Improving outcome in patients undergoing liver surgery

Improvingoutcome in patients undergoing liver surgeryKatarzyna Furrer, Michelle Lucinda DeOliveira, Rolf Graf and Pierre-Alain Clavien

Department of Visceral and Transplantation Surgery, University Hospital of Zurich, 8091-Zurich, Switzerland

Keywords

ischemia – liver – outcome – surgery

Abbreviations

ATP, adenosine tri-phosphate; BSA, body

surface area; CT, computed tomography;

DNA, deoxyribonucleic acid; ICU, intensive

care unit; MEGX, monoethylglycinexylidide;

MRI, magnetic resonance imaging; TNF-a,

tumor necrosis factor alpha

Correspondence

Pierre-Alain Clavien, MD, PhD, Department of

Visceral and Transplantation Surgery, University

Hospital of Zurich, Ramistrasse 100, 8091

Zurich, Switzerland.

Tel: 141 (0) 44 255 33 00

Fax: 141 (0) 44 255 44 49

e-mail: [email protected]

Received 8 May 2006

accepted 30 November 2006

DOI:10.1111/j.1478-3231.2006.01416.x

AbstractLiver surgery is associated with many factors, which may affect outcome.

Preoperative assessment of patient’s general condition, resectability, and liver

reserve are paramount for success. The Child–Pugh score and other scoring

systems only partially enables to assess the risk associated with liver surgery. The

presence of portal hypertension per se is a major risk factor for hepatectomy.

Intraoperatively, any attempts should be made to minimize blood loss. Low central

venous pressure and inflow occlusion best prevent bleeding. Ischemic precondi-

tioning and intermittent clamping are routinely applied in many centers to protect

against long periods of ischemia, although the mechanisms of protection remain

unclear. In this review we describe recent advances in activated pathways

associated with protection against ischemia. Postoperatively, the best factor

impacting on outcome probably resides in experienced medical care particularly

in the intensive care setting. Currently, no drug or gene therapy approaches has

reached the clinic. The future relies on new insight into mechanisms of ische-

mia–reperfusion injury.

Considerable progress has been made in many areas ofliver surgery over the past two decades including betterselection of patients for surgery, the availability ofnovel modalities to preoperatively manipulate tumorand liver volumes, novel operative techniques, and anoptimization of the postoperative management. Thedevelopment of centers of excellence with high volumeof patients and formal training of liver surgeons hasalso significantly contributed in improving outcomes.In this review, we will successively cover preoperative,intraoperative, and postoperative strategies, whichmay prevent or correct complications related to majorliver resection.

Preoperative strategies

The first step in preoperative evaluation of a candidatefor liver surgery is to secure that he/she is fit forsurgery, that the indication is adequate and the tumoris resectable. Evaluation of operability related to thegeneral condition of the patient and indications forliver resection related to specific tumors are beyondthe scope of this review. Here, we will focus on theevaluation of the liver reserve and available interven-

tion to increase the volume of a putative remnantvolume.

Preoperative imaging of liver lesions

Several imaging techniques are currently for the pre-operative assessment of liver tumors and to identifythe best strategy for resection. These techniques andtheir respective sensitivities are summarized in Table 1.

Evaluation of liver reserve

Tumor patient

A general health assessment with a careful history andphysical examination for symptoms and signs ofportal hypertension is the first step in the evaluationof patients with benign or malignant liver tumor.Before liver surgery the patient’s overall conditionshould be assessed, coexisting medical illnesses ex-cluded and the liver disease should be diagnosed andstaged. Preoperative investigations should includeradiology, full blood count with estimation of tumormarkers (a-fetoprotein, carcinoembryonic antigen,Ca19-9), assessment of liver and renal function, and a

Liver International (2007)26 c� 2007 The Authors. Journal compilation c� 2007 Blackwell Munksgaard

Liver International ISSN 1478-3223

full clotting profile. Patients over 65 years of ageshould undergo detailed evaluation of their pulmon-ary and cardiac function.

Before embarking in a major liver resection, it isparamount to identify the presence of underlying liverdiseases and to assess the liver reserve. Postoperativemortality strongly correlates with the degree of pre-existing liver impairment; for example, a near zeromortality is reported by many expert surgeons inpatients with normal liver parenchyma, while a mor-tality of 10% or more is not uncommon in patientswith underlying liver diseases.

Cirrhotic patient

In cirrhotic patients additional factors are assessed.The detection of viral and serologic markers andmeasurement of viral serologic markers for HepatitisC and B as well as the type and extent of fibrosis arecrucial.

Unfortunately, how to assess and quantify liverfunction preoperatively remains controversial as nosingle biological value or test is able to accuratelypredict postoperative liver failure. Many teams, parti-cularly in Western countries, still use the Child andTurcotte (21) scoring system described for the firsttime in 1964 to assess the operative risk in cirrhoticpatients undergoing portosystemic shunt surgery forvariceal bleeding. The initial score included five vari-ables: ascites, encephalopathy, nutritional status, andserum levels of bilirubin and albumin. Patients wereranked according to three scores A–C in relation tobest (A), moderate (B), or worse (C) prognosis.

In 1973, Pugh et al. (22) used a modified version ofthis classification for patients undergoing surgicaltransection for esophageal varices. They replaced theevaluation of the nutritional status by prothrombintime and assigned a score ranging from 1 to 3 to eachvariable. Subsequently, this classification was used topredict the outcome of surgery in cirrhotic patients ingeneral, and more recently, to stratify patients on thewaiting list for liver transplantation. The expectedpostoperative mortality was found to be 10% inpatients with Child A cirrhosis (23), 30% with ChildB cirrhosis (24), and up to 80% in Child C patients(25). Therefore, currently Child–Pugh class C cirrhosisis considered as an absolute contra-indication forhepatic surgery, while Child–Pugh class B patientsshould undergo only minor hepatic resection (e.g.� two segments). In Child–Pugh class A patients the

decision to proceed with a major hepatic resectionshould rely on additional tests, particularly the evalua-tion of concomitant portal hypertension (26).

A number of metabolic tests (Table 2) have beenproposed to assess the hepatic functional reserve.These tests include the clearance of indocyanine green(ICG) (37) caffeine (38), lidocaine (34) and lidocainederivatives test [monoethylglycinexylidide (MEGX)](37), galactose elimination capacity (31), and thetechnetium-99m galactosyl human serum albuminscan (39). Clearance of these compounds not onlydepends on hepatic metabolism but often also onhepatic blood flow. The ICG test is probably the mostpopular test, particularly in Asia. ICG is exclusivelycleared by the liver and it has been shown thatexcretion measured at 15 min (ICG R15) is a safe

Table 1. Imaging of liver lesions

Imaging tool Detection Sensitivity (%)

Ultrasound Benign liver lesions malignant liver lesions HCC 60–70 (1)64–94 (2)20–72 (3, 4)

CT Malignant liver lesions HCC 77–95 (5–7)52–98 (8, 9)

MRI Benign liver lesions malignant liver lesions HCC 70 (10)69–86 (5, 11)97 (9)

CT angiography Malignant liver lesions HCC 93–97 (12, 13)91–98 (14, 15)

MR angiography Malignant liver lesions HCC cholangiocarcinoma 97 (12)93 (14)99 (16)

FDG-PET Malignant liver lesions cololorectal cancer-liver metastases recurrence 82 (17)97 (18)

PET-CT Cololorectal cancer-liver metastases recurrence 89–93 (19, 20)

CT, computer tomography; FDG-PET, fluor-18-deoxyglucose-positron emission tomography; HCC, hepatocellular carcinoma; MRI, magnetic resonance

imaging.

Liver International (2007)c� 2007 The Authors. Journal compilation c� 2007 Blackwell Munksgaard 27

Furrer et al. Liver surgery

predictor for the limit of liver resection in cirrhoticpatients (28). Normal liver usually reveals an ICG R15of less than 10% while in cirrhotic liver reveals20–30%. As a drawback, other factors may affectICG15 particularly in elderly patients with disclosingparenchymal liver shrinkage. To enhance the value ofICG15 it has been proposed to correlate the ICG R15retention with computed tomography (CT) scan volu-metry. For example, if the ICG R15 is 15–20%, hepaticresection should be � 50% of the total liver volume(TLV) (28, 33, 40).

The dynamic liver function test based on the hepaticconversion of lidocaine to MEGX can complementestablished static liver function tests. In critically illpatients, several studies have shown that an initially

rapid decrease in MEGX test values is associated with anenhanced risk for the development of multiple organdysfunction syndrome and a poor outcome (36).Further, this decrease appears to be associated with anenhanced systemic inflammatory response. The MEGXtest has potential for investigating the pathogenesis ofmultiple organ dysfunction syndrome with regard toearly hepatic functional impairment (36).

Tests based on the rate of metabolite formation ofdrugs that are metabolized in the liver after theadministration of 14C-aminopyrine, 14C-methacetinor 14C-erythromycin, and 14CO2 exhalation gives ameasure of hepatic oxidative function (36).

The 99mTc-labeled asialoglycoprotein analog (Tc-GSA,galactosyl-human serum albumin-diethylenetriamine-

Table 2. Examples of quantitative liver function tests

Metabolic test Measurement Endpoint Value for liver dysfunction Methodology

ICG Clearance test at 5–15 min N: � 10%Child A: o 14–20% (139)Child B, C: 420%

Spectrophotometricanalysis (12)

Caffeine Clearance test at 4, 8, 12 h N: 0.094 L/h/kg, EC = 0.153 h�1,T1/2 = 4.3 h

Cirrhosis: 0.035 L/h/kg, EC = 0.061 h�1,T1/2 = 11.4 h.

HPLC (140)

GEC Elimination capacity at20–70 min

N: 8.5 mg/min/kg (141)Cirrhosis: 4–6 mg/min/kgGEC o 6 mg/min/kg: high

complications gradeGEC 46 mg/min/kg: low

complications gradeGEC (HCC) o 4mg/min/kg:

high complications gradeGEC (HCC) 4 4 mg/min/kg:

low complications grade

Spectrophotometricanalysis (10)

Tc-GSA Asialoglycoprotein receptorbinding

N: Q = 1653 ml/min,Rmax = 0.742 mg/ml (142)

M: Q = 978 ml/min,Rmax = 0.311 mg/ml

S: Q = 634 ml/min, Rmax = 0.095 mg/ml

Scintigraphy (14)

(MEGX) Dynamic real-time testat 15–30 min

N: Men o 45 year:15 minutes: 67 mg/LWomen o 45 year:15 minutes: 49 mg/LWomen o 45 year taking

contraceptives15 minutes: 25 mg/LChild A: 15 minutes: 30–25 mg/LChild C: 15 minutes: o 20 mg/Lo 10 mg/L: poor 1-year survival

HPLC (9)

Lidocaine Clearance test N: T1/2 = 1.8 h, clearance = 703 ml/minCirrhosis: T1/2 = 4.9 h,

clearance = 419 ml/min

Metaboliteformation (143)

14 [C] aminopyrine CO2 exhalation N: 55%M: 28%S: 14%

Metabolite formation(15, 143)

N, normal liver function; M, moderate impaired liver function; S, severely impaired liver function; Q, hepatic blood flow; Rmax, maximal receptor binding

rate; EC, elimination coefficient; HPLC, high performance liquid chromatography; GEC, galactose elimination capacity; ICG, indocyanine green; Tc-GSA,99mTc-galactosyl human serum albumin; MEGX, monoethylglycinexylidide.


Liver surgery Furrer et al.

pentaacetic acid) has been applied to human hepaticreceptor imaging (41). Liver scintigraphy using Tc-GSA has recently been used in some centers as amethod for the quantitative measurement of func-tional hepatocyte mass unaffected by liver tumors orbiliary obstruction (42). Another proposed test is thegalactose elimination capacity test (31). It was demon-strated in a prospective study to be a strong indepen-dent and valuable predictor for long and shortoutcome in patients with primary and secondaryhepatic tumors undergoing resection.

Besides these tests or scoring systems, the presenceof underlying liver diseases per se may affect outcomeof liver surgery. Hepatic steatosis is common and mayresult from a variety of conditions such as alcohol,chemo-therapeutics, certain industrial and biologicaltoxins, and obesity (31, 43–47). Steatosis increases therisk of liver resections and may enhance the suscept-ibility of the liver parenchyma to ischemic injury (48).Fatty liver disease may also interfere with liver regen-eration.

Liver resection in patients with steatosis is asso-ciated with an increased risk of postoperative mortal-ity when compared with patients disclosing lean livers(14% vs 2%) (49). Thus, major hepatectomy should beperformed with caution in patients with moderate tosevere (Z30%) steatosis. Although hepatic steatosis isnow an established risk factor for surgery, little isknown about the mechanisms of injury. In animalexperiments, steatosis is associated with decreasedATP production and a disturbance of sinusoidal flow(50, 51). Further contributing factors may includeKupffer cell dysfunction (52) and leukocyte adhesion(53). Steatosis plays a role when the liver is subjectedto oxidative stress (54) and may make the liverparenchyma vulnerable to ischemic injury (48). Fattyhepatocytes have reduced tolerance against ischemiawith a predominant necrotic form of cell death. Inaddition, the ability of hepatocytes to regenerate aftermajor tissue loss is impaired in the steatotic liver (55).

Hepatocellular and obstructive cholestasis are alsoimportant risk factors for liver surgery. The presenceof obstructive jaundice increases the risk of resection,even in noncirrhotic patients such as those withcholangiocarcinoma (56, 57). Chemotherapy is in-creasingly used in patients with liver cancer causingmorphologic changes including microsteatosis, fibro-sis, and inflammation. Severe steato-hepatitis can beassociated with preoperative administration of irino-tecan or oxaliplatin, especially in the obese and canaffect the ability to perform large liver resections (58).The sinusoidal obstruction, complicated by peri-sinu-soidal fibrosis and veno-occlusive lesions of the non-

tumoral liver, should be included in the list of theadverse side effects of colorectal systemic chemother-apy, in particular related to the use of oxaliplatin (59).Here also caution is advised, although no data isavailable that enables to accurately assess the riskassociated with surgery in these patients.

Preoperative estimation of future remnantliver volume

The liver has a unique regenerative ability, whichallows patients to rapidly recover from major tissueloss. Imaging techniques has been used to estimateliver regeneration after hepatectomy using differentmethods: scintigraphy (60, 61), ultrasound (62, 63),CT (64, 65) and MRI (66).

Urata et al. (67) proposed a formula tailored to theAsian population. Each formula may be prone toinherent errors. Thus the right formula has to beapplied, otherwise there will be a miscalculation ofthe future remnant liver.

In view of different body surface between Asianpopulation and people living in Western countries,actual liver volume is determined from a formulacorrelating TLV and body surface area (BSA) (68).Today radiological imaging enables us to accuratelyassess parenchyma hepatic resection rate (PHPR) aswell to predict the extent of outflow impairmentbefore certain types of liver resections (69, 70).

The PHPR has been applied for livers with anintrahepatic mass and can be calculated as follows:PHPR (%) = (resected liver volume� tumor volume)divided by (TLV� tumor volume)� 100 (28).

Resection up to 70% (or 0.6% of a ratio betweenremnant liver and patient weight) are well tolerated inpatients with normal liver.

In a clinical study of Yigitler et al. (71) the incidenceof complications after major hepatectomy includingliver failure was found similar in patients with aremnant liver volume of � 30% compared with pa-tients with a remnant liver volume of Z60%, althoughthe former group had a longer hospital and ICU stay.

Often large tumors cannot be resected because ofthe inability to preserve enough remnant liver. Animportant focus has been the development of inter-ventions to enable an increase in size of a putativeremnant liver including portal vein embolization andligation.

Preoperative portal vein embolization andportal vein ligation

Takayasu et al. (72) observed hypertrophy after portalocclusion resulting from hilar cholangiocarcinoma



and Honjo et al. (73) first reported portal ligation inpatients with hepatocellular carcinoma.

Preoperative portal vein embolisation (PVE) of ahemi-liver containing a tumor induces compensatoryhypertrophy of the contra-lateral hemi-liver. Emboli-zation is performed percutaneously by an expertinterventional radiologist usually using cyanoacrylateglue mixed with lipiodol, polyvinyl alcohol or particlesadministration (74). In 1986, Kinoshita et al. (75) firstreported on the use of PVE to limit extension of portaltumor thrombi from hepatocellular carcinoma andstrengthened the effect of transarterial embolization.In 1990, Makuuchi et al. (76) reported the first use ofpreoperative PVE performed solely to induce left liverhypertrophy before major hepatic resection in patientswith hilar cholangiocarcinoma (77).

Liver hypertrophy occurs usually within a 2–4 weeksperiod. The indication for such a procedure remains amatter of debate. Most would agree that a predictedremnant liver volume � 25–30% might justify pre-operative embolization. In cirrhotic patients, thisfigure may reach 35–40%, and the inability to inducehypertrophy may represent a contra-indication forsurgery. The implementation of preoperative contralateral portal occlusion by embolization or sutureligation effectively prevents posthepatectomy liver fail-ure (78, 79). In prospective data from Broering et al.(80) portal vein embolization resulted in a signifi-cantly more efficient increase in liver volume and ashorter hospital stay than portal vein ligation althoughportal vein ligation was found to be safe and effective.

We designed a clinical study (81) to evaluate theeffects of concomitant unilateral portal vein ligationcombined with selective intraarterial chemotherapy onsafety, ability to induce contra-lateral hypertrophy,tumor growth, and resectability. The combination ofportal vein ligation with intraarterial chemotherapywas safe and demonstrated a concomitant atrophy ofthe hemi-liver ipsi lateral to the ligated portal vein aswell as contra lateral hypertrophy and no negativeimpact on tumor growth in the regenerating hemi-liver.

Nutritional status

The purpose of nutritional support in patients under-going hepatobliliary surgery is to decrease postopera-tive morbidity and mortality. However, perioperativenutrition in patients with limited liver function afterpartial hepatic resection is still controversial. Nutri-tional intervention should restore immunity, supportsanabolism, and attenuate the catabolic response toinjury.

The use of indirect calorimetry enables the calcula-tion of the nonprotein respiratory quotient, defined asthe ratio of energy produced by carbohydrate metabo-lism to energy generated by fat oxidation, whichconfirms whether a patient has an altered pattern offuel consumption (82). In patients with an alteredpattern a nutritional regime is implemented to correctthe imbalance e.g. by enteral nutrition.

The nutritional risk factors for postoperative com-plications in hepatobliliary surgery have been estab-lished 20 years ago and include: weight loss above 14%of lean body mass weight over the previous 6 months,serum and albumin under 3 g/dl, a hematocrit of lessthan 30% and total body potassium under 85% ofnormal (83–85).

The usefulness of branched-chain amino acid(BCAA) supplementation remains controversial, butthe most recent data promote their therapeutic poten-tial in improved survival, serum albumin concentra-tion, and quality of life in patients with decompensatecirrhosis (82).

In our institution, we begin a per oral diet as soon aspossible without a nasogastric tube to prevent gastro-intestinal atrophy and preserve the normal gut flora. Ifthe patient is unable to consume a diet orally in 3–4days after liver resection, a jejunal feeding tube can beplaced for early enteral nutrition. Early enteral nutri-tion after liver resection compared with parenteralnutrition it is associated with a decreased incidenceof postoperative complications (86). The benefit ofparenteral nutrition were predominately seen in ahigh-risk group with underlying cirrhosis undergoingmajor hepatectomy (86) and in patients whereenteral feeding cannot be achieved (82). The nutri-tional support in cirrhotic patients should focus onmaintaining adequate protein and caloric intake. Stra-tegies include the consumption of frequent smallmeals and a late evening snack to reduce proteinbreakdown (82).

The potential modulation of inflammatory andcytokine reaction with immunonutrition may reducefurther infection rates and shorten ICU and hospitallength of stay (87).

Intraoperative strategies

Many factors have contributed to improved outcomein patients undergoing hepatic surgery including abetter understanding of the liver anatomy, new tools toaccurately assess the liver volume, the routine use ofintraoperative ultrasound (IOUS), anesthetic supportunder fluid restriction guidelines, hepatic vascularcontrol, and novel hepatic parenchymal transection



devices. Which of these factors best contributed toimproved outcome remains speculative.

Delineation of segmental liver anatomy allows ahepatic resection with maximum preservation of liverparenchyma, but extended hepatectomy is required inmany patients with liver tumors. Liver resection inpatients with cirrhosis, which is commonly, associatedwith hepatocellular carcinoma, needs a careful ap-proach. In our center, Child–Pugh class C is a contra-indication for hepatic resection, while Child–Pughclass B cirrhotic patient may be candidate for minorresection. For those patients Child–Pugh class A, thesurgical strategy depends on more refined evaluationof liver function reserve. Major hepatectomy is contra-indicated in patients with clinically portal hyperten-sion, whereas for those patients Child–Pugh classwithout portal hypertension, preoperative PVE maybe necessary for a minimum future remnant liver of40% after extended resection.

Bleeding during hepatic surgery correlates withshort and long-term survival rates in most studies.Therefore, strategies to prevent intraoperative hemor-rhage have become very popular, and are best achievedby inflow occlusion (Pringle maneuver (88) – Fig. 1).Additionally, the use of a low central vein pressure(CVP) by the anesthesia team is paramount to preventback flow bleeding during hepatic transection. LowCVP is optimal at the levels ranging between 1 and5 mm Hg, which does not put the patient at risk for airembolism or systemic tissue hypo-perfusion withresulting renal failure. Thus, management of fluids

and the appropriate use of catecholamine are crucial tosecure bloodless transection and optimal hemostasis(69, 89, 90).

While inflow occlusion effectively prevents bloodloss during parenchyma transection, it causes ischemicinjury to the liver. The normal liver well tolerates up to45–60 min of ischemia, but significant and irreversibleinjury may occur thereafter, particularly followingmajor hepatectomy. Livers with underlying diseases(e.g. steatosis and fibrosis) poorly tolerate ischemia,and significant injury may occur already after a 30 minperiod of ischemia. Therefore, strategies have beendeveloped to improve tolerance of the liver againstischemic injury. Currently only two strategies effec-tively confer protection in both experimental modelsand clinical studies, namely intermittent clamping,and ischemic preconditioning (Fig. 2).

Intermittent clamping of the portal triad, consistingin repeated ischemic periods (10–30 min) interruptedby short intervals of reperfusion (5–15 min), wasintroduced in clinical practice by Makuuchi in 1987(91) and is currently routinely used in many centers.The protective effects of intermittent clamping againstischemic injury have been established in clinical andexperimental studies (92, 93). For example, Belghiti etal. (92) found that intermittent clamping was superiorto continuous inflow occlusion in a series of 86patients undergoing major liver resection. A similarobservation was made by Vajdova et al. (94) whereperiods of prolonged ischemia were used.

Ischemic preconditioning involves a short periodof inflow occlusion (usually 10 min) followed usuallyby 10 min of reperfusion before the prolongedcontinuous ischemic insult, during which theparenchyma transection is performed. Ischemic

Fig. 1. Schematic drawing of the Pringle maneuver beforeresection of a tumor bearing liver segment. Anatomical positionof the clamp around the porta hepatis. The Pringle maneuverincludes occlusion of blood flow by tightening the clamp usuallyup to 45–60 min in normal liver and not more than 30 min inlivers with underlying diseases.

A

C

B

Fig. 2. Surgical protective strategies (A) continuous ischemia,(B) ischemic preconditioning, and (C) intermittent inflowocclusion. Ischemia periods are drawn in black and reperfusionperiods in white.



preconditioning was shown to be superior to contin-uous inflow occlusion in two clinical studies (95, 96).Whether ischemic preconditioning is superior to in-termittent clamping remains unknown. In a mousemodel, we could show that both strategies confer ahigh degree of protection up to 75 min of ischemia,but intermittent clamping was superior for longerperiods. We concluded that that ischemic precondi-tioning might be preferable for most liver resection asit is not associated with bleeding during the successivereperfusion periods included in intermittent clampingprotocols. However, if a long resection time is antici-pated intermittent clamping should be preferred (93).We also found in another study that longer ischemicintervals (up to 30 min) followed by 5 min of reperfu-sion are also highly protective (97). However, there areno clinical data available at this point.

How both strategies confer protection remains un-clear. Our current understanding of the underlyingbiological principle is that cells are primed by variouskinds of sub injurious stress, which trigger defensemechanisms against subsequent injury of the same ordifferent types (98–100). Although the benefit ofischemic preconditioning in the liver has already beensuggested in a clinical pilot study (95) and a largerandomized study (96), knowledge of the molecularmechanisms remains vague. We showed in a mousemodel that a short period of ischemic preconditioningcauses a sublethal oxidative stress, which subsequentlytriggers strong antioxidant and antiapoptotic effects atthe time of prolonged ischemia (101). Several media-tors have been proposed to play a critical role in theprotective pathways including adenosine, nitric oxide(102), oxidative stress (101), some heat shock proteins(Hsps) (103) and tumor necrosis factor a (TNF-a)(104–106).

In addition to the extracellular mediators, studies inheart and liver indicate that the ischemic precondi-tioning process involves activation of intracellularmessengers such as protein kinase C, adenosine mono-phosphate-activated protein kinase, p38 mitogen-acti-

vated protein kinase, Ik kinase, and signal transducersand activators of transcription-1. The downstreamconsequences of these pathways could be cytoprotec-tive by abrogation of cell death pathways (such asactivation of vacuolar adenosine triphosphatases, in-hibition of intracellular Na accumulation, and cellswelling), stimulating antioxidant and other cellularprotective mechanisms, and by initiating entry intothe cell cycle (107–109). Whether intermittent clamp-ing acts through similar mechanisms is unclear as thismodality has not been explored in depth in animalmodels. We observed similar antiapoptotic and anti-necrotic effects in both modalities suggesting that atleast in part similar pathways may be activated (68).The identification of the underlying mechanisms isparamount to enable more selective protective strate-gies and the discovery of effective drugs.

Assuming that any type of ischemia should beavoided, novel transection devices are continuouslyput on the market with the claim that they enablebloodless hepatic resection obviating the need forinflow occlusion. Although some devices or strategiesmay reach such a goal, none has gained unanimousacceptance (110). The most popular devices are shownin Table 3. They include the cavitron ultrasonicsurgical aspirator (CUSAs; Tyco Helthcare, Mans-field, MA), the water jet (Helix Hydrojets; Erbe,Tubingen, Germany), the bipolar vessel sealing(Ligasures; Valleylab, Bouler, CO), and the Tissue-Link Monopolar Floating Ball (TissueLinks; Dover,NH). CUSAs is an aspirator, which provides tissuefragmentation using ultrasonic energy (114, 111). TheHydrojets is a water jet device connected to a pencil-like hand piece, which is used to separate intrahepaticvessels and bile ducts from the surrounding parench-yma (110). LigaSures is an ultrasonic dissector thatuses bipolar electrothermal energy resulting in sealingof vessels into coagulated cords, which are then simplydivided with scissors under direct vision (112).TissueLinks is a unipolar cooled radiofrequency abla-tion device that promotes a much greater depth of

Table 3. Most common devices used in liver resection

Device Manufacturer Effect Advantages/disadvantages

CUSAs Tyco Helthcare Tissue fragmentation byultrasonic energy

Selective dissection (it leaves blood vessels, urethers,and connective tissue skeletonized and intact)

Helix Hydro-jets Erbe Tissue fragmentation by waterdissection and suction

High tissue selectivity, organ-saving resection,no trauma to surrounding tissue (110)

Ligasures Valleylab Sealing of vessels into coagulatedcords

Ineffective for thin-walled veins (little collagen in theirwalls) and on intrahepatic portal hypertension (112)

TissueLinks Tissuelink Medical Depth coagulation Ablation of the dissected surface may promote anoncological extension of surgical margins (113)



coagulation than with standard cautery. Topp et al.(113) showed that this device, accompanied by inflowocclusion, allows a depth of ablation greater than20 mm. It may be used for ablation of the dissectionsurface promoting an oncological extension of theresection margins. Very few data is currently availablevalidating or comparing these techniques, which havebeen often used without evidence of their superiorityover other available devices. Our group recently re-ported a randomized study in 100 noncirrhotic, non-cholestatic patients comparing the standard crushingtechnique performed under inflow occlusion, withthree devices marketed for bloodless transection:CUSAs, Hydrojets, and TissueLinks. The resultsshow superiority of the standard crushing techniquein terms of blood loss, speed of resection, and cost.This study however, did not investigate whether thesedevices may be beneficial for specific types of resectionor in the presence of cirrhosis (114). At this pointwe would like to speculate that the availability ofseveral of these techniques in high volume centers iscrucial to tailor the surgical approach to specificsituations. For example, while we use the simplecrushing technique in most liver resections, we usethe hydrojet for our living donor hepatectomy, andtissue link in situations where we have concerns aboutpositive margins.

Outcome of a liver resection strongly relies on theexperience of the surgeon and the team as a whole.While such a parameter is difficult to quantify, there isa clear correlation between case volume and clinicaloutcome. For example, it was observed that thehospital mortality was 1.5%, 5.3%, and 9.3% incenters performing, respectively, Z15, 7–15, and o 7liver resections per year (115). Fong at al. (116)confirmed this relationship of perioperative outcomewith surgical volume (high-volume center was definedas 4 25 cases) for hepatectomies, suggesting that thesurvival advantage remains valid even beyond theperioperative period. Thus, it is tempting to incrimi-nate the surgical skill of the team as a major factor-influencing outcome. In addition, we would like tosubmit that formal training of the surgeon in terms ofhepato-biliary fellowships including exposure to livertransplantation might become the single most impor-tant factor-affecting outcome in complex liver surgery.

Postoperative strategies

Outcome of complex surgery must also rely onoptimal postoperative care. ICU management withphysicians familiar with this population of patients isparamount for rapid recovery and early discharge. A

review on ICU management is beyond the scope of thisreview, but below we present potential promisingpharmacological approaches, which may prevent orminimize reperfusion injury.

Pharmacological approach

The use of protective drugs against ischemia–reperfu-sion injury and major hepatic tissue loss is best basedon the knowledge of pathways involved in ischemicinjury and liver regeneration. Many drugs have beenproposed, and we would refer to previous reviews formore insight into the pharmacologic approach of liverinjury (117). Here we will limit the discussion to someantioxidant drugs, pentoxiphyline, and prostaglan-dins.

Antioxidants

Liver surgery causes activation of Kupffer cells, whichare the main source of vascular reactive oxygenspecies (118). The importance of superoxide anionsin ischemic injury has been demonstrated in variousanimal models for example through the protectiveeffects of superoxide dismutase (SOD), and morerecently through the availability of transgenic animalsoverexpressing human SOD. However, evidence for abeneficial effect of antioxidant strategies in the clinicalpractice is still lacking.

Pentoxifylline

Pentoxifylline, a methylxanthine theobromine deri-vate, is a hemorrheologic drug that has been used inthe treatment of occlusive arterial disease and hemor-rhagic shock. Pentoxifylline may act through severalmechanisms. It has been shown that hepatic bloodflow and hepatocellular function were improved bypentoxifylline treatment (119, 120). A possible me-chanism of action include, intracellular elevation ofadenosine monophosphate phosphodiesterase levelswith consecutive increase of intracellular levels ofcyclic adenosine monophosphate (121). Pentoxifyllinereduces the synthesis of TNF-a synthesis, release fromKupffer cells and prevents upregulation of TNF-aexpression in a model of warm ischemic liver injuryin the mouse (106). It furthermore potentiates nitricoxide production (122). This pharmacologic agentpossesses certainly the primary function owing toimproved microcirculation and tissue oxygenationthrough reduction of blood viscosity and decreasedplatelet aggregation (123). Pentoxifylline blocks



platelet-derived growth factor (PDGF) fibroprolifera-tion (124), vascular endothelial growth factor andtissue factor (125). Yet, to this day no clinical studieshave been presented that would show a beneficialeffect of pentoxifylline on liver ischemia injury andhepatic regenerative activity (126). The beneficialeffects need to be confirmed in phase I or II studiesbefore routine use (127).

Prostaglandins

Prostaglandins are biologically active polyunsaturatedfatty acids arising from arachidonic acid. They arelocal regulatory factors and mediators of inflamma-tion in conjunction with cytoprotection. In the last 20years the cytoprotective role of prostaglandins wasinvestigated in the liver under healthy and pathologicconditions (128, 129). The liver synthesizes all pro-ducts of this cascade, and is a target of their biologicalaction. It acts in the biodegradation of prostanoidsand elimination of most of their final metabolites(130). This results in the perturbation of microcircula-tion. Prostaglandins are released mainly by activatedKupffer cells during the reperfusion phase (131). Theprotective action of prostaglandin I2 (PGI2) andprostaglandin E1 (PGE1) include their ability to reducethe release of proteases and the generation of oxygenfree radicals from activated leukocytes (129, 132).Both can improve hepatic microcirculation and stabi-lity of hepatocellular membranes (133).

PGE1 has several potential therapeutic effects, in-cluding cytoprotection, vasodilatation and inhibitionof platelet aggregation (133). The pretreatment withPGE1 reduces intracellular concentration of calciumand decreases the production of superoxide anion(134) and protects the liver against ischemia–reperfu-sion injury by reducing leukocyte-endothelial celladhesion via downregulation of adhesions molecule(ICAM-1) in the endothelium (135). Cytoprotectiveeffects of PGE1 also include the suppression of throm-boxane A2 production and a concurrent increase inPGI2 production. The clinical use of pharmacologicdoses of natural prostaglandins is limited because ofdrug-related side effects and currently there is noevidence of a benefit (136).

Gene targeting

Historically, gene therapy has been proposed for treat-ing diseases caused by inherited or spontaneous genet-ic mutations in somatic cells e.g. single gene disorders.Gene targets, such as antiapoptotic proteins (B-celllymphocytic-leukemia protooncogene-2 binding atha-nogene, Bcl-2 Bag 1) have been successfully used in

animal models. Bcl-2 and Bcl-xl can protect cells fromapoptosis induced by hypoxia and the mechanismappears to be independent of the detoxification ofreactive oxygen species (137, 138).

Hepatocyte growth factor (HGF) is a pluripotentgrowth factor displaying a remarkable ability to pro-mote tissue repair and organ regeneration after injury,possibly through inhibition of DNA fragmentationand apoptosis (139).

Ogura et al. (140) reported that recombinant HGFaccelerates serum albumin recovery quickly after re-section of cirrhotic liver. HGF gene delivery by elec-troporation (a method used in transformation and tointroduce DNA into living cells) in vivo is a potentialtherapeutic approach for hepatic resection in livercirrhosis (141).

Targeting the liver by gene therapy is a promisingnew tool that requires ethical discussion before reach-ing the clinical level.

Liver rescue system

Postoperative liver failure may result from manyfactors including a too small remnant liver, ischemicinjury, preexisting liver disease, and sepsis. The clinicalmanifestation is a septic like syndrome associated withmultiorgan failure, where the underlying mechanismsremain poorly understood. The ‘toxin hypothesis’implicates a variety of toxins that accumulate as aresult of impaired hepatic metabolism and detoxifica-tion (142). A few dialysis devices have been proposedas detoxification strategies e.g. albumin dialysis, whichutilizes the scavenging functions of albumin for theremoval of toxins. The molecular adsorbents regulat-ing system (MARS) is one such extracorporeal livesupport device where blood crosses an albumin-im-pregnated membrane. In clinical trials, the MARSsystem was found to improve hyperbilirubinemia andhepatic encephalopathy in patients with chronic andacute liver failure, but a recent meta-analysis reportedthat MARS treatment had no significant survivalbenefit, when compared with standard medical ther-apy (143). No data is currently available to indicatethat MARS has any impact in patients with liver failureafter hepatectomy.

Future perspectives

The improvement of outcome in patients undergoingliver surgery must still rely on optimal pre-, intra-, andpostoperative evaluation and management. Currentlyonly surgical strategies i.e. ischemic preconditioningand intermittent clamping have proven protective



effects against ischemic reperfusion injury and areroutinely used in clinical practice.

All other modalities need to be better evaluated inphase I or II studies before routine use. The pharma-cologic agents, e.g. antioxidants, pentoxifylline, andprostaglandins could be potentially beneficial in thefuture. Finally, gene therapy is a promising elegantalternative strategy that requires an ethical debatebefore introduction into clinical trial.

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Improving outcome in patients undergoing liver surgery

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