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Ann Thorac Surg 2005;79:2024-2031
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Renal Function After Cardiac Surgery Off- Versus On-Pump Coronary Artery Bypass: Analysis Using the Cockroft-Gault Formula for Estimating Creatinine Clearance

Department of Cardiothoracic Surgery, St. George’s Hospital, London, United Kingdom

Accepted for publication December 20, 2004.

^_* Address reprint requests to Dr Chandrasekaran, Department of Cardiothoracic Surgery, St. George’s Hospital, Blackshaw Road, London SW17 0QT, United Kingdom (E-mail: v.chandrasekaran{at}stgeorges.nhs.uk).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
BACKGROUND: Cardiopulmonary bypass (CPB) is often associated with renal dysfunction, as measured by plasma creatinine levels and hemodialysis rates. This study compared creatinine clearance (CrCl), estimated with the Cockroft and Gault formula, between patients undergoing off-pump coronary artery bypass grafting (OPCAB) versus on-pump CABG (on-CAB).

METHODS: Data of 704 consecutive patients were analyzed. Of these patients, 404 underwent OPCAB while 300 had on-CAB. Creatinine clearance, plasma creatinine levels, and clinical outcome were compared between groups. Data between patients who developed new renal impairment, compared to patients with normal postoperative renal function, were also analyzed.

RESULTS: Creatinine clearance (preoperative, 74 ± 25 vs 78 ± 29 mL/min; day 1, 74 ± 26 vs 76 ± 31 mL/min; day 4, 70 ± 26 vs 72 ± 29 mL/min) and creatinine levels (preoperative, 99 ± 25 vs 95 ± 27 µmol/L; day 1, 101 ± 29 vs 104 ± 35 µmol/L; day 4, 110 ± 44 vs 113 ± 60 µmol/L), as well as postoperative complications (stroke 1% vs 1%; hemofiltration 1.5% vs 3.7%; death 1.2% vs 2.3%), were overall similar between OPCAB and on-CAB patients. Patients with preoperative CrCl less than 50 mL/min had higher creatinine levels in the on-CAB group on day 1 (p = 0.026), although CrCl was similar between groups. Development of new CrCl less than 50 mL/min postoperatively was associated with higher rates of intraaortic balloon pump insertion, re-sternotomy, hemofiltration, intensive care and hospital stay, without difference between groups. Female sex, low body mass index, high preoperative creatinine levels, and advanced age were associated with deterioration in CrCl.

CONCLUSIONS: Currently, the rate of renal impairment is low after both OPCAB and on-CAB. No significant difference in CrCl could be demonstrated between groups. Deterioration in renal function is associated with higher rates of postoperative complications.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Cardiac surgery is often associated with dysfunction of major organs [1]. Studies in patients undergoing cardiac surgical procedures on cardiopulmonary bypass (CPB) reported significant increase in serum creatinine levels in 7.7% to 11.4% of patients, whereas a further 3.7% of patients suffered acute renal failure. The rate of postoperative dialysis was 1.4%. Preexisting renal dysfunction, advanced age, low output syndrome, and emergency operation are independent risk factors for postoperative renal impairment [2, 3]. Retrospective studies of large patient populations have also shown that preoperative renal dysfunction, as defined by elevated plasma creatinine levels, increases the likelihood of postoperative morbidity and mortality [4, 5]. Several widely used models of risk prediction in cardiac surgery consider pre-operative renal dysfunction as a risk factor for early postoperative mortality [6–8].

Elevated plasma creatinine levels comprise a highly specific marker of renal dysfunction. They are easily obtainable but depend on patient muscle mass and gender. Furthermore, patients can have significant reduction of their glomerular filtration rate (GFR) with normal plasma creatinine levels [9]. The ability of the kidneys to clear the plasma of creatinine is assessed more accurately by estimating the creatinine clearance (CrCl). The formula developed by Cockroft and Gault [10] provides a simple and accurate way of measuring CrCl. The association between preoperative renal dysfunction and postoperative morbidity and mortality is stronger when CrCl, rather than creatinine levels, is used [11].

