ARTICLE IN PRESS. Follow-up papers - Cardiac general

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1 doi: /icvts Published by European Association for Cardio-Thoracic Surgery Interactive CardioVascular and Thoracic Surgery 10 (010) Follow-up papers - Cardiac general Effect of mild renal dysfunction (s-crea 1.. mgydl) on presentation characteristics and short- and long-term outcomes of on-pump cardiac surgery patients Abstract a, b b a Aarne Jyrala *, Robert E. Weiss, Robin A. Jeffries, Gregory L. Kay a Heart Institute at Good Samaritan Hospital, Department of Cardiothoracic Surgery, Los Angeles, USA b Department of Biostatistics, UCLA School of Public Health, Los Angeles, USA Received 17 December 009; received in revised form 1 January 010; accepted 5 January 010 Objectives: The objective of this study is to evaluate differences in patient presentation and short- and long-term outcomes between patients dichotomized by the level of preoperative s-creatinine (s-crea) without renal failure and to use EuroSCORE (ES) risk stratification for validating differences and for predictive purposes. Methods: A thousand consecutive cardiac surgery patients from January 1999 through May 000 were analyzed. Patients with off-pump surgery or s-crea )00 mmolyl (). mgydl) were excluded leaving 885 patients for analysis. Group 1 (ns703) had s-crea mgydl and Group (ns18) had elevated s-crea 1.3. mgydl but no renal insufficiency. Results: Group patients were older (P ), had a higher percentage of males (Ps0.008), had lower left ventricular ejection fraction (LVEF) (Ps0.001), had higher New York Heart Association (NYHA) classification (P ), had more diabetics (Ps0.001) and had more patients with a history of congestive heart failure (CHF) (P ). Both additive ES (AES) and logistic ES (LES) variables were higher in Group patients, AES 8.45"4.8% vs. 6.05"3.80% (P ) and LES 17.7"19.1% vs. 9.57"13.3% (P ). Proportions of emergency operations and use of intra-aortic balloon pulsation (IABP) support did not differ. There were more coronary artery bypass grafting (CABG) with or without concomitant procedures in Group 1 but otherwise the procedures performed were similar. Cardiopulmonary bypass (CPB) times did not differ (Ps0.1). Operative mortality was similar (Ps0.06) but hospital mortality was higher in Group : 19y10.4% vs. 5y3.6% (P ), odds ratio (OR) Total length of stay (LOS) and length of stay in the postoperative intensive care unit (ICU) did not differ. Postoperative renal failure (PORF) (s-crea increase to ).5 mgydl or )00 mmolyl) developed in 38y4.5% patients in Group 1 and in 41y.5% patients in Group (P ), ORs5.08. Follow-up all-cause mortality was higher in Group : 68y37.4% vs. 167y3.8% (P ), ORs1.91. Both ES definitions predicted hospital mortality, LOS, ICU, PORF and long-term mortality well, while increased s-crea predicted PORF and long-term mortality in both groups. Conclusions: Mild increase in s-crea is a marker for patients with increased cardiac risk factors and the risk for poor outcomes. Both ES definitions are highly predictive of the outcomes. 010 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Serum creatinine; Cardiac surgery; Outcomes; EuroSCORE 1. Introduction Preoperative renal insufficiency is a well known and documented risk factor for adverse outcomes after cardiac surgery w1 3x. Less is known about presentation characteristics and outcomes in cardiac surgery patients with only a mild decrease in preoperative renal function. Lately this has been recognized as a determinant of less favorable outcomes w4, 5x. There is no consensus about definitions of renal insufficiency or postoperative kidney injury and reports have used different cut-off points based on serum creatinine (s-crea) levels or other parameters which make comparison of results difficult w1,, 6x. The nomenclature of degrees of renal impairment also needs refinement w3x. The study is funded by the Elma Larsson Foundation and the Los Angeles Thoracic and Cardiovascular Foundation, Los Angeles, USA. *Corresponding author Fiji Way, Marina Del Rey, CA 909, USA. Tel.: q ; fax: q address: lathoracic@hotmail.com (A. Jyrala). The EuroSCORE (ES) (Additive ES: AES, Logistic ES: LES) was created to provide a simple and objective risk scoring system to predict hospital mortality in adult cardiac surgery w7, 8x. It is based on data from approximately 0,000 patients from several European countries and is the most validated contemporary risk scoring system and is in use all over the world. Both ESs have been used for predicting outcomes like intensive care unit length of stay (ICU) (days), length of hospital stay (LOS) (days), postoperative complications and costs of cardiac surgery w9, 10x. ES points are given, when s-crea is )00 mmolyl ().5 mgydl). This level of s-crea is used in this study to exclude patients from the study population and to define postoperative renal insufficiency w1x. The objective of this study is to evaluate differences in presentation and outcomes between patients with normal s-crea and patients with elevated s-crea under 00 mmolyl (-.3 mgydl) who have no diagnosis of renal failure. ES Work in Editorial New Ideas Progress Report Protocol Institutional Report ESCVS Article Proposal for Bailout Procedure Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature Historical Pages Brief Communication Case Report

2 778 A. Jyrala et al. / Interactive CardioVascular and Thoracic Surgery 10 (010) variables are used to delineate differences and for predictive purposes.. Methods.1. Patient selection and data collection From January 1999 through May 000, 1000 consecutive patients had cardiac surgery procedures at our unit. Patients who had off-pump operations (ns44) were excluded as were patients with s-crea )00 mmolyl ().5 mg/ dl) with or without dialysis support leaving 885 patients into the study groups. Patients were dichrotomized by the level of s-crea: Group 1 (normal s-crea) ns703 with s-crea in the range mgydl and Group (elevated s-crea) ns18 with s- crea 1.3. mgydl. A database was created including patient demographics, hospital and postdischarge outcomes. The on-line calculator for ES ( was used to score patients on AES and LES and these were included in the database along with separate ES variables. Postoperative renal failure (PORF) was defined as a rise of s-crea )00 mmolyl or).5 mgydl in the postoperative period regardless of the need for dialysis support. Follow-up all-cause mortality data were acquired from the Social Security Main Death Index. The study was approved by our hospital Ethics Committee... Operative technique All patients were operated using standard median sternotomy. Ascending aorta (AoAsc) was cannulated when feasible and venous return was accomplished with vacuum assisted two-stage cannula. Bicaval or femoral cannulation was used when indicated. Operations were performed in moderate hypothermia to 34 8C and perfusion pressure was kept between 60 and 70 mmhg. Cold full blood antegrade and retrograde cardioplegia was used to arrest the heart, retrograde cardioplegia was given continuously and stopped only when it interfered with visualization and for a maximum of 10 min at a time. All patients received 1000 mg vitamin C and 600 mg allopurinol orally as antioxidants and 750 mg methylprednisolone intravenously to reduce the postoperative inflammatory reaction systemic inflammatory reaction syndrome (SIRS)..3. Statistical analysis Variables were tested for their associations with s-crea using Student t tests, x -tests or logistic regression as appropriate. Variables included age in years, baseline s- crea, individual ES variables, AES and LES, gender, New York Heart Association (NYHA) classes, diabetes, congestive heart failure (CHF), main operative diagnoses and performed