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608	www.anesthesia-analgesia.org	 March 2015 • Volume 120 • Number 3
Copyright © 2015 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000596
H
ydroxyethyl starch (HES) is commonly used as a peri-
operative intravascular volume expander to replace
blood loss, obtain hemodynamic stability, and opti-
mize tissue oxygenation. Current data suggest that HES sta-
bilizes intravascular colloid pressure and reduces the volume
required to achieve hemodynamic stability during resuscita-
tion from hypovolemia or when large fluid shifts occur.1,2
HES consists of large starch molecules, substituted with
hydroxyethyl groups to prevent degradation, which are dis-
solved in a crystalloid carrier solution.3,4
Concerns about
renal side effects with HES use were initially raised when
osmosis nephrosis-like lesions were noted during routine
kidney biopsies from renal transplant patients if the donor
had received HES.5
Vacuolization and swelling of tubular
cells were found in both the proximal and distal nephron.6–9
Further studies in animals and humans demonstrated impair-
ment of renal function after HES treatment.5,10,11
To minimize
the likelihood of renal injury, the most recent generation of
HES solutions (tetrastarches) was developed with a lower
molecular weight and molar substitution to enhance urinary
excretion and reduce tissue accumulation.3,4,12
Recently, large
trials on the use of tetrastarches for fluid resuscitation in
septic, critically ill patients demonstrated a small increase in
renal injury in patients given tetrastarch versus those given
crystalloid.13–16
In perioperative care, however, current evi-
dence does not suggest that renal injury and tetrastarch use
are correlated.2,17–21
While 2 recent trials have suggested renal
injury with synthetic colloid use, 1 trial did not specify the
colloid used22
and the other did not study tetrastarch at all.23
Acute renal failure is most commonly diagnosed using the
RIFLE criteria (Risk Injury Failure Loss End stage renal dis-
ease), which are based on sudden increases in plasma creati-
nine (p-crea) or an abrupt decrease in urine output (UO).24,25
However, p-crea is influenced by many variable factors (i.e.,
gender, nutrition, medication, muscle mass, and age), which
makes the diagnosis difficult.26–28
To overcome these chal-
lenges, several urinary biomarkers have shown promising
BACKGROUND: Although hydroxyethyl starch (HES) is commonly used as an intravascular vol-
ume expander in surgical patients, recent studies suggest that it may increase the risk of renal
failure in critically ill patients. We hypothesized that patients undergoing radical prostatectomy
and receiving HES would be more likely to develop markers of renal failure, such as increas-
ing urinary neutrophil gelatinase–associated lipocalin (u-NGAL), creatinine clearance (Ccrea), and
decreasing urine output (UO).
METHODS: In a randomized, double-blinded, placebo-controlled study, 40 patients referred for
radical prostatectomy received either 6% HES 130/0.4 or saline 0.9%; 7.5 mL/kg during the
first hour of surgery and 5 mL/kg in the following hours; u-NGAL, urine albumin, Ccrea, UO, arterial
blood pressure, and plasma concentrations of creatinine, renin, angiotensin II, aldosterone, and
vasopressin were measured before, during, and after surgery.
RESULTS: Thirty-six patients completed the study. u-NGAL, Ccrea, UO, plasma neutrophil gelatin-
ase–associated lipocalin, p-creatinine, urine albumin, and arterial blood pressure were the same
in both groups. Blood loss was higher in the HES group (HES 1250 vs saline 750 mL), while
p-albumin was reduced to a significantly lower level. P-renin and p-angiotensin-II increased in both
groups, whereas p-aldosterone and p-vasopressin increased significantly in the saline group.
CONCLUSIONS: We found no evidence of nephrotoxicity after infusion of 6% HES 130/0.4 in
patients undergoing prostatectomy with normal preoperative renal function. Hemodynamic sta-
bility and infused fluid volume were the same in both groups. We observed an increased blood
loss in the group given 6% HES 130/0.4.  (Anesth Analg 2015;120:608–18)
The Effect of 6% Hydroxyethyl Starch 130/0.4
on Renal Function, Arterial Blood Pressure, and
Vasoactive Hormones During Radical Prostatectomy:
A Randomized Controlled Trial
Anne Sophie Pinholt Kancir, MD, PhD Student,* Joergen Kühlwein Johansen, MD,†
Niels Peter Ekeloef, MD,‡ and Erling Bjerregaard Pedersen, MD, MSc§
From the *University Clinic for Nephrology and Hypertension, Department
of Medical Research and Medicine, and Department of Anesthesiology,
Holstebro Hospital and University of Aarhus, Holstebro, Denmark;
†Department of Urology, Holstebro Hospital, Holstebro, Denmark;
‡Department of Anesthesiology, Holstebro Hospital, Holstebro, Denmark;
and §University Clinic for Nephrology and Hypertension, Department of
Medical Research and Department of Medicine, Holstebro Hospital and
University of Aarhus, Holstebro, Denmark.
Accepted for publication November 13, 2014.
Funding: The study was supported by grants from Region Midt’s Research
Foundation for Health Science and the Lipmann Foundation, Denmark.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Anne Sophie Pinholt Kancir, MD, University
Clinic for Nephrology and Hypertension, Department of Medical Research
and Medicine, and Department of Anesthesiology, Holstebro Hospital and
University of Aarhus, Laegaardvej 12, 7500 Holstebro, Denmark. Address
e-mail to annesophie.kancir@gmail.com.
Section Editor: Avery Tung
Society for Critical Care Anesthesiologists
March 2015 • Volume 120 • Number 3	 www.anesthesia-analgesia.org	 609
results.29,30
Neutrophilgelatinase–associatedlipocalin(NGAL)
is produced in low concentrations in the neutrophils and the
tissues and can be measured in plasma and urine.26,27
NGAL
is filtered via the glomeruli and reabsorbed in the proximal
tubules and increases rapidly after renal injury due to an up-
regulated expression and secretion in the nephrons.27,31
Thus,
NGAL is one potential marker of acute renal failure.
We hypothesized that measurements of urinary NGAL
(u-NGAL) could reveal a potential nephrotoxicity of 6%
HES 130/0.4 in patients undergoing surgery with previous
normal renal function. HES may affect renal function dif-
ferently from crystalloid due to the different hemodynamic
properties of 6% HES 130/0.4 compared with 0.9% saline.
Subsequent changes in vasoactive hormones may also
change renal function. In the present randomized, placebo-
controlled, double-blinded study, we measured the fol-
lowing: (1) renal function, that is, u-NGAL, plasma NGAL
(p-NGAL), p-crea, creatinine clearance (Ccrea), UO, urine
albumin (u-Alb), urine aquaporine2 excretion (u-AQP2CR),
and free water clearance (CH2O); (2) blood pressure (sys-
tolic blood pressure [SBP], diastolic blood pressure [DBP],
mean arterial pressure [MAP], and heart rate [HR]); and
(3) plasma concentrations of renin (PRC), angiotensin II
(p-AngII), aldosterone (p-Aldo), and vasopressin (p-AVP)
before, during, and after radical prostatectomy.
METHODS
Ethics
The study was approved by the Danish Medicines Agency
(EudraCT: 2011-004274-28) and the Regional Committee of
Health Research Ethics (J. No. M-20110213) and registered at
ClinicalTrials.gov (NCT01486563). The study was performed
in accordance with the Declaration of Helsinki and moni-
tored by the Good Clinical Practice committee at University
of Aarhus. Written informed consent was obtained from each
patient before any study-related procedure.
Patients
Inclusion criteria were men >18 years and scheduled for
removal of the prostate under general anesthesia due to
prostate cancer. Exclusion criteria were estimated glo-
merular filtration rate <15 mL/min, need of nonsteroidal
anti-inflammatory drugs, blood donation within a month
before the surgery, and anamnestic or clinical findings that
excluded surgery according to the general procedures in the
Departments of Anesthesiology or Urology. Withdrawal cri-
teria were development of exclusion criteria, complications
during surgery such as severe bleeding with blood trans-
fusion, prolonged postoperative course due to resurgery
or infection, withdrawal of consent, unexpected increased
level of u-NGAL before intervention, and medication with
ephedrine or dexamethasone during surgery.
Recruitment
All patients were recruited from the Department of Urology,
Holstebro Hospital, Holstebro, Denmark.
Design
The study was conducted as a randomized, controlled, dou-
ble-blinded study on 40 patients undergoing elective radical
prostatectomy.
Intervention
Patients were consecutively randomized to receive either
6% HES 130/0.4 (Voluven®
) as active treatment or 0.9% iso-
tonic saline as control. Both fluids were manufactured by
Fresenius Kabi, Bad Homburg, Germany, and produced in
500-mL freeflex bags. Each bag was concealed in identical
black plastic, sealed, and marked 1 to 40. Five bags were
packed in boxes corresponding to each randomization
number. All packing and blinding were performed by the
hospital pharmacy.
The minimal infusion rate was 7.5 mL/kg in the first
hour and 5 mL/kg for each hour thereafter until the end
of recovery. If an episode of excess bleeding occurred,
more fluid could be given until hemodynamic stability was
obtained (MAP ≥60 mm Hg). The maximal dose of 6% HES
130/0.4 was 50 mL/kg/day according to the manufacturer
and the Danish Medicines Agency, Copenhagen, Denmark.
No supplemental IV fluids were given during surgery to
minimize the likelihood of bias and confounding factors.
If needed, the patients received Ringer’s acetate solution
upon discharge from recovery.
The threshold for blood transfusion was hemoglo-
bin ≤4.5 mmol/L. Hemoglobin values between 4.5 to 6.5
mmol/L resulted in a clinical evaluation of every patient
before blood transfusion. A surgical nurse assessed the
blood loss at the end of surgery as a combination of the vol-
ume of blood in the suction and in the napkins, which were
weighed before and after use.
Randomization
A randomization list was generated in blocks of 8 by staff
from the hospital pharmacy by using a webpage.a
Treatment
assignment was concealed from patients, clinicians, and
research staff until after the last visit of the last patient.
Effect Variables
The main effect variable was u-NGAL. Secondary effect vari-
ables were p-NGAL, PRC, p-ANGII, p-Aldo, p-AVP, Ccrea,
UO, p-crea, CH2O, u-Alb, u-AQP2CR, SBP, DBP, MAP, and HR.
Power Analysis
With a significance level of 5% and a power of 80%, 32
patients were needed to detect a 100 ng/mL difference in
u-NGAL with an SD of 100 ng/mL. A difference of 100 ng/
mL was considered a clinically meaningful difference to
diagnose acute kidney injury (AKI), as stated by the man-
ufacturer of the ELISAb
test we used (Bioporto, Hellerup,
Denmark). The SD was based on an assessment of the lit-
erature containing measurements of u-NGAL from both
healthy and sick patients.29,30,32
We estimated that 40 patients
should be included in the trial, 20 patients in each interven-
tion group, due to the risk of dropout and complications.
Experimental Procedures
Anesthetic Procedures Before and During Surgery
All patients received 1000 mg paracetamol and 1200 mg
gabapentin (600 mg gabapentin if the patient was ≥70 years)
a
Available at: www.randomization.com. Accessed September 19, 2014.
b
Available at: http://www.bioporto.com/Products/NGAL-ELISA-Kit-(human).
aspx. Accessed October 22, 2014.
Hydroxyethyl Starch and NGAL During Radical Prostatectomy
610   www.anesthesia-analgesia.org anesthesia  analgesia
before surgery. Fluid infusion was started together with
monitoring of SBP, DBP, electrocardiogram, HR, and arterial
oxygen saturation. Anesthesia was induced with thiopental
(5 mg/kg), fentanyl (5 μg/kg), and cisatracurium (0.1–0.15
mg/kg) and maintained with an inspired oxygen concen-
tration (0.6), isoflurane (minimum alveolar concentration
1.2–1.5), and IV increments of 0.15 μg/kg fentanyl. After tra-
cheal intubation, mechanical ventilation was set to achieve
a carbon dioxide end-tidal concentration (Pco2) of 4.5–5.5
kPa. After induction, a urine catheter and an arterial line
were placed to provide a continuous measurement of blood
pressure. If MAP decreased 60 mm Hg, the infusion of the
study fluid was increased, incremental doses of phenyleph-
rine 0.1 mg were given, or an infusion with phenylephrine
was started (0.1 mg/mL). A prophylactic dose of antibiotic
(cefuroxime 1500 mg) and antiemetic (ondansetron 4 mg)
was given before surgery.