Off-pump coronary artery bypass (OPCAB) surgery has gaining popularity worldwide in recent years [12]. The theoretical and proved disadvantages of the use of the CPB for multivessel coronary artery bypass grafting (CABG) has prompted many cardiac surgeons to convert to OPCAB practice in their units [13]. Clinical trials comparing OPCAB to on-pump CABG (on-CAB) patients have given us an excellent tool to investigate the relative importance of CPB as a cause of organ dysfunction [14]. Some of these studies identified CPB as a risk factor for the development of renal failure. Most of these reports, however, used plasma creatinine levels or incidence of postoperative dialysis as outcome measures for renal dysfunction while CrCl was not estimated [15–20].

In this study we compared estimated preoperative and postoperative CrCl between patients undergoing OPCAB and on-CABG using the Cockroft and Gault formula. Our initial hypothesis was that OPCAB might be associated with reduced rate of postoperative renal dysfunction. Univariate and multivariate logistic regression analysis was used to assess the effects of patient characteristics on the rate of postoperative adverse effects.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Patients and Collection of Data
This study involved retrospective data analysis of patients undergoing isolated CABG at the Cardiothoracic Department of St George’s Hospital, in London, United Kingdom, between August 1999 and July 2003.

Clinical data were collected prospectively in line with the appended Minimum Dataset (MDS) defined by the Society of Cardiothoracic Surgeons. The current MDS, and its associated definitions, is compatible with all existing initiatives in the UK such as the UK Heart Valve Registry, the Central Cardiac Audit Database, and the British Cardiac Intervention Society database. The definitions and data fields are also compatible with evolving European initiatives, the Society of Thoracic Surgeons, the American College of Cardiology, and the Healthcare Financing Administration in the United States [8]. Local validation of the collected data is performed regularly and external validation is being performed by the Society on 3- to 5-year cycle.

The patient population considered in the study represented the complete isolated coronary bypass practice of two surgical consultant firms (M.A.S. and V.C.). One surgeon (M.A.S.) performed only on-pump CABG, whereas the other surgeon (V.C.) performed CABG on- or off-pump between 1999 and 2001 and exclusively off-pump between 2001 and 2003. Patient referral patterns did not differ between the two firms. Patients undergoing minimally invasive direct coronary artery bypass (MIDCAB) were excluded from the data analysis. Patients dependent on hemodialysis preoperatively were also excluded. Early death was defined as death occurring during hospital stay.

Anesthetic and Operative Techniques
Standardized techniques were used for anesthesia and CPB. Anesthetic premedication included morphine (10 mg) and hyoscine (0.3 mg) administered intramuscularly. Anesthesia was introduced with midazolam (100–200 µg/kg), fentanyl (150–200 µg) and pancuronium (50–100 µg/kg), and sustained with propofol (5–10 mg/kg/hour). In the on-CAB patient group, 300 IU/kg heparin was administered to achieve an activated clotting time of over 480 seconds. The CPB circuit used during the study period at the Cardiothoracic Department of St George’s Hospital consisted of a roller pump (Stockert Instruments, Munich, Germany), a Bard William Harvey HF-570 membrane oxygenator (C.R. Bard Inc, Murray Hill, NJ) and polyvinylchloride tubing. Non-pulsatile extracorporeal circulation was used at 2.4 to 2.8 L/m²/min. Moderate hypothermia of 32°C was employed in all patients. Myocardial protection was administered with a Bard cardioplegia delivery system using initially 800 to 1000 mL cold blood antegrade cardioplegia, mixed with St Thomas’ crystalloid solution in a 4:1 ratio, with additional 300 mL every 20 minutes.

