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Anesth Analg 2000;91:296-299
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Pulmonary Thromboembolism During Liver Transplantation: Possible Association with Antifibrinolytic Drugs and Novel Treatment Options

Christopher J. O’Connor, MD*, David Roozeboom, CRNA{dagger}, Russell Brown, CCP{ddagger}, and Kenneth J. Tuman, MD*

*Department of Anesthesiology, {dagger}School of Nursing, and {ddagger}School of Perfusion Technology, Rush Medical College, Rush-Presbyterian-St. Lukes Medical Center, Chicago, Illinois

Address correspondence and reprint requests to Christopher J. O’Connor, MD, Department of Anesthesiology, Rush-Presbyterian-St. Lukes Medical Center, 1653 W. Congress Pkwy., Chicago, IL 60612. Address e-mail to coconnor{at}rpslmc.edu


   Abstract
Top
 Abstract
Introduction
 Case Reports
 Discussion
 References
 

Implications: The authors describe two cases of massive intraoperative pulmonary thromboembolism resulting in cardiovascular collapse during liver transplantation. The potential role of antifibrinolytic drugs is discussed, along with the use of treatment modalities not previously applied in this setting.


   Introduction
Top
 Abstract
 Introduction
Case Reports
 Discussion
 References
 
Intraoperative pulmonary thromboembolism is an uncommon event most often encountered during hip and knee arthroplasties, but rarely seen during liver transplantation. We present two cases of massive intraoperative pulmonary thromboembolism occurring during liver transplantation that may have been related, in part, to the use of antifibrinolytic drugs. One of these cases was complicated by paradoxical cerebral embolization. We further describe the use of systemic thrombolysis and venovenous oxygenation, in addition to surgical embolectomy, as novel treatment modalities previously unreported in this setting.


   Case Reports
Top
 Abstract
 Introduction
 Case Reports
Discussion
 References
 
Case 1
The patient was a 50-yr-old woman with a previous liver transplant who now presented with graft rejection, encephalopathy, and renal insufficiency. Her prothrombin time and partial thromboplastin time were 14 and 42 s, respectively, and the platelet count 104,000/mm3. After an uneventful anesthetic induction, bilateral internal jugular vein introducer sheaths were placed for venous access and placement of a pulmonary artery catheter. Two million kallikrein inhibiting units (KIU) of aprotinin were administered after skin incision followed by infusion of 0.5 million KIU/h. Fresh-frozen plasma was also given. After the abdomen was opened, the systolic blood pressure acutely decreased to 60 mm Hg. Isoflurane and aprotinin were discontinued, IV fluid was administered, and a dopamine infusion was begun. However, repeated 1-mg doses of epinephrine were necessary to maintain a systolic blood pressure > 80 mm Hg. Pulmonary artery pressures (PAP) increased from 25/15 to 50/25 mm Hg immediately after the event. Arterial oxygen saturation decreased to 92%, while the pulmonary artery occlusion pressure and cardiac output decreased to 10 mm Hg and 2 L/min, respectively, and central venous pressure (CVP) increased to 14 mm Hg. Emergent transesophageal echocardiography revealed a large, mobile, polyploid right atrial mass that was prolapsing into and obstructing the tricuspid valve. The right atrium was dilated, and color Doppler analysis revealed tricuspid insufficiency. Right ventricular (RV) contractility was normal, and the left ventricle was empty and hyperdynamic. Because increasing doses of vasopressors and inotropic drugs were required to maintain arterial blood pressure, the cardiac surgeons recommended surgical removal of a presumed intracardiac thrombus. A thromboelastogram obtained at this time revealed a markedly decreased reaction time (9 mm) and increased maximum amplitude (70 mm), suggestive of a hypercoagulable state. The transplant procedure was aborted, the abdomen closed, and the sternum opened. With cardiopulmonary bypass (CPB) circuits primed and available if needed, the vena cavae were temporarily occluded to stop venous inflow, a purse string suture placed in the right atrial wall, and the clot quickly extracted from the right atrium. The chest was closed, and the need for pressor support decreased significantly. After a prolonged postoperative course, the patient was eventually discharged and is awaiting transplantation.

Case 2
A 49-yr-old man with cryptogenic cirrhosis and hepatorenal syndrome requiring hemodialysis presented for a liver-kidney transplant. The patient had been admitted to the intensive care unit with worsening encephalopathy, severe ascites, and hypotension requiring vasopressor support. Laboratory values included a creatinine of 5.4 mg/dL, a platelet count of 99,000/mm3, and a prothrombin time of 28.4 s. Anesthetic induction was uneventful, and a dopamine infusion was maintained at 10 µg · kg- · min-1. A rapid infusion device was connected to both ports of a double-lumen dialysis catheter in the right subclavian vein and peripheral IV and radial artery catheters were placed. Although the right internal jugular vein was easily cannulated with an 18-gauge catheter, several attempts to pass a guidewire through the catheter were unsuccessful, and therefore, a pulmonary artery catheter was inserted via an introducer sheath placed in the right external jugular vein. Initial hemodynamic variables included a CVP of 16 mm Hg, PAP of 42/23 mm Hg, a cardiac output of 10.4 L/min, and a mixed venous oxygen saturation (SvO2) of 82%. A 5-g initial dose of {epsilon}-aminocaproic acid (EACA) was administered followed by a 1-g/h infusion. Once the liver was exposed, venovenous bypass was initiated via venous outflow catheters placed in the left femoral and portal veins and an inflow catheter placed in the left axillary vein (1). Because of persistent intraabdominal bleeding, the surgeons requested the addition of aprotinin. EACA was therefore discontinued and 2 million KIU of aprotinin were given followed by an infusion of 0.25 million KIU/h. Approximately 30 min after the start of venovenous bypass and after recipient hepatectomy, the arterial pressure acutely decreased to 60/30 mm Hg, the heart rate slowed to 60 bpm, the PAP decreased to 20/10 mm Hg, and the arterial oxygen saturation became unmeasurable. The cardiac output and mixed venous oxygen saturation also decreased significantly. Hypotension was initially unresponsive to the rapid IV infusion of blood, fluids, calcium chloride, discontinuation of aprotinin and volatile anesthetics, and an increase in the dopamine infusion rate. Epinephrine transiently restored the arterial pressure to 120/50 mm Hg, but the CVP and PAP increased to 35 and 50/39 mm Hg, respectively. Epinephrine and norepinephrine infusions were added along with 100% oxygen and positive end-expiratory pressure of 10 cm H2O. An arterial blood sample revealed a pH of 7.36, PaCO2 36 mm Hg, and PaO2 44 mm Hg. Because a pulmonary embolus was suspected, an emergent transesophageal echocardiography examination was performed, which revealed multiple diffuse, filamentous strands throughout the right atrium, right ventricle, main and right pulmonary arteries, across a patent foramen ovale into the left atrium and across the mitral valve, and on the noncoronary cusp of the aortic valve (Figure 1). Masses were also present on the pulmonic and tricuspid valves. The right atrium and RV were dilated, and the left ventricle was small and hyperkinetic. An obvious right-to-left shunt across the foramen ovale and tricuspid regurgitation were also apparent by color Doppler analysis. Maximal infusion rates of vasopressors were required to achieve a systolic blood pressure of 80 mm Hg.



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  		Figure 1. In the top photograph, an 84° multiplane transesophageal echocardiographic image reveals multiple filamentous strands (clot, white arrow) present throughout the right atrium (RA), one of which has passed through the foramen ovale into the left atrium (LA). Part of the clot is also trapped within the foramen ovale. The same clot can be seen in the bottom photograph to pass through the mitral valve. Although not seen in this 111° image, the mass was also seen to extend through the aortic valve into the ascending aorta (AO). This image also shows a large mass (clot, black arrow) attached to the pulmonic valve. PA = pulmonary artery.

 
The decision was made to administer an initial dose of 4,400 IU/kg of urokinase followed by an infusion of 4,400 IU · kg-1 · h-1. Ninety minutes after the onset of hypotension, an oxygenator was interposed within the venovenous bypass circuit and 100% oxygen administered at centrifugal pump flow rates of 2 L/min (Figure 2), after which the PaO2 increased from 40 to 259 mm Hg. The liver was then implanted and the renal transplant aborted. The procedure was completed despite profound hypotension and hypoxemia occurring after reperfusion of the liver and discontinuation of venovenous bypass. By the third postoperative day, the hypotension had resolved, all vasoactive infusions were discontinued, and oxygenation had normalized. A computed tomography scan of the head revealed multiple cerebral infarctions consistent with cerebral emboli. An echocardiogram 3 wk after surgery showed mild RV dilation and hypokinesis, but no intracardiac masses. Although the patient never regained consciousness, his hepatic allograft continued to function and he was alive 2 mo after surgery.



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  		Figure 2. Schematic illustration of the venous-venous oxygenator set-up. Standard venovenous bypass was established [as described by Paulsen et al. (1)] with removal of inferior vena caval (IVC) blood from the femoral and portal veins (venous inflow to the bypass circuit) by a centrifugal pump. After a temporary interruption of venovenous bypass and clamping of the patient return line, a heparin-coated oxygenator primed with lactated Ringer’s solution was interposed into the inflow circuit and venous blood was pumped through the heat exchanger into the oxygenator. Oxygenated blood was then returned to the superior vena cava (SVC) (venous inflow to patient) via an axillary vein catheter.

 

   Discussion
Top
 Abstract
 Introduction
 Case Reports
 Discussion
References
 
Transient air embolization is not uncommon after reperfusion of the hepatic allograft during liver transplantation (2–5), but pulmonary embolization of venous thrombi is rare and survival infrequent (6). Free-floating intracardiac thrombi complicating suspected pulmonary embolism may produce significant impairment to left heart filling, can induce severe hypoxemia, and are associated with a high mortality, even with aggressive treatment (7). Surgical embolectomy (8), systemic and local thrombolysis (9), heparin anticoagulation, and interventional catheter devices to disrupt the thrombus (10) have all been used with variable success and similar mortality rates in patients with documented intracardiac thrombi (7). IV urokinase and venovenous oxygenation, as described here, are two unique and previously unreported intraoperative treatment modalities for this life-threatening complication.

Peripheral venous thromboses with subsequent pulmonary embolization, or in situ formation of thrombus within the right heart and pulmonary arteries, are unexpected events in patients undergoing liver transplantation because of the intrinsic abnormalities in platelet function and coagulation factor synthesis that characterize end-stage liver disease. Baubillier et al. (11) reported fatal pulmonary embolism during liver transplantation that was attributed to aprotinin-induced thrombus formation around a pulmonary artery catheter. Sopher et al. (12) described two patients who developed fatal pulmonary embolism during liver transplantation; both received aprotinin intraoperatively, and in both cases, thrombectomy was unsuccessful in restoring stable hemodynamics. Manji et al. (13) reported survival from intraoperative embolization during liver transplantation using CPB to facilitate embolectomy; aprotinin was again implicated as a possible etiologic factor. The cases we describe represent additional instances in which aprotinin may have contributed to the formation of intracardiac thrombi that obstructed left heart filling, induced severe hypoxemia, and in one instance, caused paradoxical embolization resulting in cerebral infarction and severe neurologic dysfunction. Evidence suggests that aprotinin elimination is primarily renal (14). It is therefore possible that the significant renal dysfunction present in our patients reduced the clearance of aprotinin and combined with other factors favoring hypercoagulability, may have promoted thrombus formation, a conclusion supported by the markedly hypercoagulable thromboelastogram we observed. In addition, the administration of both aprotinin and EACA to our last patient may have intensified the prothrombotic potential of these two drugs.

The mechanism of clot formation in these cases is unclear. Thrombus may have formed around the pulmonary artery or central venous catheters and then embolized to the right heart and pulmonary artery, producing so-called mobile or migrating thrombi (15). The serpentine and worm-like appearance of these highly mobile thrombi, as well as their propensity for distal embolization and right heart obstruction, is consistent with previous descriptions of the appearance and behavior of free-floating intracardiac thrombi (15,16). In contrast to mobile thrombi, adherent thrombi have a large attachment to the right atrial wall and rarely embolize (15). Embolization of preexisting clot from lower extremity veins seems a less likely mechanism, given the baseline coagulation status of the patients, although a clot appeared to be present before surgery in the internal jugular or innominate vein in our last case, because passage of a wire through the internal jugular vein was difficult, suggesting possible thrombotic obstruction.

In addition to antifibrinolytic drugs and intravascular catheters, previous reports of platelet aggregates in the pulmonary arteries of patients dying unexpectedly after liver transplantation suggest that other unexplained factors may predispose to thromboemboli formation (17,18). Deficiency of the coagulation inhibitors protein C and S, along with impaired fibrinolysis, has been observed in patients with advanced liver disease and might increase the risk of thrombotic complications (19). Other possible mechanisms of hypercoagulability include release of tissue thromboplastin from the ischemic donor liver, excessive platelet and fresh-frozen plasma administration, endotoxin-induced platelet-thrombi production, and extracorporeal clot formation within the venovenous bypass circuit, none of which appeared to be present in our patients.

The treatment of pulmonary emboli occurring during liver transplantation is especially challenging because of the prohibitive risk of hemorrhage with heparin or thrombolytic agents. The efficacy of surgical embolectomy, with and without CPB, has been reported in other instances of nonoperative massive pulmonary embolism (8) and was successful in one of our cases, but was felt to be an unsuitable treatment option for our second patient because of the anatomically diffuse location of the thrombi. Thrombolysis was chosen because it can simultaneously dissolve a clot present in multiple locations (i.e., the heart, aorta, and intracerebral vessels) and is a simple and rapid treatment that can easily be instituted in the operating room (7). Although venovenous oxygenation has been used to treat the acute respiratory distress syndrome (20–22), it has never been reported for the treatment of intraoperative respiratory failure. The bypass circuit was quickly and easily assembled, and anticoagulation was not required because of the concomitant use of urokinase. The pronounced right-to-left interatrial shunt, a result of the trapped embolus and increased right atrial pressures, actually favored diversion of bypass-oxygenated venous blood from the right to the left atrium and into the systemic circulation, as demonstrated by the prompt improvement in oxygenation. Venovenous oxygenation may thus serve as a temporary measure to support oxygenation while more definitive surgical or thrombolytic treatment is established.

In conclusion, we report two cases of severe pulmonary thromboembolism occurring during liver transplantation and emphasize the potential prothrombotic role of aprotinin and EACA, as well the utility of venovenous oxygenation, systemic thrombolysis, and surgical embolectomy in the treatment of this devastating complication.


   References
Top
 Abstract
 Introduction
 Case Reports
 Discussion
 References
 

  1. Paulsen AW, Whitten CW, Ramsay MAE, et al. Considerations for anesthetic management during venoveno bypass in adult hepatic transplantation. Anesth Analg 1989;68:489.[Abstract/Free Full Text]
  2. Ellis JE, Lichtor JL, Feinstein SB, et al. Right heart dysfunction, pulmonary embolism, and paradoxical embolization during liver transplantation. Anesth Analg 1989;68:777–82.[Abstract/Free Full Text]
  3. Suriani RJ, Cutrone A, Feierman D, Konstadt S. Intraoperative transesophageal echocardiography during liver transplantation. J Cardiothorac Vasc Anesth 1996;10:699–707.[Web of Science][Medline]
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  6. Navalgund AA, Kang Y, Sarner JB, et al. Massive pulmonary thromboembolism during liver transplantation. Anesth Analg 1988;67:400–2.[Free Full Text]
  7. Chartier L, Bera J, Delomez M, et al. Free-floating thrombi in the right heart: diagnosis, management, and prognostic indexes in 38 consecutive patients. Circulation 1999;99:2779–83.[Abstract/Free Full Text]
  8. Ullmann W, Hemmer W, Hannekum A. The urgent pulmonary embolectomy: mechanical resuscitation in the operating theatre determines the outcome. Thorac Cardiovasc Surg 1999;47:5–8.[Web of Science][Medline]
  9. Pharo GH, Andonakakis A, Chandrasekaren K, et al. Survival from catastrophic intraoperative pulmonary embolism. Anesth Analg 1995;81:188–90.[Web of Science][Medline]
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  13. 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]
  14. O’Connor CJ, Brown DV, Avramov M, et al. The impact of renal dysfunction on aprotinin pharmacokinetics during cardiopulmonary bypass. Anesth Analg 1999;89:1101–7.[Abstract/Free Full Text]
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Accepted for publication May 1, 2000.




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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 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press