Hypertonic saline (7.2% NaCl) in combination with hydroxyethyl starch (HES) 200/0.5 (HSH) has been used in cardiac surgery and has shown its beneficial clinical effects (1). The primary objectives of using HSH during the perioperative period are to treat hypovolemia and to ensure adequate tissue oxygenation while avoiding fluid overload. Among the main advantageous effects were the following: reduced positive fluid balance, increased cardiac output, decreased extravascular lung water content, improved pulmonary gas exchange, shorter extubation time, and improved oxygen delivery (1–3).
However, despite that fluid resuscitation for hypovolemia is a mainstay of the medical management of cardiac surgical patients, there is considerable controversy about fluid effects on kidney function. Most of all, it refers to HES and chloride-rich solution that enter HSH (4, 5). Renal dysfunction may occur because of uptake of HES into proximal tubular epithelial cells, resulting in osmotic nephrosis or tubular obstruction caused by the production of hyperviscous urine (6), while chloride modifying renal responsiveness to vasoconstrictor agents leads to renal vascular resistance increase, which results in reductions in renal blood flow velocity and renal cortical tissue perfusion, and finally decreases glomerular filtration (7–9). Consensus statement of the European Society of Intensive Care Medicine task force on colloid volume therapy in critically ill patients recommends not to use HES with molecular weight of 200 kd or greater and/or degree of substitution of greater than 0.4 in patients with severe sepsis or risk of acute kidney injury (AKI) (10). After sepsis, cardiac surgery is the second most important cause of AKI in intensive care patients (11). Postoperative AKI, which is associated with prolonged hospital stay, is known to increase morbidity and mortality (12, 13), while also decreasing long-term survival, even after full recovery of renal function (14).
The pathogenesis of kidney injury in cardiac surgery patients is a complex interaction of hemodynamic, inflammatory, and direct nephrotoxic injuries to tubular cells (15). Aside from direct effects of starches and high chloride concentration, release of cytokines and upregulation of adhesion molecules as a result of systemic inflammatory response induced by cardiopulmonary bypass (CPB) may also affect kidney integrity (15). They further promote neutrophil migration to the kidney, activate neutrophils, and increase renal injury (16). At the same time, it has been documented by animal experiments and clinical studies that both hypertonic saline (HS) and HES 200/0.5 may beneficially modify inflammatory response. A significant increase in plasma interleukins (ILs) induced in a rat model of hemorrhagic shock was blocked by treatment with HS (17). In animal models and trauma patients, HS has prevented the inflammatory response by blocking the activation of monocytes and neutrophils (18, 19). With respect to HES 200/0.5, it has proven its ability to significantly decrease polymorphonuclear leukocyte chemotaxis through endothelial cell monolayers in the model of human cells (20). The laboratory studies demonstrated that during endotoxemia HES 200/0.5 could downregulate the transcription of inflammatory mediators in the lung, heart, and liver (21, 22). It has also been shown that HSH inhibits excessive macrophage activation during systemic inflammation in vivo (23). Thus, despite the risk of renal impairment when using HSH in cardiac surgery patients, it has been revealed that HS has beneficial effect on immunity in experiment and human studies. Therefore, the aim of our study was to evaluate the influence of 7.2% NaCl/6% HES 200/0.5 on kidney integrity and the level of inflammatory mediators in on-pump coronary artery bypass surgery (CABG) patients.
MATERIALS AND METHODS
The study was approved by the Ethics Committee of the Academician EN Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Novosibirsk, Russia (Chairperson Prof. V. Lomivorotov) under protocol number 19 on January 24, 2012, in full compliance with the ethical standards as proclaimed by the Helsinki Declaration. Written informed consent was obtained from all patients. The study has been registered on http://clinicaltrials.gov (registration no. NCT01675453).
In this single-center, prospective, randomized, single-blind pilot study, we investigated the influence of 7.2% NaCl/6% HES 200/0.5 (HyperHaes; Fresenius Kabi, Bad Homburg, Germany) on kidney integrity and the level of inflammatory mediators in 40 patients scheduled for first-time on-pump CABG. The primary end point was the incidence of AKI defined according to the Kidney Disease: Improving Global Outcomes clinical practice guideline for AKI on the basis of increase in serum creatinine (sCr) by 26.5 μmol·L−1 or greater within 48 h or increase in sCr to 1.5 times the baseline or greater (24). Secondary end points included novel biomarkers of AKI, which assessed different aspects of renal injury. Thus serum cystatin C (sCys C) was used to show changes in glomerular filtration, whereas urine neutrophil gelatinase-associated lipocalin (uNGAL) was utilized for identifying tubular stress or injury (25). Other secondary end points included plasma levels of IL-6, IL-10, intercellular adhesion molecule 1 (ICAM-1), and endothelial-leukocyte adhesion molecule (E-selectin). In addition plasma chloride concentration, fluid balance, urine output, and hemodynamics were investigated.
Overall, 490 patients were assessed for possible enrolment in the study at a tertiary cardiothoracic referral center during the period from February to August 2012 (Fig. 1). To avoid the confounding effects of poor preoperative cardiac and renal function, the following exclusion criteria were used: age older than 70 years, body mass index less than 18 kg/m2 and more than 35 kg/m, left ventricular ejection fraction less than 40%, myocardial infarction less than 6 months before surgery, stroke or transient ischemic attack less than 12 months before surgery, diabetes mellitus, glomerular filtration rate less than 90 mL·min−1, emergency surgery, and hematocrit less than 30%.
On the surgery day, by means of a computer-generated code, the patients were randomized into two groups. Each patient received once either 7.2% NaCl/6% HES 200/0.5 (HSH group, n = 20) or placebo (0.9% NaCl; control group, n = 20) at a dose of 4 mL·kg−1 for 30 min after anesthesia induction. NaCl 7.2%/6% hydroxyethyl starch is a compound solution made up of HS, containing Na 1,232 mmol·L−1, Cl 1,232 mmol·L−1, and 60 g·L−1 of HES with molecular weight of 200 kd and molar substitution ratio of 0.5 (iso-oncotic pentastarch).
All patients underwent coronary revascularization with CPB and were transferred to the intensive care unit (ICU). (For details on perioperative management, see the Supplemental Digital Content 1 http://links.lww.com/SHK/A194.)
Serum Cr was measured by a modified Jaffe method with protein precipitation using an alkaline picrate reaction (CREA-Kinetic; Analyticon Biotechnologies AG, Lichtenfels, Germany). Blood samples for measurement of sCr were taken at baseline (after induction of anesthesia), on postoperative day 1 (POD1), and POD2. Serum Cys C was detected by the measurement of immunoprecipitation at 540 nm (Konelab/T series; Thermo Scientific, Vantaa, Finland) (reference range, 0.63–1.44 mg·L−1). Urine NGAL was analyzed by a chemiluminescent microparticle immunoassay (ARCHITECT urine NGAL; Abbott Laboratories, Abbott Park, Ill) (reference range, 0.7–9.6 ng·L−1). Plasma levels of IL-6, IL-10, ICAM-1, and E-selectin were measured using enzyme-linked immunosorbent assays (Platinum ELISA; Bender MedSystems GmbH, Vienna, Austria). Reference ranges for IL-6 are less than 5 pg·mL−1; for IL-10, 2 to 24 pg·mL−1; for ICAM-1, 200 to 300 ng·mL−1; and for E-selectin, 7 to 137 ng·mL−1. For these, arterial whole blood and urine samples were immediately centrifuged at 2,800 revolutions/min for 10 min at 4°C, and the supernatants were aliquoted and stored at −90°C. Arterial blood gases as measured by Rapidlab 865 (Bayer Corporation, Cambridge, UK) were analyzed to determine plasma chloride concentration. Serum Cys C, uNGAL, and plasma levels of IL-6, IL-10, ICAM-1, E-selectin, and plasma chloride were measured at baseline (after induction of anesthesia) (T1); 5 min (T2), 2 h (T3), and 4 h after CPB (T4); and on POD1 (T5). Perioperative fluid balance, urine output, and chloride intake were analyzed at the end of surgery and on POD1.
MedCalc Statistical Software v12.1.4 was used for data analysis (MedCalc Software, Mariakerke, Belgium). The qualitative data are expressed in absolute numbers (percentage), whereas the quantitative data are presented as the median (interquartile range) because the distribution of the values for this variable was outside the normal distribution according to the Kolmogorov-Smirnov test. Therefore, for comparison of quantitative data, the Mann-Whitney test was used. Comparison of the qualitative data was performed using Fisher exact test. P < 0.05 was considered statistically significant.
All of the 40 patients enrolled were eligible for data analysis (Fig. 1). No differences were detected with respect to the demographic data, preoperative variables, and surgical characteristics between the two groups (Table 1).
There was significantly increased chloride loading in the HSH group (707 [623–712] mmol per person) compared with the control group (383 [337–399] mmol per person; P < 0.001) at the end of surgery (Fig. 2). During the period from arrival to ICU until the end of POD1, difference in chloride intake between the groups was not observed (HSH: 2,205 [1,592–2,555] mmol per person; control: 1,640 [1,363–2,123] mmol per person). The net chloride loading (surgery and POD1) was significantly higher in the HSH group (2,878 [2,242–3,293] mmol per person) compared with the control group (2,021 [1,737–2,529] mmol per person; P < 0.05).
There were no differences in baseline plasma chloride concentrations between the groups (Table 2). Plasma chloride concentration in patients of the HSH group increased at 5 min after CPB from baseline (P < 0.05) and remained significantly elevated until POD1 (P < 0.05). Values of plasma chloride in the control group also increased from baseline at 2 h, 4 h after CPB, and on POD1 (P < 0.05 for all). Plasma chloride concentration in the HSH group was higher compared with the control group at 5 min (P = 0.001), 2 h (P < 0.001), and 4 h (P = 0.001) after CPB and on POD1 (P = 0.01).
Baseline sCr levels did not differ between the patients of both groups (Table 3). The peak sCr within POD2 was significantly lower in the HSH group as compared with the control group (P = 0.02). The incidence of AKI, diagnosed as an increase in peak sCr by 26.5 μmol·L−1 or greater or an increase in peak sCr to 1.5 times the baseline or greater within POD2, was similar (P = 0.72) between the groups (HSH: four patients [20%]; control: six patients [30%]). Three AKI patients in both groups had the highest sCr values on POD1. One AKI patient in the HSH group and three AKI patients in the control group showed peak sCr values on POD2. The urine output was significantly higher in the HSH group compared with the control group at the end of the surgery (P = 0.01) and on POD1 (P < 0.01; Table 4). The net fluid balance showed significantly lower values at the end of the surgery in the HSH group as compared with those in the control group (P = 0.01).
Figure 3A shows that there was a significantly lower peak value for sCys C in the HSH group (0.83 [0.73–0.89] mg·L−1) compared with the control group (1.02 [0.88–1.15] mg·L−1; P = 0.001). There was no difference between the baseline sCys C values of the groups (Fig. 3B). Patients in the HSH group had lower sCys C concentrations at 5 min, 2 h, and 4 h after CPB when compared with those in the control group (P < 0.01 for all). Values of sCys C on POD1 in the HSH group were not different from those in the control group. In the HSH group, sCys C at 5 min (0.72 [0.65–0.79] mg·L−1) and 2 h (0.72 [0.63–0.82] mg·L−1) after CPB decreased from baseline values (P < 0.05 for both), whereas increase in sCys C values from baseline was seen in the control group at 4 h after CPB (0.91 [0.82–1.1] mg·L−1; P < 0.05) and on POD1 (0.91 [0.77–1.13] mg·L−1; P < 0.05).
Patients in the HSH group had similar peak postoperative uNGAL concentrations (33 [15–38] ng·mL−1) compared with patients in the control group (30 [21–50] ng·mL−1; Fig. 3C). Urine NGAL levels in patients both group at baseline and at 5 min and 2 h after CPB were equivalent and did not exceed the upper normal values (Fig. 3D). In both groups, uNGAL levels had increased at 4 h after CPB (HSH: 10 [7–34] ng·mL−1; control: 13 [10–20] ng·mL−1) compared with baseline values (P < 0.05) and continued to increase on POD1 (HSH: 17 [12–30] ng·mL−1; control: 30 [18–58] ng·mL−1; P < 0.05). Urine NGAL level on POD1 was significantly lower in the HSH group compared with the control group (P < 0.05).
As shown in Figure 4A, the baseline plasma levels of IL-6 were similar between the groups. Significantly elevated IL-6 concentrations compared with baseline were observed in both groups at all further time points (P < 0.05), with peak values at 2 h after CPB. Treatment with HSH significantly reduced the level of IL-6 (12.6 [6.5–40.8] pg·mL−1) at 4 h after CPB compared with the control group (39.4 [21–130.6] pg·mL−1; P < 0.05). Baseline plasma values of IL-10 were comparable in both groups (Fig. 4B). A marked increase in IL-10 level was observed at 5 min, 2 h, and 4 h after CPB compared with baseline (P < 0.05 for all) in both groups; however, there were no differences on POD1. In the HSH group, IL-10 concentration (15.5 [3.55–33.5] pg·mL−1) was significantly decreased at 4 h after CPB compared with the control group (33.3 [17–87.5] pg·mL−1; P < 0.05).
No statistically significant difference was found in baseline levels of ICAM-1 between the groups (Fig. 4C). A marked decrease in ICAM-1 concentration was observed at 5 min after CPB in both groups (P < 0.05), whereas in the control group ICAM-1 level was increased on POD1 compared with baseline value (P < 0.05). Concentration of ICAM-1 was significantly lower in the HSH group compared with the control group at 4 h after CPB (428.7 [312–511.5] ng·mL−1 vs. 530 [405.3–579.5] ng·mL−1; P < 0.05) and on POD1 (421.3 [323.5–561.8] ng·mL−1 vs. 559.2 [538.7–632.7] ng·mL−1; P < 0.05). As shown in Figure 4D, baseline plasma levels of E-selectin were comparable in both groups. An increase in E-selectin concentration compared with baseline was observed only in the control group at 2 h and 4 h after CPB and on POD1 (P < 0.05 for all). There were significantly lower E-selectin levels at 4 h after CPB (24.2 [14.9–33.0] ng·mL−1 vs. 51.1 [28.7–92.2] ng·mL−1; P < 0.05) and on POD1 (22.4 [13.8–27.4] ng·mL−1 vs. 50.3 [24.4–93.6] ng·mL−1; P < 0.05) in the HSH group compared with the control group.
Details on the analysis of hemodynamic are described in the Supplemental Digital Content 2 (http://links.lww.com/SHK/A195).
There were no significant differences between the groups in terms of drainage loss, inotropic support, ICU stay, and total length of hospital stay (Table 1).
Acute kidney injury is one of the most serious complications following cardiac surgery (15). Renal injury is the net result of several perioperative insults (25); hypoperfusion is among the main. Hence, maintaining volume status by means of the appropriate use of fluid replacement is crucial for prevention of AKI development (26–28). At the same time, despite providing adequate intravascular volume, fluids may also enhance the risk of nephrotoxicity (5, 6). Today, there is a controversy about renal safety of different colloids and crystalloids in volume replacement therapy in cardiac surgical patients (4, 29). In the present study, combined solution that includes colloid (6% HES 200/0.5) as well as crystalloid (7.2% NaCl) has been investigated with regard to the incidence of adverse renal effects in patients who underwent on-pump CABG. It has been shown that HES is an independent risk factor of AKI following cardiac surgery (4). Degradation products of HES are cleared primarily via the kidney (30). Cellular injury begins with the uptake of nonmetabolized molecules by pinocytosis into proximal tubule cells. The molecules create an oncotic gradient, leading to the accumulation of intracellular water, severe cytoplasmic swelling, and vacuolization, as well as disruption of cellular integrity (6, 31, 32). Furthermore, animal and human studies suggest that solutions with high amount of chloride may have detrimental renal effects (8, 33). A recently performed retrospective observational study in patients undergoing noncardiac surgery has shown that postoperative renal dysfunction occurred more often in patients with postoperative hyperchloremia (5).
Despite the presence of HES 200/0.5 in the investigated solution and the development of the increase in chloride concentration, we found that there were no differences in the incidence of AKI between patients of both groups. All of AKI patients have corresponded to the first stage of the Kidney Disease: Improving Global Outcomes clinical practice guideline. In addition, we found that in the HSH group peak sCr value was significantly lower as compared with the control group. Furthermore, in patients of the HSH group, the urine output was higher at the end of surgery and on POD1 compared with the control group.
Because sCr has numerous limitations as a diagnostic marker of glomerular filtration, we have used sCys C as a better measure of renal excretory function (34, 35). This low-molecular-weight protein is produced at a relatively constant rate, freely filtered, and not secreted, and its metabolism is largely unaltered by sex, age, or diet (34). Serum Cys C has been found to be superior to sCr for discrimination of normal from impaired kidney function (35). In our study, according to peak sCys C values, which were observed primarily on POD1, glomerular filtration did not have additional alteration in patients of the HSH group. The differences in sCys C values between the groups in the hours immediately following CPB were possibly caused by the higher diuresis in the HSH group during the study.
The AKI is a clinical syndrome characterized by a rapid loss of the renal excretory function and is diagnosed by the raised creatinine and/or decreased urine output (25). However, these diagnostic criteria mainly represent glomerular renal function. According to the contemporary model, AKI implies not only kidney dysfunction, but also tubular damage, which may precede reduction in renal excretory function as determined using sCr (24). In the present study for assessment potential derangement in tubular damage, we have used uNGAL. It is a 25-kd polypeptide found to be rapidly induced and released in experimental ischemic and toxic AKI; its urine concentration increases proportionally to severity and duration of renal injury (36). In this study, we established that HSH did not increase tubular damage in patients who underwent CABG. There were no significant differences in uNGAL peak levels. Moreover, urine level of this biomarker was significantly lower in the HSH group on POD1 compared with the control group.
Besides nephrotoxic injury of fluids, another factor that could account for the development of AKI in cardiac surgery is CPB-induced inflammatory response (15). Thus, following cardiac surgery, IL-6 levels of greater than 100 pg·mL−1 and IL-10 of greater than 30 pg·mL−1 have been found to be associated with a significant increase in the risk of AKI in the postoperative period (37). It has been shown in an animal study that IL-6 mediates a cytokine-dependent cell-mediated immune response that exacerbates renal injury (38), whereas IL-10 inhibits inflammatory and cytotoxic pathways implicated in AKI (39). It is known that ICAM-1 is required for leukocyte adhesion during AKI, whereas E-selectin is essential for leukocyte extravasation in the kidney after renal ischemia (40, 41). The administration of antibodies to these adhesion molecules protects the kidney against ischemic injury in mice models (42). The present study has shown that on-pump CABG induces the generation of both cytokines and adhesion molecules after surgery. However, patients in the HSH group had significantly lower levels of IL-6 and IL-10 at 4 h after CPB as compared with those in the control group. Another finding is the reduction of ICAM-1 and E-selectin levels after HSH administration at 4 h after CPB and on POD1. These results suggest that by downregulating inflammatory mediators production, HSH may help prevent AKI following cardiac surgery. This is consistent with the studies demonstrating immunomodulatory effects of both HS and HES in a variety of cases (17–23) However, because of the design of the research, the authors did not investigate and therefore cannot state whether one of these components or their combination itself influenced inflammatory markers.
The causes of AKI are multifactorial and are not limited to ischemia, inflammation, and nephrotoxin administration (15, 25). To avoid the influence of established risk factors for AKI, in the present study, we deliberately recruited a homogeneous cohort of patients without comorbidities, such as preoperative kidney dysfunction, diabetes mellitus, obstructive pulmonary disease, reduced left ventricular function, or prior cardiac and emergency surgery (43). This pathological background can be exacerbated by aortic cross-clamp time more than 100 min, cardiogenic shock, inotropic support, and transfusion of packed red blood cells. These conditions, which also contribute to kidney impairment, were excluded. The study protocol is devoid the development of significant hypoperfusion that is believed to be a leading risk factor for and contributor to the onset of AKI (26).
There are a number of limitations to our study. It is a single-center study of low-risk patients undergoing CABG-only surgery, so the results cannot be translated to cardiac surgery patients in high-risk settings. The sample size is relatively small. The anesthesiologists caring for the patients during surgery were not blinded to patient allocation. The lack of blinding may have led to changes in care during the period of the study, which may have influenced the results. Hydroxyethyl starch–related nephrotoxicity is known to be dose-dependent (44). We used HSH at a dose of 4 mL·kg−1; this was much lower than that used in the trials that reported HES administration to be associated with renal impairment. We have investigated biomarkers of AKI in the immediate postoperative period and have not taken a longer period. At last, it is very difficult to relate specific alterations in the inflammatory response and kidney integrity with the use of HSH. These interactions are highly complex (15, 44), and results relevant to these could not be specified within the scope of this study. Despite significant progress has been made in defining the major components of inflammatory response its end result within the kidney is not well known.
In conclusion, this is the first study evaluating kidney integrity in cardiac surgical patients with the use of HSH. Our data demonstrated that HSH does not lead to the increase in AKI incidence when used for the volume therapy in on-pump CABG patients. NaCl 7.2%/6% hydroxyethyl 200/0.5 starch usage enhanced neither tubular injury nor alteration of glomerular filtration. Moreover, the administration of HSH can reduce at least the level of the inflammatory mediators after on-pump CABG. As they play an important role in AKI, HSH could diminish kidney damage after cardiac surgery. Additional studies are required to determine the immunomodulatory value of HSH and its potential role on kidney integrity in cardiac surgical patients.
The authors thank the research and ICU staff who participated in the study.
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Hypertonic saline/hydroxyethyl starch; supraphysiological concentration of chloride; acute kidney injury; inflammation; cytokines; adhesion molecules; coronary artery bypass surgery
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