Background: In critically ill patients, adverse effects of 6% hydroxyethyl starch 130/0.4 on renal function have been described. Patients undergoing cardiac surgery are also at risk for the development of acute kidney injury. The present study aimed to determine a possible relationship between the perioperative administered volume of 6% hydroxyethyl starch 130/0.4 and the incidence of postoperative acute kidney injury in cardiac surgery patients. Methods: We conducted a retrospective cohort study in which we included patients who underwent cardiac bypass- and cardiac valve surgery, or a combination of these. The main study endpoint was acute kidney injury, defined as a 1.5 times increase in serum creatinine from the preoperative value within 7 days postoperative. We compared the incidence of acute kidney injury between patients who received one unit-, two units- and more than two units 6% hydroxyethyl starch 130/0.4. Results: In total 3743 patients were included. The overall incidence of acute kidney injury was 10.6%. No significant difference was observed in the incidence and severity of AKI in relation to the number of units HES administered. Conclusion: In cardiac surgical patients, volumes up to 1500 ml of 6% hydroxyethyl starch 130/0.4 were not related to the incidence of acute kidney injury. Probably the contribution of other risk factors for AKI during cardiac surgery is of more importance. Therefore, it is reasonable to assume that administering HES up to the supposedly safe amount of 50ml/kg body weight per day to patients undergoing cardiac surgery, might not affect renal function.
The development of acute kidney injury (AKI) after cardiac surgery with cardio pulmonary bypass (CPB) is associated with substantial morbidity and mortality. The incidence of AKI after cardiac surgery varies between 5% and 20%, while 1% to 2% of these patients require renal replacement therapy. Several patient- and intraoperative characteristics are well-known risk factors for the development of postoperative AKI: a history of diabetes, renal insufficiency, cardiac failure, type- and duration of surgery, intraoperative hypotension and the use of vasopressors. In a recent cohort study of 3,869 cardiac surgery patients, 22,4% of the patients suffered from ‘mild’ stage one AKI, which was associated with a 1.3 absolute risk difference in mortality. The authors stated that interventions that prevent or mitigate AKI after cardiac surgery might yield substantial clinical benefit. One of these interventions might be the replacement of 6% hydroxyethyl starch 130 / 0.4 (HES) as volume expander and prime solution of the heart lung machine. This is in agreement with several studies in which septic and other critically ill patients were more likely to require renal replacement therapy after receiving HES for fluid therapy. As a consequence, the European Medicines Agency (EMA) stated that HES should no longer be used in patients with sepsis or burn injuries or in critically ill patients. Despite these safety concerns, the use of HES is common practice in cardiac surgery as fluid replacement and as part of the prime solution of the heart lung machine. The contribution of HES to the incidence of AKI during the course of cardiac surgery with CPB is still unclear. Most studies on HES and AKI focus either on patients in the intensive care unit (ICU) or on fluid management during resuscitation. Although it was suggested that the use of tetra starches during general surgery does not adversely affect renal function it is unclear whether the use of HES during cardiac surgery is safe with respect to renal function. With this present retrospective cohort study we aimed to asses whether there was a relationship between the perioperative administered volume of HES and the incidence of postoperative AKI in cardiac surgical patients. Secondary objectives were to identify the effects of HES related AKI on length of stay in the ICU, length of stay in the hospital and in-hospital mortality.
Patients and Methods
We performed a single-centre retrospective cohort study in the OLVG Hospital (OLVG), Amsterdam, the Netherlands. With the approval of the local medical ethics committee and according to the principles of good clinical practice we examined data on consecutive patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) between January 2008 and December 2013. Data were retrieved from the patient data management system (PDMS) MetaVision Anesthesia Information Management System (iMDsoft, Needham, MA) and XCare (McKesson Care 2013). Patients were included if they met the following criteria: age 18 years and older; scheduled for CABG, - cardiac valve surgery, - combined CABG with cardiac valve surgery and the use of CPB during surgery. Patients were excluded according to the following criteria: age younger than 18 years, surgery other than CABG and/or cardiac valve surgery, repeat operations, off pump surgery and preoperative dialysis. All procedures were preformed through median sternotomy with a standard anaesthetic and surgical perioperative management protocol. All patients received at least one unit (500ml) of 6% hydroxyethyl tetra starch (HES) with a molecular weight of 130,000 and a substitution of 0.4. to prime the heart lung machine. During surgery and in the ICU, HES was administered to treat haemodynamic instability or to substitute blood loss according to the judgment of the anaesthesiologist or intensivist. Post-bypass cardiac insufficiency was treated with a continuous administration of norepinephrine, dopamine or enoximone if necessary AKI was defined as an increase in serum creatinine SCr to ≥ 1.5 times baseline value, which is known to have occurred within the first 7 days after surgery. The severity of AKI is defined as follows: stage 1: 1.5–1.9 times baseline increase in the SCr; stage 2: 2.0 – 2.9 times baseline increase in the SCr; stage 3: 3.0 times baseline increase in the SCr or the initiation of renal replacement therapy (RRT). This is according to the definitions of the Kidney Disease: Improving Global Outcomes (KDIGO) organisation .
The secondary outcomes were length of stay on the ICU defined in days postoperative and length of stay in the hospital defined in days postoperative and the incidence of in hospital mortality defined as death occurring in hospital during postoperative admission. In all patients SCr was determined one day preoperative and this value was considered baseline. Postoperative, the SCr was again measured in the ICU and on the nursing ward. We collected SCr levels up to the 7th day postoperative. Severity of AKI was classified according to the highest postoperative SCr level within 7 days postoperative. In relation to the primary outcome, we also evaluated the amount of HES administered during surgery and during 24 hours postoperative recovery period. The following patient characteristics were collected from the PDMS: age, sex, weight, height, type of surgery, ASA class, diabetes, COPD, peripheral vascular disease, preoperative renal insufficiency, left ventricular ejection fraction below 35%, and anemia. The following intraoperative variables were collected: anaemia, mean arterial blood pressure (MAP) below 55mmHg during surgery, blood transfusion, cross-clamp time and the administration of inotropes and vasoconstrictors. In addition, duration of surgery, time on cardiopulmonary bypass (CPB time) Patients were divided into three groups according to the units of HES administered during surgery and during 24 hours postoperative. Patients who had received one unit of HES were assigned to group one, those who had received two units of HES were assigned to group two and those who had received more than two units of HES were assigned to group three. Categorical data are presented in numbers and percentages and continuous data are presented with mean and standard deviation or median and interquartile range if applicable. To explore differences in demographics between the three groups, the Kruskal-Wallis test was used to compare continuous variables depending on the distribution. Differences in the distribution of nominal variables between the three groups were explored using the Chi-square test. To analyse the incidence of AKI between the three groups, absolute risk differences (ARD) with 95% confidence intervals were calculated using the Wilson’s procedure . Differences in lengths of stay on the ICU and in the hospital were calculated by means of Kaplan-Meier with Log Rank (Mantel Cox) statistics. Differences in mortality rate were calculated with a 95% confidence intervals using the Wilson’s procedure.
Two important parameters, the duration of surgery and the duration of intraoperative MAP below 55mmHg, were considered as confounders with the use of Directed Acyclic Graphs (DAGs) .To adjust for the influence of confounding we used multivariable logistic regression analysis with AKI as the dependent variable and units HES, duration of intraoperative MAP and duration of surgery as independent variables. The statistical analysis was performed with SPSS statistics version 18.0 (SPSS Inc, Chicago, IL).A p-value lower than 0.05 was considered statistically significant. In order to verify the reliability of the data, the data of every 50th patient in our database was checked for accuracy by comparing it with the Patient Data Management System and other relevant sources. Missing values were addresed for as appropriate by imputing the mean or the last known value.
The digital records of 4612 cardio thoracic surgical patients were studied. In total 3743 patients met the inclusion criteria (Figure 1). Patient characteristics are shown in Table 1. Several patient and intraoperative characteristics were found to be unequally distributed over the three groups: peripheral vascular disease, ASA class, type of surgey, time related variables (duration of surgery, perfusion time and cross-clamp time, and the intraoperative duration of hypotension), vasopressor use, packed cells and haemofiltration during bypass. Primary and secondary outcomes are shown in Table 2. The absolute risk difference (ARD) in incidence of AKI between the three groups was not statistically significant. The odds ratios for overall AKI did not reach significance after adjusting for two potential confounders; the duration of surgery and the intraoperative duration of mean arterial pressure below 55mmHg. Adjusted odds ratios for overall AKI in group 2 and 3 were 0.9 (95%CI 0.7 to 1.2) and 0.9 (95%CI 0.7 to 1.2) respectively compared to group 1. In group 3 significantly more severe AKI, stage 3 was found than in group 1, with an ARD of 1.7% (95%CI 0.3 to 3.4). However, the odds ratios for severe stage 3 AKI in group 3 compared to group 1 lost significance after adjusting for confounding. Adjusted odds ratios for severe stage 3 AKI in group 2 and 3 were 1.2 (95%CI 0.7 to 1.9) and 1.2 (95%CI 0.7 to 2.0) respectively compared to group 1. On average patients in group 3 stayed 0.4 days longer in the ICU than patients of group 1 (p <0.001) and stayed 0.3 days longer than patients of group 2 (p 0.03). Furthermore patients from group 3 stayed on average one day longer in the hospital when compared to patients from group 1 and 2 (resp. p 0.01 and p 0.03). Total mortality during hospital stay was 2.6%. In group 3 more patients died than in group 1 with an ARD of 1.4% (95%CI 0.1 to 3.1). The diagnoses of death are presented in Appendix 1. Two patients who were assigned to group 1 died from renal insufficiency. Exploring the data using a conceptual framework and backward stepwise regression, AKI was statistically significant related to haemofiltration during CPB, total administered amount of norepinephrine and enoximone, and postoperative haemoglobin in this cohort of patients. The reliability of the data was checked for accuracy by comparing it with the Patient Data Management System and other relevant sources. No significant inaccuracies in the registration of the administered amount of HES were found.
In the present study, no significant difference was observed in the incidence and severity of AKI in relation to the number of units HES administered during CABG and cardiac valve surgery. AKI stage 3 was more frequently observed in patients who received two or more units HES compared to patients receiving
Figure 1. Patient Allocation
only one unit HES. However, the duration of surgery and the duration of intraoperative MAP below 55mmHg were considered to be important confounders in the relationship between postoperative AKI and the units HES administered. Indeed, after adjusting for these confounders no statistically significant difference between the severity of AKI and the number of units HES administered was observed. Other variables such as intraoperative vasopressor use and intraoperative blood transfusion may also be associated with AKI but must not be considered confounders. The administration of HES is mainly triggered by blood loss, so the administration of vasopressors and blood transfusion happens thereafter and thus might not influence the decision to administer colloids . While two patients died secondary to renal insufficiency, no relationship between mortality and the amount of HES administered could be demonstrated. These findings are in accordance with a recent meta-analysis showing no differences in mortality in a subgroup analysis of 872 cardiac surgery patients from 10 studies . In addition, we observed that the increase in the length of hospital stay in relation to units HES administered, although statistically significant, was small and therefore clinically not important.
In the present study, with patients scheduled for cardiac surgery with CPB, the overall incidence of AKI was around 10.6%, which is in agreement with the reported incidence in the literature [19, 20]. The KDIGO (Kidney Disease: Improving Global Outcomes) strict definition of AKI based on SCr values from laboratory results with 7 days postoperative follow-up were followed. In addition only a few authors consistently reported AKI using internationally defined criteria, which may account for systematic underreporting . In critically ill patients in the ICU, a detrimental effect of the administration of HES on renal function was reported. Those patients were more likely to require renal replacement therapy after receiving HES for fluid therapy [9,10]. The conclusions of these studies were supported by a systematic review that also raised serious concerns about the use of HES . One of the hypotheses about the mechanism that causes AKI after the administration HES is the property of HES to accumulate in the reticuloendothelial tissues. Indeed, kidney lesions resembling osmotic nefrosis have been observed due to the deposit of HES molecules [21, 22]. Concomitant with the reports in critically ill patients, we expected a dose dependent detrimental effect of HES on renal function in our study with patients after CPB.
Table 1. Demographics: Pre-, Intra- and Postoperative Patient Characteristics
There are several possible explanations for the lack of a dose dependent effect of HES on the incidence of AKI after cardiac surgery in the present study. First, clinical differences between cardiac surgery patients and critically ill patients may be important. HES seem to be particularly harmful when administered to patients with a compromised microcirculation and consequently capillary leakage of HES molecules. In addition, the amount of HES almost never exceeded 50ml/kg body weight per day, the supposedly safe amount prescribed by the manufacturer (Fresenius Kabi N.V.). Probably the contribution of other risk factors for AKI is of more importance. Indeed, cardiac surgery specific characteristics also contribute to the occurrence of AKI. For example, in our cohort the following perioperative characteristics were found to be related to AKI; haemofiltration during CPB, indices of heart failure, postoperative Hb, CABG procedures and ASA class 3.
Table 2. Outcome: Acute Kidney Injury (AKI), Mortality, Length of Stay in the Intensive Care Unit and in Hospital
Our study has several limitations. It is a retrospective cohort study in which a group of patients receiving no HES was not included. Therefore we were not able to determine the background risk for AKI in patients undergoing cardiac surgery without the use of HES. However, a recent study comparing colloids and crystalloids in cardiac surgery did not find a significant increase in serum creatinine values in the HES group compared to Ringer’s lactate . Secondly, apart from its retrospective design, it is a single centre study, which might limit generalizability. In addition, several patient and intraoperative characteristics were found to be unequally distributed over the three groups. This is a logical consequence of the patient allocation in groups. The patients that receive more units of HES appear to have more prolonged and complex procedures with more blood loss. The use of HES is common practice in cardiac surgery as fluid replacement, particularly because of its presumed effectiveness in expanding intravascular volume compared to isotonic crystalloid solutions . HES is also used as part of the prime solution of the heart lung machine, in order to prevent a haemodilution-derived fall in the plasma colloidal oncotic pressure.
Whether the administration of HES can be considered completely safe remains unclear. Beside a possible effect on renal function, HES may adversely affect blood coagulation, which may result in more blood loss. Although HES might cause AKI in critically ill patients, the present study, regarding cardiac surgery patients, demonstrated that there is no statistically significant difference in the incidence of AKI in relation the volume of HES administered. Probably the contribution of other risk factors for AKI during cardiac surgery might be of more importance. Therefore, it is reasonable to assume that administering HES up to the supposedly safe amount of 50ml/kg body weight per day to patients undergoing cardiac surgery, might not affect renal function.
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