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Ann Thorac Surg 2007;84:1264-1271
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Renal Failure After Cardiac Surgery: Timing of Cardiac Catheterization and Other Perioperative Risk Factors
Danny Del Duca, MDa,*,
Sameena Iqbal, MDb,
Elham Rahme, PhDc,
Peter Goldberg, MDd,
Benoit de Varennes, MDa
a Division of Cardiovascular Surgery, McGill University Health Centre, Montreal, Quebec, Canada
b Division of Nephrology, McGill University Health Centre, Montreal, Quebec, Canada
c Division of Epidemiology and Biostatistics, McGill University Health Centre, Montreal, Quebec, Canada
d Division of Critical Care Medicine, McGill University Health Centre, Montreal, Quebec, Canada
Accepted for publication May 7, 2007.
Abbreviations and Acronyms ARF = acute renal failure; CI = confidence interval; CPB = cardiopulmonary bypass; GFR = glomerular filtration rate; MDRD = modification of diet in renal disease; NAC = N-acetylcysteine; OR = odds ratio; Scr = serum creatinine
* Address correspondence to Dr Del Duca, Division of Cardiovascular Surgery, Montreal General Hospital, 1650 Cedar Ave, Room C9.169, Montreal, PQ H3G 1A4, Canada (Email: danny.delduca{at}mail.mcgill.ca).
| Adult cardiac surgery:
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Abstract
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Background: The incidence of acute renal failure after cardiac surgery remains high, and the ability to predict renal failure using well-defined baseline risk factors is important. The relationship between the timing of preoperative cardiac catheterization and the incidence of postoperative renal failure has not been previously described.
Methods: Perioperative variables for 649 patients over 12 months were prospectively collected. Variables included medical comorbidities, preoperative glomerular filtration rate calculated using the simplified Modification of Diet in Renal Disease equation, and date of cardiac catheterization. Endpoints were (A) renal failure defined as a rise in serum creatinine greater than 25% by the third postoperative day or renal dysfunction requiring the initiation of dialysis, and (B) hospital mortality.
Results: The incidence of renal failure and renal failure requiring dialysis were 24.0% and 4.2%, respectively. After multivariate analysis, age, cardiopulmonary bypass time, baseline glomerular filtration rate less than 60 mL/min (odds ratio [OR] 1.69; 95% confidence interval [CI]: 1.09 to 2.62; p = 0.047), and cardiac catheterization performed within 5 days before operation (OR 1.82; 95% CI: 1.17 to 2.84; p = 0.010) were independently associated with acute renal failure. Developing postoperative renal failure was independently related to hospital mortality (OR 3.70; 95% CI: 1.59 to 9.09; p = 0.003).
Conclusions: Cardiac catheterization performed within 5 days before operation, baseline glomerular filtration rate less than 60 mL/min, and prolonged cardiopulmonary bypass duration are significant risk factors for acute renal failure after cardiac surgery. Acute renal failure after cardiac surgery is a significant predictor of hospital mortality.
The incidence of acute renal failure (ARF) after cardiac surgery is 1% to 30% [1]. The development of renal failure not only increases patient morbidity but also predisposes them to other complications during the perioperative period. Acute renal failure requiring renal replacement therapy develops in 1% to 5% of patients and is one of the most important independent risk factors for postoperative mortality [1, 2]. Overall, the mortality associated with ARF after cardiac surgery ranges from 28% to 63% [3, 4]. The ability to predict postoperative ARF using well-defined baseline risk factors not only allows for earlier diagnosis and treatment, but may also lead to more effective prophylaxis in the preoperative setting and significantly improve patient outcome.
A number of risk factors for the development of ARF after cardiac surgery have been previously described [1, 4] and include baseline renal insufficiency (creatinine > 120 umol/L), advanced age, diabetes mellitus, and peripheral vascular disease. Left ventricular ejection fraction less than 50%, the use of intra-aortic balloon pump device, and prolonged cardiopulmonary bypass (CPB) times are risk factors generally associated with reduced renal perfusion pressures. Other risk factors include emergency and reoperation cases [4]. Based on these variables, several groups have proposed predictive scoring algorithms that incorporate risk factors to determine operative renal risk stratification profiles [4–6]. The patients undergoing cardiac surgery at our institution commonly have more than one of the above baseline risk factors, yet the influence of these variables on the postoperative renal function of our patients has not been evaluated. Moreover, contrast-induced nephropathy is a widely reported complication of preoperative cardiac catheterization, especially among patients with baseline renal impairment, but the relationship between the timing of this procedure and the incidence of postoperative ARF has not been described.
The goals of this study were to (1) identify the perioperative risk factors associated with the development of ARF after cardiac surgery at our institution, and the effect of preoperative glomerular filtration rate (GFR) estimated using the simplified Modification of Diet in Renal Disease (MDRD) equation [7] in predicting postoperative ARF; (2) evaluate whether cardiac catheterization performed within 5 days before surgery significantly increases the incidence of postoperative ARF, compared with performing this procedure at an earlier time; and (3) measure the association between postoperative ARF and hospital mortality.
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Patients and Methods
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Patients
Subjects were adult patients undergoing cardiac surgery from January 1 to December 31, 2003, at a university-affiliated tertiary care institution. Data for all consecutive patients were entered into a computerized database by a clinical research nurse, and this database was retrospectively reviewed for patient selection into the study by the author (D.D.). Baseline variables (recorded on the day before surgery) included age, sex, height, weight, body surface area, calculated preoperative GFR, serum creatinine, serum blood urea nitrogen, albumin, presence of baseline ventricular dysfunction (ejection fraction < 50%), diabetes mellitus, peripheral vascular disease, hypertension, chronic obstructive pulmonary disease requiring regular bronchodilator therapy, Parsonnet score [8], intra-aortic balloon pump device, postoperative blood loss and transfusion volume requirements, and date of cardiac catheterization. Daily serum creatinine during the first 5 postoperative days was also recorded.
All patients underwent a standard preoperative cardiac catheterization. At our institution, it is common practice to limit the volume of contrast given to all patients, especially those with documented renal impairment. The volume of contrast administered during cardiac catheterization was not recorded for this study. Exclusion criteria included patients on dialysis before surgery, cardiac transplantation, ventricular-assist devices, aortic dissection, and emergency operations. Primary endpoints were ARF, defined as a rise in serum creatinine of greater than 25% by the third postoperative day or renal dysfunction requiring the initiation of dialysis, and overall hospital mortality. This study was approved by our institution’s Director of Professional Services (acting Institutional Review Board for retrospective studies), and the need for individual patient consent was waived as all data were retrospectively reviewed.
Modification of Diet in Renal Disease Equation
Glomerular filtration rates used in all analyses were calculated using baseline serum creatinine (Scr) in the following formula: GFR = 186 x (Scr–1.154) x (age–0.203) x (0.742 if patient is female) x (1.212 if patient is black).
All patients in this study were assumed to be Caucasian as data regarding patient ethnicity and race were not included in our prospective database. More than 95% of the patient population at our institution is Caucasian.
Statistical Analysis
Statistical analysis was performed using the SAS System, version 8e (SAS Institute, Cary, North Carolina). Patient characteristics at baseline were summarized using proportions or means, and standard deviations as appropriate. Student’s t tests or Wilcoxon’s rank-sum and Kruskal-Wallis tests were used to compare clinical variables between patients having postoperative ARF and patients who did not, for normally and nonnormally distributed data, respectively. A multivariate stepwise logistic regression model was used to assess the effect of perioperative variables on the occurrence of ARF while controlling for the effect of possible confounders. Variables with bivariate significance (p 
0.05) were entered into the regression model. For this analysis, the odds ratio (OR) and 95% confidence interval (CI) for each significant variable are reported. The variable of interest "cardiac catheterization within 5 days of operation" was forced into the multivariate regression model, as described by Hosmer and Lemeshow [9]. A second logistic regression model assessed the effect of developing ARF on hospital mortality while controlling for possible confounders. Because hospital mortality in patients having ARF was assessed over an average of 14 days, compared with 9 days for the nonacute renal failure patients, a sensitivity analysis was performed for hospital mortality at 7 days for both groups to control for the possible confounding effects of different follow-up periods. Additional logistic regression analyses were performed to assess the risk of developing ARF according to the specific timing of cardiac catheterization with respect to the date of operation, and to verify the influence of the following additional perioperative variables on the development of ARF: intravenous hydration (defined as crystalloid given at least 1 mL · kg–1 · h–1 for 6 hours, or a crystalloid bolus of at least 500 mL) within 24 hours preceding surgery, N-acetylcysteine (NAC) use (dose 600 mg orally, twice daily for 48 hours) within 72 hours preceding surgery, intraoperative aprotinin use, postoperative hemoglobin level, and blood transfusion volume requirements within 48 hours after surgery.
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Results
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From January 1 to December 31, 2003, 728 consecutive adult patients underwent 749 cardiac operations. After retrospective review of the patient database, 79 patients were excluded and the remaining 649 were included in the study. Excluded patients were 11 heart transplants, 2 heart-lung transplants, 19 ventricular assist device implantations, 3 aortic dissections, and 44 emergency operations. Baseline patient demographics, biochemistry, medical comorbidities, and perioperative variables are shown in Table 1. The mean baseline blood urea nitrogen and GFR among those patients having had cardiac catheterization within 5 days of surgery was 6.6 ± 2.8 mmol/L and 75 ± 22.2 mL/min, respectively. They were very similar to the values observed among patients having had cardiac catheterization more than 5 days before operation (7.1 ± 4.9 mmol/L and 71.4 ± 22.2 mL/min). However, there was a significantly greater proportion of patients undergoing urgent operation among those who had cardiac catheterization performed within 5 days of surgery, compared with more than 5 days before surgery (82.1% versus 47.8%, p < 0.0001).
Timing of Cardiac Catheterization
To justify our a priori choice of 5 days to define our variable of interest "catheterization within 5 days of operation," we examined the effect of the delay between cardiac catheterization and operation on developing postoperative ARF. The periods 0 to 1, 0 to 2, 0 to 3, 0 to 4, and 0 to 5 days before operation were assessed in separate logistic regression models. Table 2
presents the results of these models. Although none of the variables were found to carry statistical significance, likely owing to the small sample sizes in each group, the risk of developing ARF was still elevated at 5 days after catheterization. The variable 0 to 5 days was selected for use in subsequent analyses, as it was one of the study’s a priori objectives [9]. The strength of the association between renal failure and the timing of the catheterization seems to become evident as the time period shortens, but a separate 
2 trend analysis did not demonstrate a statistically significant trend, as the delay between catheterization and operation is shortened (p = 0.517).
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Table 2 Logistic Regression Analysis of Risk of Development of Acute Renal Failure After Cardiac Surgery Given Time Period Between Cardiac Catheterization and Operation
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Acute Renal Failure
Acute renal failure occurred in a total of 156 patients (24.0%). In 147 patients (22.7%), there was a rise in serum creatinine greater than 25% by the third postoperative day, and 27 patients (4.2%) had renal dysfunction requiring the initiation of dialysis. Eighteen patients (2.8%) had both an increase in serum creatinine greater than 25% by the third postoperative day and underwent the initiation of dialysis. Variables associated with the development of ARF after surgery using bivariate analysis are shown in Table 3. These included advanced age, height, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, peripheral vascular disease, Parsonnet score, low postoperative serum albumin, prolonged CPB and cross-clamp times, hemoglobin on the first postoperative day, requirement for postoperative blood transfusion, length of hospitalization, and baseline calculated GFR less than 60 mL/min. When variables with bivariate significance were entered into the multivariate regression model, age, CPB time, baseline GFR less than 60 mL/min, and cardiac catheterization performed within 5 days before operation were independently associated with ARF (Table 4). A separate bivariate analysis of 176 patients found that patients who had postoperative ARF had lower preoperative hemoglobin levels (121 ± 19 g/L versus 132 ± 18 g/L, p = 0.001), and higher blood transfusion volume requirements within 48 hours after surgery (1,036 ± 1,303 mL versus 397 ± 608 mL, p = 0.002), but neither of these variables carried a significant association with ARF after multivariate analysis (data not shown). There was no association between postoperative ARF and the use of preoperative hydration, preoperative NAC, or intraoperative aprotinin use, after bivariate analysis (data not shown). Overall, 9.1% of patients received preoperative intravenous hydration: 13.5% of the patients with GFR less than 60 mL/min and 7.3% of the patients with GFR greater than 60 mL/min. In addition, 5.1% of patients received NAC during the preoperative period, which represented 13.5% of the patients with GFR less than 60 mL/min, and 1.6% of those with GFR greater than 60 mL/min.
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Table 3 Bivariate Analysis of Perioperative and Demographic Variables Associated With the Development of Acute Renal Failure After Cardiac Surgery
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Table 4 Multivariate Analysis of Perioperative and Demographic Variables Associated With the Development of Acute Renal Failure After Cardiac Surgery
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Hospital Mortality
Overall postoperative hospital mortality was 5.2%. Table 5
shows the variables associated with hospital mortality after bivariate analysis. After multivariate regression analysis, urgent operation, Parsonnet score, CPB time, and postoperative ARF were all independent predictors of hospital mortality (Table 6). The development of postoperative ARF increased the risk of hospital mortality by at least threefold (OR 3.70; 95% CI: 1.59 to 9.09; p = 0.003). When the multivariate analysis was repeated for hospital mortality at 7 days, to control for the possible confounding effects of different follow-up periods, the following three variables still had statistically significant associations with hospital mortality: Parsonnet score (OR 1.07; 95% CI: 1.03 to 1.12; p = 0.0003); CPB time (OR 1.02; 95% CI: 1.01 to 1.03; p = 0.002); and postoperative ARF (OR 4.11; 95% CI: 1.15 to 14.5; p = 0.03).
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Table 5 Bivariate Analysis of Perioperative and Demographic Variables Associated With Hospital Mortality After Cardiac Surgery
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Table 6 Multivariate Analysis of Perioperative and Demographic Variables Associated With Hospital Mortality After Cardiac Surgery
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Comment
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Despite improved awareness of the pathophysiology of ARF, enhanced preoperative management strategies, and shorter operative times, the incidence of renal failure after cardiac surgery, and its associated mortality, remain high. Chertow and coworkers [2] found that ARF was associated with early mortality after cardiac surgery after statistical adjustment for comorbidity and other postoperative complications. Impairment in renal function negatively influences immunocompetence, the oxygen free-radical scavenger system, and generates new oxidant and metabolic stress that contributes to the dysfunction of other organs. In addition, current cardiac surgical patient populations are significantly older, have a higher incidence of previous cardiac surgery, and are more likely to have advanced comorbid conditions, placing them at further risk for renal failure. This study identifies several important risk factors for the development of ARF after cardiac surgery. It also confirms that this complication may be among the most important predictors of hospital mortality. After multivariate analysis, acute renal failure carried the strongest association as an independent predictor of mortality after surgery, despite controlling for sensitive markers of patient comorbidity such as the Parsonnet score.
Having cardiac catheterization within the 5-day period before operation was found to be independently correlated with postoperative ARF. This association carried multivariate significance as a risk factor for postoperative ARF and has not been previously described. The reported incidence of contrast-induced nephropathy after coronary angiography is 1% to 15% [10]. Renal insufficiency tends to develop 24 to 96 hours after contrast administration, and several risk factors, including age, low ejection fraction, diabetes mellitus, and volume of contrast, have been identified [10–13]. Postcatheterization nephropathy is a well-known complication of cardiac catheterization among patients with chronic renal insufficiency. Contrast agents cause vasoconstriction-mediated medullary ischemia, and direct cytotoxicity on glomerular cells. Our findings suggest that patients having undergone cardiac catheterization within the 5-day period preceeding surgery may be more vulnerable to further renal deterioration perioperatively. Interestingly, the mean preoperative GFR of patients having had catheterization within 5 days of operation was similar to that of patients having had catheterization greater than 5 days before operation. The proportion of patients requiring urgent operation was significantly higher among those having had cardiac catheterization within 5 days of surgery, compared with those having had catheterization beyond 5 days. This finding suggests a more critical spectrum of cardiac disease in the former patient population.
Calculations using the simplified MDRD equation showed that 79.2% of our patients had a baseline GFR of less than 90 mL/min and 28.9% had a GFR of less than 60 mL/min before operation. Although none of these patients was dialysis-dependent preoperatively, these results suggest that many had notable baseline renal dysfunction and had a significant predisposition for perioperative renal complications. When entered into the regression analysis, baseline GFR below 60 mL/min carried multivariate significance as a risk factor for the development of postoperative ARF. These findings confirm the direct influence of baseline renal dysfunction on subsequent renal complications after surgery and underline the predictive value of the MDRD equation.
Estimated baseline GFR less than 60 mL/min using the MDRD equation may represent a reasonable criterion for use in selecting patients for routine preoperative renal optimization regimens. Several authors have shown that preoperative optimization protocols in patients undergoing major elective surgery significantly reduce postoperative morbidity and mortality, especially among higher risk surgical cases [14, 15]. The use of 0.45% saline hydration protocols in patients with chronic renal insufficiency undergoing cardiac angiography has been shown to provide protection against acute contrast-induced nephropathy [16]. More recent data have shown that prehydration with sodium bicarbonate, which has buffering and antioxidant properties, may be more effective than saline [17]. Our results indicate that, at our institution, the use of preoperative intravenous volume replacement in cases with evidence of renal dysfunction (GFR < 60 mL/min) was performed in only 13.5% of patients. One may hypothesize that performing cardiac catheterization within 5 days of operation may be associated with greater volume depletion due to the osmotic effect of the contrast load. However, our results did not show a significant difference in preoperative blood urea nitrogen levels between those patients undergoing catheterization within 5 days of operation and those undergoing catheterization greater than 5 days before operation.
Our results confirm that CPB duration is associated with postoperative ARF. Boldt and coworkers [3] found that patients with bypass times greater than 90 minutes showed significantly more pronounced kidney damage than did those with bypass times less than 70 minutes, as assessed by sensitive kidney-specific functional protein assays. The unphysiologic, nonpulsatile flow during bypass, activation of inflammatory cascades, and coagulation abnormalities may all be responsible for part of the observed alterations in renal function [3]. In addition, during bypass, the renal parenchyma is exposed to lower perfusion pressures and reduced oxygen tension. These results are consistent in suggesting a deleterious effect caused by longer pump times, and underline the significance of optimizing perioperative renal protection for cases in which longer CPB periods are anticipated, such as complex operations, reoperation cases, and combined coronary artery bypass grafting and valvular surgery.
Cardiac surgery, and cardiopulmonary bypass in particular, are associated with significant physiologic oxidative stress. This stress is related to ischemia-reperfusion processes which, in addition to generating reactive oxygen species, are also associated with a state of systemic inflammation that may contribute to postoperative organ dysfunction, including renal failure [18, 19]. N-acetylcysteine is a nonspecific antioxidant and vasodilator that functions as an oxygen free-radical scavenger. This agent also inhibits oxygen radical generation by polymorphonuclear leukocytes in vitro and in vivo [20, 21]. The use of NAC in perioperative renal optimization strategies has been previously studied, but these results have generally been conflicting. Burns and coworkers [22] reported a randomized, placebo-controlled trial involving 295 patients that concluded that NAC did not prevent postoperative renal dysfunction, complications, or mortality. However, the patient population studied was younger and had milder renal dysfunction compared with other studies evaluating high-risk cardiac surgical populations. Conversely, a randomized, placebo-controlled trial by Fischer and coworkers [23], which also involved a younger study population (mean age 66 years), did show a significantly lower incidence of renal dysfunction among patients receiving NAC perioperatively. However, the study used a smaller sample size, and patients had normal baseline renal function. These reports underline the importance of identifying a high-risk patient group that may facilitate the targeted application of renal optimization protocols and guide future studies. Predicting postoperative renal failure using clearly defined risk factors, such as an estimated GFR of less than 60 mL/min by the MDRD equation, may be helpful in this setting. Our results indicate that, at our institution, only 13.5% of cases with evidence of baseline renal dysfunction (GFR < 60 mL/min) received preoperative NAC.
Among the limitations of this study, the small sample size was probably the most significant. The small sample size produced wide confidence intervals and reduced odd ratios in certain cohorts including diabetes mellitus and chronic obstructive pulmonary disease, both of which failed to show multivariate significance as renal failure risk factors in our regression model. This effect was also observed in our analysis of the timing of cardiac catheterization with respect to the date of operation, where none of the variables showed statistical significance, and may have played a role in our failure to demonstrate a significant benefit of preoperative hydration on postoperative renal function. All patients in this study were assumed to be Caucasian when calculating GFR using the MDRD equation, as our database did not include ethnicity or racial background data. As GFR estimates are 1.212 times greater for black patients, the severity of our patients’ baseline renal dysfunction may have been slightly underestimated, despite the fact that the large majority of patients at our institution are Caucasian.
The present study confirms that age, longer CPB time, and baseline renal dysfunction (particularly GFR < 60 mL/min) are independently associated with the development of ARF after cardiac surgery. It also specifically demonstrates that having cardiac catheterization within 5 days before surgery is a significant risk factor for postoperative ARF. The incidence of postoperative renal failure and renal failure requiring dialysis at our institution were 24.0% and 4.2%, respectively. These values are consistent with those published in the literature [1–4]. Our findings underline the importance of routine preoperative identification of those patients having risk factors for the development of ARF, including patients with evidence of baseline renal dysfunction, and particularly those with an estimated GFR of less than 60 mL/min by the MDRD equation. Patients with milder degrees of baseline kidney impairment but other important renal risk factors such as advanced age or diabetes should also be identified.
Predicting postoperative ARF using clearly defined risk factors may facilitate the targeted application of renal optimization protocols in the preoperative period. The optimal regimen for preoperative renal protection in patients undergoing cardiac surgery awaits further confirmation through randomized controlled trials involving the use of saline, bicarbonate, and NAC. Evidence-based data relating these renal optimization strategies to the timing of operation after catheterization will also be helpful in determining the safest approach to scheduling elective surgery. Efforts to maximize the delay between cardiac catheterization and operation beyond at least 5 days, when clinically feasible, may allow more recovery from the effects of contrast nephropathy, especially in patients with impaired baseline renal function.
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Abstract
Introduction
