Effects of the Postoperative Administration of Diltiazem on Renal Function After Coronary Artery Bypass Grafting

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1 Effects of the Postoperative Administration of Diltiazem on Renal Function After Coronary Artery Bypass Grafting Susumu Manabe, MD, Hiroyuki Tanaka, MD, PhD, Tomoya Yoshizaki, MD, Noriyuki Tabuchi, MD, PhD, Hirokuni Arai, MD, PhD, and Makoto Sunamori, MD, PhD Department of Cardiothoracic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan Accepted for publication June 25, Address reprint requests to Dr Tanaka, Tokyo Medical and Dental University, Graduate School of Medicine, Department of Cardiothoracic Surgery, Yushima, Bunkyo-ku, Tokyo , Japan; Background. Radial artery grafts are used for coronary artery bypass grafting (CABG), and postoperative antispasm therapy with diltiazem is performed widely. Some investigators have warned that diltiazem administration after cardiac surgery is harmful to renal function. We designed a retrospective study to investigate the renal and hemodynamic effects of the postoperative administration of diltiazem in patients undergoing CABG. Methods. Subjects were 90 consecutive CABG patients. All were treated with diltiazem during surgery (a 0.1 mg/kg bolus injection followed by continuous infusion at 2 g kg 1 min 1 ). In the 50 patients (diltiazem group) with a radial artery graft, intravenous diltiazem administration was continued until the oral intake of diltiazem (90 mg/d) was begun to avoid graft spasms. In the remaining 40 patients without a radial artery graft, diltiazem was not continued postoperatively (control group). Postoperative renal function, assessed by serum creatinine level and creatinine clearance, and hemodynamic variables (heart rate, arterial pressure, pulmonary wedge pressure, cardiac index, left ventricular stroke work index) was compared between the two groups. Results. Renal function: Serum creatinine concentrations on postoperative days 1 through 7 were lower, and the endogenous creatinine clearance in the early postoperative period was higher in diltiazem group than in control group, although the differences were not significant. Hemodynamics: Heart rate was lower in diltiazem group than in the control group, but blood pressure, pulmonary wedge pressure, cardiac index, left ventricular stroke work index, and urinary output were similar between the groups. Conclusions. Our results confirmed that intravenous diltiazem treatment in patients undergoing CABG is not harmful to renal function. (Ann Thorac Surg 2005;79:831 6) 2005 by The Society of Thoracic Surgeons Diltiazem, a benzothiazepine calcium blocker, is reported to have various antivasospastic, myocardial protective, and antiarrhythmic effects and is commonly used perioperatively during cardiac surgery [1]. We previously investigated the renal effect of the continuous intraoperative administration of diltiazem and verified its protective effect [2]. Because of the benefits of intravenous diltiazem, we have used it routinely in all patients during cardiac surgery. During the last decade, use of this drug to prevent postoperative graft spasms has increased because of the widespread use of the radial artery (RA) for coronary artery bypass grafting (CABG) [3]. In 1999, we also began to use the RA as the second or third arterial graft in addition to the left internal mammary artery in CABG procedures. Intravenous diltiazem was continued after intraoperative administration to avoid postoperative spasms in patients undergoing CABG with an RA graft. Young and colleagues [4] reported, however, that intravenous diltiazem administration during the perioperative period could lead to renal dysfunction. After this report, a few conflicting reports appeared on the effects of diltiazem on renal function in surgical patients [5, 6], and the controversy regarding the actual renal effect of intravenous diltiazem was unresolved. Therefore, we conducted a retrospective study to investigate the renal and hemodynamic effects of the postoperative administration of diltiazem in patients undergoing CABG. Patients and Methods The study group consisted of 90 consecutive patients who had undergone elective CABG in our department between 1998 and Patients undergoing emergency surgery and chronic dialysis patients were excluded from the study. Medical records were reviewed and data were extracted. All patients had informed consent based on the Helsinki Declaration regarding ethical principles of medical research involving human subjects. The RA graft was used in 50 of the 90 CABG patients. These 50 patients, who were treated with the continuous administration of diltiazem during and after surgery, comprised the diltiazem group. The remaining 40 patients did not receive an RA graft because RA grafting had not yet been introduced in our institution 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 832 MANABE ET AL Ann Thorac Surg RENAL EFFECT OF DILTIAZEM 2005;79:831 6 or because of positive Allen test results. Diltiazem was administered in these 40 patients only during surgery, and administration was discontinued after aortic declamping. These 40 patients comprised the control group. The operation was performed under moderate hypothermic (32 to 34 C) extracorporeal circulation at a flow rate of 2.4 L min 1 m 2 in all patients. Diltiazem was administered during the operation in both groups. The diltiazem was administered by a bolus injection of 0.1 mg/kg immediately after pericardiotomy and was continuously infused at 2 g kg 1 min 1 until aortic declamping. In the control group, diltiazem administration was discontinued when the aortic clamp was removed. In the diltiazem group, continuous administration was continued at 2 g kg 1 min 1 after declamping until the oral administration of diltiazem (90 mg/d) became possible. The plasma concentration of diltiazem was measured postoperatively in 4 patients randomly selected from the diltiazem group. Mean standard deviation (SD) plasma concentrations on day 1 and 2 after surgery were ng/ml and ng/ml, respectively. After the operation, cardiac output, heart rate, and blood pressure were determined in the intensive care unit (ICU) every 6 hours for 36 hours in both groups. Dobutamine and dopamine were used to maintain the cardiac index above 2.2 L min 1 m 2. Systolic blood pressure was maintained between 110 mm Hg and 140 mm Hg. Dopamine and norepinephrine were used to treat hypotension, and the continuous intravenous administration of nitroglycerine was used to control hypertension. When urinary output was 0.5 ml kg 1 h 1 or less, furosemide was used to increase it to at least 0.5 ml kg 1 h 1. Serum creatinine levels and endogenous creatinine clearance (CCr) were measured 48 hours before surgery as the baseline value for each patient. CCr was calculated as CCr urine creatinine level urine volume (ml/ min)/plasma creatinine level and was corrected for body surface area. Serum creatinine levels and endogenous CCr were measured every 6 hours for 36 hours after surgery in the ICU, and serum creatinine levels were checked every day after the patient was moved to the ward. Urine output was obtained by way of an indwelling urinary catheter. These measurement were made every 6 hours. All test results are expressed as mean SD. Hemodynamic variables and renal function assessed by serum creatinine concentration and endogenous CCr were compared between the two groups. Differences in preoperative values between the two groups concerning baseline patient characteristics were analyzed by Student s t test or Fisher s exact probability test. Differences in postoperative values between the two groups concerning renal or hemodynamic indices were compared by using analysis of variance with repeated measurements by mixed model. If the interaction between group and time existed, the comparison between groups was conducted by t test in each time point and then the p value was calculated by the Bonferroni method. Statistical significance was accepted at a p level of less than Results Patient Characteristics Patient characteristics are shown in Table 1. Significant differences were not observed between the two groups in age, sex, preoperative serum creatinine levels, preoperative CCr, preoperative left ventricular ejection fraction, aortic clamping time, extracorporeal circulation time, number of bypasses, patients who had inotropic support, or maximum infusion rate of dopamine, dobutamine, or norepinephrine. Severe renal dysfunction (creatinine 2.0 mg/dl) was not identified in any patient in either group, but moderate renal dysfunction (1.2 mg/dl creatinine 2.0 mg/dl), was identified in 5 patients (12.5%) in the control group and 6 patients (12%) in the diltiazem group. Renal Function Acute renal failure requiring hemodialysis did not occur in either group. A transient decrease in renal function was identified in 5 control group patients and in 2 diltiazem group patients, and each of these patients recovered gradually without hemodialysis. Changes in serum creatinine levels are shown in Figure 1. Serum creatinine levels were lower in the diltiazem group than in the control group at each time point, but the difference was not significant (p ). The serum creatinine level tended to rise on day 1 after surgery and gradually returned to the preoperative value by day 7 after surgery. Changes in endogenous CCr are shown in Figure 2. CCr values were higher in the diltiazem group than in the control group at each time point, but the difference was not significant (p ). In the control group, CCr was decreased at 6 hours after surgery but recovered gradually. In the diltiazem group, CCr did not decrease at 6 hours after surgery; it increased just after the operation was finished. Urinary output remained at similar levels in both groups and was not statistically different between the groups (Fig 3). Hemodynamics Changes in hemodynamics are shown in Figures 3 and 4. Heart rate was significantly lower (p ) in the diltiazem group than in the control group. Atrioventricular conduction block was not identified in any patient. Systolic blood pressure at all time points was maintained between 110 mm Hg and 140 mm Hg; there were no differences between the two groups. Cardiac index, pulmonary wedge pressure, and left ventricle stroke work index remained at a similar level in both groups and was not statistically different between the groups. Comment The perioperative intravenous infusion of diltiazem provides antiischemic and antiarrhythmic protection in pa-

3 Ann Thorac Surg MANABE ET AL 2005;79:831 6 RENAL EFFECT OF DILTIAZEM Table 1. Baseline Patient Characteristics in the Two Groups Control (n 40) Diltiazem (n 50) p Value Age (years) Sex ratio (male) Creatinine (mg/dl) CCr (ml min 1 m 2 ) LVEF (%) ACT (min) ECT (min) Vessels bypassed Inotropic support (%) DOA 5% 8% 0.68 DOB 100% 94% 0.25 NOR 65% 60% 0.67 Maximum infusion rate ( ) DOA DOB NOR ACT aortic clamping time; CCr creatinine clearance; DOA dopamine; DOB dobutamine; ECT extracorporeal circulation time; LVEF left ventricular ejection fraction; NOR norepinephrine. tients undergoing CABG [1]. Several studies have shown that diltiazem is useful in preventing a decrease in renal function secondary to cardiopulmonary bypass [2, 7]. Additionally, ever since reintroduction of the RA graft for CABG in the mid-1990s, diltiazem has been considered one of the most common antispasm treatments and has been widely used in patients undergoing CABG with an RA graft [3]. Young and colleagues [4] found in their retrospective study that the prophylactic use of intravenous diltiazem in CABG patients was associated with increased renal dysfunction. They reported that diltiazem administration during and after cardiac surgery caused an increased serum creatinine concentration and an increased incidence of acute renal failure that required dialysis. Their results conflicted with our previous results that intraoperative diltiazem infusion, which is one of our routine strategies for myocardial protection, also has a beneficial effect on postoperative renal function [2]. The reason for the contradictory findings is unclear. Thus, we retrospectively evaluated whether the postoperative continuous intravenous diltiazem infusion after intraoperative infusion negatively affects postoperative renal function in patients undergoing CABG. In the present study, serum creatinine levels did not increase during postoperative week 1 after intraoperative and postoperative diltiazem administration, suggesting that the intraoperative and subsequent administration of diltiazem was not associated with increased renal dysfunction. Similarly, CCr in the diltiazem group showed a higher tendency than that in the control group, although the difference was not significant. Continuous diltiazem treatment prevented the decline in CCr observed in the control group at 6 hours after surgery. These results may 833 Fig 1. Time course of serum creatinine concentration (mean standard deviation) in relation to coronary artery bypass grafting in control and diltiazem groups. The difference in serum creatinine concentration was not statistically significant between the groups (p ). suggest an additional renal protective effect by continuing intravenous diltiazem administration after surgery in CABG patients and do not support the suggestion by Young and colleagues that the use of diltiazem in cardiac surgery increases the risk of renal dysfunction. Our findings also conform with recent reports in which beneficial renal effects of diltiazem were noted in cardiac surgical patients [5, 7]. In general, the renal effects of Ca blockers are considered to reduce renal vascular resistance and increase renal blood flow [8, 9]: selective dilatation of the afferent arterioles increases the glomerular filtration rate (GFR) [9, 10], and increased amount of sodium are eliminated as a result of the Ca blocker s effect on the uriniferous tubules and the inhibition of aldosterone [11 13]. These pharmacologic properties can be applied to patients undergoing cardiac surgery. Our previous prospective study showed that diltiazem administration during cardiopulmonary bypass decreases renal vascular resistance and increases renal blood flow, resulting in an increased GFR [2]. Zanardo and colleagues [7] also reported from their prospective study that intraoperative and postoperative diltiazem administration increased GFR and urine output. Piper and associates [14] suggested that diltiazem may preserve renal tubular integrity after cardiac surgery Fig 2. Time course of endogenous creatinine clearance (mean standard deviation) in relation to coronary artery bypass grafting in control and diltiazem groups. The difference in endogenous creatinine clearance was not statistically significant between the groups (p ).

4 834 MANABE ET AL Ann Thorac Surg RENAL EFFECT OF DILTIAZEM 2005;79:831 6 Fig 3. Time course of hemodynamic variables (heart rate [top], systolic blood pressure [middle], and urine output [bottom]) after coronary artery bypass grafting in control and diltiazem groups. as assessed by the excretion of indicators of acute renal failure such as -glutathion S-transferase, -microglobulin, and N-acetyl-b-glucosaminidase. It is not clear why our results regarding the renal effect of diltiazem conflict with those of the Young group. However, we believe that one important factor regulating the renal effect of diltiazem is the systemic hemodynamic condition of the patient. The renal actions of Ca blockers are greatly affected by renal vascular tonus. Furthermore, the GFR-increasing action of Ca blockers is proven to disappear under hypotensive conditions [8]. Therefore, hemodynamic conditions should be carefully monitored when a Ca blocker is used. Seitelberger and colleagues [1] reported that the continuous administration of diltiazem (1.67 g min 1 kg 1 ) reduces heart rate significantly, although this is quite acceptable if no hemodynamic instability is present. However, Brodman and colleagues [15] encountered a 32% incidence of hypotension, bradycardia, or heart block during diltiazem treatment (1 g min 1 kg 1 ). Our postoperative strategy for management of CABG Fig 4. Time course of hemodynamic variables (cardiac index [top], pulmonary wedge pressure [middle] and left ventricular stroke work index [bottom]) after coronary artery bypass grafting in control and diltiazem groups. patients is to maintain blood pressure strictly between 110 mm Hg and 140 mm Hg. If hypotension occurs, we use a catecholamine aggressively to increase blood pressure above 110 mm Hg so as to maintain the driving pressure for in situ bypass grafts such as the internal mammary artery or the right gastroepiploic artery, which we routinely try to use as bypass grafts. Thus, we were able to achieve results similar to those of Seitelberger and colleagues [1] in regard to the hemodynamic consequences of diltiazem treatment. Although data are not provided in detail, Young and colleagues [4] reported that blood pressure tended to be rather low in their diltiazem group. As they pointed out, such hypotension after surgery may have negatively affected the kidneys. The difference in systemic blood pressure control between their study and that of the present study may explain the different effects on renal function. Furthermore, Yavuz and colleagues [5] reported that the combined use of diltiazem with dopamine increased CCr and osmotic and free water clearance, although diltiazem

5 Ann Thorac Surg MANABE ET AL 2005;79:831 6 RENAL EFFECT OF DILTIAZEM alone did not show a renal protective effect. Their results also support the importance of maintaining hemodynamic stability during diltiazem treatment. The present study was conducted in patients with almost normal renal function and the result cannot be extrapolated to patients with renal dysfunction. However, the effect of diltiazem on patients with renal dysfunction who underwent CABG was studied and reported by Bergman and colleagues [16]. They reported that diltiazem can be used safely in patients who have mild-to-moderate renal dysfunction and undergo cardiac surgery with cardiopulmonary bypass, because diltiazem was found to improve glomerular function 3 weeks after cardiac surgery. Limitations of the present study include the inherent confines of retrospective, nonrandomized data collection. Although the patients characteristics did not differ statistically, unmeasured variables affecting the selection of therapy may have confounded the analysis. The study period of the control group is earlier than that of the diltiazem group, because the control group included some patients operated on before the introduction of RA grafting in our institution. However, the fundamental operative procedure did not change during this period. The present study could not demonstrate the relevant renal protective effect of diltiazem. This might result from the relatively small patient number of our study to detect a small difference with a large variance in value of creatinine clearance between the groups. In conclusion, our retrospective study confirmed the safety of postoperative diltiazem antispasm therapy for CABG patients. Renal function was not impaired: creatinine clearance and creatinine concentration showed a favorable tendency, and maintenance of hemodynamic stability required only a small amount of inotropic support. References Seitelberger R, Hannes W, Gleichauf M, et al. Effects of diltiazem on perioperative ischemia, arrhythmias, and myocardial function in patients undergoing elective coronary bypass grafting. J Thorac Cardiovasc Surg 1994;107: Amano J, Suzuki A, Sunamori M, et al. Effect of calcium antagonist diltiazem on renal function in open heart surgery. Chest 1995;107: Acar C, Ramsheyi A, Pagny JY, et al. The radial artery for coronary artery bypass grafting: clinical and angiographic results at five years. J Thorac Cardiovasc Surg 1998;116: Young EW, Diab A, Kirsh MM. Intravenous diltiazem and acute renal failure after cardiac operations. Ann Thorac Surg 1998;65: Yavuz S, Ayabakan N, Goncu MT, et al. Effect of combined dopamine and diltiazem on renal function after cardiac surgery. Med Sci Monit 2002;8: Amar D, Fleisher M. Diltiazem treatment does not alter renal function after thoracic surgery. Chest 2001;119: Zanardo G, Michielon P, Rosi P, et al. Effects of a continuous diltiazem infusion on renal function during cardiac surgery. J Cardiothorac Vasc Anesth 1993;7: Rodger L, Epstein M. Effect of calcium antagonist on renal hemodynamics. Am J Physiol 1985;249:F Ohashi H, Ishiguro M, Yasue T, et al. Effects of diltiazem hydrochloride on the reduction of blood pressure, and cardiac and renal functions in essential hypertensive patients with renal dysfunction. Int J Clin Pharmacol Ther Toxicol 1987;25: Russell JD, Churchill DN. Calcium antagonists and acute renal failure. Am J Med 1989;87: Krishna GG, Riley LJ Jr., Deuter G, et al. Natriuretic effect of calcium-channel blockers in hypertensives. Am J Kidney Dis 1991;18: Reams GP, Lau A, Messina C, Villarreal D, Bauer JH. Efficacy, electrocardiographic and renal effects of intravenous diltiazem for essential hypertension. Am J Cardiol 1987;60:78I 84I. 13. Chellingsworth MC, Kendall MJ. Effects of nifedipine, verapamil and diltiazem on renal function. Br J Clin Pharmacol 1988;25: Piper SN, Kumle B, Maleck WH, et al. Diltiazem may preserve renal tubular integrity after cardiac surgery. Can J Anaesth 2003;50: Brodman RF, Frame R, Camacho M, et al. Routine use of unilateral and bilateral radial arteries for coronary artery bypass graft surgery. J Am Coll Cardiol 1996;28: Bergman AS, Odar-Cederlof I, Westman L, et al. Diltiazem infusion for renal protection in cardiac surgical patients with preexisting renal dysfunction. J Cardiothorac Vasc Anesth 2002;16: INVITED COMMENTARY In 1998, we reported a higher incidence of renal dysfunction and overt renal failure among cardiac surgery patients who were treated with intravenous diltiazem compared with a historical control group who did not receive diltiazem. Our analysis was prompted by a clinical perception of increased renal dysfunction after routine adoption of diltiazem therapy. The formal results were surprising because most prior studies had reported beneficial effects of diltiazem on kidney function. Nonetheless, we abandoned the routine use of diltiazem and published our experience both to inform others of a potential problem and to suggest the need for additional studies. Subsequently, several investigators apparently agreed that the matter deserved further study. Uniformly contrary results have been published by Yavuz and colleagues (reference 5), Amar and colleagues (reference 6), and now Manabe and associates. Amar and coworkers actually executed a randomized trial of diltiazem versus placebo in thoracic surgery patients, a noteworthy accomplishment that we could not match owing to the difficulty of recruiting patients into a trial with an undesirable primary outcome. These and earlier studies (including another study from the Tokyo group by Amano and colleagues) tend to refute the alleged harmful renal effects of intravenous diltiazem in this setting. Repetition of findings is one of the most important criteria for establishing the veracity of observational findings by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur