group differences (p ?
0.07 for both data). MCF-Int decreased significantly after sur-
gery and 5 hours after surgery only in the unbalanced group
without reaching significant group differences (p ? 0.08). At
POD 1, CT-Int, CFT-Int, and MCF-Int have reached baseline
data again.
CT-Ext and CFT-Ext were normal at baseline and signifi-
cantly increased immediately after surgery in both groups with-
out showing significant group differences. Both were signifi-
cantly longer in the balanced group 5 hours after surgery.
MCF-Ext reduced significantly after surgery and 5 hours there-
after only in the unbalanced group, again without significant
differences between the 2 groups (p ? 0.07). All data returned
to baseline at POD 1.
Platelet function induced by all three inductors (TRAP, Col,
ADP) was significantly decreased after surgery and 5 hours
thereafter in both groups. This decrease was significantly larger
after surgery in the unbalanced than in the balanced group.
Platelet function returned to baseline data in both groups at
POD 1 and no further significant group differences were seen
(Fig 6).
DISCUSSION
The ideal plasma substitute to correct hypovolemia in car-
diac surgery patients is a much-discussed issue. The Food and
Drug Administration (FDA) approved a change in the labelling
Table 2. Fluid In- and Output (Cumulative)
Until End of Surgery?
5 Hours after Surgery Until 1st PODUntil 2nd POD
Crystalloids (mL)
HES-balanced group
HES-unbalanced group
Colloids (mL)
HES-balanced group
HES-unbalanced group
Total blood loss (mL)
HES-balanced group
HES-unbalanced group
Urine output (mL)
HES-balanced group
HES-unbalanced group
Blood/blood products (units)
PRBC (total number/group)
HES-balanced group
HES-unbalanced group
FFP (total number/group)
HES-balanced group
HES-unbalanced group
2,560 ? 240
2,440 ? 240
3,080 ? 290
3,000 ? 270
3,840 ? 640
3,970 ? 590
5,090 ? 750
5,050 ? 680
1,250 ? 280
1,350 ? 260
1,730 ? 350
1,830 ? 330
2,710 ? 520
2,820 ? 490
2,950 ? 530
3,050 ? 560
510 ? 140
620 ? 120
930 ? 290
1,030 ? 220
1,210 ? 330
1,360 ? 290
1,380 ? 460
1,510 ? 410
690 ? 320
800 ? 310
1,590 ? 440
1,700 ? 520
3,920 ? 780
4,040 ? 600
6,580 ? 960
6,700 ? 990
27
32
30
34
30
36
32
38
4
6
666
1010 10
Abbreviations: ?, including priming; HES, hydroxyethyl starch; FFP, fresh frozen plasma; PRBC, packed red blood cells; POD, postoperative
day; mean ? standard deviation (SD).
Table 3. Hemodynamics in the Two Groups
Prior to Surgery End of Surgery5 Hours after Surgery1st POD 2nd POD
MAP (mmHg)
HES-balanced
HES-unbalanced
HR (beats/min)
HES-balanced
HES-unbalanced
PCWP (mmHg)
HES-balanced
HES-unbalanced
CVP (mmHg)
HES-balanced
HES-unbalanced
CI (L/min/m2)
HES-balanced
HES-unbalanced
73 ? 10
75 ? 11
75 ? 11
76 ? 10
76 ? 12
80 ? 10
83 ? 10
81 ? 11
80 ? 9
81 ? 11
66 ? 13
65 ? 11
85 ? 7
83 ? 10
82 ? 6
80 ? 11
85 ? 6
84 ? 9
83 ? 8
82 ? 10
11 ? 2
10 ? 2
11 ? 3
12 ? 2
13 ? 3
11 ? 4
11 ? 4
12 ? 2
13 ? 3
13 ? 2
9 ? 3
10 ? 2
11 ? 3
10 ? 3
11 ? 3
10 ? 3
12 ? 2
11 ? 4
12 ? 3
13 ? 2
1.96 ? 0.2
2.01 ? 0.2
2.67 ? 0.4
2.57 ? 0.3
2.45 ? 0.3
2.42 ? 0.3
2.71 ? 0.3
2.69 ? 0.5
2.86 ? 0.3
2.77 ? 0.5
Abbreviations: MAP, mean arterial blood pressure; HR, heart rate; PCWP, pulmonary capillary wedge pressure; CVP, central venous pressure;
CI, cardiac index; POD, postoperative day.
402BOLDT ET AL

Page 5

of the first-generation hydroxyethyl starch (HES) with a Mw
?450 kD and a MS ?0.7 dissolved in saline, applying specif-
ically to cardiopulmonary bypass surgeries16: “Hetastarch is not
recommended for use as a CPB prime, while the patient is on
CPB, or in the immediate period after CPB has been discon-
tinued because of the risk of increasing coagulation abnormal-
ities and bleeding in patients whose coagulation status is al-
ready impaired.”
It is mandatory to distinguish the different HES preparations
because their different physicochemical properties are associ-
ated with differences in the extent and duration of plasma
volume expansion, accumulation, effects on blood rheology,
coagulation, and organ function.12The change from a first-
generation HES with a high Mw and a high MS to a third-
generation HES with a lower Mw (130 kD) and a lower MS
(?0.5) resulted in significantly less unwanted adverse effects,
eg, on accumulation and coagulation.12,13Dissolving such mod-
ern HES preparation in a plasma-adapted (“balanced”) solution
instead of in unbalanced (“abnormal“) saline solution may be
another step to further improve volume replacement strate-
gy.7,9,17
One finding of the present study was that when using the new
balanced HES given along with a balanced crystalloid, BE
remained almost unchanged, while BE was significantly de-
creased in the unbalanced volume replacement regimen. This
result of BE is an agreement with a prospective, randomized,
double-blinded study in cardiac surgery patients, in which the
same balanced HES 130/0.4 was given together with Ringer’s
Table 4. Use of Catecholamines and Diuretics
End of Surgery 5 Hours after SurgeryPOD 1 POD 2
Norepinephrine (number of patients/range [?g/kg/min])
HES-balanced
HES-unbalanced
Epinephrine (number of patients/range [?g/kg/min])
HES-balanced
HES-unbalanced
Dobutamine (number of patients/range [?g/kg/min])
HES-balanced
HES-unbalanced
Furosemide (number of patients/median cumulative [mg])
HES-balanced
HES-unbalanced
6/2-6
7/2-8
2/3-5
4/2-3
3/1-3
2/3
1/5
1/8
—
—
1/4
2/2-6
3/4-5
4/2-6
1/6
1/8
10/2-5
12/2-6
14/2-5
15/3-6
2/1-2
3/2-3
—
—
—
—
9/20
10/18
5/20
7/40
4/55
5/50
Abbreviations: POD, postoperative day; HES, hydroxyethyl starch.
Fig 1.
tion (SD); POD, postoperative day; *p < 0.05 different from the other
group;?p < 0.05 different from baseline.
Base excess (BE) in the 2 groups. Mean ? standard devia-
Fig 2.
transferase-alpha (alpha-GST, normal value: 3.5 ? 11.1 ?g/L [mean ?
2 SD]), and neutrophil gelatinase-associated lipocalin (NGAL) (nor-
mal values in healthy volunteers 5.3 ng/mL [range 0.7-9.8 ng/mL]) in
the 2 groups. Dashed lines indicate normal range; mean ? standard
deviation (SD); POD, postoperative day; *p < 0.05 different from the
other group,?p < 0.05 different from baseline data.
Changes in serum creatinine levels (sCr), glutathione
403 BALANCED HES IN CARDIAC SURGERY