Cardiac Surgery in Patients With End-Stage Liver Disease

REVIEW ARTICLE Paul G. Barash, MD Giovanni Landoni, MD Section Editors

Cardiac Surgery in Patients With End-Stage Liver Disease Geraldine C. Diaz, DO,* and John F. Renz, MD, PhD†

A

NESTHETIC MANAGEMENT of a patient with endstage liver disease (ESLD) undergoing major cardiac surgery remains a significant clinical challenge. Morbidity typically results from sepsis, multisystem organ failure, or hepatic insufficiency. Previous limitations to only emergency indications have been relaxed, resulting in an increase in the incidence of major cardiac surgery in patients with ESLD.1,2 A review of the New York State Department of Health Cardiac Surgery Registry from 1998 through 2006 showed a 22% increase in the performance of cardiac surgical procedures in patients with known liver disease.3 This occurred despite liver disease being identified within this registry as a highly significant, independent predictor of poor outcome.3 Several factors have increased the eligibility of the cirrhotic patient for major cardiac surgery. Foremost, the past 2 decades have witnessed a dramatic advancement in the medical management and life expectancy of patients with cirrhosis.4,5 The introduction of prophylactic ␤-blockers to decrease portal hypertension, the widespread application of endoscopic modalities to treat esophageal varices, the availability of the transjugular intrahepatic portosystemic shunt (TIPS), spontaneous bacterial peritonitis prophylaxis, and effective medications to suppress hepatitis viral replication have increased the life expectancy of patients with ESLD.5 Increased longevity has contributed to the increased incidence of hepatocellular carcinoma,6,7 a complication of cirrhosis, and coronary artery disease in cirrhotic patients.2,8,9 The refinement of cardiac and hepatic transplantation subspecialties has improved dramatically the treatment of patients with isolated organ failure. The natural progression of these accomplishments is the extension of expertise to dual-organ failure. Indeed, the annual incidence of combined heart-liver transplantation (CHLT) has more than doubled since 2000 (Fig 1)10 and all North American centers that have published on cardiac surgery in the setting of ESLD enjoy robust cardiac and hepatic transplantation programs. CLINICAL CONSIDERATIONS FOR CARDIAC SURGERY IN PATIENTS WITH ESLD

Cardiac surgery in patients with ESLD is associated with significant morbidity and mortality.1,11 The principal source of morbidity is the gastrointestinal (GI) tract; cardiovascular complications are less common.2 The most frequently reported GI complications after cardiac surgery include cholestasis (65%), hemorrhage (25%), and mesenteric ischemia (14%).12-15 He-

patic failure accounts for approximately 4% of observed GI complications but is associated with a mortality ⬎70%.15 Estimating operative morbidity is difficult. Although liver disease is a recognized risk factor for mortality and complications after cardiac surgery, the widely recognized disease severity scores for cardiac surgery, including the New York Heart Association Functional Classification16 and the European System for Cardiac Operative Risk Evaluation (EuroSCORE),17 do not adjust for liver disease. Thus, one must derive a prognosis by considering cardiac and hepatic diseases independently. Morbidity and mortality from cardiac surgery in cirrhotic patients correlate to the severity of liver disease.18-21 The ChildTurcotte-Pugh (CTP) classification has been the traditional standard for the evaluation of patients with cirrhosis (Table 1).22 Initially developed to predict surgical mortality after portocaval shunting, the CTP classification is a disease severity index that assigns points to 5 different parameters of hepatic function, creating 3 functional classes of cirrhosis: A, B, and C.22 The Model for ESLD (MELD) score is a more powerful predictor of ESLD mortality23 that largely has superseded the CTP classification; however, the association of MELD with morbidity and mortality from cardiac surgery has not been validated prospectively. The initial comparison of the CTP classification with the MELD as a predictor of outcome after cardiac surgery using cardiopulmonary bypass (CPB) in cirrhotic patients was a retrospective study by Suman et al.24 The outcome measurements were hepatic decompensation and death within 3 months of surgery. In their analysis, hepatic decompensation and mortality significantly correlated to CTP class, CTP score, and MELD score. A CTP threshold score ⬎7 emerged as the most sensitive predictor of postoperative mortality, with a sensitivity of 86%, specificity of 92%, negative predictive value of 97%,

From the *Department of Anesthesia and Critical Care and †Division of Abdominal Organ Transplantation, Department of Surgery, University of Chicago, Chicago IL. Address reprint requests to Geraldine Diaz, DO, Department of Anesthesia and Critical Care, University of Chicago, 5841 S Maryland Avenue, MC4028, Chicago, IL 60637. E-mail: [email protected]. edu © 2012 Published by Elsevier Inc. 1053-0770/xx0x-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.09.018 Key words: cirrhosis, liver disease, cardiac surgery, combined heart-liver transplantation, cardiothoracic surgery

Journal of Cardiothoracic and Vascular Anesthesia, Vol xx, No x (Month), 2012: pp xxx

1

2

Diaz and Renz

Table 2. Cardiac Surgical Morbidity and Mortality Correlate With Severity of Liver Disease by Child-Pugh Class

20

Study

15 10 5 0 1992

1994

1996

1998

2000

2002

2004

2006

2008

2010

Fig 1. Annual incidence of combined heart-liver transplantation procedures in the United States.10

and positive predictive value of 67%, respectively.24 A significant threshold value for MELD could not be established, perhaps because the MELD is not as sensitive as the CTP class in evaluating portal hypertension and ascites, 2 complications that frequently antagonize postoperative recovery. Filsoufi et al25 performed a retrospective study of cirrhotic patients undergoing major cardiac surgery at the Mt Sinai Medical Center from 1998 through 2004. This study identified a significant correlation among CTP class, preoperative thrombocytopenia, and hospital mortality that did not exist for the MELD. In addition, CTP class correlated with 1-year survival and the incidence of a major postoperative complication. These data led Filsoufi et al25 to conclude that CTP class remains the best means of predicting mortality from cardiac surgery. Additional retrospective studies have verified thrombocytopenia as a poor prognostic indicator.9,26 The identification of thrombocytopenia as an outcomes predictor highlights the sensitivity of CTP class for portal hypertension versus the MELD. Preoperative platelet count varies inversely to CTP class, with thrombocytopenia secondary to splenic sequestration a surrogate for the degree of portal hypertension.25 This has been supported by additional studies linking thrombocytopenia with the extent of fibrosis and the presence of esophageal varices.27,28 Recent data from the United States,29 Europe,30,31 and Japan9 have suggested an increasing power of the MELD to predict outcomes in cardiac surgery in cirrhotic patients. Thielmann et al30 retrospectively evaluated 57 patients with noncardiac ESLD who underwent cardiac surgery using CPB and com-

Table 1. Child-Turcotte-Pugh Classification22 Measurement

1 Point

2 Points

3 Points

Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (s above normal) Ascites Encephalopathy (grade)

⬍2.0 ⬎3.5 1.0-3.0

2.0-3.0 2.8-3.5 4.0-6.0

⬎3.0 ⬍2.8 ⬎6.0

none none

Slight I-II

Moderate III-I

Grade

Total Points

Surgical Risk

A B C

5-6 7-9 10-15

Good Moderate Poor

Morbidity Klemperer et al18 Bizouarn et al11 Hayashida et al19 Suman et al24 Lin et al20 An et al21 Filsoufi et al25 Mortality Klemperer et al18 Bizouarn et al11 Hayashida et al19 Suman et al24 Lin et al20 An et al21 Filsoufi et al25 Vanhuyse et al31

Year

n

A (%)

B (%)

C (%)

1998 1999 2004 2004 2005 2007 2007

13 12 18 44 18 24 27

25 50 60 10 39 53 22

100 100 100 66 80 100 56

— — 100 100 80 100 100

1998 1999 2004 2004 2005 2007 2007 2012

13 12 18 44 18 24 27 34

0 20 0 3 0 6 11 18

80 50 50 42 0 67 18 40

— — 100 100 100 67 100

pared the MELD, CTP class, and EuroSCORE for predicting mortality. Their analysis showed the MELD to be superior to the CPT class and EuroSCORE. Ailawadi et al29 determined the MELD was an effective method for risk stratification across patients with ESLD and that a MELD score ⬎15 strongly predicted mortality in patients undergoing tricuspid valve surgery. Although other studies have not validated a linear correlation between the MELD and mortality, several investigators have suggested a potential “threshold” MELD score of 13-15 beyond which mortality noticeably increases.29,31,32 This approximates a borderline CPT classification of B/C.9 A definitive comparison of CTP class with the MELD score will require a large, prospective, randomized trial that is unlikely to occur soon. Currently, all available data have suggested cardiac surgery can be performed safely in patients with CTP class A (Table 2). Significantly higher morbidity and mortality should be anticipated in patients with CTP classes B and C; however, the actual risk in these groups likely has been underestimated in reported series owing to careful patient selection. Additional retrospective studies have suggested increased serum total bilirubin and low serum cholinesterase concentration as potential preoperative indicators18,33; however, these have not been validated prospectively and serum cholinesterase is not immediately available in North America. PROPERTIES OF CIRRHOSIS THAT PREDISPOSE TO COMPLICATIONS IN CARDIAC SURGERY

The physiologic challenge of cardiac surgery is tolerated poorly in the setting of cirrhosis. Risks associated with all major cardiac surgical procedures, including anesthesia, largevolume transfusion, coagulopathy, and disseminated intravascular coagulation, are amplified in the presence of liver disease. However, the physiologic stress of hypotension, hypoperfusion, and ischemia-reperfusion are the principal elements of hepatic injury. CPB imposes physiologic, immunologic, and metabolic demands on the liver. The hemodynamics of CPB is nonphysi-

Cardiac surgery and end-stage liver disease

ologic, specifically nonpulsatile flow, low cardiac output, and hypotension. Significantly increased levels of circulating endogenous catecholamines released at the initiation of CPB decrease hepatic perfusion by approximately 20% and hepatic arterial blood flow by 20%-45% through vasoconstriction.34 Decreased arterial flow disrupts circulatory distribution within the liver, resulting in an imbalanced oxygen supply. Decreased hepatic venous oxygen saturation and increased hepatosplanchnic oxygen extraction have been observed.34 Gårdebäck et al35 observed a 21% decrease in oxygen delivery to the liver and a 46% decrease in oxygen consumption by the liver during 32°F CPB. Decreased oxygen delivery potentiates further catecholamine release, free radical formation, and the generation of vasoactive small molecules within the circulation. Visceral ischemia-reperfusion injury is exacerbated by arterial atherosclerosis, stenosis or occlusion of visceral vessels, and aneurysms that are common in patients with cardiac disease. Poor hepatosplanchnic perfusion antagonizes intestinal mucosal injury, predisposing to endotoxemia, proinflammatory cytokine release, and the systemic inflammatory response syndrome (SIRS). Vasoactive small molecules generated by intestinal anaerobic metabolism, necrotic cellular debris, and translocated bacteria are transported to the liver through the portal vein. This compounds the SIRS response within the liver, increasing the hepatic reserve necessary to facilitate recovery. Thus, hepatic ischemia and necrosis are not solely the result of inadequate arterial supply, but an ischemia-induced loss of the intestinal barrier, resulting in small bowel injury, bacterial translocation, absorption of endotoxin, and an acceleration of SIRS. When the hepatic reserve is exceeded, sepsis, hemorrhage, or multisystem organ failure ensues.36 The biliary system is the most metabolically active component of the liver and the principal recipient of the hepatic arterial supply. Active transport is required for biliary epithelia to pump conjugated bilirubin against a concentration gradient from hepatocytes into biliary canaliculi. Thus, the biliary system is exquisitely sensitive to arterial ischemia and biliary dysfunction, the earliest indicator of ischemic liver injury.36 Ischemia-induced biliary dysfunction is the etiology of the frequently observed cardiac surgical complications of “post-pump jaundice” and acalculous cholecystitis described ⬎20 years ago.37 Increased hepatic transaminases do not indicate hepatic arterial insufficiency reliably because liver-specific alanine and aspartate aminotransferases are released from hepatocytes that have significant potential for anaerobic metabolism. Furthermore, alanine and aspartate aminotransferases are not distributed uniformly throughout the liver but are most concentrated in the periportal zones, whereas the centrilobular zones are the most susceptible to early ischemic injury.36,38 Increased alkaline phosphatase and ␥-glutamyl transpeptidase are more sensitive predictors of acute biliary ischemia than transaminases but do not correlate linearly to the extent of hepatic injury.38 PROPERTIES OF CARDIAC SURGERY THAT PREDISPOSE TO COMPLICATIONS IN PATIENTS WITH CIRRHOSIS

Hypotension, hypoperfusion, coagulopathy, hemorrhage, and transfusion are routine elements of cardiac surgery that impair hepatic metabolism. Contact activation of factor XII by the extracorporeal circuit stimulates inflammation by the acti-

3

vation of the intrinsic coagulation pathway, kallikrein, and complement. This is cascaded through platelet aggregation, debris, and microemboli formed within the bypass tubing.39-41 An emerging hypothesis is the potential of improved outcomes through CPB avoidance. In patients with normal hepatic function, prospective, randomized trials have shown CPB does not affect significantly the development of GI complications.42-44 However, limited observational data from patients with known liver disease have suggested an advantage to avoiding CPB. Gaudino et al45 initially described improved outcomes in cirrhotic patients undergoing cardiac surgery in the absence of CPB when they reported a small retrospective series of coronary revascularizations. Improved outcomes in CPT class B and C cirrhotic patients undergoing cardiac surgery without CPB subsequently have been reported by several groups as small retrospective series or case reports.1,19,46-50 Filsoufi et al25 reported the largest series of cirrhotic patients undergoing cardiac surgery without CPB that included 5 coronary revascularization procedures and 4 pericardiectomies. Avoidance of CPB did not affect transfusion requirements but there was no mortality observed in patients who had revascularization without CPB versus mortality in all CTP classes using CPB.25 Of course, retrospective data are not randomized and certainly reflect a selection bias for disease severity and cardiac procedure. PREOPERATIVE PREPARATION OF PATIENTS WITH CIRRHOSIS UNDERGOING MAJOR CARDIAC SURGERY

The current medical management of ESLD has improved dramatically patients’ health and quality of life.4,5 As a result, the clinical presentation of ESLD is more subtle and diagnosis much more difficult. However, because the morbidity and mortality of cardiac surgery correlate to the severity of liver disease,1,18,19,20 it is imperative to explore thoroughly any suggestion of potential liver disease in a patient presenting for cardiac surgery during the preoperative evaluation to avert preventable morbidity and mortality. Because there are so few specific therapies available for acute liver injury, an ounce of prevention is truly worth a pound of cure. Overt jaundice, poorly controlled ascites, profound encephalopathy, and a recent history of GI hemorrhage suggest advanced liver failure and a poor prognosis. Subtle historic findings that mandate investigation include new-onset sleep disorders, progressive fatigue, disordered concentration, and confabulation. A history of hepatitis or jaundice, significant alcohol use for a substantial period, or use of high alcohol content beverages warrants further investigation. Early physical signs of ESLD include constructional apraxia (inability to copy diagrams), palmar erythema, spider telangiectasia, caput medusae, and gynecomastia. Altered handwriting, particularly signing one’s name, is a very sensitive indicator of encephalopathy. Early laboratory signs of portal hypertension include thrombocytopenia (platelet count ⬍150,000); normochromic, normocytic anemia; increased prothrombin time or international normalized ratio; and evidence of poor nutrition, including low total protein, serum albumin, transferrin, retinol binding protein, or prealbumin. Transaminases typically are normal in the setting of cirrhosis and are not predictive of ESLD.

4

The etiology of chronic liver disease can assist in predicting the difficulty of cardiac surgery. There are 3 fundamental etiologic classifications of ESLD: metabolic liver disease (familial amyloid polyneuropathy, ␣-1 antitrypsin deficiency, polycystic liver disease), cholestatic liver disease (primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis), and noncholestatic cirrhosis (viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis). The degree of portal hypertension and hepatic reserve vary among classifications. Patients with metabolic liver disease rarely exhibit portal hypertension and have normal hepatic reserve. Their risk from cardiac surgery is increased minimally. Patients with cholestatic liver disease exhibit cirrhosis secondary to chronic cholestasis from biliary obstruction. These patients have intermittent cholangitis that precipitates liver failure and typically manifest portal hypertensive complications only in very advanced disease. Their hepatic reserve only modestly increases the risk from cardiac surgery. Noncholestatic cirrhosis represents the overwhelming majority of the ESLD patient population. In this group, the principal cause of morbidity is portal hypertensive complications and they exhibit minimal hepatic reserve. Careful attention to CPT score, history, physical examination, and laboratory data are essential to assess the risk of cardiac surgery accurately in patients with noncholestatic cirrhosis. If opportunity permits, 2 very helpful clinical predictors of hepatic reserve include improvement of the prothrombin time and international normalized ratio in response to the administration of vitamin K and serum protein responses (particularly prealbumin, transferrin, retinol binding protein) to nutritional therapy. The importance of preoperative nutritional support is essential because a lack of response to the administration of vitamin K or nutritional therapy failure portends a minimal hepatic reserve and a dismal prognosis. Serologic studies, diagnostic imaging, transhepatic pressure gradient measurement, and transjugular liver biopsy should be performed sequentially as indicated to evaluate suspected liver disease. Although imperative to determine the etiology of liver disease, this algorithm avoids percutaneous liver biopsy in most patients. Serologies diagnose viral and metabolic liver diseases that occasionally require a liver biopsy. If hepatitis B viral infection is diagnosed, eradicating viral replication before elective surgery through definitive antiviral therapy is prerequisite to prevent postoperative acute viral hepatitis. Routine abdominal ultrasound can document cirrhosis and assist in identifying a large, precirrhotic liver in the setting of chronic injury. Cross-sectional modalities, whether magnetic resonance imaging or computerized tomography, are very sensitive at determining cirrhosis, splenomegaly, abdominal varices, or the development of a spontaneous splenorenal shunt. Transjugular hepatic venous pressure measurement facilitates the calculation of a transhepatic pressure gradient with a low incidence of morbidity. A transhepatic pressure gradient ⬎12 mmHg implies cirrhosis and prompts consideration of a liver biopsy, which can be included in this procedure with minimal additional risk. If the biopsy shows at least stage II fibrosis, the patient has ESLD. A normal transhepatic pressure gradient implies portal hypertension secondary to right heart failure. Medical management of portal hypertension is paramount, including the administration of nonselective ␤-blockers if car-

Diaz and Renz

diac function is maintained. Prophylaxis for portal hypertensive gastropathy is indicated; however, octreotide and somatostatin analogs that cause splanchnic vasoconstriction have no role in prophylaxis but are indicated for the treatment of GI hemorrhage. Preoperative application of TIPS is a theoretically attractive maneuver to decrease portal hypertension in patients awaiting elective cardiac surgery. Unfortunately, few data exist to support this intervention. Semiz-Oysu et al51 reported TIPS use in 2 cirrhotic patients with portal hypertension before cardiac surgery using CPB. In each case, there was significant hepatic decompensation that ultimately recovered but delayed the planned cardiac procedure. Cardiac surgery was well tolerated by these patients, leading the investigators to assert preoperative TIPS decreased major surgical complications through the improvement of fluid imbalance and the decrease of bleeding risk. However, serious complications associated with TIPS include exacerbation of encephalopathy, hepatic decompensation, and cardiac failure. In the absence of larger clinical series data or prospective randomized trials, this technique must be applied very judiciously because hepatic decompensation or cardiac failure prompted by TIPS can alter the patient’s outcome dramatically. OPERATIVE STRATEGIES FOR PATIENTS WITH CIRRHOSIS UNDERGOING MAJOR CARDIAC SURGERY

The principal goals of operative planning for patients with cirrhosis undergoing major cardiac surgery include optimization of splanchnic perfusion, management of coagulopathy, thermoregulation, avoidance of fluid/electrolyte perturbations, and prevention of hepatic decompensation. Achievement of these objectives requires increased monitoring and heightened vigilance to avert morbidity. Coagulopathy is a routine concern in the performance of cardiac surgery; however, in the setting of limited hepatic reserve, very careful monitoring is required to avert bleeding diatheses or exceed the hepatic reserve. Increasing data have suggested routine coagulation studies do not assess accurately the hematologic aberrations associated with ESLD.52 The liver is the principal source of coagulation protein synthesis, including thrombopoietin, coagulation factors II, V, VII, IX, X, XI, and XII, anticoagulation protein C, protein S, and antithrombin. Thus, liver disease affects coagulation through thrombocytopenia, abnormal platelet function, altered coagulation protein synthesis, and impaired fibrinolysis. Coagulation synthesis impairment with ESLD progression is unknown but increasing data have shown patients fluctuate between hyper- and hypocoagulable states through a multifactorial process that includes hepatic decompensation, systemic inflammation secondary to bacterial translocation or spontaneous bacterial peritonitis, and intermittent GI hemorrhage.52 Routine coagulation tests assay thrombin generation as a function of procoagulant factors but do not assay the inhibition of thrombin by anticoagulant factors. Intraoperative monitoring of the cirrhotic patient requires greater information on thrombus formation to guide transfusion therapy. Whole blood testing by thromboelastography is a rapid, bedside assay that offers information enabling goal-directed transfusion therapy. Because there are no evidence-based threshold values governing platelet count and international normalized ratio values for

Cardiac surgery and end-stage liver disease

placement of central venous monitors, thromboelastography provides valuable data on a patient’s degree of coagulopathy and indicates how optimization can be achieved before the insertion of invasive monitoring.52 Administration of other products affecting coagulation should be based on intraoperative events supplemented with thromboelastography. The role of recombinant factor VII is controversial. Currently, there are no published data on the use of recombinant factor VII in cirrhotic patients undergoing cardiac surgery. Hemodilution has been reported in noncirrhotic patients to improve hepatic arterial and portal flow.53 However, patients with cirrhosis manifest hypoalbuminemia and low oncotic pressure and poorly tolerate large volume shifts. Excessive volume resuscitation antagonizes tissue edema, coagulation, and hepatic oxygen delivery secondary to venous congestion. The data on hemodilution in cirrhotic patients undergoing are inconclusive. With respect to hemoglobin, 2 clinical reports54,55 and an experimental study56 have shown an inverse relation between hematocrit on CPB and postoperative mortality in patients with ESLD. When anticipating CPB, perioperative strategies that minimize the duration of CPB and transfusion requirements have a beneficial effect on hepatic function. Technical modification of CPB, including perfusion flow rate, temperature, tubing length, pump speed, and volume loading, have shown an advantage.36,57 Efficient circuits with low prime volumes decrease tubing surface area and blood-air interfaces. This decreases contact activation of the potential inflammatory response and the morbidity associated with CPB.58 Total hepatic blood flow is preserved at higher perfusion flow rates (⬎2.3 L/min). If high flow rates cannot be achieved, the addition of pulsatile perfusion and hypothermia (28°C) significantly improves hepatic perfusion.59 The optimal temperature for the preservation of hepatic function during CPB is unknown. Hepatosplanchnic oxygenation is higher under mild hypothermic (32°C) versus normothermic CPB,60 but indocyanine green clearance is impaired at lower temperatures.61 Current data have suggested the optimum CPB protocol for preserving hepatic circulation requires a high perfusion rate with pulsatile or nonpulsatile flow at 37°C and a CPB duration ⬍70 minutes.62 Nitric oxide, melatonin, N-acetylcysteine, and growth hormone have shown a protective effect on hepatic injury in experimental cardiac surgical models but have not yet been subjected to clinical trials.63-65 POSTOPERATIVE MANIFESTATIONS OF LIVER INJURY AFTER CARDIAC SURGERY

Hepatic dysfunction after cardiac surgery ranges from transient hyperbilirubinemia to overt liver failure. The outcome depends on the hepatic reserve and the ability to compensate for the physiologic trespass of cardiac surgery.33 Early postoperative unconjugated hyperbilirubinemia may reflect intravascular hemolysis associated with CPB, a mechanical valve leak, or extravascular hemolysis of transfused red cells and is not a reliable indicator of hepatic injury. Unconjugated hyperbilirubinemia is characteristically transient and typically shows improvement within 72 hours.

5

Protracted conjugated hyperbilirubinemia is observed in 20%-35% of patients and was described initially as “post-pump jaundice,” defined as a serum bilirubin level ⬎3 mg/dL within 7-10 days after surgery.66-69 Cholestasis from ischemic injury impairs digestion and nutrient use and predisposes to cholangitis that accelerates hepatic injury. Hyperbilirubinemia is accentuated during prolonged or complicated operative procedures, particularly in the presence of cardiogenic shock requiring vasopressors, intra-aortic balloon pump, or prolonged mechanical ventilation, and is associated with increased mortality.69,70 Outcomes do not correlate with increased transaminases but significantly correlate with peak serum bilirubin and the resolution of cholestasis within 2 weeks of surgery. Prolonged cholestasis beyond 7 days is a marker of substantial hepatic ischemic injury, morbidity, and mortality.67 When total bilirubin exceeds 10 mg/dL ⬎7 days after surgery, mortality exceeds 20%.70 To optimize recovery, it is essential to recognize conjugated hyperbilirubinemia early. Other causes of continuing hepatic injury, such as viral replication from hepatitis A or B, cytomegalovirus, Epstein-Barr virus or Herpes viridae, toxins, or technical considerations, must be evaluated while concomitantly providing hemodynamic support to maintain hepatic perfusion and metabolic support to augment available hepatic reserve by enteral nutrition, prevention of hemorrhage, aversion of iatrogenic injury, and prevention of sepsis. Overwhelming ischemic liver injury is termed shock liver, which is characterized by serum transaminases ⬎10 times the upper limit of normal within 48 hours of surgery. Shock liver represents overwhelming ischemic injury to the biliary tree and hepatocytes, resulting in acute liver failure as manifest by metabolic acidosis, hyperlactatemia, hemodynamic instability, coagulopathy, and hypoglycemia. Available data have suggested predictors of shock liver include female sex, a history of cardiac failure, diabetes, hypertension, and protracted CPB duration.71 Treatment of shock liver is supportive and directed at eliminating or minimizing ongoing injury with the prevention of additional metabolic stress from ischemia, hemorrhage, or sepsis. ALGORITHM FOR MANAGEMENT OF CORONARY ARTERY DISEASE IN CIRRHOTIC PATIENTS

Sufficient data have emerged to formulate an algorithm for approaching cardiac surgery in cirrhotic patients. In the presence of advanced liver disease, it is intuitive to avoid cardiac surgery if at all possible. Optimizing medical management, lifestyle modification to decrease risk, and emphasizing percutaneous procedures, where applicable, minimize potential morbidity. Indeed, multiple reports have indicated successful percutaneous transluminal coronary angioplasty performed in cirrhotic patients awaiting orthotopic liver transplantation (OLT).72 When cardiac surgery is mandated, preoperative preparation begins with concomitant assessment of cardiac and hepatic functions. Cardiac function is best assessed by echocardiography, whereas hepatic function is estimated through the CPT class and MELD score. Patients with CPT class A cirrhosis and a MELD score ⬍11 tolerate cardiac surgery well with or without CPB.

6

Diaz and Renz

For patients with advanced liver disease manifesting a CPT B classification or a MELD score ⬎12-⬍14, estimated myocardial function is the key to clinical decision making. Patients with CPT B class and good myocardial function tolerate most cardiac procedures, with avoidance of CPB preferred. For CPB-mandated procedures, preoperative medical optimization of portal hypertension improves outcomes in these high-risk procedures.51 Patients with poor myocardial function and advanced liver disease as indicated by a CPT B classification or a MELD score ⬎12-⬍14 represent patients with true dualorgan failure who are best approached by CHLT, as described below. Indications for CHLT can be categorized broadly as true dual-organ failure, as observed in hemochromatosis and cardiac cirrhosis, or as a procedure to optimize the performance of a single organ as observed in CHLT for familial amyloidosis. In cases of true dual-organ failure, cardiac failure occurs in the setting of hepatic failure complicated by portal hypertension, coagulopathy, and thrombocytopenia. In CHLT for familial amyloidosis, liver transplantation is performed to protect the transplanted cardiac allograft. In this situation, there is isolated cardiac failure without portal hypertension. Although the indications for CHLT portend varying degrees of surgical difficulty, overall survival has been excellent regardless of etiology (Table 3).73,74 Patients with ESLD manifesting a CPT classification C, a MELD score ⬎14, or a history of portal hypertensive complications (hemorrhage, spontaneous bacterial peritonitis) will not tolerate the stress of cardiac surgery. For patients with good myocardial function, pre-emptive evaluation for OLT is a strategic consideration because a combined cardiac procedure at OLT (concomitant cardiac surgery and OLT [CCOLT]) may be the most practical solution, whereas CHLT is the only salient option for patients with poor cardiac function. Building on their experience in performing cardiac surgery in patients awaiting OLT, Morris et al75 reported the first successful CCOLT in a patient who underwent coronary arterial bypass grafting using CPB at OLT. Since their report,

Table 3. Overall Survival for Combined Heart-Lung Transplantation Survival (%) Study

SRTR Data

n

al73

1992-2004 1992-2005

Porrett et Barshes et al74 Familial amyloidotic polyneuropathy Cardiac cirrhosis HCV Alcoholic liver disease Hemochromatosis PBC Cryptogenic cirrhosis ␣-1 antitrypsin PSC SLE

1y

3y

5y

33 36 11

80

70

91

91

82

6 5 4 4 2 1 1 1 1

83 80 100 100 100 alive died died alive

— — 100 100 —

— — 66 100 —

Abbreviations: HCV, hepatitis C virus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SLE, systemic lupus erythematosus; SRTR, Scientific Registry of Transplant Recipients.

multiple subsequent case reports have verified acceptable outcomes in the performance of coronary arterial bypass grafting, with and without CPB, and the performance of aortic valve replacement at OLT.75-78 Axelrod et al79 reported a series of 5 CCOLT recipients who had significant coronary artery disease in ⱖ2 coronary arteries with preserved left ventricular function. Outcomes were good, with 4 of the 5 patients discharged and alive at 1 year. The only fatality was secondary to recurrent hepatitis C unrelated to CCOLT.79 The largest and most recent data are from DeStephano et al80 who reported a series of 5 patients undergoing coronary arterial bypass grafting with CPB and 4 patients undergoing aortic valve replacement at OLT. The investigators reported excellent results, with 1 death observed that was unrelated to a coronary event or hepatic allograft function. Surgical techniques common to all reports of CCOLT included the use of intraoperative transesophageal echocardiography and the performance of venovenous bypass during OLT. Later cardiac surgery after successful OLT yields satisfactory outcomes because hepatic function is normal. Filsoufi et al81 reported the 5-year survival of 12 OLT recipients undergoing cardiac surgery was similar to the general population; however, 33% of the OLT recipients exhibited postoperative transient liver dysfunction. CONCLUSIONS

Although cardiac surgery in the presence of ESLD is increasing, there are unique properties of cardiac surgery that predispose to complications in cirrhotic patients. The mechanisms that contribute to liver injury during cardiac surgery include hypoperfusion, ischemia-reperfusion injury, CPB, and contact activation of SIRS. Postoperative hepatic injury occurs when ischemic stress exceeds the hepatic metabolic reserve, with morbidity correlating to the severity of liver disease as determined by CPT class and MELD score. The lack of a clinical assay to measure functional hepatic reserve and monitor splanchnic perfusion and elementary therapies for reversing hepatic injury requires clinicians to rely on an astute preoperative evaluation coupled with exquisite intraoperative management and postoperative care to optimize outcomes. It is imperative to explore thoroughly any suggestion of potential liver disease during the preoperative evaluation to avert preventable morbidity and mortality. In the presence of advanced liver disease, optimal medical management and percutaneous therapy are preferred. When surgery is necessary, the etiology of ESLD, severity of liver disease, complications of portal hypertension, and left ventricular function should be included in selecting the optimal surgical approach. If surgery must occur, the CPB duration must be avoided or minimized, transfusion must be optimized, and higher perfusion flow rates at 37°C must be attempted. Predictors of mortality include serum total bilirubin, acetylcholinesterase, platelet count, and CPB duration. A high index of suspicion postoperatively will lead to earlier treatment directed at eliminating or minimizing ongoing hepatic injury and preventing additional metabolic stress from ischemia, hemorrhage, or sepsis. Surgical options depend on the severity of liver disease and myocardial function. Options include cardiac surgery at

Cardiac surgery and end-stage liver disease

7

OLT for decompensated cirrhotic patients with preserved myocardial function and CHLT in cases of prohibitive dual-

organ failure. Cardiac surgery after liver transplantation is well tolerated.

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