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The effect of aprotinin on risk of acute renal failure requiring dialysis after on-pump cardiac surgery.

SUMMARY

The use of aprotinin in cardiac surgery to reduce perioperative bleeding and transfusion is controversial. We assessed the effect of aprotinin on the risk of acute renal failure in 423 patients who underwent on pump cardiac surgery between January 1, 2005 and December 31, 2006. Of these 423 patients, 318 (75.2%) received aprotinin (median dose=3.0 million KIU, standard deviation=2.8 million KIU; interquartile range: 2 million KIU to 4 million KIU). Aprotinin was more likely to be used in patients who did not cease aspirin before surgery, in urgent or emergency surgery, who had impaired left ventricular function, a longer period of bypass and aortic cross-clamp time, and with both coronary artery bypass graft and valvular surgery performed. The overall incidence of acute renal failure requiring dialysis was 2.8%. The use of aprotinin was not associated with a reduction in transfusion nor an increased risk of renal failure requiring dialysis, atrial fibrillation, cerebrovascular accident or mortality in the univarate analyses. In the multivariate analysis, only preoperative serum creatinine concentration (odds ratio [OR] 1.06 per 10 [micro]mol/l increment in creatinine, 95% confidence interval [CI]. 1.01 to 1.14, P=0.029) and urgency of the surgery (urgent vs. scheduled surgery. OR 12.8, CL. 2.3 to 70.8, P=0.004; emergency vs. scheduled surgery: OR 23.1, CL 3.0 to 180.2, P=0.003) were significantly associated with an increased risk of acute renal failure requiring dialysis. The use of low-dose aprotinin did not significantly reduce perioperative transfusion requirements and was not a significant risk factor for acute renal failure requiring dialysis in our patients.

Key Words: aprotinin, renal failure, antifibrinolytics

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Cardiac surgery is associated with a significant risk of bleeding requiring blood transfusion and re-operation (1). In on-pump cardiac surgery, the use of cardiopulmonary bypass may activate systemic inflammation and fibrinolysis which contributes to the increased risk of postoperative bleeding requiring transfusion and surgical re-exploration. One of many approaches to reduce perioperative bleeding and transfusion in cardiac surgery is the use of an antifibrinolytic agent during cardiopulmonary bypass. According to the latest practice guidelines for perioperative blood transfusion and adjuvant therapies by the American Society of Anesthesiologists, antifibrinolytic therapy may be useful in reducing allogeneic blood transfusion for patients at high risk of excessive bleeding (2). Recent systematic reviews suggested that aprotinin, a serine protease inhibitor derived from bovine lungs, is useful and may in fact be significantly more effective than lysine analogues in reducing perioperative transfusion and re-operation (1,3).

The use of aprotinin in cardiac surgery has been called into question recently when a large observational study suggested that the use of aprotinin in cardiac surgery may increase the risk of acute renal failure (4). The results of this study were, however, not substantiated by some other observational studies (5-7). Aprotinin was commonly used in many cardiothoracic units in Australia until the manufacturer of aprotinin (Bayer AG) temporarily suspended the marketing of the drug very recently because of a concern about its safety profile. Data on the safety profile of aprotinin from Australian cardiothoracic units are sparse (8). We aim in this study to assess the effects of aprotinin on the risk of acute renal failure requiring dialysis.

MATERIALS AND METHODS

This retrospective cohort study utilised the clinical databases of the intensive care unit (ICU) and cardiothoracic operating theatre of Royal Perth Hospital in Western Australia. All data were collected prospectively and subsequently retrieved from the ICU and operating theatre databases. The study was deemed to be a "Clinical Audit" by the Hospital Ethics Committee and as such, a formal human research ethics committee approval was waived.

All on-pump cardiac surgical patients between January 1, 2005 and December 31, 2006 were included except those who died in the operating theatre and those who were dialysis-dependent before their cardiac surgery. The usual practice of this cardiothoracic unit was to cease aspirin or other anti-platelet agents for at least five days before elective surgery, unless there was a strong medical indication to continue the drug. The use of blood products including red blood cells, platelets and fresh frozen plasma was selective and determined by the blood test results and clinical condition of the patient. The use of aprotinin was also selective and the dose was determined by the duty cardiothoracic anaesthestists.

The outcomes analysed in this study included intraoperative and postoperative transfusion requirements, bleeding requiring surgical re-exploration, maximum postoperative creatinine concentrations, maximum postoperative renal Sequential Organ Failure Assessment (SOFA) Score (9), the requirement for acute renal replacement therapy, occurrence of postoperative atrial fibrillation or cerebrovascular accident, length of ICU and hospital stay and hospital mortality. No patients were lost to follow-up or had missing mortality and renal failure data.

The clinical predictors of acute renal failure considered included patient's age, gender, co-morbidities such as diabetes mellitus and hypertension, preoperative serum creatinine concentrations, whether it was a re-do cardiac surgery, coronary artery bypass graft alone or with valve surgery, cardiopulmonary bypass time, aorta cross-clamp time, the status of the left ventricular function before surgery, urgency of the cardiac surgery, the total amount of allogeneic blood transfusion and the use of aprotinin during cardiopulmonary bypass. In this study, emergency surgery was defined as surgery required within 24 hours and urgent surgery was defined as surgery required within a few days.

In the univariable analyses, continuous variables were analysed by t-tests, categorical variables and continuous variables with skewed distributions were analysed by chi-square tests and Mann-Whitney tests, respectively. The association between the potential clinical predictors of renal failure after cardiac surgery and postoperative renal failure requiring renal replacement therapy was analysed by multivariate logistic regression analyses. In the multivariate analyses, variables were removed in a stepwise manner if the P value was more than 0.25 during the multivariate modelling process, starting from the variable with the highest P value. The final multivariate model contained only predictive variables associated with a P value <0.25. In this study a P value <0.05 was regarded as statistically significant and all statistical tests were performed with SPSS for Windows (version 13.0, SPSS Inc., 2005, IL, U.S.A.).

RESULTS

Among a total of 423 consecutive on-pump cardiac surgical patients between January 1, 2005 and December 31, 2006, 318 patients received aprotinin during their surgery. The mean dose of aprotinin used was 3.3 million KIU (median 3.0 million KIU, standard deviation: 2.8 million KIU, interquartile range: 2 million KIU to 4 million KIU). The patients who received aprotinin had a shorter period of time between the cessation of aspirin and surgery, were more likely to have impaired left ventricular function, urgent or emergency cardiac surgery, both coronary artery bypass graft and heart valve surgery performed and a longer period of bypass and aortic cross-clamp time (Table 1).

As expected from the shorter period from cessation of aspirin, more complicated surgery and a longer bypass time associated with the aprotinin group, these patients received more intraoperative transfusion of red blood cells, fresh frozen plasma and platelets. Postoperatively, the aprotinin group received slightly fewer blood transfusions but the total blood transfusions including both the intraoperative and postoperative period was not significantly different between the two groups (Table 2). Although the aprotinin group was associated with a slightly higher maximum renal SOFA score postoperatively, the incidence of acute renal failure requiring renal replacement therapy was not significantly different in the univariate analysis (Table 2). Apart from a longer length of hospital stay, the use of aprotinin was also not associated with an increased risk of other postoperative complications including surgical re-exploration for bleeding, atrial fibrillation, cerebrovascular accident and hospital mortality.

In the multivariate analysis, only preoperative creatinine concentrations (odds ratio [OR] 1.07 for every 10 [micro]mol/l increment in preoperative creatinine, 95% confidence interval [CI] 1.01 to 1.14, P=0.027), age (OR 1.12 for every year increase in age, 95% CI 1.02 to 1.22, P=0.013), total amount of allogeneic blood transfusion (OR 1.27 for every unit of red cells transfusion, 95% CI 1.08 to 1.50, P=0.003) and urgency of the operation were significant risk factors for acute renal failure requiring renal replacement therapy. The use of aprotinin was not associated with a higher risk of acute renal failure requiring renal replacement therapy (OR 0.27, 95% CI 0.06 to 1.20, P=0.085), after adjusting for other risk factors of acute renal failure (Table 3).

DISCUSSION

This study showed that the major risk factors for acute renal failure after on-pump cardiac surgery were preoperative renal function, age, amount of allogeneic transfusion and the urgency of surgery. Aprotinin was commonly used in our patients who underwent complicated cardiac surgery and those who were at high risk of bleeding. The use of aprotinin did not appear to increase the risk of acute renal failure requiring dialysis.

Aprotinin is metabolised by lysosomal enzymes in the kidneys, has a high affinity for the proximal tubule of nephrons and can increase serum creatinine concentrations transiently (10-12). A slight increase in the renal SOFA score and maximum postoperative serum creatinine concentrations after the use of aprotinin in our patients was consistent with the results of these earlier clinical studies. A recent observational study suggested that aprotinin might have a dose-dependent effect on the risk of acute renal failure in cardiac surgery (4). This study was, however, limited by a number of methodological problems (13) and its findings were not entirely substantiated by many other observational studies and systematic reviews (1,3,5-7). A recent meta-analysis showed that only the use of high-dose aprotinin (>4 million KIU plus maintenance 0.5 million KIU/h during bypass) was associated with an increased risk of acute renal dysfunction (defined as an increment of serum creatinine concentration >44 [micro]mol/l) (relative risk 1.47 for high-dose vs. 1.01 for low-dose regimen: 2 million KIU plus 0.25 million KIU/h maintenance during bypass) but not acute renal failure requiring dialysis when compared with placebo (3). Our findings were, albeit limited, consistent with the results of this meta-analysis in that the relatively low-doses of aprotinin used were not significantly associated with an increased risk of acute renal failure requiring dialysis, after adjusting for other risk factors of acute renal failure (3,5-7). We are aware that the dose-dependent renal toxicity of aprotinin in cardiac surgery remains controversial (13) and high-doses of aprotinin have also been reported to cause acute renal failure after spinal surgery (14). Whether the use of an ultra-low dose of aprotinin (1 million KIU) or even topical application of aprotinin can result in significant reduction in perioperative bleeding without the risk of causing acute renal impairment remains uncertain but merits further investigation by large randomised controlled studies (13,15,16).

Our results confirmed the findings of other studies that pre-existing renal impairment, total amount of blood transfusion and non-elective cardiac surgery are the major risk factors for acute renal failure requiring dialysis (13,17). We could not, however, confirm other known risk factors of acute renal failure after cardiac surgery such as diabetes mellitus, ejection fraction less than or equal to 40%, previous cardiac surgery and procedure other than coronary artery bypass grafting in this study. This is most likely due to the small sample size of our cohort and the low incidence of acute renal failure requiring dialysis.

This study has significant limitations. First, observational studies are prone to bias. Selection bias, as evidenced by the selected use of aprotinin in the sicker group of cardiac patients in this study, may not be fully adjusted for in an observational study. Second, the sample size of this cohort was small (n=423) and the incidence of renal failure requiring dialysis was low (2.8%). This reduced the power of the study to detect the potential effect of aprotinin on the risk of acute renal failure requiring dialysis. Furthermore, the clinical decision to initiate renal replacement therapy will depend on many factors including acidosis, hyperkalaemia and pulmonary oedema that are not considered in this study. Finally this was a single-centre study including only adult cardiac surgical patients treated with relatively small doses of aprotinin, and hence our results are not generalisable to paediatric cardiac surgery or when larger doses of aprotinin are used (18).

In summary, the use of a relatively small dose of aprotinin in patients who were at high risk of bleeding did not increase the risk of acute renal failure requiring dialysis, after adjusting for other risk factors for acute renal failure. The relevance of our results will depend on whether the effectiveness and safety of a lower dose of aprotinin can be confirmed by large randomised controlled trials in different perioperative settings.

Address for reprints: Dr K. M. Ho, Intensive Care Unit, Royal Perth Hospital, WA. 6000.

Accepted for publication on February 21, 2008.

REFERENCES

(1.) Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007; 4:CD001886.

(2.) American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology 2006; 105:198-208.

(3.) Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007; 115:2801-2813.

(4.) Mangano DT, Tudor IC, Dietzel C; for the Multicenter Study of Perioperative Ischemia Research Group, Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354:353-365.

(5.) Furnary AP, Wu Y, Hiratzka IF, Grunkemeier GL, Page US 3rd. Aprotinin does not increase the risk of renal failure in cardiac surgery patients. Circulation 2007;116(11 Suppl):I127-133.

(6.) Kertai MD, Varga KS, Royston D, London MJ, Szabolcs Z, Grebenik CR et al. Aprotinin and perioperative complications in cardiac surgery. J Cardiovasc Surg (Torino) 2007; 48:761-772.

(7.) Van der Linden PJ, Hardy JF, Daper A, Trenchant A, De Hert SG. Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome? Br J Anaesth 2007; 99:646-652.

(8.) Daly DJ, Myles PS, Smith JA, Knight JL, Clavisi O, Bain DL et al; ANZCA Trials Group. Anticoagulation, bleeding and blood transfusion practices in Australasian cardiac surgical practice. Anaesth Intensive Care 2007; 35:760-768.

(9.) Kajdacsy-Balla Amaral AC, Andrade FM, Moreno R, Artigas A, Cantraine F, Vincent JL. Use of the sequential organ failure assessment score as a severity score. Intensive Care Med 2005; 31:243-249.

(10.) Davis R, Whittington R. Aprotinin. A review of its pharmacology and therapeutic efficacy in reducing blood loss associated with cardiac surgery. Drugs 1995; 49:954-983.

(11.) Lemmer JH Jr, Stanford W, Bonney SL, Chomka EV, Karp RB, Laub GW et al. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg 1995; 59:132-136.

(12.) Coleman CI, Rigali VT, Hammond J, Kluger J, Jeleniowski KW, White CM. Evaluating the safety implications of aprotinin use: the Retrospective Evaluation of Aprotinin in Cardio Thoracic Surgery (REACTS). J Thorac Cardiovasc Surg 2007; 133:1547-1552.

(13.) Dietrich W, Busley R, Boulesteix AL. Effects of aprotinin dosage on renal function: an analysis of 8,548 cardiac surgical patients treated with different dosages of aprotinin. Anesthesiology 2008; 108:189-198.

(14.) Okubadejo GO, Bridwell KH, Lenke LG, Buchowski JM, Fang DD, Baldus CR et al. Aprotinin may decrease blood loss in complex adult spinal deformity surgery, but it may also increase the risk of acute renal failure. Spine 2007; 32:2265-2271.

(15.) Parvizi R, Azarfarin R, Hassanzadeh S. Ultra-low dose aprotinin effects on reducing the need for blood transfusion in cardiac surgery. Saudi Med J 2007; 28:49-53.

(16.) Baric D, Biocina B, Unic D, Sutlic Z, Rudez I, Vrca VB et al. Topical use of antifibrinolytic agents reduces postoperative bleeding: a double-blind, prospective, randomized study. Eur J Cardiothorac Surg 2007; 31:366-371.

(17.) Wijeysundera DN, Karkouti K, Dupuis JY, Rao V, Chan CT, Granton JT et al. Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery. JAMA 2007; 297:1801-1809.

(18.) Arnold DM, Fergusson DA, Chan AK, Cook RJ, Fraser GA, Lim W et al. Avoiding transfusions in children undergoing cardiac surgery: a meta-analysis of randomized trials of aprotinin. Anesth Analg 2006; 102:731-737.

A. RAAJKUMAR *, K. M. HO ([dagger]), C. COKIS ([double dagger]), N. SLADE ([section]) Intensive Care Unit, Royal Perth Hospital, Perth, Western Australia, Australia

* M.B., B.S., F.C.A.R.C.S.I., Intensive Care Unit Senior Registrar.

([dagger]) M.B., B.S., M.P.H., F.R.C.P(Glasg), F.A.N.Z.C.A., F.J.F.I.C.M., Consultant Intensivist.

([double dagger]) M.B., B.S., F.A.N.Z.C.A., Consultant Cardiac Anaesthetist, Department of Anaesthesia.

([section]) L.C.C.P (U.K.), Senior Perfusionist.
TABLE 1
The difference in preoperative and intraoperative characteristics
of the patients with or without aprotinin during cardiac surgery

Variables Aprotinin No aprotinin P value
 (n=318) (n=105)

Age, y (SD) 58.3 (15.9) 59.5 (14.3) 0.490

Preop creatinine 102.3 (54.9) 95.2 (36.6) 0.140
([micro]mol/l)

Preop haemoglobin (g/l) 130.1 (26.2) 135.7 (24.4) 0.205

Hypertension, no. (%) 163 (51.3) 62 (59.0) 0.180*

Diabetes mellitus, no. (%) 84 (26.4) 26 (24.8) 0.800*

Preop without aspirin, 5.6 (4.4) 6.7 (3.8) 0.020*
days (SD)

Left ventricular function, 0.020*
no. (%)

Normal 183 (51) 68 (65)

Mildly impaired 50 (16) 13 (12)

Moderately impaired 31 (10) 17 (16)

Severely impaired 54 (17) 7 (7)

Urgency of the operation*, 0.01*
no. (%)

Scheduled 194 (61) 80 (76)

Urgent 82 (26) 20 (19)

Emergency 42 (13) 5 (5)

Bypass time, min (SD) 114.1 (49.4) 85.6 (38.8) 0.01

Cross-clamp time, 76.9 (53.5) 51.1 (26.9) 0.01
min (SD)

CABG with valve surgery, 55 (17.3) 7 (6.7) 0.01*
no. (%)

* P value generated by non-parametric tests such as chi-square
or Mann-Whitney test. * urgent implies operation needed to be
performed within days and emergency implies operation needed
to be performed within 24 hours. SD=standard deviation.

TABLE 2
The difference in intraoperative and postoperative outcomes
inpatients with or without aprotinin

Variables Aprotinin No aprotinin P value#
 (n=318) (n=105)

Intraoperative transfusion

RBC, units (SD) 2.3 (2.7) 1.5 (2.1) 0.002

FFP, units (SD) 2.6 (3.1) 1.1 (2.3) 0.001

Platelets, units (SD) 5.5 (6.5) 2.4 (4.5) 0.001

Postoperative transfusion 1.2 (2.8) 1.6 (2.8) 0.019
RBC, units (SD)

Total RBC transfusion, units 3.4 (4.0) 3.0 (3.6) 0.244
(SD)

Surgical re-exploration, 23 (7.2) 11 (10.5) 0.303
no. (%)

Postoperative atria] 81 (25.5) 22 (21.0) 0.431
fibrillation, no. (%)

Postoperative maximum 18.6 (71.5) 18.3 (80.1) 0.143
tropinin [micro]g/l (SD)

Postoperative cerebrovascular 5 (1.6) 0 (0) 0.339
accident, no. (%)

Postoperative maximum 123.8 (75.3) 114.0 (78.7) 0.270
creatinine, [micro]mol/l (SD)

Postoperative maximum SOFA 1.0 (1.5) 0.6 (1.2) 0.010
score (SD)

Renal replacement therapy, 6 (1.9) 6 (5.7) 0.080
no. (%)

ICU stay, days (SD) 3.0 (5.0) 2.6 (3.9) 0.088

Hospital stay, days (SD) 17.9 (14.9) 14.6 (11.3) 0.017

Hospital mortality, no. (%) 16 (5.0) 3 (2.9) 0.428

*P value generated by non-parametric tests such as chi-square or
Mann-Whitney test. RBC=red blood cells, FFP=fresh frozen plasma,
SOFA=Sequential Organ Failure Assessment score, SD=standard
deviation.

TABLE 3
The final multivariate model showing the predictors of acute renal
failure requiring renal replacement therapy after cardiac surgery

Variables Odds ratio P value
 (95% confidence interval)

Age 1.12 (1.02-1.22) [odds ratio 0.013
 per year increment in age]

Preoperative creatinine 1.07 (1.01-1.14)* [odds 0.027
 ratio per 10 [micro]mol/l
 increment in preoperative
 creatinine concentrations]

Total red cells transfusion 1.27 (1.08-1.50) [odds ratio 0.003
 per unit of red cells
 transfused]

Urgency of the operation: 0.040

Scheduled 1

Urgent 6.43 (1.11-37.30) 0.038

Emergency 17.03 (1.61-179.85) 0.018

Received aprotinin 0.27 (0.06-1.20) 0.085

CABG with valve surgery 4.51 (0.76-26.98) 0.099

Gender, hypertension, diabetes mellitus, redo cardiac surgery (yes
or no), bypass graft with valve (yes or no), bypass time, cross-clamp
time and left ventricular function were included initially in the
model but not retained in the final model (P value >0.25). Hosmer
and Lemeshow chi-square and the Nagelkerke [R.sup.2] of the final
model was 10.36 (P=0.241) and 0.421, respectively.
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Author:Raajkumar, A.; Ho, K.M.; Cokis, C.; Slade, N.
Publication:Anaesthesia and Intensive Care
Geographic Code:8AUST
Date:May 1, 2008
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