Glomerular filtration rate (GFR) is an important clinical indicator of renal function. Its estimate can be used as an independent predictor of both long- and short-term survival after cardiac surgery.1,2 Kidney impairment commonly complicates cardiac surgery when acute kidney injury (AKI) compounds the effects of pre-existing disease.3 Besides several other factors, the kidneys' inefficient oxygen delivery system and high-metabolic rate make them vulnerable to ischemia-reperfusion injury.
The incidence of new-onset dialysis after cardiac surgery depends on the surgical procedures applied. Although about 1% to 2% of patients after coronary bypass grafting require dialysis after surgery, up to 5% to 30% in patients after heart transplantation or left ventricular assist device implantation develop dialysis-dependent renal failure.4–6
Currently, several techniques are available to perform coronary bypass grafting. The most recent development in perfusion techniques was the introduction of the minimized extracorporeal circulation systems (MECC) to combine both advantages of extracorporeal circulation (ECC) and reduced inflammatory response and blood conservation.7,8 Reduced volume shifts and blood handling and conservation, advanced myocardial protection, and lower heparinization are expected to reduce side effects of conventional cardiopulmonary bypass (CPB) and may contribute to improved patient outcome.
Because MECC systems usually do not require an additional venous reservoir, significantly higher mean arterial pressures (MAPs) are monitored during CPB and thus might improve renal perfusion and oxygen delivery.
In this study, we evaluated the impact of minimized and conventional CPB on acute renal dysfunction within the early postoperative period after coronary bypass grafting.
Patients and Methods
Patients and Study Design
The study was designed as a retrospective observational study. The initial study sample comprised 4,915 patients who underwent coronary bypass grafting between January 2000 and July 2008 at the University Medical Center Regensburg. Institutional Board Review approval was obtained, but the requirement of individual patient consent was waived because of the study's retrospective design and the data collection from routine care. After exclusion of 184 patients because of incomplete documentation, the final study sample comprised 4,731 patients.
Data Collection and Variables
Data were prospectively collected and entered in the institution's database. We reviewed the patient's medical records. Primary outcome variable was new-onset kidney injury defined according to the Society of Thoracic Surgeons as at least twofold creatinine rise to a value exceeding 2.0 mg/dL and/or a decline in estimated glomerular filtration rate (eGFR) by at least 50% within the first 48 hours after surgery.9 A secondary outcome variable was temporary postoperative dialysis.
Preoperative risk factors such as diabetes, chronic obstructive pulmonary disease were defined as in the EuroSCORE criteria.10 Emergency patients were operated on immediately after admission, whereas urgent patients were operated on within 24 hours after admission. Oliguria was defined as urine output <500 mL within 24 hours.
Serum creatinine (SCr) was measured preoperatively in mg/dL at the day of hospital admission. For further analysis, the peak SCr value within the 48 hours after surgery was used. SCr was determined with an enzymatic-photometric assay (Roche Diagnostics, Grenzach-Wyhlen, Germany). GFR was estimated with the abbreviated Modification of Diet in Renal Disease (MDRD) formula and was expressed in mL/min/1.73 m2:
MDRD-eGFR = 186.3 × SCr−1.154 × age−0.203 × 0.742 (if female)
For further evaluation and based on the current clinical practice guidelines for chronic disease, patients were grouped into chronic kidney disease (CKD) classes according to their eGFR.11
Surgery was performed through a median sternotomy. Patients on the MECC system received only 150 IE/kg heparin because of the completely heparin coated tubes, whereas patients on the conventional bypass system required 350–400 IE/kg to achieve sufficient activated clotting times (ACTs). Target ACTs of 250–300 s for MECC and ≥450 s for conventional extracorporeal circulation (CECC) were consiedered sufficient. Further details are summarized by Puehler et al 12 Perfusion for both systems during bypass was performed according our institution's protocol. MAP was kept between 40 and 60 mm Hg. Target mean cardiac indices during bypass were between 2.2 (MECC) and 2.6 (ECC). All operations were performed with mild (34°C) hypothermia.
All operations were performed by six senior cardiothoracic surgeons who were familiar with both CECC and MECC systems. Three of them operated on approximately 60% of patients, whereas the remaining three operated on 40% of patients.
Data were analyzed with SPSS 16.0.2 for Windows (SPSS Inc., Chicago, IL) and Stata 10 SE (Stata Corp., College Station, TX). Differences between normally distributed continuous data were analyzed with the t test and presented as mean differences with 95% confidence intervals (CIs). The Mann-Whitney U test was used for non-normally distributed data and appropriate CIs were calculated as proposed by Bonett and Price.13 Overall differences between more than two groups were analyzed with the analysis of variance or, where appropriate, with the Kruskal-Wallis test. Fisher's exact test was used for categorical variables in a 2 × 2 table, otherwise for 2 × k tables chi-square test was used. Two-sample test of proportion was used to calculate the difference and CI between binomial proportions.14
Logistic EuroSCORE was calculated with the downloadable Excel-sheet (www.euroscore.org) and expressed as mean with 95% CIs. SigmaPlot 10.0 (www.systat.de) was used to create figures. Data are shown as mean with standard deviation or, where appropriate, as median with interquartile range.
Demographic data are summarized in Table 1. There were several statistically significant differences between CECC and MECC, however, for most variables without clinical significance. In both groups, female patients were significantly (p < 0.001) older than males (CECC: 65.5 ± 8.8 versus 68.8 ± 8.5, mean difference 3.3 years, 95% CI 2.44–3.92; MECC: 66.1 ± 8.8 versus 68.9 ± 8.7, mean difference 2.8 years, 95% CI 1.83–3.75). The logistic EuroSCORE as a measurement of risk for perioperative mortality did not differ between both groups.
Because of the more difficult fluid management, all patients but four with preoperative dialysis were operated with CECC.
Patients who underwent CABG with MECC experienced significantly shorter bypass, cross-clamp, and reperfusion times (Table 2). However, the extent and the clinical impact proved to be quite small. In addition, monitoring of MAP and systemic vascular resistance (SVR) during ECC revealed higher values in MECC (Table 3 and Figure 1). The pump flow as one determinant of SVR proved also to be significantly higher in minimized systems (Figure 1). Thus, minimized systems allow improved perfusion with higher MAPs and SVRs with a significantly reduced pump flow. The need for administration of the vasoactive drug neosynephrine was significantly lower in the MECC group (61%) compared with the CECC group (81%) with a difference of 20% (95% CI, 17–22). In addition, the median doses differed between both groups (ECC: 2 mg (1; 3) versus MECC: 1 mg (0.3; 1), p < 0.001).
Because of less hemodilution in MECC, both the minimal and the maximal hemoglobin values were significantly higher compared with conventional bypass systems, which also had an increased need for red blood cell transfusion (Table 2). Patients operated on with MECC required on average only one red blood cell transfusion during the hospital stay.
Although ventilation time and stay at the intensive care unit did not differ between groups, patients who were operated with MECC l eft the hospital on average 1 day earlier and had a significantly lower incidence of severe postoperative delirium (Table 2; Figure 2).
Preoperative eGFR and SCr
We observed an age-dependent decline in preoperative eGFR (Figure 3). The age-dependent decline in eGFR was largest between age groups 50–60 and 60–70 (median difference, −12 mL/min/1.73 m2; 95% CI, −13.1 to −11.3) and second largest between age groups 60–70 and 70–80 (median difference, −10 mL/min/1.73 m2; 95% CI, −13.5 to −6.4). Patients older than 80 years experienced a median decline of −8 mL/min/1.73 m2 (95% CI, −12 to −2) compared with patients aged 70–80 years.
The median eGFR exceeded 60 mL/min/1.73 m2 in all age groups. However, 22.3% (n = 1,037) of all patients had an age-dependent preoperative eGFR <60 mL/min/1.73 m2 corresponding to a CKD class 3–5 (Figure 4). Almost every second patient older than 80 years who underwent CABG had an impaired preoperative renal function. Interestingly, 12% of patients younger than 40 years showed renal impairment. This finding might reflect multiple comorbidities among very young patients undergoing CABG.
Patients operated on MECC had a slightly lower preoperative incidence of CKD stages 3–5 compared with patients on CECC (MECC: 334 of 1,667, 20% versus ECC: 728 of 3,046, 24%, p = 0.02). Because of a slightly higher proportion of men in the ECC group, the median preoperative SCr values differed between both groups [ECC, 1 (0.8; 1.2) versus MECC, 0.9 (0.8; 1.1); p < 0.001]. Thus, mean eGFR values were different in both groups (ECC, 78 ± 27 mL/min/1.73 m2 versus MECC, 80 ± 24 mL/min/1.73 m2; mean difference 2; 95% CI, 0.36–3.5; p = 0.02). However, this difference was small and without clinical significance.
Postoperative eGFR and SCr
Within the first postoperative 48 hours significantly fewer patients in the MECC group developed a decline in eGFR (511 of 1,667, 30.7%) compared with patients after CECC (1,386 of 3,046, 45.5%) with a mean difference of 14.8% (95% CI, 12–18; p < 0.001). Table 4 summarizes the extent of eGFR decline in both groups. By definition of AKI, the incidence of eGFR decrease by ≥50% did not differ between both groups (p = 0.20), which implies that MECC does not prevent AKI but provides an advantage in terms of renal protection within the early postoperative period. Thus, MECC data in this study have no predictive value for acute kidney failure after cardiac surgery.
In addition, only a very few patients had an at least twofold rise in SCr exceeding 2 mg/dL within the first 48 hours after surgery (ECC: n = 13, 0.4%; MECC: n = 8, 0.5%, not significant). Among patients with postoperative eGFR decline, we observed a mean decrease of 15.4% (95% CI, −21 to −7) in the ECC group and 16.1% decrease in the MECC group (95% CI, −22 to −7.5) without statistical significance.
Temporary Postoperative Dialysis
Within the first 30 days after surgery, none of the patients developed permanent renal failure in either group. Temporary dialysis was required in 61 patients (61 of 3,046; 2%) after CECC and in 16 patients (16 of 1,685; 0.9%) after MECC (difference, 1.1%; 95% CI, 0.4–1.7; p < 0.001). The mean onset of temporary dialysis was 4 days postoperative and almost all patients (n = 60) received only a short-term renal support [median duration 4 days (mean, 7.3 ± 8.8)]. Primary reasons for temporary renal support were as follows: low-cardiac output syndrome with concomitant oliguria (n = 30), oliguria despite maximal diuretic stimulation (n = 25), severe metabolic acidemia with pH ≤7.2 (n = 6), and six patients with drug-resistant hyperkalemia (K+ >6.5 mmol/L). Fifty of 77 patients (65%) with temporary renal support had a preoperative eGFR <60 mL/min/1.73 m2.
eGFR and Actual Mortality
Because eGFR have been shown to be one of the strongest independent predictors for mortality, we examined the impact of preoperative eGFR on in-hospital mortality. An eGFR <60 mL/min/1.73 m2 increased the odds for mortality almost fourfold (CECC: odds ratio 3.6, 95% CI 2.6–4.9, p < 0.001) compared with the reference group with an eGFR >60 mL/min/1.73 m2. In the MECC group, impaired renal function increased the odds for mortality almost fivefold (odds ratio, 4.9; 95% CI, 2.8–8.6; p < 0.001). There were 92 of 728 (12.8%) nonsurvivors in the CECC group with a preoperative eGFR <60 mL/min/1.73 m2 and 29 of 334 (8.7%) nonsurvivors in the MECC group (difference, 4.1%; 95% CI, 0.2–7.9; p = 0.05).
AKI still remains a common and serious complication after cardiac surgery. The temporal pattern of the eGFR decline and creatinine rise depends on the specific operation performed15 being lowest in uncomplicated CABG procedures. In the setting of cardiac surgery, impaired renal function has been shown to be independently associated with higher short- and long-term mortality even after adjustment for multiple comorbid diseases.16,17
The overall incidence of postoperative AKI after CABG has been recently shown to be approximately 3.3% in a large cohort study.18 However, patients with impaired preoperative renal function had an incidence of acute renal failure of almost 9% and required more frequently postoperative dialysis. We report here an incidence of 1.6% for temporary postoperative dialysis and thus our data are well in line with recent reports.
There is one report that evaluated the impact of MECC systems on organ damage and renal tubular injury by measurement of urine N-acetyl-glucosaminidase and IL-6.19 Both markers were significantly increased in the CECC group compared with MECC and most likely, as the authors argue, due to the lower hematocrit and hemoglobin values triggering a more severe organ-dependent inflammation and hypoxia. Other groups also confirmed the decreased systemic inflammation and organ injury after MECC.20–22
Our study adds to the growing evidence that patients operated on minimized CPB systems may benefit in several terms. Besides less hemodilution (thus decreased transfusion requirement), higher MAP and SVR during CPB, significant fewer patients showed a decline in eGFR within the early postoperative period reflecting the potential renoprotective intraoperative management. However, the incidence of acute renal failure within 48 hours after surgery, defined by a decline in eGFR by ≥50%, has been shown to be indifferent between both groups. Thus, we could not demonstrate a predictive value of MECC for acute renal failure in this study.
On the other hand, the focus on these very early events seems not to be appropriate to reflect the postoperative course of patients because even subtle changes in eGFR have been shown associated with a tremendous increase in early mortality and hospital stay.16,23 Proper identification of preoperative renal dysfunction can easily be made by eGFR calculation or by using one of the novel predictive models for AKI such as the simplified renal index.24 Early postoperative identification of renal failure remained and still remains a critical issue in the clinical setting and as our data show, currently widely used surrogate biomarker of AKI such as SCr have limited value and several shortcomings. Several novel serum biomarkers have been evaluated to predict acute kidney failure in cardiac surgery such as interleukin-18, neutrophil gelatinase-associated lipocalin (NGAL), and cystatin C. It seems that NGAL and cystatin C have excellent discriminatory and predictive performance in the prediction of AKI as early as at intensive care unit (ICU) arrival.25
Our data show that MECC systems seem to exert a small renoprotective effect because fewer patients had a postoperative decline in eGFR. Reduced priming volume and hemodilution, improved myocardial protection, and reduced inflammatory response are the main contributors to that finding. However, MECC and ECC do not differ in the incidence of severe (≥50%) eGFR decrease. Thus, the renoprotective effect of MECC is rather weak and AKI cannot be prevented by MECC. Our study only shows limited benefit for the minimized extracorporeal system in terms of kidney function and is mainly restricted to lower transfusion needs and a slightly reduced hospital stay. The advantages of MECC have been somewhat challenging to define.
Despite similar demographic and operative data, significantly more patients required temporary renal replacement therapy after conventional CPB compared with the minimized system in first week after surgery. This finding, however, should be carefully weighed against a more complex risk profile, which is not adequately reflected in simple demographic data. First, slightly more emergency patients with increased preoperative risk have been operated with ECC and might have contributed to the higher incidence of postoperative dialysis. Second, a more difficult coronary morphology and impaired ventricular function might have tempted surgeons to prefer ECC to MECC in some individuals to have a reliable backup. Third, we cannot rule out surgeon bias.
Strengths and Limitations
This is the largest contemporary single-center analysis of AKI in patients undergoing bypass grafting with two different CPB systems. However, this study does contain certain limitations. First, given that this is a retrospective observational study, conclusions are necessarily limited in their application and causality cannot be determined. Second, postoperative renal function was estimated with the MDRD equation, which uses SCr and weight (as a measure of muscle mass). During the postoperative period, these estimates may not be accurate because of imbalances between creatinine production and elimination, which can be caused by various factors including changing renal function, muscle breakdown and injury, liver dysfunction, and various medications. Third, the duration of follow-up was limited to the period of hospitalization. Thus, postdischarge complications could not be accounted for in this analysis.
MECC exerts only very limited renoprotective effects in the early postoperative period most likely due to improved hemodynamic management during CPB. However, the incidence of a decline in eGFR of ≥50% similarly occurred in both conventional and minimized bypass group and thus the renoprotective effects of MECC seem rather weak. Our findings call for a randomized controlled trial to evaluate the effects of MECC on renal perfusion during cardiac surgery. An impaired preoperative eGFR is associated with increased risk for mortality irrespective what CPB system is used.
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