Asian Cardiovasc Thorac Ann 2003;11:304-308
© 2003 Asia Publishing EXchange Ltd
Beneficial Effect of Aspirin on Renal Function Post-Cardiopulmonary Bypass
Rabin Gerrah, MD,
Uzi Izhar, MD
Department of Cardiothoracic Surgery, Hebrew University-Hadassah Medical School, Jerusalem, Israel
For reprint information contact: Rabin Gerrah, MD Tel: 972 2 6776960 Fax: 972 2 6438005 email: rmger{at}yahoo.com Department of Cardiothoracic Surgery, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel.
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ABSTRACT
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Urine thromboxane, plasma creatinine, and creatinine clearance were determined perioperatively in 20 patients undergoing coronary bypass surgery. Ten patients took aspirin until the day of surgery, and 10 discontinued aspirin at least one week before surgery. A significant increase in urine thromboxane following establishment of cardiopulmonary bypass was observed only in the control group. Plasma creatinine increased in the control group on the 1st postoperative day (from 81.9 ± 13.2 to 97.6 ± 13.2 µmol•L-1, p = 0.02) and decreased next day to the preoperative level (82.7 ± 9 µmol•L-1, p = 0.03). In the aspirin group, creatinine remained unchanged on the 1st postoperative day (89.4 ± 14.2 vs. 87.2 ± 7.7 µmol•L-1, p = 0.6), and increased significantly on the 2nd day (101.4 ± 8.5 µmol•L-1, p = 0.01). The aspirin group had higher creatinine levels (p < 0.0001) and lower creatinine clearance (60.2 ± 16.5 vs. 82 ± 25.7 mL•min-1, p < 0.0001) than the control group on the 2nd postoperative day. A significant positive correlation was seen between urine thromboxane and creatinine on day 2 in both groups (r = 0.6). Aspirin administrated before coronary surgery may have a beneficial effect on renal function, probably mediated by its antiplatelet activity and thromboxane inhibition.
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INTRODUCTION
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Normal renal function following extracorporeal circulation is of major prognostic importance. Periods of reduced perfusion pressure and the systemic inflammatory response occurring during cardiopulmonary bypass (CPB) may potentially deteriorate renal function, from subtle impairment to endstage renal failure.1 Thromboxane A2, an arachidonic acid metabolite, is released from almost all organs including the kidneys following ischemic injury.2 Thromboxane (Tx) is a very potent vasoconstrictor that may decrease renal blood flow. It has been demonstrated that inhibition of Tx synthesis improves creatinine clearance.3 In an animal model, it has been shown that increased production of Tx following CPB was associated with myocardial dysfunction and pulmonary hypertension.4
Aspirin directly reduces platelet aggregation and Tx production. It is widely used in patients with coronary artery disease who undergo coronary artery bypass grafting (CABG). It increases vein graft patency, and it has been reported recently that preoperative use of aspirin decreases operative mortality.5 Most patients are asked to discontinue aspirin 7–10 days prior to elective surgery in order to decrease operative bleeding. In these patients, Tx levels are expected to increase to normal values at the time of surgery. Patients who undergo CABG urgently, in whom aspirin has not been discontinued, are expected to have low levels of circulating Tx. Although the effect of Tx may subside rapidly after CPB, the production of Tx following CPB in animal models has been related to myocardial dysfunction and pulmonary hypertension.6–8 This study was undertaken to examine the effect of preoperative aspirin administration on renal function in patients undergoing CABG, focusing on urine Tx.
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PATIENTS AND METHODS
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Twenty consecutive patients undergoing CABG during May and July 2000 were enrolled in a prospective study. Patients were categorized into two groups: 10 received 100 mg of aspirin daily until the day of operation, and 10 who had never taken aspirin, or had contraindications to use of the drug, or in whom aspirin was discontinued electively at least 7 days before the day of surgery served as controls. Exclusion criteria included preoperative renal dysfunction, reoperation, recent myocardial infarction, poor left ventricular function (ejection fraction < 35%), and New York Heart Association functional class III–IV, because increased plasma Tx has been reported in these patients.9–12 The urgency of each operation was recorded. An urgent operation was defined as one performed within 48 hours of cardiac catheterization, or in patients with angina refractory to medical treatment.
Standard techniques of CPB with moderate hypothermia (28°C–32°C) were used in all patients. Myocardial protection was achieved with warm blood cardioplegia given antegradely, retrogradely, or both. The left internal mammary artery was harvested in all patients. The hematocrit was kept between 20% and 25% during CPB. Intraoperative use of fluids, blood, and blood products was recorded. The level of TxB2, a more stable derivative of TxA2 was determined by an enzyme-linked immunosorbent assay (ELISA) method (all kits and reagents were purchased from R&D Systems, Minneapolis, MN, USA). To exclude a direct effect of aspirin on renal function and glomeruli, plasma aspirin levels were also measured in all patients before surgery, using reflectance spectrophotometry with a Vitros System 950 (Ortho Clinical Diagnostics, Inc., Rochester, NY, USA) in a sensitivity range of 1–40 mg•dL-1. Postoperative complications and outcome including intensive care unit and hospital stay were recorded. Blood samples for creatinine (Cr) level and platelet count were taken from all patients at 4 different times: T1, the day before the surgery; T2, 30 minutes after establishment of CPB; T3, 24 hours after termination of the operation (postoperative day 1); and T4, 48 hours after termination of the operation.
The collected data were entered into a statistical database as either continuous or categorical variables for comparative statistical analysis. Data are expressed as mean ± standard deviation, with range values where applicable. Nonparametric tests were used mostly because of the small number of cases in the study and the control groups. For comparison between the 2 groups, the Mann-Whitney U test was applied. Within groups, the Wilcoxon rank test was used for quantitative data, and the chi-squared test was used for categorical data. The correlation between comparable variables was processed with the Pearson correlation, with a value of r equal to or greater than 0.4 being considered significant. The influence of different potential variables on Tx levels was studied by a multivariate general linear model. A value of p = 0.05 or less was considered significant.
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RESULTS
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There were no significant differences in the preoperative demographic data between the two groups (Table 1
). There was no hospital mortality. None of the patients developed acute renal failure during the hospital stay.
The Tx level in urine was significantly lower (p < 0.0001) in the aspirin group compared to the control group at T1 (Figure 1). Following establishment of CPB (T2), the urine Tx level increased considerably in the control group, from 1106 ± 343 to 1697 ± 437 pg•mL-1 (p = 0.009). A nonsignificant increase was noted in the aspirin group, from 698 ± 252 to 816 ± 154 pg•mL-1 (p = 0.3). Looking at times T2 to T3, Tx levels increased further in the aspirin group, from 816 ± 154 to 1347 ± 221 pg•mL-1 (p = 0.002), but decreased in the control group, from 1697 ± 437 to 1028 ± 159 pg•mL-1 (p = 0.002). In both groups, Tx levels at T4 were similar to the preoperative values, however, significantly higher levels of Tx were still detected in the aspirin group compared to the control group, 1269 ± 215 vs. 770 ± 360 pg•mL-1, p < 0.0001. A significant positive correlation was seen between urine Tx levels and Cr on postoperative day 2 in both groups (r = 0.6).
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Figure 1. Perioperative changes in urine thromboxane. CPB = cardiopulmonary bypass, POD1 = postoperative day 1, POD2 = postoperative day 2.
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From T1 to T2, the plasma creatinine level decreased in both groups from 81.9 ± 13.2 to 76.5 ± 10.59 µmol•L-1, p = 0.007 in the control group, and from 89.4 ± 14.2 to 70.8 ± 13.7 µmol•L-1, p = 0.005, in the aspirin group. This was followed by increases in both groups from T2 to T3 (Figure 2). At T4, a decline in Cr level was noted only in the study group where it reached 82.7 ± 9 µmol•L-1 which was significantly lower than the control group level of 101.4 ± 8.5 µmol•L-1, p = 0.005 (Figure 2).
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Figure 2. Perioperative changes in serum creatinine. CPB = cardiopulmonary bypass, POD1 = postoperative day 1, POD2 = postoperative day 2.
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From T1 to T2, the platelet count decreased in both groups, from 321 ± 104 x 106/mL to 116 ± 31 x 106/mL (p = 0.007) in the control group, and from 324 ± 73 x 106/mL to 111 ± 25 x 106/mL (p = 0.005) in the aspirin group. In both groups, there was a gradual increase in platelet count from T2 to T4, but no significant differences were observed between the two groups at T3 and T4.
Creatinine clearance decreased consistently following the operation (Figure 3). Both groups had significantly lower creatinine clearance in postoperative day 2 compared to the preoperative value: 82 ± 25.7 vs. 97 ± 31.1 mL•min-1 (p = 0.02) in the control group, and 60.2 ± 16.5 vs. 82.4 ± 26.6 mL•min-1 (p = 0.003) in the aspirin group. However, the aspirin group had significantly higher creatinine clearance at T4 compared to the control group: 82 ± 25.7 vs. 60.2 ± 16.5 mL•min-1 (p < 0.0001).
