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Anesth Analg 2001;92:1418-1421
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Aprotinin Administration and Pulmonary Thromboembolism During Orthotopic Liver Transplantation: Report of Two Cases

Michael G. Fitzsimons, MD, Robert A. Peterfreund, MD, PhD, and Douglas E. Raines, MD

Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts

Address correspondence and reprint requests to Michael G. Fitzsimons, MD, Massachusetts General Hospital, Department of Anesthesia and Critical Care, 55 Fruit St., Boston, MA 02114.


   Introduction
Top
 Introduction
Case Reports
 Discussion
 References
 
Orthotopic liver transplantation (OLT) is the primary curative procedure for patients with end-stage liver disease. This procedure is frequently associated with massive blood loss because of both the nature of the operation and the coagulopathy that accompanies the underlying disorder. Bontempo et al. (1) demonstrated that the quantity of blood transfused during surgery correlates inversely with survival. The use of aprotinin during OLT has been advocated to decrease intraoperative blood loss (2–4). Other studies have argued against the routine use of aprotinin during liver transplantation because definite benefits have not been demonstrated (5,6) and complications may occur. Fatal pulmonary thromboembolization during liver transplantation associated with aprotinin administration has been described (7–10). We report two additional cases of pulmonary thromboembolization in liver transplant patients treated with aprotinin.


   Case Reports
Top
 Introduction
 Case Reports
Discussion
 References
 
Case 1
A 41-yr-old man with hepatitis C, cirrhosis, portal hypertension, bleeding esophageal varices, and mild encephalopathy presented for OLT. A preoperative evaluation showed no significant history of cardiac, pulmonary, renal or endocrine disease. The patient had a baseline prothrombin time of 15 s (reference range, 11.4–13.4) and a partial thromboplastin time of 33.1 s (reference range, 22.1–34.1). His platelet count was 67,000/mm3 and his hematocrit was 42.7%. In addition to standard monitors, an arterial catheter, a 14-gauge peripheral IV, a left internal jugular double lumen 12-gauge catheter, and a right internal jugular triple lumen 7F catheter were placed. Rapid sequence induction of general anesthesia was accomplished with propofol, succinylcholine, and fentanyl. The anesthetic was maintained with oxygen, nitrous oxide, isoflurane, and pancuronium. He was initially hemodynamically stable. Aprotinin was administered soon after induction with a test dose of 1 mL (10,000 kallikrein inhibitory units [KIU]) followed by an initial dose of 1,000,000 KIU over 35 min and then a continuous infusion of 250,000 KIU per hour. Hypotension was noted during the preanhepatic phase and treated with lactated Ringer’s solution, red blood cells, fresh frozen plasma, and phenylephrine. The case proceeded uneventfully and an inferior vena cava (IVC) test clamp was applied. Profound hypotension was noted and treated with clamp removal, fresh frozen plasma, calcium chloride, and packed red blood cells with resolution. The test clamp was reapplied and tolerated well. During the anhepatic phase, hypotension recurred resistant to phenylephrine. Norepinephrine was begun and stabilized the blood pressure. The suprahepatic IVC, infrahepatic IVC, and the portal vein anastomoses were completed, and the cross-clamps were released. The blood pressure gradually decreased followed by the appearance of large "v" waves on the central venous pressure tracing. The radial arterial pressure waveform became nonpulsatile (Fig. 1). Resuscitation was initiated with volume, calcium, epinephrine, and chest compressions. Ventricular tachycardia followed. A sternotomy was performed, and direct cardiac compressions were initiated. No arterial tracing was observed despite an adequately filled right ventricle. Surgical exploration of the right ventricle and pulmonary artery revealed a large formed blood clot in both branches of the pulmonary artery and attached to the valve leaflets. Cardiopulmonary bypass was initiated and the transplant surgery proceeded with completion of the hepatic artery and biliary duct anastomosis. Attempts to wean the patient from bypass, including institution of intraaortic balloon counter pulsation, were unsuccessful and resuscitation was terminated. Autopsy results demonstrated bilateral pulmonary thromboemboli with pulmonary hemorrhage involving the left lower, right middle, and right lower lobes. Clot was also noted in the IVC and attached to the valve leaflets on the right side of the heart.



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  		Figure 1. Electrocardiogram and pressure tracings after graft reperfusion (Case 1). Electrocardiogram lead II and a mid-chest lead (indicated as V) tracings are illustrated with simultaneous radial artery (Art.) and central venous pressure (CVP) tracings. The pressure scales are in millimeters of mercury. Cardiopulmonary resuscitation indicates closed chest cardiac compressions.

 
Case 2
A 60-yr-old woman with hepatitis C, cirrhosis, coagulopathy, splenomegaly, ascites, and encephalopathy presented for OLT. Her medical history was significant for Pott’s disease, tobacco abuse, and insulin-dependent diabetes mellitus. A preoperative evaluation showed no cardiac, pulmonary, or renal dysfunction. Her baseline prothrombin time was 15.9 s and partial thromboplastin time was 29.9 s. The platelet count was 104,000/mm3. In addition to standard monitors, a right radial arterial catheter, a left double lumen 12-gauge internal jugular catheter, and a pulmonary artery catheter via the right internal jugular vein were placed. Rapid sequence induction of general anesthesia was accomplished with sodium pentothal, fentanyl, and succinylcholine. The anesthetic was maintained with oxygen, nitrous oxide, and cisatracurium. She was given an initial bolus of 2 million KIU of aprotinin shortly after induction and maintained on a continuous infusion at 500,000 KIU per hour. Although initially hemodynamically stable, the patient developed markedly increased right atrial filling pressures, a low cardiac output, and hemodynamic collapse during the anhepatic phase of the procedure before reperfusion. She was successfully resuscitated, stabilized, and transported to the intensive care unit. A postoperative transesophageal echocardiogram showed a large thrombus in the right atrium. The clot was successfully treated with thrombolytic therapy. After a long course in the intensive care unit, complicated by hepatic graft dysfunction and sepsis, the patient died.


   Discussion
Top
 Introduction
 Case Reports
 Discussion
References
 
The use of antifibrinolytic agents ({epsilon}-aminocaproic acid, tranexamic acid, or aprotinin) has been advocated during OLT because of a hyperfibrinolytic state and resulting coagulopathy which often occur after reperfusion. Dzik (11) stated that the fibrinolysis appears to result from a sudden release of tissue plasminogen activator (t-PA) together with the inability to clear t-PA from the bloodstream in the anhepatic state.

Aprotinin is a naturally occurring single chain polypeptide protease inhibitor with a molecular weight of 6512 kd derived from bovine lung. Several mechanisms of action have been proposed to explain its antifibrinolytic effects including inhibition of plasmin, plasma kallikrein, and tissue kallikreins by the formation of reversible enzyme inhibitor complexes (12). Hunt et al. (13) and Cottam et al. (14) suggested that inhibition of kallikrein reduces formation of bradykinin, a potent stimulator of t-PA release. Plasmin generated by t-PA is a fibrinolytic enzyme that cleaves fibrin. The activity of plasmin is inhibited by aprotinin (15). The consequences of surgery promoting thrombus formation include venous stasis, tissue factor release, and direct surgical trauma. Antifibrinolytics such as aprotinin will inhibit the body’s tendency to lyse newly formed clot. Welte et al. (16), however, argued that there was no difference in t-PA release comparing control and aprotinin groups undergoing liver transplantation and also questioned the significance of t-PA–induced fibrinolysis in patients undergoing OLT.

Patrassi et al. (2) studied 14 consecutive patients undergoing OLT. They noted that the aprotinin-treated group received less units of red blood cells (48.7% less), fresh frozen plasma, and autologous blood. They also noted that the length of operation was on average 1.8 hours shorter. The incidence of primary nonfunction of the donor liver was less in the aprotinin-treated group. Mallett et al. (3) also reported that intraoperative transfusion of blood products in an aprotinin group was less than half that of controls, and that the operative times were also reduced. Grosse et al. (17) compared two groups of patients undergoing OLT. These investigators noted that the group receiving prophylactic aprotinin had smaller intraoperative transfusion requirements. Porte et al. (18) performed a randomized, double-blinded placebo-controlled multicenter trial involving 137 patients. Patients were randomized into three separate groups to receive either large-dose or regular-dose aprotinin or placebo. Intraoperative blood loss was significantly less in the aprotinin-treated group with a reduction of 60% in the large-dose group and 44% in the regular-dose group. These authors recommended routine use of aprotinin.

In contrast, two studies have disputed the apparent benefit of aprotinin during transplantation. Garcia-Huete et al. (6) performed a randomized, double-blinded, prospective study on 80 consecutive patients undergoing OLT. They noted that the intraoperative requirements of packed red cells, fresh frozen plasma, platelets, and cryoprecipitate were similar. The outcomes were also similar in the two groups. Welte et al. (16) performed a study on 20 patients and likewise noted that transfusion requirements did not differ between controls and aprotinin-treated patients.

The optimal regimen for aprotinin administration during OLT is also a point of debate. Soilleux et al. (19) compared large- and small-dose aprotinin regimens by measuring intraoperative transfusion requirements of packed red blood cells, fresh frozen plasma, platelets, and intraoperative blood salvage. The large-dose group received an initial aprotinin bolus of 2 million KIU followed by a continuous infusion of 500,000 KIU per hour. The small-dose group received a bolus of 500,000 KIU followed by 150,000 KIU per hour. No difference in transfusion requirements was noted between large- and small-dose treatment with aprotinin during the entire course of the surgery. A second study, performed by Ickx et al. (20), compared a continuous infusion of 3 million protease inhibitor units per hour (equivalent to 360,000 KIU per hour) to a variable infusion of aprotinin based on the thromboelastogram tracing and according to clinical need. The mean administration rate was 1.5 million protease inhibitor units per hour (equivalent to 180,000 KIU per hour). No difference in blood loss during the operation or on the first postoperative day was noted between the groups. Although Porte et al. (18) found a significant benefit to the use of aprotinin, they provided no definite evidence that a large-dose regimen was more effective than a regular-dose regimen.

Three previous cases of pulmonary artery embolism in the setting of aprotinin administration during liver transplantation have been reported. Our cases are unique for several reasons. Sopher et al. (7) reported two cases of pulmonary thromboembolism in the setting of aprotinin administration. The first patient received prior administration of {epsilon}-aminocaproic acid. They suggested that the use of both antifibrinolytics may have had a synergistic effect. Our patients received solely aprotinin. The second case of pulmonary thromboembolism they described occurred in a patient who was septic for several weeks before transplantation and was also receiving a second transplant. Sepsis induces disseminated intravascular coagulation, which may have predisposed the patient to pulmonary thromboembolism. Finally, both of the reported patients were placed on veno-venous bypass, which may activate the coagulation cascade, further predisposing to thrombosis. Neither of our patients was placed on veno-venous bypass.

Baubillier et al. (8) suggested that the presence of a pulmonary artery catheter may have contributed to embolism in a patient treated with aprotinin. They suggested that the trauma of placing two introducer sheath devices in the same vein may cause excessive endothelial damage resulting in thrombus formation. We note that our patients did not receive a "double stick" to the internal jugular vein. A pulmonary artery catheter was present in only one of the cases we report.

The issue of venous stasis as a cause of thrombus formation should be considered. Both of our patients were ambulatory before surgery. The postmortem analysis on the patient who died intraoperatively failed to reveal a distal source of the clot. We hypothesize that the clot may have formed in the central circulation during the operation.

The use of aprotinin during OLT was beneficial in several studies, and it is generally viewed as safe. Unfortunately, case reports suggest the possibility of thrombosis and pulmonary embolism with tragic results, arguing against routine use. The indications for liver transplantation are diverse and include alcoholic cirrhosis, hepatitis, toxic liver failure, cancer, and biliary disease. We suggest that more studies need to be done on the use of aprotinin in subpopulations to determine which patients truly benefit from its use and which patients may manifest adverse reactions.


   Acknowledgments
 
The authors thank Dr. Theodore A. Alston and Dr. Walter H. Dzik for their help in revising the manuscript.


   References
Top
 Introduction
 Case Reports
 Discussion
 References
 

  1. Bontempo FA, Lewis JH, Van Thiel DH, et al. The relationship of preoperative coagulation findings to diagnosis, blood usage, and survival in adult liver transplantation. Transplantation 1985; 39: 532–6.[Web of Science][Medline]
  2. Patrassi GM, Viero M, Sartori MT, et al. Aprotinin efficacy on intraoperative bleeding and transfusion requirements in orthotopic liver transplantation. Transfusion 1994; 34: 507–11.[Web of Science][Medline]
  3. Mallett S, Rolles K, Cox D, et al. Intraoperative use of aprotinin (Trasylol) in orthotopic liver transplantation. Transplant Proc 1991; 23: 1931–2.[Web of Science][Medline]
  4. Mallett SV, Cox D, Burroughs AK, Rolles K. Aprotinin and reduction of blood loss and transfusion requirements in orthotopic liver transplantation. Lancet 1990; 336: 886–7.
  5. Groh J, Welte M, Azad SC, et al. Does aprotinin affect blood loss in liver transplantation? Lancet 1992; 340: 173.[Medline]
  6. Garcia-Huete L, Domenech P, Sabate A, et al. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 1997; 26: 1143–8.[Medline]
  7. Sopher M, Braunfeld M, Shackleton C, et al. Fatal pulmonary embolism during liver transplantation. Anesthesiology 1997; 87: 429–32.[Web of Science][Medline]
  8. Baubillier E, Cherqui D, Khalil M, et al. A fatal thrombotic complication during liver transplantation after aprotinin administration. Transplantation 1994; 57: 1664–6.[Web of Science][Medline]
  9. O’Connor CJ, Roozeboom D, Brown C, Tuman KJ. Pulmonary thromboembolism during liver transplantation: possible association with antifibrinolytic drugs and novel treatment options. Anesth Analg 2000; 91: 296–9.[Abstract/Free Full Text]
  10. Manji M, Isaac JL, Bion J. Survival from massive intraoperative pulmonary thromboembolism during orthotopic liver transplantation. Br J Anaesth 1998; 80: 685–7.[Abstract/Free Full Text]
  11. Dzik WH. Massive transfusion in the adult patient: lessons from liver transplantation. In: Jefferies LC, Brecher ME, eds. Massive transfusion. Bethesda, MD: American Association of Blood Banks, 1994: 65–93.
  12. Bechstein WO, Riess H, Blumhardt G, et al. Aprotinin in orthotopic liver transplantation. Semin Thromb Hemost 1993; 19: 262–7.[Web of Science][Medline]
  13. Hunt BJ, Cottam S, Segal H, et al. Inhibition by aprotinin of tPA-mediated fibrinolysis during orthotopic liver transplantation. Lancet 1990; 336: 381.[Web of Science][Medline]
  14. Cottam S, Hunt B, Segal H, et al. Aprotinin inhibits tissue plasminogen activator-mediated fibrinolysis during orthotopic liver transplantation. Transplant Proc 1991; 23: 1933.[Web of Science][Medline]
  15. Yost CS. Clinical utility and cost effectiveness of aprotinin to reduce operative bleeding. Am J Anesthesiol 1996; 233–41.
  16. Welte M, Groh J, Azad S, et al. Effect of aprotinin on coagulation parameters in liver transplantation. Semin Thromb Hemost 1993; 19: 297–9.[Web of Science][Medline]
  17. Grosse H, Lobbes W, Frambach M, et al. The use of high dose aprotinin in liver transplantation: the influence on fibrinolysis and blood loss. Thromb Res 1991; 63: 287–97.[Web of Science][Medline]
  18. Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicenter randomised double-blind study. Lancet 2000; 355: 1303–9.[Web of Science][Medline]
  19. Soilleux H, Gillon MC, Mirand A, et al. Comparative effects of small and large aprotinin doses on bleeding during orthotopic liver transplantation. Anesth Analg 1995; 80: 349–52.[Abstract]
  20. Ickx B, Pradier O, Degroote F, et al. Effect of two different dosages of aprotinin on perioperative blood loss during liver transplantation. Semin Thromb Hemost 1993; 19: 300–1.[Web of Science][Medline]
Accepted for publication February 2, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press