Acute Kidney Injury After On-Pump or Off-Pump Coronary Artery Bypass Grafting in Elderly Patients Wilko Reents, MD, Michael Hilker, MD, PhD, Jochen B€ orgermann, MD, PhD, Marc Albert, MD, Katrin Pl€ otze, PhD, Michael Zacher, MD, Anno Diegeler, MD, PhD, and Andreas B€ oning, MD, PhD Cardiovascular Clinic Bad Neustadt, Bad Neustadt; Department of Cardiothoracic Surgery, University Medical Center, Regensburg; Clinic for Heart, Thoracic and Cardiovascular Surgery, Heart and Diabetes Centre NRW, Ruhr University Bochum, Bad Oeynhausen; Department of Cardiac and Vascular Surgery, Robert Bosch Hospital, Stuttgart; Department of Cardiac Surgery, University Heart Center Dresden; Department of Cardiovascular Surgery, Justus-Liebig University Gießen, Germany
Background. An exploratory analysis of the German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) trial was performed to investigate the effect of off-pump coronary artery bypass grafting (CABG) on kidney function after the operation. Methods. Data on kidney function were available from 1,612 patients, representing 67% of the study population. Preoperative kidney function was graded according to the glomerular filtration rate. Acute kidney injury (AKI) within the first week after the operation was defined and classified according to the Acute Kidney Injury Network (AKIN) criteria. The incidence and severity of AKI was compared between patients operated on on-pump or offpump. Results. Impaired kidney function was seen in 642 patients (40%), and 19 patients had preexisting end-stage kidney disease. AKI of any severity occurred in half of all patients undergoing CABG, with AKIN stage 1
accounting for most of the cases. The incidence and severity of AKI in patients undergoing on-pump vs offpump CABG was AKIN stage 1: 298 (37%) vs 329 (42%); AKIN stage 2: 38 (5%) vs 43 (5%); and AKIN stage 3: 44 (6%) vs 44 (6%), which did not differ significantly (p [ 0.174). New renal replacement therapy was necessary in 3.2% (on-pump) and in 2.7% (off-pump) of all patients. Stratification according to preoperative kidney function yielded comparable frequencies of AKI for on-pump and off-pump CABG. Conclusions. AKI was common in elderly patients undergoing CABG, but deterioration of kidney function requiring renal replacement therapy was a rare event. Off-pump CABG was not associated with decreased rates or reduced severity of AKI in elderly patients.
A
perioperative period, and the systemic inflammatory response induced by a major operation [1, 5, 6]. Off-pump coronary artery bypass grafting (CABG) may interfere with some of these factors. Cardiopulmonary bypass (CPB), with the contact of blood components to artificial surfaces, is a presumed cause of inflammation [2], and avoidance of CPB may therefore attenuate the systemic inflammatory response. The German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) study randomly assigned patients aged 75 years or older to CABG with (on-pump) or without (off-pump) CPB [7]. We speculated that CABG without CPB might influence the incidence and magnitude of AKI in an especially vulnerable patient population.
cute kidney injury (AKI) describes a clinical syndrome characterized by a sudden decline of the excretory kidney function, with accumulation of urea and creatinine and decreased urinary output [1]. After cardiac operations, AKI of varying severity occurs in up to onethird of all patients and approximately 2% require temporary renal replacement therapy [2]. The occurrence of an AKI is independently associated with increased shortterm and long-term death [3, 4]. A preventive or therapeutic strategy to mitigate the burden of AKI would therefore be of substantial value. The pathogenesis of AKI after cardiac operations is multifactorial and may develop from a combination of impaired autoregulation caused by comorbidities and drugs, affected renal perfusion due to altered hemodynamics during the operation and in the
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
Patients and Methods Accepted for publication Jan 28, 2014. Presented at the Fiftieth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 25–29, 2014. Address correspondence to Dr Reents, Cardiovascular Clinic Bad Neustadt, Salzburger Leite 1, 97616 Bad Neustadt, Germany; e-mail: wilko. [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
GOPCABE Study The GOPCABE study was a controlled, randomized, multicenter trial conducted from June 2008 through September 2011 at 12 German institutions. The study was approved by the respective ethics committee of each participating center, and all patients provided written, 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.01.088
2
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
informed consent. Patients were randomly assigned to CABG with or without CPB. Patients scheduled for isolated, first-time CABG were eligible if they were aged at least 75 years. Exclusion criteria were any additional cardiovascular disease necessitating a concomitant operation, previous pericardiotomy, any condition requiring an immediate (ie, within 24 hours after hospital admission) surgical procedure, a planned minimally invasive direct CABG procedure (CABG using left anterior thoracotomy), or the inability or unwillingness of the patient to provide consent. Randomization was performed after the baseline patient data, including the target vessels, had been entered into a central, Internet-based, password-protected data template. Treatment assignment was according to a blocked randomization scheme with a blinded block length of 8, stratified according to the participating center. The primary end point of the GOPCABE study was a composite of death or major adverse events (myocardial infarction, stroke, acute renal failure requiring dialysis, repeat revascularization) within 30 days and at 1 year after the operation. The trial was registered at www. clinicaltrials.gov, trial number NCT00719667.
Chronic Kidney Disease and AKI The initial GOPCABE trial protocol did not include numerical recording of baseline creatinine values, nor was a detailed analysis of kidney function planned as a prespecified end point. For post hoc exploratory analysis of kidney function in a large patient sample randomly assigned to on-pump or off-pump CABG, we asked all participating centers to provide the serum creatinine values before and from day 0 to day 7 after CABG. The glomerular filtration rate (GFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation: 186 (serum creatinine/88.4)1.154 (age)0.203 (0.742 if female). Kidney function before CABG was graded from I to V according to the GFR as proposed by the Kidney Disease Outcome Quality Initiative [8]. In this classification, kidney function is defined as normal with a GFR of more than 89 mL/min/1.73 m2 (stage I), minimally reduced with a GFR between 60 and 89 mL/min/1.73 m2 (stage II), moderately reduced with a GFR between 30 and 59 mL/min/1.73 m2 (stage III), severely reduced with a GFR between 15 and 29 mL/min/1.73 m2 (stage IV), and end-stage kidney failure with a GFR below 15 mL/min/ 1.73 m2 or renal replacement therapy (stage V). Patients with preexisting stage V chronic kidney disease were excluded from further analysis of postoperative kidney function. AKI within the first week after CABG was defined and classified according to the criteria proposed by the Acute Kidney Injury Network (AKIN) [9] as AKIN stage 1: increase creatinine 1.5 from baseline or increase of >0.3 mg/dL within 48 hours; AKIN stage 2: increase creatinine 2 from baseline; and AKIN stage 3: increase in creatinine 3 from baseline or creatinine >4 mg/dL with an acute increase >0.5 mg/dL within 48 hours or new-onset renal replacement therapy. The incidence and severity of AKI was compared between patients operated
Ann Thorac Surg 2014;-:-–-
on on-pump or off-pump. Comparison of AKI was further stratified according to preoperative kidney function.
Statistical Analysis Analysis was done on an intention-to-treat basis. The continuity-corrected c2 test was used for comparison of the incidence and various degrees of AKI between patients operated on on-pump or off-pump. Mantel-Haenszel c2 tests were used to adjust for study center effects. Baseline characteristics were compared with the c2 test, t test, or Kruskal-Wallis test, as appropriate. Dichotomous data are presented as number and percentage. Continuous data are shown as mean or median and standard deviation. All statistical analyses were performed with SPSS 20.0 software (IBM Corp, Armonk, NY).
Results From June 2008 to September 2011 the GOPCABE study randomly assigned 2,539 patients to on-pump or offpump CABG. Exclusion after randomization for various reasons and loss to follow-up resulted in 2,394 patients available for analysis. A detailed description of patient enrollment has been published previously [7]. Serum creatinine values were obtained from 1,612 patients (67%) of the GOPCABE study population. Excluded from further analysis were 19 patients who had preexisting end-stage kidney failure (CKD stage V) before CABG. The remaining 1,593 patients constituted the study population for the evaluation of kidney function and AKI after CABG. CABG procedures were on-pump in 804 patients and off-pump in 789. The baseline characteristics are reported in Table 1 [10, 11] and were well balanced between both groups. The only exception was a higher percentage of patients with insulin-dependent diabetes mellitus randomized to off-pump CABG (13.9% vs 10.2%). The mean age was 78 years (range, 75 to 90 years), and approximately one-third of the patients were women. Myocardial infarction had occurred previously in 37%, and left ventricular function was impaired in 32%. The extent of coronary artery disease was 3-vessel disease or left main stem involvement in 89% of the patients. As expected in this age group, comorbid conditions, such as peripheral vascular disease, previous stroke, or a history of atrial fibrillation, were present in a substantial proportion of patients. Kidney function and the degree of chronic kidney disease before CABG was well balanced between both groups (Table 2 [8]). Kidney function was impaired in 638 patients (40%), with a GFR below 60 mL/min/1.73 m2 (CKD stage III to IV). AKI of any severity occurred in 793 patients (50%), with AKIN stage 1 accounting for most of the cases (Table 3 [9, 12]). There was no significant difference in the incidence and severity of AKI in patients undergoing on-pump or off-pump CABG (p ¼ 0.174). Stratification according to preoperative kidney function yielded comparable frequencies of AKI for on-pump and off-pump CABG (Table 4; Figure 1 [9]). The incidence of acute renal failure requiring renal replacement therapy was similar between the groups, at 3.2% for on-pump and
Ann Thorac Surg 2014;-:-–-
Table 1. Baseline characteristics
a
Variable
Female gender Age, y Body mass index, kg/m2 Insulin-dependent diabetes mellitus Chronic obstructive pulmonary disease Peripheral vascular diseasec Pulmonary arterial hypertensiond Previous Stroke Myocardial infarction Percutaneous coronary intervention History of atrial fibrillation Implanted pacemaker Left ventricular ejection fraction >0.50 0.30–0.50 89 mL/min/1.73 m2) II (GFR 60–89 mL/min/1.73 m2) III (GFR 30–59 mL/min/1.73 m2) IV (GFR 15–29 mL/min/1.73 m2)
117 363 303 21
97 393 268 31
(14.6) (45.1) (37.7) (2.6)
(12.3) (49.8) (34) (3.9)
a
8.1 6.6 3.7 3.4
8.2 6.9 3.8 3.8
Continuous data are shown as the means standard deviation and b Statistical difference between dichotomous data as number (%). c groups indicated by p < 0.05. Includes cerebrovascular disease, peripheral arterial disease with stenosis >50% or occlusion or aortic aneud rysm at any site. Defined as a systolic pulmonary artery pressure e Defined as the presence of one or more of the following: >60 mm Hg. cardiogenic shock or resuscitation within 48 hours before hospital admission, mechanical ventilation, inotropic support or intraaortic balloon f pump. The operative risk was estimated on the basis of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) [10] and the Koronar Chirurgie score [11]. The Koronar Chirurgie score is constructed yearly using the current registry data of all coronary artery bypass grafting procedures in Germany.
Renal function is graded from I to IV according to the classification proposed by the Kidney Disease Outcome Quality Initiative [8].
CABG ¼ coronary artery bypass grafting; rate.
GFR ¼ glomerular filtration
large sample of elderly patients undergoing CABG [7]. One component of the combined end point was acute renal failure requiring new renal replacement therapy, which occurred within 30 days after surgery in 2.4% of the patients assigned to off-pump CABG and in 3.1% assigned to on-pump CABG (p ¼ 0.36). A more detailed analysis of kidney function after CABG was feasible in two-thirds of the original study population, and the findings can be summarized as follows: 1. At baseline, 40% of all patients aged older than 75 years had impaired kidney function (GFR 0.3 mg/dL within 48 hours; RIFLE risk: increased creatinine 1.5 from baseline; AKIN stage 2, RIFLE injury: increased creatinine 2 from baseline; AKIN stage 3, RIFLE failure: increased creatinine 3 from baseline or creatinine >4 mg/dL with an increase >0.5 mg/dL within 48 hours or new-onset renal replacement therapy. CABG ¼ coronary artery bypass grafting.
4
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
Ann Thorac Surg 2014;-:-–-
Table 4. Acute Kidney Injury Stratified According to Kidney Function At Baselinea
Variable
Preserved Renal Function No. (%)
AKI 1 No. (%)
AKI 2 No. (%)
AKI 3 No. (%)
New-Onset RRT No. (%)
30-Day Mortality No. (%)
78 (67) 67 (69)
32 (27) 26 (27)
6 (5) 2 (2)
1 (1) 2 (2)
. .
. .
219 (60) 215 (55)
112 (31) 152 (39)
17 (5) 18 (5)
15 (4) 8 (2)
8 (2) 3 (1)
8 (2.2) 9 (2.3)
118 (39) 86 (32)
149 (49) 139 (52)
15 (5) 22 (8)
21 (7) 21 (8)
15 (5) 12 (5)
8 (2.6) 6 (2.2)
9 (43) 5 (16)
5 (24) 12 (39)
. 1 (3)
7 (33) 13 (42)
I (GFR >89 mL/min/1.73 m2) On-pump Off-pump II (GFR 60–89 mL/min/1.73 m2) On-pump Off-pump III (GFR 30–59 mL/min/1.73 m2) On-pump Off-pump IV (GFR 15–29 mL/min/1.73 m2) On-pump Off-pump
3 (14) 6 (19)
1 (4.8) 2 (6.5)
a
Preoperative renal function is graded from I to IV according to the classification proposed by the Kidney Disease Outcome Quality Initiative [8]. Acute kidney injury (AKI) as defined and classified according to the criteria proposed by the Acute Kidney Injury Network [9].
