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Ann Thorac Surg 1995;59:132-136
© 1995 The Society of Thoracic Surgeons

Aprotinin for Coronary Artery Bypass Grafting: Effect on Postoperative Renal Function

Departments of Surgery and Radiology, The University of Iowa College of Medicine, Iowa City, Iowa, and Miles Inc, West Haven, Connecticut, and Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, and Department of Surgery, Deborah Heart and Lung Center, Brown Mills, New Jersey, and Departments of Radiology and Surgery, The University of Chicago, Chicago, Illinois, and Department of Cardiovascular Diseases and Section of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota

Accepted for publication July 16, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Two hundred sixteen patients undergoing coronary artery bypass graft procedures were randomized to receive either high-dose aprotinin or placebo. Clinically important postoperative renal insufficiency was infrequent, with a single patient (0.9%) from each group requiring dialysis. Although increases in the serum creatinine level occurred postoperatively in more patients who received aprotinin (20/108) than in those given placebo (13/108), the difference between the two groups was not statistically significant (p = 0.186), and the increases were generally small and transient. Likewise, there was no difference between the groups in terms of the incidence of abnormal serum electrolyte levels, blood urea nitrogen levels, or urinalysis findings, or in the frequency of abnormal creatinine clearance rates. Under the conditions described, aprotinin use does not appear to be associated with a significant risk of serious renal toxicity.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 136.

Aprotinin, a serine protease inhibitor derived from bovine lung, has been shown to decrease postoperative bleeding and blood product transfusion requirements in patients undergoing open heart operations [1–10]. The use of aprotinin has become widespread in Europe, and multiple studies investigating its use are under way in the United States. Concern has been raised, however, that the incidence of postoperative renal dysfunction may be increased in patients undergoing open heart procedures who receive the drug [10–12]. We recently completed a multicenter trial evaluating the efficacy and safety of aprotinin use in patients undergoing coronary artery bypass graft procedures [9]. We also rigorously evaluated the postoperative renal function in this group of patients whose preoperative creatinine levels were in a relatively normal range and who were randomized to receive either high-dose aprotinin or placebo.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patient Characteristics
The study population consisted of 216 patients at five participating centers who were undergoing isolated primary or repeat coronary artery bypass graft procedures using cardiopulmonary bypass (Table 1). The patients were randomized (double-blinded) to receive either high-dose aprotinin (108 patients) or placebo (108 patients). Patients with a preoperative serum creatinine level exceeding 1.9 mg/dL were excluded, as were patients with diabetes mellitus whose preoperative serum creatinine level exceeded the upper limit of normal for the laboratory of the participating hospital. The study was approved by the institutional review board of each participating hospital.

Surgical Technique and Intraoperative Anticoagulation
Details of the surgical technique, such as method of cardiac protection and order of anastomoses, were carried out in accordance with the usual protocol of the participating surgeons. In all but 1 patient, hypothermic hyperkalemic cardioplegia solution was used to produce cardiac arrest for the period of aortic cross-clamping, during which the systemic temperature was maintained at 26° to 30°C. In this 1 patient, deep hypothermia and fibrillatory arrest were used because of difficulties with exposing the aorta due to adhesions. This patient received placebo. Profound hypothermic circulatory arrest was not used.

Anticoagulation during the time of cardiopulmonary bypass was managed by one of two methods. In most patients, the Hepcon/System 4 or the Hepcon/HMS device (Medtronic HemoTec, Englewood, CO) was used to calculate the heparin loading dose. During cardiopulmonary bypass, blood heparin levels were measured periodically on the same instrument using the heparin-protamine titration test on the same instrument [12], and additional heparin was administered as indicated. Using this technique, the blood heparin levels were generally maintained at greater than 2.5 mg/kg of the patient's weight. After the patient was weaned from cardiopulmonary bypass, the Hepcon system was used to determine the appropriate dose of protamine. For the remaining patients, a fixed-dose heparin schedule was used (loading heparin dose of 300 USP U/kg and an additional dose of 150 USP U/kg administered after every 90-minute period of bypass). When this method was used, the protamine dose was 1.3 mg per 100 units of heparin administered.

Data Collection and Statistical Methods
The volume of urine produced each hour during operation was recorded. With the start of operation designated as time zero, the urine output during each 8-hour interval was measured for 40 hours after the operation. Four-hour timed urine specimens were obtained preoperatively and on postoperative days 1 and 2, and an 8-hour overnight timed urine specimen was obtained on postoperative days 3, 4, and 7 for the calculation of creatinine clearances. Urinalyses were performed preoperatively; on postoperative days 1, 2, 3, 4, and 7; and at the time of the patient's follow-up visit 4 to 6 weeks after operation.