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Figure 3. Perioperative changes in creatinine clearance. CPB = cardiopulmonary bypass, POD1 = postoperative day 1, POD2 = postoperative day 2.
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There were no significant differences in operative parameters between the two groups, as shown in Table 2. The postoperative data are summarized in Table 3. There were no significant differences in fluid infusion in the first 24 hours or in urine output. Chest tubes drainage was higher in the aspirin group compared to the control group, but the need for blood and blood products was similar in both groups, and no significant difference was observed in hemoglobin levels at discharge (Table 3). Aspirin was not detected in the therapeutic range in any blood sample of either group. The intensive care unit stay in the control group was significantly longer than that of the study group, but total hospital stay was similar for both groups.
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DISCUSSION
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Aspirin has a major role in the treatment and prevention of coronary artery disease. The inhibition of platelet aggregation by aspirin reduces the risk of occlusion of the atherosclerotic constricted coronary artery and subsequent myocardial ischemia.12,13 Aspirin has been discontinued routinely before surgery to prevent postoperative bleeding. However, the better long-term prognosis after CABG in patients who were treated with aspirin makes the issue more controversial.5 In present daily practice, except for peptic-related gastrointestinal complications, no other major side-effects or complications are related to aspirin. Thromboxane has attracted attention by many researchers because of its special properties. It is a potent vasoconstrictor and platelet-aggregation agent, and it is released from almost every ischemic organ and degranulating platelets. During CPB, platelets are activated and degranulated, and they produce and release a substantial amount of Tx.14 Considerably raised Tx levels during CPB, as detected in our study, have been reported previously.15,16 These features make Tx an agent with deleterious effects, which, at the same time, may be a predictor of tissue injury.
Renal injury following CPB is a well-known and widely investigated phenomenon. Normal preoperative renal function is of major importance because of its association with patient outcome. The pathophysiologic mechanism of such injury is complex, and Tx plays an important role in it.17 The potent vasoactive effect of Tx on the kidneys is mediated directly by the kidney tissue and also by other ischemic organs, and it may occur during extracorporeal circulation or in the postoperative period, because of hypoperfusion. It has been reported that high Tx levels have an association with renal injury.18 Most studies have used a selective Tx-receptor blocking agent or a Tx-production inhibitor to investigate the effects of Tx elimination on organ function.19 These studies have the specificity of determining the direct action and inhibition of Tx.
In this study, we investigated the association between inhibition of Tx production by aspirin and renal function in patients undergoing CABG. As expected, the Tx level was significantly lower in the aspirin group. Lower Tx levels in all time intervals in the aspirin group could be related to a secondary effect of Tx on the kidneys. During an uneventful postoperative course, the renal impact of CPB begins to manifest on the second postoperative day, but renal function usually remains within the normal range.20 This is explained by the fact that renal dysfunction following CPB is not immediately evident after surgery when the patient is still hemodiluted. The deleterious effect of Tx may continue during this postoperative time as well as during the CPB period. Such postoperative renal changes are reflected in serum Cr levels immediately postoperatively. Comparison of serum Cr levels after surgery revealed an interesting difference between the two groups. The Cr level was expected to peak at the same time in both groups as there was no direct manipulation that could change this pattern, however, the peak Cr levels appeared to occur at least 24 hours earlier in the aspirin group (Figure 2
). This difference is probably due to the lower Tx levels present in the study group. One can postulate that the earlier decline in plasma Cr in the study group might be explained by faster recovery of renal function, with secretion of waste products including Cr and Tx. This improved renal recovery may be due partly to the lower Tx levels and less renal vasoconstriction, as well as to a secondary pathway related to aspirin, which improves renal function, reduces ischemia, and decreases renal Tx production. The fact that there was no significant difference in platelet count between the groups, and both groups had a good correlation between Cr and Tx level, supports this hypothesis.
Whatever the molecular or biochemical basis of this phenomenon, the earlier decline in plasma Cr in the aspirin group could be attributed exclusively to aspirin. A reduction of Cr such as that seen in the aspirin group might predict a better outcome in patients after cardiac surgery, especially CABG. This finding could be of greater importance in patients with preoperative renal dysfunction. Possibly, in some cases, a slight improvement in renal function might make the difference between full-blown renal failure and reversible renal dysfunction following CABG. The main limitation of this study was the small number of subjects in both groups, which were compared using nonparametric tests. Larger groups may be needed for a more powerful inference.
Potentially greater postoperative bleeding remains a major disadvantage of aspirin. Despite the fact that the aspirin-treated patients bled more than the control group, no significant difference in blood transfusion requirement was seen between groups. Furthermore, no patient in the aspirin group needed reexploration because of bleeding. Thus, it was concluded that aspirin has a beneficial effect on renal function in patients undergoing CABG. Preoperative inhibition of Tx synthesis reduced the Tx levels significantly after CPB, and this is associated with improved renal recovery after CPB.
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REFERENCES
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|---|
- Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest
1997;112:676–92.[Abstract/Free Full Text]
- Castallani S, Paladini B, Pannicia R, Pannicia R, Di Serio C, Valloti B, et al. Increased renal formation of thromboxane A2 and prostaglandin F2 alpha in heart failure. Am Heart J
1997;133:94–100.[Medline]
- Chatziantoniou C, Papanicolaou N. The role of prostaglandin and thromboxane synthesis by the glomeruli in the development of acute renal failure. Eicosanoids
1989;2:157–61.[Medline]
- Papanicolaou N, Hatziantoniou C, Dontas A, Gkikas EL, Paris M, Gkikas G, et al. Is thromboxane a potent antinatriuretic factor and is it involved in the development of acute renal failure? Nephron
1987;45:277–82.[Medline]
- Dacey LJ, Munoz JJ, Johnson ER, Leavitt BJ, Maloney CT, Mortin JR, et al. Effect of preoperative aspirin use on mortality in coronary artery bypass grafting patients. Ann Thorac Surg
2000;70:1986–90.[Abstract/Free Full Text]
- Hashimoto K, Miyamoto H, Suzuki K, Horikoshi S, Matsui M, Arai T, et al. Evidence of organ damage after cardiopulmonary bypass. The role of elastase and vasoactive mediators. J Thorac Cardiovasc Surg
1992;104:666–73.[Abstract]
- Byrne JG, Appleyard RF, Sun SC, Couper GS, Sloane JA, Laurence RG, et al. Cardiac-derived thromboxane A2. An initiating mediator of reperfusion injury? J Thorac Cardiovasc Surg
1993;105:689–93.[Abstract]
- Cave AC, Manche A, Derias NW, Hearse DJ. Thromboxane A2 mediates pulmonary hypertension after cardiopulmonary bypass in the rabbit. J Thorac Cardiovasc Surg
1993;106:959–67.[Abstract]
- Lelcuk S, Alexander F, Valeri CR, Shepro D, Hechtman HB. Ischemia stimulates tissue thromboxane synthesis. Surg Forum
1984;35:76–8.
- Bhat AM, Sacks H, Osborne JA, Lefer AM. Protective effect of the specific thromboxane receptor antagonist, BM-13505, in reperfusion injury following acute myocardial ischemia in cats. Am Heart J
1989;117:799–803.[Medline]
- Mullase K, Fornabaio D. Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin sensitive mechanism. Circ Res
1988;62:668–78.[Abstract/Free Full Text]
- Hennekens CH, Dyken ML, Fuster V. Aspirin as a therapeutic agent in cardiovascular disease. Circulation
1997;96:2751–3.[Free Full Text]
- Reilley IA, Fitzgerald GA. Aspirin in cardiovascular disease. Drugs
1988;35:154–76.
- Colman RW. Platelet and neutrophil activation in cardiopulmonary bypass. Ann Thorac Surg
1990;49:32–4.[Abstract]
- Ylikorkala O, Saarela E, Viinikka L. Increased prostacyclin and thromboxane production in man during cardiopulmonary bypass. J Thorac Cardiovasc Surg
1981;82:245–7.[Abstract]
- Davies GC, Sobel M, Salzman EW. Elevated plasma fibrinopeptide A and thromboxane B2 levels during cardiopulmonary bypass. Circulation
1980;61:808–14.[Abstract/Free Full Text]
- Arima T, Shiramatsu T, Matsuura M, Nakamura S, Matsumoto I, Hori T. Changes in urinary thromboxane level in man during cardiopulmonary bypass: effect of thromboxane on renal tubules. Prostaglandins
1990;39:319–38.[Medline]
- Stork JE, Rahman MA, Dunn MJ. Eicosanoids in experimental and human renal disease. Am J Med
1986;80:34–45.[Medline]
- Fiddler GI, Lumley P. Preliminary clinical studies with thromboxane synthase inhibitors and thromboxane receptor blockers. A review. Circulation
1990;81(Suppl I):I69–78.
- Abel RM, Buckley MJ, Austen WG, Barnett GO, Beck CH, Fischer JE. Acute postoperative renal failure in cardiac surgical patients. J Surg Res
1976;20:341–8.[Medline]
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ABSTRACT
INTRODUCTION
