Geraldine C. Diaz, DO , Vivek Moitra, MD ,

Robert N. Sladen, MB ChB, MRCP(UK), FRCP(C),

FCCMb,*aDepartment of Anesthesiology, University of Arizona, Tucson, AZ 85724, USA

bDivision of Critical Care, Department of Anesthesiology, College of Physicians and Surgeons

of Columbia University, 630 West 168th Street, New York, NY 10032, USA

Hepatic injury in cardiac surgery is a rare complication but is associatedwith signicant morbidity and mortality.

A high index of suspicion postoperatively will lead to earlier treatment ineliminating/minimizing ongoing hepatic injury while preventing additionalmetabolic stress from ischemia, hemorrhage, or sepsis. The evidence-basisfor perioperative renal risk factors remains hampered by the inconsistentdenitions for renal injury. Although acute kidney injury (as dened bythe Risk, Injury, Failure, Loss, End-stage [RIFLE] criteria) has become ac-cepted, it does not address pathogenesis and bears little relevance to cardiacsurgery. Although acute renal failure (ARF) requiring renal replacementtherapy (RRT) after cardiac surgery is rare, it has a devastating impacton morbidity and mortality and further studies on protective strategiesare essential.

Hepatic protection during cardiac surgery

Impact of hepatic and gastrointestinal complications

Gastrointestinal complications reported after cardiac surgery are listed inTable 1. Although they occur infrequently, in fewer than 5% of cases, theyare serious events that substantially increase morbidity and may be associ-Hepatic and Renal Protection DuringCardiac Surgery

a b

Anesthesiology Clin

26 (2008) 565590ated with mortality as high as 67% [13]. Hepatic failure accounts foronly 4% of gastrointestinal complications (0.1% overall incidence) but is

* Corresponding author.

E-mail address: rs543@columbia.edu (R.N. Sladen).

1932-2275/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.anclin.2008.05.001 anesthesiology.theclinics.com

associated with mortality exceeding 70% [4]. These data are likely to com-pound as age, comorbidity, and medical complexity gradually increase inthe population undergoing cardiac surgery.

Table 1

Gastrointestinal complications after cardiac surgery

Complication Incidence, %

Hyperbilirubinemia 65

Gastrointestinal hemorrhage 25

Mesenteric ischemia 14

Pancreatitis 11

Cholecystitis 7

Perforated peptic ulcer 4

Hepatic failure 4

Data from Refs. [14].

566 DIAZ et alSurgical procedures of any kind are poorly tolerated in patients withcirrhosis, but cardiac surgery in particular is associated with exceptionallyhigh morbidity and mortality [48]. Potential operative risk can be assessedby the Child-Pugh Classication (Tables 2 and 3). A retrospective analysisof cirrhotic patients undergoing cardiac surgery between 1989 and 2003revealed an overall morbidity rate of 61% and mortality rate of 17% [6].Patients in Child-Pugh Class A experienced a morbidity rate of 40% withoutan appreciable increase in mortality. Postoperative morbidity in patients inChild-Pugh Classes B and C was 100%, and included infection, renal failure,respiratory failure, gastrointestinal hemorrhage, and hepatic insuciency.Mortality rate was 50% in Child-Pugh Class B patients and 100% inChild-Pugh Class C patients. These outcomes have been conrmed in

Table 2

Child-Turcotte-Pugh score for cirrhosisParameter 1 2 3

Serum bilirubin (mg/dL) !2 23 O3Serum albumin (g/dL) O3.5 33.5 !3PT (sec O control) 14 46 O6CNS (coma grade) Normal Confused (12) Coma (34)

Ascites None Easily controlled Poorly controlled

Table 3

Child-Turcotte-Pugh class and preoperative risk assignment

Class A B C

Score 56 79 1015

Risk Minimal Moderate Severe

Operative mortality 0%10% 4%31% 19%76%

Data from Refs. [4,9,10].

a prospective study [5]. In short, elective cardiac surgery using cardiopulmo-nary bypass (CPB) should not be attempted in patients with end-stage liverdisease (ESLD) complicated by ascites, variceal hemorrhage, orencephalopathy.

Multiple factors contribute to hepatic insuciency following cardiacsurgery (Box 1). Visceral complications are typically a manifestation ofa complicated operative course in a patient with limited physiologic reserve[9,10]. Predictors for the occurrence of a gastrointestinal complicationinclude advanced age, poor postoperative cardiac function, large transfu-sion requirement, arrhythmias, renal dysfunction, ventilation requirementexceeding 24 hours, requirement for reoperation, and poor New York HeartAssociation (NYHA) functional classication [1,3].

Splanchnic perfusion and hepatic injury

567HEPATIC AND RENAL PROTECTIONBox 1. Factors contributing to hepatic insufficiency after cardiacsurgery [4,9,10]

Factors related to cardiopulmonary bypass (CPB)Nonpulsatile perfusionHypothermiaCoagulopathy

Surgical complicationsHypoperfusionIschemia/reperfusion injuryDisseminated intravascular coagulopathy (DIC)Multiple blood transfusionsAnticipation of possible hepatic injury during cardiac surgery is predicatedon an understanding of the physiology of splanchnic perfusion and its impacton liver function. The abdominal viscera, including the liver, pancreas, stom-ach, spleen, and small and large intestine, constitute about 10% of ideal bodyweight, but the hepato-splanchnic circulation consumes 30% of the cardiacoutput and contains 25% of the total circulating blood volume [11]. The he-patic artery, a branch of the celiac trunk, is the only direct arterial supply tothe liver and accounts for approximately 20% of total hepatic blood ow [4].Arterial inow to the foregut viscera (stomach, pancreas, spleen) derives fromthe celiac trunk; the midgut (ileum) from the superior mesenteric artery; andthe hindgut (colon and rectum) from the inferior mesenteric artery. Venouseuent from the abdominal viscera transits to the liver via the portal veinPatient factorsSplanchnic atherosclerosis, anatomic anomaliesHepatic disease (impaired reserve)

and represents about 80% of total hepatic blood ow [4]. The oxygen extrac-tion ratio of splanchnic blood is high, up to 0.35, with a total body oxygenconsumption of 20 to 40 mL/kg/M2 because the viscera are metabolically ac-tive in absorption, digestion, and excretion [4,11]. Hepatic venous eux rep-resents the total hepato-splanchnic blood ow that has been processed by theliver for circulation throughout the body.

Hepatic arterial and portal venous ow are interdependent in a physio-logic response variously termed the hydrodynamic interaction, hepatic arte-rial buer response, or reciprocity of ow [1115]. Preliminary evidencesuggests hydrodynamic interaction is regulated by intrahepatic productionof adenosine [12]. Alteration of ow in the hepatic artery initiates regulatorycompensation in the portal vein, and vice versa, thus maintaining total liverblood ow relatively constant. This is evident by the vascular dynamics ofportal hypertension: as portal venous ow changes from hepatopedal (tothe liver) to hepatofugal (away from the liver) with progression of cirrhosis,there is compensatory hypertrophy of the hepatic artery.

The sympatho-adrenal system regulates liver blood ow through alpha-adrenergic vasoconstriction in the hepatic artery and intestinal and intrahe-patic portal vein. However, the portal vein is devoid of beta-2 receptors sothat only the hepatic artery can respond to sympathetically mediated vaso-dilation. Alpha-adrenergic stimulation increases hepatic arterial and portalvascular resistance by as much as 25%; contraction of capacitance vesselsincreases eective circulating blood volume up to 15% [4,11]. Chronic eleva-tions in portal venous resistance occur with brosis, thrombosis, or veno-occlusive disease; hepatic arterial resistance is chronically elevated byatherosclerosis. Unlike the renal, coronary, and cerebral circulations, autor-egulation does not exist in the portal circulation, and its ow is linearlyrelated to perfusion pressure [4,16,17].

Although the liver appears to benet from a dual blood supply, the arte-rial and portal venous systems dier fundamentally, with minimal overlap.The primary role of the portal venous system is to channel the splanchniccirculation to the liver. This is an essential physiologic pathway: the splanch-nic venous euent is poorly oxygenated and replete with metabolites,metabolic by-products, toxins, products of digestion, bacteria, drugs, andgut-derived visceral hormones. The portal vein aords the liver rst-pass at metabolism, detoxication, and immuno-surveillance of splanchnicblood before its release into the systemic circulation. The cells bathed by theportal vein are hepatocytes and bone marrowderived immunoregulatorycells that include macrophages, dendritic, Ito, and Kuppfer cells. Theyhave relatively low oxygen demand and account for the resiliency of the liverin the face of hypotension, hypovolemia, and hypoperfusion. As a conse-

568 DIAZ et alquence, moderate splanchnic ischemia more commonly manifests as anupper gastrointestinal bleed, bowel ischemia, and/or pancreatitis. Directliver injury and hepatic necrosis rarely result from inadequate arterial sup-ply alone. It is usually caused by concomitant ischemia-induced loss of the

tem,helia

engage in active transport as they pump conjugated bilirubin from hepato-

cytes into biliary canaliculi against a concentration gradient. As a conse-quence, the biliary system is the most sensitive component of the liver toischemia, and biliary dysfunction is the earliest indicator of ischemic liverinjury. Ischemia-induced biliary dysfunction provides the explanation forthe high incidence of post-pump jaundice and acalculous cholecystitisfollowing cardiac surgery initially observed more than 20 years ago [19].Thus, elevations of alkaline phosphatase and gamma-glutamyl transpepti-dase (GGT) are more sensitive predictors of acute hepatic ischemia.However, their levels do not linearly correlate to extent of hepatic injury.

The impact of cardiac surgery upon hepatic function

Pathogenesis of liver injuryHepatic injury during cardiac surgery is multifactorial. Like any other

procedure, exposure to volatile anesthetic agents may induce mild hepato-toxicity from reductive metabolites or, rarely, major immuno-toxicityfrom oxidative metabolites. Surgical procedures complicated by severehemorrhagic or cardiogenic shock may cause direct or indirect ischemicinjury, especially when high doses of vasopressors are used.

The most important potential factor aecting liver function is CPB,which creates a nonphysiologic state of nonpulsatile ow, low cardiacoutput, and hypotension that imposes physiologic, immunologic, andmetabolic stress on the liver. There is a signicant increase in levels of circu-lating endogenous catecholamines at the initiation of CPB, which decreasehepatic perfusion through vasoconstriction [20]. Splanchnic blood ow de-are most susceptible to early ischemic injury [18].The primary function of the hepatic artery is to supply the biliary sys

the most metabolically active component of the liver. Biliary epitintestinal barrier resulting in small bowel injury, bacterial translocation,absorption of endotoxin, and acute inammation within the liver [4]. Apo-ptosis and necrosis of hepatic sinusoidal cells impair detoxication, bacterialclearance, and immunoregulation, and may ultimately progress to a systemicinammatory response syndrome (SIRS), multisystem organ failure, anddeath.

Hepatic ischemia is not reliably reected by elevations in transaminases.The release of liver-specic alanine aminotransferase (ALT) and aspartateaminotransferase (AST) is a sensitive marker of viral or immune-mediatedhepatocyte destruction, but not early hepatic ischemia. The reason is thatALT and AST are not uniformly distributed through the liver and aremost concentrated in the periportal zones, whereas the centrilobular zones

569HEPATIC AND RENAL PROTECTIONcreases by approximately 20%, and hepatic arterial blood ow by 20% to45% during CPB [13].

A second important CPB-induced phenomenon is contact activation.A circulating procoagulant, Hagemann factor (Factor XII), is activated

by contact with the extracorporeal circuit, which in turn simultaneously ac-tivates the intrinsic coagulation pathway, kallikrein (and brinolysis) andcomplement. The latter initiates an inammatory reaction involving activa-tion of platelets, neutrophils, monocytes, and macrophages with increasedblood concentrations of cytokines and leukotrienes.

A third, but often occult pathway of CPB-induced organ injury is embo-lism. Platelet aggregates and debris from the bypass tubing contribute tomicroemboli formation, and the plasticizer coating of bypass tubing canact as a toxin [21]. Activation of the coagulation and brinolytic pathwayspredisposes to atheroembolic disease that is discovered in more than 20% ofearly postoperative deaths [22,23]. When encountered in autopsy specimens,atheroembolic disease of the mesenteric bed was the most common regiondocumented [22].

Thus, during cardiac surgery, CPB routinely sets up a response character-ized by vasoconstriction and inammation. The consequences to the liverdepend on the duration of CPB, hepatic reserve, and the hemodynamic con-sequences of the cardiac surgical procedure.

During CPB, subtle changes in mucosal blood ow, mucosal microcircu-lation, and hepatic sinusoidal perfusion are the principal contributors tosplanchnic ischemia [4]. Dramatic decreases in arterial ow lead to circula-tory maldistribution and an imbalance in oxygen supply:demand ratiowithin the liver. Hepatic mitochondrial function, as measured by arterialketone body ratios, appears to be altered during and after CPB; this eectextends through the rst postoperative day [24].

Increased hepato-splanchnic oxygen extraction and low hepatic venousoxygen saturation have been reported during and after CPB [2527]. De-creased oxygen delivery potentiates catecholamine release, free radical for-mation, and generation of vasoactive small molecules into the circulation[13]. Poor perfusion within the hepato-splanchnic axis exacerbates intestinalmucosal injury and predisposes to endotoxemia, pro-inammatory cytokinerelease, and SIRS [28,29]. When hemorrhage causes hypovolemia and hypo-tension, hepatic arterial ow is preserved by reciprocity of ow, but theresulting portal hypoperfusion exacerbates liver injury.

As elucidated above, acute splanchnic ischemia activates hepatic andsystemic inammation that is the principal mechanism for remote organdysfunction and the progression of multisystem organ failure [11,30]. Bowelischemia facilitates translocation of lipopolysaccharide endotoxin into theportal circulation, stimulating macrophages to release tumor necrosis factor,which activates neutrophils and lymphocytes and releases additional inam-matory cytokines. In the liver, endothelial cell injury disrupts immunologicsurveillance and detoxication [31]. Sinusoidal disruption and congestion

570 DIAZ et alinterferes with clearance of gut-derived bacteria and cytokines and permitsspillover of endotoxin into the systemic circulation, accelerating SIRS [32].

When SIRS is severe, progressive activation of the coagulation, brino-lytic (kallikrein), and complement cascades results in increased endothelial

mitsof normal within 48 hours of cardiac surgery with gradual resolution. Cho-

lestasis originates from ischemic injury to the biliary epithelia responsiblefor canalicular excretion of bilirubin. This impairs digestion and nutrientuse, and predisposes to cholangitis that accelerates hepatic injury. Hyperbi-lirubinemia and elevated transaminases are accentuated in the setting ofSerum transaminases are typically elevated two to ve times the upper licell permeability and permits transvascular migration of activated leuko-cytes into tissues, with additional vascular and parenchymal injury [33,34].This inammatory reaction compounds splanchnic ischemia and acceleratesrelease of vasoactive substances during and after CPB [34].

Clinical manifestations of liver injuryHepatic dysfunction following cardiac surgery ranges from transient

hyperbilirubinemia to overt liver failure. The hepatic consequences of thephysiologic trespass of cardiac surgery with CPB are directly proportionalto the degree of preexisting hepatic insuciency [35]. Even in the face ofstable hemodynamics, splanchnic ischemia may progress when visceralmetabolic demand is increased, or it may be accelerated by complicationsof surgery including poor cardiac function, high levels of vasopressor infu-sions, and continued mechanical ventilation. As previously described, trans-aminitis is not a sensitive marker of acute hepatic ischemia after CPBbecause hepatocytes are protected against short periods of hypoxia. Whileclose monitoring and early diagnosis of postoperative liver injury may im-prove outcomes, the most important step is prevention. It is critical to iden-tify even mild degrees of liver disease preoperatively so that steps can betaken to modify or minimize the surgical procedure (see later in thisarticle), and to optimize hepatic and splanchnic perfusion during surgeryand the immediate postoperative period.

Transient unconjugated hyperbilirubinemia. Early postoperative unconju-gated hyperbilirubinemia generally reects intravascular hemolysis associ-ated with CPB or a mechanical valve leak, or extravascular hemolysis oftransfused red cells, and is not an indicator of hepatic injury. Unconjugatedhyperbilirubinemia is characteristically transient, and starts to resolvewithin 72 hours.

Protracted cholestasis (conjugated hyperbilirubinemia). More protractedconjugated hyperbilirubinemia (ie, cholestasis) is quite common, occurringin 20% to 35% of patients, especially in those with preoperative cholestasis.It was initially described as post-pump jaundice, dened as a serum bili-rubin higher than 3 mg/dL within 7 to 10 days after surgery [19,3638].

571HEPATIC AND RENAL PROTECTIONa complicated operative course, especially with cardiogenic shock requiringhigh doses of vasoactive drugs, intra-aortic balloon pump counterpulsation,prolonged mechanical ventilation, and sepsis, and are associated withincreased mortality (11% versus 2%) [38,39]. Outcome of patients with

naseand

the pattern of resolution within 2 weeks of surgery. Prolonged cholestasis

dae. Hemodynamic support is important to maintain hepatic perfusion,

with metabolic support to augment available hepatic reserve by enteralnutrition, prevention of hemorrhage, aversion of iatrogenic injury, andprevention of sepsis.

Severe ischemic early liver injury. Severe ischemic early liver injury is alsoreferred to as shock liver, and is characterized by severe transaminitisexceeding 10 times the upper limit of normal within 48 hours of surgery.In contrast to the biliary epithelial injury of cholestasis, it represents over-whelming injury to the hepatocytes, and manifests as acute liver failurewith metabolic acidosis, hyperlactatemia, hemodynamic instability, coagul-opathy, and hypoglycemia. Retrospective observation suggests that patientsare more likely to be women, with a history of cardiac failure, diabetes,hypertension, and protracted CPB [40]. Postoperatively, patients havehigher pulmonary artery occlusion and central venous pressures, lower car-diac output, increased requirement for inotropic support and mechanicalassist devices, renal failure, mechanical ventilation greater than 48 hours,and death. Once recognized, treatment of shock liver is supportive onlyand directed at eliminating or minimizing ongoing injury and preventingadditional metabolic stress from ischemia, hemorrhage, or sepsis.

Risk factors for hepatic injury during cardiac surgerybeyond 7 days is a marker of substantial hepatic ischemic injury, morbidity,and mortality [36]. When total bilirubin exceeds 10 mg/dL more than 7 daysafter surgery, mortality exceeds 20% [39].

The severity of cholestasis reects the balance between surgical stress andthe individuals metabolic reserve. Thus, its exact incidence is dicult topredict and directly correlates with clinical events. In Japan, antipyreneclearance provides a reliable estimate of preoperative functional hepaticreserve. It correlates with peak postoperative serum bilirubin and the needfor intensive care among patients undergoing mitral and tricuspid valvesurgery; however, this assay is not readily available in the United States.Furthermore, quantitative assays of functional hepatic reserve have notbeen validated in Western populations. To optimize the chance of recovery,it is essential to recognize conjugated hyperbilirubinemia early. Other causesof continuing hepatic injury should be evaluated, such as viral replicationwith hepatitis A or B, cytomegalovirus, Epstein-Barr virus, or herpes viri-cholestasis is not predictable by the rather uctuant pattern of transamielevation; rather, it correlates with the peak value of hyperbilirubinemia572 DIAZ et alBecause there is so little specic therapy for acute liver injury, identifyingpatients at risk for hepatic injury preoperatively is the most eective methodto decrease postoperative morbidity and mortality. This allows planningperioperative management to optimize splanchnic perfusion, increases

ientsntly

receives better medical care, enjoys a higher quality of life, and appears

healthier than ever before.

By the time the patient presents with hyperbilirubinemia, ascites, enceph-alopathy, gastrointestinal hemorrhage, coagulopathy, or physical signs ofliver failure (eg, palmar erythema, spider telangectasia, caput medusae,gynecomastia) it is too latedthese are manifestations of end-stage liverdisease. More subtle ndings that mandate investigation include new-onsetsleep disorders, progressive fatigue, disordered concentration, confabulation,constructional apraxia (inability to copy diagrams), thrombocytopenia(platelet count!150 k), a history of hepatitis or jaundice, signicant alcoholuse for a substantial time period, or use of highalcohol content beverages.

The Child-Pugh score is not a sensitive predictor of early liver disease.Serologic studies, diagnostic imaging, transhepatic pressure gradient mea-surement, and transjugular liver biopsy should be sequentially performedas indicated to evaluate suspected liver disease. This algorithm avoids percu-taneous liver biopsy in the majority of patients.

Serologic studies diagnose viral or metabolic liver disease. It is imperativeto establish the etiology of an observed transaminitis. Evaluation shouldbegin with viral studies and may ultimately indicate a liver biopsy. If hepa-titis B viral infection is diagnosed, denitive antiviral therapy is a prioritywith the goal of eradicating viral replication before elective surgery.

Routine abdominal ultrasound can document cirrhotic changes but canalso be helpful in identifying a large, precirrhotic liver in the setting oflong-term injury. Magnetic resonance imaging or computerized tomographyare very eective at demonstrating cirrhotic changes within the liver as wellas the presence of abdominal varices or the development of a spontaneoussplenorenal shunt. Hepatic venous pressure measurement and calculationof a transhepatic pressure gradient is performed via cannulation of the inter-nal jugular vein and is a very safe procedure with a low incidence of compli-cations. This technique is particularly useful in distinguishing portalhypertension of cirrhosis from portal hypertension secondary to right heartfailure. A transhepatic pressure gradient greater than 12 mm Hg implies cir-rhosis, and prompts consideration of a liver biopsy, which can be includedwith only a small additional risk. If this reveals stage II brosis or greater,the patient has end-stage liver disease and is at very high risk of liver injuryor failure with surgery.

Strategies for perioperative hepatic protectionvigilance, and improves the probability of early diagnosis. More patwith cirrhosis will present for cardiac surgery because this group curre573HEPATIC AND RENAL PROTECTIONAvoidance of cardiopulmonary bypassThere are as yet no denitive data that show that cardiac surgery without

CPB is of benet to patients with underlying liver disease. Although thesuggestion has been made that cirrhotic patients demonstrate improved

thatalthough mesenteric ischemia occurred more frequently with CPB, more

patients had gastrointestinal bleeding with o-pump CABG. Mortalitywas similar following either type of surgery when a gastrointestinal compli-cation occurred.

Retrospective studies suggest that changes in splanchnic perfusion aresimilar whether or not CPB is used, but some prospective studies suggesta potential advantage to o-pump CABG. Gastric tonometry was used toevaluate splanchnic perfusion in one prospective, randomized study of54 low-risk patients undergoing CABG either o-pump or with pulsatileCPB by a single surgeon and with a well-dened anesthetic protocol.Although the degree of gastric intramucosal acidosis was similar betweenthe two groups, patients who underwent o-pump CABG had more pro-longed recovery [43].

In a prospective, nonrandomized, study of 38 patients scheduled for elec-tive CABG either o-pump or with CPB, the latter was associated witha greater increase in serum alcohol dehydrogenase and alphaglutathione-S-transferase levels, which are more sensitive markers of hepatocellulardamage than ALT and AST. Serum enzymes became elevated shortly afterthe initiation of CPB, peaked at the end of surgery, and returned to baselinewithin 24 hours. However, no dierence was observed between the groupswith respect to clinical outcomes [44].

Lidocaine is metabolized during its rst pass through the liver by hepaticmixed function oxidases to form the metabolites monoethylglycine-xylidide(MEGX) and glycine-xylidide. Formation of MEGX is dependent on thecytochrome P450 system and reects hepatic blood ow and liver function.The MEGX:lidocaine ratio is a sensitive indicator of hepatic injury; it hasbeen advocated as a predictor of survival in chronic liver disease and mul-tiple organ failure in surgical intensive care patients [4547]. In a prospective,randomized controlled trial of 40 patients, the MEGX:lidocaine ratio wasnot signicantly dierent whether patients underwent CABG o-pump orusing CPB [48]. Transaminase elevation was less in the o-pump CABGgroup, but there were no dierences in clinical outcome.

Modication of cardiopulmonary bypassPerioperative strategies that minimize the duration of CPB time and

transfusion requirements have a benecial eect on liver outcome. Liverfunction, assayed by MEGX:lidocaine ratio and serum alpha-glutathione-gastrointestinal complications [4,41,42]. Interestingly, one study notedoutcomes with o-pump coronary artery bypass grafting (CABG) [6,7]; ret-rospective studies comparing cirrhotic patients undergoing CABG with andwithout CPB have demonstrated no dierence in the overall incidence of

574 DIAZ et alS-transferase, is best preserved when the duration of CPB times isconstrained to less than 70 minutes [49]. The incidence of gastrointestinalcomplications increases with prolonged CPB [1,3,50], although their predic-tion remains dicult in the individual patient [9,51].

atilepreservation is optimal [14].Ecient circuits that have low prime volumes substantially decrease sur-face area and blood-air interfaces. This decreases contact activation of thepotential inammatory response and the morbidity associated with CPB [54].

Modication of the operative and anesthetic techniqueEchocardiographic assessment of the aorta, careful cannulation, precise

aortic cross-clamping, and avoidance of the intra-aortic balloon pump inpatients with signicant atherosclerosis decreases the incidence of gas bub-ble microembolization and atheromatous embolization that can incite gas-trointestinal complications. However, a large, prospective, randomizedstudy on the use of intra-aortic lters to trap atheromatous emboli didnot aect the rate of gastrointestinal complications [55].

Hemodilution has been reported to improve hepatic arterial and portalow [12]. However, patients with cirrhosis inevitably have hypoalbumine-mia and low oncotic pressure and tolerate large volume shifts poorly. Theresulting tissue edema and volume overload decreases hepatic oxygen deliv-ery. Two clinical reports [56,57] and an experimental study [58] demonstratean inverse relationship between hematocrit on CPB and postoperativemortality.

In patients with normal liver function, preoperative crystalloid hydration(1.5 mL/kg/h) before surgery has a favorable eect on hepatic blood owbefore induction [59]. Unfortunately, this small study did not evaluateused, a nonpulsatile protocol is preferable; with a low ow rate, pulsTechnical modication of the conduct of CPB, including perfusion owrate, temperature, tubing length, pump speed, and volume loading havedemonstrated an advantage with at least preliminary data supportingspecic practices. During CPB, total hepatic blood ow is better preservedat higher perfusion ow rates. For example, total hepatic blood ow issignicantly improved with a CPB ow rate of 2.4 versus 1.2 L/min/m2;at the low ow rate the addition of pulsatile perfusion and hypothermia(28C) signicantly improved hepatic blood ow but did not make a dier-ence at the high ow rate [13].

The optimal temperature for preservation of hepatic function duringCPB is not established. There is evidence that hepato-splanchnic oxygena-tion is better preserved with mild hypothermic (32C) than normothermicCPB [52], but at 30C indocyanine green clearance is signicantly decreased[53]. Perfusion at 28C slightly increases portal blood ow but decreaseshepatic arterial ow. It has been advocated that the optimum CPB protocolfor preserving the hepatic circulation requires a high perfusion rate with pul-satile or nonpulsatile ow at 37C. If hypothermia and a high ow rate is

575HEPATIC AND RENAL PROTECTIONpatients with underlying liver disease. A prospective, randomized study onthe administration of 6% hetastarch to cardiac surgical patients to optimizestroke volume during surgery suggested that hemodynamic improvement(lower heart rate, elevated stroke volume) was associated with less gut

ativeadministration of low-dose milrinone, a noncatecholamine inodilator,

improves splanchnic perfusion in healthy patients undergoing CABG [63].However, inotropic agents with vasoconstrictor activity may increasesplanchnic vascular resistance to the point that the benet of improvedcardiac output is negated, resulting in splanchnic ischemia. For example,epinephrine infusion in cardiac surgery patients increases cardiac outputbut this is not associated with an improvement in ow-dependent liver func-tion but rather with a decrease in gastric mucosal perfusion [64].

Other pharmacologic interventions may have a favorable impact ongastrointestinal complications after cardiac surgery. Administration of aspi-rin therapy within 48 hours after revascularization in a multicenter, prospec-tive, observational study on patients undergoing CABG was associated withsignicantly decreased mortality and a 62% decrease in the incidence ofgastrointestinal infarction [65]. On the other hand, the potent steroid, dexa-methasone, did not protect against perioperative abdominal organ damagein patients undergoing CABG despite attenuating cytokine release and SIRS[66]. Nitric oxide, melatonin, N-acetylcysteine, and growth hormone haveeach demonstrated a protective eect on hepatic injury in experimental car-diac surgery models, but have not yet been subjected to clinical trials[46,67,68].

SummaryHepatic injury in cardiac surgery is a rare complication but is associated

with signicant morbidity and mortality. Its infrequent nature supports thelivers robust reputation when subjected to short periods of ischemia. Post-operative hepatic injury occurs when the ischemic stress exceeds the hepaticmetabolic reserve. Mechanisms that contribute to liver injury during cardiacsurgery include hypoperfusion, ischemia-reperfusion injury, the nonphysio-logic nature of CPB and contact activation of the inammatory response.The lack of a clinical assay to measure functional hepatic reserve impedeseorts to identify preoperative predictors of hepatic injury. This is compli-infusion improves splanchnic blood ow during CPB [62]. Periopermucosal acidosis (measured by gastric tonometry) and fewer postoperativecomplications and shorter intensive care and hospital stay [60]. In cirrhoticpatients with low plasma oncotic pressure, the benet of colloid loading onhepatic perfusion is likely to be greater than that of crystalloid loading, butthis remains to be studied.

Vasoactive drugs have varying eects on splanchnic perfusion. Hepaticclearance of indocyanine green is equally improved by low-dose dopamineand the inodilator, dopexamine, presumably because hepatic blood ow isincreased concomitantly with increased cardiac output [61]. Dopexamine

576 DIAZ et alcated by rudimentary techniques at monitoring splanchnic perfusion andelementary therapies for reversing hepatic injury. Thus, for the immediatefuture, the clinician must rely on astute preoperative evaluation coupledwith exquisite intraoperative care to optimize outcomes. A high index of

Impact of acute kidney injury

Preoperative risk factorsThere are a number of preoperative risk factors that are predictive ofpostoperative renal dysfunction after cardiac surgery. These include femalegender, advanced age, diabetes mellitus, ventricular dysfunction, left maincoronary artery disease, chronic obstructive pulmonary disease, preexistingAcute kidney injury (AKI) is a major cause of increased morbidity andmortality after cardiac surgery, whether or not renal replacement therapy isrequired. There is considerable evidence to support this statement. In a studyfrom the Duke University database on 2672 patients undergoing electiveCABG with CPB, AKI requiring RRT occurred in only 0.7% of patents,but was associated with 28% mortality, compared with 1% in patients with-out AKI. AKI not requiring RRT, dened as a perioperative increase in se-rum creatinine of 1 mg/dL or more, occurred in 7.9% of patients and wasassociated with 14%mortality [69]. In a prospective cohort study on 4118 pa-tients who underwent cardiac and thoracic aortic surgery in Austria, an in-crease of serum creatinine of more than 0.5 mg/dL at 48 hours after surgerywas associated with a mortality of 32.5%, compared with 2.1% in patientswho had a slight decrease [70]. The exact cause-and-eect relationship be-tween slight increases in perioperative serum creatinine and markedelevation in postoperative mortality is unknown, but is likely related to itsassociation with impaired cardiac function and other organ dysfunction.A retrospective study from France observed that an increase of 20%in perioperative serum creatinine was associated with a signicant increasein ICU length of stay, andwith other organ system failure in 80%of cases [71].

What is undisputed is that perioperative AKI after cardiac surgery leads toincreased intensive care and hospital length of stay and signicantly increasedmorbidity and mortality that is not diminished by RRT. Clearly, our focusshould be on the prevention of AKI. Preventative strategies involve preoper-ative optimization of renal function, judicious perioperative uid balance,and the administration of renoprotective pharmacologic agents.

Perioperative renal risk factorsRenal protection during cardiac surgerysuspicion postoperatively will lead to earlier treatment directed at eliminat-ing or minimizing ongoing hepatic injury while preventing additional meta-bolic stress from ischemia, hemorrhage, or sepsis.

577HEPATIC AND RENAL PROTECTIONsepsis, liver disease, and preexisting renal insuciency [69,7274]. In a retro-spective study of more than 4000 patients at the Cleveland Clinic, a preoper-ative serum creatinine greater than 1.9 mg/dL was associated with anexponential increase in postoperative acute renal failure, requirement for

Sub-sequently, administration of aprotinin became established as prophylactic

hemostatic management of high-risk (eg, repeat sternotomy) patientsundergoing CPB [88].

There have been numerous reports of an association between aprotininadministration and elevation in postoperative serum creatinine [8991],apparently through its eects on kinin pathways that alter intrarenal he-modynamics [92,93]. Aprotinin may cause vasoconstriction of the aerentIn addition, platelet activation and thromboxane release is prevented.RRT, and mortality [75]. In addition to diastolic hypertension, isolated sys-tolic or wide pulse pressure hypertension is associated with a signicantly in-creased risk of perioperative AKI [76]. There is some evidence for a geneticbasis for renal risk. Patients who have inherited the epsilon-4 allele ofapolipoprotein have decreased AKI compared with patients who have otheralleles [77].

Intraoperative risk factors and pathogenesis of AKICardiopulmonary bypass. Risk of perioperative AKI appears to be increasedby prolonged duration of CPB and aortic cross-clamping time [73]. Patientswho undergo more complex procedures, such as combined CABG and valvesurgery, have a greater risk of AKI than those undergoing CABG alone[73,78].

Risk of AKI is signicantly increased by hemodilution or anemia on CPBto a hematocrit of less than 22%, although the mechanism has not beenelucidated [79,80]. There is evidence that avoidance of CPB (o-pump orbeating heart surgery) is associated with less evidence of AKI by intermedi-ate indicators (tubular enzymuria, Cystatin C, serum creatinine) [81,82] aswell as outcome [83]. However, most studies are small, and in low-riskpatients the benet does not appear to be signicant [84].

Nonpulsatile ow and contact activation on CPB provoke the release ofvasoconstrictor hormones (epinephrine, angiotensin) as well as inamma-tory cytokines that may induce AKI [85,86]. In addition, the kidney maysuer a classic ischemia-reperfusion injury during CPB or states of lowow during surgery. This may be exacerbated by atheromatous embolism.The etiology of AKI is multifactorial, but the most common pathophysiol-ogy in postoperative ARF is acute tubular necrosis (ATN) [73].

Aprotinin. More than 20 years ago, David Royston reported that adminis-tration of high doses of the serine protease inhibitor aprotinin dramaticallydecreased blood loss after CPB [87]. When plasma concentrations ofgreater than 150 kallikrein inactivator units (KIU) per mL are achieved,kallikrein, plasmin, and CPB-induced brinolysis are eectively inhibited.

578 DIAZ et alarteriole, which reduces glomerular perfusion pressure and renal excretoryfunction. This adverse eect may be exacerbated by the presence of angio-tensin-converting enzyme inhibitors, which prevent compensatory eerentarteriolar constriction [94]. In 2006, Mangano and colleagues [95]

tininin November 2007 (http://www.fda.gov/cder/drug/early_comm/aprotinin.

ials.ltra-ther

6% hydroxyethyl starch or 5% albumin was administered to 50 patients

undergoing cardiac surgery [101].

Tight glycemic controlIn 2001, the seminal study by van den Berghe and colleagues [102]

demonstrated that tight postoperative glycemic control (blood sugar 80 to110 mg/dL) decreased mortality by 50%; there was also a 41% reductionin ARF requiring RRT. Of the 1548 patients studied, most underwent car-diac surgery. A subsequent large observational study suggested that theintroduction of tight postoperative glycemic control decreased the newdevelopment of AKI by 75% [103].

In diabetic patients undergoing cardiac surgery, intraoperative hypergly-cemia (blood sugar O200 mg/dL) is associated with a sevenfold increase inthe incidence of severe postoperative morbidity [104]. A retrospective anal-ysis of more than 3500 diabetic cardiac surgical patients observed a decreasein postoperative mortality from 5% to 2.5% when a subcutaneous insulinistered and AKI has not been subjected to randomized, controlled trThere was no dierence in intermediate markers of AKI (glomerular tion rate [GFR], serum creatinine, cystanin C, tubular enzymuria) whehtm).

Interventions to provide perioperative renal protection

HydrationIt appears intuitive that judicious volume expansion to maintain cardiac

output and renal blood ow would provide perioperative renal protection.However, the relationship between the volume of perioperative uid admin-Food and Drug Administration (FDA) suspended marketing of apropublished an observational study based on propensity analysis of morethan 4000 patients receiving aprotinin or other brinolytic agents (epsilonamino caproic acid and tranexamic acid). They concluded that use of apro-tinin is associated with a doubling of the risk of ARF requiring RRT.These ndings stirred considerable controversy, resulting in studies thatboth supported [96,97] or opposed [98,99] Manganos conclusions. The dif-culty with all nonrandomized studies is that aprotinin is administered tohigh-risk patients who have increased risk of AKI. Moreover, there is ev-idence that risk of AKI is directly proportional to the volume of red cellsadministered [99]. Most recently, the Canadian BART Trial [100] washalted by the Data Safety Monitoring Board because of increased30-day mortality in patients receiving aprotinin. As a consequence, the

579HEPATIC AND RENAL PROTECTIONregimen was changed to continuous insulin infusion [105]. However, thesendings were not conrmed by a prospective, randomized controlled trialof tight intraoperative control (insulin infusion to keep blood sugar 80 to100 mg/dL) versus conventional management (bolus insulin if blood sugar

operative period. However, the hepatic metabolism of dopamine shows

eser-vation of GFR and serum creatinine [116119]. Similar results have been

reported for patients undergoing major vascular surgery with infrarenal aor-tic cross-clamping [120]. However, other studies in high-risk cardiac surgeryor vascular surgery with aortic cross-clamping were unable to nd a benetof fenoldopam on renal function compared with dopamine or sodium nitro-prusside [121,122]. A large randomized placebo-controlled study found nobenet to the administration of fenoldopam in the prevention of contrast-induced nephropathy [123]. Nonetheless, a recent meta-analysis of 16 studiesIn several small prospective studies of cardiac surgery patients, low-fenoldopam infusion (0.30.5 mcg/kg/min) has been associated with prwide variation and plasma pharmacokinetics vary up to 30-fold in healthyindividuals [107]. Thus, there is the potential that low-dose dopaminemay elicit in beta1- or even alpha-adrenergic stimulation, resulting in un-wanted tachycardia and hypertension. Its renoprotective role has beenquestioned [14,107110] and three systematic reviews found no evidenceof benet [111113]. However, dopamine may still be a useful inotropicagent that can improved renal perfusion and urine output by increasingcardiac contractility [114].

Fenoldopam. Fenoldopam, a synthetic phenol derivative of dopamine, isa selective DA1 receptor agonist that increases renal blood ow in a dose-dependent manner [115]. Unlike dopamine, it has no beta- or alpha-adrenergic activity and its pharmacokinetics are predictable. Its only adverseeect is mild hypotension and a reex increase in heart rate.

doseO200 mg/dL) in 400 patients with and without diabetes undergoing cardiacsurgery with CPB [106]. There was no dierence in postoperative AKI andin fact patients undergoing tight intraoperative control had a signicantlyincreased incidence of stroke.

Thus, although intraoperative hyperglycemia increases risk of AKI indiabetic patients, the evidence that tight intraoperative control attenuatesthis risk remains conicting.

Dopaminergic agentsDopamine. Dopamine is a naturally occurring catecholamine that hasdose-dependent eects on dopaminergic, beta1- and alpha-adrenergic re-ceptors. It acts as a dopaminergic agonist on DA1 receptors in the renalvasculature, tubule, and collecting duct, increases renal blood ow andacts as a diuretic and a natriuretic. For many years low-dose dopamine(!3 mg/kg/min) has been advocated as a renal protective agent in the peri-

580 DIAZ et alon 1290 patients concluded that fenoldopam consistently and signicantlyreduced the risk for AKI, need for RRT, ICU length of stay and in-hospitalmortality [124]. This suggests that further large, multicenter, appropriatelypowered trials with fenoldopam are warranted.

geryand postoperatively in 126 patients [125]. Dopamine infusion had no eect

porta renoprotective eect. In a small study on 23 patients, prophylactic addition

gery[117,129], presumably because the mechanism of AKI is more closely related

rinewith worsened function [132]; in another, diltiazem infusion enhanced uto ischemia-reperfusion injury than nephrotoxicity. In a larger (n 254)prospective randomized trial, administration of perioperative N-acetylcysteine did not prevent ARF in cardiac surgery patients with chronicrenal insuciency [130]; however subgroup analysis suggested a signicantbenet in those patients who underwent CPB.

Calcium channel blockersCalcium channel blockers promote renal vasodilatation and increase

renal blood ow and glomerular ltration rate. They inhibit angiotensinaction in the glomerulus and decrease circulating interleukin-2 receptors[131]. Few studies have evaluated their renoprotective role in cardiac sur-gery. In one study, administration of intravenous diltiazem was associatedHowever, a similar benet has not been found in cardiac surof mannitol to the pump prime did not decrease tubular enzymuria [126].

N-acetylcysteineN-acetylcysteine is an antioxidant that directly scavenges reactive oxygen

species, and there is considerable evidence to support its use to preventcontrast-induced nephropathy [127,128].added to the priming solution on CPB but there is little evidence to supon serum creatinine compared with placebo, but furosemide infusion wasassociated with an increase in serum creatinine twice as high as the othergroups. The mechanism of detrimental eect of furosemide was not eluci-dated, but presumably intravascular hypovolemia from excessive diuresisis one obvious factor.

MannitolMannitol is an osmotic diuretic and free radical scavenger that can

prevent tubular obstruction by sloughed proximal tubular cells and therebyattenuate experimental ischemia-reperfusion injury. Mannitol is routinelymin), and saline placebo were administered throughout cardiac surFurosemideFurosemide inhibits sodium absorption in the medullary portion of the

loop of Henle, causing diuresis and natriuresis. It may limit medullary hyp-oxia by decreasing tubular cell workload and thus oxygen consumption.However, there is little evidence to support its use a renoprotective agent.Low-dose dopamine (2 mg/kg/min), furosemide infusion (0.5 mg/kg/

581HEPATIC AND RENAL PROTECTIONoutput and decreased tubular enzymuria [133].There is considerable evidence that calcium channel blockers have

a specic renoprotective eect against the nephrotoxic eects of calcineurininhibitors (cyclosporine A, tacrolimus) used for immunosuppression [131].

utedto the hypotensive eect of ANP, which was greater in the non-oliguric pa-

tients and may have injured intact or partially damaged nephrons. A subse-quent randomized prospective study that focused on 222 patients witholiguric acute renal failure only, found no dierence in renal outcome be-guric renal failure (NORF). The disparity in these results may be attribThis benet has been demonstrated in the preoperative graft preservation inpatients undergoing renal transplantation [134], but has yet to be tested inthe heart transplant population.

Natriuretic peptidesThe natriuretic peptides are formed by the endogenous synthesis of

chains of 22 to 32 amino acids of similar structure. They specically opposethe sympathoadrenal, renin-angiotensin, aldosterone, and arginine vaso-pressin systems via multiple mechanisms [135]. They thereby counteractthe vasoconstrictor and antinatriuretic responses induced by hypovolemia,and induce vasodilation and natriuresis that protect against hypervolemiaand hypertension. The vasodilator and renal eects of the natriuretic pep-tides are mediated by cyclic guanosine monophosphate (cGMP), which in-creases glomerular ltration fraction by aerent arteriolar vasodilation.They are rapidly inactivated by natriuretic peptide C-type receptors aswell as cellular neutral endopeptidases.

Atrial (A-type) natriuretic peptide (ANP) is synthesized by modied atrialmyocytes and released by atrial stretch; plasma ANP increases pari passuwith central venous pressure [136]. Brain (B-type) natriuretic peptide(BNP) is synthesized in the right and left ventricles, and is released by ventric-ular dilation. Assay of BNP (and its precursor, N-terminal-pro-BNP) has be-come established as an emergency room diagnostic tool for acute cardiacfailure, and BNP levels correlate with outcome in acute myocardial ischemiaas well as heart failure. C-type natriuretic peptide (CNP) is synthesized in theendothelium of the great vessels. Urodilatin, a 22-amino acid peptide, is syn-thesized in the kidney and appears to have less vasodilator activity thanANP.

Anaritide. Anaritide is the human recombinant formulation of ANP. Intra-venous administration decreases systemic blood pressure by arterial andvenodilation, increases GFR, induces natriuresis, and reverses renovascularhypertension.

After demonstrating promise as a rescue agent in experimental ATN,anaritide rescue in a large, 504-patient randomized multicenter study hadequivocal results [137]. After a 24-hour infusion of anaritide, patients witholiguric ATN (urine output!400 mL/day) had signicantly improved dial-ysis-free survival, but outcome was actually worse in patients with non-oli-

582 DIAZ et altween anaritide and placebo [138]. The only dierence was that patients re-ceiving anaritide were signicantly more hypotensive. These data appear toemphasize the importance of maintenance of renal perfusion pressure inacute renal failure because renal autoregulation is impaired [139].

diuresis with improvement in pulmonary congestion, edema, and anasarca

ome

dierences, which require sample sizes of 1000 subjects or more. Nonetheless,although ARF requiring RRT after cardiac surgery is rare (!2%), it hasa devastating impact on morbidity and mortality and further studies onprotective strategies are essential. Of great interest too is the mechanismwhereby slight increases in postoperative serum creatinine (ie, mild to mod-erate AKI) are associated with such substantial increases in postoperativemorbidity and mortality. Finally, the etiology of AKI is multifactorial andcomplex, so it is little surprise that no single intervention has emerged asa magic bullet. At this stage, the pharmacologic interventions that showthe most promise are fenoldopam and nesiritide; both require larger random-ized studies to establish their value.

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Hepatic and Renal Protection During Cardiac SurgeryHepatic protection during cardiac surgeryImpact of hepatic and gastrointestinal complicationsSplanchnic perfusion and hepatic injury

pdfOutline placeholderThe impact of cardiac surgery upon hepatic functionPathogenesis of liver injuryClinical manifestations of liver injuryTransient unconjugated hyperbilirubinemiaProtracted cholestasis (conjugated hyperbilirubinemia)Severe ischemic early liver injury

Risk factors for hepatic injury during cardiac surgeryStrategies for perioperative hepatic protectionAvoidance of cardiopulmonary bypassModification of cardiopulmonary bypassModification of the operative and anesthetic techniqueSummary

Renal protection during cardiac surgeryImpact of acute kidney injuryPerioperative renal risk factorsPreoperative risk factorsIntraoperative risk factors and pathogenesis of AKICardiopulmonary bypassAprotinin

Interventions to provide perioperative renal protectionHydrationTight glycemic controlDopaminergic agentsDopamineFenoldopam

FurosemideMannitolN-acetylcysteineCalcium channel blockersNatriuretic peptidesAnaritideNesiritide

Summary

References