Urine and Blood Sampling
Urine was collected for 24 hours from all patients on the day
before surgery (urine 1, baseline). Urine was also collected
beginning with the start of surgery and lasting 4 hours
(urine 2, surgery). Postoperatively, urine was collected until
the next morning at 8:00 am (urine 3, postsurgery). At dis-
charge 1, additional urine sample was obtained (urine 4, dis-
charge). The patients then collected a 24-hour urine sample
at home on the day before the 15-day follow-up visit at the
hospital (urine 5, follow-up). Blood samples were drawn
through a venous cannula just before the start of the inter-
vention. In the recovery room after surgery, blood samples
were drawn within the first hour after arrival. In total, 140
mL blood was drawn from each patient.
Biochemical Analyses
All urine and blood samples were centrifuged for 10 min-
utes at 3500 G and 4°C and then plasma was separated from
blood cells. All samples were then kept frozen at −80°C
or −20°C until assayed. They were centrifuged again just
before the assays were performed to minimize any impuri-
ties in the samples. Every analysis was done at the same
time by the same laboratory technician to minimize vari-
ability in the results.
U-NGAL and p-NGAL were determined by a commer-
cial ELISA assay. Minimal detection level was 1.6 pg/mL.
Variations were interassay max 7.2% in urine, max 4.6%
in plasma, intra-assay max 4.9% in urine, and max 4.5% in
plasma. All samples were analyzed with kits from the same
batch.32
U-AQP2 was measured by radioimmunoassay.
Antibodies were increased in rabbits to a synthetic peptide
corresponding to the 15 COOH-terminal amino acids in
human AQP2 to which was added an NH2-terminal cysteine
for conjugation and affinity purification. Minimal detection
level was 34 pg per tube. Coefficients of variation were 11.7%
(interassay) and 5.9% (intra-assay).33,34
PRC was determined
by radioimmunoassay from CIS Bio International, Gif-Sur-
Yvette Cedex, France. Minimal detection level was 1 pg/mL
and coefficients of variation were 0.9% to 3.6% (intra-assay)
and 3.7% to 5.0% (interassay) in the range of 4 to 263 pg/
mL. P-Aldo was determined by radioimmunoassay, using
a commercial kit from Demeditec Diagnostics GmbH, Kiel,
Germany, minimal detection level was 25 pmol/L and coef-
ficients of variation were 9.0% (interassay) and 8.5% (intra-
assay). P-AngII and p-AVP were extracted from plasma
with C18 Sep-Pak (Water Associates, Milford, MA) and sub-
sequently determined by radioimmunoassay. The antibody
against AngII was obtained from the Department of Clinical
Physiology, Glostrup Hospital, Denmark. Minimal detec-
tion level was 2 pmol/L. The coefficients of variation were
12% (interassay) and 8% (intra-assay). The antibody against
AVP was a gift from Professor Jacques Dürr, MD, H. Lee
Moffitt Cancer Center, Memorial Hospital of Tampa, Saint
Joseph’s Hospital, Tampa General Hospital, Tampa, Florida.
Minimal detection level was 0.2 pmol/L. The coefficients of
variation were 13% (interassay) and 9% (intra-assay).35,36
Routine analyses were done at the Department of Clinical
Biochemistry, Holstebro Hospital.
Hemodynamic Data
SBP, DBP, and HR were recorded continuously through-
out the surgery with Infinity Delta XL®
(Dräger, Lübeck,
Germany). All values during surgery were noted in 5-min-
ute intervals. In the recovery period, values were noted in
15-minute intervals and S/5™ CompactAnesthesia Monitor
(Datex-Ohmeda; GE Healthcare Finland, Oy Helsinki,
Finland) was used. All values were divided into 5 different
time periods (baseline, preincision, incision, postincision,
and recovery period), and the average of those periods was
calculated and used for analyses.
Calculations
Clearance (C) of substance X was calculated as CX = UX/
(PX × UO), where UX denotes concentration of x in urine, PX
denotes concentration of x in plasma, and UO is the rate of
urine excretion.
MAP was calculated according to the formula MAP =
(SBP − DBP)/3 + DBP.
Statistics
All patients who received the assigned study intervention
and did not encounter any exclusion criteria were included
in the analysis. Demographic data for HES and control
patients are presented in Table 1.
To determine whether parametric or nonparametric
analysis should be performed, the continuous outcome
variables were assessed for normal distribution visually
and by the Shapiro-Wilks test. Parametric analyzed data are
presented as mean (SD); nonparametric analyzed data as
median (25%–75% quartiles); frequency data are presented
as number (%). P values are reported as 2-sided values, and
to correct for multiple comparisons, we required a P value
≤0.01 to obtain statistical significance.
Nonparametric statistics were used to analyze the major-
ity of the outcome variables in Table 2 (perioperative man-
agement). No statistics were needed in Table 3. In Table 4
(renal function) nonparametric statistics were mostly used,
and in Table  5 (vasoactive hormones) all variables were
considered nonnormally distributed. The Mann-Whitney
U test was used to analyze the difference between the
groups (HES versus saline). A Friedman test was applied
in Table 4 to determine whether there were any statistical
differences between the medians within each group (HES
March 2015 • Volume 120 • Number 3	 www.anesthesia-analgesia.org	 611
or saline). Pairwise comparisons, using Wilcoxon signed
rank test, were performed as a post hoc analysis with a
Bonferroni correction for multiple comparisons. Each pair-
wise comparison was performed as a comparison with the
baseline value. In Table 4, either 3 or 4 pairwise compari-
sons were performed in each group as appropriate. In Table
5, we compared the values before and after intervention
within each group with a Wilcoxon signed rank test.
Parametric statistics were used for all hemodynamic
variables (Table 6), Ccrea (Table 4), and some perioperative
variables in Table 2 because they were considered normally
distributed. An unpaired t test determined the difference
between the groups (HES versus saline). In Table 6, a Welch
t test was used for some comparisons because homogeneity
of variances was violated, as assessed by the Levene test for
equality of variance. To determine whether there was any
statistical difference between the means, an analysis of vari-
ance with repeated measures was used within each group
(HES or saline) in Tables 4 and 6. The assumption of spheric-
ity was assessed by Mauchly test of sphericity; if violated,
a Greenhouse-Geisser correction was applied. A post hoc
analysis with a Bonferroni adjustment for multiple pairwise
comparisons was performed using a paired t test comparing
values with the baseline. Three pairwise comparisons were
performed for the variable Ccrea in each group (Table 4), and
in Table 6, we did 4 comparisons within each group.
Statistics were performed using PASW version 20.0.0 for
Mac (SPSS Inc., Chicago, IL).
RESULTS
Demographics
Between January 2012 and June 2013, 51 patients were con-
secutively screened to participate in the trial (Fig. 1). Eleven
patients were not eligible due to the use of nonsteroidal anti-
inflammatory drugs (2 patients) and unwillingness to par-
ticipate (9 patients). Thus, 40 patients were included with 20
patients randomized to receive 6% HES 130/0.4 and 20 to
saline 0.9%. Two patients in the HES group were excluded
due to bleeding requiring blood transfusion. In the saline
group, 2 patients were excluded due to treatment with
dexamethasone (1 patient) and ephedrine (1 patient) dur-
ing surgery. Thus, 18 patients (90%) completed the study in
each group. The 2 groups were comparable regarding age,
body mass index, comorbidities, antihypertensive medi-
cation, office blood pressure, and screening biochemistry
(Table 1). During the entire trial, there were no protocol vio-
lations. One patient in the HES group (No. 18) was excluded
because he had a very high baseline value of u-NGAL.
Fluid Infusion and Blood Loss During Operation
The amounts of intervention fluid (2500 vs 2500 mL) and
supplemental fluid (Ringer’s acetate solution; 50 vs 50 mL)
were the same in the 2 groups. Furthermore, no difference
was found in the number of patients receiving phenyleph-
rine (13 vs 17, P = 0.18) and the amount of phenylephrine
used per patient (0.8 vs 1.1 mg, P = 0.38; Table 2). Figure 2
shows that the blood loss was significantly higher in the
HES group than in the saline group (1256 vs 747 mL, P =
0.008). In addition, 7 patients in the HES group versus 1
patient in the saline group had a blood loss exceeding 1.5 L
during surgery (Fig. 2). Only one of these patients received
a blood transfusion (HES group).
Urine NGAL
All patients were discharged with a urinary catheter, and
most had leukocytes and hemoglobin in the urine at follow-
up (Table 3). Thus, measurements of u-NGAL at follow-up
were not included in the analyses because u-NGAL would
be falsely elevated due to the presence of leukocytes or
blood in the urine sample. The effect of 6% HES 130/0.4 or
saline 0.9% on u-NGAL and u-NGAL adjusted for creatinine
is shown in Table 4. U-NGAL was the same in both groups
at all times regardless of expression as a concentration or
adjusted for creatinine. U-NGAL increased significantly in
both groups, when compared with baseline levels, but the
increases were very modest
u-Alb Excretion and u-Alb/Creatinine Ratio
Table 4 shows u-Alb and urine-albumin-adjusted-for-creati-
nine increased similarly in both groups during surgery and
admission. A significant increase was shown in both groups
Table 1.  Baseline Characteristics
Variables HES (n = 18) NaCl ( = 18)
Age (year)a
64 (4.8) 66 (5.1)
Body mass indexa
25.7 (3.7) 25.3 (3.5)
Weight (kg)a
80.7 (12.5) 78.2 (12.7)
Comorbidities, no. (%)
 Hypertensionb
5 (27.8) 5 (27.8)
 Heart disease
  PCIb
0 0
  CABGb
0 0
  Heart failureb
0 0
 COPDb
2 (11.1) 1 (5.6)
 Diabetes mellitus
  Type Ib
0 0
  Type IIb
1 (5.6) 1 (5.6)
 Strokeb
0 1 (5.6)
 Otherb
8 (44.4) 9 (50.0)
Antihypertensive treatment, no. (%)
 ACE inhibitors/ATIIrbb
4 (22.2) 4 (22.2)
 Calcium channel blockersb
1 (5.6) 3 (16.7)
 Beta-blockersb
1 (5.6) 2 (11.1)
 Diureticsb
2 (11.1) 1 (5.6)
 Anticoagulationb
0 3 (16.7)
Office blood pressure (mm Hg)
 SBPa
146 (18.0) 150 (9.5)
 DBPa
87 (10.4) 87 (9.3)
 Pulsea
72 (14.5) 67 (7.6)
Screening biochemistry
 p-K (mmol/L)a
4.0 (0.31) 3.8 (0.27)
 p-Na (mmol/L)a
142 (1.5) 141 (1.5)
 p-alb (g/L)a
44 (2.8) 43 (2.5)
 p-crea (μmol/L)a
83 (13.6) 79 (13.1)
 eGFR (mL/min)a
83 (14.7) 88 (16.5)
 p-Hgb (mmol/L)a
9.2 (0.81) 9.4 (0.39)
UO (mL/day)a
1845 (1446; 2575) 1920 (1399; 2364)
ACE = angiotensin-converting enzyme; ATIIrb = angiotensin-II-receptor
blocker; CABG = coronary artery bypass graft; COPD = chronic obstructive
pulmonary disease; DBP = diastolic blood pressure; eGFR = estimated
glomerular filtration rate; HES = 6% hydroxyethyl starch 130/0.4; NaCl =
saline 0.9%; p-alb = plasma albumin; p-crea = plasma creatinine; p-Hgb =
plasma hemoglobin; p-K = plasma potassium; p-Na = plasma sodium; PCI
= percutaneous cardiovascular intervention; SBP = systolic blood pressure;
UO = urine output.
a
Continuous data; mean (SD).
b
Nominal data; number (%).
Hydroxyethyl Starch and NGAL During Radical Prostatectomy
612   www.anesthesia-analgesia.org anesthesia  analgesia
at all times when comparing the values with baseline. Even
at follow-up on day 14, the values were still elevated.
Ccrea, AQP2CR, CH2O, and UO
Ccrea, AQP2CR, CH2O, and UO are shown in Table 4. Ccrea
decreased to the same extent in both groups during surgery
but increased again after surgery. No significant difference
was found between the groups at any time.
The excretion of U-AQP2CR was significantly higher in
the saline group compared with the HES group during
and after surgery (surgery [urine 2]: 307 vs 417 ng/mmol,
P = 0.005; postsurgery [urine 3]: 147 vs 218 ng/mmol,
Table 2.  Perioperative Management
Variables HES (n = 19) NaCl (n = 19) P
Time periods (hh:mm)
 Duration of anesthesiaa
3:08 (0:31) 3:08 (0:33) 0.963
 Duration of the surgerya
1:45 (0:27) 1:45 (0:28) 0.981
 Duration of the recovery periodb
2:40 (2:07; 3:00) 2:32 (2:15; 3:11) 0.556
Length of hospital stayb
2.5 (2.5; 2.8) 2.5 (2.5; 2.5) 0.338
ETco2 (kPa)a
4.6 (0.30) 4.5 (0.31) 0.338
Intervention fluid IV (mL)b
2500 (2000; 2500) 2500 (2500; 2500) 0.274
Ringer’s acetate IV (mL)b
50 (0; 1000) 50 (0; 1000) 1.000
Blood loss (mL)a
1256 (669) 747 (331) 0.008
Patients needing phenylephrine, no. (%)c
13 (72) 17 (94) 0.177
Phenylephrine dose (mg)b
0.8 (0.4; 1.5) 1.1 (0.4; 3.5) 0.378
a
Values considered normally distributed; mean (SD); difference between groups analyzed by unpaired t test.
b
Values considered nonnormally distributed; median (25%–75% quartiles); difference between groups analyzed by Mann-Whitney U test.
c
Frequency data; number (%); difference between groups analyzed by Fischer exact test.
HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%; ETco2 = end-tidal CO2.
Table 3.  Urine Neutrophil Gelatinase–Associated Lipocalin (ng/mL) and Results of the Urine Test Strips
Patient Intervention
Urine 1 Urine 1 Urine 2 Urine 3 Urine 4 Urine 5 Urine 5
test strip baseline surgery postsurgery discharge follow-up test strip
02 HES 15 15 13 29 56 +
06 HES 58 17 14 24 16 +
07 HES + 35 24 21 75 61 +
08 HES 24 65 9 71 23 +
09 HES + 25 14 13 44 322 +
11 HES 9 5 12 11 9 +
14 HES 34 42 5 17 105 +
16 HES 14 41 14 52 17 +
18 HES + 229 108 138 272 − +
24 HES 3 4 7 56 10 +
26 HES 9 4 13 72 179 +
28 HES 35 5 11 68 22 +
29 HES 25 25 10 − 215 +
31 HES 11 46 10 − 11 +
33 HES 18 9 4 9 12 +
35 HES 11 98 5 69 − +
37 HES 11 6 11 65 36 −
39 HES 11 23 16 39 180 +
01 NaCl 4 7 14 20 8 +
03 NaCl 9 31 15 15 15 +
04 NaCl 16 2 4 21 21 +
05 NaCl 28 9 9 43 16 +
10 NaCl 18 19 9 19 19 +
12 NaCl 7 4 6 13 18 +
13 NaCl 11 3 27 − 18 +
17 NaCl 22 40 25 69 26 +
19 NaCl 10 13 20 37 11 +
22 NaCl 7 15 13 24 33 +
23 NaCl 19 22 16 173 248 +
25 NaCl 12 5 23 86 229 +
27 NaCl 10 11 12 50 31 +
30 NaCl + − 23 9 27 − +
34 NaCl 2 5 3 29 12 +
36 NaCl 18 26 13 56 322 +
38 NaCl 10 10 18 145 222 +
40 NaCl 14 7 8 36 40 +
The values marked with gray are excluded from the analysis of urinary neutrophil gelatinase–associated lipocalin because of a high content of leucocytes, nitrite,
or hemoglobin. No test strips were performed in urine 2–4.
+ = leucocytes, hemoglobin, and/or nitrite; − = missing value/test; HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%.
March 2015 • Volume 120 • Number 3	 www.anesthesia-analgesia.org	 613
P  0.0005). U-AQP2CR excretion increased during surgery
in both groups but was normalized at follow-up.
CH2O increased from −0.4 to 1.3 mL/min in the HES
group, but only from 0.0 to 0.8 mL/min in the saline group
during surgery. UO did not change significantly after the
intervention both between and within the groups.
p-NGAL, Plasma Albumin, and p-crea
P-NGAL, plasma albumin (p-Alb), and p-crea are shown
in Table 5. No significant difference was found between the
groups in p-NGAL after intervention. However, within the
saline group, p-NGAL increased significantly after interven-
tion. P-Alb was significantly lower in the HES group after
intervention compared with the saline group (P  0.0001,
postsurgery) as well as within both groups after interven-
tion (Table 5). In both groups, p-crea increased significantly
after intervention, but to the same extent.
Vasoactive Hormones in Plasma
The changes in the vasoactive hormones are shown in
Table 5. PRC increased to the same extent in both groups
while p-ANGII remained almost unchanged. P-Aldo was
significantly increased in the saline group compared with
the HES group after intervention. P-AVP increased in both
groups after intervention.
Blood Pressure and HR
During the entire surgery and in the recovery period, SBP,
DBP, and MAP were similar in both groups. SBP, DBP, and
MAP decreased during anesthesia and in the recovery
period. However, patients in the HES group had a signifi-
cantly higher HR at baseline, before, and after surgery com-
pared with the saline group (Table 6).
DISCUSSION
The primary study outcome was to clarify whether HES had
a nephrotoxic effect as measured by increases in u-NGAL,
Ccrea, u-Alb, and p-crea and decreases in UO during and/
or after surgery. We found no evidence of nephrotoxicity in
patients given up to 2500 mL of HES during surgery. Instead,
we found evidence supporting better intravascular volume
expansion in patients given 6% HES 130/0.4 as demonstrated
by lower p-AVP, p-Alb, and p-Aldo levels and equal volume
of infused fluid despite more bleeding in the HES group.
Table 4.  Renal Function
Urine 1 Urine 2 Urine 3 Urine 4 Urine 5
Pa
baseline surgery postsurgery discharge follow-up
U-NGAL (ng/mL)b
 HES 15 (11; 30) 17.(6; 42) 11 (8; 14) 52 (24; 69) — 0.0001
 NaCl 11 (8; 18) 11 (5; 22) 13 (9; 19) 33 (20; 55)* — 0.0001
P 0.086 0.175 0.363 0.278 —
U-NGALCR (ng/μmol)b
 HES 2 (1; 3) 5 (4; 12)** 2 (1; 2) 4 (4; 6) — 0.0001
 NaCl 1 (1; 2) 4 (3; 6)* 2 (2; 4) 5 (3; 7)* — 0.0001
P 0.107 0.108 0.087 0.474 —
U-Alb (mg/L)b
 HES 6 (2; 7) 105 (68; 151) 140 (106; 216)* 350 (148; 591)* 104 (51; 163)** 0.0001
 NaCl 4 (3; 9) 76.0 (61; 147)** 134 (111; 200)* 345 (172; 691)* 77 (40; 120)** 0.0001
P 0.774 0.622 0.713 0.575 0.322
U-AlbCR (mg/mmol)b
 HES 0.6 (0.3; 0.9) 40.1 (27.3; 52.1)* 23.1(18.5; 32.0)** 37.5 (25.6; 54.1)* 17.2 (7.6; 25.1) 0.0001
 NaCl 0.5 (0.4; 1.0) 26.3 (19.3; 67.5)* 30.3 (20.8; 38.6)* 39.4 (30.2; 73.8)* 13.1 (9.3; 22.4) 0.0001
P 0.787 0.323 0.192 0.235 0.783
 Ccrea (mL/min)c
 HES 134 (28) 63 (39) 113 (26) — 124 (27) 0.0001
 NaCl 124 (30) 65 (34) 116 (27) — 114 (27) 0.0001
P 0.322 0.876 0.761 — 0.286
U-AQP2CR (ng/mmol)b
 HES 140 (123; 157) 307 (199; 342)** 147 (139; 184) 145 (121; 203) 134 (124; 158) 0.001
 NaCl 146 (124; 172) 417 (261; 538)* 218 (192; 260) 179 (137; 228) 147 (135; 171) 0.0001
P 0.318 0.005 0.0005 0.373 0.041
CH2O (mL/min)b
 HES −0.4 (−1.1; 0.9) 1.3 (0.5; 2.3) 0.5 (−0.4; 1.9) — — 0.046
 NaCl 0.0 (−1.2; 0.8) 0.8 (0.2; 2.4) 1.4 (0.8; 2.1) — — 0.024
P 0.693 0.953 0.114 — —
UO (mL/min)b
 HES 1.3 (1.0; 1.8) 2.0 (1.5; 2.7) 1.5 (1.1; 2.4) — 1.7 (1.5; 2.2) 0.108
 NaCl 1.4 (1.0; 1.7) 1.6 (1.4; 2.9) 2.1 (1.6; 2.5) — 1.9 (1.4; 2.4) 0.031
P 0.858 0.673 0.168 — 0.570
CH2O = free water clearance; Ccrea = creatinine clearance; HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%; u-alb = urine albumin; u-AlbCR = urine
albumin adjusted for creatinine; u-AQP2CR = urine aquaporine-2 adjusted for creatinine; u-NGAL = urine neutrophil gelatinase–associated lipocalin; u-NGALCR =
urine neutrophil gelatinase–associated lipocalin adjusted for creatinine; UO = urine output.
a
P value showing the difference between medians in each group analyzed by Friedmann test or analysis of variance with repeated measures as appropriate; post
hoc analysis with Bonferroni correction; comparisons with baseline value within each group.
b
Variables considered nonnormally distributed; median (25%–75% quartiles); difference between groups was analyzed by Mann-Whitney U test.
c
Variables considered normally distributed; mean (SD); difference between groups was analyzed by unpaired t test.
*P  0.001; **P  0.01.
Hydroxyethyl Starch and NGAL During Radical Prostatectomy
614   www.anesthesia-analgesia.org anesthesia  analgesia
As has been done previously in patients after cardiac
surgery, we used u-NGAL to screen for AKI.29,30
In the pres-
ent study, u-NGAL increased slightly in the postoperative
period, but to the same extent in both groups. This increase
might be explained by surgical and hemodynamic stress.
In addition, we used chloride-rich solutions (0.9% normal
saline) in both the intervention and control groups, which
may have had a direct effect on the risk of AKI.37
At follow-
up, several patients in both groups had leukocytes and
blood in their urine, potentially resulting in a falsely ele-
vated u-NGAL.31,38
Thus, follow-up data were not included
in the analysis of u-NGAL. P-NGAL was the same before
and after surgery between the groups. Although a signifi-
cant increase was measured within the saline group, the dif-
ference was very modest and without clinical significance.
Previously, renal effects of tetrastarch and crystalloids have
been compared using p-crea, UO, or Ccrea. In 1 study, tran-
siently higher levels of p-crea were measured in patients
receiving HES after cardiac surgery compared with crys-
talloid. However, the increase was modest, within normal
ranges, and there were no differences between the groups
after 72 hours.19
In addition, several other surgical studies,
a review, and 1 meta-analysis found no evidence of renal
impairment after perioperative infusions with tetrastarc
hes.2,17–21,39–42
Recently, the use of tetrastarch was associated with
increased mortality and use of renal-replacement therapy
in patients with sepsis.13–16
However, patients in these stud-
ies were severely ill with sepsis, had multiorgan failure, and
renal impairment before inclusion.13–16
Furthermore, the
patients differed from ours due to a damaged glycocalyx
barrier.43,44
In October 2013, these data generated new recom-
mendations from the European Medicines Agency (EMA)
Table 5.  Vasoactive Hormones, p-NGAL, p-Alb, and
p-crea
Presurgery Postsurgery P
P-NGAL (ng/mL)
 HES 84 (68; 103) 81 (69; 99) 0.817
 NaCl 83 (69; 101) 87 (78; 121) 0.003
P 0.845 0.211
P-Alb (g/L)
 HES 41 (40; 42) 26 (25; 30) 0.0001
 NaCl 42 (40; 42) 35 (34; 37) 0.0001
P 0.485 0.0001
P-crea (μmol/L)
 HES 82 (72; 91) 90 (82; 105) 0.0001
 NaCl 79 (76; 84) 88 (78; 104) 0.001
P 0.644 0.476
PRC (pg/mL)
 HES 5.2 (3.6; 8.8) 13.1 (8.1; 22.3) 0.0001
 NaCl 6.3 (3.4; 12.1) 12.6 (5.1; 38.2) 0.0001
P 0.791 0.957
P-ANGII (pg/mL)
 HES 9.0 (7.5; 11.5) 10.0 (5.0; 19.5) 0.067
 NaCl 9.0 (5.8; 16.5) 11.5 (8.5; 26.3) 0.081
P 0.889 0.194
P-Aldo (pmol/L)
 HES 119 (58; 188) 110 (57; 201) 0.766
 NaCl 101 (57; 140) 288 (208; 601) 0.0001
P 0.462 0.0001
P-AVP (pg/mL)
 HES 0.2 (0.2; 0.2) 9.9 (1.7; 15.0) 0.0001
 NaCl 0.3 (0.2; 0.6) 15.0 (12.4; 15.0) 0.0001
P 0.121 0.006
All variables are considered nonnormally distributed; median (25%–75%
quartiles); difference between groups was analyzed by Mann-Whitney U test;
difference within groups was analyzed by Wilcoxon signed rank test.
HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%; p-NGAL =
neutrophil gelatinase–associated lipocalin; p-Alb = plasma albumin; p-Aldo
= plasma aldosterone; p-AngII = plasma angiotensin II; p-AVP = plasma
vasopressin; p-Crea = plasma creatinine; PRC = renin.
Table 6.  Hemodynamic Values
Baseline Preincision Incision Postincision Recovery Pa
HR (beats/min)
 HES 78 (13) 62 (12)* 60 (8)* 67 (11) 72 (10) 0.0001
 NaCl 64 (7) 56 (7)** 56 (7) 61 (9) 63 (7) 0.0001
P 0.001b
0.045b
0.068b
0.037b
0.003b
SBP (mm Hg)
 HES 151 (10) 107 (17)* 98 (12)* 116 (17)* 126 (12)* 0.0001
 NaCl 150 (12) 104 (13)* 89 (9)* 111 (22)* 126 (20)** 0.0001
P 0.902 0.474 0.089 0.486 0.628b
DBP (mm Hg)
 HES 93 (8) 67 (10)* 60 (8)* 69 (17)* 69 (5)* 0.0001
 NaCl 89 (9) 62 (8)* 55 (7)* 67 (15)* 67 (11)* 0.0001
P 0.272 0.169 0.329 0.781 0.555b
MAP (mm Hg)
 HES 112 (8) 81 (12)* 73 (9)* 84 (14)* 88 (6)* 0.0001
 NaCl 109 (9) 76 (9)* 67 (7)* 82 (17)* 86 (13)* 0.0001
P 0.489 0.242 0.194 0.620 0.882b
All variables are considered normally distributed; mean (SD); difference between groups was analyzed by unpaired t test.
DBP = diastolic blood pressure; HES = 6% hydroxyethyl starch 130/0.4; HR = heart rate; MAP = mean arterial pressure; NaCl = saline 0.9%; SBP = systolic blood
pressure; Baseline = just before anesthesia; Preincision = just after anesthesia, but before surgery; Incision = during surgery; Postincision = time after surgery,
but before recovery; Recovery = during recovery.
a
P value showing difference between means in each group was analyzed by analysis of variance with repeated measures; post hoc analysis with Bonferroni
correction using unpaired t test; comparisons performed with baseline value within each group.
b
A Welch t test was used for the comparison as homogeneity of variances was violated, assessed by the Levene test for equality of variance; all P values ≤0.045.
*P  0.001; **P  0.01.
March 2015 • Volume 120 • Number 3	 www.anesthesia-analgesia.org	 615
restricting the use of products containing HES in patients
with septicemia, renal impairment, and burns but not in
patients with acute hypovolemia due to blood loss. However,
these findings might not translate to patients with normal
renal function undergoing surgery. In this study, we used an
initial administration of the project fluid to balance the effect
of anesthesia followed by more project fluid to compensate
for bleeding. Because the starch solutions are designed for
acute resuscitation, our use of colloid in this study may con-
flict with the current EMA guidelines and does not reflect
current clinical practice. The aim of this study, however,
was to test a possible nephrotoxic effect of HES and not to
study the current use of HES during anesthesia and surgery.
Therefore, to eliminate confounders and bias, we chose a
randomized, controlled, double-blinded design with the
above-mentioned fluid administration. Finally, this study
was planned and performed before the current EMA guide-
lines were introduced. Our present results indicate that up to
2500 mL of 6% HES 130/0.4 given IV during prostatectomy
does not have a nephrotoxic effect on perioperative renal
function if preoperative renal function was normal.
During surgery and recovery, SBP, DBP, and MAP did
not differ between groups. Patients in both groups received
the same amount of fluid, and similar amounts of phenyl-
ephrine were used in both groups. Two patients in the HES
group had to be excluded due to blood loss and transfusions
during surgery. Although these 2 patients were not included
in the analyses, median blood loss (1250 vs 750 mL) as well
as the number of patients with a blood loss exceeding 1.5
L (7 vs 1) was larger in the HES group. However, only 1
additional patient in the HES group needed a blood trans-
fusion during the hospital stay. This increase in blood loss
in the HES group is reasonable because both in vivo and
in vitro studies have demonstrated increased bleeding ten-
dency and increased blood loss due to impaired coagulation
after HES treatment.20,45–48
Infusion of HES delays initiation
of thrombin generation, impairing platelet function and
clot strength. Two previous studies found increased blood
loss during surgery after infusion with 6% HES 130/0.4.
However, both studies combined HES and saline and were
not double blinded.20,49
We found that HR was significantly
increased in the HES group at baseline before intervention
and throughout the study, which may have been by chance.
However, a compensatory phenomenon in response to the
increased blood loss during 6% HES 130/0.4 infusion can-
not be excluded. In previous surgical studies, the majority
Eligible paƟents (n=51)
Non-eligible (n=11)
Used daily NSAID (n=2)
Not willing to parƟcipate (n=9)
Completed follow-up and included in analysis
(n=18)
Excluded (n=2)
Received blood transfusion due to excessive
bleeding during surgery (n=2)
Allocated to receive HES 130/0.4 (n=20)
Excluded (n= 2)
Received Ephedrine during surgery (n=1)
Received Dexamethasone during surgery
(n=1)
Allocated to receive Isotonic Saline 0.9% (n=20)
Completed follow-up and included in analysis
(n=18)
Randomized (n=40)
Figure 1. Flow chart of assessment,
randomization, and completion. NSAID
= nonsteroidal anti-inflammatory drugs;
HES = 6% hydroxyethyl starch 130/0.4.
Hydroxyethyl Starch and NGAL During Radical Prostatectomy
616   www.anesthesia-analgesia.org anesthesia  analgesia
found no difference in the hemodynamic effects of colloids
and crystalloids,2,17,18,39,48
with only 1 study observing an
increased MAP after tetrastarch infusion.50
Comparison
with the present study is difficult because some studies
were not double blinded, different ratios of colloids versus
crystalloids were used, and often both groups received crys-
talloids or colloids as supplemental fluids.
PRC and p-AngII increased in both groups due to a
stimulation of the renin–angiotensin–aldosterone system
by the decrease in arterial blood pressure during general
anesthesia. We found that P-Aldo increased significantly in
the saline group, while remaining unchanged in the HES
group. This finding is consistent with the results of another
study, which compared 3 older HES solutions (200/0.5,
200/0.62, and 450/0.7) with Ringer’s solution and found
increased levels of p-Aldo in the Ringer’s solution group.51
HES infusion expands plasma volume to a greater extent
than saline.1–4,52
This observation is supported by the lower
p-Alb in the HES group compared with the saline group.
The decrease in blood pressure and baroreceptor stimula-
tion might explain the considerable increase in p-AVP in
some patients during surgery, which explains the increase
in u-AQP2 above baseline during and after surgery.34
It has
been well documented that this increase reflects an increased
water transport from the tubules to the intracellular space
via AQP2 water channels in the principal cells in the dis-
tal part of the nephron,33,34,53
which corresponds with our
findings of a higher CH2O in the HES group during surgery.
We thus found more pronounced water reabsorption via the
AQP2 water channels after infusion with saline 0.9% com-
pared with 6% HES 130/0.4. Abetter volume expansion was
shown during surgery after infusion with 6% HES 130/0.4
demonstrated by the lower p-AVP, p-Alb, and p-Aldo levels
and the increased levels of water reabsorption in the saline
group despite the higher blood loss in the HES group.
The major strength of this study is the randomized, dou-
ble-blinded, placebo-controlled design and limited variability
in study conditions regarding operative procedures, anesthe-
sia, and recovery period. Only 3 different surgeons operated
and were equally represented in the groups. We included a
24-hour urine sample to assess kidney function both before
and at follow-up 14 days after surgery. We did not design our
trial to evaluate the long-term effect (28/90 days follow-up)
of HES on renal function because a delayed nephrotoxic effect
of HES would be unlikely when no signs of renal impairment
were seen within 14 days after surgery. This approach is sup-
ported by another surgical trial, which found no nephrotoxic-
ity after a 28-day postoperative follow-up period.54
To avoid
adverse effects of chloride on renal function, we used solu-
tions with the same chloride concentration in both groups
to eliminate the risk of bias due to hyperchloremic acidosis.
While U-NGAL is an established marker of renal damage, it
can also be confounded by infection and blood in the urine.
In addition, our study had a small sample size and may very
well have been inadequate to evaluate the hemodynamic dif-
ferences between the groups properly.
In conclusion, we found no evidence of nephrotoxicity
in patients undergoing prostatectomy with normal preop-
erative renal function after infusion of up to 2500 mL of
6% HES 130/0.4. The use of HES suggested a greater vol-
ume expansion effect as demonstrated by lower p-AVP,
p-Alb, and p-Aldo levels in spite of equal volume of fluid
infused. Furthermore, we observed an increased bleeding
tendency in the HES group, with 2 excluded patients due
to blood loss. E
DISCLOSURES
Name: Anne Sophie Pinholt Kancir, MD, PhD student.
Contribution: This author helped design the study, conduct
the study, analyze the data, write the manuscript, and statisti-
cal work.
Attestation: Anne Sophie Pinholt Kancir has seen the original
study data, reviewed the analysis of the data, approved the
final manuscript, and is the author responsible for archiving
the study files.
Name: Joergen Kühlwein Johansen, MD.
Contribution: This author helped design the study and con-
duct the study.
Attestation: Joergen Kühlwein Johansen approved the final
manuscript.
Name: Niels Peter Ekeloef, MD.
Contribution: This author helped design the study, conduct the
study, analyze data, and write the manuscript.
Attestation: Niels Peter Ekeloef has seen the original study
data, reviewed the analysis of the data, and approved the final
manuscript.
Name: Erling Bjerregaard Pedersen, MD, MSc.
Contribution: This author helped design the study, conduct the
study, analyze the data, and write the manuscript.
Attestation: Erling Bjerregaard Pedersen has seen the original
study data, reviewed the analysis of the data, and approved the
final manuscript.
This manuscript was handled by: Avery Tung, MD.
Figure 2. Blood loss (mL) shown for each of the 36 patients.
Horizontal lines mark the median blood loss in each group. HES =
6% hydroxyethyl starch 130/0.4; saline = isotonic saline 0.9%.
March 2015 • Volume 120 • Number 3	 www.anesthesia-analgesia.org	 617
ACKNOWLEDGMENTS
The authors greatly acknowledge the skillful assistance of
laboratory technicians: Anne Mette Ravn, Kirsten Nygaard,
HenrietteVorupSimonsen,andSusanRasmussen.Furthermore,
the authors thank nurse Susanne Slot, all the nurses and anes-
thesiologists of the Department of Anesthesiology, Lars Høst,
MD, Niels T. Mikkelsen, MD, and the nursing staff of the
Department of Urology, for their help and practical assistance
during the study.
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Kancir et al-2015-anesthesia_&_analgesia

  • 1. 608 www.anesthesia-analgesia.org March 2015 • Volume 120 • Number 3 Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000596 H ydroxyethyl starch (HES) is commonly used as a peri- operative intravascular volume expander to replace blood loss, obtain hemodynamic stability, and opti- mize tissue oxygenation. Current data suggest that HES sta- bilizes intravascular colloid pressure and reduces the volume required to achieve hemodynamic stability during resuscita- tion from hypovolemia or when large fluid shifts occur.1,2 HES consists of large starch molecules, substituted with hydroxyethyl groups to prevent degradation, which are dis- solved in a crystalloid carrier solution.3,4 Concerns about renal side effects with HES use were initially raised when osmosis nephrosis-like lesions were noted during routine kidney biopsies from renal transplant patients if the donor had received HES.5 Vacuolization and swelling of tubular cells were found in both the proximal and distal nephron.6–9 Further studies in animals and humans demonstrated impair- ment of renal function after HES treatment.5,10,11 To minimize the likelihood of renal injury, the most recent generation of HES solutions (tetrastarches) was developed with a lower molecular weight and molar substitution to enhance urinary excretion and reduce tissue accumulation.3,4,12 Recently, large trials on the use of tetrastarches for fluid resuscitation in septic, critically ill patients demonstrated a small increase in renal injury in patients given tetrastarch versus those given crystalloid.13–16 In perioperative care, however, current evi- dence does not suggest that renal injury and tetrastarch use are correlated.2,17–21 While 2 recent trials have suggested renal injury with synthetic colloid use, 1 trial did not specify the colloid used22 and the other did not study tetrastarch at all.23 Acute renal failure is most commonly diagnosed using the RIFLE criteria (Risk Injury Failure Loss End stage renal dis- ease), which are based on sudden increases in plasma creati- nine (p-crea) or an abrupt decrease in urine output (UO).24,25 However, p-crea is influenced by many variable factors (i.e., gender, nutrition, medication, muscle mass, and age), which makes the diagnosis difficult.26–28 To overcome these chal- lenges, several urinary biomarkers have shown promising BACKGROUND: Although hydroxyethyl starch (HES) is commonly used as an intravascular vol- ume expander in surgical patients, recent studies suggest that it may increase the risk of renal failure in critically ill patients. We hypothesized that patients undergoing radical prostatectomy and receiving HES would be more likely to develop markers of renal failure, such as increas- ing urinary neutrophil gelatinase–associated lipocalin (u-NGAL), creatinine clearance (Ccrea), and decreasing urine output (UO). METHODS: In a randomized, double-blinded, placebo-controlled study, 40 patients referred for radical prostatectomy received either 6% HES 130/0.4 or saline 0.9%; 7.5 mL/kg during the first hour of surgery and 5 mL/kg in the following hours; u-NGAL, urine albumin, Ccrea, UO, arterial blood pressure, and plasma concentrations of creatinine, renin, angiotensin II, aldosterone, and vasopressin were measured before, during, and after surgery. RESULTS: Thirty-six patients completed the study. u-NGAL, Ccrea, UO, plasma neutrophil gelatin- ase–associated lipocalin, p-creatinine, urine albumin, and arterial blood pressure were the same in both groups. Blood loss was higher in the HES group (HES 1250 vs saline 750 mL), while p-albumin was reduced to a significantly lower level. P-renin and p-angiotensin-II increased in both groups, whereas p-aldosterone and p-vasopressin increased significantly in the saline group. CONCLUSIONS: We found no evidence of nephrotoxicity after infusion of 6% HES 130/0.4 in patients undergoing prostatectomy with normal preoperative renal function. Hemodynamic sta- bility and infused fluid volume were the same in both groups. We observed an increased blood loss in the group given 6% HES 130/0.4.  (Anesth Analg 2015;120:608–18) The Effect of 6% Hydroxyethyl Starch 130/0.4 on Renal Function, Arterial Blood Pressure, and Vasoactive Hormones During Radical Prostatectomy: A Randomized Controlled Trial Anne Sophie Pinholt Kancir, MD, PhD Student,* Joergen Kühlwein Johansen, MD,† Niels Peter Ekeloef, MD,‡ and Erling Bjerregaard Pedersen, MD, MSc§ From the *University Clinic for Nephrology and Hypertension, Department of Medical Research and Medicine, and Department of Anesthesiology, Holstebro Hospital and University of Aarhus, Holstebro, Denmark; †Department of Urology, Holstebro Hospital, Holstebro, Denmark; ‡Department of Anesthesiology, Holstebro Hospital, Holstebro, Denmark; and §University Clinic for Nephrology and Hypertension, Department of Medical Research and Department of Medicine, Holstebro Hospital and University of Aarhus, Holstebro, Denmark. Accepted for publication November 13, 2014. Funding: The study was supported by grants from Region Midt’s Research Foundation for Health Science and the Lipmann Foundation, Denmark. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Anne Sophie Pinholt Kancir, MD, University Clinic for Nephrology and Hypertension, Department of Medical Research and Medicine, and Department of Anesthesiology, Holstebro Hospital and University of Aarhus, Laegaardvej 12, 7500 Holstebro, Denmark. Address e-mail to annesophie.kancir@gmail.com. Section Editor: Avery Tung Society for Critical Care Anesthesiologists
  • 2. March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 609 results.29,30 Neutrophilgelatinase–associatedlipocalin(NGAL) is produced in low concentrations in the neutrophils and the tissues and can be measured in plasma and urine.26,27 NGAL is filtered via the glomeruli and reabsorbed in the proximal tubules and increases rapidly after renal injury due to an up- regulated expression and secretion in the nephrons.27,31 Thus, NGAL is one potential marker of acute renal failure. We hypothesized that measurements of urinary NGAL (u-NGAL) could reveal a potential nephrotoxicity of 6% HES 130/0.4 in patients undergoing surgery with previous normal renal function. HES may affect renal function dif- ferently from crystalloid due to the different hemodynamic properties of 6% HES 130/0.4 compared with 0.9% saline. Subsequent changes in vasoactive hormones may also change renal function. In the present randomized, placebo- controlled, double-blinded study, we measured the fol- lowing: (1) renal function, that is, u-NGAL, plasma NGAL (p-NGAL), p-crea, creatinine clearance (Ccrea), UO, urine albumin (u-Alb), urine aquaporine2 excretion (u-AQP2CR), and free water clearance (CH2O); (2) blood pressure (sys- tolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP], and heart rate [HR]); and (3) plasma concentrations of renin (PRC), angiotensin II (p-AngII), aldosterone (p-Aldo), and vasopressin (p-AVP) before, during, and after radical prostatectomy. METHODS Ethics The study was approved by the Danish Medicines Agency (EudraCT: 2011-004274-28) and the Regional Committee of Health Research Ethics (J. No. M-20110213) and registered at ClinicalTrials.gov (NCT01486563). The study was performed in accordance with the Declaration of Helsinki and moni- tored by the Good Clinical Practice committee at University of Aarhus. Written informed consent was obtained from each patient before any study-related procedure. Patients Inclusion criteria were men >18 years and scheduled for removal of the prostate under general anesthesia due to prostate cancer. Exclusion criteria were estimated glo- merular filtration rate <15 mL/min, need of nonsteroidal anti-inflammatory drugs, blood donation within a month before the surgery, and anamnestic or clinical findings that excluded surgery according to the general procedures in the Departments of Anesthesiology or Urology. Withdrawal cri- teria were development of exclusion criteria, complications during surgery such as severe bleeding with blood trans- fusion, prolonged postoperative course due to resurgery or infection, withdrawal of consent, unexpected increased level of u-NGAL before intervention, and medication with ephedrine or dexamethasone during surgery. Recruitment All patients were recruited from the Department of Urology, Holstebro Hospital, Holstebro, Denmark. Design The study was conducted as a randomized, controlled, dou- ble-blinded study on 40 patients undergoing elective radical prostatectomy. Intervention Patients were consecutively randomized to receive either 6% HES 130/0.4 (Voluven® ) as active treatment or 0.9% iso- tonic saline as control. Both fluids were manufactured by Fresenius Kabi, Bad Homburg, Germany, and produced in 500-mL freeflex bags. Each bag was concealed in identical black plastic, sealed, and marked 1 to 40. Five bags were packed in boxes corresponding to each randomization number. All packing and blinding were performed by the hospital pharmacy. The minimal infusion rate was 7.5 mL/kg in the first hour and 5 mL/kg for each hour thereafter until the end of recovery. If an episode of excess bleeding occurred, more fluid could be given until hemodynamic stability was obtained (MAP ≥60 mm Hg). The maximal dose of 6% HES 130/0.4 was 50 mL/kg/day according to the manufacturer and the Danish Medicines Agency, Copenhagen, Denmark. No supplemental IV fluids were given during surgery to minimize the likelihood of bias and confounding factors. If needed, the patients received Ringer’s acetate solution upon discharge from recovery. The threshold for blood transfusion was hemoglo- bin ≤4.5 mmol/L. Hemoglobin values between 4.5 to 6.5 mmol/L resulted in a clinical evaluation of every patient before blood transfusion. A surgical nurse assessed the blood loss at the end of surgery as a combination of the vol- ume of blood in the suction and in the napkins, which were weighed before and after use. Randomization A randomization list was generated in blocks of 8 by staff from the hospital pharmacy by using a webpage.a Treatment assignment was concealed from patients, clinicians, and research staff until after the last visit of the last patient. Effect Variables The main effect variable was u-NGAL. Secondary effect vari- ables were p-NGAL, PRC, p-ANGII, p-Aldo, p-AVP, Ccrea, UO, p-crea, CH2O, u-Alb, u-AQP2CR, SBP, DBP, MAP, and HR. Power Analysis With a significance level of 5% and a power of 80%, 32 patients were needed to detect a 100 ng/mL difference in u-NGAL with an SD of 100 ng/mL. A difference of 100 ng/ mL was considered a clinically meaningful difference to diagnose acute kidney injury (AKI), as stated by the man- ufacturer of the ELISAb test we used (Bioporto, Hellerup, Denmark). The SD was based on an assessment of the lit- erature containing measurements of u-NGAL from both healthy and sick patients.29,30,32 We estimated that 40 patients should be included in the trial, 20 patients in each interven- tion group, due to the risk of dropout and complications. Experimental Procedures Anesthetic Procedures Before and During Surgery All patients received 1000 mg paracetamol and 1200 mg gabapentin (600 mg gabapentin if the patient was ≥70 years) a Available at: www.randomization.com. Accessed September 19, 2014. b Available at: http://www.bioporto.com/Products/NGAL-ELISA-Kit-(human). aspx. Accessed October 22, 2014.
  • 3. Hydroxyethyl Starch and NGAL During Radical Prostatectomy 610   www.anesthesia-analgesia.org anesthesia analgesia before surgery. Fluid infusion was started together with monitoring of SBP, DBP, electrocardiogram, HR, and arterial oxygen saturation. Anesthesia was induced with thiopental (5 mg/kg), fentanyl (5 μg/kg), and cisatracurium (0.1–0.15 mg/kg) and maintained with an inspired oxygen concen- tration (0.6), isoflurane (minimum alveolar concentration 1.2–1.5), and IV increments of 0.15 μg/kg fentanyl. After tra- cheal intubation, mechanical ventilation was set to achieve a carbon dioxide end-tidal concentration (Pco2) of 4.5–5.5 kPa. After induction, a urine catheter and an arterial line were placed to provide a continuous measurement of blood pressure. If MAP decreased 60 mm Hg, the infusion of the study fluid was increased, incremental doses of phenyleph- rine 0.1 mg were given, or an infusion with phenylephrine was started (0.1 mg/mL). A prophylactic dose of antibiotic (cefuroxime 1500 mg) and antiemetic (ondansetron 4 mg) was given before surgery. Urine and Blood Sampling Urine was collected for 24 hours from all patients on the day before surgery (urine 1, baseline). Urine was also collected beginning with the start of surgery and lasting 4 hours (urine 2, surgery). Postoperatively, urine was collected until the next morning at 8:00 am (urine 3, postsurgery). At dis- charge 1, additional urine sample was obtained (urine 4, dis- charge). The patients then collected a 24-hour urine sample at home on the day before the 15-day follow-up visit at the hospital (urine 5, follow-up). Blood samples were drawn through a venous cannula just before the start of the inter- vention. In the recovery room after surgery, blood samples were drawn within the first hour after arrival. In total, 140 mL blood was drawn from each patient. Biochemical Analyses All urine and blood samples were centrifuged for 10 min- utes at 3500 G and 4°C and then plasma was separated from blood cells. All samples were then kept frozen at −80°C or −20°C until assayed. They were centrifuged again just before the assays were performed to minimize any impuri- ties in the samples. Every analysis was done at the same time by the same laboratory technician to minimize vari- ability in the results. U-NGAL and p-NGAL were determined by a commer- cial ELISA assay. Minimal detection level was 1.6 pg/mL. Variations were interassay max 7.2% in urine, max 4.6% in plasma, intra-assay max 4.9% in urine, and max 4.5% in plasma. All samples were analyzed with kits from the same batch.32 U-AQP2 was measured by radioimmunoassay. Antibodies were increased in rabbits to a synthetic peptide corresponding to the 15 COOH-terminal amino acids in human AQP2 to which was added an NH2-terminal cysteine for conjugation and affinity purification. Minimal detection level was 34 pg per tube. Coefficients of variation were 11.7% (interassay) and 5.9% (intra-assay).33,34 PRC was determined by radioimmunoassay from CIS Bio International, Gif-Sur- Yvette Cedex, France. Minimal detection level was 1 pg/mL and coefficients of variation were 0.9% to 3.6% (intra-assay) and 3.7% to 5.0% (interassay) in the range of 4 to 263 pg/ mL. P-Aldo was determined by radioimmunoassay, using a commercial kit from Demeditec Diagnostics GmbH, Kiel, Germany, minimal detection level was 25 pmol/L and coef- ficients of variation were 9.0% (interassay) and 8.5% (intra- assay). P-AngII and p-AVP were extracted from plasma with C18 Sep-Pak (Water Associates, Milford, MA) and sub- sequently determined by radioimmunoassay. The antibody against AngII was obtained from the Department of Clinical Physiology, Glostrup Hospital, Denmark. Minimal detec- tion level was 2 pmol/L. The coefficients of variation were 12% (interassay) and 8% (intra-assay). The antibody against AVP was a gift from Professor Jacques Dürr, MD, H. Lee Moffitt Cancer Center, Memorial Hospital of Tampa, Saint Joseph’s Hospital, Tampa General Hospital, Tampa, Florida. Minimal detection level was 0.2 pmol/L. The coefficients of variation were 13% (interassay) and 9% (intra-assay).35,36 Routine analyses were done at the Department of Clinical Biochemistry, Holstebro Hospital. Hemodynamic Data SBP, DBP, and HR were recorded continuously through- out the surgery with Infinity Delta XL® (Dräger, Lübeck, Germany). All values during surgery were noted in 5-min- ute intervals. In the recovery period, values were noted in 15-minute intervals and S/5™ CompactAnesthesia Monitor (Datex-Ohmeda; GE Healthcare Finland, Oy Helsinki, Finland) was used. All values were divided into 5 different time periods (baseline, preincision, incision, postincision, and recovery period), and the average of those periods was calculated and used for analyses. Calculations Clearance (C) of substance X was calculated as CX = UX/ (PX × UO), where UX denotes concentration of x in urine, PX denotes concentration of x in plasma, and UO is the rate of urine excretion. MAP was calculated according to the formula MAP = (SBP − DBP)/3 + DBP. Statistics All patients who received the assigned study intervention and did not encounter any exclusion criteria were included in the analysis. Demographic data for HES and control patients are presented in Table 1. To determine whether parametric or nonparametric analysis should be performed, the continuous outcome variables were assessed for normal distribution visually and by the Shapiro-Wilks test. Parametric analyzed data are presented as mean (SD); nonparametric analyzed data as median (25%–75% quartiles); frequency data are presented as number (%). P values are reported as 2-sided values, and to correct for multiple comparisons, we required a P value ≤0.01 to obtain statistical significance. Nonparametric statistics were used to analyze the major- ity of the outcome variables in Table 2 (perioperative man- agement). No statistics were needed in Table 3. In Table 4 (renal function) nonparametric statistics were mostly used, and in Table  5 (vasoactive hormones) all variables were considered nonnormally distributed. The Mann-Whitney U test was used to analyze the difference between the groups (HES versus saline). A Friedman test was applied in Table 4 to determine whether there were any statistical differences between the medians within each group (HES
  • 4. March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 611 or saline). Pairwise comparisons, using Wilcoxon signed rank test, were performed as a post hoc analysis with a Bonferroni correction for multiple comparisons. Each pair- wise comparison was performed as a comparison with the baseline value. In Table 4, either 3 or 4 pairwise compari- sons were performed in each group as appropriate. In Table 5, we compared the values before and after intervention within each group with a Wilcoxon signed rank test. Parametric statistics were used for all hemodynamic variables (Table 6), Ccrea (Table 4), and some perioperative variables in Table 2 because they were considered normally distributed. An unpaired t test determined the difference between the groups (HES versus saline). In Table 6, a Welch t test was used for some comparisons because homogeneity of variances was violated, as assessed by the Levene test for equality of variance. To determine whether there was any statistical difference between the means, an analysis of vari- ance with repeated measures was used within each group (HES or saline) in Tables 4 and 6. The assumption of spheric- ity was assessed by Mauchly test of sphericity; if violated, a Greenhouse-Geisser correction was applied. A post hoc analysis with a Bonferroni adjustment for multiple pairwise comparisons was performed using a paired t test comparing values with the baseline. Three pairwise comparisons were performed for the variable Ccrea in each group (Table 4), and in Table 6, we did 4 comparisons within each group. Statistics were performed using PASW version 20.0.0 for Mac (SPSS Inc., Chicago, IL). RESULTS Demographics Between January 2012 and June 2013, 51 patients were con- secutively screened to participate in the trial (Fig. 1). Eleven patients were not eligible due to the use of nonsteroidal anti- inflammatory drugs (2 patients) and unwillingness to par- ticipate (9 patients). Thus, 40 patients were included with 20 patients randomized to receive 6% HES 130/0.4 and 20 to saline 0.9%. Two patients in the HES group were excluded due to bleeding requiring blood transfusion. In the saline group, 2 patients were excluded due to treatment with dexamethasone (1 patient) and ephedrine (1 patient) dur- ing surgery. Thus, 18 patients (90%) completed the study in each group. The 2 groups were comparable regarding age, body mass index, comorbidities, antihypertensive medi- cation, office blood pressure, and screening biochemistry (Table 1). During the entire trial, there were no protocol vio- lations. One patient in the HES group (No. 18) was excluded because he had a very high baseline value of u-NGAL. Fluid Infusion and Blood Loss During Operation The amounts of intervention fluid (2500 vs 2500 mL) and supplemental fluid (Ringer’s acetate solution; 50 vs 50 mL) were the same in the 2 groups. Furthermore, no difference was found in the number of patients receiving phenyleph- rine (13 vs 17, P = 0.18) and the amount of phenylephrine used per patient (0.8 vs 1.1 mg, P = 0.38; Table 2). Figure 2 shows that the blood loss was significantly higher in the HES group than in the saline group (1256 vs 747 mL, P = 0.008). In addition, 7 patients in the HES group versus 1 patient in the saline group had a blood loss exceeding 1.5 L during surgery (Fig. 2). Only one of these patients received a blood transfusion (HES group). Urine NGAL All patients were discharged with a urinary catheter, and most had leukocytes and hemoglobin in the urine at follow- up (Table 3). Thus, measurements of u-NGAL at follow-up were not included in the analyses because u-NGAL would be falsely elevated due to the presence of leukocytes or blood in the urine sample. The effect of 6% HES 130/0.4 or saline 0.9% on u-NGAL and u-NGAL adjusted for creatinine is shown in Table 4. U-NGAL was the same in both groups at all times regardless of expression as a concentration or adjusted for creatinine. U-NGAL increased significantly in both groups, when compared with baseline levels, but the increases were very modest u-Alb Excretion and u-Alb/Creatinine Ratio Table 4 shows u-Alb and urine-albumin-adjusted-for-creati- nine increased similarly in both groups during surgery and admission. A significant increase was shown in both groups Table 1.  Baseline Characteristics Variables HES (n = 18) NaCl ( = 18) Age (year)a 64 (4.8) 66 (5.1) Body mass indexa 25.7 (3.7) 25.3 (3.5) Weight (kg)a 80.7 (12.5) 78.2 (12.7) Comorbidities, no. (%)  Hypertensionb 5 (27.8) 5 (27.8)  Heart disease   PCIb 0 0   CABGb 0 0   Heart failureb 0 0  COPDb 2 (11.1) 1 (5.6)  Diabetes mellitus   Type Ib 0 0   Type IIb 1 (5.6) 1 (5.6)  Strokeb 0 1 (5.6)  Otherb 8 (44.4) 9 (50.0) Antihypertensive treatment, no. (%)  ACE inhibitors/ATIIrbb 4 (22.2) 4 (22.2)  Calcium channel blockersb 1 (5.6) 3 (16.7)  Beta-blockersb 1 (5.6) 2 (11.1)  Diureticsb 2 (11.1) 1 (5.6)  Anticoagulationb 0 3 (16.7) Office blood pressure (mm Hg)  SBPa 146 (18.0) 150 (9.5)  DBPa 87 (10.4) 87 (9.3)  Pulsea 72 (14.5) 67 (7.6) Screening biochemistry  p-K (mmol/L)a 4.0 (0.31) 3.8 (0.27)  p-Na (mmol/L)a 142 (1.5) 141 (1.5)  p-alb (g/L)a 44 (2.8) 43 (2.5)  p-crea (μmol/L)a 83 (13.6) 79 (13.1)  eGFR (mL/min)a 83 (14.7) 88 (16.5)  p-Hgb (mmol/L)a 9.2 (0.81) 9.4 (0.39) UO (mL/day)a 1845 (1446; 2575) 1920 (1399; 2364) ACE = angiotensin-converting enzyme; ATIIrb = angiotensin-II-receptor blocker; CABG = coronary artery bypass graft; COPD = chronic obstructive pulmonary disease; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%; p-alb = plasma albumin; p-crea = plasma creatinine; p-Hgb = plasma hemoglobin; p-K = plasma potassium; p-Na = plasma sodium; PCI = percutaneous cardiovascular intervention; SBP = systolic blood pressure; UO = urine output. a Continuous data; mean (SD). b Nominal data; number (%).
  • 5. Hydroxyethyl Starch and NGAL During Radical Prostatectomy 612   www.anesthesia-analgesia.org anesthesia analgesia at all times when comparing the values with baseline. Even at follow-up on day 14, the values were still elevated. Ccrea, AQP2CR, CH2O, and UO Ccrea, AQP2CR, CH2O, and UO are shown in Table 4. Ccrea decreased to the same extent in both groups during surgery but increased again after surgery. No significant difference was found between the groups at any time. The excretion of U-AQP2CR was significantly higher in the saline group compared with the HES group during and after surgery (surgery [urine 2]: 307 vs 417 ng/mmol, P = 0.005; postsurgery [urine 3]: 147 vs 218 ng/mmol, Table 2.  Perioperative Management Variables HES (n = 19) NaCl (n = 19) P Time periods (hh:mm)  Duration of anesthesiaa 3:08 (0:31) 3:08 (0:33) 0.963  Duration of the surgerya 1:45 (0:27) 1:45 (0:28) 0.981  Duration of the recovery periodb 2:40 (2:07; 3:00) 2:32 (2:15; 3:11) 0.556 Length of hospital stayb 2.5 (2.5; 2.8) 2.5 (2.5; 2.5) 0.338 ETco2 (kPa)a 4.6 (0.30) 4.5 (0.31) 0.338 Intervention fluid IV (mL)b 2500 (2000; 2500) 2500 (2500; 2500) 0.274 Ringer’s acetate IV (mL)b 50 (0; 1000) 50 (0; 1000) 1.000 Blood loss (mL)a 1256 (669) 747 (331) 0.008 Patients needing phenylephrine, no. (%)c 13 (72) 17 (94) 0.177 Phenylephrine dose (mg)b 0.8 (0.4; 1.5) 1.1 (0.4; 3.5) 0.378 a Values considered normally distributed; mean (SD); difference between groups analyzed by unpaired t test. b Values considered nonnormally distributed; median (25%–75% quartiles); difference between groups analyzed by Mann-Whitney U test. c Frequency data; number (%); difference between groups analyzed by Fischer exact test. HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%; ETco2 = end-tidal CO2. Table 3.  Urine Neutrophil Gelatinase–Associated Lipocalin (ng/mL) and Results of the Urine Test Strips Patient Intervention Urine 1 Urine 1 Urine 2 Urine 3 Urine 4 Urine 5 Urine 5 test strip baseline surgery postsurgery discharge follow-up test strip 02 HES 15 15 13 29 56 + 06 HES 58 17 14 24 16 + 07 HES + 35 24 21 75 61 + 08 HES 24 65 9 71 23 + 09 HES + 25 14 13 44 322 + 11 HES 9 5 12 11 9 + 14 HES 34 42 5 17 105 + 16 HES 14 41 14 52 17 + 18 HES + 229 108 138 272 − + 24 HES 3 4 7 56 10 + 26 HES 9 4 13 72 179 + 28 HES 35 5 11 68 22 + 29 HES 25 25 10 − 215 + 31 HES 11 46 10 − 11 + 33 HES 18 9 4 9 12 + 35 HES 11 98 5 69 − + 37 HES 11 6 11 65 36 − 39 HES 11 23 16 39 180 + 01 NaCl 4 7 14 20 8 + 03 NaCl 9 31 15 15 15 + 04 NaCl 16 2 4 21 21 + 05 NaCl 28 9 9 43 16 + 10 NaCl 18 19 9 19 19 + 12 NaCl 7 4 6 13 18 + 13 NaCl 11 3 27 − 18 + 17 NaCl 22 40 25 69 26 + 19 NaCl 10 13 20 37 11 + 22 NaCl 7 15 13 24 33 + 23 NaCl 19 22 16 173 248 + 25 NaCl 12 5 23 86 229 + 27 NaCl 10 11 12 50 31 + 30 NaCl + − 23 9 27 − + 34 NaCl 2 5 3 29 12 + 36 NaCl 18 26 13 56 322 + 38 NaCl 10 10 18 145 222 + 40 NaCl 14 7 8 36 40 + The values marked with gray are excluded from the analysis of urinary neutrophil gelatinase–associated lipocalin because of a high content of leucocytes, nitrite, or hemoglobin. No test strips were performed in urine 2–4. + = leucocytes, hemoglobin, and/or nitrite; − = missing value/test; HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%.
  • 6. March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 613 P  0.0005). U-AQP2CR excretion increased during surgery in both groups but was normalized at follow-up. CH2O increased from −0.4 to 1.3 mL/min in the HES group, but only from 0.0 to 0.8 mL/min in the saline group during surgery. UO did not change significantly after the intervention both between and within the groups. p-NGAL, Plasma Albumin, and p-crea P-NGAL, plasma albumin (p-Alb), and p-crea are shown in Table 5. No significant difference was found between the groups in p-NGAL after intervention. However, within the saline group, p-NGAL increased significantly after interven- tion. P-Alb was significantly lower in the HES group after intervention compared with the saline group (P 0.0001, postsurgery) as well as within both groups after interven- tion (Table 5). In both groups, p-crea increased significantly after intervention, but to the same extent. Vasoactive Hormones in Plasma The changes in the vasoactive hormones are shown in Table 5. PRC increased to the same extent in both groups while p-ANGII remained almost unchanged. P-Aldo was significantly increased in the saline group compared with the HES group after intervention. P-AVP increased in both groups after intervention. Blood Pressure and HR During the entire surgery and in the recovery period, SBP, DBP, and MAP were similar in both groups. SBP, DBP, and MAP decreased during anesthesia and in the recovery period. However, patients in the HES group had a signifi- cantly higher HR at baseline, before, and after surgery com- pared with the saline group (Table 6). DISCUSSION The primary study outcome was to clarify whether HES had a nephrotoxic effect as measured by increases in u-NGAL, Ccrea, u-Alb, and p-crea and decreases in UO during and/ or after surgery. We found no evidence of nephrotoxicity in patients given up to 2500 mL of HES during surgery. Instead, we found evidence supporting better intravascular volume expansion in patients given 6% HES 130/0.4 as demonstrated by lower p-AVP, p-Alb, and p-Aldo levels and equal volume of infused fluid despite more bleeding in the HES group. Table 4.  Renal Function Urine 1 Urine 2 Urine 3 Urine 4 Urine 5 Pa baseline surgery postsurgery discharge follow-up U-NGAL (ng/mL)b  HES 15 (11; 30) 17.(6; 42) 11 (8; 14) 52 (24; 69) — 0.0001  NaCl 11 (8; 18) 11 (5; 22) 13 (9; 19) 33 (20; 55)* — 0.0001 P 0.086 0.175 0.363 0.278 — U-NGALCR (ng/μmol)b  HES 2 (1; 3) 5 (4; 12)** 2 (1; 2) 4 (4; 6) — 0.0001  NaCl 1 (1; 2) 4 (3; 6)* 2 (2; 4) 5 (3; 7)* — 0.0001 P 0.107 0.108 0.087 0.474 — U-Alb (mg/L)b  HES 6 (2; 7) 105 (68; 151) 140 (106; 216)* 350 (148; 591)* 104 (51; 163)** 0.0001  NaCl 4 (3; 9) 76.0 (61; 147)** 134 (111; 200)* 345 (172; 691)* 77 (40; 120)** 0.0001 P 0.774 0.622 0.713 0.575 0.322 U-AlbCR (mg/mmol)b  HES 0.6 (0.3; 0.9) 40.1 (27.3; 52.1)* 23.1(18.5; 32.0)** 37.5 (25.6; 54.1)* 17.2 (7.6; 25.1) 0.0001  NaCl 0.5 (0.4; 1.0) 26.3 (19.3; 67.5)* 30.3 (20.8; 38.6)* 39.4 (30.2; 73.8)* 13.1 (9.3; 22.4) 0.0001 P 0.787 0.323 0.192 0.235 0.783  Ccrea (mL/min)c  HES 134 (28) 63 (39) 113 (26) — 124 (27) 0.0001  NaCl 124 (30) 65 (34) 116 (27) — 114 (27) 0.0001 P 0.322 0.876 0.761 — 0.286 U-AQP2CR (ng/mmol)b  HES 140 (123; 157) 307 (199; 342)** 147 (139; 184) 145 (121; 203) 134 (124; 158) 0.001  NaCl 146 (124; 172) 417 (261; 538)* 218 (192; 260) 179 (137; 228) 147 (135; 171) 0.0001 P 0.318 0.005 0.0005 0.373 0.041 CH2O (mL/min)b  HES −0.4 (−1.1; 0.9) 1.3 (0.5; 2.3) 0.5 (−0.4; 1.9) — — 0.046  NaCl 0.0 (−1.2; 0.8) 0.8 (0.2; 2.4) 1.4 (0.8; 2.1) — — 0.024 P 0.693 0.953 0.114 — — UO (mL/min)b  HES 1.3 (1.0; 1.8) 2.0 (1.5; 2.7) 1.5 (1.1; 2.4) — 1.7 (1.5; 2.2) 0.108  NaCl 1.4 (1.0; 1.7) 1.6 (1.4; 2.9) 2.1 (1.6; 2.5) — 1.9 (1.4; 2.4) 0.031 P 0.858 0.673 0.168 — 0.570 CH2O = free water clearance; Ccrea = creatinine clearance; HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%; u-alb = urine albumin; u-AlbCR = urine albumin adjusted for creatinine; u-AQP2CR = urine aquaporine-2 adjusted for creatinine; u-NGAL = urine neutrophil gelatinase–associated lipocalin; u-NGALCR = urine neutrophil gelatinase–associated lipocalin adjusted for creatinine; UO = urine output. a P value showing the difference between medians in each group analyzed by Friedmann test or analysis of variance with repeated measures as appropriate; post hoc analysis with Bonferroni correction; comparisons with baseline value within each group. b Variables considered nonnormally distributed; median (25%–75% quartiles); difference between groups was analyzed by Mann-Whitney U test. c Variables considered normally distributed; mean (SD); difference between groups was analyzed by unpaired t test. *P 0.001; **P 0.01.
  • 7. Hydroxyethyl Starch and NGAL During Radical Prostatectomy 614   www.anesthesia-analgesia.org anesthesia analgesia As has been done previously in patients after cardiac surgery, we used u-NGAL to screen for AKI.29,30 In the pres- ent study, u-NGAL increased slightly in the postoperative period, but to the same extent in both groups. This increase might be explained by surgical and hemodynamic stress. In addition, we used chloride-rich solutions (0.9% normal saline) in both the intervention and control groups, which may have had a direct effect on the risk of AKI.37 At follow- up, several patients in both groups had leukocytes and blood in their urine, potentially resulting in a falsely ele- vated u-NGAL.31,38 Thus, follow-up data were not included in the analysis of u-NGAL. P-NGAL was the same before and after surgery between the groups. Although a signifi- cant increase was measured within the saline group, the dif- ference was very modest and without clinical significance. Previously, renal effects of tetrastarch and crystalloids have been compared using p-crea, UO, or Ccrea. In 1 study, tran- siently higher levels of p-crea were measured in patients receiving HES after cardiac surgery compared with crys- talloid. However, the increase was modest, within normal ranges, and there were no differences between the groups after 72 hours.19 In addition, several other surgical studies, a review, and 1 meta-analysis found no evidence of renal impairment after perioperative infusions with tetrastarc hes.2,17–21,39–42 Recently, the use of tetrastarch was associated with increased mortality and use of renal-replacement therapy in patients with sepsis.13–16 However, patients in these stud- ies were severely ill with sepsis, had multiorgan failure, and renal impairment before inclusion.13–16 Furthermore, the patients differed from ours due to a damaged glycocalyx barrier.43,44 In October 2013, these data generated new recom- mendations from the European Medicines Agency (EMA) Table 5.  Vasoactive Hormones, p-NGAL, p-Alb, and p-crea Presurgery Postsurgery P P-NGAL (ng/mL)  HES 84 (68; 103) 81 (69; 99) 0.817  NaCl 83 (69; 101) 87 (78; 121) 0.003 P 0.845 0.211 P-Alb (g/L)  HES 41 (40; 42) 26 (25; 30) 0.0001  NaCl 42 (40; 42) 35 (34; 37) 0.0001 P 0.485 0.0001 P-crea (μmol/L)  HES 82 (72; 91) 90 (82; 105) 0.0001  NaCl 79 (76; 84) 88 (78; 104) 0.001 P 0.644 0.476 PRC (pg/mL)  HES 5.2 (3.6; 8.8) 13.1 (8.1; 22.3) 0.0001  NaCl 6.3 (3.4; 12.1) 12.6 (5.1; 38.2) 0.0001 P 0.791 0.957 P-ANGII (pg/mL)  HES 9.0 (7.5; 11.5) 10.0 (5.0; 19.5) 0.067  NaCl 9.0 (5.8; 16.5) 11.5 (8.5; 26.3) 0.081 P 0.889 0.194 P-Aldo (pmol/L)  HES 119 (58; 188) 110 (57; 201) 0.766  NaCl 101 (57; 140) 288 (208; 601) 0.0001 P 0.462 0.0001 P-AVP (pg/mL)  HES 0.2 (0.2; 0.2) 9.9 (1.7; 15.0) 0.0001  NaCl 0.3 (0.2; 0.6) 15.0 (12.4; 15.0) 0.0001 P 0.121 0.006 All variables are considered nonnormally distributed; median (25%–75% quartiles); difference between groups was analyzed by Mann-Whitney U test; difference within groups was analyzed by Wilcoxon signed rank test. HES = 6% hydroxyethyl starch 130/0.4; NaCl = saline 0.9%; p-NGAL = neutrophil gelatinase–associated lipocalin; p-Alb = plasma albumin; p-Aldo = plasma aldosterone; p-AngII = plasma angiotensin II; p-AVP = plasma vasopressin; p-Crea = plasma creatinine; PRC = renin. Table 6.  Hemodynamic Values Baseline Preincision Incision Postincision Recovery Pa HR (beats/min)  HES 78 (13) 62 (12)* 60 (8)* 67 (11) 72 (10) 0.0001  NaCl 64 (7) 56 (7)** 56 (7) 61 (9) 63 (7) 0.0001 P 0.001b 0.045b 0.068b 0.037b 0.003b SBP (mm Hg)  HES 151 (10) 107 (17)* 98 (12)* 116 (17)* 126 (12)* 0.0001  NaCl 150 (12) 104 (13)* 89 (9)* 111 (22)* 126 (20)** 0.0001 P 0.902 0.474 0.089 0.486 0.628b DBP (mm Hg)  HES 93 (8) 67 (10)* 60 (8)* 69 (17)* 69 (5)* 0.0001  NaCl 89 (9) 62 (8)* 55 (7)* 67 (15)* 67 (11)* 0.0001 P 0.272 0.169 0.329 0.781 0.555b MAP (mm Hg)  HES 112 (8) 81 (12)* 73 (9)* 84 (14)* 88 (6)* 0.0001  NaCl 109 (9) 76 (9)* 67 (7)* 82 (17)* 86 (13)* 0.0001 P 0.489 0.242 0.194 0.620 0.882b All variables are considered normally distributed; mean (SD); difference between groups was analyzed by unpaired t test. DBP = diastolic blood pressure; HES = 6% hydroxyethyl starch 130/0.4; HR = heart rate; MAP = mean arterial pressure; NaCl = saline 0.9%; SBP = systolic blood pressure; Baseline = just before anesthesia; Preincision = just after anesthesia, but before surgery; Incision = during surgery; Postincision = time after surgery, but before recovery; Recovery = during recovery. a P value showing difference between means in each group was analyzed by analysis of variance with repeated measures; post hoc analysis with Bonferroni correction using unpaired t test; comparisons performed with baseline value within each group. b A Welch t test was used for the comparison as homogeneity of variances was violated, assessed by the Levene test for equality of variance; all P values ≤0.045. *P 0.001; **P 0.01.
  • 8. March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 615 restricting the use of products containing HES in patients with septicemia, renal impairment, and burns but not in patients with acute hypovolemia due to blood loss. However, these findings might not translate to patients with normal renal function undergoing surgery. In this study, we used an initial administration of the project fluid to balance the effect of anesthesia followed by more project fluid to compensate for bleeding. Because the starch solutions are designed for acute resuscitation, our use of colloid in this study may con- flict with the current EMA guidelines and does not reflect current clinical practice. The aim of this study, however, was to test a possible nephrotoxic effect of HES and not to study the current use of HES during anesthesia and surgery. Therefore, to eliminate confounders and bias, we chose a randomized, controlled, double-blinded design with the above-mentioned fluid administration. Finally, this study was planned and performed before the current EMA guide- lines were introduced. Our present results indicate that up to 2500 mL of 6% HES 130/0.4 given IV during prostatectomy does not have a nephrotoxic effect on perioperative renal function if preoperative renal function was normal. During surgery and recovery, SBP, DBP, and MAP did not differ between groups. Patients in both groups received the same amount of fluid, and similar amounts of phenyl- ephrine were used in both groups. Two patients in the HES group had to be excluded due to blood loss and transfusions during surgery. Although these 2 patients were not included in the analyses, median blood loss (1250 vs 750 mL) as well as the number of patients with a blood loss exceeding 1.5 L (7 vs 1) was larger in the HES group. However, only 1 additional patient in the HES group needed a blood trans- fusion during the hospital stay. This increase in blood loss in the HES group is reasonable because both in vivo and in vitro studies have demonstrated increased bleeding ten- dency and increased blood loss due to impaired coagulation after HES treatment.20,45–48 Infusion of HES delays initiation of thrombin generation, impairing platelet function and clot strength. Two previous studies found increased blood loss during surgery after infusion with 6% HES 130/0.4. However, both studies combined HES and saline and were not double blinded.20,49 We found that HR was significantly increased in the HES group at baseline before intervention and throughout the study, which may have been by chance. However, a compensatory phenomenon in response to the increased blood loss during 6% HES 130/0.4 infusion can- not be excluded. In previous surgical studies, the majority Eligible paƟents (n=51) Non-eligible (n=11) Used daily NSAID (n=2) Not willing to parƟcipate (n=9) Completed follow-up and included in analysis (n=18) Excluded (n=2) Received blood transfusion due to excessive bleeding during surgery (n=2) Allocated to receive HES 130/0.4 (n=20) Excluded (n= 2) Received Ephedrine during surgery (n=1) Received Dexamethasone during surgery (n=1) Allocated to receive Isotonic Saline 0.9% (n=20) Completed follow-up and included in analysis (n=18) Randomized (n=40) Figure 1. Flow chart of assessment, randomization, and completion. NSAID = nonsteroidal anti-inflammatory drugs; HES = 6% hydroxyethyl starch 130/0.4.
  • 9. Hydroxyethyl Starch and NGAL During Radical Prostatectomy 616   www.anesthesia-analgesia.org anesthesia analgesia found no difference in the hemodynamic effects of colloids and crystalloids,2,17,18,39,48 with only 1 study observing an increased MAP after tetrastarch infusion.50 Comparison with the present study is difficult because some studies were not double blinded, different ratios of colloids versus crystalloids were used, and often both groups received crys- talloids or colloids as supplemental fluids. PRC and p-AngII increased in both groups due to a stimulation of the renin–angiotensin–aldosterone system by the decrease in arterial blood pressure during general anesthesia. We found that P-Aldo increased significantly in the saline group, while remaining unchanged in the HES group. This finding is consistent with the results of another study, which compared 3 older HES solutions (200/0.5, 200/0.62, and 450/0.7) with Ringer’s solution and found increased levels of p-Aldo in the Ringer’s solution group.51 HES infusion expands plasma volume to a greater extent than saline.1–4,52 This observation is supported by the lower p-Alb in the HES group compared with the saline group. The decrease in blood pressure and baroreceptor stimula- tion might explain the considerable increase in p-AVP in some patients during surgery, which explains the increase in u-AQP2 above baseline during and after surgery.34 It has been well documented that this increase reflects an increased water transport from the tubules to the intracellular space via AQP2 water channels in the principal cells in the dis- tal part of the nephron,33,34,53 which corresponds with our findings of a higher CH2O in the HES group during surgery. We thus found more pronounced water reabsorption via the AQP2 water channels after infusion with saline 0.9% com- pared with 6% HES 130/0.4. Abetter volume expansion was shown during surgery after infusion with 6% HES 130/0.4 demonstrated by the lower p-AVP, p-Alb, and p-Aldo levels and the increased levels of water reabsorption in the saline group despite the higher blood loss in the HES group. The major strength of this study is the randomized, dou- ble-blinded, placebo-controlled design and limited variability in study conditions regarding operative procedures, anesthe- sia, and recovery period. Only 3 different surgeons operated and were equally represented in the groups. We included a 24-hour urine sample to assess kidney function both before and at follow-up 14 days after surgery. We did not design our trial to evaluate the long-term effect (28/90 days follow-up) of HES on renal function because a delayed nephrotoxic effect of HES would be unlikely when no signs of renal impairment were seen within 14 days after surgery. This approach is sup- ported by another surgical trial, which found no nephrotoxic- ity after a 28-day postoperative follow-up period.54 To avoid adverse effects of chloride on renal function, we used solu- tions with the same chloride concentration in both groups to eliminate the risk of bias due to hyperchloremic acidosis. While U-NGAL is an established marker of renal damage, it can also be confounded by infection and blood in the urine. In addition, our study had a small sample size and may very well have been inadequate to evaluate the hemodynamic dif- ferences between the groups properly. In conclusion, we found no evidence of nephrotoxicity in patients undergoing prostatectomy with normal preop- erative renal function after infusion of up to 2500 mL of 6% HES 130/0.4. The use of HES suggested a greater vol- ume expansion effect as demonstrated by lower p-AVP, p-Alb, and p-Aldo levels in spite of equal volume of fluid infused. Furthermore, we observed an increased bleeding tendency in the HES group, with 2 excluded patients due to blood loss. E DISCLOSURES Name: Anne Sophie Pinholt Kancir, MD, PhD student. Contribution: This author helped design the study, conduct the study, analyze the data, write the manuscript, and statisti- cal work. Attestation: Anne Sophie Pinholt Kancir has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files. Name: Joergen Kühlwein Johansen, MD. Contribution: This author helped design the study and con- duct the study. Attestation: Joergen Kühlwein Johansen approved the final manuscript. Name: Niels Peter Ekeloef, MD. Contribution: This author helped design the study, conduct the study, analyze data, and write the manuscript. Attestation: Niels Peter Ekeloef has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Name: Erling Bjerregaard Pedersen, MD, MSc. Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript. Attestation: Erling Bjerregaard Pedersen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. This manuscript was handled by: Avery Tung, MD. Figure 2. Blood loss (mL) shown for each of the 36 patients. Horizontal lines mark the median blood loss in each group. HES = 6% hydroxyethyl starch 130/0.4; saline = isotonic saline 0.9%.
  • 10. March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 617 ACKNOWLEDGMENTS The authors greatly acknowledge the skillful assistance of laboratory technicians: Anne Mette Ravn, Kirsten Nygaard, HenrietteVorupSimonsen,andSusanRasmussen.Furthermore, the authors thank nurse Susanne Slot, all the nurses and anes- thesiologists of the Department of Anesthesiology, Lars Høst, MD, Niels T. Mikkelsen, MD, and the nursing staff of the Department of Urology, for their help and practical assistance during the study. REFERENCES 1. McIlroy DR, Kharasch ED. Acute intravascular volume expan- sion with rapidly administered crystalloid or colloid in the set- ting of moderate hypovolemia. Anesth Analg 2003;96:1572–7 2. Feldheiser A, Pavlova V, Bonomo T, Jones A, Fotopoulou C, Sehouli J, Wernecke KD, Spies C. Balanced crystalloid com- pared with balanced colloid solution using a goal-directed hae- modynamic algorithm. Br J Anaesth 2013;110:231–40 3. 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