When CABG was performed without CPB, anticoagulation was achieved using 150 U/kg of heparin. The activated clotting time was maintained above 250 seconds. Heparin was reversed by protamine at the end of the procedure. The operation was performed through median sternotomy using the Guidant (Guidant, IN) stabilization device. Mean arterial blood pressure was maintained between 50 and 70 mmHg during the procedure by means of repositioning the heart and selective use of vasoconstrictors. Other measures to improve cardiac output such as elevation of feet and increasing the heart rate were used as appropriate. A standby perfusionist with bypass circuit primed was available for all cases. Intraoperative autotransfusion of shed mediastinal blood was carried out with the DIDECO ELECTA Cell Separator (DIDECO, Mirandola, Italy) in both on- and off-pump cases. The mean arterial pressure was maintained at 60 mmHg with increments of metaraminol when necessary, in both groups. Esophageal echocardiography was used intra-operatively to assess right and left ventricular function and to identify localised wall motion abnormalities. The presence of aortic atherosclerotic plaques was not recorded routinely. Protamine was used at the end of the procedure to reverse activated clotting time to pre-operative values.

Estimation of Renal Function
Routine preoperative and postoperative plasma creatinine assessment was carried out in all patients. Postoperative measurements were carried out routinely on the first and fourth postoperative day or otherwise when clinically indicated. Plasma creatinine levels were measured using an automatic analyzer. Values were entered into the Cockroft and Gault equation in order to estimate CrCl after correction for patient gender and weight [10]. The Cockroft and Gault equation is expressed as follows:

(1)

(2)

Age is given in years and weight is given in kilograms. A value of 50 mL/min is accepted as the lowest limit of normal renal function [9]. Plasma creatinine levels are calculated in µmol/L by our laboratory. Values were converted into mg/dL for use in the above equations.

Statistical Analysis
Classification tables for dichotomous data were compared using Pearson’s Chi-square test or Fisher’s exact test. Odds ratios with 95% confidence intervals were calculated for all compared variables. Distributions of continuous data were observed and t tests or Mann-Whitney tests were performed accordingly for comparisons of groups. Similarly paired samples t test or Wilcoxon tests for related samples were used for repeated measurements. Plasma creatinine adjusted morbidity was compared between groups using univariate and multivariate logistic regression analysis and likelihood ratio tests were used to assess statistical significance. Comparisons were made initially between patients undergoing CABG off-CPB vs on-CPB. Renal function was dichotomized between CrCl less than 50 mL/min and greater than 50 mL/min. Patients with normal preoperative CrCl (>50 mL/min) were divided into those who maintained CrCl greater than 50 mL/min postoperatively and those with reduced postoperative CrCl to less than 50 mL/min. The p values less than 0.05 indicate a statistically significant difference between patient groups. All analyses were carried out using the statistical software SPSS 11.0 (SPSS Inc, Chicago, IL).

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
A total of 704 consecutive patients underwent CABG during the study period and were included in this analysis. Of these patients, 17 (2.4%) required postoperative hemofiltration although none of these patient required long-term renal support after discharge from hospital. There were 7 (1%) postoperative nonfatal strokes and 12 (1.7%) early deaths. Of these deaths, 2 were caused by major gastrointestinal hemorrhage, 1 by stroke, and 9 by multiorgan failure.

Patients Undergoing OPCAB Versus On-CAB
Of the 704 patients, 404 underwent OPCAB while in 300 patients CPB was used. There were no intraoperative conversions from OPCAB to on-CAB. Preoperative, intraoperative, and postoperative characteristics in the 2 groups are shown in Table 1. The two groups displayed similar characteristics with the exemption of the following: Rates of patients with three-vessel disease and of patients receiving three or more coronary anastomoses (higher in the on-CAB group), number of patients receiving arterial grafts only (higher in the OPCAB group), number of patients receiving intraaortic balloon pump (IABP) (higher in the on-CAB group). Mean length of stay on the intensive care unit was longer in the on-CAB group.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

Our initial hypothesis was that OPCAB is associated with a reduced rate of postoperative renal dysfunction in comparison to patients undergoing on-CAB. Analysis of renal function, however, demonstrated only mild deterioration in both groups. Mean CrCl decreased from 74 (± 25) to 70 (± 26) mL/min and from 78 (± 29) to 72 (± 29) mL/min after OPCAB and on-CAB, respectively. Median values remained similar to mean values suggesting normal distribution of samples (Table 2). A similar trend was observed when plasma creatinine levels were measured. Hemofiltration was performed in 1.5% of patients in the OPCAB group and in 3.7% of patients in the on-CAB groups. There was no statistically significant difference in postoperative rates of hemofiltration. Numbers of diseased coronary vessels were different between groups, although regression analysis showed that this parameter did not correlate with alteration in renal function. The two patient groups were otherwise similar with regard to preoperative, intraoperative, and postoperative characteristics with the exemption of longer intensive care stay in the on-CAB group (Table 1).

We subsequently turned our attention to patients with normal preoperative renal function, as defined by CrCl of over 50 mL/min. We compared these patients to those with preoperative renal dysfunction in relation to their CPB status. A CrCl of less than 50 mL/min is commonly accepted as the lowest normal value for patients of all ages and both genders [9, 11]. Similar to our findings for the overall group, patients with normal preoperative renal function performed similarly in the OPCAB and on-CAB groups. In patients with renal dysfunction, creatinine levels were significantly higher in the on-CAB group on the first postoperative day but CrCl did not differ between groups postoperatively. Results in this group are presented as median values with their interquartile range, as groups were relatively small and normal distribution could not be assumed (Table 3).

Finally, we analyzed renal function in patients with normal preoperative CrCl divided into a group that maintained normal CrCl and a group that displayed CrCl less than 50 mL/min postoperatively. In the latter group, mean CrCl decreased significantly from 62 (± 12) to 45 (± 12) mL/min on the fourth postoperative day (p < 0.001) while mean plasma creatinine levels increased significantly from 99 (± 19) to 151 (± 87) µmol/L (p < 0.001). Univariate and multivariate logistic regression analysis showed that female sex, advanced age, and low body mass index were associated with deterioration in renal function in patients with preoperative CrCl of over 50 mL/min (Table 4). Low body mass index has been previously identified as a risk factor for morbidity after cardiac surgery [21, 22].

Expectedly, patients developing renal dysfunction post-operatively were significantly more likely to require hemofiltration. Hemofiltration was employed when urine output less than 0.5 mL/kg/hr, could not be reversed despite optimization of intravascular volume and pharmacologic therapy and caused acid balance derangement or intra-vascular volume overloading. These patients were also more likely to have an IABP inserted and to undergo resternotomy for hemorrhage. They had significantly longer intensive care and overall hospital stay (Table 4). Mortality was 2.3% as compared with 0.6% in patients without postoperative renal dysfunction (p = 0.1). Higher morbidity in these patients was probably the result of factors that also lead to renal injury. Reduced CrCl was, therefore, probably simply a surrogate marker for events such as low cardiac output syndrome or sepsis.

The results of this study did not confirm our hypothesis, possibly due to the fact that the degree of postoperative renal dysfunction remained low both after OPCAB and on-CAB. It is well recognized that cardiac surgery often leads to major organ dysfunction, including renal injury. The contribution of the extra-corporeal circulation device to the development of renal injury is, however, not entirely clear. CPB is associated with the development of systemic inflammatory response, endothelial damage and subsequent tissue edema and organ dysfunction. Interestingly, systemic inflammation is also observed in patients undergoing cardiac surgery off-CPB, albeit on a smaller scale [14]. Renal dysfunction after cardiac surgery with CPB was reported in 7.7% of patients while 1.4% of patients required dialysis. Mortality and hospital stay are significantly increased in these patients. Independent preoperative predictors of renal dysfunction include advanced age, congestive heart failure, nonelective surgery, angina class III or IV, hypertension, diabetes mellitus, and preoperative creatinine levels greater than 124 µmol/L [2, 4].

Previous studies assessed the degree of renal injury after OPCAB in comparison to procedures performed on-CPB. In some studies, investigators measured biochemical markers of renal injury while other studies focused primarily on clinical parameters. In one randomized trial, creatinine clearance was significantly higher in the on-CPB group intraoperatively, but it deteriorated as compared with OPCAB during the first 48 postoperative hours. Urinary N-acetyl-b-glucosaminidase (NAG), a marker of renal tubular damage, remained significantly lower in the OPCAB group both during and after surgery [23]. A further study reported increased signs of oxidative stress, as measured by urinary concentrations of hypoxanthine, xanthine and malondialdehyde, in the on-CAB group while these effects where minimal after OPCAB [24]. A small randomized study found that OPCAB induced significantly less changes in biochemical markers of renal injury, such as microalbuminuria, free water clearance, NAG levels, and free hemoglobin [25], although these were not different between groups in another randomized study [26]. In a small case-controlled trial, serum creatinine levels were significantly lower and creatinine clearance was significantly higher in the OPCAB group [27]. Overall, results from these trials suggest strongly that levels of renal injury markers increase significantly after CABG on-CPB. This effect is reduced when surgery is performed without CPB.

Most of the studies performing clinical comparisons were not randomised and therefore subjected to potential bias with regard to renal complications. In a study similar to ours, regression analysis did not identify CPB as predictor of change in postoperative CrCl [28]. This study, however, included only 55 patients in the OPCAB group. Karthik and colleagues [29] constructed a propensity score for risk adjusted comparison of patients undergoing nonelective CABG off- or on-CPB. The incidence of renal impairment, as assessed by increase in creatinine levels greater than 200 µmol/L, was significantly higher in the on-CPB group (p = 0.006). In a similar analysis of propensity-matched pairs of patients, the rate of renal failure requiring dialysis was 1.5% in the on-CPB group vs 0% off-pump (p = 0.03) [16]. The incidence of postoperative dialysis in a large cohort of diabetic patients undergoing OPCAB was 0.87% vs 2.75% in the on-CPB group (p = 0.036) [18]. Rates of renal failure not requiring dialysis were similar between the two groups. In a recent meta-analysis, rates of renal failure were lower in OPCAB patients (odds ratio 0.62, 95% confidence interval 0.50–0.78, p = 0.00003) [17].

The above literature provides evidence that cardiac surgery without CPB is associated with reduced rates of renal impairment in the postoperative period. The benefit becomes statistically significant provided that the on-CAB patient group develops renal dysfunction. The main potential reason our study showed no further differences with regards to renal function between the two groups is that postoperative renal dysfunction is mild in our on-CPB patients. Mean increase in creatinine levels and mean decrease in CrCl levels were overall insignificant between the preoperative period and the fourth postoperative day, and off-CPB surgery was unable to achieve further improvement. The use of CPB did not increase the rate of patients with preoperative normal CrCl (> 50 mL/min) who developed CrCl less than 50 mL/min after surgery.

The main methodological weakness of our study is the dichotomization of patients into having normal or abnormal CrCl using 50 mL/min as our cut-off point. As mentioned above, however, this method is often used in the literature. A further weakness is the lack of randomization. It is likely that bias in our study is reduced by the fact that patient allocation between the two services follows a random pattern and depends mainly on the calendar day each service provides regional cover. CrCl estimates were routinely performed only on postoperative days 1 and 4 unless more frequent tests were clinically indicated.

In summary, this study indicated that coronary artery bypass grafting can be performed with minimal effect on postoperative renal function. The use of on- or off-cardiopulmonary bypass techniques does not significantly affect postoperative estimated creatinine clearance or plasma creatinine levels. Rates of hemofiltration tend, however, to be higher in the on-CPB patient group. A minority of patients display deterioration in creatinine clearance with no difference between groups.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): George Asimakopoulos Mazin A. Sarsam Venkatachalam Chandrasekaran Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Asimakopoulos, G. Articles by Chandrasekaran, V. Search for Related Content PubMed PubMed Citation Articles by Asimakopoulos, G. Articles by Chandrasekaran, V. Related Collections Coronary disease