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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

Kancir, Anne Sophie Pinholt MD, PhD Student; Johansen, Joergen Kühlwein MD; Ekeloef, Niels Peter MD; Pedersen, Erling Bjerregaard MD, MSc

doi: 10.1213/ANE.0000000000000596
Critical Care, Trauma, and Resuscitation: Research Report

BACKGROUND: Although hydroxyethyl starch (HES) is commonly used as an intravascular volume 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 increasing 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 gelatinase–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 stability 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.

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.

Hydroxyethyl starch (HES) is commonly used as a perioperative intravascular volume expander to replace blood loss, obtain hemodynamic stability, and optimize tissue oxygenation. Current data suggest that HES stabilizes intravascular colloid pressure and reduces the volume required to achieve hemodynamic stability during resuscitation 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 dissolved 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 impairment 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 evidence 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 disease), which are based on sudden increases in plasma creatinine (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 challenges, several urinary biomarkers have shown promising results.29,30 Neutrophil gelatinase–associated lipocalin (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 differently 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 following: (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 (systolic 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.

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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 monitored by the Good Clinical Practice committee at University of Aarhus. Written informed consent was obtained from each patient before any study-related procedure.

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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 glomerular 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 criteria were development of exclusion criteria, complications during surgery such as severe bleeding with blood transfusion, 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.

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Recruitment

All patients were recruited from the Department of Urology, Holstebro Hospital, Holstebro, Denmark.

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Design

The study was conducted as a randomized, controlled, double-blinded study on 40 patients undergoing elective radical prostatectomy.

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Intervention

Patients were consecutively randomized to receive either 6% HES 130/0.4 (Voluven®) as active treatment or 0.9% isotonic 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 hemoglobin ≤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 volume of blood in the suction and in the napkins, which were weighed before and after use.

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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.

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Effect Variables

The main effect variable was u-NGAL. Secondary effect variables were p-NGAL, PRC, p-ANGII, p-Aldo, p-AVP, Ccrea, UO, p-crea, CH2O, u-Alb, u-AQP2CR, SBP, DBP, MAP, and HR.

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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 manufacturer of the ELISAb test we used (Bioporto, Hellerup, Denmark). The SD was based on an assessment of the literature 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 intervention group, due to the risk of dropout and complications.

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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) 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 concentration (0.6), isoflurane (minimum alveolar concentration 1.2–1.5), and IV increments of 0.15 μg/kg fentanyl. After tracheal 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 phenylephrine 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.

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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 discharge 1, additional urine sample was obtained (urine 4, discharge). 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 intervention. 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.

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Biochemical Analyses

All urine and blood samples were centrifuged for 10 minutes 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 impurities in the samples. Every analysis was done at the same time by the same laboratory technician to minimize variability in the results.

U-NGAL and p-NGAL were determined by a commercial 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 coefficients 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 subsequently determined by radioimmunoassay. The antibody against AngII was obtained from the Department of Clinical Physiology, Glostrup Hospital, Denmark. Minimal detection 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.

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Hemodynamic Data

SBP, DBP, and HR were recorded continuously throughout the surgery with Infinity Delta XL® (Dräger, Lübeck, Germany). All values during surgery were noted in 5-minute intervals. In the recovery period, values were noted in 15-minute intervals and S/5™ Compact Anesthesia 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.

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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.

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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.

Table 1

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 majority of the outcome variables in Table 2 (perioperative management). 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 or saline). Pairwise comparisons, using Wilcoxon signed rank test, were performed as a post hoc analysis with a Bonferroni correction for multiple comparisons. Each pairwise comparison was performed as a comparison with the baseline value. In Table 4, either 3 or 4 pairwise comparisons 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.

Table 2

Table 2

Table 3

Table 3

Table 4

Table 4

Table 5

Table 5

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 variance with repeated measures was used within each group (HES or saline) in Tables 4 and 6. The assumption of sphericity 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.

Table 6

Table 6

Statistics were performed using PASW version 20.0.0 for Mac (SPSS Inc., Chicago, IL).

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RESULTS

Demographics

Between January 2012 and June 2013, 51 patients were consecutively 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 participate (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) during surgery. Thus, 18 patients (90%) completed the study in each group. The 2 groups were comparable regarding age, body mass index, comorbidities, antihypertensive medication, office blood pressure, and screening biochemistry (Table 1). During the entire trial, there were no protocol violations. One patient in the HES group (No. 18) was excluded because he had a very high baseline value of u-NGAL.

Figure 1

Figure 1

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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 phenylephrine (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).

Figure 2

Figure 2

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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

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u-Alb Excretion and u-Alb/Creatinine Ratio

Table 4 shows u-Alb and urine-albumin-adjusted-for-creatinine increased similarly in both groups during surgery and admission. A significant increase was shown in both groups at all times when comparing the values with baseline. Even at follow-up on day 14, the values were still elevated.

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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, 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.

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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 intervention. 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 intervention (Table 5). In both groups, p-crea increased significantly after intervention, but to the same extent.

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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.

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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 significantly higher HR at baseline, before, and after surgery compared with the saline group (Table 6).

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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.

As has been done previously in patients after cardiac surgery, we used u-NGAL to screen for AKI.29,30 In the present 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 elevated 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 significant increase was measured within the saline group, the difference 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, transiently higher levels of p-crea were measured in patients receiving HES after cardiac surgery compared with crystalloid. 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 tetrastarches.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 studies 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 recommendations from the European Medicines Agency (EMA) 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 conflict 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 guidelines 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 phenylephrine 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 transfusion 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 tendency 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 cannot be excluded. In previous surgical studies, the majority 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 crystalloids 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 stimulation 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 distal 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% compared with 6% HES 130/0.4. A better 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, double-blinded, placebo-controlled design and limited variability in study conditions regarding operative procedures, anesthesia, 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 supported by another surgical trial, which found no nephrotoxicity after a 28-day postoperative follow-up period.54 To avoid adverse effects of chloride on renal function, we used solutions 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 differences between the groups properly.

In conclusion, we found no evidence of nephrotoxicity in patients undergoing prostatectomy with normal preoperative renal function after infusion of up to 2500 mL of 6% HES 130/0.4. The use of HES suggested a greater volume 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.

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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 statistical 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 conduct 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.

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ACKNOWLEDGMENTS

The authors greatly acknowledge the skillful assistance of laboratory technicians: Anne Mette Ravn, Kirsten Nygaard, Henriette Vorup Simonsen, and Susan Rasmussen. Furthermore, the authors thank nurse Susanne Slot, all the nurses and anesthesiologists 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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FOOTNOTES

a Available at: www.randomization.com. Accessed September 19, 2014.
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b Available at: http://www.bioporto.com/Products/NGAL-ELISA-Kit-(human).aspx. Accessed October 22, 2014.
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