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.
Statistics were performed using PASW version 20.0.0 for Mac (SPSS Inc., Chicago, IL).
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.
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).
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-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.
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.
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.
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 significantly higher HR at baseline, before, and after surgery compared with the saline group (Table 6).
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.
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.
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.
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.
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