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Anesth Analg 2003;96:1258-1264
© 2003 International Anesthesia Research Society


CARDIOVASCULAR ANESTHESIA

Renal Dysfunction After Cardiac Surgery with Normothermic Cardiopulmonary Bypass: Incidence, Risk Factors, and Effect on Clinical Outcome

Sophie Provenchère, MD*, Gaetan Plantefève, MD*, Gilles Hufnagel, MD{dagger}, Eric Vicaut, MD{ddagger}, Cyrille de Vaumas, MD*, Jean-Baptiste Lecharny, MD*, Jean-Pol Depoix, MD*, François Vrtovsnik, MD{dagger}, Jean-Marie Desmonts, MD*, and Ivan Philip, MD*

*Département Anesthésie-Réanimation and {dagger}Service de Néphrologie, Hôpital Bichat-Claude Bernard; and {ddagger}Laboratoire de Biophysique, Hôpital Fernand Widal, Paris, France

Address correspondence and reprint requests to S. Provenchère, MD, Département d’Anesthésie, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75877 Paris Cedex 18, France. Address e-mail to sophie.provenchere{at}bch.ap-hop-paris.fr


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Renal dysfunction is a frequent and severe complication after conventional hypothermic cardiac surgery. Little is known about this complication when cardiopulmonary bypass (CPB) is performed under normothermic conditions (e.g., more than 36°C). Thus, we prospectively studied 649 consecutive patients undergoing coronary artery bypass surgery or valve surgery with normothermic CPB. The association between renal dysfunction (defined as a >=30% preoperative-to-maximum postoperative increase in serum creatinine level) and perioperative variables was studied by univariate and multivariate analysis. Renal dysfunction occurred in 17% of the patients. Twenty-one (3.2%) patients required dialysis. Independent preoperative predictors of this complication were: advanced age, ASA class >3, active infective endocarditis, radiocontrast agent administration <48 h before surgery, and combined surgery. When all the variables were entered, active infective endocarditis, radiocontrast agent administration, postoperative low cardiac output, and postoperative bleeding were independently associated with renal dysfunction. The in-hospital mortality rate was 27.5% when this complication occurred (versus 1.6%; P < 0.0001). Furthermore, postoperative renal dysfunction was independently associated with in-hospital mortality (odds ratio, 4.1 [95% confidence interval, 1.3–12.8]). We conclude that advanced age, active endocarditis, and recent (within 48 h) radiocontrast agent administration, as well as postoperative hemodynamic dysfunction, are more consistently predictive of postoperative renal dysfunction than CPB factors.

IMPLICATIONS: We found that postoperative renal dysfunction was a frequent and severe complication after normothermic cardiac surgery, independently associated with poor outcome. Independent predictors of this complication were advanced age, active endocarditis, and recent (within 48 h) radiocontrast agent administration (the only preoperative modifiable factor), as well as postoperative hemodynamic dysfunction.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Despite advances in surgical and anesthetic techniques, cardiac surgery continues to be associated with substantial morbidity. Postoperative renal dysfunction is one of the most frequent and serious complications encountered in this context. Many studies have focused on the incidence, risk factors, possible mechanisms, and poor outcome of this complication after cardiac surgery (1–9). Using absolute or relative preoperative-to-postoperative changes in serum creatinine concentration as criteria for renal dysfunction, several authors found an incidence of 7%–30% (2,3,6,7,9). The observed incidence seems to vary, depending on many factors, such as the study population, exclusion criteria, and criteria for defining renal dysfunction (10,11). One percent to 3% of patients are reported to develop renal dysfunction requiring dialysis. These patients are at substantial risk for postoperative death (2).

Previous studies were conducted in patients undergoing hypothermic cardiopulmonary bypass (CPB). Indeed, hypothermic perfusion has been considered a good organ protection strategy. Over the last several years, the most substantial change in cardiac surgery has been the trend toward increased CPB temperatures (12–14). At normothermia (temperature >36°C), CPB duration is shorter and, in the postoperative period, less bleeding and increased stability of patient temperature may be seen. Although concerns have been raised about the safety of normothermic CPB in patients at risk of renal dysfunction (14), few data are available concerning the incidence of renal dysfunction after cardiac surgery with normothermic CPB (15).

Because CPB is routinely performed at normothermia at our institution, we decided to prospectively study a large cohort of consecutive patients: (a) to determine the incidence of postoperative renal function impairment after normothermic cardiac surgery, (b) to identify the independent predictors of this complication, and (c) to investigate the effect of renal dysfunction on outcome.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This prospective study was conducted over a 10-mo period and included consecutive adult patients scheduled to undergo coronary artery bypass grafting (CABG), valve surgery (valve replacement or mitral valvuloplasty), or both (combined surgery). The protocol was approved by the local ethics committee, which waived the need for written informed consent. Patients with severe preoperative acute renal failure (defined as an increase in serum creatinine of more than 50% more than the baseline value), chronic renal insufficiency requiring dialysis, or septic shock were not included. Of the 657 patients enrolled, five were excluded from analysis because of death during the first 24 postoperative h (n = 2) or missing data (n = 3). Three patients with acute renal failure secondary to delayed complications (occurring after one week: mediastinitis, n = 2; hemorrhagic shock, n = 1) were excluded.

The primary outcome measure was the frequency of postoperative renal dysfunction and the identification of independent predictors of this complication. For this purpose, serum creatinine values were recorded before and after surgery (daily in the intensive care unit [ICU] and then every 2 or 3 days until discharge). Postoperative renal dysfunction was defined as a >=30% increase in preoperative-to-maximum postoperative serum creatinine level within 7 days after surgery. Postoperative renal dysfunction was considered as moderate or severe, depending on the percentage increase in serum creatinine (30%–50% and >50%, respectively; values defined a priori). Need for dialysis was recorded. Dialysis was used only in case of severe acute renal failure, according to published recommendations: volume overload, hyperkalemia, or metabolic acidosis (11).

Secondary outcome measures were length of stay in the ICU, total length of stay, and the in-hospital mortality (defined as death occurring at any time from 24 h after surgery until discharge from hospital).

Anesthesia management was standardized for all patients (midazolam, large-dose fentanyl, and pancuronium bromide) and complied with routine practice at our hospital (16,17). Monitoring was performed with radial artery and pulmonary artery catheters. Antifibrinolytic therapy, either tranexamic acid (15 mg/kg twice) or aprotinin (2 x 106 KIU pre-CPB, 2 x 106 KIU in prime, and 500,000 KIU/h during surgery), was systematically administered. IV prophylactic antibiotic treatment over the first 24 h consisted of cefamandole (60 mg · kg-1 · d-1) or vancomycin (30 mg · kg-1 · d-1) plus aminoglycoside (gentamicin, 3 mg · kg-1 · d-1) in case of allergy to cephalosporins.

CPB management and myocardial protection were also standardized for all patients, as previously described (16,17). CPB was nonpulsatile; membrane oxygenators were used in all cases. Flow rates of 2.4 L · min-1 · m-2 were used, and mean arterial blood pressure (MAP) was maintained at more than 50 mm Hg by first increasing pump flow or, if the blood pressure did not improve, by a bolus administration of phenylephrine. During CPB, normothermia (bladder temperature >36°C) was maintained with a perfusion temperature of 37°C.

The following demographic variables were collected for each patient: age, body weight, height, body surface area, body mass index, and sex. The following other preoperative variables were evaluated: history of hypertension, diabetes mellitus, peripheral vascular disease, myocardial infarction, active infective endocarditis (according to the Duke criteria (18), in patients still treated by antibiotics), New York Heart Association functional class, ASA class, left ventricular systolic function assessed by either echocardiography or ventriculography (rated altered, mildly depressed, or normal: left ventricular ejection fraction <30%, 30%–50%, or >50%, respectively), type of heart disease and surgery, previous heart surgery, intraaortic balloon counterpulsation, current diuretic, angiotensin converting enzyme inhibitor or calcium-blocking drug therapy, preoperative aminoglycoside or vancomycin therapy, and radiocontrast agent injection (ioxaglate meglumine, an ionic low-osmolar contrast agent; Hexabrix®, Guerbet, Roissy, France) within 48 h before surgery and surgical priority (elective, urgent within 24 h, and emergent).

Preoperative renal function was assessed by baseline serum creatinine level and creatinine clearance, calculated by the Cockcroft-Gault formula (19,20). Preexistent renal impairment was defined as a baseline creatinine clearance <60 mL/min. Creatinine clearance was the variable used in the statistical analysis.

Intraoperative variables evaluated were CPB and aortic cross-clamping durations, minimal hematocrit, maximal value of plasma hemoglobinemia, packed red cell transfusion, TM-50 (product of the difference between 50 mm Hg and MAP <50 mm Hg and the time in minutes that MAP remained <50 mm Hg) (8), type of antibiotic prophylaxis, type of antifibrinolytic (tranexamic acid or aprotinin), intra-CPB use of vasopressor (phenylephrine) or vasodilator (nicardipine) drug, diuresis during CPB, diuretic injection, intra-CPB ultrafiltration, and post-CPB catecholamine infusion.

Postoperative explanatory variables evaluated were hemodynamic status assessed by the requirement for catecholamines infusion (epinephrine, norepinephrine, dopamine, or dobutamine at a dose of >5 µg · kg-1 · min-1 for more than 2 h), the occurrence of low cardiac output (cardiac index <2 L · min-1 · m-2 for more than 4 h), and the use of intraaortic balloon counterpulsation. Perioperative myocardial damage was assessed by cardiac troponin I determination 20 h after surgery (17). Postoperative bleeding was assessed by total chest drainage, return to operating room within 48 h after surgery, and the administration of blood units. Postoperative mechanical ventilation duration was recorded. Criteria of discharge from the ICU and from the hospital were those frequently used in our institution.

Values are expressed as mean ± SD, median (25th–75th percentiles), or percentage as appropriate. Potential association between perioperative variables and postoperative renal dysfunction were first tested by univariate analysis using Student’s t-test, a nonparametric test (Mann-Whitney), or the {chi}2 test for categorical data. The variables identified by univariate analysis were then analyzed with multivariate procedure using forward stepwise logistic regression with a maximum likelihood ratio method (P value of entry 0.05). To avoid overestimating the number of independent predictors, we selected these variables with conservative criteria as follows: the limit to enter or remove variables in the regression equation must have a 5% probability value, and the ratio between the corresponding regression coefficient and its standard error had to be more than 2. Odds ratio and their 95% confidence intervals (CI) were calculated. All P values were two-tailed, and a P value of <0.05 was considered significant. All tests were performed using Biomedical data package (BMDP, University of California at Los Angeles, CA).

The association between postoperative renal dysfunction and in-hospital mortality rate was explored using another independent statistical analysis, with the same statistical methodology, using univariate analysis and then stepwise logistic regression to determine predictors of in-hospital mortality rate. A receiver-operating characteristic curve was also performed to analyze the accuracy of different levels of increase in serum creatinine to predict in-hospital death.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
A total of 649 patients were studied (mean age, 61 ± 16 yr). Patient demographics and baseline characteristics are shown in Table 1. Median preoperative values of serum creatinine and creatinine clearance were 95 µmol/L (82–110) and 66 mL/min (51–86), respectively. Two-hundred-fifty-seven (34%) patients had an estimated creatinine clearance <60 mL/min (median value of 47 mL/min [37–53]).


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Table 1. Demographic and Baseline Patient Characteristics (n = 649)
 
Postoperative renal dysfunction occurred in 112 of 649 patients (17.2%; 95% CI, 14.3%–20.1%). Thirty-seven patients (5.7%) had a moderate increase in serum creatinine level (30%–50%); 75 (11.5%) patients had a >=50% increase. Twenty-one patients (3.2%; 95% CI, 1.8%–4.6%) required dialysis. Peak serum creatinine level occurred within the first 72 postoperative h in 63% of the patients.

Postoperative renal dysfunction was more frequent in patients with preoperative renal impairment (19.4% versus 11.4%; P < 0.001). Conversely, we found no association between the requirement of dialysis and preoperative renal impairment or age. None of the patients with a preoperative serum creatinine level >200 µmol/L (seven patients) required dialysis. Sex was not associated with postoperative renal dysfunction. We found no association between type of surgery (CABG versus valve surgery) and occurrence of renal dysfunction (16% versus 14%; not significant). Preoperative variables associated in univariate analysis with postoperative renal dysfunction are reported in Table 2. Multivariate analysis showed that renal dysfunction was associated with advanced age, active infective endocarditis, ASA class >3, administration of radiocontrast agent within 48 h, and combined surgery (Table 3).


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Table 2. Univariate Analysis: Perioperative Factors Associated with Postoperative Renal Dysfunction
 

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Table 3. Multivariate Analysis of Postoperative Renal Dysfunction: Preoperative Variables
 
Bladder temperature was 35.1°C ± 0.3°C before the onset of CPB and 36.7°C ± 0.2°C at the end of CPB, with no difference among patients with or without postoperative renal dysfunction. CPB duration was longer in the group developing postoperative renal dysfunction (P < 0.0001). We found no association between the type of antifibrinolytic drug and the incidence of postoperative renal dysfunction. TM-50 value, which reflects intra-CPB hypotension, was not different comparing the two groups of patients. Postoperative variables associated with postoperative renal dysfunction are reported in Table 2.

When all preoperative variables were entered in the multivariate analysis model, radiocontrast agent, active infective endocarditis, postoperative low cardiac output, and postoperative bleeding were found to be independently associated with renal dysfunction (Table 4).


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Table 4. Multivariate Analysis of Postoperative Renal Dysfunction: Perioperative Variables
 
Length of stay in ICU was significantly longer in patients who had renal dysfunction (6 [3–16] versus 2 [2–3] days for patients without renal dysfunction; P < 0.0001). Similarly, total length of stay was longer for patients who had renal dysfunction (15 [10–27] versus 11 [9–13] days; P < 0.0001). As shown in Table 5, ICU and total lengths of stay were associated with the severity of renal dysfunction.


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Table 5. Length of Stay Among Patients Without Postoperative Renal Dysfunction and Those with Different Degree of Postoperative Renal Dysfunction
 
The in-hospital mortality rate among all patients without postoperative renal dysfunction was 1.6%. In contrast, 27.5% of the patients with this complication died (P < 0.0001). The in-hospital mortality rate was strongly associated with the percent change in serum creatinine (Fig. 1). Figure 2 shows receiver-operating characteristic curve analysis for different thresholds of change in serum creatinine for the occurrence of in-hospital death: cutoff values of 30% and 50% increase in creatinine appeared in the best range (with the maximum sensitivity + specificity) of values predicting in-hospital death.



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Figure 1. Association between postoperative renal dysfunction (assessed by the percentage increase in serum creatinine) and in-hospital mortality. The in-hospital mortality rate increased with the percent change in serum creatinine (P < 0.0001). In multivariate analysis, renal dysfunction was independently associated with in-hospital mortality.

 


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Figure 2. Receiver operating characteristic curve for the prediction of in-hospital death with different changes in serum creatinine. Points for a 30% and 50% increase in serum creatinine are depicted. Cr = serum creatinine concentration.

 
In the multivariate analysis designed to identify predictors of in-hospital death, postoperative renal dysfunction was an independent risk factor of mortality. Adjusted odds ratios for mortality were 4.1 (1.3–12.8) for all patients who developed renal dysfunction and 15.5 (4.1–59.4) for those requiring dialysis. The other independent predictors were diabetes, altered left ventricular function, emergent surgery, total blood loss, and postoperative cardiac troponin I (data not shown).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our study showed that renal dysfunction is a frequent complication after normothermic cardiac surgery. We found that the most important prognostic factors for the occurrence of this complication were preoperative patient characteristics (advanced age, ASA class >3, active infective endocarditis, and radiocontrast agent administration <48 hours before surgery) as well as postoperative hemodynamic status. Postoperative renal dysfunction is a severe event that independently affects outcome.

Our single-center study ensured a certain degree of homogeneity in perioperative management of all the patients because all our protocols of care were standardized. Furthermore, we exhaustively collected perioperative variables, allowing the collection of data such as nephrotoxic drug exposure, radiocontrast agent administration within 48 hours, intraoperative hypotension, and major postoperative complications. As in other studies (1,2,6), we included patients scheduled for either CABG or valve surgery. Our results clearly showed no difference between the two types of surgery. To represent our routine population, we also included high-risk patients with either active bacterial endocarditis, those undergoing emergency procedures, or those with preoperative renal function impairment. We found an incidence of preoperative renal function impairment (estimated creatinine clearance, by the Cockcroft-Gault formula, <60 mL/min) similar to that reported by Fortescue et al. (21) in a large cohort of patients who underwent CABG. The inclusion of these high-risk patients accurately reflects the increasing severity of illness of our cardiac surgery patients. The potential limitation of our single-center study is counterbalanced by the results of Mangano et al. (6) who found that the occurrence of renal dysfunction in patients undergoing cardiac surgery was fairly constant across centers, suggesting that patient-specific rather than center-specific factors accounted for any increased risk.

Because there is a lack of consensus criteria to define acute renal failure (22), the choice of our definition requires discussion. In the context of cardiac surgery, subclinical renal dysfunction, as measured using various markers of renal tubular damage, has been described in patients after CPB in the absence of overt changes in plasma urea and creatinine concentrations and creatinine clearance. Clinical relevance of such subclinical changes is unknown. We chose an increase of 30% of serum creatinine that represents a substantial reduction of glomerular filtration (23). Such a low threshold has never been studied in cardiac surgery. Our results showed that even moderate renal dysfunction is associated with a poor prognosis, which strongly supports our choice. Our definition of perioperative renal dysfunction might explain the incidence we report, and thus, any comparison with the literature must be cautious. It is noteworthy that the mean percentage increase in serum creatinine in our patients approximates the value reported by Swaminathan et al. (15) (19% and 24%, respectively).

CPB, per se, may induce ischemic or toxic insult to the kidney. Indeed, nonpulsatile blood flow, decreased renal plasma flow, increased renal vascular resistances, increase in endothelin-1 plasma levels (larger after hypothermic CPB), renal filtration of proinflammatory cytokines, and free plasma hemoglobin are all factors that may induce transient renal damage with impairment of renal functional reserve and tubular function (5,24). However, these changes are not sufficiently severe to affect routine renal function variables such as creatinine concentration (5,7,24). In our statistical analysis, neither the duration of CPB nor the intensity of arterial hypotension during CPB (expressed by the TM-50) were independent risk factors of renal dysfunction, which is in accordance with other studies (8,25). Experimental studies have suggested that perfusion temperature of CPB does not influence the change in the measured indices of renal function (26,27). In a small series of patients, other studies have shown that perfusion temperature is not involved in post-CPB changes in renal function (28,29). Although ours was not a comparative study, the large patient cohort yielded similar results to those observed with hypothermic perfusion, suggesting that factors other than a well-conducted CPB per se may be involved. These results are supported by a study in which no association was found between CPB temperature and renal dysfunction (15).

Preoperative patient characteristics as well as markers of poor postoperative cardiac function were strongly associated with postoperative renal dysfunction, as after hypothermic CPB. Among the preoperative variables, advanced age was found to be an independent predictor of this complication, as it was in other studies (1,3,6,9,30). Our results also showed that the incidence of postoperative renal dysfunction after cardiac surgery is more frequent in patients with preoperative renal insufficiency, although it was not significant in multivariate analysis. We also found that an ASA score >III was an independent risk factor. In our series, such a functional classification frequently reflected a poor hemodynamic status requiring aggressive medical therapy or emergent surgery. Furthermore, some patients are likely to receive potentially toxic treatments. For example, in our study, some had received immediate preoperative radiocontrast agent injection, which interestingly, seemed to be an independent risk factor. Exposure to radiocontrast agent, like CPB, has been associated with an increase in endothelin-1 concentrations. It has been shown that hydration may be an effective means of preventing acute decreases in renal function after the administration of radiocontrast agents (31). On the contrary, cardiac surgery patients often receive diuretic therapy and thus have some degree of perioperative hypovolemia. Finally, a clinical setting combining many of these risk factors is active infective endocarditis, which represented 7% of our patients. It is not surprising that our statistical analysis showed it to be the highest preoperative risk factor for the development of postoperative renal dysfunction. Additionally, during the perioperative period, toxic factors and ischemic injury because of renal hypoperfusion (reflected by a low cardiac output and postoperative bleeding) may together contribute to alter renal function.

The occurrence of postoperative renal dysfunction was associated with a poor prognosis independent of comorbid conditions. This result is in agreement with other studies in which acute renal failure was conservatively defined (e.g., 50% increase of serum creatinine concentration or requirement of dialysis) (2,3,6,9). Interestingly, we found that even a lesser degree of alteration of renal function after cardiac surgery was an independent risk factor of in-hospital mortality. Such an increase in mortality with relatively small increments in serum creatinine level has also been reported after radiocontrast procedures (32,33). Finally, postoperative renal dysfunction also significantly increased ICU and total lengths of stay. This last point has been underlined by Mangano et al. (6), who reported results very similar to ours.

What is the impact of our results on clinical practice? The poor prognosis of this frequent complication (34) and the ineffectiveness of pharmacological prevention of renal dysfunction (e.g., dopamine, calcium channel blockers, and diuretic drugs) encourage us to focus on preoperative identification of risk factors with a special attention for modifiable ones. Delaying surgery, whenever possible, after radiographic-contrast agent injection may be beneficial, especially for elderly patients and those with preexisting chronic renal insufficiency (33). In the same manner, hydration should be performed before the surgery in case of preoperative functional renal impairment.

In conclusion, our study shows that renal dysfunction is a common and severe complication after normothermic cardiac surgery. Preoperative patient status and postoperative hemodynamic function were found to be more consistently predictive of postoperative renal dysfunction than were CPB-related factors. Our results, as well as those of previous authors, suggest that the risk of renal dysfunction is not substantially influenced by perfusion temperature. The only modifiable preoperative risk factor that was identified was the recent administration of radiocontrast agent.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 19, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press