CABG ¼ coronary artery bypass grafting;
GFR ¼ glomerular filtration rate;
accounting for most cases. New renal replacement therapy was necessary in 3% of all patients. 3. AKI of any severity occurred more frequently in patients with impaired kidney function before CABG. 4. Event rates of AKI were similar for off-pump and on-pump CABG. In patients with preexisting kidney disease, the surgical technique had no detectable effect on the incidence or severity of AKI. Preexisting kidney disease has been repeatedly identified as a strong predictor of AKI after operations [13–16]. The GOPCABE study population included a substantial proportion of patients with impaired kidney function preoperatively. Our findings may therefore be especially applicable to a particularly vulnerable patient population with preexisting kidney disease. The rate of 3% requiring new renal replacement therapy is within the reported range of 1% to 6% [16], yet ranging at the upper boundary. Two recent, large-scale randomized
Fig 1. Acute kidney injury (AKI), as defined and classified according to the criteria proposed by the Acute Kidney Injury Network (AKIN) [9], is shown stratified according to kidney function at baseline (red ¼ preserved renal function; green ¼ AKI 1; light blue ¼ AKI 2; dark blue ¼ AKI 3) and illustrates the data in Table 4. (I–IV ¼ renal function before CABG, graded from I to IV according to the classification proposed by the Kidney Disease Outcome Quality Initiative [8]; y-axis ¼ number of patients.)
RRT ¼ renal replacement therapy.
trials investigated off-pump and on-pump CABG [17, 18]. The percentage of patients with preexisting kidney disease, defined as serum creatinine exceeding 1.5 mg/dL, was 7.9% in the Veterans Affairs Randomized On/Off Bypass (ROOBY) trial population. Although the incidence of AKI was not reported, new renal replacement therapy within 30 days after the operation was necessary for 0.9% of all patients [17]. The primary publication of the Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study (CORONARY) trial did not report the rate of patients with preexisting kidney disease [18]; however, Garg and associates [19] performed a detailed analysis evaluating kidney function of the CORONARY patient population. Here 23% (717 of 3,089 patients) had preexisting kidney disease as defined by a GFR of less than 60 mL/min. Overall, 1.2% of these patients needed new renal replacement therapy, 0.6% of the patients with preserved kidney function and 3.1% of those with
Ann Thorac Surg 2014;-:-–-
preexisting kidney disease. It is therefore reasonable to assume that the 3% rate of new renal replacement therapy in the GOPCABE study population was primarily caused by the high number of patients with impaired kidney function at baseline. AKI of any severity as defined by the AKIN [1] was a common event that occurred in half of all patients, and AKIN stage 1 accounted for most patients. Applying the AKIN criteria, AKI rates in the range of 30% have been reported [13, 18]. The AKIN criteria may be quite sensitive for detecting subtle changes in kidney function, especially the creatinine increase of 0.3 mg/dL within 48 hours. But this criterion might be misleading if the creatinine values obtained within 24 hours after CABG (day 0 and day 1) are included. The increase on the day of the operation and the subsequent drop of the estimated GFR, as shown in Figure 2, probably does not reflect changes in kidney function. A more plausible explanation is that the decrease of creatinine values on the day of CABG is caused by hemodilution and that the following GFR decrease is also influenced by normalization of water homeostasis. The initial RIFLE (risk of renal dysfunction; injury to the kidney; failure of kidney function; loss of kidney function; and end-stage kidney disease) criteria [12] do not include the creatinine increase within 48 hours for defining the mildest form of AKI (RIFLE category: risk), whereas the RIFLE categories injury and loss are similar to AKIN stage 2 and 3, respectively. AKI defined according to the RIFLE criteria may therefore avoid an artificially high rate caused by initial hemodilution but may miss more subtle changes of kidney function thereafter. Analysis of our data by applying the RIFLE criteria resulted in lower rates of AKI (Table 3). Here only 26% of
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
5
all patients had AKI of any severity (RIFLE categories: risk, injury, or failure). Remaining to be elucidated is which definition of AKI fits best to describe meaningful changes of kidney function within the first week after CABG. Each definition of AKI leads to similar results between off-pump and on-pump CABG, underscoring the robustness of our findings. In a large patient sample that included a substantial proportion of patients with an increased risk for AKI, we were unable to detect any effect of the surgical technique on kidney function after CABG. The effect of off-pump CABG on kidney function is still controversial. Observational and randomized studies comparing on-pump and off-pump CABG both found conflicting evidence, and available meta-analyses also reached contradictory results [16]. An evaluation of AKI across 22 randomized trials with 4,819 patients found a 40% relative risk reduction associated with off-pump CABG [20]. But as stated in the accompanying editorial, “different definitions of AKI used in the individual trials and methodological concerns precluded definitive conclusions about the treatment effect.” A meta-analysis encompassing more than 240,000 patients found a benefit for off-pump CABG only in the observational studies (odds ratio, 0.54; 95% confidence interval, 0.39 to 0.77), whereas the difference was not significant in the aggregate randomized trials (odds ratio, 0.61; 95% confidence interval, 0.25 to 1.47) [21]. Actually, the largest single randomized trial (CORONARY) found an absolute 4.1% risk reduction of any AKI for off-pump CABG, defined according to the AKIN criteria [18]. This reduced risk was entirely caused by a decreased occurrence of AKI stage 1 within 30 days after CABG. More
Fig 2. Mean glomerular filtration rate after on-pump (blue line) and off-pump (red line) coronary artery bypass grafting (CABG).
6
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
severe forms of AKI or new renal replacement therapy were similar between both groups. A detailed analysis of early and late kidney function in the CORONARY study population is anticipated [19]. In summary, we found that AKI was common in elderly patients undergoing CABG. Mild forms of AKI accounted for the most of the cases. With 1,593 patients, of whom 40% had impaired kidney function at baseline, this study actually represents the largest high-risk patient sample evaluating kidney function after on-pump or off-pump CABG in a randomized trial. Off-pump CABG was not associated with decreased rates or reduced severity of AKI in elderly patients.
Ann Thorac Surg 2014;-:-–-
10. 11.
12.
13. 14.
References 1. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet 2012;380:756–66. 2. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006;1:19–32. 3. Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes in serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 2004;15:1597–605. 4. Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Longterm risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 2009;53:961–73. 5. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med 2007;357:797–805. 6. Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis and therapy. J Clin Invest 2004;114:5–14. 7. Diegeler A, B€ orgermann J, Kappert U, et al; for the GOPCABE Study Group. Off-pump versus on-pump coronary artery bypass grafting in elderly patients. N Engl J Med 2013;368:1189–98. 8. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: evaluation, classification, and stratification. Part 4: definition and classification of stages of chronic kidney disease. Am J Kidney Dis 2002;39(Suppl 1):S46–75. 9. Mehta RL, Kellum JA, Shah SV, et al; and the Acute Kidney Injury Network. Acute Kidney Injury Network: report of an
15. 16. 17.
18.
19.
20.
21.
initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. Roques F, Michel P, Goldstone AR, Nashef SA. The logistic EuroSCORE. Eur Heart J 2003;24:1–2. Badreldin AM, Kania A, Ismail MM, et al. KCH, the German preoperative score for isolated coronary artery bypass surgery: is it superior to the logistic EuroScore? Thorac Cardiovasc Surg 2011;59:399–405. Bellomo R, Ronco C, Kellum JA, Metha RL, Palevsky P, and the ADQI workgroup. Acute renal failure–definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the Acute Dialysis Quality Initiative (ADQI) group. Crit Care 2004;8:R204–12. Karkouti K, Wijeysundera DN, Yau TM, et al. Acute kidney injury after cardiac surgery: focus on modifiable risk factors. Circulation 2009;119:495–502. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney injury prediction following elective cardiac surgery: AKICS score. Kidney Int 2007;72:624–31. Brown JR, Cochran RP, Leavitt BJ, et al. Multivariable prediction of renal insufficiency developing after cardiac surgery. Circulation 2007;116:I139–43. Mariscalco G, Lorusso R, Dominici C, Renzulli A, Sala A. Acute kidney injury: a relevant complication after cardiac surgery. Ann Thorac Surg 2011;92:1539–47. Shroyer AL, Grover FL, Hattler B, et al; for the Veterans Affairs Randomized On/Off Bypass (ROOBY) Study Group. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med 2009;361:1827–37. Lamy A, Devereaux PJ, Prabhakaran D, et al; for the CORONARY investigators. Off-pump or on-pump coronary artery bypass grafting at 30 days. N Engl J Med 2012;366: 1489–97. Garg AX, Devereaux PJ, Yusuf S, et al. Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY): kidney substudy analytic protocol of an international randomised controlled trial. BMJ Open 2012;2:e001080. Seabra VF, Alobaidi S, Balk EM, et al. Off-pump coronary artery bypass surgery and acute kidney injury: a metaanalysis of randomized controlled trials. Clin J Am Soc Nephrol 2010;5:1734–44. Wijeysundera DN, Beattie WS, Djaiani G, et al. Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol 2005;46:872–82.
DISCUSSION DR MARC RUEL (Ottawa, Ontario, Canada): I think this is very interesting. The renal story with off-pump is very complicated. As you know, recently there was a task force from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) that met together, and this was led by Davy Cheng and Janet Martin. We pulled the data from the randomized controlled trials (RCTs), and there was benefit on 30-day renal injury of offpump vs on-pump surgery. Now, there have been large series before that have carefully propensity matched those patients, including ours, that Dr Elmistekawy presented at the American Association for Thoracic Surgery (AATS) 2 years ago with thousands of patients; we, to our surprise, found no difference. And we looked at the data from all sides, and as off-pump enthusiasts, we couldn’t find anything. It is very intriguing that now in an RCT setting, you, similarly, don’t find anything. With this in mind, I think the difference may be technical, a little bit like graft patency. Perhaps we keep our off-pump patients a little bit too underfilled? Off-pump coronary artery
bypass grafting (OPCAB) patients tend to come out of the operating room with central venous pressures (CVPs) of 7, 6, 5, and we don’t really jump on it, while the on-pump patients come out with CVPs of 14, 15, plus they already have this third space volume that might help preserve their renal function. Thus careful goals of care and resuscitation for OPCAB patients might help better tease out the real benefits of off-pump surgery on renal function. Dr Guyton, any comments? DR ROBERT A. GUYTON (Atlanta, GA): I agree entirely with you, Marc. The question is whether or not your database contains sufficient information about the perioperative management with regard to vasopressors and the intakes and outputs and so forth and the status of the patient arriving in the intensive care unit, and I presume, unfortunately, since this was an industrysponsored study primarily, it probably does not have that data. With this wealth of patients randomized, the question is not on-pump vs off-pump, but can you tease out some lessons for us or some areas to create hypotheses for perioperative
Ann Thorac Surg 2014;-:-–-
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
7
management, because I do think this is a fertile ground for investigation and improvement in our therapies.
perhaps it is not the best thing for the kidneys. Certainly at my institution, I don’t think that we jump on this enough.
DR REENTS: Two things to say about that. First, I disagree that the German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) trial was an industrysponsored trial. This was an investigator-initiated trial. We wanted to investigate the potential benefit of off-pump coronary artery bypass grafting (CABG), especially in the particularly vulnerable group of elderly patients. This was a randomized trial comparing two surgical techniques, off-pump or on-pump CABG, with the best possible supportive care afterward. Patient management during and after surgery was done according to the respective institutional practice. The only difference was if the patient was operated on on-pump or off-pump.
DR ELSAYED ELMISTEKAWY (Ottawa, Ontario, Canada): A good presentation. We have studied and published a case-matched study dealing with this same, and we came to the conclusion almost identical to you. My question is, should we take the renal function out from the equation of selecting onpump, off-pump for our patients? Thank you.
DR GUYTON: I didn’t mean to imply the study was tainted in any way. I just meant that it is more likely that the data gathering might have been a little less expensive and that these days it is very difficult to include all the pieces in your data that you want, and I suspect that it is not there. DR REENTS: But I think we should just stick to the point that it was a randomized trial comparing on-pump and offpump CABG. And what has changed in recent years I think is that there are now new data from several randomized trials accurately designed and executed. I refer to the talk by Dr Shroyer about the Veterans Affairs Randomized On/Off Bypass (ROOBY) trial and the Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study (CORONARY) trial and ours, which are large-scale trials comparing on-pump and off-pump CABG. DR GUYTON: So much of the important discoveries have been serendipitous discoveries in the analyses of databases that were not necessarily part of the original intent, and that was my question, as to whether or not there is sufficient data to try to tease out other suggestive therapies in this large group. But I am fine with you sticking with your original intent. DR RUEL: I think Dr Guyton’s point is, also, that a patient coming out of the operating room with a CVP of 7 may not be interpreted as bad perioperative care. It may be just something that we leave with little bit of Levophed at 0.05 mg/kg/min, but
DR RUEL: The question is should we stop determining whether we are going to allocate on-pump vs off-pump based on the potential preservation of renal function? What is your opinion? DR REENTS: The intent of this investigation was to look at if you got a particular benefit for a dedicated technique regarding kidney function, because we know that even subtle impairments in kidney function are associated with increased mortality. So it may be a nice surrogate parameter looking at it. It was triggered by the CORONARY results seeing that they had a benefit with off-pump CABG. It was just a post hoc exploratory analysis of our GOPCABE study data. DR JOHN D. PUSKAS (Atlanta, GA): I have a comment. When we have a patient with impaired renal function going to the operating room for coronary revascularization, that has to be one of our important foci in that operation, and whether we choose to do the operation on-pump with perhaps higher than usual pump pressures, mean arterial pressures, or off-pump taking care to be well volume resuscitated and avoiding hypotension, avoiding high doses of pressors, we can take care of those kidneys with either operative strategy. And when we do, we usually take care of the kidneys at the expense of the lung with either operative strategy. If you want to be wet and well perfused with the kidneys in the intensive care unit, you may have a slightly more difficult time getting that patient extubated promptly. So those are strategies that apply to either operative approach. DR REENTS: I would absolutely agree with that. The most important thing is what happens with hemodynamics within the operating room. If you do an off-pump operation, you have to stay tuned with excellent hemodynamics, and the same is true if you go on-pump with that. But we couldn’t find a difference or a benefit for a specific technique.
Background. An exploratory analysis of the German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) trial was performed to investigate the effect of off-pump coronary artery bypass grafting (CABG) on kidney function after the operation. Methods. Data on kidney function were available from 1,612 patients, representing 67% of the study population. Preoperative kidney function was graded according to the glomerular filtration rate. Acute kidney injury (AKI) within the first week after the operation was defined and classified according to the Acute Kidney Injury Network (AKIN) criteria. The incidence and severity of AKI was compared between patients operated on on-pump or offpump. Results. Impaired kidney function was seen in 642 patients (40%), and 19 patients had preexisting end-stage kidney disease. AKI of any severity occurred in half of all patients undergoing CABG, with AKIN stage 1
accounting for most of the cases. The incidence and severity of AKI in patients undergoing on-pump vs offpump CABG was AKIN stage 1: 298 (37%) vs 329 (42%); AKIN stage 2: 38 (5%) vs 43 (5%); and AKIN stage 3: 44 (6%) vs 44 (6%), which did not differ significantly (p [ 0.174). New renal replacement therapy was necessary in 3.2% (on-pump) and in 2.7% (off-pump) of all patients. Stratification according to preoperative kidney function yielded comparable frequencies of AKI for on-pump and off-pump CABG. Conclusions. AKI was common in elderly patients undergoing CABG, but deterioration of kidney function requiring renal replacement therapy was a rare event. Off-pump CABG was not associated with decreased rates or reduced severity of AKI in elderly patients.
A
perioperative period, and the systemic inflammatory response induced by a major operation [1, 5, 6]. Off-pump coronary artery bypass grafting (CABG) may interfere with some of these factors. Cardiopulmonary bypass (CPB), with the contact of blood components to artificial surfaces, is a presumed cause of inflammation [2], and avoidance of CPB may therefore attenuate the systemic inflammatory response. The German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) study randomly assigned patients aged 75 years or older to CABG with (on-pump) or without (off-pump) CPB [7]. We speculated that CABG without CPB might influence the incidence and magnitude of AKI in an especially vulnerable patient population.
cute kidney injury (AKI) describes a clinical syndrome characterized by a sudden decline of the excretory kidney function, with accumulation of urea and creatinine and decreased urinary output [1]. After cardiac operations, AKI of varying severity occurs in up to onethird of all patients and approximately 2% require temporary renal replacement therapy [2]. The occurrence of an AKI is independently associated with increased shortterm and long-term death [3, 4]. A preventive or therapeutic strategy to mitigate the burden of AKI would therefore be of substantial value. The pathogenesis of AKI after cardiac operations is multifactorial and may develop from a combination of impaired autoregulation caused by comorbidities and drugs, affected renal perfusion due to altered hemodynamics during the operation and in the
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
Patients and Methods Accepted for publication Jan 28, 2014. Presented at the Fiftieth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 25–29, 2014. Address correspondence to Dr Reents, Cardiovascular Clinic Bad Neustadt, Salzburger Leite 1, 97616 Bad Neustadt, Germany; e-mail: wilko. [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
GOPCABE Study The GOPCABE study was a controlled, randomized, multicenter trial conducted from June 2008 through September 2011 at 12 German institutions. The study was approved by the respective ethics committee of each participating center, and all patients provided written, 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.01.088
2
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
informed consent. Patients were randomly assigned to CABG with or without CPB. Patients scheduled for isolated, first-time CABG were eligible if they were aged at least 75 years. Exclusion criteria were any additional cardiovascular disease necessitating a concomitant operation, previous pericardiotomy, any condition requiring an immediate (ie, within 24 hours after hospital admission) surgical procedure, a planned minimally invasive direct CABG procedure (CABG using left anterior thoracotomy), or the inability or unwillingness of the patient to provide consent. Randomization was performed after the baseline patient data, including the target vessels, had been entered into a central, Internet-based, password-protected data template. Treatment assignment was according to a blocked randomization scheme with a blinded block length of 8, stratified according to the participating center. The primary end point of the GOPCABE study was a composite of death or major adverse events (myocardial infarction, stroke, acute renal failure requiring dialysis, repeat revascularization) within 30 days and at 1 year after the operation. The trial was registered at www. clinicaltrials.gov, trial number NCT00719667.
Chronic Kidney Disease and AKI The initial GOPCABE trial protocol did not include numerical recording of baseline creatinine values, nor was a detailed analysis of kidney function planned as a prespecified end point. For post hoc exploratory analysis of kidney function in a large patient sample randomly assigned to on-pump or off-pump CABG, we asked all participating centers to provide the serum creatinine values before and from day 0 to day 7 after CABG. The glomerular filtration rate (GFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation: 186 (serum creatinine/88.4)1.154 (age)0.203 (0.742 if female). Kidney function before CABG was graded from I to V according to the GFR as proposed by the Kidney Disease Outcome Quality Initiative [8]. In this classification, kidney function is defined as normal with a GFR of more than 89 mL/min/1.73 m2 (stage I), minimally reduced with a GFR between 60 and 89 mL/min/1.73 m2 (stage II), moderately reduced with a GFR between 30 and 59 mL/min/1.73 m2 (stage III), severely reduced with a GFR between 15 and 29 mL/min/1.73 m2 (stage IV), and end-stage kidney failure with a GFR below 15 mL/min/ 1.73 m2 or renal replacement therapy (stage V). Patients with preexisting stage V chronic kidney disease were excluded from further analysis of postoperative kidney function. AKI within the first week after CABG was defined and classified according to the criteria proposed by the Acute Kidney Injury Network (AKIN) [9] as AKIN stage 1: increase creatinine 1.5 from baseline or increase of >0.3 mg/dL within 48 hours; AKIN stage 2: increase creatinine 2 from baseline; and AKIN stage 3: increase in creatinine 3 from baseline or creatinine >4 mg/dL with an acute increase >0.5 mg/dL within 48 hours or new-onset renal replacement therapy. The incidence and severity of AKI was compared between patients operated
Ann Thorac Surg 2014;-:-–-
on on-pump or off-pump. Comparison of AKI was further stratified according to preoperative kidney function.
Statistical Analysis Analysis was done on an intention-to-treat basis. The continuity-corrected c2 test was used for comparison of the incidence and various degrees of AKI between patients operated on on-pump or off-pump. Mantel-Haenszel c2 tests were used to adjust for study center effects. Baseline characteristics were compared with the c2 test, t test, or Kruskal-Wallis test, as appropriate. Dichotomous data are presented as number and percentage. Continuous data are shown as mean or median and standard deviation. All statistical analyses were performed with SPSS 20.0 software (IBM Corp, Armonk, NY).
Results From June 2008 to September 2011 the GOPCABE study randomly assigned 2,539 patients to on-pump or offpump CABG. Exclusion after randomization for various reasons and loss to follow-up resulted in 2,394 patients available for analysis. A detailed description of patient enrollment has been published previously [7]. Serum creatinine values were obtained from 1,612 patients (67%) of the GOPCABE study population. Excluded from further analysis were 19 patients who had preexisting end-stage kidney failure (CKD stage V) before CABG. The remaining 1,593 patients constituted the study population for the evaluation of kidney function and AKI after CABG. CABG procedures were on-pump in 804 patients and off-pump in 789. The baseline characteristics are reported in Table 1 [10, 11] and were well balanced between both groups. The only exception was a higher percentage of patients with insulin-dependent diabetes mellitus randomized to off-pump CABG (13.9% vs 10.2%). The mean age was 78 years (range, 75 to 90 years), and approximately one-third of the patients were women. Myocardial infarction had occurred previously in 37%, and left ventricular function was impaired in 32%. The extent of coronary artery disease was 3-vessel disease or left main stem involvement in 89% of the patients. As expected in this age group, comorbid conditions, such as peripheral vascular disease, previous stroke, or a history of atrial fibrillation, were present in a substantial proportion of patients. Kidney function and the degree of chronic kidney disease before CABG was well balanced between both groups (Table 2 [8]). Kidney function was impaired in 638 patients (40%), with a GFR below 60 mL/min/1.73 m2 (CKD stage III to IV). AKI of any severity occurred in 793 patients (50%), with AKIN stage 1 accounting for most of the cases (Table 3 [9, 12]). There was no significant difference in the incidence and severity of AKI in patients undergoing on-pump or off-pump CABG (p ¼ 0.174). Stratification according to preoperative kidney function yielded comparable frequencies of AKI for on-pump and off-pump CABG (Table 4; Figure 1 [9]). The incidence of acute renal failure requiring renal replacement therapy was similar between the groups, at 3.2% for on-pump and
Ann Thorac Surg 2014;-:-–-
Table 1. Baseline characteristics
a
Variable
Female gender Age, y Body mass index, kg/m2 Insulin-dependent diabetes mellitus Chronic obstructive pulmonary disease Peripheral vascular diseasec Pulmonary arterial hypertensiond Previous Stroke Myocardial infarction Percutaneous coronary intervention History of atrial fibrillation Implanted pacemaker Left ventricular ejection fraction >0.50 0.30–0.50 89 mL/min/1.73 m2) II (GFR 60–89 mL/min/1.73 m2) III (GFR 30–59 mL/min/1.73 m2) IV (GFR 15–29 mL/min/1.73 m2)
117 363 303 21
97 393 268 31
(14.6) (45.1) (37.7) (2.6)
(12.3) (49.8) (34) (3.9)
a
8.1 6.6 3.7 3.4
8.2 6.9 3.8 3.8
Continuous data are shown as the means standard deviation and b Statistical difference between dichotomous data as number (%). c groups indicated by p < 0.05. Includes cerebrovascular disease, peripheral arterial disease with stenosis >50% or occlusion or aortic aneud rysm at any site. Defined as a systolic pulmonary artery pressure e Defined as the presence of one or more of the following: >60 mm Hg. cardiogenic shock or resuscitation within 48 hours before hospital admission, mechanical ventilation, inotropic support or intraaortic balloon f pump. The operative risk was estimated on the basis of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) [10] and the Koronar Chirurgie score [11]. The Koronar Chirurgie score is constructed yearly using the current registry data of all coronary artery bypass grafting procedures in Germany.
Renal function is graded from I to IV according to the classification proposed by the Kidney Disease Outcome Quality Initiative [8].
CABG ¼ coronary artery bypass grafting; rate.
GFR ¼ glomerular filtration
large sample of elderly patients undergoing CABG [7]. One component of the combined end point was acute renal failure requiring new renal replacement therapy, which occurred within 30 days after surgery in 2.4% of the patients assigned to off-pump CABG and in 3.1% assigned to on-pump CABG (p ¼ 0.36). A more detailed analysis of kidney function after CABG was feasible in two-thirds of the original study population, and the findings can be summarized as follows: 1. At baseline, 40% of all patients aged older than 75 years had impaired kidney function (GFR 0.3 mg/dL within 48 hours; RIFLE risk: increased creatinine 1.5 from baseline; AKIN stage 2, RIFLE injury: increased creatinine 2 from baseline; AKIN stage 3, RIFLE failure: increased creatinine 3 from baseline or creatinine >4 mg/dL with an increase >0.5 mg/dL within 48 hours or new-onset renal replacement therapy. CABG ¼ coronary artery bypass grafting.
4
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
Ann Thorac Surg 2014;-:-–-
Table 4. Acute Kidney Injury Stratified According to Kidney Function At Baselinea
Variable
Preserved Renal Function No. (%)
AKI 1 No. (%)
AKI 2 No. (%)
AKI 3 No. (%)
New-Onset RRT No. (%)
30-Day Mortality No. (%)
78 (67) 67 (69)
32 (27) 26 (27)
6 (5) 2 (2)
1 (1) 2 (2)
. .
. .
219 (60) 215 (55)
112 (31) 152 (39)
17 (5) 18 (5)
15 (4) 8 (2)
8 (2) 3 (1)
8 (2.2) 9 (2.3)
118 (39) 86 (32)
149 (49) 139 (52)
15 (5) 22 (8)
21 (7) 21 (8)
15 (5) 12 (5)
8 (2.6) 6 (2.2)
9 (43) 5 (16)
5 (24) 12 (39)
. 1 (3)
7 (33) 13 (42)
I (GFR >89 mL/min/1.73 m2) On-pump Off-pump II (GFR 60–89 mL/min/1.73 m2) On-pump Off-pump III (GFR 30–59 mL/min/1.73 m2) On-pump Off-pump IV (GFR 15–29 mL/min/1.73 m2) On-pump Off-pump
3 (14) 6 (19)
1 (4.8) 2 (6.5)
a
Preoperative renal function is graded from I to IV according to the classification proposed by the Kidney Disease Outcome Quality Initiative [8]. Acute kidney injury (AKI) as defined and classified according to the criteria proposed by the Acute Kidney Injury Network [9].
CABG ¼ coronary artery bypass grafting;
GFR ¼ glomerular filtration rate;
accounting for most cases. New renal replacement therapy was necessary in 3% of all patients. 3. AKI of any severity occurred more frequently in patients with impaired kidney function before CABG. 4. Event rates of AKI were similar for off-pump and on-pump CABG. In patients with preexisting kidney disease, the surgical technique had no detectable effect on the incidence or severity of AKI. Preexisting kidney disease has been repeatedly identified as a strong predictor of AKI after operations [13–16]. The GOPCABE study population included a substantial proportion of patients with impaired kidney function preoperatively. Our findings may therefore be especially applicable to a particularly vulnerable patient population with preexisting kidney disease. The rate of 3% requiring new renal replacement therapy is within the reported range of 1% to 6% [16], yet ranging at the upper boundary. Two recent, large-scale randomized
Fig 1. Acute kidney injury (AKI), as defined and classified according to the criteria proposed by the Acute Kidney Injury Network (AKIN) [9], is shown stratified according to kidney function at baseline (red ¼ preserved renal function; green ¼ AKI 1; light blue ¼ AKI 2; dark blue ¼ AKI 3) and illustrates the data in Table 4. (I–IV ¼ renal function before CABG, graded from I to IV according to the classification proposed by the Kidney Disease Outcome Quality Initiative [8]; y-axis ¼ number of patients.)
RRT ¼ renal replacement therapy.
trials investigated off-pump and on-pump CABG [17, 18]. The percentage of patients with preexisting kidney disease, defined as serum creatinine exceeding 1.5 mg/dL, was 7.9% in the Veterans Affairs Randomized On/Off Bypass (ROOBY) trial population. Although the incidence of AKI was not reported, new renal replacement therapy within 30 days after the operation was necessary for 0.9% of all patients [17]. The primary publication of the Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study (CORONARY) trial did not report the rate of patients with preexisting kidney disease [18]; however, Garg and associates [19] performed a detailed analysis evaluating kidney function of the CORONARY patient population. Here 23% (717 of 3,089 patients) had preexisting kidney disease as defined by a GFR of less than 60 mL/min. Overall, 1.2% of these patients needed new renal replacement therapy, 0.6% of the patients with preserved kidney function and 3.1% of those with
Ann Thorac Surg 2014;-:-–-
preexisting kidney disease. It is therefore reasonable to assume that the 3% rate of new renal replacement therapy in the GOPCABE study population was primarily caused by the high number of patients with impaired kidney function at baseline. AKI of any severity as defined by the AKIN [1] was a common event that occurred in half of all patients, and AKIN stage 1 accounted for most patients. Applying the AKIN criteria, AKI rates in the range of 30% have been reported [13, 18]. The AKIN criteria may be quite sensitive for detecting subtle changes in kidney function, especially the creatinine increase of 0.3 mg/dL within 48 hours. But this criterion might be misleading if the creatinine values obtained within 24 hours after CABG (day 0 and day 1) are included. The increase on the day of the operation and the subsequent drop of the estimated GFR, as shown in Figure 2, probably does not reflect changes in kidney function. A more plausible explanation is that the decrease of creatinine values on the day of CABG is caused by hemodilution and that the following GFR decrease is also influenced by normalization of water homeostasis. The initial RIFLE (risk of renal dysfunction; injury to the kidney; failure of kidney function; loss of kidney function; and end-stage kidney disease) criteria [12] do not include the creatinine increase within 48 hours for defining the mildest form of AKI (RIFLE category: risk), whereas the RIFLE categories injury and loss are similar to AKIN stage 2 and 3, respectively. AKI defined according to the RIFLE criteria may therefore avoid an artificially high rate caused by initial hemodilution but may miss more subtle changes of kidney function thereafter. Analysis of our data by applying the RIFLE criteria resulted in lower rates of AKI (Table 3). Here only 26% of
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
5
all patients had AKI of any severity (RIFLE categories: risk, injury, or failure). Remaining to be elucidated is which definition of AKI fits best to describe meaningful changes of kidney function within the first week after CABG. Each definition of AKI leads to similar results between off-pump and on-pump CABG, underscoring the robustness of our findings. In a large patient sample that included a substantial proportion of patients with an increased risk for AKI, we were unable to detect any effect of the surgical technique on kidney function after CABG. The effect of off-pump CABG on kidney function is still controversial. Observational and randomized studies comparing on-pump and off-pump CABG both found conflicting evidence, and available meta-analyses also reached contradictory results [16]. An evaluation of AKI across 22 randomized trials with 4,819 patients found a 40% relative risk reduction associated with off-pump CABG [20]. But as stated in the accompanying editorial, “different definitions of AKI used in the individual trials and methodological concerns precluded definitive conclusions about the treatment effect.” A meta-analysis encompassing more than 240,000 patients found a benefit for off-pump CABG only in the observational studies (odds ratio, 0.54; 95% confidence interval, 0.39 to 0.77), whereas the difference was not significant in the aggregate randomized trials (odds ratio, 0.61; 95% confidence interval, 0.25 to 1.47) [21]. Actually, the largest single randomized trial (CORONARY) found an absolute 4.1% risk reduction of any AKI for off-pump CABG, defined according to the AKIN criteria [18]. This reduced risk was entirely caused by a decreased occurrence of AKI stage 1 within 30 days after CABG. More
Fig 2. Mean glomerular filtration rate after on-pump (blue line) and off-pump (red line) coronary artery bypass grafting (CABG).
6
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
severe forms of AKI or new renal replacement therapy were similar between both groups. A detailed analysis of early and late kidney function in the CORONARY study population is anticipated [19]. In summary, we found that AKI was common in elderly patients undergoing CABG. Mild forms of AKI accounted for the most of the cases. With 1,593 patients, of whom 40% had impaired kidney function at baseline, this study actually represents the largest high-risk patient sample evaluating kidney function after on-pump or off-pump CABG in a randomized trial. Off-pump CABG was not associated with decreased rates or reduced severity of AKI in elderly patients.
Ann Thorac Surg 2014;-:-–-
10. 11.
12.
13. 14.
References 1. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet 2012;380:756–66. 2. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006;1:19–32. 3. Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes in serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 2004;15:1597–605. 4. Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Longterm risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 2009;53:961–73. 5. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med 2007;357:797–805. 6. Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis and therapy. J Clin Invest 2004;114:5–14. 7. Diegeler A, B€ orgermann J, Kappert U, et al; for the GOPCABE Study Group. Off-pump versus on-pump coronary artery bypass grafting in elderly patients. N Engl J Med 2013;368:1189–98. 8. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: evaluation, classification, and stratification. Part 4: definition and classification of stages of chronic kidney disease. Am J Kidney Dis 2002;39(Suppl 1):S46–75. 9. Mehta RL, Kellum JA, Shah SV, et al; and the Acute Kidney Injury Network. Acute Kidney Injury Network: report of an
15. 16. 17.
18.
19.
20.
21.
initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. Roques F, Michel P, Goldstone AR, Nashef SA. The logistic EuroSCORE. Eur Heart J 2003;24:1–2. Badreldin AM, Kania A, Ismail MM, et al. KCH, the German preoperative score for isolated coronary artery bypass surgery: is it superior to the logistic EuroScore? Thorac Cardiovasc Surg 2011;59:399–405. Bellomo R, Ronco C, Kellum JA, Metha RL, Palevsky P, and the ADQI workgroup. Acute renal failure–definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the Acute Dialysis Quality Initiative (ADQI) group. Crit Care 2004;8:R204–12. Karkouti K, Wijeysundera DN, Yau TM, et al. Acute kidney injury after cardiac surgery: focus on modifiable risk factors. Circulation 2009;119:495–502. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney injury prediction following elective cardiac surgery: AKICS score. Kidney Int 2007;72:624–31. Brown JR, Cochran RP, Leavitt BJ, et al. Multivariable prediction of renal insufficiency developing after cardiac surgery. Circulation 2007;116:I139–43. Mariscalco G, Lorusso R, Dominici C, Renzulli A, Sala A. Acute kidney injury: a relevant complication after cardiac surgery. Ann Thorac Surg 2011;92:1539–47. Shroyer AL, Grover FL, Hattler B, et al; for the Veterans Affairs Randomized On/Off Bypass (ROOBY) Study Group. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med 2009;361:1827–37. Lamy A, Devereaux PJ, Prabhakaran D, et al; for the CORONARY investigators. Off-pump or on-pump coronary artery bypass grafting at 30 days. N Engl J Med 2012;366: 1489–97. Garg AX, Devereaux PJ, Yusuf S, et al. Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY): kidney substudy analytic protocol of an international randomised controlled trial. BMJ Open 2012;2:e001080. Seabra VF, Alobaidi S, Balk EM, et al. Off-pump coronary artery bypass surgery and acute kidney injury: a metaanalysis of randomized controlled trials. Clin J Am Soc Nephrol 2010;5:1734–44. Wijeysundera DN, Beattie WS, Djaiani G, et al. Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol 2005;46:872–82.
DISCUSSION DR MARC RUEL (Ottawa, Ontario, Canada): I think this is very interesting. The renal story with off-pump is very complicated. As you know, recently there was a task force from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) that met together, and this was led by Davy Cheng and Janet Martin. We pulled the data from the randomized controlled trials (RCTs), and there was benefit on 30-day renal injury of offpump vs on-pump surgery. Now, there have been large series before that have carefully propensity matched those patients, including ours, that Dr Elmistekawy presented at the American Association for Thoracic Surgery (AATS) 2 years ago with thousands of patients; we, to our surprise, found no difference. And we looked at the data from all sides, and as off-pump enthusiasts, we couldn’t find anything. It is very intriguing that now in an RCT setting, you, similarly, don’t find anything. With this in mind, I think the difference may be technical, a little bit like graft patency. Perhaps we keep our off-pump patients a little bit too underfilled? Off-pump coronary artery
bypass grafting (OPCAB) patients tend to come out of the operating room with central venous pressures (CVPs) of 7, 6, 5, and we don’t really jump on it, while the on-pump patients come out with CVPs of 14, 15, plus they already have this third space volume that might help preserve their renal function. Thus careful goals of care and resuscitation for OPCAB patients might help better tease out the real benefits of off-pump surgery on renal function. Dr Guyton, any comments? DR ROBERT A. GUYTON (Atlanta, GA): I agree entirely with you, Marc. The question is whether or not your database contains sufficient information about the perioperative management with regard to vasopressors and the intakes and outputs and so forth and the status of the patient arriving in the intensive care unit, and I presume, unfortunately, since this was an industrysponsored study primarily, it probably does not have that data. With this wealth of patients randomized, the question is not on-pump vs off-pump, but can you tease out some lessons for us or some areas to create hypotheses for perioperative
Ann Thorac Surg 2014;-:-–-
REENTS ET AL AKI AFTER ON-PUMP OR OFF-PUMP CABG IN ELDERLY
7
management, because I do think this is a fertile ground for investigation and improvement in our therapies.
perhaps it is not the best thing for the kidneys. Certainly at my institution, I don’t think that we jump on this enough.
DR REENTS: Two things to say about that. First, I disagree that the German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) trial was an industrysponsored trial. This was an investigator-initiated trial. We wanted to investigate the potential benefit of off-pump coronary artery bypass grafting (CABG), especially in the particularly vulnerable group of elderly patients. This was a randomized trial comparing two surgical techniques, off-pump or on-pump CABG, with the best possible supportive care afterward. Patient management during and after surgery was done according to the respective institutional practice. The only difference was if the patient was operated on on-pump or off-pump.
DR ELSAYED ELMISTEKAWY (Ottawa, Ontario, Canada): A good presentation. We have studied and published a case-matched study dealing with this same, and we came to the conclusion almost identical to you. My question is, should we take the renal function out from the equation of selecting onpump, off-pump for our patients? Thank you.
DR GUYTON: I didn’t mean to imply the study was tainted in any way. I just meant that it is more likely that the data gathering might have been a little less expensive and that these days it is very difficult to include all the pieces in your data that you want, and I suspect that it is not there. DR REENTS: But I think we should just stick to the point that it was a randomized trial comparing on-pump and offpump CABG. And what has changed in recent years I think is that there are now new data from several randomized trials accurately designed and executed. I refer to the talk by Dr Shroyer about the Veterans Affairs Randomized On/Off Bypass (ROOBY) trial and the Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study (CORONARY) trial and ours, which are large-scale trials comparing on-pump and off-pump CABG. DR GUYTON: So much of the important discoveries have been serendipitous discoveries in the analyses of databases that were not necessarily part of the original intent, and that was my question, as to whether or not there is sufficient data to try to tease out other suggestive therapies in this large group. But I am fine with you sticking with your original intent. DR RUEL: I think Dr Guyton’s point is, also, that a patient coming out of the operating room with a CVP of 7 may not be interpreted as bad perioperative care. It may be just something that we leave with little bit of Levophed at 0.05 mg/kg/min, but
DR RUEL: The question is should we stop determining whether we are going to allocate on-pump vs off-pump based on the potential preservation of renal function? What is your opinion? DR REENTS: The intent of this investigation was to look at if you got a particular benefit for a dedicated technique regarding kidney function, because we know that even subtle impairments in kidney function are associated with increased mortality. So it may be a nice surrogate parameter looking at it. It was triggered by the CORONARY results seeing that they had a benefit with off-pump CABG. It was just a post hoc exploratory analysis of our GOPCABE study data. DR JOHN D. PUSKAS (Atlanta, GA): I have a comment. When we have a patient with impaired renal function going to the operating room for coronary revascularization, that has to be one of our important foci in that operation, and whether we choose to do the operation on-pump with perhaps higher than usual pump pressures, mean arterial pressures, or off-pump taking care to be well volume resuscitated and avoiding hypotension, avoiding high doses of pressors, we can take care of those kidneys with either operative strategy. And when we do, we usually take care of the kidneys at the expense of the lung with either operative strategy. If you want to be wet and well perfused with the kidneys in the intensive care unit, you may have a slightly more difficult time getting that patient extubated promptly. So those are strategies that apply to either operative approach. DR REENTS: I would absolutely agree with that. The most important thing is what happens with hemodynamics within the operating room. If you do an off-pump operation, you have to stay tuned with excellent hemodynamics, and the same is true if you go on-pump with that. But we couldn’t find a difference or a benefit for a specific technique.
