JTCS Speed Up Your Browser
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Christoph Ochsenfahrt
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wendel, H. P.
Right arrow Articles by Hoffmeister, H.-E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wendel, H. P.
Right arrow Articles by Hoffmeister, H.-E.

J Thorac Cardiovasc Surg 1995;109:1164-1172
© 1995 Mosby, Inc.

CARDIOPULMONARY BYPASS,
MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Lower cardiac troponin T levels in patients undergoing cardiopulmonary bypass and receiving high-dose aprotinin therapy indicate reduction of perioperative myocardial damage

Hans Peter Wendel, PhDa, Wolfgang Heller, PhDa, Josef Michel, MDa, Gabriel Mayer, MDc, Christoph Ochsenfahrt, MDa, Uwe Graeter, MDa, Jochen Schulze, MDa, Hans-Martin Hoffmeister, MDb, Hans-Eberhardt Hoffmeister, MDa


Tübingen, Germany

Received for publication Sept. 14, 1993. Accepted for publication Sept. 8, 1994. Address for reprints: Hans Peter Wendel, PhD, Department of Thoracic and Cardiovascular Surgery, University of Tubingen, 72076 Tubingen, Germany.

Abstract

Nowadays in many European heart centers the activation of the fibrinolytic system, always occurring during cardiopulmonary bypass, is routinely reduced by high-dose application of the proteinase inhibitor aprotinin (total of >4 million KIU). In this study parameters of myocardial ischemic injury were investigated with the aim of identifying further benefits of aprotinin, particularly the protection of the myocardium during the ischemic period of aortic crossclamping. Forty patients with coronary artery disease who underwent aorta-coronary bypass grafting were randomly and in a double-blind fashion divided into two groups, one that received high-dose aprotinin therapy and one that received only saline solution. Markers such as troponin T, with high specificity for detection of myocardial ischemia and infarction, and markers with more general specificity such as creatine kinase, its isoenzyme, and lactate dehydrogenase showed significantly increased values after ischemia in both groups. In patients who received high-dose aprotinin therapy 3 days after cardiopulmonary bypass all parameters measured showed significantly lower levels compared with those in the control group. Therefore we can presume that the application of high-dose aprotinin provides myocardial protection from perioperative ischemic injury. (J THORACCARDIOVASCSURG1995;109:1164-72)

Despite well-established procedures such as hypothermia and cardioplegia, perioperative myocardial infarction during cardiopulmonary bypass (CPB) still occurs more frequently than in 6% of the cases. Go Go 1-3 This incidence is still problematic and difficult to diagnose in less severe cases. It represents an unsolved phenomenon in clinical consideration of prognostic implications. Go 1 For diagnosis of perioperative myocardial infarction changes in plasma concentrations of creatine kinase (CK), its isoenzyme (CK-MB), and lactate dehydrogenase (LDH) are generally measured in connection with analysis of the electrocardiogram or myocardial scintigraphy. Go Go 1,4 With the development of a new one-step enzyme immunoassay for cardiac troponin T by Katus and co-workers Go 5 a much more cardiac-specific and sensitive method for detection of perioperative myocardial ischemic injury is now available. Go Go 6-8

Cardiac troponin T belongs to the tropomyosin-binding proteins of the troponin regulatory complex, which is located on the thin myofilaments (actin, tropomyosin, and troponin). It differs from skeletal troponin T by 6 to 11 amino acid residues Go Go 9,10 and therefore if detected in serum is a highly specific marker for destruction of cardiac myocytes.

Postoperative bleeding is still a major complication in heart operations, Go Go 11,12 the reasons for which are multifactoral: the contact of the blood with the artificial devices of the CPB circuit causes a drop in platelet count and a reduction in platelet functional activity. Go Go Go 11,13-16 In addition, there is an activation of the contact pathway of intrinsic coagulation (that is, factor XII and the kallikrein-kinin systems), Go Go 17-22 a reinforced activation of the fibrinolytic andcomplement systems, Go Go Go 19,23,24 and degranulation of neutrophils. Go Go 25-27

In recent years it has been demonstrated repeatedly that high-dose aprotinin therapy in heart operations significantly reduces postoperative blood loss by direct and indirect inhibition of fibrinolysis Go Go 28-37 along with a reduced, probably plasmin-mediated, degranulative effect on the adhesion glycoproteins (glycoprotein Ib) of the platelet membrane. Go Go 38-45

In this randomized double-blind study findings in 40 patients undergoing CPB were investigated for further benefits of the serine proteinase inhibitor aprotinin with regard to myocardial protection from ischemic injury during the period of aortic crossclamping.