Serum creatinine and electrolyte levels were determined in all patients preoperatively and in the surviving patients on postoperative days 1, 2, 3, 4, and 7. Additionally, the serum creatinine levels were determined at the time of the patient's postoperative visit 4 to 6 weeks after the operation. All adverse events related to renal function were reported by the investigators.

Statistical tests were two-tailed and were performed with an level of 0.05. Categorical values were analyzed using either a Fisher's exact test or a ² test. Fisher's exact tests were employed if at least one fourth of the cells had expected values of less than 5; otherwise, ² tests were employed. Data from the five centers were compiled and analyzed by the Statistics and Data Systems Department of Miles, Inc (statistician, Lawrence A. Schwartz, MS).

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Demographic Variables, Surgical Variables, and Operative Mortality
The demographic and surgical variables were similar for the patients in both the aprotinin and placebo groups (see Table 1). The overall operative mortality rate was 4.6%, with 6 of the 108 patients in the aprotinin group and 4 of the 108 patients in the placebo group dying within 30 days of operation or before discharge from the hospital (p = 0.517, not significant).

Clinical Parameters of Renal Function
Postoperative renal failure requiring dialysis occurred in 1 patient in each group. As reported by the investigators, the incidence of clinically significant postoperative renal failure or insufficiency was similar for both groups of patients, occurring in 6 patients (5.6%) in the aprotinin group and in 5 (4.6%) in the placebo group.

Urine Output
The urine output during operation averaged 229 mL/h in the patients who received aprotinin and 205 mL/h in the patients who received placebo (p = 0.138; not significant). Likewise, there were no significant differences between the two groups in the mean volume of urine produced by the patients during operation during the early postoperative period, when the output was measured at 8-hour intervals (Table 2).

The change in the postoperative serum creatinine levels in patients with mild preoperative renal dysfunction (preoperative creatinine levels, 1.3 to 1.8 mg/dL) was also examined. In the aprotinin group, 6 of 33 (18.2%) patients with elevated preoperative creatinine levels exhibited postoperative increases of 0.5 mg/dL or greater. For the group of patients with elevated preoperative creatinine levels who received placebo, a comparable increase in the creatinine level occurred in 6 of 40 (15.0%) patients.

The increases in the creatinine levels observed in the patients who received aprotinin were temporary in all but 2 patients. In 13 of the 15 aprotinin-treated patients whose postoperative creatinine levels were greater than 0.5 mg/dL and who were discharged from the hospital, the serum creatinine level returned to either normal or within 0.3 mg/dL of the preoperative level by the time of discharge or at follow-up 4 to 6 weeks after operation. In the two exceptions, the creatinine level at discharge was greater than the preoperative level (by 0.6 mg/dL in 1 patient and by 0.4 mg/dL in the other), but follow-up determinations were not reported.

There were no significant differences between the two groups with regard to the frequency of abnormal postoperative creatinine clearances. Twenty-nine of 42 aprotinin-treated patients (69%) whose preoperative creatinine clearances had been normal, for whom data were available, had creatinine clearances that were below normal during the postoperative period. Twenty-four of 40 patients (60.0%)in the placebo group had abnormally low postoperative creatinine clearances.

Serum Electrolytes, Blood Urea Nitrogen, and Urinalysis
There were no significant differences between the aprotinin and placebo groups in terms of the postoperative incidence of abnormal (either higher or lower than normal) serum levels of sodium, potassium, chloride, bicarbonate, or blood urea nitrogen.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Because of the risks associated with blood product transfusion and the fact that there is a limited supply of donated blood, considerable interest has been generated among both the public and medical communities in developing methods to reduce the need for perioperative transfusions. The effectiveness of aprotinin in reducing the bleeding and transfusion needs in patients undergoing open heart procedures has been documented in a number of reports [1–11, 13]. There has been speculation, however, that aprotinin might adversely affect the kidneys, because approximately 90% of an administered dose is known to collect in the brush border of the convoluted tubules [14], and large doses administered to animals cause the kidneys to become pale and swollen. In rats, aprotinin has an antidiuretic effect that was evident in a state of expanded extracellular fluid volume, an effect that may be a consequence of kallikrein inhibition [15, 16]. In normovolemic dogs, aprotinin had no effect on the glomerular filtration rate or renal blood flow, but sodium excretion was increased and potassium excretion was decreased [17]. Whether the observed renal effects are the result of a direct toxic influence, inhibition of serine protease (such as kallikrein) activity, alterations in the intrarenal blood flow distribution, or other factors is not known.

Blauhut and associates [5] determined renal function indices in 26 patients, half of whom received high-dose aprotinin. No difference in postoperative creatinine clearance was observed between the two groups, but osmolar clearance and sodium excretion were higher in the aprotinin-treated patients for a short time after operation. Fraedrich and associates [18] measured urinary protein excretion in patients who were randomized to receive either high-dose aprotinin or placebo during coronary artery bypass procedures. Significant increases in the diuresis of -1-microglobulin, N-acetyl-glucoaminidase, and aminopeptidase occurred in the patients treated with aprotinin, and this was interpreted as evidence that renal tubular ``overload'' occurred as the result of reversible tubular damage. There were, however, no differences in the serum creatinine levels and creatinine clearances between the two groups.

Clinical reports describing aprotinin use in patients undergoing open heart operations have raised the possibility that the drug is associated with increased postoperative serum creatinine levels. D'Ambra and associates [11], in a multi-center study, randomized 212 patients undergoing cardiac valve replacement to receive high-dose aprotinin, low-dose aprotinin, or placebo. Postoperative creatinine increases of more than 0.5 mg/dL occurred in 30%, 14%, and 8% of the patients, respectively. The difference in the postoperative increase in the creatinine level was statistically significant for the high-dose aprotinin group as compared with the placebo group, but not for the low-dose aprotinin group. There were also no significant differences in the incidence of creatinine increases of more than 2.0 mg/dL among the three groups. Cosgrove and associates [10], in a single-center study, compared the effects of high-dose aprotinin, low-dose aprotinin, and placebo in 169 patients who underwent repeat coronary artery bypass procedures. Postoperative creatinine increases of more than 0.5 mg/dL occurred in 25%, 20%, and 18% of the patients, respectively; however, these differences were not statistically significant. The findings from these two studies therefore suggest that aprotinin use may be associated with a mild elevation in the postoperative serum creatinine levels. Conversely, multiple single-center and multicenter studies, involving large numbers of patients, have not identified a significant adverse effect of aprotinin on postoperative renal function [2, 5, 6, 8].

Sundt and colleagues [19] reported the use of high-dose aprotinin in 20 patients undergoing thoracic or thoracoabdominal aorta procedures in which hypothermic circulatory arrest was used. Thirteen patients suffered renal dysfunction and 5 required dialysis postoperatively. The incidence of postoperative renal failure was higher in the aprotinin-treated patients than it was in the age-matched (but not randomized) control subjects. It has been suggested that, in the special situation of circulatory stasis and profound hypothermia, the protective mechanisms that usually operate to prevent intravascular thrombosis may be impaired by aprotinin [12]. Others have reported that in experimental studies, adverse effects of aprotinin on renal function may be temperature dependent [20, 21].

In our study, there was no significant difference between the aprotinin and placebo groups in intraoperative or early postoperative urine production. This is in contrast to the findings reported by Bidstrup and colleagues [1], who found that aprotinin use was associated with a greater urine output. The reason for this difference is not evident but appears to be of little clinical consequence.

Our results suggest that a temporary, modest postoperative increase in serum creatinine levels may occur in a small number of patients who receive aprotinin during open heart operations using moderate hypothermia, but that this does not translate into an increase in the incidence of clinically significant adverse events related to renal function. It is important to note that we did not investigate the use of aprotinin in patients with severe preoperative renal dysfunction or in patients undergoing procedures using profound hypothermic circulatory arrest. Nevertheless, this study does indicate that, under the conditions described, the risk of clinically significant renal impairment due to aprotinin use appears to be small.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported by Miles Inc, West Haven, Connecticut.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Lemmer, Northwest Surgical Associates, 2226 NW Pettygrove, Portland, OR 97210.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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10. Cosgrove DM III, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031–8.[Abstract]
11. D'Ambra MN, Akins CW, Blackstone EH, et al. Aprotinin in primary cardiac valve replacement reduces bleeding, increases creatinine. Circulation 1992;86(Suppl 1):I495.
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lemmer, J. H. Articles by Schaff, H. V. Search for Related Content PubMed PubMed Citation Articles by Lemmer, J. H., Jr Articles by Schaff, H. V.