Case 3—1995 three patients requiring both coronary artery bypass surgery and orthotopic liver transplantation

CASE CONFERENCE A l a n J. Schwartz, MD, M S E d Frederick A. Hensley, Jr, M D

CASE 3 1995 Three Patients Requiring Both Coronary Artery Bypass Surgery and Orthotopic Liver Transplantation Joseph J. Morns, MD, Chrmtopher L. Hellman, MD, Bradley J. Gawey, MD, Michael A.E. Ramsay, MD, Timothy R. Valek, MD, Thomas C. Gunning, MD, Thomas H. Swygert, MD, Linda Shore-Lesserson, MD, Farshad Lalehzarian, MD, Kenneth L. Brayman, MD, PhD, FACS, and Troyen A. Brennan, MD

Case 1"

A 46-year-old 63-kg woman with a history of type II diabetes melhtus and heavy tobacco use presented with symptoms of congestive heart failure and angina precipitated by severe anemia. Cardiac enzymes obtained were not elevated. Therapy with digoxin, diuretics, and nitrates was initiated. Endoscopic examination showed bleeding esophageal varices. Past medical history was significant for hepatic cirrhosis believed to be secondary to methotrexate therapy for psoriasis, with no history of alcohol abuse, jaundice, or encephalopathy Cardiac catheterization showed severe quadruple-vessel atherosclerotlc coronary artery disease (CAD) with moderate hypoklnesis of the left ventricle and severe hypokmesis of the inferior and posterobasal walls and an ejection fraction of 0 5 to 0.6. Preoperative laboratory data included hematocrlt (HCT) 37%, prothrombin time (PT) 14.9 seconds, glucose 215 mg/dL, creatmine 0.6

*J J Morris, MD, C.L. Hellman, MD, and B J Gawey, MD Joseph J Morns, MD, Christopher L Hellman, MD, Bradley J Gawey, MD, Michael A E Ramsay, MD, Timothy R. Valek, MD, Thomas C. Gunmng, MD, and Thomas H Swygert,MD, Department of Anesthesiology and Pare Management, Baylor Umvemty Medtcal Center, Dallas, TX, and Department of Anesthesiology and Pam Management, Umversay of Texas Southwestern Medwal Center, Dallas, TX, Lmda Shore-Les~erson, MD, and Farshad Lalehzanan, MD, Department of Anestheszology, Mount Smat Medical Center, New York, NY,, Kenneth L Bmyman, MD, PhD, FACS, Multtorgan Transplantatwn, Department of Surgery, Umversay of Pennsylvama School of Medtcme, Hospttal of the Umvetsay of Pennsylvama, Phdadelphta, and Troyen A. Brennan, MD, Department of Health Pohcy and Management, Harvard School of Pubhc Health, Boston, MA Address repnnt requests to Mtchael Ramsay, MD, Department of Anesthesiology and Pare Management, Baylor Umverstty Medlcal Center, 3500 Gaston Ave, Dallas, TX 75246 or Lmda ShoreLesserson, MD, Department of Anesthesiology, Mount Smat Medtcal Center, 1 Gustave L Levy Pl, Box 1010, New York, NY10029 Copyright © 1995 by W B Saunders Company 1053-0770/95/0903-001853 00/0 Key words coronary artery surgery, hver transplantatton, cost/ benefit analysts

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mg/dL, total protein 4.1 g/dL, albumin 2.2 g/dL, total bllirubln 0.3 mg/dL, alkaline phosphatase 55 Ix/L, serum aspartate aminotransferase (AST) 11 Ix/L, blood urea nitrogen (BUN) 18 mg/dL, platelet count 93,000/mm 3. Electrolytes were normal The patient was scheduled for elective quadruple coronary artery bypass grafting (CABG) using the left internal mammary artery for the left anterior descending coronary artery. The patient was premedicated with mldazolam, 0.08 mg/kg. Pulmonary and radial artery catheters were inserted before induction of anesthesia Initial hemodynamic measurements included cardiac output (CO) 5.3 L/mm, pulmonary artery pressure (PAP) 27/16 mmHg, systemic vascular resistance (SVR) 503 dyn- s' cm -5, central venous pressure (CVP) 10 mmHg, pulmonary artery occlusion pressure (PAOP) 15 mmHg, heart rate 90 bpm, and systemic blood pressure (BP) 128/70 mmHg. Stable induction of anesthesm consisted of midazolam, 0.25 mg/kg, and sufentanil, 8 ~xg/kg, and neuromuscular blockade was achieved with pancuronlum, 0.08 mg/kg. The patient was ventilated with an air/oxygen mixture (F102 of 0.5) The basehne actwated coagulation time (ACT) was 127 seconds Heparin, 400 Ix/kg, was administered before cardiopulmonary bypass (CPB) with a resultant ACT of greater than 700 seconds. The duration of nonpulsatlle CPB was 133 minutes. The coagulation profile after protamine administration (300 mg) included a normal ACT of 116 seconds and a thrombin clot time (TCT) of 13 seconds, increased PT of 16.5 seconds and partial thromboplastin time (PTT) of 45 seconds, decreased fibrinogen of 133 mg/dL, and an HCT of 24%. An infusion of norepinephrlne and phentolamlne was required temporarily after CPB to treat a persistently low systemic vascular resistance. No blood products were administered intraoperatively. Cardiac output was 6.8 L/rain on arrival in the intensive care unit (ICU). The patient did well initially and was extubated 10 hours postoperatively. On the second postoperatwe day, the patient became increasingly lethargic and hypoxemlc and reqmred reintubation. A significant upper gastromtestlnal tract hemorrhage was subsequently discovered that was attributed to esophageal varices A blood ammonia level was elevated to 145 mm/L. Despite sclerotherapy and a

Journal of Cardlothoractc and VascularAnesthesta,

Vol 9, No 3 (June),1995 pp 322-332

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CASE 3 - - 1 9 9 5

trial of intravenous (IV) vasopressIn, massive bleeding continued until a splenorenal shunt was performed. A liver biopsy also was performed that showed extensive cirrhosis. Evidence of fulmlnant hepatic failure ensued with the development of encephalopathy and massive ascites. Dopamine was infused for pressure support, and lactulose and neomycin were administered for ammonia reduction. The placement of a Denver shunt did not relieve the accumulation of ascltic fluid. Poor sternal wound healing and associated infection resulted in dehiscence requiring Irrigation, drainage, and rewiring. A tracheostomy was inserted for prolonged mechanical ventilation. Renal failure ensued, and a subsequent kidney biopsy was consistent with development of the hepatorenal syndrome. Thirty-two days after CABG surgery, orthotopic liver transplantation (OLT) was performed, and native liver pathology showed advanced, well-established cirrhosis. Twenty-one units of packed red blood cells (PRBC), 10 units of fresh frozen plasma (FFP), 30 units of platelets, and 20 units of cryoprecipltate were required mtraoperatively while dobutamine and dopamlne were infused for cardiovascular support. The liver graft functioned well initially, and the patient recovered adequately with return of pulmonary, renal, and mental function. The patient was weaned from ventilatory support 1 week after transplantation. Subsequently, however, the patient began to accumulate ascltes, and 2 weeks after OLT, became severely acidotic. Surgical reexploration showed a thrombosed portal vein and infarcted donor liver Sepsis and laver failure ensued, and the patient died within 2 months of her initial presentation.

normal. The decision was made to perform CABG surgery before hepatic transplantation. The patient was premedicated with dlazepam, 15 mg, metoclopramide, 10 rag, and ranitldine, 150 mg, orally. After placement of radial and pulmonary artery catheters, a modified rapid-sequence induction was performed while holding cricoid pressure using dlazepam, 0.1 mg/kg, fentanyl, 30 Ixg/kg, etomldate, 0.15 mg/kg, and succinylcholine 1.3 mg/kg. Maintenance anesthesia consisted of incremental fentanyl, isoflurane, and pancuronium, 0.08 mg/kg, for muscle relaxation, and mannltol, 12.5 gm, was administered to increase urine output The basehne ACT was 158 seconds. The patient's prebypass thrombocytopenla and hypofibrinogenemia were shown in a thromboelastograph (TEG) #1 (Fig 1). Hemodynamics were stable during reduction and the prebypass period. Heparin (400 Ix/kg) was administered before CPB with a resultant ACT of more than 1,000 seconds. Hemodynamic stability continued through the bypass period with a mean arterial pressure (MAP) during bypass of 60 mmHg. Total nonpulsatile CPB lasted 90 minutes, and weaning from CPB was uncomplicated. However, a bleedlng surgical field existed, and an infusion of desmopressin acetate (16 Ixg) was administered empirically over 15 minutes. Despite adequate heparln reversal with protamine, 500 rag. as demonstrated by a normal TCT of 15 seconds, the initial postbypass laboratory values and TEG #2 (Fig 1) indicated a severe coagulopathy. Postbypass laboratory values included a PT of 32 seconds, PTT of 77

Case 2/ A 63-year-old 90-kg man with end-stage live1 disease (ESLD) secondary to Laennec's cirrhosis presented with progressive weakness and massive ascites requiring weekly paracentesis. The patient could walk only two blocks because of fatigue. He denied any chest pain or history of myocardial infarction but previously smoked cigars for 35 years and consumed ethanol heavily for 40 years. He had a 30-year history of hypertension, which resolved upon development of ESLD. During liver transplantation evaluation, cardiac catheterization showed normal left ver.tricular function but advanced CAD involving the left main, anterior descending, and right coronary arteries. The patient's past medical history did not include episodes of gastrointestinal bleeding or encephalopathy. Long-term medications included furosemlde, aldactone, and folate. Physical examination showed an alert male with severe muscle wasting and prominent ascites. Preoperative laboratory data included a hemoglobin of 9.8 g/dL, fibrinogen 86 mg/dL, AST of 60 ix/L, serum alanine aminotransferase (ALT) of 47 ix/L, platelet count 35,900/mm 3, PT 16.3 seconds, PTT 35.9 seconds, bleeding time longer than 10 minutes, albumin 3.4 g/dL, and a creatanine clearance of 71 mL/min. The electrocardiogram (ECG) showed a normal sinus rhythm with left-axis deviation. Pulmonary function tests were tJ J Morns, MD, C L Hellman, MD. and B J Gawey, MD

PATIENT #2

0

PRE-INClSION

POST BYPASS AND PROTAMINE REVERSAL

POST FFP, 4u PLAT, 10u CRYOPPT, 20u

POST FFP, lu PLAT, 10u AND END OF SURGERY

Fig 1. Thromboelastographic pattern of the patmnt m Case 2 Severe coagulopathy is demonstrated by the postbypass TEG Reactton time, maximum amplitude, and clot formation rate tmproved after sequential transfusion of platelets, FFP, and cryoprecipitate Transfusion of FFP and platelets normalized the TEG pattern by the end of surgery

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seconds, platelet count of less than 20,000/mm 3, hemoglobin of 6.7 g/dL, and fibrinogen of 55 mg/dL. This was treated with 10 umts of platelets, 4 umts of FFP, 1 unit each of PRBC and cell saver red cells, and 20 umts of cryoprecipitate. The repeat laboratory values included a PT of 22.5 seconds, PTT of 78.9 seconds, platelet count of 63,000/ mm 3, a hemoglobin of 6.7 g/dL, and a fibrinogen of 198 mg/dL. Because of an abnormal TEG # 3 (Fig 1) and a perslstently bleeding surgical field, 10 umts of platelets, 1 unit of cell saver blood and PRBC, and an additional umt of FFP were admm]stered. The repeat laboratory values measured 90 minutes from the completion of CPB were PT 17.8 seconds, PTF 55.9 seconds, platelet count 91,000/mm 3, hemoglobin 7.1 g/dL, and fibrinogen 209 mg/dL. TEG #4 (Fig 1) showed a normal pattern with no evidence of fibrmolysis and the coagulation parameters approached preoperative values. Furosemide, followed by bumetanide, was administered to aid m diuresis. The patient was taken to the ICU with nitroglycerin, hdocaine, and renal-dose dopamine (3 ixg/kg/ min) infusions. The postoperative course was uneventful, and by postoperative day 5, liver function and coagulation data did not differ appreciably from preoperative values. Subsequently, there was no evidence of ascites, encephalopathy, or additional renal dysfunction. The patient was discharged home on postoperative day 8 and placed back on the active liver transplantation hst 6 weeks after his CABG surgery. Approximately 7 months after CABG surgery, the patient underwent a successful and uneventful OLT. Case 35 A 61-year-old man presented for combined CABG and OLT. His past history was remarkable for liver cirrhosis caused by the hepatitis C virus complicated by ascites and encephalopathy. There was no history of esophageal varices or upper gastrointestinal bleeding. A routine preoperatwe exercise stress test showed sdent myocardial ischemia, and cardiac catheterization showed severe tnple-vessel disease with good left ventricular function. Preoperative medications included atenolol, lactulose, furosemide, spironolactone, omeprazole, and vitamin K. Examination showed an alert and oriented man with mild ascites and jaundice. Few petechiae were present on his trunk, and he was in no apparent distress. Preoperative laboratory results included a platelet count of 109,000/mm 3, PT/control 14.6/11.9 seconds, PTT/control 29.8/28.5 seconds, fibrinogen 120 mg/dL, normal electrolytes, and BUN/creatinine 24/1.8 mg/dL. The ECG and chest x-ray were within normal hmlts. After the placement of a radial arterial catheter, right internal jugular pulmonary artery catheter, and two 8.5 F peripheral venous catheters for rapid infusion, preoxygenatlon was begun. Anesthesia was mduced with 5 ixg/kg of fentanyl, 0.3 mg/kg of etomidate, and 1.5 mg/kg of succinylcholine in a rapid-sequence fashion as endotracheal intuba-

:~L Shore-Lesserson, MD, and F Lalehzarian, MD Aprotinin was supphed by Miles Inc Pharmaceuticals, West Haven, CT.

CASE 3--1995

tlon proceeded uneventfully. After a 1-mL test dose of aprotinin was administered (10,000 Kalhkrem inhibiting units [KIU]), the loading dose of 2 million KIU was infused followed by an infusion of 500,000 K/U/hour. Two million K/U of aprotinin were also added to the oxygenator priming solution. The heparinizatlon protocol for CPB included administration of 300 units/kg directly into the right atrium with intermittent monitoring by the cehte ACT to keep the ACT greater than 800 seconds. CPB was conducted using a bubble oxygenator, hemofiltratlon, and mild, hypothermia. Three bypass grafts were performed including a left internal mammary arterial graft. Total aortic cross-clamp time was 44 minutes, and total CPB time was 75 minutes. The patient received two units of PRBC for a hematocnt of 18% on CPB. Separation from CPB was accomplished without the use of vasopressors. There was no evidence of cardiac dysfunction or regional wall motion abnormahty on transesophageal echocardiography. Low-dose dopamme was begun to augment renal blood flow as urine output had been minimal throughout the procedure. After heparin neutralizauon with protamine (10 mg of protamine for each 1,000 units of heparin), continued mediastinal bleeding was treated with FFP to replace a presumed factor deficiency as measured by standard coagulation tests and TEG. After evidence of clotting, the sternum was temporardy approximated with surgical wires and a few subcutaneous sutures; it would be permanently closed after the liver transplantation. The patient was then prepared for subsequent OLT. Platelets and cryoprecipitate were infused to correct thrombocytopenia and hypofibrinogenemia. The aprotinm mfusion was continued throughout the surgical procedure until the 7 million KIU supply was exhausted. The preanhepatic phase was notable for an episode of acute surgical blood loss, which necessitated transfusion of PRBCs, FFP, cryoprecipitate, and platelets. Venovenous bypass was initiated, and the anhepatic phase was tolerated without hemodynamic or metabolic complications. The duration of the anhepatic phase was prolonged (2 hours 23 minutes) because of difficulty securing the suprahepatic vena caval anastomosis. The chest was opened to facilitate exposure from above the diaphragm, and eventual vascular control was obtained. Fibrin strands and clots were present in the mediastmum and were believed to be evidence of adequate hemostatic management at this point. After securing the final venous anastomosis, reperfusion of the donor liver proceeded without any arrhythmias or metabolic derangements. Thirty minutes after reperfusion, the anesthetic course was complicated by hypotension, acidosis, and a highoutput low-resistance state responding to an epinephrine infusion after correction of the acidosis. Continued bleeding, which was also now evident m the chest cavity, necessitated the infusion of additional homologous blood component therapy. When hemostasls was achieved, 10 hours after the abdominal skin incision, the patient was transported to the surgical ICU m stable condition. He remained on low-dose dopamlne (2.5 ixg/kg/min) for con-

CASE 3--1995

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tinued oligurla but had been successfully weaned off epinephrine. On postoperative day 2, the patient was extubated. He was awake and responsive. However, his renal function deteriorated further, and he required hemodlalysis. His prolonged postoperative course was remarkable for the following: On postoperative day 3, he had severe segmental atelectasis requiring reintubation. On postoperative day 12, it was noted that the patient was aphasic and had a right hemiparesis. Neurologic work-up showed evidence of a left temporal cerebral infarction of unknown age on computed tomography and the presence of central pontine myelinolysis on magnetic resonance imaging. He underwent an intensive rehabihtatlon program In the hospital and experienced some improvements in his cognitwe function. Six months postoperatively he was still bedridden and aphasic. Although his renal function slowly continued to improve, he required hemodialysis three times weekly. DISCUSSION§

Patients with ESLD presenting for OLT have occasionally been found to have severe, concurrent CAD. The presence of both ESLD and severe CAD poses a therapeutic dilemma, and the question of which organ system to address first must be answered. OLT in the presence of CAD entails the risk of myocardial lschemia and potential infarction. The patient with ESLD typically has a high cardiac output with low SVR, which could pose a problem in maintaining perfusion pressure across stenotic coronary lesions. Severe hemodynamic instability may occur during hepatectomy and is especially common after reperfuslon of the grafted liver.l Normalization of cardiac output and SVR over a period of time after OLT could also increase the chance of myocardial lschemia. For these reasons, CABG is the procedure that is usually performed first if the coronary lesions are not suitable for angioplasty. With this in mind, special consideration must be given to the coagulation abnormalities and hemodynamics in the patient with ESLD undergoing CABG. CPB could exacerbate an underlying coagulopathy and may decrease hepanc blood flow, potentially precipitating fulminant hepatic failure and encephalopathy. 2 The metabolic functions of the diseased liver also may be impaired, resulting in prolonged activity of pharmacologic agents. Possible perturbations in pulmonary function include hypoxia secondary to pulmonary shunts, ventilation abnormalities caused by massive ascItes, and, rarely, pulmonary hypertension. 3 Renal dysfunction is often present, resulting in varying degrees of water retention, hyponatremla, hypokalemia or hyperkalemia, and oliguria. Severe CAD may be considered a contraind~catlon to OLT, or it may be amenable to treatment such that the risk of OLT is considered acceptable. If the CAD is not suitable for percutaneous transluminal coronary angioplasty (PTCA), then CABG must be considered. Six of the 835 adult patients undergoing OLT at the authors' institution

§J J Morns, MD, C.L Hellman, MD, and B.J. Gawey, MD.

since 1985 have required pretransplant PTCA as part of the OLT work-up, and 19 had CABG before OLT. Of the 19 who had CABG before OLT, only 2 (ie, the 2 case reports) had the CABG after the onset of ESLD. These two cases demonstrate some of the possible complications of patients with both ESLD requiring OLT and severe CAD requiring CABG. If CABG is performed before OLT, the risk of postoperative fulminant liver failure, as occurred in case 1, is significant. This may be caused by a combination of the risks inherent to the procedure: induction of anesthesia, nonpulsatile CPB, the total time of CPB, and the need for perioperatlve vasoactive infusions, all potentially resulting in reduced oxygen delivery to the hepatocytes. Case 2 illustrates a successful outcome when CABG is performed before OLT, and after 1 year the patient is doing well Alternatively, if OLT is performed before CABG, the patient is at great risk of sustaining severe, and potentially irreversible, myocardial dysfunction after reperfusion of the grafted liver. The relative risks to a given patient must be carefully considered before a decision is made concerning which procedure to initially undertake, or whether they should be performed together DISCUSSION (CON)II

The Combined Procedure

In conjunction with meticulous surgical technique and careful preoperative evaluation, the occurrence of high-risk combined procedures such as CABG and OLT may become more prevalent. The medical and ethical issues surrounding this case create an interesting controversy. In its formative years, liver transplantation was reserved for the few fortunate patients who did not have any relative contralndications to such surgery. Today, more patients qualify for and receive OLT because of increased donor awareness and the increased experience and skill of the transplant surgeons. A high degree of patient motivation, a supportive family network, absence of other systemic illnesses, other than CAD, and absence of central nervous system pathology are what made case 3 a candidate for such a procedure. After extensive collaboration among the cardiac surgical and the liver transplant surgical and supportive teams, the decision to perform a combined procedure was reached. The patient's primary presenting complaints of jaundice, ascites, and encephalopathy confirmed his need for liver transplantation. However, there are excessive metabolic and hemodynamic swings that occur during OLT, mostly associated with the anhepatic and post-reperfuslon phases The ischemic myocardium may not tolerate this degree of stress, and thus the patient in case 3 underwent CABG immediately before transplantation. The presence of severe liver dysfunction and coagulopathy in association with cardiac surgery presents a real risk of hemorrhage after exposure to the CPB circuit. Most agree that the hemostatlc defect induced by extracorporeal circulation that contributes most to postoperative bleeding is

[IL. Shore-Lesserson, MD, and F Lalehzanan. MD

326

platelet dysfunction. 4 Mechanical trauma to platelets stimulates alpha granule release. The impaired capacity of platelet surface receptors leads to postbypass defects in adhesion and aggregation. The extensive air/blood interface of the bubble oxygenator is also a potent stimulus for platelet activation. Most of this platelet dysfunction5 occurs during the initial blood contact with the perfusion system. 6,7 Additionally, dilution of existing coagulation factors and clinical or subclinical fibrinolysis occur in association with extracorporeal circulation, s,9 The hematologic insults incurred during CPB are usually well-tolerated in the hematologically healthy patient In those with coagulation factor deficiencies and thrombocytopenia, the potential for massive hemorrhage could be devastating. In order to minimize the known risks of each individual surgical procedure, CABG followed immediately by OLT using venovenous bypass was planned. The possibility of simultaneous CABG and hepatectomy on CPB was considered; however, the additional time spent on CPB and the need for systemic anticoagulation made this option less desirable. There are few reports in the literature describing the need for concomitant OLT and procedures requiring CPB. However, these procedures have been multiple organ transplantations in which healthy donor organs were grafted to the host. The simultaneous occurrence of coronary artery revascularizatlon and OLT has yet to be reported. In July 1993, the governor of Pennsylvania, Robert Casey, underwent combined heart and liver transplantations caused by extensive infiltration of these organs by systemic amyloidosis. At the Children's Hospital at the University of Pittsburgh, combined liver and heart transplantation has been successful in a number of children I° despxte the fact that initial attempts with the combined procedure failed because of technical difficulties. II One child with homozygous familial type IIa hypercholesterolemia 12,I3 required liver transplantation to correct the absolute deficiency of low-density lipoprotein (LDL) receptors The child suffered from severe atherosclerotac and cardiomyopathic valvular disease caused by hypercholesterolemia and had undergone two prior cardiac operations. After heartliver transplantation, cholesterol levels decreased dramatically. Follow-up reports after hospital discharge were uneventful. Another child with a ddated cardiomyopathy assocmted with intrahepatic biliary atresia had a doubleorgan transplant./4 Both heart and liver grafts were performed on total CPB. No documentation of blood loss or hemorrhagic complications was reported. The University of Madrid Department of Surgery 15,I6 recommended a two-stage procedure for a patient with familial hypercholesterolemia. The cardiac transplantation is performed initially. After a few weeks of convalescence, the cardiac graft is better able to handle the intervention of liver transplantation. This sequential approach minimizes hepatic ischemm time, the risk of intercurrent infection, and the risk of hemorrhage associated with systemic anticoagulation during the procedure. However, in such situations, the procedures are being performed on patients with normal or near-normal coagulation status. The patient with hepatic cirrhosis represents a more

CASE 3--1995

complex hematologic dilemma. When portal hypertension ISpresent, increased intrahepatic pressure causes extravasation of plasma and parenchymal congestion, which adversely affect the normal coagulation and fibrinolytlc systems. A patient with Budd-Chiari syndrome and portal hypertension underwent OLT requiring an atrioatrial anastomosis caused by a previous dorsocramal liver resection and hepatoatrial anastomosis. 17 This procedure was performed with the utilization of CPB facilitating the atrial anastomosis. The degree of hemorrhage and transfusion requirements was believed to be minimized by the use of CPB because it simplified the complex vascular procedure, used lower MAPs, and shortened the operative time. Wallwork et al I8 reported a case of liver, heart, and lung replacement in a woman with severe pulmonary hypertension, cardiopulmonary failure, and end-stage primary biliary cirrhosis. CPB was initiated using superior vena cava and femoral venous outflow with return to the ascending aorta. After transplantation of the heart-lung en-bloc, the hepatectomy was performed on partial bypass with the heart beating. Despite a CPB duration of 209 minutes, major bleeding was not encountered. The patient survived and was discharged from the hospital 46 days postoperatwely. In case 3, the consensus among the surgical teams was to first perform the CABG and remove the patient from the extracorporeal circuit and then proceed with the OLT. Emphasis was placed on maintaining a short CPB time and full reversal of heparln effect. The right atrium and ascending aorta were decannulated before the OLT. The hemodynamic alterations during hepatectomy were tempered by venovenous bypass draining the left femoral and portal veins and infusing the left axillary vein as inflow. Aprotinin was used because it has been shown to reduce perioperatwe blood loss and transfusion requirements in repeat 19,2°and primary cardiac surgical patients. 6,2°-24There have also been documented blood-saving benefits for patients on preoperative aspirin therapy, patients with uremic platelet dysfunction,25 and for patients with endocardatis. 2°,26 The mechanisms by which aprotinin reduces the hemostatic derangements in cardiac surgery are still being studied. It is currently believed that aprotmln reduces hemorrhagic sequelae primarily by its inhibition of plasmin (fibrinolysis) and secondary plasmin-related effects. At the dose currently used (2 million KIU followed by 500,000 KIU/hr), plasma levels of aprotinin are high enough to reliably achieve plasmin inhibition More recently aprotinln has been reported to reduce blood loss in liver transplantation. 27 Fibrinolysis is frequently observed in the TEG during the anhepatic and post-reperfuslon stages. Very high levels of tissue plasminogen activator (tPA) are present during OLT. 28 Especially during the anhepatac phase the liver does not clear tPA, nor does the liver produce its usual plasminogen inactivators. Thus, the transplantation of a liver graft may induce subclinical or frank disseminated intravascular coagulation. 29 Aprotinm administration has been associated with significant reductions in the transfusion of blood products,

CASE 3--1995

operative time, and ICU stay in liver recipients. 3° This difference is attributed to its profound inhibition of hyperfibrmolysis evidenced clinically and by thromboelastography.31,32 Because of the occurrence of acute surgical blood loss and a prolonged anhepatie phase, the patient m case 3 received homologous blood products totaling 33 units of PRBC, 30 units of FFP, 18 umts of platelet concentrates, and 30 units of cryoprecipitate. It is thus very difficult to evaluate the impact, if any, of the use of aprotinm on intraoperative transfusion requirements m this case.

Renal Dysfunctton The patient in case 3 had mild renal dysfunction before surgery (creatmine = 1.8 mg/dL). Creatinine in itself is an adequate indicator of satisfactory renal function in uncomplicated OLT. A serum creatinine greater than 3.0 mg/dL unassociated with the hepatorenal syndrome is generally considered a contradindication to OLT due to an increased incidence of perioperative mortality. 33 Hepatorenal syndrome before liver transplantation is often reversible after transplantation. This patient was belaeved not to have the hepatorenal syndrome before OLT, although a preoperative renal biopsy was not performed. His mild degree of renal impairment probably represented intrinsic renal disease. He was exposed to a number of hemodynamic derangements, specifically CPB nonpulsatile perfusion and post-reperfusion hypotension, which usually are associated with transient oliguria Additionally, the potent immunosuppressant drugs cyclosporine A and FKS06 are notoriously nephrotoxic. This patient was receiving cyclosporine A as part of his immunosuppressive regimen. The incidence of renal dysfunction in association with aprotlnin therapy is unknown. 34 Early studies were performed under experimental conditions, such as shock and ~schemia, and may not reflect the in wvo activity of the drug. Conflicting reported effects of aprotinin include normal and abnormal electrolytes, normal or diminished glomerular filtrataon, and normal or increased urinary output. A recent study by Blauhut et a124specifically studied the renal sequelae of high-dose aprotinin in a surgacal population undergoing CPB. They found normal or improved creatinine clearances, osmolar clearances, and fractional excretions of sodium in their aprotinin patients relative to a group of controls. Also, Royston et a125found no change in kidney functaon an a group of patients with uremia given aprotinin to reduce bleeding after CPB. Renal function post-transplantation is intamately linked to liver graft function. Intraoperatively, when oliguria develops, renal-dose dopamine and prostaglandin E1 infusions often augment renal perfusion. 3s If fluid overload is present and ohguria persists, patients will require hemofiltration or hemodialysis Patients with poor early graft function ( < 5% of transplant patients) experience oligurlc renal dysfunction after OLT. In the patient in case 3, the number of potential hepatorenal, hemodynamic, and nephrotoxac insults to the kidney makes it difficult to distinguish an exact cause for his renal failure. In all likelihood, he will remain on hemodialysis indefinitely.

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COMMENTARY: CABG BEFORE OLT¶

The incidence of severe CAD in patients undergoing OLT has not been previously reported. Of the 608 patients, 40 years or older, who have undergone OLT at this institution, only 34 patients (5.6%) had documented evidence of CAD. Evidence from several studies supports the concept that protection from ischemm heart disease is afforded by cirrhosis of any etiology.36-38 In cirrhotlcs, peripheral vasodilatation lowers arterial pressure, thus modifying one major risk factor for the development of coronary atherosclerosxs. 39 Furthermore, chronic ethanol intake may offer additional protection from CAD by increasing the levels of high-density-lipoprotein cholesterol and decreasing platelet adhesiveness. 4°-44 Although ethanol abuse may initially exacerbate existing arterial hypertension, the hypotensive effects of ESLD may predominate once cirrhosis has developed. 4546 For patients with ESLD undergoing surgery, problems with hemostasis can be expected. Difficulties with the surgical control of large vascular shunts may be encountered, and abnormalities of both platelet count and function along with the decreased hepatic production of factors I, II, V, VII, IX, and X may lead to significant hemorrhage. 47 Poor nutritional status, gastrointestinal bleeding, and congestive splenomegaly can lead to thrombocytopenia. Portal hypertension with collateralization and increased capillary fragility make surgical hemostasis more difficult. 48 Flbrinolysis may be enhanced by both the decreased clearance of plasminogen activator and decreased synthesis of plasminogen activator inhibitor. 49 If the surgery requires the use of CPB, then additional hemostatlc perturbations may occur. Patients with normal preoperative hepatic function who undergo cardiac surgery and CPB are at substantial risk of postoperative bleeding related to both surgical trauma and CPB-related acquired defects in hemostasis. As many as 3% of patients may have to undergo mediastinal reexploration after CPB due to hemorrhage. 5°42 Initiation of CPB causes the hemodilution of coagulation proteins and platelets by as much as 30% to 45%, which persists for at least 24 hours. The severity of further reductions in platelet number during CPB is correlated with total pump rime. This reflects platelet destruction by shearing forces and turbulence, as well as platelet removal by the pump oxygenator, extracorporeal orcult, and by the formation of intravascular microthrombi. These significant quantitative changes are usually well tolerated without excessive bleeding; however, no studies substantiating this in patients with ESLD have been performed. Indeed, the patient in case 2 had a preoperative platelet count of only 39,000/mm 3 and after 90 minutes of CPB this dropped below 20,000/ram 3. This postbypass platelet count was substantially below the average level reported by numerous investigators who measured platelet loss following CPB in patients with normal preoperative liver function. 51,53-56 A more common problem is an acquired, qualitative

¶M.A.E. Ramsay, MD. and T.R Valek, MD

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platelet defect, the severity of which is determined by total CPB time. 51,57,58 Although several mechanisms have been proposed for this dysfunctaon, including protamlne lnhibitaon of platelet aggregation, a definitive explanation has yet to be found. Although fibrlnolysis does occur to a small degree during CPB, hemorrhage due to fibrinolysls is not usually observed clinically. 51,53,58-59The significance of fibrinolysis in patients with ESLD undergoing CPB has not been studied. Intentional anticoagulatlon with heparIn potentially exposes the patient with ESLD to an additional risk for hemorrhage. As a result of impaired metabolism, patients with poor liver function are very sensitive to the effects of heparm. Heparin sensitivity is related to an increased duration of action, and bears no relevance to the initial anticoagulant effect. Therefore, the amount of heparin lmtially required to heparlnize the patient is the same irrespective of liver dysfunction. The introduction of additional heparln during OLT is avoided, and at this institution, heparin is not added to either the venovenous bypass circuit or the pressure monitoring lines during OLT. Also, blood collected before autotransfusion is washed with a solution containing a maximum of 20,000 units of heparin per liter, as this has been shown to offer no risk of subsequent heparlnization after washing. 6° The risk of further hepatic damage during CPB to an already compromised liver must also be a concern. Severe jaundice (bilirubin levels greater than 6 rng/dL) after surgery employing CPB occurs in 6% of patients with normal preoperative hepatic function. Hepatic dysfunction in this setting appears to be more dependent on hemodynamic status before and after CPB than on the direct effect of CPB, and function will usually improve if postoperative hemodynamlcs and nutrition are kept normal 61 Changes in hepatic blood flow (HBF) during CPB may contribute to hepatic dysfunction. The liver has a dual blood supply with reciprocal interaction between the hepatic artery and portal vein and a complicated control mechanism. For patients with portal hypertension, an increased proportion of the total HBF is supplied by the hepatic artery. Therefore, a decrease in MAP or arterial oxygenation is more likely to produce further hepatic damage in patients with ESLD and portal hypertension, as compared to normal patients. Several studies have attempted to measure changes in HBF during CPB. Although nonpulsatlle flow is the most common method employed during CPB, disturbances in organ blood flow and metabolism have been postulated to occur with this unphyslologic flow pattern. 62 Studies involving patients without ESLD undergoing nonpulsatde CPB have demonstrated HBF decreases ranging from 30% to 43%, whereas pulsatile flow appeared to maintain baseline values. 63,64 These studies estimated total HBF using the indocyanine green (ICG) dilutlonal technique. The use of ICG clearance as a measure of HBF, however, has been shown to be unjustified. 65 Addmonally, total HBF is not a measurement of "nutritional" liver blood flow and adequate studies measuring changes in nutritional liver blood flow including oxygen delivery, oxygen consumption, and hepatic venous oxygen saturation during CPB have not

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been performed. The effects of anesthesia, surgical site, and the type and length of CPB on hepatic function in patients with preexisting ESLD also have not been fully studied. The patient with ESLD can also have varying degrees of renal dysfunction present due to a decreased effective plasma volume accompanied by sodium (Na +) and water retention caused by increased renin-angiotensin activity and increased antidiuretic hormone activity. CPB can aggravate pre-existing renal disease, with renal failure occurring in 1.2% to 13% of patients who have had bypass. 66-68 Mannitol, given to the patient in case 2, was intended to protect renal function by increasing renal blood flow, increasing glomerular filtration, and reducing injury after ischemla. 69 Loop diuretics, also given to this patient, were intended to enhance diuresis by inhibiting Na + and C1- reabsorption in the thick ascending limb. Still controversial today is the use of pulsatile CPB to improve renal performance. The majority of studies suggest that pulsatile perfusion does maintain more normal renal metabolism, reduces renin release, and preserves outer cortical blood flow, thus better preserving renal function. 7°-73 However, there are contrasting studies that fail to find benefit, and because of the inconsistent studies, along with added cost and complexity of pulsatile flow, many institutions excluswely use nonpulsatile CPB. 74,75 Damaged liver function can significantly alter the pharmacodynamics and pharmacoklnetics of various anesthetic drugs. As effective HBF decreases and hepatic microsomal activity is depressed, drug metabolism is reduced. Drugs with a high intrinsic clearance and extraction ratio, (eg, fentanyl, lidocalne, propofol) would have greater alterations in metabolism than drugs with a low intrinsic clearance and extraction ratio (eg, diazepam, phenobarbital). Clearance, as a measurement of the rate of elimination, may be either increased because of enzyme induction or decreased because of reduced HBF, reduced functional liver mass, altered liver metabolism, and decreased level of plasma enzymes such as chohnesterase. 76 Benzodiazepines should be avoided in patients with indications of early encephalopathy. Studies have shown that hepatic encephalopathy has been associated with increased gammaamlnobutyric acid (GABA) neurotransmlssion in the brain, which may be Increased by benzodiazepines. 77,7~ Titration of drug to effect is important with these patients because some effects are additive while others are opposing. Although not presently a standard monitor of coagulation during cases employing CPB, the TEG helped guide hemotherapy for these patients. The TEG affords a continuous in vitro measurement of the quality of clot formation and retraction, and is a better predictor of postbypass hemorrhage than the ACT. 79 COMMENTARY. OLT BEFORE CABG#

OLT in the presence of CAD exposes the patient to the risks of myocardial lschemia and potential Infarction. Patients with either three-vessel or left main CAD who

#T C. Gunning, MD, and T H. Swygert, MD

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undergo noncardiac surgery are at an increased risk of postoperative myocardial infarction. One- or two-vessel CAD, conversely, carries only a relatively low risk of perioperatwe infarction in this setting. 8° Patients with ESLD characteristically possess a hyperdynamlc circulation with an increased CO and a decreased SVR. These circulatory changes are postulated to be the result of numerous arteriovenous (AV) shunts and a resultant decrease In peripheral impedance. This may also be associated with arterial hypoxemia due to the development of right-to-left intrapulmonary shunts in the presence of pulmonary hypertension. Therefore, maintaining an adequate balance between oxygen supply and demand is extremely important. This is difficult to do during OLT because of hemodynamic instability resulting from sudden reductions in venous return Reperfusion of the grafted liver is often associated with hemodynamic instability with profound hypotension, decreases in SVR, cardiac arrhythmias, and increased filling pressures, sl Potent vasopressors used to treat severe hypotenslon after reperfusion (ie, norepinephrine or epinephrine) can occasionally have mixed effects in improving systemic pressure but reducing perfusion of the tissues. Blood flow through AV shunts may be increased at the expense of the resistance vessels through a "steal" mechanism, thereby not improving oxygen delivery to the cells. 82 This challenge during reperfusion must be met by an already hyperdynamic heart with severe CAD, with the potential for severe morbidity and mortality COMMENTARY SURGICAL PERSPECTIVE**

The case presentations and their discussions illustrate the difficulnes in attempting to perform OLT in patients with severe CAD. In case #1 as described by Morris et al, the patient with cirrhosis and severe CAD underwent CABG before OLT. No blood products were reqmred intraoperatively for the CABG despite the fact that the patient's preoperative PT was 14.9 seconds. However, endoscopic evaluation of this patient preoperatively showed that she had esophageal varices. The extent of the bleeding of these varices and the temporal relationship of the bleeding to the cardiac surgery is not described. Not surprisingly, on the second postoperative day after the CABG procedure, the patient was noted to be lethargic and an upper gastrointestinal tract hemorrhage was discovered. An attempt was made to perform sclerotherapy to control bleeding and vasopressln was instituted. Ulnmately, the bleeding was controlled with a splenorenal shunt. This patient went on to develop rapidly progressive hepatic failure and worsening of ascltes. A Denver shunt was placed, a tracheostomy was performed, and when renal failure ensued, the patient was dialyzed and eventually underwent OLT. After this surgery, a thrombosed portal vein and infarction of the donor liver were noted. The patient ultimately died of sepsis and liver failure. In the second case presented by Morris et al, the patient underwent formal liver transplantation evaluation and

~K. Brayman, MD, PhD. FACS

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advanced CAD was found. There was no history of angina in this patient. The patient underwent a pretransplant CABG in preparation for OLT. Not surprisingly, because the patient's preoperative PT was 16.3 seconds, his bleeding time greater than 10 minutes, and his platelet count was 36,000/cm 3, the post-bypass period was complicated by bleeding despite reversal of heparm with protamine and administration of desmopressin. The TEG after CAB indicated a severe coagulopathy. Postbypass, the patient had a PT of 32 seconds and a platelet count of less than 20,000/cm 3. Eventually, the elevated PT and other abnormalities of coagulation were corrected by infusion of platelets and FFP to a point where the bleeding was normalized and they approached preoperative values. The patient was transferred to the ICU where he underwent an uneventful postoperative course. Approximately 7 months after CABG surgery, the patient underwent a successful OLT procedure. In case #3, presented by Shore-Lesserson et al, combmed CABG and OLT was performed for a panent with hepatitis C-related ESLD complicated by ascites and encephalopathy. In this patient, there was no history of esophageal varices or upper gastrointestinal bleeding. The routine preoperative work-up showed silent myocardial lschemia and cardiac catheterization confirmed the presence of severe triple-vessel disease. Similar to the second case, following CPB and attempts at reversal of heparin with protamine, continued mediastinal bleeding was noted and was treated with FFP. The OLT was performed immediately after the CABG. The pre-anhepatic phase was notable for an excessive amount of blood loss Unfortunately, technical difficulties were encountered and the duration of the anhepatic phase was prolonged due to difficulties securing the superhepatic vena caval anastomosis. Thirty minutes after reperfusion, the anesthetic course was comphcated by hypotension, acidosis, and a high output/low resistance state. After surgery, the patient developed renal failure, pulmonary atelectasis, and stroke. Central pontine myelinolysis was also confirmed. Ultimately, the panent's renal function improved slowly, but he remained dialysis dependent, and was msntutionalized because he was bedridden and aphasic. The combination of ESLD and portal hypertension with severe CAD and unstable angina is being seen with increasing frequency due to liberalization of criteria for liver transplantation. In most cases, the physicians and surgeons elect to perform the CABG first. Not surprisingly, such patients can suffer bleeding after cardiac surgery. The risk of gastrointestinal hemorrhage following cardiac surgery remains. In the first case, a decision to control gastrointestinal hemorrhage with additional surgery (splenorenal shunt) was made. An alternative approach to control the bleeding would have been to place a TIPPS (transjugular intrahepatic portosystemic shunt). The TIPPS procedure has proven remarkably successful at controlling portal hypertension and bleeding in cirrhotic patients. 83-85 In the patient described in the first case report, a TIPPS would have been a reasonable alternative to the splenorenal shunt that was performed.

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330

While ascites can occur following the TIPPS procedure, usually the opposite is true and ascites resolves following relief of elevations of the portal pressure. It is not mentioned m the case report whether the splenorenal shunt was taken down at the time of the OLT. Following transplantation, surgical re-exploration revealed a thrombosed portal vein and infarcted donor liver. Diversion of the portal flow through a splenorenal shunt following the transplant is a risk factor for portal vein thrombosis. It would have been reasonable to hgate the splenorenal shunt at the time of the OLT to prevent this complicatton. In their discussion, Morris et al correctly outline that the presence of ESLD and severe atherosclerotIc CAD poses a therapeutic dilemma. The dilemma surrounds which organ system to address first. Orthotopic liver transplantation, especially during the anhepatic phase, represents a significant risk for a heart with severe CAD. Myocardial ischemia, infarction, and ventricular dysfunction are problematic in the setting of an OLT procedure. Cardiac compromise is especially dangerous during reperfusion of the grafted liver. Overall, I agree that CABG is the procedure that should be performed first if the coronary artery lesions are not suitable for PTCA. Certainly, the patient with ESLD represents a particular risk for CABG. Indeed, at many centers, severe CAD is considered a contraindlcatIon to OLT and the CAD is managed medically. Clearly, an attempt to perform combined CABG and OLT is fraught with a number of potential hazards as illustrated in the third case. Foremost among these risks is uncontrolled bleeding. From the case description, it is unclear whether the bleeding encountered during the OLT procedure had more to do with the difficulties with the suprahepatlc cavil anastomosis or the post-CPB heparin state. Given the fact that a limited number of livers are available for transplantation, the use of livers in high-risk settings is currently under re-evaluation. In the third case, a less than satisfactory result was obtained when the attempt was made to perform the OLT at the same time as the CABG. The author believes that the best way to manage these cases is for the CABG to be performed first and the OLT performed at a subsequent surgery. Although the risk for bleeding is high in patients with ESLD being placed on CPB, most of the bleeding can be controlled. Indeed, a prophylactic TIPPS may be indicated in patients with persistent portal hypertension and a history of gastrointestinal bleeding. Overall, the pursuit of OLT in high-risk recipients such as the ones described in these case reports

must be scrutinized for the cost-effectiveness of these procedures. COMMENTARY. HEALTH POLICY PERPECTIVEtt

I am impressed with the exquisite anesthetic and surgical care provided to these very sack patients. While a number of medical issues concermng preoperative evaluation deserve discussion, I prefer to raise some more provocative, health policy issues. I am curious about two statistics that are not in these discussions. The first is the survival of patients requiring CABG before undergoing OLT. The increased morbidity and risk for mortality of these patients is illustrated by the demise of the patient in the first case. The second set of statistics that intrigued me are the total costs of care for these patients. I would suspect that they mount into hundreds of thousands of dollars. I ask these questions because there is every indication that society is less prepared to provide unchecked resources for all sick patients. This is best illustrated by the experiment in explicit rationing under the Oregon Medicaid waiver. Oregon has divided all of medical care into more than 700 treatment pairs, and the state will decide what is fundable under the annual Medicaid budget. While the Medicaid budget at th~s nine for 1995 is not settled, it seems unlikely that these patients would be approved for transplantation in Oregon. More importantly, most experts m health care management expect that capitated payment for medical services will be the rule m health care financingwithin a decade. It is already the case for up to 50% of patients in southern California. In capitated plans, primary care providers are encouraged to act as gatekeepers, often with the use of a hospital risk pool. Moreover, specialists may be prepaid on a capitated basis. In such a situation, I question whether many physicians would refer the patients in these case studies for liver transplantation; or whether heads of surgical programs would sanction this sort of therapy if it clearly would eat into a capitated pool. Although not to suggest that these patients do not deserve treatment, we can expect that the funds available for medical care will moderate or even decline. We may soon face a day in which patients who need CABG and OLT simply are not referred for such therapy. Anesthesiologists and surgeons should be prepared to address such situations when they arise. ttT.A Brennan

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