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Eur J Cardiothorac Surg 2001;20:38-41
© 2001 Elsevier Science NL

Reduced blood loss by aprotinin in thoracic surgical operations associated with high risk of bleeding.

A placebo-controlled, randomized phase IV study

T. Kyrissa, H. Wurstb, G. Friedela, R. Jakib, H. Toomesa

a Department of Thoracic Surgery, Center of Pneumology and Thoracic Surgery, Schillerhoehe Hospital, Gerlingen, Germany
b Department of Anesthesiology and Intensive Medicine, Schillerhoehe Hospital, Gerlingen, Germany

Received 16 March 2001; received in revised form 12 April 2001; accepted 14 April 2001.

Corresponding author. Tel.: +49-7156-203-2259; fax: +49-7156-203-2008
e-mail: kyriss{at}klinik-schillerhoehe.de


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objective: Although the blood-saving effect of aprotinin has been well documented in cardiac surgery and lung transplantation, its use in lung surgery has received less attention. We present our experience with the intraoperative application of aprotinin in lung resections with a predicted high risk of bleeding. Methods: Thirty-eight patients undergoing major thoracic surgical procedures were randomized into treatment and placebo groups. The treatment group (n=18) received a bolus of 2x106 kallikrein inhibitor units (KIU) of aprotinin followed by 5x105 KIU/h during surgery. The placebo group (n=20) received an isotonic saline infusion instead. Results: There was no significant difference between the groups concerning diagnosis, co-morbidity, age, sex, height, and weight. The mean intraoperative blood loss in the treatment group was significantly reduced (342 vs. 808 ml, P<0024), postoperative blood loss was also reduced (623 vs. 1282 ml, P<0.0007) and the need for blood transfusion was less (14 vs. 60, n.s.). No severe side effects of aprotinin were registered. Re-thoracotomy was necessary in two patients of the placebo group because of postoperative bleeding. Conclusion: Aprotinin reduces the perioperative blood loss and the need for blood transfusion in thoracic surgical procedures in patients with an increased risk of bleeding.

Key Words: Aprotinin • Intraoperative blood loss • Thoracic surgery • Pulmonary resection


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
The antifibrinolytic agent aprotinin (Antagosan®, Aventis Pharma, D-Bad Soden, Trasylol®, Bayer Vital, D-Leverkusen) is successfully applied in heart surgery to reduce intraoperative blood loss and the need for blood transfusion [1–5]. In thoracic surgery this substance has so far only been used occasionally [6–8]. This is primarily due to the fact that the most frequent thoracic surgical procedures, i.e. the anatomical resection in case of lung cancer and video-assisted thoracic surgery are rarely associated with a blood loss of more than 300 ml. In surgery for inflammatory pulmonary disease and resection of recurrent tumors, however, the bleeding hazard is very high because of extensive adhesions rich in blood vessels. For oncological and hygienic reasons, however, blood-saving methods such as the employment of the Cellsaver® cannot be used in these procedures. It was the aim of this placebo-controlled, randomized observational study to investigate whether the blood-saving effect of aprotinin can be used in thoracic surgical procedures with an increased risk of bleeding.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
Between 8/1999 and 11/2000, 38 patients (14 women, 24 men) were included in the randomized and placebo-controlled study. The inclusion criteria were:

Exclusion criteria were:

The patients were randomized into the treatment or placebo group on the day of surgery during pre-medication by the anesthetist using a computer-generated random list. The anesthetist was the only person to know whether aprotinin was applied or not. This approach was intended to avoid a possible influence on the surgeons during dissection and hemostasis. In the treatment group, a test dose of 10 000 KIU (kallikrein inhibitor units) aprotinin was administered during induction of anesthesia to exclude allergic reactions to the drug followed by an initial bolus of 2 000 000 KIU via a separate venous line over 20 min. During surgery, 500 000 KIU/h were given as continuous infusion via an infusion pump. In the placebo group, the corresponding volume of a saline solution was administered using the same set of pumps.

The amount of intraoperative blood loss through suction was measured whereas blood loss into swabs was disregarded. Postoperatively, the drainage volumes were recorded after 6 and 24 h. Blood hemoglobin, platelet count, PTT, Quick’s value, and serum creatinine were determined preoperatively, postoperatively on the day of surgery, and on post-operative day (POD) 1 and 7. The need for packed red blood cells and blood products was registered. Complications and allergic reactions were documented.

Any personal, anamnestic, clinical and surgical data were recorded prospectively on a documentation sheet and entered into a spreadsheet program (Excel®). Statistical analysis was performed using the Mann–Whitney-U-test for not normally distributed data (StatView®). P-values <0.05 were considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
During the study period (8/1999–11/2000) 38 patients (14 women and 24 men) were included and randomized (treatment group n=18, placebo group n=20). The mean ages in the groups were 51.8 and 50.8 years, respectively (n.s.). There was no significant difference in the personal data between both groups (Table 1). In the treatment and the placebo group, nine and ten patients, respectively, were operated upon for a recurrent tumor and equally nine and ten patients, respectively, for an intrathoracic inflammatory disease (Table 2).


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  		Table 1. Patient characteristics

 

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  		Table 2. Diagnoses

 
3.1. Laboratory parameters
The mean values of preoperative blood hemoglobin (13.1 vs. 13.4 mg/dl), blood platelets (304444 vs. 295150/µl), partial thromboplastin time (34.6 vs. 35.0 s), Quick's value (97 vs. 95.5%) and serum creatinine (0.84 vs. 0.82 mg/dl) were not significantly different between the treatment and the placebo group. The analyses on POD 1 showed the following values: serum hemoglobin 10.9 vs. 10.3 mg/dl, blood platelets 252056 vs. 246250/µl, partial thromboplastin time 52.4 vs. 58.7 s, Quick's value 81 vs. 74% and serum creatinine 1.0 vs. 0.87 mg/dl (differences n.s.). On POD 7 the analyses were as follows: serum hemoglobin 11.6 vs. 11.3 mg/dl, blood platelets 328888 vs. 362750/µl, partial thromboplastin time 41.5 vs. 40.6 s, Quick's value 83 vs. 89% and serum creatinine 0.89 vs. 0.69 mg/dl (differences n.s.). All patients received heparin 200 U/kg bw/24 h on the intensive care unit.

3.2. Surgical procedures
Table 3 details the procedures performed. Altogether, 34 thoracotomies, 18 of them re-thoracotomies and four sternotomies, three of them re-sternotomies were performed. Thirty interventions were performed for a recurrent tumor or an inflammatory disease (treatment group n=14, placebo group n=16). Eight patients underwent primary surgery for inflammatory disease (treatment group n=4, placebo group n=4). Mean duration of surgery was 212 in the treatment group vs. 206 min in the placebo group (difference n.s.). In the treatment group a mean of 3.6 million units of aprotinin were administered.


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  		Table 3. Interventions

 
3.3. Blood loss and drainage volume
The mean intraoperative blood loss was significantly lower in the treatment group compared with the placebo group (342 vs. 808 ml, P<0.0024). In the treatment group, the mean drainage volumes 6 h (262 vs. 578 ml, P<0.0013) and 24 h postoperatively (623 vs. 1282 ml, P<0.0007) were also significantly lower than in the placebo group. The total intraoperative blood and postoperative drainage loss was also significantly lower in the treatment group (Table 4).


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  		Table 4. Blood loss and drainage volumes

 
3.4. Transfusions
In the treatment group (n=18) three patients received 14 units of packed red blood cells, in the placebo group (n=20) ten patients received 60 units of packed red blood cells. The highest blood hemoglobin value at the time of transfusion was 8.6 mg/dl, all other patients had lower Hb values at the time of transfusion. In order to improve blood coagulation, four patients of the placebo group received a total of 23 units of fresh frozen plasma, while only one patient of the treatment group received four units of fresh frozen plasma. The number of packed red blood cells as well as the total number of blood products required is just non-significant in the two-tailed test with P<0.07, while the difference in the one-tailed test is significant with P<0.03.

3.5. Incompatibility reactions and complications
There were no clinical signs of an allergic or anaphylactic reaction in the peri- or post-operative period. In both groups other serious complications occurred. In the treatment group, one patient died from septic multiple organ failure on POD 5. This patient had been suffering from echinococcosis of several organs for many years and underwent re-thoracotomy for treatment of infection in the presence of major pulmonary abscess formation and pleural empyema. In view of the underlying disease, the clinical course and the result of autopsy, we considered this serious lethal complications not to be associated with the administration of aprotinin. In the placebo group, two patients had to undergo re-thoracotomy for severe bleeding within the first 12 postoperative hours for hemostasis.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
Aprotinin was discovered in bovine organs in 1930 and was for the first time applied clinically in 1953 for the therapy of acute pancreatitis and later for shock therapy as well, however without convincing results. In 1987, Royston reported on a significant reduction of perioperative blood loss during heart surgery by aprotinin [4]. In the following years, this substance turned out to be highly efficient compared with a placebo as to the reduction of perioperative blood loss and the need for transfusion in cardiac surgery [1,2,5]. A high dose of aprotinin is superior to other coagulation-activating substances such as tranexamic acid (e.g. Anvitoff®, Ugurol®) with regard to the reduction of blood loss and need for transfusion [3].

In the present investigation, aprotinin was applied according to the dosage regimen recommended by Royston and Dietrich and established in heart surgery (test dose, initial bolus, continuous infusion) [5,9]. As to surgery without extracorporeal circulation, ‘high-dose’ in literature generally means bolus injection of 2x106 KIU (280 mg) 20 min prior to surgery followed by a continuous infusion for the time of surgery of 5x105 KIU/h (70 mg/h) [7,10].

Aprotinin is a natural polypeptide which develops its complex effect on the coagulation system as a proteinase inhibitor. By the formation of reversible enzyme inhibitor complexes it acts as an inhibitor of plasmin, tissue kallikrein and plasma kallikrein thus having an antifibrinolytic and coagulation-activating effect. The antifibrinolytic effects of the substances are dose-dependent [3,5]. After a rapid distribution within the extracellular space, the elimination half-lives of the substance range from 5.3 to 8.3 h [1]. This means that an effect can be expected up to several hours after the end of surgery. In spite of numerous investigations, the diverse interactions between the substance and the mechanism of hemostasis are not fully known [3].

Postoperative bleeding, above all after extensive adhesiotomy in inflammatory conditions or after previous surgery, is a threatening complication in thoracic surgery. In the present study, there was a significant difference between the treatment and the placebo group in terms of intraoperative blood loss and postoperative drainage volumes. Only three of 18 patients of the treatment group received packed red blood cells compared with 10 of 20 patients in the placebo group. Extracorporeal circulation was not applied in our study cohort. In lung transplantation, aprotinin reduced perioperative blood loss as well as the need for packed red blood cells [6]. A placebo-controlled double blind study showed the blood-saving effect of aprotinin in pulmonary resection for bronchial carcinomas without extracorporeal circulation [7].

Aprotinin is generally tolerated well in dosages intended to reduce perioperative blood loss [1,3]. In literature, however, allergic reactions and elevated serum creatinine values are also reported [1,3,9,11]. Being an allogenic protein, aprotinin has antigenic properties. The incidence of allergic reactions observed in clinical studies with high-dose aprotinin is reported to range between <0.1 to 0.6% [3]. Allergies seem to be more likely in patients who have already received the agent during previous surgery [3,9]. In a retrospective study of 248 patients undergoing heart surgery with a re-exposure to aprotinin, Dietrich found temporary adverse reactions in seven cases (2.8%) [9]. The incidence of allergic reactions after re-exposure to aprotinin is reported to be 2.8 to 6% in literature [9]. However, case reports even described fatal anaphylactic shock reactions after re-exposure [11]. In the present study, none of the patients showed any of those side effects or complications which have so far been described in association with aprotinin application. However, only patients were included in the study who had not been given aprotinin previously.

Clinical investigations on the efficiency and risk of aprotinin application showed a temporary postoperative increase in serum creatinine in several cases [1,3]. In the present study, those patients having received aprotinin had a higher mean serum creatinine value on POD 7 than preoperatively. This observation can be explained on a pharmacokinetic basis. Following glomerular filtration, aprotinin is actively reabsorbed in the proximal tubule and stored temporarily in the renal phagolysosomes. This seems to overload the tubular re-absorption mechanism of the kidney [3]. Nevertheless, comparative investigations of patients with restricted renal function showed no differences as to pharamcokinetics or side effects [1]. In case of lung transplantation or pulmonary resection, no thromboembolic complications have so far been observed in association with aprotinin exposure [6–8].

In our treatment group, one patient died from septic multiple organ failure on POD 5. This patient had been suffering from echinococcosis of several organs for many years and underwent re-thoracotomy for treatment of infection in the presence of major pulmonary abscess formation and pleural empyema. In view of the underlying disease, the clinical course and the result of autopsy, we considered this serious lethal complications not to be associated with the administration of aprotinin. In the placebo group, two patients had to undergo re-thoracotomy for severe bleeding within the first 12 postoperative hours for hemostasis; in the treatment group there was no re-intervention. Since aprotinin is derived from bovine lungs, the possibility of transmission of bovine viral or other infections has to be mentioned.

In thoracic surgical interventions associated with an increased risk of bleeding due to inflammatory conditions or previous surgery, aprotinin significantly reduces perioperative blood loss. The need for blood transfusion can thus be reduced.


   Footnotes
 
Dedicated to H. Toomes on the occassion of his 60th anniversary.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

  1. Davis R., Whittington R. Aprotinin: a review of its pharmacology and therapeutic efficiency in reducing blood loss associated with cardiac surgery. Drugs 1995;49:233-260.
  2. Dietrich W., Baransky A., Hahnel C. High-dose aprotinin in cardiac surgery. Three years experience in 1784 patients. J Cardiothorac Vasc Anesth 1992;6:324-327.[Medline]
  3. Peters D., Noble S. Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs 1999;2:233-260.
  4. Royston D., Taylor K., Bidstrup B., Sapaford R. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-1291.[Medline]
  5. Royston D. High-dose aprotinin therapy: a review of the first 5 years experience. J Cardiothorac Vasc Anesth 1992;6:76-100.[Medline]
  6. Jaquiss R., Huddleston C., Spray T. Use of aprotinin in pediatric lung-transplantation. J Heart Lung Transplant 1995;14(2):302-307.[Medline]
  7. Kätzel R., Keuper H., Wiedemann B., Brethner L., Voigt B. Effects of aprotinin application on perioperative changes in hemostasis and fibrinolysis and its consequence for blood loss and transfusion requirement in lung surgery. Infusionsther Transfusionsmed 1998;25(4):236-245.
  8. Kesten S., Hoyas A., Chaparro C., Maurer J. Aprotinin reduces blood loss in lung transplant recipients. Ann Thorac Surg 1995;59(4):877-879.[Abstract/Free Full Text]
  9. Dietrich W., Späth P., Ebell A., Richter J. Prevalence of anaphylactic reactions to aprotinin: analysis of 248 re-exposures to aprotinin in heart operations. J Thorac Cardiovasc Surg 1997;113:194-201.[Abstract/Free Full Text]
  10. Dobkowski W., Murkin J., Grant D., Wall W. High dose aprotinin significantly reduces allogenic blood and blood product exposure. Anesth Analg 1998;86(2):abstract 437.
  11. Diefenbach C., Abel M., Limpers J., Ruskowski H., Buzello W. Fatal anaphylactic shock after aprotinin re-exposure in cardiac surgery. Anesth Analg 1995;80(4):830-831.[Medline]



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