JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Dietrich, W. Articles by Kriner, M. Search for Related Content PubMed PubMed Citation Articles by Dietrich, W. Articles by Kriner, M. Related Collections Cardiovascular Coagulation Pharmacology

---

CARDIOVASCULAR ANESTHESIA

High-Dose Aprotinin in Cardiac Surgery: Is High-Dose High Enough?

An Analysis of 8281 Cardiac Surgical Patients Treated with Aprotinin

Wulf Dietrich, MD, PhD^*, Raimund Busley, MD^*, and Monika Kriner, MSc

From the *Department of Anesthesiology, German Heart Center Munich; and Institute for Statistics and Epidemiology, Medical Faculty, Technical University, Munich, Germany.

Address correspondence and reprint requests to W. Dietrich, MD, PhD, German Heart Center Munich, Technical University, Munich, Germany. Address e-mail to dietrich{at}dhm.mhn.de.

	Abstract

Top Abstract Introduction METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
In this retrospective analysis we tested the hypothesis that aprotinin doses of more than 6 x 10⁶ kallikrein inhibiting units (KIU) per patient may be more effective in reducing bleeding compared with the high-dose regimen of 5–6 x 10⁶ KIU aprotinin. The aprotinin doses administered for 8281 adult cardiac surgical patients were correlated to body weight and time of operation and calculated in KIU per kg body weight and minute of operation. Linear and logistic regression models were designed to detect potential associations between dose and postoperative bleeding, transfusion, and other covariates. The 6-h chest tube drainage in the lowest quartile dosing group was 447 ± 319 mL (mean ± sd) compared with 360 ± 290 mL in the highest quartile dosing group (P < 0.001). The proportion of patients requiring allogeneic blood transfusion was reduced from 55% to 47% comparing the lowest with the highest dosing group (P < 0.01). Aprotinin dose was also an independent predictor for rethoracotomy for surgical hemostasis (1.9% in the highest quartile to 2.4% in the lowest dosing quartile; P < 0.01). The risk of renal failure requiring dialysis (2.3% in the highest dosing group vs 3.3% in the lowest dosing group; P < 0.01) or impairment of renal function (creatinine increase of 2 mg/dL postoperatively, 6.4% in the highest dosing group vs 10.0% in the lowest dosing group; P < 0.01) was lower with higher doses of aprotinin. Thus, there was no association between aprotinin dose and renal function. Our results support the hypothesis that a more individualized aprotinin regimen with potentially higher doses may optimize the effectiveness of aprotinin therapy in cardiac surgery.

	Introduction

Top Abstract Introduction METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The administration of high-dose aprotinin to reduce bleeding in cardiac surgery was introduced by Royston et al. almost 20 years ago (1). Since then, many studies have confirmed the effectiveness of this dosing regimen regarding reduction of blood loss and allogeneic blood transfusion (2,3). No additional studies are required to prove the blood-sparing effect of aprotinin in cardiac surgery (4).

This dosing regimen of aprotinin was introduced in cardiac surgery as the "Hammersmith" or high-dose regimen. Later on, lower aprotinin doses were investigated mostly for economic reasons because of the expense of the drug (5). However, a clear link between dose and bleeding tendency could be established (6): the higher the aprotinin dose, the greater the efficacy (7).

The high-dose regimen was developed to achieve aprotinin plasma concentrations of >200 kallikrein inhibiting units (KIU)/mL plasma to inhibit biologic kallikrein activity by 50% (8). The rationale for this high concentration was to inhibit platelet activation (1) and the activation of the intrinsic pathway of coagulation (9) with the consequence of reduced bleeding tendency and less inflammatory activation (10). However, this dose was based solely on theoretical calculation and was not confirmed in the clinical setting. Almost all studies measuring aprotinin plasma concentrations revealed much lower concentrations than the expected 200 KIU/mL, especially at the end of cardiopulmonary bypass (CPB) (11–14).

The high-dose regimen is a mixture of fixed dose, the 2 x 10⁶ KIU bolus to the patient and to the pump prime, and a time-dependent maintenance dose by continuous infusion of 5 x 10⁵ KIU/h. Depending on the duration of operation, this regimen results in a total aprotinin dose of 5–6 x 10⁶ KIU.

The dose is not weight-adjusted. Weight-adjusted doses have been proposed (15) but have not been extensively studied for safety and efficacy. Surprisingly, although the target aprotinin plasma concentration was not achieved in most studies (9,11,12), doses exceeding the high-dose regimen have not been tested so far.

The total administered dose of aprotinin varies in daily routine because, due to the continuous infusion, patients with longer operations may receive considerably more aprotinin than the recommended total dose of 6 x 10⁶ KIU. To investigate the association of aprotinin dose with bleeding tendency, we performed a retrospective analysis of our institutional database. The aim of the present investigation was to test the hypothesis that larger doses of aprotinin may be associated with reduced postoperative bleeding compared with lower doses.

	METHODS

Top Abstract Introduction METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
We analyzed the data of all adult patients undergoing cardiac surgery with the help of CPB treated with aprotinin (Trasylol®, Bayer, Leverkusen, Germany) between January 1, 1995 and December 31, 2003. The data used in this analysis were retrieved from the institutional database that includes data collected as part of the national quality assurance project of cardiac anesthesia (16). The database prospectively collects a comprehensive list of 238 prespecified items in all consecutive patients, including demographic, clinical, transfusion, and other outcome data. A study nurse, who was blinded to details of the present study, completed missing values of variables of interest from the medical records. The ethics committee of the medical faculty of the Technical University Munich approved the protocol. Because of the retrospective setting without a specific study intervention, informed consent was not obtained from the patients.

After identification of all adult patients receiving aprotinin, patients with maximum and minimum 5% duration of operation were excluded from the analysis, assuming, that patients with very long or extremely short operation times were outliers and would skew the results. In the remaining patients, the total aprotinin dose was divided by individual body weight and the skin incision-to-skin closure duration of operation in minutes, since the study is based on the assumption that a given amount of aprotinin administered over a shorter duration of operation to a patient with a lower body weight results in higher plasma concentrations, and thus, may be more effective than the same dose given to heavy patients over a longer duration of operation. This calculation resulted in an aprotinin dose in KIU per kilogram body weight and minute of operation (KIU/kgBW/min). In addition, the same calculation was performed with the duration of CPB instead of time of operation. The preoperative risk was assessed by the Cleveland Clinic Risk Score (15) in all patients.

The definite aprotinin dosing was at the discretion of the attending anesthesiologist. In almost all cases, a slightly modified high-dose protocol was applied. For safety reasons, and in contrast to the original description, the first bolus of the drug was postponed after sternotomy and not given until the surgeon was ready to cannulate the aorta quickly in case of a hypersensitivity reaction to the drug. Since the continuous infusion of 5 x 10⁵ KIU/h is not able to maintain constant plasma concentrations (12), some anesthesiologists used a continuous infusion of 1 x 10⁶ KIU/hour and repeated a bolus of 1 x 10⁶ KIU aprotinin after 120 min of CPB. The infusion was not stopped at a total dose of 6 x 10⁶ KIU. Therefore, this regimen resulted in much higher doses in operations lasting longer. Because not all anesthesiologists in the department adopted this technique, the different practice patterns resulted in a wide variation of total aprotinin doses.

Anesthesia was performed with sufentanil, midazolam, and propofol, supplemented with inhaled sevoflurane; neuromuscular blockade was achieved by either pancuronium bromide or rocuronium. CPB was performed in standard technique. The membrane oxygenator was primed with 1500–1800 mL crystalloid solution, the flow rate was set to 2.4 L/m², and the patient was moderately cooled to 32°C. Either cold crystalloid or blood cardioplegia was used to rest the heart. Intraoperative blood salvage by cardiotomy suction and retransfusion of the shed blood during CPB was used in all patients. Anticoagulation for CPB was achieved with porcine unfractionated heparin with a dose of 375 U/kg and controlled with the activated clotting time (ACT) with a target ACT of 480 s. If the ACT was <480 s an additional bolus of 125 U/kg heparin was added. After separation from CPB, heparin was antagonized by protamine chloride in a 1:1 ratio to the initial dose of heparin.

Postoperatively, the patients' lungs were ventilated in the intensive care unit until the patients warmed up to 37°C, the oxygenation, hemodynamics, and neurologic function were sufficient, and blood loss was <100 mL/h. Indication for repeat surgical hemostasis was driven by clinical judgment and a blood loss exceeding 200 mL in 2 consecutive hours.

Allogeneic packed red blood cells were transfused if the hematocrit decreased to <18% during CPB, below 21%–24% in the postoperative period, or if the patient's physiologic signs indicated a need to improve oxygen supply.

Renal dysfunction was defined as postoperative creatinine of at least 2 mg/dL or an increase over preoperative baseline levels of at least 0.7 mg/dL. Renal failure required new dialysis support.

Eighty-six items were considered relevant to the current study and entered in the dataset for statistical analysis. Continuous variables are given as mean ± sd. Categorical data are reported in percentages. The three primary end points were blood loss 6 h postoperatively, the amount of allogeneic blood transfusion during the hospital stay, and the occurrence of a rethoracotomy for bleeding. As mentioned, 10% of the patients were excluded from the analyses, namely those with the longest and shortest operation times. Type of operation was coded for coronary artery bypass graft (CABG), aorta ascending replacement, aortic valve replacement (AVR), mitral valve replacement or repair (MVR/R), combined aortic and mitral valve operation (A/MVR), and combined CABG and valve replacement (CABG plus valve). Patients with other operations were excluded. Collinearity diagnostics were performed by calculating the Spearman's rank correlation coefficient and the variance inflation factor (17) for all potential covariates. Multiple linear and logistic regression models were performed to detect potential associations between the outcome of one of the end points and the covariates age, gender, preoperative risk score, body weight, type of operation, aprotinin dose in KIU/kgBW/min, and previous cardiac surgery. Stepwise forward procedures with an inclusion significance level of 5% and an exclusion significance level of 10% were applied. To exemplify the results, the patients were divided into four groups according to the quartiles of the aprotinin dose in KIU/kgBW/min. Baseline characteristics of interest were compared using the Mann-Whitney test for continuous and the ² test for categorical covariates.

The impact of aprotinin dose on renal function was assessed with a multivariate logistic regression model, with renal failure as a dependent variable and all covariables that could be associated with aprotinin dose or hemorrhage as predictor variables. The discriminate power of these models was assessed by determination of the area under the receiver-operating-curve (c-statistics). Linear logistic regression models were constructed with aprotinin dose as an independent variable and the highest postoperative creatinine concentration or the difference between pre- and postoperative creatinine concentration respectively as the dependent variable.

SPSS statistical software (version 13) (SPSS, Chicago, IL) was used for statistics. A P value of <0.05 (two-tailed) was considered to indicate statistical significance.

	RESULTS

Top Abstract Introduction METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
We evaluated 9,746 patients, of which 8281 were included in the final analysis (Fig. 1). Demographics and intraoperative patient characteristics are presented in Table 1. The Spearman's correlation coefficient yielded no clue that the potential covariates were jointly correlated. Besides, we observed variance inflation factor values <2 for all variables (Tables 4 and 5). Thus there is no hint of multicollinearity of the predictors. Therefore, the authors assumed independence of the variables in the following analyses. The association between aprotinin dose and 6 h postoperative blood loss is given in Figure 2. The mean total aprotinin dose was 5.38 ± 0.86 x 10⁶ KIU with a variation from 1 to 12 x 10⁶ KIU. Totally 911 patients received a total aprotinin dose exceeding the 6 x 10⁶ KIU standard high-dose.

View larger version (15K): [in this window] [in a new window]   Figure 1. Study design and main results. In this analysis, 128 patients were excluded because data for one of the variables were missing.

View larger version (47K): [in this window] [in a new window]   Figure 2. Box plots of aprotinin dose in KIU/kg/min of operation and 6 h blood loss. While the aprotinin dose increased with the dosing quartile, the blood loss decreased over the cohorts.

The analysis of the four dosing groups demonstrated a reduction of postoperative chest tube drainage with increased dose (Table 2, Fig. 2): the higher the dose per kilogram body weight and minute of operation the lower was the postoperative 6 h blood loss. Transfusion requirements were also significantly reduced in patients with higher aprotinin doses. Since there was no proportionate distribution of types of operation, we compared the results for patients undergoing only CABG surgery (n = 4762) separately (Table 3). The results from this homogenous subgroup did not differ from that of the whole study population.

The results of the multiple regression models for the dependent variables 6 h blood loss (R² = 0.225) and amount of allogeneic blood (R² = 0.401) are shown in Tables 4 and 5. The c-index for the logistic regression model (rethoracotomy) was 0.648 (Table 6). All models demonstrate that the higher the aprotinin dose, the lower the blood loss, the amount of allogeneic blood, and the incidence of rethoracotomy, respectively. One-hundred KIU more of aprotinin/kgBW/min results in 11.7 mL less blood loss in 6 h, or 100 additional KIU of aprotinin/kgBW/min decreases the probability of a rethoracotomy about 20% (OR = 0.998; CI 0.997–1.000). Female patients had a reduced bleeding tendency (24-h chest tube drainage: 565 ± 434 vs 711 ± 477 mL; P < 0.001) (ß = –63.1; CI –82.47 to –43.72) but a higher total transfusion requirement (2.46 ± 3.3 vs 1.46 ± 3.1 U; P < 0.001) (ß = 0.46; CI 0.28–0.65) as compared to male patients.

The adjustment of our dosing calculation on CPB duration instead of duration of operation did not alter the results substantially (data not shown).

Linear and logistic regression analysis did not demonstrate an association between aprotinin dose and renal outcome. The c-index for the logistic regression model with renal failure as an outcome was 0.811 (Table 7). Preoperative creatinine, preoperative risk score, preoperative ejection fraction, and age were predictors for the increase of postoperative creatinine and the difference in pre- to postoperative creatinine. There was even a small (CI –0.001 to 0.00; P < 0.001) inverse association between aprotinin dose and postoperative creatinine increase. Higher aprotinin doses per kgBW and minute of operation postoperative was associated with less renal impairment. This analysis was also performed with the total dose of aprotinin in KIU and the maximum postoperative creatinine as a dependent variable (data not shown). Again, in this model there was no association between total dose of aprotinin and renal impairment.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The present observational study data provide some evidence that higher doses of aprotinin in comparison to the traditional high-dose or Hammersmith regimen proposed by Royston et al. (1) may be associated with less bleeding and reduced transfusion requirement in cardiac surgery. Our models demonstrate that apart from the aprotinin dose other variables influence bleeding and transfusion requirement. However, in all models aprotinin dose remained a significant predictor. We attained a dose of 447 ± 65 KIU/kg/min in the upper quartile of dose. In comparison, the traditional high-dose given to an 80 kg patient in a 4 h operation would theoretically result in a dose of 310 KIU/kg/min, which is 44% less than our highest dosing quartile. No doubt, the current high-dose regimen is a potent and effective tool for reducing bleeding in cardiac surgery (18). However, the current data call into question whether a total amount of 5–6 x 10⁶ KIU treatment, regardless of duration of operation or body weight, is really the most effective dose for all aprotinin indications. Future, randomized, controlled trials should investigate this question.

We selected blood loss via chest tube drainage as the primary end point of our investigation because it most objectively reflects the drug's influence on bleeding. Gender, preoperative risk score, type of operation, and aprotinin dose were independently associated with bleeding tendency. Although a higher risk score was significantly more prevalent in the fourth dose quartile, blood loss was significantly reduced in this patient group. There was an uneven distribution of types of operations among the dose groups: patients undergoing AVR had a significantly shorter operation times and were therefore over-represented in the higher dose group. Hence, we tested our model in the homogeneous subgroup of patients undergoing CABG surgery separately and found similar results compared with the entire patient population (Table 3).

The optimal dose of aprotinin in cardiac surgery is still a matter of discussion: in response to the first promising results, the high-dose regimen of aprotinin has been subject to extensive research and an almost innumerable amount of studies (19) have confirmed the primary results. Surprisingly, studies with higher doses have not been performed, despite the early consideration of Royston that higher doses may be more effective for some indications (10). Instead, subsequent studies investigated lower doses. These studies were not based merely on pharmacologic considerations, but rather, were driven by economic concerns caused by the expense of the drug (5,6).

Admittedly, the established high-dose regimen, or even a lower dose of aprotinin, is effective in reducing bleeding and transfusion requirements in most cardiac surgical patients (2,3). Aprotinin, at currently recommended dosing, completely inhibits plasmin, an important enzymatic pathway that appears to contribute to impaired platelet function and bleeding and may also, with high plasma concentrations, attenuate thrombin generation. The target aprotinin plasma concentration was set to 200 KIU/mL (10), which should inhibit biologic kallikrein by 50% (8). However, this is a rather arbitrary number. Why should we inhibit kallikrein by just 50% and not by more or less? Do we really clinically accomplish this task with the so-called high-dose regimen? It was demonstrated that the target plasma concentration of 200 KIU/mL could not be achieved with the currently recommended dosing (12). Although we have stunning clinical information about the use of aprotinin in cardiac surgery, there are many open questions about the mode of action of this drug and the most effective dose or plasma concentration.

With respect to our own results (9,12), we proposed modifying the dosing of aprotinin. Because of the possibility of anaphylactic reactions (20), we postponed the first bolus and the continuous infusion of aprotinin until the surgeon was ready to initiate CPB. Instead, we increased the continuous infusion rate to 1 x 10⁶ KIU/h and, in pump runs >120 min, we repeated a bolus injection of 1 x 10⁶ KIU to avoid a decline of aprotinin plasma concentration.

Recent studies claimed there was a negative effect of aprotinin on renal function (21), which ought to be dose-dependent (22). In the present dataset, we could not identify such a dose-effect: regression analysis identified preoperative creatinine (OR 2.61, CI 2.07–3.28; P < 0.001), preoperative risk score (OR 1.13; CI 1.07–1.19; P < 0.001), and age (OR 1.03; CI 1.01–1.06, P = 0.01) as predictors of the incidence of postoperative renal dialysis. In contrast, there was even a small inverse association between dose and renal function. These different results may be caused by the fact that, in the cited studies (21,22), aprotinin was selectively limited to patients with the highest risk of hemorrhage and, presumably, to those patients with a higher risk of postoperative renal impairment. It is questionable whether propensity scoring could correct this possible bias (23). In contrast to these studies, in our investigation, aprotinin had a broader indication and patients of all risk groups received aprotinin.

There are some potential limitations in the present study. For example, it is based on the retrospective analysis of a large institutional database with all the inherent limitations of retrospective analyses. This analysis permits only associations and cannot imply causation. It can only be hypothesis-generating, since none of the hypotheses tested in this investigation was prespecified. It was just recently emphasized (24,25) that only the analysis of large databases may accomplish the generation of hypotheses if there are only slight differences in outcome. A second limitation of the current study is that it could not consider plasma concentrations of aprotinin. The underlying consideration is that higher doses of aprotinin given over a shorter time period are more effective because they may result in higher plasma concentrations. This sounds reasonable, but has not yet been proven by clinical studies measuring plasma concentrations of aprotinin. Third, there may be unknown influences, not identified as potential predictors for bleeding or transfusion requirement in the regression analysis, that were not identified in this investigation, and therefore, could not be controlled for. Finally, our analysis provided no evidence of a dose-dependent association of aprotinin on renal function. However, since all patients received aprotinin and since we excluded all patients without that drug, we can only state that the dose had no impact; we cannot preclude any general effect of aprotinin on renal function. The incidence of renal dysfunction and renal insufficiency was much lower in our dataset than that reported in other studies (22). The study was not designed to investigate other possible side effects.

	CONCLUSIONS

Top Abstract Introduction METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The implications of our findings are several-fold. They do not prove, but only suggest the hypothesis, that higher doses of aprotinin may be more effective compared to lower doses as achieved with the traditional high-dose regimen. The traditional, and effective, high-dose regimen is a fixed-dosed regarding body weight and partially disregarding the duration of the operation. It is conceivable that the "one-size-fits-all" approach may not generate optimal results, and that a more individualized high-dose regimen could optimize the effectiveness of aprotinin administration. The current study supports this consideration.

	Footnotes

 
Accepted for publication July 7, 2006.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. Royston D, Taylor KM, Bidstrup BP, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289–91.[ISI][Medline]
2. Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940–7.[ISI][Medline]
3. Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004;128:442–8.[Abstract/Free Full Text]
4. Young C, Horton R. Putting clinical trials into context. Lancet 2005;366:107–8.[ISI][Medline]
5. Lemmer JH, Dilling EW, Morton JR, et al. Aprotinin for primary coronary artery bypass grafting: A multicenter trial of three dose regimens. Ann Thorac Surg 1996;62:1659–67.[Abstract/Free Full Text]
6. Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236–44.[Abstract/Free Full Text]
7. Smith PK, Muhlbaier LH. Aprotinin: safe and effective only with the full-dose regimen. Ann Thorac Surg 1996;62:1575–7.[Free Full Text]
8. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneim Forsch/Drug Res 1983;33:479–94.[Medline]
9. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation pattern in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119–26.[ISI][Medline]
10. Royston D. High-dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vasc Anesth 1992;6:76–100.[Medline]
11. Bidstrup BP, Royston D, Sapsfort RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989;97:364–72.[Abstract]
12. Dietrich W, Schopf K, Spannagl M, et al. Influence of high-and low-dose aprotinin on activation of hemostasis in open heart operations. Ann Thorac Surg 1998;65:70–7.[Abstract/Free Full Text]
13. Mossinger H, Dietrich W, Braun SL, et al. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg 2003;75:430–7.[Abstract/Free Full Text]
14. Nuttall GA, Fass DN, Oyen LJ, et al. A study of a weight-adjusted aprotinin dosing schedule during cardiac surgery. Anesth Analg 2002;94:283–9.[Abstract/Free Full Text]
15. Royston D, Cardigan R, Gippner-Steppert C, Jochum M. Is perioperative plasma aprotinin concentration more predictable and constant after a weight-related dose regimen? Anesth Analg 2001;92:830–6.[Abstract/Free Full Text]
16. Schirmer U, Dietrich W, Luth JU, Baulig W. The extended cardio-anaesthetic data-set—modular completion of the DGAI Kerndatensatz Anasthesie. Anasthesiologie & Intensivmedizin 2000;41:683–91.
17. Belsley D, Kuh E, Welsch R. Regression diagnostics: identifying influential data and sources of collinearity. New York: Wiley, 1980.
18. Henry DA, Moxey AJ, Carless PA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001;1:CD001886.[Medline]
19. Fergusson D, Glass KC, Hutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clin Trials 2005;2:218–32.[Abstract/Free Full Text]
20. Dietrich W, Späth P, Zühlsdorf M, et al. Anaphylactic reactions to aprotinin reexposure in cardiac surgery—relation to antiaprotinin immunoglobulin G and E antibodies. Anesthesiology 2001;95:64–71.[ISI][Medline]
21. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327–38.[ISI][Medline]
22. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353–65.[Abstract/Free Full Text]
23. Levy JH. Aprotinin versus tranexamic acid: the controversy continues. Transfusion 2006;46:319–20.[ISI][Medline]
24. Tremper KK. Anesthesia information systems: developing the physiologic phenotype database. Anesth Analg 2005;101:620–1.[Free Full Text]
25. Hunter D. First, gather the data. N Engl J Med 2006;354:329–31.[Free Full Text]

This article has been cited by other articles:

				D. L. Ngaage, A. R. Cale, M. E. Cowen, S. Griffin, and L. Guvendik Aprotinin in primary cardiac surgery: operative outcome of propensity score-matched study. Ann. Thorac. Surg., October 1, 2008; 86(4): 1195 - 1202. [Abstract] [Full Text] [PDF]

				M. C. Grant, Z. Kon, A. Joshi, E. Christenson, S. Kallam, N. Burris, J. Gu, and R. S. Poston Is Aprotinin Safe to Use in a Cohort at Increased Risk for Thrombotic Events: Results From a Randomized, Prospective Trial in Off-Pump Coronary Artery Bypass Ann. Thorac. Surg., September 1, 2008; 86(3): 815 - 822. [Abstract] [Full Text] [PDF]

				A. D. Shaw, M. Stafford-Smith, W. D. White, B. Phillips-Bute, M. Swaminathan, C. Milano, I. J. Welsby, S. Aronson, J. P. Mathew, E. D. Peterson, et al. The Effect of Aprotinin on Outcome after Coronary-Artery Bypass Grafting N. Engl. J. Med., February 21, 2008; 358(8): 784 - 793. [Abstract] [Full Text] [PDF]

				P. J. Van der Linden, J.-F. Hardy, A. Daper, A. Trenchant, and S. G. De Hert Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome? Br. J. Anaesth., November 1, 2007; 99(5): 646 - 652. [Abstract] [Full Text] [PDF]

				W. Dietrich, A. Ebell, R. Busley, and A.-L. Boulesteix Aprotinin and Anaphylaxis: Analysis of 12,403 Exposures to Aprotinin in Cardiac Surgery Ann. Thorac. Surg., October 1, 2007; 84(4): 1144 - 1150. [Abstract] [Full Text] [PDF]

				M. D. McEvoy, S. T. Reeves, J. G. Reves, and F. G. Spinale Aprotinin in Cardiac Surgery: A Review of Conventional and Novel Mechanisms of Action Anesth. Analg., October 1, 2007; 105(4): 949 - 962. [Abstract] [Full Text] [PDF]

				M. Buerke, D. Pruefer, D. Sankat, J. M. Carter, U. Buerke, M. Russ, A. Schlitt, I. Friedrich, J. Borgermann, C. F. Vahl, et al. Effects of Aprotinin on Gene Expression and Protein Synthesis After Ischemia and Reperfusion in Rats Circulation, September 11, 2007; 116(11_suppl): I-121 - I-126. [Abstract] [Full Text] [PDF]

				C. W. Hogue and M. J. London Aprotinin Use During Cardiac Surgery: A New or Continuing Controversy? Anesth. Analg., November 1, 2006; 103(5): 1067 - 1070. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Dietrich, W. Articles by Kriner, M. Search for Related Content PubMed PubMed Citation Articles by Dietrich, W. Articles by Kriner, M. Related Collections Cardiovascular Coagulation Pharmacology

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999