procedures. Outcomes included binary variables operative mortality and hospitaly30-day mortality. For discharged patients we analyzed long-term survival. Additional outcomes were LOS, ICU, LOS)10 days, ICU ) days, appearance of PORF, AES )5% and LES )4.9%. Groups were compared on these outcomes using x -tests, logistic regression and t tests as appropriate. Long-term survival of discharged patients was estimated using Kaplan Meier plots and survival differences between groups were tested using log-rank tests. Computations were done in R version.7.. wr Development Core Team (008)x. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN , URL: Results 3.1. Patient presentation Group patients were older (P ) and there were fewer females in Group (Ps0.008). Left ventricular ejection fraction (LVEF) was lower in Group (Ps0.001) and there were more patients with diabetes (Ps0.001) and with a history of CHF (P ). Group patients had significantly higher average AES and LES values (both ). Group had more high-risk patients (AES )5%) and very high-risk patients (LES )4.9%) (both ). Mean NYHA-class was higher in Group :.90"0.75, median 3 vs. Group 1:.53"0.76, median (P ) and consequently more patients in NYHA class III IV (70.3% vs. 47.7%, P ). Coronary artery disease (CAD) with or without concomitant heart diseases was the main operative diagnosis in both groups. Demographic data are summarized in Table Early outcomes Performed procedures were similar in both groups and are summarized in Table. Cardiopulmonary bypass (CPB) times were similar (Ps0.1). Table 3 compares the two groups on outcomes. Operative mortality was low in both groups and was borderline not significant (Group 1 ns6y0.9% vs. Group ns5y.7%, Ps0.06). Total hospital mortality was significantly higher in Group (19y10.4% vs. 5y3.6%, P , ORs3.16). LOS and ICU did not differ between the groups. There were more patients requiring prolonged ICUyLOS () days/ )10 days consecutively) in Group but the difference was not statistically significant. PORF (s-crea ). mgydl) developed in 79 operative survivors (8.9%): ns38y5.4% in Group 1 and ns41y.5% in Group, P , ORs5.08. Of the PORF patients, seven of 38 patients in Group 1 (18.4%) and 15 of 41 patients (36.6%) in Group needed renal replacement (dialysis support), Ps In both groups, the preoperative s-crea level was higher in patients who developed PORF: Group 1 with renal failure ns38, s-crea 0.97"0.1, without renal failure ns665, s-crea 0.88"0.1, Ps0.01 and Group with renal failure ns41, s-crea 1.60"0., without renal failure ns141, s-crea 1.50"0., Ps Follow-up Total follow-up for hospital survivors (ns841 patients) was 69,03 months, mean 8.9"7.4 months, median 93 months and range months.

3 A. Jyrala et al. / Interactive CardioVascular and Thoracic Surgery 10 (010) Table 1 Demographic data of Group 1 and patients Group 1 Group Group 1 (n) Group (n) P-value (m"s.d.)y% (m"s.d.)y% Age (years) 65.5" " Females 35.7% 5.7% BMI 7.6" " LVEF 0.49" " Baseline s-crea (mgydl) 0.89" " AES 6.05" " LES 9.57" " High-risk (AES )5) 54.% 75.8% Very high-risk (LES )4.9) 8.8%.4% NYHA Class 1 5.3% 1.6% NYHA Class 47.1% 8.0% NYHA Class % 47.% NYHA Class % 1.4% Diabetes 36.4% 50.5% CHF 3.3% 51.0% Emergency surgery 6.7% 6.0% Stable CAD 47.3% 46.7% Unstable AP 3.8%.% Recent AMI*.9% 9.7% ASyAI 1.1% 1.6% MRyMS 9.4% 4.9% Endocarditis 0.1%.% Dissection 0.1% 1.1% Miscellaneous 3.0% 0.5% *Acute myocardial infarction within 90 days before surgery. BMI, body mass index; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association functional; CHF, congestive heart failure; AES, additive EuroSCORE; LES, logistic EuroSCORE; AP, angina pectoris; CAD, coronary artery disease; AMI, acute myocardial infarction; ASyAI, aortic valve disease; MRyMS, mitral valve classification; S.D., standard deviation. Table Procedures performed Procedure Group 1 (%) Group (%) Group 1 (n) Group (n) P-value OR 95% CI for OR CABG only (1.06,.1) CABGqAVR (0.35, 1.63) CABGqMVR (0.66,.9) CABGqMVRqAVR (.86, ) AVR (0.18, 1.6) MVR (0., 1.34) AVRqAoAsc repair (0.15, 9.56) AVRqMVR (0.1, 4.9) MVRqTVR (0.5, 9.39) Dissection repair (0.17, 13.66) Others (0.07, 1.19) CPB (min"s.d.) 108" " CABG, coronary artery bypass grafting; AVR, aortic valve replacement; MVR, mitral valve repair or replacement; AoAsc, ascending aorta; TVR, tricuspid valve repair or replacement; CPB, cardiopulmonary bypass time in min; S.D., standard deviation. OR, Odds of event in Group yodds of event in Group 1. Table 3 Outcomes Outcome Group 1 Group Group 1 Group P-value m 1 m 95% CI for (m"s.d.) (m"s.d.) (n) (n) m 1 m LOS (days)* 7.9" " ( 1.40, 0.30) ICU (days)* 1.74" " ( 0.60, 0.4) (%) (%) (n) (n) OR Operative mortality (0.78, 13.05) Hospital mortality (1.6, 6.13) LOS )10 days* (0.87,.39) ICU ) days* (0.9,.73) Follow-up mortality* (1.33,.74) Postoperative renal failure (3.06, 8.43) LOS, length of stay in the hospital; ICU, length of stay in the postoperative intensive care unit; S.D., standard deviation. *Hospital survivors. Work in Editorial New Ideas Progress Report Protocol Institutional Report ESCVS Article Proposal for Bailout Procedure Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication

4 780 A. Jyrala et al. / Interactive CardioVascular and Thoracic Surgery 10 (010) There was a highly significant difference in all-cause follow-up mortality between the groups: Group 1 ns167y 3.8% vs. Group ns68y37.4%, P , ORs1.91. This is shown in the Kaplan Meier survival plots in Fig. 1. Patients at risk yearly and yearly mortality is presented in Table EuroSCORE Predicted hospital mortality by AES in Group 1 was 10% (AES 6.05%) and by LES 9.57%. The observed mortality was 3.6%, so both ES overestimated hospital mortality. In Group, AES prediction for hospital mortality was 15% (AES 8.45%) and by LES 17.7%. The observed hospital mortality was 10.4%. Both ES showed a highly significant difference between the groups (both P ) indicating that Group patients had significantly more cardiac risk factors than Group 1 patients. Age difference and poor LVEF (EF -0.3) were significantly higher in Group patients and most other variables were worse off or equal in the two groups although the differences did not reach the level of statistical significance. The individual ES variables are summarized in Table 5. Both ES variables predicted all outcomes well in both groups. Adding s-crea into the ES predictions improved prediction for all other outcomes except LOS and ICU. Fig. 1. Kaplan Meyer survival estimates for Groups 1 and patients. Dotted lines: 95% CI. ns Study limitations This is a retrospective study from a single unit. Since the aim of this study is only to describe the value of s-crea increase to detect patients with poor outcomes and Table 4 Patients at risk and mortality per year during the follow-up time up to 8 years Year 1 Year Year 3 Year 4 Year 5 Year 6 Year 7 Year 8q Hospital survivors Group Group ny% Mortality Group 1 33y4.9 0y3.1 1y1.9 19y3.1 19y3. 15y.6 8y5.0 1y3.9 Group 8y4.9 8y5. 8y5.5 10y7. 11y8.6 8y6.8 5y4.6 9y8.7 Table 5 EuroSCORE variables Variable Group 1 Group Group 1 Group P-value OR 95% CI for OR (%) (%) (ns703) (ns18) Age 60 years or over (1.3,.8) Female (0.4, 0.91) Chronic pulmonary disease (0.86,.) Extracardiac arteriopathy (0.91,.09) Neurology dysfunction (0.5,.38) Previous cardiac surgery (0.64, 1.9) s-crea )00 mmolyl Active endocarditis (0.7, 1.5) Critical preoperative status (0.77, 3.54) Unstable angina (0.74, 1.93) EF (1.85, 4.83) EF (0.7, 1.4) Recent myocardial infarct (0.97,.07) Pulmonary hypertension (0.18, 1.6) Emergency (0.41, 1.8) Other than isolated CABG (0.61, 1.3) Surgery on thoracic aorta (0.44, 5.04) Postinfarct septal rupture EF, ejection fraction; CABG, coronary artery bypass grafting. OR, Odds of event in Group yodds of event in Group 1.

5 A. Jyrala et al. / Interactive CardioVascular and Thoracic Surgery 10 (010) describe the value of using s-crea and standard error (SE) algorithms for predictive purposes the shortcomings should be acceptable. 5. Comments Slightly elevated s-crea levels without obvious renal insufficiency is common among mixed cardiac surgery patients, 18 patients (0.6%) in this study. With the increasing age of cardiac surgery patients and with increasing amounts of diabetes, hypertension, CHF and arteriosclerotic disease the amount of patients with decreased renal function is inevitably increasing. Several studies have demonstrated that mild renal insufficiency defined in a variety of ways has a great impact on short- and long-term outcomes in patients undergoing cardiac surgery w1 6x. Glomerular filtration rate (GFR) is the recommended measurement of the level of renal insufficiency w11x. There is no linear correlation between GFR and s-crea and some patients may have low GFR with normal s-crea (51y7.3% of Group 1 patients in this study had chronic kidney disease (CKD) class 3A, GFR -60 mlyminy1.73 m. Mean age was 74 years and all were females, outcomes did not differ from patients with GFR )60 mlyminy1.73 m ). Since we have used ES for risk evaluation and for predictive purposes it is logical to use s-crea levels for separating the groups. s-crea is a very sensitive indicator of impaired renal function and is readily available but lacks the ability to assess renal impairment due to its dependence on gender, age, body mass, race and other issues. Using the definitions of s-crea the two groups were clearly separated and both by ordinary demographic variables and ES thus justifying the use of s-crea for prediction of outcomes w5x. Patients with renal insufficiency have higher in-hospital mortality than patients without normal s-crea w1, 13x. Patients with increased s-crea levels but without renal insufficiency have also been reported to have higher inhospital mortality than patients with normal s-crea w14x. In this study, operative mortality was similar between the groups but hospitaly30-day mortality was significantly higher in Group and both s-crea levels and ES were good predictors for this outcome. ICU and LOS were similar between the groups. Both ESs were good predictors for LOS and ICU but s-crea did not have predictive power for these outcomes. Renal failure developed in 79 patients and s-crea was a good predictor for renal failure as reported earlier w1x. Both ES variables predicted the occurence of renal failure. Neither s-crea nor ES predicted the appearance of PORF which requires dialysis w15x. CPB times were similar between the groups (Ps0.09) but marginally longer in patients developing PORF (Ps0.054), no difference in CPB times were noted between patients who needed dialysis and patients with PORF but with no need for dialysis (Ps0.55). All-cause follow-up mortality was significantly higher in Group patients and has been reported earlier w6, 16x. Both ES algorithms and s-crea levels were predictors of late death in both groups (Table 6). In summary, patients with elevated s-crea levels have a much higher incidence of cardiovascular risk factors than patients with normal s-crea. The incidence of diabetes and CHF is higher in Group and both have an impact on renal function and increase the likelihood of late renal dysfunctionyfailure and cardiac related events. There are more males in Group probably due to the higher incidence of arteriosclerotic diseases in males, which is often asymptomatic and undiagnosed. Work in Editorial New Ideas Progress Report Protocol Institutional Report ESCVS Article Proposal for Bailout Procedure Negative Results Follow-up Paper Table 6 Adding creatinine level (linear and binary) to a model with only AESyLES as a predictor Outcome Variable Linear creatinine Creatinine )1. mgydl Est S.E. T P-value Est S.E. T P-value Length of stay* AES Creatinine Time in ICU* AES Creatinine Hospital death AES Creatinine Postoperative AES renal failure Creatinine Long-term survival* AES Creatinine Length of stay* LES Creatinine Time in ICU* LES Creatinine Hospital death LES Creatinine Postoperative LES renal failure Creatinine Long-term survival* LES Creatinine LOS, length of stay in the hospital; ICU, length of stay in the postoperative intensive care unit. *Hospital survivors. Est, parameter estimate; S.E., standard error; T, T-value. AES, additive EuroSCORE; LES, logistic EuroSCORE. State-of-the-art Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication

6 78 A. Jyrala et al. / Interactive CardioVascular and Thoracic Surgery 10 (010) Conclusions Elevated s-crea level is a reliable marker for patients having increased amounts of cardiovascular risk factors and by this virtue is a marker for less than optimal short- and long-term outcomes. All modifiable risk factors should be optimized preoperatively in these patients and they should have a very thorough follow-up with optimal control of diabetes, CHF and other modifiable issues. Elevated s-crea predicts the appearance of PORF and there is a correlation between late deaths and s-crea levels. Both AES and LES variables separate the groups well and have a good predictive power for all outcomes and may also be used for quality control issues and predictions of resource utilization w10, 11x. References w1x Devbhandari MP, Duncan AJ, Grayson AD, Fabri BM, Keenan KJM, Bridgewater B, Jones MT, Au J. Effect of risk-adjusted, non-dialysisdependent renal dysfunction on mortality and morbidity following coronary artery by-pass surgery: a multi-center study. Eur J Cardiothorac Surg 006;9: wx Hirose H, Amano A, Takahashi A, Nagano N. Coronary artery bypass grafting for patients with non-dialysis-dependent renal dysfunction (serum creatinine)ors.0 mgydl). Eur J Cardiothorac Surg 001; 0: w3x Lassnigg A, Schmid ER, Hiesmayr M, Falk C, Druml W, Bauer P, Schmidlin D. Impact of minimal increases in serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med 008;36: w4x Simon C, Luciani R, Capuano F, Miceli A, Roscitano A, Tonelli E, Sinatra R. Mild and moderate renal dysfunction: impact on short-term outcome. Eur J Cardiothorac Surg 007;3: w5x Zakeri R, Freemantle N, Barnett V, Lipkin GW, Bonser RS, Graham TR, Rooney SJ, Wilson IC, Cramb R, Keogh BE, Pagano D. Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting. Circulation 005;11(9 Suppl):I70 I75. w6x Filsoufi F, Rahmanian PB, Castillo JG, Chikwe J, Carpentier A, Adams DH. Early and late outcomes of cardiac surgery in patients with moderate to severe preoperative renal dysfunction without dialysis. Interact CardioVasc Thorac Surg 007;7: w7x Nashef SAM, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R, The EuroSCORE Study Group. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16:9 13. w8x Roques F, Michel P, Goldstone AR, Nashef SAM. The logistic EuroSCORE. Eur Heart J 003;4:1. w9x Nilsson J, Algotsson L, Höglund P, Lührs C, Brandt J. EuroSCORE predicts intensive care unit stay and costs of open heart surgery. Ann Thorac Surg 004;78: w10x Pinna Pintor P, Bobbio M, Colangelo S, Veglia F, Marras R, Diena M. Can EuroSCORE predict direct costs of cardiac surgery? Eur J Cardiothorac Surg 003;3: w11x Wang F, Dupuis JY, Nathan H, Williams K. An analysis of the association between preoperative renal dysfunction and outcome in cardiac surgery: estimated creatinine clearance or plasma creatinine level as measures of renal function. Chest 003;14: w1x Cooper WA, O Brien SM, Thourani VH, Guyton RA, Bridges CR, Szczech LA, Petersen R, Peterson ED. Impact of renal dysfunction on outcomes of coronary artery bypass surgery. Results from the Society of Thoracic Surgeons National Adult Cardiac Database. Circulation 005;113: w13x Howell NJ, Keogh BE, Bonser RS, Graham TR, Mascaro J, Rooney SJ, Wilson IC, Pagano D. Mild renal dysfunction predicts in-hospital mortality and post-discharge survival following cardiac surgery. Eur J Cardiothorac Surg 008;34: w14x Kilo J, Margreiter JE, Ruttmann E, Laufer G, Bonatti JO. Slightly elevated serum creatinine predicts renal failure requiring hemofiltration after cardiac surgery. Heart Surgery Forum 005;8:E34 E38. w15x Doddakula K, Al-Sarraf N, Gately K, Hughes A, Tolan M, Young V, McGovern E. Predictors of acute renal failure requiring renal replacement therapy post cardiac surgery in patients with preoperatively normal renal function. Interact CardioVasc Thorac Surg 007;6: w16x Diez C, Mohr P, Kuss O, Osten B, Silber R-E, Hoffman H-S. Impact of preoperative renal dysfunction on in-hospital mortality after solitary valve and combined valve and coronary procedures. Ann Thorac Surg 009;87: