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Ann Thorac Surg 1998;65:1316-1319
© 1998 The Society of Thoracic Surgeons

Intravenous Diltiazem and Acute Renal Failure After Cardiac Operations

Eric W. Young, MDa, Anas Diab, MDa, Marvin M. Kirsh, MDa

a Nephrology and Cardiothoracic Surgery Sections, Veterans Affairs Medical Center and University of Michigan Medical School, Ann Arbor, Michigan, USA

Accepted for publication December 18, 1997.

Address reprint requests to Dr Young, Nephrology Section (111-J), VA Medical Center, 2215 Fuller Rd, Ann Arbor, MI 48105


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Perioperative administration of intravenous diltiazem to patients undergoing cardiac procedures has been shown to decrease the incidence of ischemia and arrhythmias. However, after adopting this practice in our cardiac surgery program, we perceived an increased incidence of postoperative renal dysfunction.

Methods. A directed record review of postoperative renal function was conducted for consecutive patients undergoing cardiac operation for the time periods before and after adoption of prophylactic intravenous diltiazem (0.1 mg · kg-1 · h-1 for 24 hours). The two groups were compared using {chi}2 and two-sample t tests. The risk of development of postoperative renal failure was modeled with logistic regression.

Results. Diltiazem-treated patients (n = 271) were similar to the control patients (n = 143) in terms of age (64 versus 61 years; p = 0.14), ejection fraction (0.46 versus 0.47; p = 0.61), baseline serum creatinine level (1.2 versus 1.1 mg/dL; p = 0.27), prevalence of comorbid conditions, and surgical characteristics. The prevalence of left main coronary artery disease was lower in the diltiazem group than the control group (39% versus 52%; p = 0.01). During the 7-day postoperative period, the average peak serum creatinine level was higher in the diltiazem group (1.7 ± 0.9 mg/dL; mean ± 1 standard deviation) than the control group (1.5 ± 0.5 mg/dL; p = 0.003). The incidence of acute renal failure requiring dialysis was 4.4% in the diltiazem group versus 0.7% in the control group (p = 0.04). There was no difference in length of hospitalization or mortality. The risk of acute renal failure was strongly associated with intravenous diltiazem (adjusted odds ratio [AOR] 6.3; p = 0.08), age (AOR 2.5 per 10 years; p = 0.07), baseline serum creatinine (AOR 4.8 per 1 mg/dL; p = 0.02), the presence of left main coronary disease (AOR 5.3; p = 0.02), and the presence of cerebrovascular disease (AOR 4.5; p = 0.05).

Conclusions. Our retrospective analysis suggests that prophylactic use of intravenous diltiazem in patients undergoing cardiac operations was associated with increased renal dysfunction. Further studies of the risk and benefits of intravenous diltiazem in this setting should be undertaken.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Several studies have shown that prophylactic, perioperative infusion of intravenous diltiazem to patients undergoing cardiac operation lowers the postoperative incidence of cardiac ischemia and arrhythmias [1–5]. On the basis of emerging favorable evidence for this treatment, we began administering intravenous diltiazem to all patients undergoing cardiac procedures. After institution of this practice, we perceived an increased incidence of mild azotemia and acute renal failure. On the basis of this clinical observation, we undertook a systematic evaluation of renal function in the postoperative period. This evaluation suggested a deleterious renal effect of intravenous diltiazem and prompted a change in our practice.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
The study was an observational record review conducted at the Ann Arbor Veterans Affairs Medical Center, a regional referral center for cardiac operation within the Veterans Affairs system. All cardiac procedures and protocols are directed by a single attending surgeon. Both the surgeon and the major practice protocols were well established for several years before the time period of the study. The practice of routinely administering intravenous diltiazem to every patient undergoing a cardiac operation was initiated in August 1993 based on published reports of efficacy and safety. In general, diltiazem was started after initiation of anesthesia at a dose of 0.1 mg · kg-1 · h-1 and was continued for 24 hours. Patients were believed to show satisfactory results in terms of postoperative cardiac ischemia and arrhythmias.

For this study, a standardized set of data was collected retrospectively for consecutive patients who had undergone cardiac operations before and after adoption of the diltiazem protocol. The hospital computer information system was the major source for clinical, laboratory, catheterization, operative, and outcome data. Additional information was obtained from records maintained by the dialysis unit and the cardiac surgery service. Laboratory data were specifically obtained for the first 7 days of the postoperative period. Acute renal failure was defined by dialysis treatment for the usual clinical indications.

The diltiazem-treated patients were compared with the group of patients who underwent operation immediately before August 1993 and who had not received diltiazem. Baseline characteristics and outcome data were compared using the two-sample t test for continuous data and the {chi}2 test for categorical data. The risk of developing acute renal failure requiring dialysis was modeled using logistic regression. Covariates were selected on an empiric, interactive basis, guided by univariate comparisons and clinical judgment. Analyses were performed with SAS (version 6.10, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Data were available for essentially all patients who underwent cardiac operation from 1/1/93 until 9/30/94 when the routine administration of intravenous diltiazem ceased. All patients underwent coronary artery bypass grafting and 16% also underwent valve procedures. Baseline characteristics for the historic control group and the diltiazem-treated patients are shown in Table 1. The two groups were similar in terms of age, baseline serum creatinine concentration, cardiac function, comorbid conditions, and duration of aortic cross-clamping and bypass pump exposure. Among measured characteristics, the groups differed only in the prevalence of left main coronary artery disease, which was more common in the control group.


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  		Table 1. Baseline Characteristics by Intravenous Diltiazem Treatment Status

 
Several important clinical outcomes are shown in Table 2. During the postoperative period, the peak serum creatinine concentration (taken as the maximum value during the first 7 postoperative days) and the change in serum creatinine were significantly higher in the diltiazem-treated group compared with the control group. As shown in Figure 1, the serum creatinine concentration gradually diverged in the two groups, reaching significance on day 6 after operation. The incidence of acute renal failure requiring dialytic intervention was also significantly higher in the diltiazem group (4.4%) than in the control group (0.7%). There were no significant differences in length of hospitalization or mortality in these generally elderly male patients with multiple comorbid conditions (Table 2).


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  		Table 2. Clinical Outcomes by Intravenous Diltiazem Treatment Status

 


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  		Fig 1. Time course of serum creatinine concentration (mean ± standard error of the mean) after cardiac operation in patients who received (solid line) and did not receive (dotted line) intravenous diltiazem. The ordinate scale is collapsed to better illustrate group differences. The groups were significantly different at day 6 (p = 0.02) and day 7 (p = 0.004).

 
The probability of development of acute renal failure requiring dialysis was modeled to determine whether other measured factors were confounding the apparent effect of intravenous diltiazem (Table 3). The diltiazem effect was robust to the modeling process with an adjusted odds ratio of 6.3 in the final model (p = 0.08). The risk of development of acute renal failure was also strongly associated with age, baseline serum creatinine concentration, the presence of left main coronary artery occlusion, and cerebrovascular disease. The Homer-Lemeshow goodness of fit statistic yielded a p value of 0.91, allowing rejection of the hypothesis of no fit between the data and model. The rescaled R2 value of the model was 0.30.


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  		Table 3. Logistic Regression Model of Predictors of Acute Renal Failure

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
This observational study examined the association between exposure to intravenous diltiazem and renal dysfunction after a cardiac operation. A consecutive group of patients who received intravenous diltiazem were compared with a earlier group of patients who had not received diltiazem. The measured baseline characteristics of the two groups were similar except for a higher prevalence of left main coronary artery disease in the control group (Table 1). The peak serum creatinine concentration after operation was significantly higher in the diltiazem group than in the control group. The daily creatinine concentration slowly diverged in the two groups throughout the 7-day observation period. More important, the incidence of acute renal failure requiring dialysis, although quite low overall, was significantly higher in the diltiazem group than in the control group. Mortality and duration of hospitalization were not significantly different, although there was a trend toward longer hospitalization in the diltiazem group.

The major limitation of the study is the lack of prospective randomization. Although there were no known differences in surgical procedures between the two study periods other than the introduction of intravenous diltiazem, we cannot exclude a subtle, systematic, unmeasured difference in practice that could have confounded the attribution of renal dysfunction to intravenous diltiazem. We attempted to limit the possibility of confounding by using multivariate regression to model the risk of acute renal failure, adjusting for measured characteristics (Table 3). With this approach, the risk of acute renal failure was strongly associated with the administration of intravenous diltiazem, although the association was of borderline statistical significance (p = 0.08) owing to the relatively small number of cases with acute renal failure. Nonetheless, the large magnitude of the risk (adjusted odds ratio, 6.3) suggests that the effect is clinically important and independent of other measured clinical characteristics.

Risk factors have been studied for acute renal failure in a variety of settings [6–8], including cardiac operation [9–13]. In addition to intravenous diltiazem, we found several other factors that predicted the development of acute renal failure (Table 3). The risk of acute renal failure increased 2.5-fold with every 10-year increment in age. Age has been identified as a risk factor in other studies of acute renal failure [6, 7, 11–13] and is potentially explained by the decline in renal function and functional reserve capacity with aging. An elevated baseline serum creatinine also predicted the subsequent development of acute renal failure with a 4.8-fold increase in risk for every 1 mg/dL increment in serum creatinine concentration. This association is also well described [8–13] and, as for age, undoubtedly relates to decreased renal reserve capacity. Patients with left main coronary artery disease and cerebrovascular disease had a substantially higher risk of developing acute renal failure. These conditions are probably markers for both severity of coronary disease and the presence of generalized atherosclerosis, perhaps including the renal arteries. Left main coronary artery disease was an important risk factor, although it was more prevalent in the control group.

The observed association between diltiazem and renal dysfunction is noteworthy because calcium channel blockers have been shown to have some efficacy in the prevention or treatment of acute renal failure [14–19]. The putative efficacy of these drugs relates to lowering the intracellular concentration of calcium, an important factor in acute cellular injury [20–22]. At least one study involving patients undergoing cardiac operations found that intravenous diltiazem ameliorated the decline in renal function in the immediate 10-hour postoperative period [19]. However, renal function and outcomes were not followed beyond 10 hours and studies in other clinical situations have found that calcium channel blockers were not helpful for preserving renal function or preventing renal failure [23, 24]. It is likely that the effect of calcium channel blockers on renal function depends on the agent, route of delivery, and clinical situation because these agents have the potential to influence many determinants of kidney function including cellular metabolism and systemic hemodynamics.

The mechanism by which renal dysfunction may have occurred in our patients is unclear. One obvious possibility is that systemic blood pressure was lower in the diltiazem-treated patients, resulting in decreased renal perfusion and hemodynamically mediated prerenal azotemia. However, the delayed onset of azotemia among diltiazem-treated patients and the development of acute renal failure requiring dialysis in some patients are more consistent with renal injury (ie, acute tubular necrosis) than with prerenal azotemia. Nonetheless, low blood pressure could have contributed to the development of acute renal failure.

Intravenous diltiazem is indicated for the acute treatment of supraventricular tachyarrhythmias. The drug is given as a bolus injection or as a continuous infusion for up to 24 hours at doses similar to what we used. Our findings suggest that the risk of renal failure is increased when diltiazem is administered as an infusion in the setting of cardiopulmonary bypass. Clinicians who use intravenous diltiazem in this fashion should be alert to potential renal complications.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Doctor Young was supported by a Health Services Research and Development Career Development Award from the Department of Veterans Affairs.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Hannes W., Fasol R., Zajonc H., et al. Diltiazem provides anti-ischemic and anti-arrhythmic protection in patients undergoing coronary bypass grafting. Eur J Cardiothorac Surg 1993;7:339-345.
  2. Donegani E., Costa P., De Paulis R., et al. Myocardial protection by perioperative diltiazem drip: a clinical evaluation. Thorac Cardiovasc Surg 1986;34:168-171.[Medline]
  3. Brautigam P., Just H., Freudenberg N. Treatment with diltiazem preoperatively in open heart surgery for myocardial protection: experimental studies in dogs with chronic healed myocardial infarction. Clin Cardiol 1990;13:837-840.[Medline]
  4. Koike R. The protective effect of diltiazem, a calcium channel blocker on myocardial ischemia during open heart surgery—an analysis of electrolyte changes in myocardial cells. Nippon Kyobu Geka Gakkai Zasshi 1990;38:358-369.[Medline]
  5. Seitelberger R., Hannes W., Gleichauf M., Keilich M., Christoph M., Fasol R. Effects of diltiazem on perioperative ischemia, arrhythmias, and myocardial function in patients undergoing elective coronary bypass grafting. J Thorac Cardiovasc Surg 1994;107:811-821.[Abstract/Free Full Text]
  6. Wilkins R.G., Faragher E.B. Acute renal failure in an intensive care unit: incidence, prediction and outcome. Anaesthesia 1983;38:628-634.[Medline]
  7. Shusterman N., Strom B.L., Murray T.G., Morrison G., West S.L., Maislin G. Risk factors and outcome of hospital-acquired acute renal failure. Clinical epidemiologic study. Am J Med 1987;83:65-71.[Medline]
  8. Novis B.K., Roizen M.F., Aronson S., Thisted R.A. Association of preoperative risk factors with postoperative acute renal failure. Anesth Analg 1994;78:143-149.[Abstract/Free Full Text]
  9. Yeboah E.D., Petrie A., Pead J.L. Acute renal failure and open heart surgery. Br Med J 1972;1:415-418.
  10. Frost L., Pedersen R.S., Lund O., Hansen O.K., Hansen H.E. Prognosis and risk factors in acute, dialysis-requiring renal failure after open-heart surgery. Scand J Thorac Cardiovasc Surg 1991;25:161-166.[Medline]
  11. Andersson L.G., Ekroth R., Bratteby L.E., Hallhagen S., Wesslen O. Acute renal failure after coronary surgery—a study of incidence and risk factors in 2009 consecutive patients. Thorac Cardiovasc Surg 1993;41:237-241.[Medline]
  12. Zanardo G., Michielon P., Paccagnella A., et al. Acute renal failure in the patient undergoing cardiac operation. Prevalence, mortality rate, and main risk factors. J Thorac Cardiovasc Surg 1994;107:1489-1495.[Abstract/Free Full Text]
  13. Mangos G.J., Brown M.A., Chan W.Y.L., Horton D., Trew P., Whitworth J.A. Acute renal failure following cardiac surgery: incidence, outcomes and risk factors. Aust NZ J Med 1995;25:284-289.[Medline]
  14. Wagner K., Albrecht S., Neumayer H.H. Prevention of posttransplant acute tubular necrosis by the calcium antagonist diltiazem: a prospective randomized study. Am J Nephrol 1987;7:287-291.[Medline]
  15. Schrier R.W., Burke T.J. Calcium-channel blockers in experimental and human acute renal failure. Adv Nephrol 1988;17:287-299.
  16. Russell J.D., Churchill D.N. Calcium antagonists and acute renal failure. Am J Med 1989;87:306-315.[Medline]
  17. Frei U., Harms A., Bakovic-Alt R., Pichlmayr R., Koch K.M. Calcium channel blockers for kidney protection. J Cardiovasc Pharmacol 1990;16:S11-S15.
  18. Tataranni G., Malacarne F., Farinelli R., et al. Beneficial effects of verapamil in renal-risk surgical patients. Ren Fail 1994;16:383-390.[Medline]
  19. Zanardo G., Michielon P., Rosi P., et al. Effects of a continuous diltiazem infusion on renal function during cardiac surgery. J Cardiothoracic Vasc Anesth 1993;7:711-716.[Medline]
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