PATIENTS AND METHODS

Forty patients with coronary artery disease who underwent elective aorta-coronary bypass grafting were entered in this study. Approval for this study was given by the local ethical committee and, after being fully informed verbally, all participating patients gave written consent.

Exclusion criteria were reoperations, preoperative low left ventricular function (ejection fraction <=30%, left ventricular end-diastolic pressure >=20 mm Hg), preoperative hemoglobin level 12 gm/dl or less, serum creatinine level 2 mg/dl or greater, acquired or hereditary thrombopathia, allergic diathesis, and previous application of aprotinin. Acetylsalicylic acid therapy was stopped at least 7 days before operation. Patients with preoperative autologous blood transfusion or intraoperative or postoperative infusion of fresh frozen plasma were not accepted.

Patients were randomly and in a double-blind fashion assigned to two groups: 20 patients received high-dose aprotinin (Trasylol) and 20 patients were administered physiologic saline solution (GoTable I). Aprotinin and the placebo were provided by the manufacturer (Bayer AG, Leverkusen, Germany) in identical bottles that differed only in the random numbers on their labels.


View this table:
[in this window]
[in a new window]
  		Table I. Blood sampling time and aprotinin/heparin application schedule before, during, and after ECC
 
Anesthesia was standardized for all patients and involved induction by fentanyl (Fentanyl-Janssen), thiopental (Trapanal), midazolam (Dormicum), and vecuronium (Norcuron) and maintenance by fentanyl, midazolam, and vecuronium. A dose of 3.5 mg/kg body weight heparin (Liquemin) was given shortly before the start of CPB. Activated clotting time was measured with the use of Hemotec kaolin cartridges (Medtronic Cardiopulmonary, Anaheim, Calif.) to avoid artificially prolonged activated clotting time values in the presence of aprotinin. Go 46 If activated clotting time levels dropped below 480 seconds further heparin was administered. The heparin was antagonized with protamine hydrochloride in the ratio of 1:1 shortly after extracorporeal circulation (ECC) was completed.

Surgical and bypass procedures were standardized.

Oxygenation was done by a Cobe CML-Excel membrane oxygenator (Cobe Laboratories, Lakewood, Colo) with a blood flow of 2.4 L/m2 per minute in hypothermia (rectal temperature 28° C). Myocardial protection was achieved by 30 ml/kg body weight cold (4° C) cardioplegic solution (HTK Bretschneider, F. Köhler Chemie, Alsbach, Germany).

Postoperative blood loss was measured by thoracic drainage volumes in 2-hour periods until removal of chest tubes.

Serial preoperative and postoperative electrocardiograms were registered on a 12-channel system and assessed for the occurrence of new Q waves or a greater than 50% R reduction in at least two chest leads.

Cardiac muscle troponin T levels were measured by a one-step enzyme immunoassay Go 5 (Boehringer Mannheim, Mannheim, Germany) with use of two highly specific monoclonal antibodies directed against two different epitopes of cardiac troponin T molecule Levels of enzymes CK, CK-MB, and LDH were determined with test kits from Boehringer Mannheim. Monitoring of aprotinin plasma levels was conducted according to the method of Mueller-Esterl and associates Go 47 with use of an enzyme-linked immunosorbent assay. Kallikrein inhibition capacity was measured by determining plasma inhibition of plasma kallikrein with the chromogenic peptide substrate S 2302 (Chromogenix, Mölndal, Sweden).

Statistical analysis was done by the SPSS statistical software package (SPSS Inc, Chicago, Ill.). Results are expressed as mean values plus or minus the standard deviation. Differences between mean values were assessed by univariate analysis of variance and Student's t test. P values of 0.05 or less were considered significant.

RESULTS

Demography
The distribution of demographic data showed homogeneous collectives. The two patient groups did not differ significantly in age, weight, height, body surface area, red cell volume, crossclamping time, number of grafts, or duration of operation (GoTable II).


View this table:
[in this window]
[in a new window]
  		Table II. Demographic data and distribution of operative procedures
 
Infarction rate
In two patients of the entire population perioperative myocardial infarction could be diagnosed by new Q waves in electrocardiogram. Both patients came from the placebo group and were excluded from statistical analysis of all parameters reported. Both cases had the highest peak values of CK (628 and 1863 U/L), CK-MB (58 and 94 U/L), LDH (578 and 1788 U/L), and troponin T (18.2 and 12.1 ng/ml).

Aprotinin monitoring (Fig 1)
Serum aprotinin concentrations were determined 15 and 45 minutes after total ECC. At both sampling times the concentrations were much higher than the required 200 KIU/ml. Mean values of the samples were 341.8 ± 60.9 and 251.7 ± 53.5 KIU/ml, respectively. Therefore, analogous to these levels, very high levels of kallikrein inhibition capacity up to 387.8% ± 88.4% (sampling time 3) were obtained in the aprotinin group. This demonstrates clearly that sufficient aprotinin for complete inhibition of plasma kallikrein with use of this regimen of application was obtained.



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 1.Black columns (mean ± standard deviation) show significantly increased kallikrein inhibition (KKI, left ordinate) in aprotinin group in correlation with concentrations of aprotinin (line; KIU/ml, right ordinate).

 
Blood loss and blood transfusion
Blood loss (Fig. 2) from the thoracic drainage volumes when the tubes were removed was significantly lower in the aprotinin group (p = 0.021). The total in the placebo group was 1353.6 ± 746.5 ml and in the group treated with aprotinin was only 878.9 ± 438.0 ml. By means of high-dose aprotinin therapy a reduction in blood loss of 35.1% could be achieved. In the aprotinin group 50% of the patients did not need any donor blood in comparison with only 18% in the control group. Therefore the aprotinin group received on average 1.25 units of blood and the patients in the placebo group 3.18 units.



View larger version (25K):
[in this window]
[in a new window]
  		Fig. 2. Cumulative blood loss (mean ± standard deviation). Patients treated with high-dose aprotinin had significant postoperative reduction in blood loss from thoracic drainage tubes from first 2 hours after arrival (A) in intensive care unit until drainage tube removal (DR).

 
Infarction markers
Troponin T (Fig. 3)
Preoperative values of troponin T were below the detectable level. Myocardial perfusion after the total ECC period showed significantly elevated release of troponin T in both groups. In the aprotinin group only three patients had serum concentrations higher than 5 ng/ml, whereas seven patients in the control group (without the two excluded infarction cases) had concentrations higher than this level. In all postoperative determinations the placebo group without aprotinin showed significantly (p <= 0.01) higher values on the first postoperative day.



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 3. Significantly increased troponin T values (mean ± standard deviation) in all patients after ECC in comparison with preoperative values. After aortic crossclamping period patients with high-dose aprotinin therapy showed markedly reduced serum concentrations of troponin T. Two patients with diagnosed myocardial infarction (lines) showed high elevated levels.

 
Enzymes.
Elevated CK levels were measured postoperatively in the placebo group (Fig. 4). Because of the high standard deviation and small group size no statistically significant differences could be detected, but there was a strong trend toward lower values in the aprotinin group. On the third postoperative day the control group had a mean level of 191.7 ± 446.4 U/L and the aprotinin group only 80.3 ± 62.6 U/L. Levels of both the isoform CK-MB (Fig. 5) and LDH (Fig. 6) showed a large increase after ischemia. Mean values on the third postoperative day were significantly lower (p <= 0.01) in the aprotinin group.



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 4. After operation levels of CK (mean ± standard deviation) increased significantly in both groups; however, lower values were seen in patients receiving high-dose aprotinin therapy.

 


View larger version (23K):
[in this window]
[in a new window]
  		Fig. 5. After bypass, patients from control group showed higher levels of CK-MB (mean ± standard deviation) than those in aprotinin group. Difference was significant 3 days after CPB.

 


View larger version (24K):
[in this window]
[in a new window]
  		Fig. 6. LDH levels (mean ± standard deviation) in patients receiving high-dose aprotinin therapy were significantly lower than those in control group on third day after operation.

 
DISCUSSION

The results of reduced blood loss from thoracic drainages indicate the well-known beneficial effect of aprotinin in CPB. We therefore recommend the routine application of this proteinase inhibitor to minimize blood transfusion and the associated risk of infection.

In this study with high-dose aprotinin therapy we were able to demonstrate a suspected protective effect on the myocardium. Common enzymatic diagnostic indicators of perioperative myocardial infarction are not specific enough in cardiac operations to differentiate between destruction of skeletal and myocardial tissues. Go Go 7,48 With the use of electrocardiograms or myocardial scintigraphy it is also difficult to diagnose myocardial necrosis, especially in patients with previous myocardial infarction. We therefore only diagnose a perioperative myocardial infarction from the electrocardiogram in those patients in whom new significant signs of a transmural myocardial infarction were displayed after operation. Minor changes in the T wave that may be a result of multiple causes do not have a sufficient diagnostic accuracy. They were therefore not taken into consideration for the diagnosis of a perioperative transmural infarction. Thus a limitation of this study is the fact that the perioperative electrocardiogram does not provide a "gold standard" (which other studies confirm Go 1 ) with the result that minor nontransmural myocardial infarctions cannot be excluded in both groups.

With the introduction of a new one-step enzyme immunoassay for cardiac troponin T, Go 5 an extremely sensitive method for detectionof myocardial cell necrosis is now available. Go Go 6-8 With this specific marker we can detect the efficacy of different procedures of myocardial protection and surgical techniques. All the infarction parameters measured in this study showed corresponding results. Incidence of new Q waves correlated with markedly increased levels of enzymes and troponin T. In nearly all patients undergoing CPB ischemic tissue damage occurred, but in the group treated with high-dose aprotinin a significantly smaller injury was detectable.

Fifteen years ago, Diaz and associates Go 49 conducted histologic investigations in dogs with regional ischemia and found both lower CK levels and less myocardial destruction in the aprotinin group. Up to now only a few publications have appeared that deal with this subject in human beings. Hjelms and colleagues Go 50 found no difference in treatment with or without aprotinin in their investigations on human CPB. However, they only applied very small doses of 200,000 KIU initially and then 20,000 KIU/hour. On the basis of our experience and knowledge to date blood loss and presumably myocardial protection cannot be influenced with use of such a small dosage of aprotinin. Go Go 28-36 However,corresponding to our results, Sunamori and associates Go Go 51-53 found lower enzyme levels in patients who received aprotinin. With the administration of aprotinin by intravenous injections preceding aortic clamping, by intracardiac perfusion after aortic clamping, or with the use of both methods Gabrielescu and colleagues Go 54 detected normalized histochemical reactions of proteases together with the ultrastructural organization of the myocardial fibers in experiments with monkeys, mice, and rats.

The mechanism of the protective effect on the myocardium cannot yet be explained. One possibility is that inhibition of local or circulating kinins, or both types of kinins, may be involved inasmuch as activation and aprotinin-dependent inhibition of kinin systems in CPB have been documented. Go 33 Our results show markedly and significantly enhanced kallikrein inhibition in the aprotinin group (Fig. 1). Higher levels of kallikrein would lead to increased release of bradykinin from high-molecular-weight kininogen. Elevated bradykinin levels are possibly responsible for increased myocardial capillary permeability and the occurrence of interstitial edema. Additionally, the inhibition of membrane serine proteinases by aprotinin may intercept membrane permeabilization, thus impairing the proteolytic cascades triggered by anoxia. Bayley and Fawzi Go 55 showed that the application of aprotinin protects the myocardial fibers from the lytic action of proteases on the sarcolemma by preventing the splitting of sarcolemmal fixing sites of Ca2+ and the extracellular Ca2+ penetration into the cell. In rabbits with experimental myocardial ischemia an aprotinin-dependent limitation of proteolysis in the cytoplasmatic and mitochondrial-lysosomal fractions was found Go 55 together with a membrane stabilizing effect. Go 56

Whatever the reason for its efficacy we suggest that high-dose aprotinin therapy in patients undergoing CPB is of therapeutic benefit not only in reducing blood loss, but also in protecting the myocardium against ischemic injury.

Acknowledgments

This paper is dedicated to Prof. Dr. W. Heller on his sixty-fifth birthday.

Footnotes

From the Department of Thoracic and Cardiovascular Surgerya and the Department of Internal Medicine III,b University of Tübingen, Tübingen, Germany, and Bayer AG, Wuppertal, Germany. Back

References

  1. Force T, Hibbert P, Weeks GW, et al. Perioperative myocardial infarction after coronary artery bypass surgery: clinical significance and approach to risk stratification. Circulation 1990;82:903-12.[Abstract/Free Full Text]
  2. Conti VR, Bertranou EG, Blackstone EH, Kirklin JW, Digerness ST. Cold cardioplegia versus hypothermia for myocardial protection. J THORAC CARDIOVASC SURG 1978;76:577-86.[Abstract]
  3. Stiles QR, Kirklin JW. Myocardial preservation symposium. J THORAC CARDIOVASC SURG 1981;82:870-82.[Medline]
  4. Cummins B, Auckland ML, Cummins P. Cardiac-specific troponin T radioimmunoassay in the diagnosis of acute myocardial infarction. Am Heart J 1987;113:1333-44.[Medline]
  5. Katus HA, Loser S, Hallermayer K, et al. Development and in vitro characterization of a new immunoassay of cardiac troponin T. Clin Chem 1992;38:386-93.[Abstract/Free Full Text]
  6. Braun S, Beer U, Löschenkohl K, Barankay A, Sebening F, Vogt W. Troponin T, Kreatinkinase-Isoformen und Glykogenisophosphorylase BB bei kardiochirurgischen Eingriffen [Abstract]. Eur J Clin Chem Clin Biochem 1991;29:610.
  7. Mair J, Wieser Ch, Seibt I, et al. Troponin T to diagnose myocardial infarction in bypass surgery. Lancet 1991;337:334-5.
  8. Mair J, Dienstl F, Puschendorf B. Cardiac troponin T in the diagnosis of myocardial injury. Crit Rev Clin Lab Sci 1992;29:31-57.[Medline]
  9. Pearlstone JR, Carpenter MR, Smillie LB. Amino acid sequence of rabbit cardiac troponin T. J Biol Chem 1986;261:16795-810.[Abstract/Free Full Text]
  10. Briggs MM, Schachat F. N-terminal amino acid sequences of three functionally different troponin T isoforms from rabbit fast skeletal muscle. J Mol Biol 1989;206:245-9.[Medline]
  11. Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1991;76:1680-97.[Abstract/Free Full Text]
  12. Kalmar P, Krebber HJ, Pokar H, et al. Bioadhesives in cardiac and vascular surgery. Thorac Cardiovasc Surg 1982;30:230-1.[Medline]
  13. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985;29:236-61.[Medline]
  14. Uden DL, Seay RE, Kriesmer PJ, Cipolle RJ, Payne R. The effect of heparin on three whole blood activated clotting tests and thrombin time. Trans Am Soc Artif Intern Organs 1991;37:88-91.
  15. Fish K, Sarnquist C, von Steenis C, et al. Prospective randomized study of the effect of prostacyclin on platelets and blood loss during coronary bypass operations. J THORAC CARDIOVASC SURG 1986;91:436-42.[Abstract]
  16. Rocha ER, Llorens R, Paramo R, Arcas R, Cuesta B, Trenor A. Does desmopressin acetate reduce blood loss after surgery in patients on cardiopulmonary bypass. Circulation 1988;77:1419-23.
  17. Schapira M, Despland E, Scott CF, Boxer LA, Colman RW. Purified human plasma kallikrein aggregates human blood neutrophils. J Clin Invest 1982;69:1199-202.
  18. Stancikova M, Rybak M, Simonianova K, Ondrasik M. Influence of human plasma kallikrein on lysosomal enzyme release from polymorphonuclear leucocytes. Agents Actions 1991;32:209-12.[Medline]
  19. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. F XII [Review]. Blut 1990;61:258-66.[Medline]
  20. Gallimore MJ. Plasma-Prekallikrein. Hamostaseologie 1987;7:166-71.
  21. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Studies on components of the plasma kallikrein-kinin system in patients undergoing cardiopulmonary bypass. In: Greenbaum LW, Margolis H, eds. Kinins IV: advances in experimental medicine and biology. Vol. 198 B. New York: Plenum Press, 1986:385-91.
  22. Gallimore MJ, Fuhrer G, Heller W, Hoffmeister HE. The effects of plasma kallikrein and ß F XIIa on blood components circulating in a cardiopulmonary bypass machine [Abstract]. Thromb Haemost 1989;62:68.
  23. Kirklin JK, Westaby S, Blackstone E, Kirklin JW, Chenoweth D, Pacifico A. Complement and the damaging effect of cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1993;86:845-57.[Abstract]
  24. Craddock PR, Hammerschmidt D, White JG, Dalmasso AP, Jacob HS. Complement (C5a)-induced granulocyte aggregation in vitro. J Clin Invest 1977;60:260-4.
  25. Gnanadurai TV, Branthwaite MA, Colbeck JF, Welman E. Lysosomal enzyme release during cardiopulmonary bypass. Anaesthesia 1977;32:743-8.[Medline]
  26. Wachtfogel YT, Kucich U, Greenplate J, et al. Human neutrophil degranulation during extracorporeal circulation. Blood 1987;69:324-30.[Abstract/Free Full Text]
  27. Wachtfogel YT, Kucich U, James HL, et al. Human plasma kallikrein releases neutrophil elastase during blood coagulation. J Clin Invest 1983;72:1672-7.
  28. Alajmo F, Calamai GF, Perna A, Melissano G. High dose aprotinin: hemostatic effects in open heart surgery. Ann Thorac Surg 1989;48:536-9.[Abstract]
  29. Bidstrup B, Royston D, Sapsford R, Taylor K. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin. J THORAC CARDIOVASC SURG 1989;97:364-72.[Abstract]
  30. Dietrich W, Barankay A, Dilthey G, et al. Reduction of homologous blood requirement in cardiac surgery by intraoperative aprotinin application: clinical experience with 152 patients. Thorac Cardiovasc Surg 1989;37:92-8.[Medline]
  31. Fraedrich G, Weber C, Bernard C, Hettwer A, Schlosser V. Reduction of blood transfusion requirement in open heart surgery by administration of high dose aprotinin: preliminary result. Thorac Cardiovasc Surg 1989;37:89-91.[Medline]
  32. Royston D, Bidstrup B, van Oeveren W, Mueller W, Fritz H, Wildevuur C. Reduction in blood loss following open heart surgery: beneficial effect of high dose aprotinin. Anaesth Intensive Med 1986;17:20-5.
  33. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Aprotinin in cardiopulmonary bypass: effects on the Hageman factor (FXII)-kallikrein system and blood loss. Blood Coagul Fibrinolysis 1992;3:99-104.[Medline]
  34. Royston D. High dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vasc Anesth 1992;76-100.
  35. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-29.[Medline]
  36. Dietrich W, Hähnel C, Richter JA. Routine application of high-dose aprotinin in open heart surgery: a study in 1,784 patients. Anesthesiology 1990;73(A1):46.[Medline]
  37. Katz W, Mammen EF, Thal AP. Inhibition of fibrinolysis during extracorporeal circulation. Surg Forum 1965;16:63-4.[Medline]
  38. Wildevuur CR, Eijsman L, Roozendaal KJ, Harder MP, Chang M, van-Oeveren W. Platelet preservation during cardiopulmonary bypass with aprotinin. Eur J Cardiothorac Surg 1989;3:533-8.[Abstract]
  39. Van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CR. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1990;99:788-96.[Abstract]
  40. Lu H, Soria C, Commin PL, et al. Hemostasis in patients undergoing extracorporeal circulation: the effect of aprotinin (Trasylol). Thromb Haemost 1991;66:633-7.[Medline]
  41. Lavee J, Savion N, Smolinsky A, Goor DA, Mohr R. Platelet protection by aprotinin in cardiopulmonary bypass: electron microscopic study. Ann Thorac Surg 1992;53:477-81.[Abstract]
  42. Cramer EM, Lu H, Caen JP, Soria C, Tenza D. Different redistribution of platelet glycoproteins Ib and IIb-IIIa after plasmin stimulation. Blood 1991;77:694-9.[Abstract/Free Full Text]
  43. Huang H, Ding W, Su Z, Zhang W. Mechanism of the preserving effect of aprotinin on platelet function and its use in cardiac surgery. J THORAC CARDIOVASC SURG 1993;106:11-8.[Abstract]
  44. Wildevuur CRH, Eijsman L, Roozendaal KJ, Harder MP, Chang M, van Oeveren W. Platelet preservation during cardiopulmonary bypass with aprotinin. Eur J Cardiothorac Surg 1989;3:533-8.
  45. Lu H, Soria C, Commin P-L, et al. Hemostasis in patients undergoing extracorporeal circulation: the effect of aprotinin (Trasylol). Thromb Haemost 1991;66:633-7.
  46. Wendel HP, Heller W, Gallimore MJ, Bantel H, Muller-Beißenhirtz H, Hoffmeister HE. The prolonged activated clotting time (ACT) with aprotinin depends on the type of activator used for measurement. Blood Coagul Fibrinolysis 1993;4:41-5.[Medline]
  47. Mueller-Esterl W, Oettl A, Truscheit E, Fritz H. Monitoring of aprotinin plasma levels by an enzyme-linked immunosorbent assay (ELISA). Fresenius Z Anal Chem 1984;317:718-9.
  48. Katus HA, Schoeppenthau M, Tanzeem A, et al. Non-invasive assessment of perioperative myocardial cell damage by circulating cardiac troponin T. Br Heart J 1991;5:259-64.
  49. Diaz PE, Fishbein MC, Davis MA, Askenazi J, Maroko PR. Effect of the kallikrein inhibitor aprotinin on myocardial ischemic injury after coronary occlusion in the dog. Am J Cardiol 1977;40:541-9.[Medline]
  50. Hjelms E, Waldorff S, Steiness E, Bergsten O. Aprotinin does not add protective effect to cold cardioplegia during coronary artery bypass surgery. Scand J THORAC CARDIOVASC SURG 1986;20:11-3.[Medline]
  51. Sunamori M, Amano J, Kameda T, Okamura T, Ozeki M, Suzuki A. Additive protection of aprotinin, protease inhibitor to cold cardioplegia from ischemic myocardium. Jpn Circ J 1980;44:71-5.
  52. Sunamori M, Suzuki A. Improved efficacy of intra-aortic balloon pumping by pharmacological myocardial protection for postoperative pump failure after coronary revascularization. Jpn J Surg 1988;18:61-7.[Medline]
  53. Sunamori M, Innami R, Fujiwara H, Yokoyama M, Suzuki A. Significant role of protease inhibition by aprotinin in myocardial protection from prolonged cardioplegia with hypothermia. Adv Exp Med Biol 1988;240:399-404.[Medline]
  54. Gabrielescu E, Butur G, Nicolau N, Ciobanu A, Nutu O. Histochemical investigation of myocardial proteases in heart anoxia, under protection with cardioplegic solution and protease inhibitors. Rev Roum Morphol Embriol Physiol (Physiol) 1989;26:101-10.
  55. Bayley IE, Fawzi AB. Calcium-binding to cardiac myocytes protected from proteolytic enzyme activity. Biochem Biophys Acta 1985;839:199-208.[Medline]
  56. Yakushev VS, Lifshits RI, Slobodin VB, Kamilov FK, Efimenko GP. Effect of an inhibitor of trypsin-like enzymes on some metabolic processes in the heart muscle during the acute period of experimental ischemia. Kardiologia 1975;15:114-8.




This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Christoph Ochsenfahrt
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wendel, H. P.
Right arrow Articles by Hoffmeister, H.-E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wendel, H. P.
Right arrow Articles by Hoffmeister, H.-E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS