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Clinical Investigations: SURGERY |

Off-Pump Coronary Revascularization Attenuates Transient Renal Damage Compared With On-Pump Coronary Revascularization* FREE TO VIEW

Berthus G. Loef, MD; Anne H. Epema, PhD; Gerjan Navis, PhD; Tjark Ebels, PhD; Wim van Oeveren, PhD; Robbert H. Henning, PhD
Author and Funding Information

*From the Cardiothoracic ICU (Dr. Loef), the Department of Anesthesiology (Dr. Epema), the Department of Nephrology (Dr. Navis), the Department of Cardiopulmonary Surgery (Drs. Ebels and van Oeveren), and the Department of Clinical Pharmacology (Dr. Henning), University Hospital Groningen, Groningen, the Netherlands.

Correspondence to: Berthus G. Loef, MD, Cardiothoracic ICU, Department of Cardiopulmonary Surgery, University Hospital Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands; e-mail: B.G.Loef@thorax.azg.nl



Chest. 2002;121(4):1190-1194. doi:10.1378/chest.121.4.1190
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Study objectives: Cardiopulmonary bypass (CPB) represents a specific risk factor for renal damage during coronary revascularization. The purpose of this study was to compare the perioperative renal damage in patients undergoing on-pump and off-pump coronary surgery.

Design and patients: The progress and extent of renal damage was prospectively studied in two groups of patients undergoing cardiac surgery without concomitant morbidity, undergoing elective coronary revascularization with (n = 12) and without (n = 10) CPB. Markers of glomerular function (creatinine clearance) and damage (microalbuminuria), and markers of tubular function (fractional excretion of sodium [FENa] and free water clearance) and damage (N-acetyl-β-D glucosaminidase [NAG]) were evaluated. Measuring plasma concentrations of free hemoglobin assessed hemolysis. Plasma and urinary specimens were obtained at the following points: (1) baseline; (2) heparinization; (3) the end of CPB or completing graft for off-pump surgery; (4) skin closure; (5) the sixth hour in the ICU; and (6) the second postoperative day. Free water and creatinine clearances, FENa, and the urinary excretion of microalbumin and NAG were calculated for the corresponding time intervals.

Setting: University hospital.

Results: We found that off-pump coronary revascularization induced significantly less changes in microalbuminuria, FENa, free water clearance, NAG, and free hemoglobin as compared with operations with CPB. Markers returned to baseline within 2 days after the operation, and there was no clinical or laboratory evidence of overt renal dysfunction in both groups.

Conclusion: Off-pump coronary surgery attenuates transient renal injury compared with traditional on-pump coronary artery bypass grafting.

Figures in this Article

Renal dysfunction is a serious complication of coronary revascularization with cardiopulmonary bypass (CPB) and results in increased morbidity, mortality, and prolonged hospital stay.1 The pathogenesis of this complication is usually multifactorial. General risk factors associated with postoperative renal dysfunction are preexisting renal disease, advanced age, and postoperative low cardiac output state.12 In addition, CPB represents a specific risk factor during cardiac surgery. The injurious action of CPB on renal function is caused by several mechanisms, including nonpulsatile perfusion and increased levels of circulating catecholamines, cytokines, and free hemoglobin.3These effects result in damage to glomerular as well as tubular structures that, in turn, can produce renal dysfunction especially in the presence of additional risk factors.4The renal risk associated with CPB may be avoided by a new surgical technique, off-pump coronary revascularization, which is performed on the beating heart and hence does not use CPB.5 This study assessed the contribution of CPB to perioperative renal damage by obtaining functional parameters and levels of specific markers related to glomerular and tubular function in patients undergoing on-pump and off-pump coronary revascularization.

Patients

After institutional approval and informed consent, we prospectively studied consecutive patients scheduled for elective on-pump (n = 12) and off-pump (n = 10) coronary artery revascularization. Included were patients with a normal renal function as assessed by a serum creatinine level of < 120 μmol/L and normal urinalysis findings. All patients had one-vessel or two-vessel disease and normal cardiac index (ejection fraction > 45%) and cerebral and hepatic function. None of the patients received angiotensin-converting enzyme inhibitors or diuretics. Patients with diabetes, recent myocardial infarction, hypertension, unstable angina, or recent use of radiocontrast were excluded, because these conditions are associated with increased baseline levels of the urinary markers used in this study. The choice of the procedure was at the surgeon’s discretion.

Anesthetic Management

Anesthesia was administered according to a fixed protocol. Premedication consisted of diazepam, 10 to 15 mg po, 2 h preoperatively. After insertion of peripheral venous and radial arterial cannulae under local analgesia, anesthesia was induced with sufentanil, 2.5 μg/kg, and midazolam, 0.1 mg/kg. Tracheal intubation was achieved with pancuronium, 0.1 mg/kg, and the lungs were ventilated with air and oxygen (fraction of inspired oxygen of 0.4). A flow-directed pulmonary artery catheter was inserted into the right internal jugular vein, and an indwelling bladder catheter was used for urine collection. Anesthesia was maintained with sufentanil, midazolam, and pancuronium.6 After induction, hydroxyethyl starch 6% solution and lactated Ringer’s solution were used to obtain a mean arterial pressure (MAP) of > 60 mm Hg to maintain filling pressures and cardiac output. Transfusions of packed cells were administered at a hemoglobin level < 5.5 mmol/L. In the ICU, inotropic support with dopamine was started at a cardiac index < 2.2 L/min/m2. Diuretics or mannitol were not used during this study.

CPB

All CPB patients received dexamethasone, 1 mg/kg, after the induction of anesthesia according to the standard of care in our institution. Nonpulsatile CPB was performed with a roller pump and flat sheet membrane oxygenator (Cobe Excel; Cobe Laboratories; Lakewood, CO). The extracorporeal circuit was primed with 500 mL of hydroxyethyl starch 6% and 1,000 mL of lactated Ringer’s solution. Flow during CPB was maintained at 2.2 L/min/m2 during moderate hypothermia (32°C) with α-stat regulation of blood pH. Cold St. Thomas solution was infused into the aortic root to maintain cardioplegia during aortic cross-clamping. During CPB, the MAP was allowed to vary between 60 mm Hg and 90 mm Hg. Deviations beyond this range were corrected with phenylephrine or nitroglycerine administration. All patients for the off-pump procedure also received 500 mL of hydroxyethyl starch 6% and lactated Ringer’s infusion to maintain MAP before grafting. In both groups, distal anastomoses were completed first.

Renal Markers

Glomerular function was determined by measuring creatinine clearance, while tubular function was assessed from fractional excretion of sodium (FENa) and free water clearance. In addition, the urinary albumin excretion was used as an index of glomerular capillary damage, while tubular damage was estimated from the excretion of N-acetyl-β-D-glucosaminidase (NAG). Destruction of RBCs during the operation was measured by changes in the plasma concentration of free hemoglobin. Plasma and urinary osmolality, serum concentrations of sodium and creatinine, and urinary concentrations of sodium, creatinine, microalbumin, and NAG were measured during six periods: (1) at baseline, induction of anesthesia; (2) after heparinization; (3) at the end of CPB in the on-pump group and completion of the last distal anastomosis in the off-pump group; (4) at skin closure; (5) at the end of the first 6 h in the ICU; and (6) on the second postoperative day. From these data, the FENa, free water, and creatinine clearances, and the urinary excretion of microalbumin and NAG for the corresponding time intervals were calculated by standard formulas.

Laboratory Methods

Urine samples were stored at − 20°C for the determination of sodium, creatinine, osmolality, albumin, and NAG. Plasma samples were transported to the laboratory immediately, and sodium, creatinine, free hemoglobin, and osmolality were determined using a Vitros analyzer (Ortho Clinical Diagnostics; Beerse, Belgium) and an Osmomat analyzer (Gonotec; Salm and Kipp; the Netherlands). Urine microalbumin was determined by a nephelometric method according to the instructions of the manufacturer (DADE-Behring;Leusden, the Netherlands). Urinary NAG was measured by the colorimetric method of Lockwood and Bosmann.7

Statistical Analysis

The number of patients in both groups was calculated to detect a difference of 50% between the studied markers with a power of 0.8 and an α risk of 0.05. Results are presented as mean ± SEM unless stated otherwise. Measurements of microalbumin and NAG are expressed as ratio to creatinine concentration to correct for changes in urinary flow. The results were analyzed using two-way repeated analysis of variance, Student’s t test, Mann-Whitney test, χ2 test, or correlation analysis. Statistical significance was accepted at p < 0.05.

The two patient groups were similar in age, sex, weight, height, and preoperative serum creatinine level (Table 1 ). All patients had an uneventful operation and postoperative stay. The use of blood transfusions (on-pump, 0.58 ± 0.15 U of 220 mL; off-pump, 0.40 ± 0.16 U, p = 0.9) and inotropic support (p = 0.39) was not different in both groups. There was no clinical or laboratory evidence of overt postoperative renal dysfunction in either group. Urine output during surgery and in the postoperative period did not differ between groups (Fig 1 ), suggesting that renal perfusion was equally adequate.

The time course of the renal glomerular variables is shown in Figure 2 , top left, A, and middle left, B. At baseline, glomerular variables were similar and within the normal range in both groups. Glomerular function, assessed from creatinine clearance, remained unaffected in both groups throughout the entire observation period (Fig 2, top left, A). During the first postoperative hours, a transient but statistically not significant increase in calculated creatinine clearance was observed in off-pump patients. Urinary microalbumin excretion, a marker of glomerular capillary damage, was increased in the on-pump group, showing a peak at the end of CPB, followed by a gradual return to baseline values at the second postoperative day (Fig 2, middle, B). In contrast, urinary microalbumin excretion did not change in the in the non-CPB patients.

The time course of tubular variables is given in Figure 2, bottom left, C; top right, D; and bottom right, E. At baseline, no differences between variables were found. Fractional excretion of sodium increased significantly in the on-pump patients after the start of bypass, with a return to baseline only at the second postoperative day, while no change was observed in the off-pump patients (Fig 2, bottom right, C). Free water clearance was significantly decreased during bypass in on-pump patients but was unaffected in off-pump patients (Fig 2, top right, D). Finally, urinary excretion of NAG was increased during bypass but afterwards returned to baseline values (Fig 2, bottom right, E). Urinary NAG excretion remained at baseline levels in off-pump patients during the entire period. Furthermore, we evaluated the differences in the number of anastomoses and duration of surgery (Table 1) and the glomerular and tubular injury by performing correlation analysis. No correlation was found between the number of anastomoses, the duration of surgery, and the parameters expressed in the area under curve values within the on-pump group (data not shown).

To confirm damage to erythrocytes during CPB, plasma levels of free hemoglobin were measured. Plasma levels of free hemoglobin were normal before bypass in both groups. As anticipated, free hemoglobin increased during bypass in the on-pump patients, but remained unchanged in the off-pump patients (Fig 3 ).

This study in cardiac surgical patients with normal preoperative renal function shows that CPB induces transient renal injury, as evidenced by a decrease in tubular function and increased levels of markers of glomerular and tubular damage. Changes in these parameters were essentially confined to the intraoperative and immediate postoperative period and returned to baseline levels within 2 days. In contrast, these parameters did not change in the off-pump patients. Baseline measurements of parameters of glomerular and tubular damage were the same in both groups, indicating that the observed renal injury was confined to the intraoperative period.

The presence of glomerular damage in CPB patients was reflected by the increase of microalbuminuria in the absence of detectable changes in creatinine clearance. Glomerular damage is presumably due to transient impairment of the glomerular capillary permselectivity.8Possibly, a reduction in tubular reabsorption of filtered albumin further contributes to the microalbuminuria in CPB patients.9 Tubular cell damage in CPB patients was evidenced by a decreased tubular sodium reabsorption, a decreased free water clearance, and the increase in urinary excretion of NAG, a specific and sensitive marker for loss of tubular cell integrity.

This is the first study combining functional measurements and assessment of damage parameters demonstrating a preservation of renal function in off-pump surgery compared with CPB. The increase in FENa, microalbuminuria, and NAG obtained in patients undergoing coronary revascularization with CPB is in agreement with those reported previously.1012 However, the time course of changes in NAG found in our CPB patient group differs noticeably from that reported previously.12 Whereas we observed normalization in CPB within 2 days postoperatively, NAG excretion did not return to baseline values by then in the study of Ascione et al.12Further, although both studies found a reduction of renal damage in the off-pump group, a similar discrepancy in time course was observed for the excretion of NAG and microalbuminuria. This difference in time course may have been caused by differences in patient characteristics or perioperative treatment, such as hemodynamic management, recent use of radiocontrast, or nephrotoxic medication. The values of free hemoglobin observed in this study are in the range reported for CPB.13 Increased hemolysis during CPB may be caused by cardiotomy suction, high suction pressures, duration of perfusion, occlusive roller pumps, and turbulent flow in the oxygenator.

CPB-associated renal dysfunction is attributed to multiple factors.3Although these factors may cause renal impairment by themselves, they are merely thought to set the stage for additional insults, including low cardiac output or hypotension, to elicit overt CPB-associated renal failure.4 The results obtained in our study are in agreement with this supposition. In accordance with the low risk status of the patients, no overt renal functional impairment was apparent during or after surgery. Off-pump cardiac surgery in our study prevents transient renal injury. At present, it is still unclear to what extent the preservation of the beating heart during surgery prevents acute renal failure.

A limitation of this study is that it was observational and not randomized. However, the groups consisted of consecutive patients, and the patient characteristics and baseline measurements were similar. We studied healthy patients, because several studies1415 demonstrated increased levels of renal markers in patients with diabetes, hypertension, and vascular disease. These concomitant renal risk factors were excluded in this study to avoid additional influence on the levels of these markers. In conclusion, this study in low-risk patients shows that on-pump coronary surgery induces reversible subclinical renal damage both at the glomerular and tubular levels, whereas off-pump revascularization attenuates this damage.

Abbreviations: CPB = cardiopulmonary bypass; FENa = fractional excretion of sodium; MAP = mean arterial pressure; NAG = N-acetyl-β-D-glucosaminidase

Table Graphic Jump Location
Table 1. Patient Characteristics and Operative Data*
* 

Data are presented as mean ± SEM unless otherwise indicated.

Figure Jump LinkFigure 1. Urine output in the groups studied (mean ± SEM) at five sample points: (1) heparinization, (2) end of bypass or completion of distal anastomoses in off-pump group, (3) skin closure, (4) first 6 h in the ICU, and (5) second postoperative day.Grahic Jump Location
Figure Jump LinkFigure 2. Changes in creatinine clearances (Cl Creat; top left, A), microalbuminuria (MA; middle left, B), FENa (bottom left, C), free water clearance (Cl water; top right, D), and urinary NAG (bottom right, E) in the two groups studied (mean ± SEM) at five sample points: (1) heparinization; (2) end of bypass or completion of distal anastomoses; (3) skin closure; (4) first 6 h in the ICU; and (5) second postoperative day. creat = creatinine.Grahic Jump Location
Figure Jump LinkFigure 3. Changes in plasma-free hemoglobin (Hb) in the two groups studied (mean ± SEM) at five sample points: (1) heparinization; (2) end of bypass or completion of distal anastomoses in off-pump group; (3) skin closure; (4) first 6 h in the ICU; and (5) second postoperative day. Normal range for free hemoglobin is 0 to 20 μmol/L.Grahic Jump Location

The authors thank H. John Krijnen for assistance in preparing the manuscript.

Mangano, CM, Diamondstone, LS, Ramsay, JG, et al (1998) Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization.Ann Intern Med128,194-203. [PubMed]
 
Conlon, PJ, Stafford-Smith, M, White, WD, et al Acute renal failure following cardiac surgery.Nephrol Dial Transplant1999;14,1158-1162. [PubMed] [CrossRef]
 
Ramsay, JG The respiratory, renal, and hepatic systems: effect of cardiac surgery and cardiopulmonary bypass. Mora, CT eds.Cardiopulmonary bypass1995,147-168 Springer-Verlag. New York, NY:
 
Hilberman, M, Myers, BD, Carrie, BJ, et al Acute renal failure following cardiac surgery.Thorac Cardiovasc Surg1979;77,880-888
 
Mariani, MA, Boonstra, PW, Grandjean, JG, et al Minimally invasive coronary artery bypass grafting without cardiopulmonary bypass.Eur J Cardiothorac Surg1997;11,881-887. [PubMed]
 
Van der Maaten, JM, Epema, AH, Huet, RC, et al The effect of midazolam at two plasma concentrations on hemodynamics and sufentanil requirement in coronary artery surgery.J Cardiothorac Vasc Anesth1996;10,356-363. [PubMed]
 
Lockwood, TD, Bosmann, HB The use of urinary N-acetyl-β-glucosaminidase in human renal toxicology: II. Partial biochemical characterization and excretion in humans and release from the isolated perfused rat kidney.Toxicol Appl Pharmacol1979;49,323-336. [PubMed]
 
Brezis, M, Rosen, S Hypoxia of the renal medulla: its implication for disease.N Engl J Med1995;332,647-655. [PubMed]
 
Eppel, GA, Osicka, TM, Pratt, LM, et al The return of glomerular-filtered albumin to the rat renal vein.Kidney Int1999;55,1861-1870. [PubMed]
 
Westhuyzen, J, McGiffin, DC, McCarthy, J, et al Tubular nephrotoxicity after cardiac surgery utilising cardiopulmonary bypass.Clin Chim Acta1994;228,123-132. [PubMed]
 
Ip-Yam, PC, Murphy, S, Baines, M, et al Renal function and proteinuria after cardiopulmonary bypass: the effects of temperature and mannitol.Anesth Analg1994;78,842-847. [PubMed]
 
Ascione, R, Lloyd, CT, Underwood, MJ, et al On-pump versus off-pump coronary revascularization: evaluation of renal function.Ann Thorac Surg1999;68,493-498. [PubMed]
 
De Somer, F, Foubert, L, Vanackere, M, et al Impact of oxygenator design on hemolysis, shear stress, and white blood cell and platelet counts.J Cardiothorac Vasc Anesth1996;10,884-889. [PubMed]
 
Guder, WG, Hofmann, W Markers for the diagnosis and monitoring of renal tubular lesions.Clin Nephrol1992;38,S3-S7. [PubMed]
 
Winocour, PH Microalbuminuria.BMJ1992;304,1196-1197. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Urine output in the groups studied (mean ± SEM) at five sample points: (1) heparinization, (2) end of bypass or completion of distal anastomoses in off-pump group, (3) skin closure, (4) first 6 h in the ICU, and (5) second postoperative day.Grahic Jump Location
Figure Jump LinkFigure 2. Changes in creatinine clearances (Cl Creat; top left, A), microalbuminuria (MA; middle left, B), FENa (bottom left, C), free water clearance (Cl water; top right, D), and urinary NAG (bottom right, E) in the two groups studied (mean ± SEM) at five sample points: (1) heparinization; (2) end of bypass or completion of distal anastomoses; (3) skin closure; (4) first 6 h in the ICU; and (5) second postoperative day. creat = creatinine.Grahic Jump Location
Figure Jump LinkFigure 3. Changes in plasma-free hemoglobin (Hb) in the two groups studied (mean ± SEM) at five sample points: (1) heparinization; (2) end of bypass or completion of distal anastomoses in off-pump group; (3) skin closure; (4) first 6 h in the ICU; and (5) second postoperative day. Normal range for free hemoglobin is 0 to 20 μmol/L.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Patient Characteristics and Operative Data*
* 

Data are presented as mean ± SEM unless otherwise indicated.

References

Mangano, CM, Diamondstone, LS, Ramsay, JG, et al (1998) Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization.Ann Intern Med128,194-203. [PubMed]
 
Conlon, PJ, Stafford-Smith, M, White, WD, et al Acute renal failure following cardiac surgery.Nephrol Dial Transplant1999;14,1158-1162. [PubMed] [CrossRef]
 
Ramsay, JG The respiratory, renal, and hepatic systems: effect of cardiac surgery and cardiopulmonary bypass. Mora, CT eds.Cardiopulmonary bypass1995,147-168 Springer-Verlag. New York, NY:
 
Hilberman, M, Myers, BD, Carrie, BJ, et al Acute renal failure following cardiac surgery.Thorac Cardiovasc Surg1979;77,880-888
 
Mariani, MA, Boonstra, PW, Grandjean, JG, et al Minimally invasive coronary artery bypass grafting without cardiopulmonary bypass.Eur J Cardiothorac Surg1997;11,881-887. [PubMed]
 
Van der Maaten, JM, Epema, AH, Huet, RC, et al The effect of midazolam at two plasma concentrations on hemodynamics and sufentanil requirement in coronary artery surgery.J Cardiothorac Vasc Anesth1996;10,356-363. [PubMed]
 
Lockwood, TD, Bosmann, HB The use of urinary N-acetyl-β-glucosaminidase in human renal toxicology: II. Partial biochemical characterization and excretion in humans and release from the isolated perfused rat kidney.Toxicol Appl Pharmacol1979;49,323-336. [PubMed]
 
Brezis, M, Rosen, S Hypoxia of the renal medulla: its implication for disease.N Engl J Med1995;332,647-655. [PubMed]
 
Eppel, GA, Osicka, TM, Pratt, LM, et al The return of glomerular-filtered albumin to the rat renal vein.Kidney Int1999;55,1861-1870. [PubMed]
 
Westhuyzen, J, McGiffin, DC, McCarthy, J, et al Tubular nephrotoxicity after cardiac surgery utilising cardiopulmonary bypass.Clin Chim Acta1994;228,123-132. [PubMed]
 
Ip-Yam, PC, Murphy, S, Baines, M, et al Renal function and proteinuria after cardiopulmonary bypass: the effects of temperature and mannitol.Anesth Analg1994;78,842-847. [PubMed]
 
Ascione, R, Lloyd, CT, Underwood, MJ, et al On-pump versus off-pump coronary revascularization: evaluation of renal function.Ann Thorac Surg1999;68,493-498. [PubMed]
 
De Somer, F, Foubert, L, Vanackere, M, et al Impact of oxygenator design on hemolysis, shear stress, and white blood cell and platelet counts.J Cardiothorac Vasc Anesth1996;10,884-889. [PubMed]
 
Guder, WG, Hofmann, W Markers for the diagnosis and monitoring of renal tubular lesions.Clin Nephrol1992;38,S3-S7. [PubMed]
 
Winocour, PH Microalbuminuria.BMJ1992;304,1196-1197. [PubMed]
 
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