Management of complications of cirrhosis in patients awaiting liver transplantation

Management of complications of cirrhosis in patientsawaiting liver transplantation

Andres Cardenas, Pere Gines*

Liver Unit, Institut de Malalties Digestives, Hospital Clinic, IDIBAPS, University of Barcelona, Villaroel 170, 08036 Barcelona, Spain

1. Introduction

Up to the late 1970’s patients with decompensated

cirrhosis in form of ascites, hepatorenal syndrome (HRS),

hepatic encephalopathy (HE), spontaneous bacterial perito-

nitis (SBP), gastroesophageal variceal bleeding and/or

hepatocellular carcinoma had a grim prognosis and therapy

was mainly symptomatic and palliative. Introduction of

orthotopic liver transplantation (OLT) more than 20 years

ago as an established therapy for decompensated liver

disease significantly changed the outcome of patients with

advanced cirrhosis [1]. Although OLT was a major step in

management of decompensated cirrhosis, it took at least a

decade to realize that influencing the pre-transplant status of

patients would translate into better post-transplant outcomes

[2,3]. Since listing criteria for OLT in cirrhosis include

complications such as ascites, HRS, variceal bleeding,

hepatic encephalopathy, SBP, among others, optimal

therapy of these is warranted in order to assure that patients

reach OLT and have a good post-transplant outcome. The

goals of pre-operative care include the appropriate manage-

ment of decompensated liver disease with interventions

such as diuretics for ascites, antibiotic prophylaxis against

SBP, the use of beta-blockers or banding for the primary or

secondary prophylaxis of variceal bleeding, endoscopic

variceal banding plus vasoconstrictors for active variceal

bleeding, use of oral synthetic disaccharides such as

lactulose to prevent recurrences of hepatic encephalopathy,

therapeutic paracentesis with albumin for refractory ascites

and vasoconstrictors with albumin for HRS. Because the

complications of cirrhosis can be life threatening, a patient’s

clinical status while listed must be assessed very frequently.

Standard medical care of these patients should include

screening for colorectal, prostate, breast, and cervical

0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Pub

doi:10.1016/j.jhep.2004.12.007

* Corresponding author. Tel.: C34 93 227 5499; fax: C34 93 451 5522.

E-mail address: [email protected] (P. Gines).

cancer. Smoking cessation is of key importance. If the

patient has a history of alcoholism proper measures to

ensure abstinence such as an alcohol rehabilitation program

must be offered. In addition patients should be vaccinated

against hepatitis A and B. This article will focus on the

management of ascites, dilutional hyponatremia, HRS, SBP,

hepatic encephalopathy, and variceal bleeding in patients

awaiting OLT. Hepatocellular carcinoma, commonly

encountered in compensated and decompensated cirrhotics

should also be managed aggressively, however, this topic is

beyond the scope of this review and has been recently

reviewed elsewhere [4].

2. Ascites

Ascites is the most common complication of cirrhosis

and is associated with 50% mortality at 2 years if patients do

not receive OLT [5,6]. It is one of the most frequent reasons

for referral for evaluation of OLT in the United States and

Europe [7,8]. Ascites in cirrhosis is the first manifestation of

the kidney’s inability to handle sodium which occurs mainly

due to activation of sodium retaining factors as a

consequence of a homeostatic response to arterial under-

filling [9]. Recently the International Ascites Club defined

ascites into three groups: in Grade 1 ascites fluid is detected

only by ultrasound; in Grade 2, ascites is moderate with

symmetrical distention of the abdomen; and in Grade 3

ascites is large or tense with marked abdominal distention

[10]. The evaluation of patients with ascites involves several

steps, but the most important is a diagnostic paracentesis

and abdominal ultrasound. Diagnostic paracentesis is

required in all patients listed for transplantation requiring

hospitalization and those with any evidence of clinical

deterioration such as fever, abdominal pain, gastrointestinal

bleeding, hepatic encephalopathy, or hypotension [11].

Tests that need to be ordered are cell count, culture in blood

Journal of Hepatology 42 (2005) S124–S133

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Fig. 1. Treatment strategies for Grade 2 and 3 ascites. Low sodium diet

is recommended with 70–90 mmol/day. Recommended diuretics

include spironolactone (50–200 mg/day) or amiloride (5–10 mg/day).

Low doses of furosemide (20–40 mg/day) may be added to increase

natriuresis in patients with peripheral edema. Albumin replacement is

8 g per liter tapped. Diuretics may be increased every week up to

400 mg/day of spironolactone and 160 mg/day of furosemide if there is

no response. [This figure appears in colour on the web.]

A. Cardenas, P. Gines / Journal of Hepatology 42 (2005) S124–S133 S125

culture bottles (10 mL of fluid injected at the bedside),

albumin, and total protein. The difference between the

serum albumin concentration and ascites albumin concen-

tration (serum-ascites albumin gradient) in patients with

cirrhosis and ascites is usually greater than 1.1 g/dL [12].

Abdominal ultrasonography in patients with ascites de novo

or already listed is important in order to rule out

hepatocellular carcinoma and/or portal vein thrombosis.

The importance of treating ascites properly relates to an

overall better outcome in the pre-transplant phase by

decreasing the risk of SBP, hospital admissions and

providing a better quality of life for the patient.

2.1. Management

The mainstay of therapy is implementation of a low

sodium diet with 70–90 mmol/day (approximately 1.5–

2 gr of salt/day) as well as diuretics. A nutritionist is very

helpful in these cases. Grade 1 ascites does not need to be

treated, but it is advisable that these patients refrain from

excessive salt intake as this can lead to positive sodium

balance and fluid retention. Diuretics are indicated for all

those patients with Grade 2 ascites. The best initial

regimen is either spironolactone (50–200 mg/day)

or amiloride (5–10 mg/day). Low doses of furosemide

(20–40 mg/day) may be useful in the beginning (particu-

larly in patients with peripheral edema or anasarca) [13].

The goal in these patients is to achieve a reasonable

weight loss of 0.5 kg/day until no ascites or edema is

clinically present. Patients with Grade 3 ascites are best

managed by total paracentesis with albumin adminis-

tration (8 g per liter of fluid removed) after the tap in

order to prevent the post-paracentesis circulatory dysfunc-

tion [13,14]. This option is safe, effective, has signifi-

cantly less side effects than diuretics and gets patients out

of the hospital fast. Albumin is better than other plasma

expanders (dextran-70, polygeline, and saline) for large-

volume paracentesis greater than 5 L [15,16]. Since many

of these patients have marked sodium retention they need

to be started or continued on relatively high doses of

diuretics after paracentesis together with a low sodium

diet (Fig. 1).

About 10% of patients with ascites are refractory to

treatment with diuretics [10]. In refractory ascites, patients

do not respond to highest doses of diuretics (spironolactone

400 mg/day and furosemide 160 mg/day) or develop side

effects (hyperkalemia, hyponatremia, hepatic encephalo-

pathy, or renal failure) that prohibit their use. Patients may

be treated either by repeated large-volume paracentesis plus

albumin or transjugular intrahepatic portosystemic shunts

(TIPS). Therapeutic paracentesis is the most accepted

initial treatment and patients, on average, require a tap

every 2–4 weeks. The majority may be treated as

outpatients, making this option easy to perform and

inexpensive. TIPS by reducing portal pressure decreases

ascites and its reaccumulation as well as diuretic

requirements. Although TIPS is very effective, it frequently

obstructs (70% in 1 year) and may cause hepatic

encephalopathy, congestive heart failure and hemolytic

anemia [10,17]. Newer polytetrafluoroethylene-covered

prostheses improve TIPS patency, decrease the number of

clinical relapses and reinterventions without increasing the

risk of encephalopathy [18]. Five clinical trials comparing

TIPS vs. repeated paracentesis in patients with refractory

ascites show that TIPS is associated with a lower rate of

ascites recurrence, but a higher rate of hepatic encephalo-

pathy compared with those of patients treated with

paracentesis and albumin [19–23]. There is also conflicting

evidence in regards to survival because some studies have

shown survival benefit with TIPS whereas others have not

shown any difference in survival. An important aspect to

consider when treating patients is cost. The price of treating

patients with refractory ascites with TIPS is much higher

than the cost of repeated paracentesis plus albumin [21].

Therefore, large-volume paracentesis appears to be the

treatment of choice because of its wider applicability, lower

cost and less side effects when compared to TIPS.

Additionally there is no strong evidence indicating that

TIPS improves either the likelihood of reaching liver

transplantation or post-transplantation outcome. TIPS can

be a good option for patients with preserved liver function

without hepatic encephalopathy, with loculated fluid, or

those unwilling to undergo frequent paracentesis (Fig. 2).

Finally the presence TIPS may create technical difficulties

for the surgeon at the time transplantation in some patients,

although this seems to be uncommon in high-volume and

experienced centers [24,25].

Fig. 2. Treatment strategy for patients with refractory ascites.

*Consider use of Transjugular intrahepatic portosystemic shunt

(TIPS) in patients with preserved hepatic function, no hepatic

encephalopathy, compartmentalized fluid, and those having repeated

paracentesis more than 3–4! per month. [This figure appears in

colour on the web.]

A. Cardenas, P. Gines / Journal of Hepatology 42 (2005) S124–S133S126

3. Dilutional hyponatremia

Dilutional hyponatremia in cirrhotic patients is defined as

serum sodium %130 mEq/L in the presence of an expanded

extracellular fluid volume, as indicated by the presence of

ascites and/or edema [26]. This complication of cirrhotic

patients with ascites has recently gained attention given that

several reports indicate that when serum sodium concen-

tration is combined with the Model for End-Stage liver

disease (MELD) it improves the prognostic accuracy of

MELD score in patients awaiting OLT [27–29]. Dilutional

hyponatrema occurs in 30–35% of hospitalized patients

with cirrhosis and ascites [30,31]. This type of hypona-

tremia is secondary to an impaired capacity of the kidneys to

excrete solute-free water due to non-osmotic hypersecretion

of arginine vasopressin (the antidiuretic hormone). Dilu-

tional hyponatremia must be distinguished from true

hyponatremia which commonly occurs in the setting of

volume depletion without ascites and edema due to

overdiuresis secondary to excessive diuretic use.

The clinical consequences of dilutional hyponatremia in

patients with cirrhosis are not completely understood and

are currently being assessed. Because serum sodium

concentration is the major determinant of the osmolality

in the extracellular fluid, the existence of dilutional

hyponatremia is associated with hypoosmolality of the

extracellular fluid. This hypoosmolality causes a shift of

water from the extracellular to the intracellular compart-

ment, which may theoretically affect cell function. It seems

that the major effect of dilutional hyponatremia occurs in

the brain. Brain cells of patients with cirrhosis and

hyponatremia have reduced intracellular content of some

organic osmolytes, particularly myo-inositol, which may

help to prevent the development of brain cell edema as a

consequence of passage of water from the extracellular to

the intracellular compartment [32]. These changes could

affect cell function and predispose to the development of

disturbances in neurological function. Preliminary studies

from our group suggest that dilutional hyponatremia is a

major predisposing factor to the development of hepatic

encephalopathy in patients with cirrhosis (P. Gines,

unpublished data). Further studies in this area are required

to establish this possible pathogenic relationship.

Other potential clinical consequences of dilutional

hyponatremia are the neurological complications that can

occur after a rapid correction of serum sodium levels. It has

been known for many years that in patients without liver

disease with hyponatremia of different etiologies the rapid

correction of hyponatremia may lead to the development

central pontine myelinolysis (CPM), a severe condition with

high mortality in which shrinkage of cerebral tissues leads

to demyelination of pontine and extrapontine neurons

causing seizures and coma [33]. Studies in small series of

patients and isolated reports have described the occurrence

of neurological complications, particularly CPM, in patients

with cirrhosis after OLT [34,35]. In most, if not all cases

CPM was associated with a rapid increase in serum sodium

levels after transplantation, exceeding 20 mEq/L or more

during a period of 24 h [34]. Therefore, every effort should

be made to avoid rapid increases in serum sodium

concentration in patients with cirrhosis transplanted with

low serum sodium levels. In the future, improvement of

serum sodium levels before transplantation with the use of

vasopressin receptor antagonists drugs may help prevent

significant fluctuations in serum sodium levels and sub-

sequent development of neurological complications post-

transplantation (see below).

3.1. Management

The first step in the management of dilutional hypona-

tremia is fluid restriction and discontinuation of diuretics.

Water restriction at 1000 mL/day helps prevent the

progressive decrease in serum sodium concentration but

usually does not correct hyponatremia in most cases [36].

Currently, several pharmaceutical companies are develop-

ing drugs that are active orally and act by selectively

antagonizing the specific receptors (V2 receptor) of arginine

vasopressin. These agents act in the distal collecting ducts of

the kidneys, by increasing solute-free water excretion and,

thus, improving serum sodium concentration in hypona-

tremic patients. Recent reports in patients with cirrhosis

and ascites indicate that these drugs are effective in

improving serum sodium concentration in hyponatremic

patients [36,37]. Large Phase II and III multicenter clinical

trials are currently being conducted in aims of learning more

about the efficacy and safety of these drugs. These

compounds if approved for clinical use could be useful in

managing decompensated cirrhotic patients listed for OLT.

Table 2

Prevention of hepatorenal syndrome

Clinical situation Intervention Comment

Spontaneous

bacterial

peritonitis [40]

Albumin (1.5 g/kg iv

at diagnosis of the

infection and 1 g/kg

after 2 days)

Reduces incidence of renal

failure from 30 to 10% and

improves survival from 29

to 10%

Alcoholic

hepatitis [41]

Oral pentoxifylline

400 mg p.o. t.i.d. for

1 month

Reduces the incidence of

HRS and mortality to 8

and 24%, respectively vs.

controls 35 and 46%,

respectively


4. Hepatorenal syndrome

HRS is a functional renal failure without any identifiable

kidney pathology that occurs in about 10% of patients with

advanced cirrhosis [9,38]. The diagnosis of HRS is currently

made using criteria to exclude other causes of renal failure

that can occur in cirrhosis (Table 1). HRS is commonly seen

in patients awaiting OLT and remains one of the most

challenging complications of cirrhosis to manage given that

there are limited treatments. It may develop acutely or

subacutely. Type 1 HRS is an acute and rapidly progressive

form of renal failure (serum creatinine O2.5 mg/dL) that

may occur spontaneously or be precipitated by events such as

SBP, alcoholic hepatitis or large volume paracentesis

without albumin expansion. The expected survival of type

1 HRS is of only 2 weeks if not treated or transplanted [39]. In

type 2 HRS, renal failure is usually less severe (serum

creatinine 1.5–2.5 mg/dL) and shows little or no rapid

progression compared to that of type 1 HRS. Prevention of

HRS has been a major step improving care for patients listed

for OLT. There are two clinical situations in which HRS can

be prevented; SBP and alcoholic hepatitis [40,41] (Table 2).

4.1. Management

Although OLT is undoubtedly the best treatment for

HRS, successful pharmacological therapy prior to OLT is

equally important in assuring an optimal outcome similar to

that of patients without HRS. Systemic vasoconstrictors

with plasma expansion are the therapy of choice for HRS

now that several uncontrolled studies have confirmed a

beneficial role in HRS [42–51]. Vasoconstrictors are used

because the initial event in the pathogenesis of HRS is an

arterial splanchnic vasodilation causing activation of

endogenous vasoconstrictors systems with subsequent

renal vasoconstriction. Intravenous terlipressin along with

albumin as a plasma expander is associated with a

significant improvement of renal function and reduction of

serum creatinine to less than 1.5 mg/dL in approximately

60–75% of patients treated for at least 5 days [42–48]. With

this protocol, recurrence is uncommon. Unfortunately,

terlipressin is not available in many countries including

the United States and, therefore, other options such as alpha-

adrenergic agonists are a reasonable alternative given that

they are widely available. Midodrine, an alpha-adrenergic

Table 1

Diagnostic criteria of hepatorenal syndrome proposed by the

International Ascites Club [38]

1. Low glomerular filtration rate, as indicated by serum

creatinine greater than 1.5 mg/dl

2. Exclusion of shock, ongoing bacterial infection,

volume depletion and use of nephrotoxic drugs

3. No improvement in renal function despite stopping

diuretics and volume repletion with 1.5 L of saline

4. No proteinuria or ultrasonographic evidence of

obstructive uropathy or parenchymal renal disease

agonist in association with octreotide, a glucagon inhibitor,

and albumin has also proved efficatious in HRS [49,50].

Noradrenaline, another alpha agonist, in combination with

albumin expansion also improves renal function in HRS

[51]. The recommended doses and duration of vasocon-

strictor therapy are summarized in Fig. 3. In three studies,

patients that responded to therapy of HRS (decrease of

creatinine to !1.5 mg/dL) with terlipressin plus albumin

and octreotide, midodrine and albumin had an increased

survival compared to those that did not respond to this

therapy [43,44,50].

The primary goal of phamacological therapy is normal-

ization of renal function so that suitable transplant

candidates can undergo OLT with less morbidity and have

similar survival compared to that of patients without HRS.

A recent study from our Unit revealed that patients treated

sucessfully with vasopressin analogues and albumin before

OLT had a similar post-transplantation outcome and

survival similar to patients transplanted without HRS [52].

This study supports the concept that HRS should be treated

aggresively before OLT because improvements in renal

function are associated with better outcomes.

TIPS may improve renal function in HRS. In one recent

study of 14 patients with type 1 HRS treated with

midodrine, octreotide, and albumin, 10 had a good response

Fig. 3. Treatment strategy for patients with hepatorenal syndrome.

Terlipressin is widely used in Europe but is not available in many

countries including the United States. [This figure appears in colour on

the web.]


(serum creatinine remained stable at !1.5 mg/dL for 3

days) and were subsequently treated with TIPS if not

contraindicated by INR O2.0, serum bilirubin O5 mg/dL,

and a Child-Pugh score O12 [50]. Five patients underwent

TIPS with very good outcome with one of them successfully

receiving living donor OLT. Interestingly renal function

continued to improve and completely normalized in these

five patients. Of the five that responded to vasoconstrictors

and albumin but did not get TIPS, two underwent successful

OLT, but three died as a consequence of liver failure, sepsis

and arrhythmia. There was improved survival in all

responders, but the real impact of TIPS in improving

survival is difficult to assess given the low number of

patients treated.

4.2. Orthotopic liver transplantation for patients

with hepatorenal syndrome

OLT is the optimal treatment for suitable candidates

with HRS. Unfortunately, transplantation for HRS is

limited by the fact that many of these patients may die

before the operation due to prolonged waiting in the list in

most centers. Priority for OLT in the United States is

based on the MELD score which includes three variables;

bilirubin, serum creatinine and international normalized

ratio (INR) [53]. This scoring system is objective,

includes serum creatinine and predicts survival in

cirrhotics. The score ranges from 6 to 40. Its role in

predicting prognosis in patients with HRS has recently

been confirmed in our Unit in 105 cirrhotic patients with

HRS (P. Gines, unpublished results). Patients with type 1

HRS with a MELD score R20 showed an extremely poor

outcome with a median survival of 1 month and those

with type 2 HRS and a score !20 showed a slightly

better outcome with a median survival of 11 months,

while patients with type 2 HRS and a score O20 had an

intermediate outcome, with a median survival of three

months. In the whole group, the two independent

predictive factors of survival were MELD score and

type of HRS. Other centers outside the United States have

different allocation systems that give higher priority to

patients with HRS. Regardless of the system used for

organ allocation, patients with HRS must be appropriately

treated before transplantation. Since cyclosporine and

tacrolimus treatment may contribute to renal impairment

post-operatively, these drugs should not be given until

diuresis and improvement of renal function is observed,

usually in 3–4 days after transplantation.

5. Bacterial infections and spontaneous bacterial

peritonitis

Bacterial infections are one of the most feared problems

that complicate the course of patients with advanced liver

disease. It is estimated that they occur at admission or

during hospitalization in 20–60% of patients [54]. A recent

prospective study conducted in our Unit between 1998 and

2000 showed that among all admissions, bacterial infections

were present in 32% of cases either at entry or during

hospitalization [55]. Of these the majority were secondary

to SBP (24%), other common causes included urinary tract

infection, pneumonia and bacteremia secondary to invasive

procedures. Only 39% of SBP were culture positive and

among these 84% were due to Gram-negative bacteria.

Aerobic Gram-positive bacteria, mostly Streptococcus

viridans, Staphylococcus aureus and Enterococcus fecalis

were isolated in approximately 20% cases [55].

The prevalence of SBP in hospitalized cirrhotic patients

ranges between 10 and 30% [54]. The 1-year survival

probability after an episode is only 40% and therefore,

patients should be evaluated for OLT once they are cured

[54,56]. The clinical spectrum of SBP is variable and ranges

from no symptoms to fever, chills, abdominal pain, and/or

hepatic encephalopathy to a severe picture of peritonitis.

The diagnosis of SBP relies on the examination of

peritoneal fluid. The diagnosis is made when the poly-

morphonuclear cell count is greater than 250/mm3 or when

urine strips for leukocyte estearase are positive (3 or 4C)

[11–13,54]. For this reason and because of the high

prevalence of SBP in patients with ascites, diagnostic

paracentesis should be performed routinely in all cirrhotic

patients admitted to the hospital with ascites and in

hospitalized patients with systemic or local signs suggestive

of SBP (i.e. fever, leukocytosis, shock, abdominal pain,

rebound tenderness, ileus), hepatic encephalopathy or renal

failure [11–13]. Important clinical features of SBP are the

frequent development of renal function impairment during

the infection and the high recurrence rate [56,57].

5.1. Management of spontaneous bacterial peritonitis

Empiric antibiotic therapy must be commenced when the

PMN count in ascitic fluid is R250/mm3 and before

microbiologic results are obtained. Therapy with an

intravenous third-generation cephalosporin (cefotaxime

2 g every 8–12 h; ceftriaxone 1 g/24 h) for at least 5–7

days, is recommended [11–13]. Therapy modification

depends on results from cultures. Response to therapy

should be monitored by clinical signs, cell blood count and

PMN in ascitic fluid. Therapy should be stopped when

clinical signs of infection have disappeared and cell blood

count and PMN count in the ascitic fluid have normalized.

SBP resolves in approximately 90% of cases if treated

with the above regimens. The most important predictor of

survival in patients with SBP is the development of renal

failure during the infection [57]. Administration of albumin

at a dose of 1.5 g/kg at the diagnosis and 1 g/kg 48 h later

prevents renal failure and reduces mortality from 30 to 10%

[40]. Since recurrence of SBP occurs in 70% of cases and

constitutes a major cause of death in these patients,

prophylaxis is recommended [11,56]. Because most cases


are caused by Gram-negative bacteria from the intestinal

flora, quinolones such as norfloxacin or ciprofloxacin have

been used with good results and are recommended by the

International Ascites Club [11]. Although long-term

norfloxacin (400 mg/day) is very effective in the prevention

of SBP recurrence (secondary prophylaxis) an emerging

problem has been that of quinolone resistance which may

lead to repeat episodes of SBP or other infections caused by

quinolone resistant bacteria [55]. Unfortunately, it seems

that in years to come more episodes of microorganisms

resistant to quinolones are going to complicate the clinical

course of cirrhotic patients with previous episodes of SBP.

6. Hepatic encephalopathy

Hepatic encephalopathy (HE) is a complex neuropsy-

chiatric syndrome due to hepatic failure. In patients listed

for OLT it is a recurrent theme given that in the last decade

no major breakthrough in therapy has been available.

Patients may exhibit episodic, persistent or minimal features

of HE [58]. HE is diagnosed clinically and with exclusion of

other causes of changes in mental status. In some cases HE

may be difficult to diagnose as other disorders may mimic

its clinical features. Brain imaging (magnetic resonance,

computed tomography, positron emission tomography) may

be helpful in excluding other conditions and in some cases

may help securing a diagnosis, nonetheless there are still

being investigated as a diagnostic tool in HE [58,59].

6.1. Management

The mainstay of therapy is based on supportive care,

identification and removal of precipitating factors, reduction

of nitrogenous load from the gut and assessment of long

term therapy. Common precipitating factors such as

gastrointestinal hemorrhage, infections (in particular

SBP), renal and electrolyte disturbances, psychoactive

medications, volume depletion, constipation, excessive

dietary protein and the presence of shunts (TIPS and/or

surgical portosystemic shunts) should be sought after and

corrected if possible. Although protein restriction of 1.0–

1.5 protein/kg/day has been recommended in HE, recent

data indicate that a normal protein diet is safe and in fact

nutritionally better for patients with episodic hepatic

encephalopathy [60]. Reduction of nitrogenous load by

means of colonic cleansing with non-absorbable disacchar-

ides like lactulose is a standard therapeutic measure that is

very useful in patients that cannot tolerate the oral route

[61]. For acute encephalopathy if patients are awake, oral

lactulose is the first line pharmacological treatment [61].

The recommended dose is 15–45 mL orally every 6–8 h

adjusted to achieve three soft bowel movements, profuse

diarrhea should be avoided. Antibiotics may be used as an

alternative or addition to nonabsorbable dissacharides.

Several oral antibiotics have been used, however, the most

commonly used are neomycin (3–6 g/day), metronidazol

(250 mg/day) and most recently rifaximin (1200 mg/day)

[61,62]. However, their efficacy has not been demonstrated.

Rifaximin is as good as lactulose in all types of encephalo-

pathy and seems to be a promising and safe nonbsorbable

antibiotic but experience is limited [62]. Information on

other therapies such ornithine-aspartate, flumazenil, and

bromocriptine is limited and recommendations cannot be

made on the basis of randomized studies. Usually, episodic

hepatic encephalopathy responds within a few days. Failure

to respond should prompt a search for causes of intractable

encephalopathy such as large spontaneous portosystemic

shunts. Given the widespread use of TIPS in decompensated

cirrhosis, the frequency of hepatic encephalopathy has

increased [17]. In this setting, revision of the stent with

reduction of its diameter may be helpful in selected cases.

7. Variceal bleeding

When cirrhosis is diagnosed, varices are present in

about 30–40% of compensated patients and in 60% of

those who present with ascites [63,64]. Gastrointestinal

bleeding due to ruptured gastro-esophageal varices is a

frequent and severe complication of cirrhosis. It may occur

in patients with relatively preserved liver function as well

as patients with advanced decompensated cirrhosis.

Mortality from variceal bleeding has dramatically changed

in the last 3 decades due to better endoscopic and

pharmacologic therapies and implementation of special-

ized intensive care units [65,66]. Nonetheless variceal

bleeding is still often severe and about 5–8% of patients

die within 48 h from uncontrolled bleeding [67]. Mortality

rates at 6 weeks have decreased from 30 to 50% in the

1970s to 15–17% currently [65,66]. Poor prognostic factors

are active bleeding at endoscopy, bacterial infection, and

hepatic venous pressure gradient (HVPG) greater than

20 mmHg early after admission, and renal failure [64,68].

Rebleeding within the first 6 weeks ranges from 30 to 40%,

with nearly half of these occurring with the first week of

the index bleed [67].

7.1. Management

The management of portal hypertension encompasses

therapy aimed at prevention in patients who have never bled

(primary prophylaxis), those who are actively bleeding and

those who have bled (secondary prophylaxis).

The prevention of the first bleeding should begin with

screening endoscopy in cirrhotic patients candidates to

prophylatic therapies. If no varices or very small varices are

found a repeat endoscopy is recommended in 2 years. Those

with medium or large sized varices should be treated

indefinitely with non-selective beta-blockers (i.e. proprano-

lol or nadolol) if there are no contraindications. These drugs

are given in a stepwise fashion, increasing the dose until

Fig. 4. Treatment strategy for patients with acute variceal bleeding.

Shunt surgery is reserved for patients with Child A cirrhosis. [This

figure appears in colour on the web.]


the resting heart rate decreases by 25% with respect to

baseline, with a heart rate between 50 and 60 beats/min [64,

69]. Those who do not tolerate or cannot take beta-blockers

due to side effects, should be offered endoscopic variceal

band ligation until eradication of varices. Both pharmaco-

logical therapy and endoscopic therapy reduce the risk of

bleeding by 40–50% [70]. Randomized controlled trials

have shown that variceal banding is as effective as beta-

blockers for preventing a first variceal bleed [71–74].

Nonetheless the choice of either beta-blockade vs. endo-

scopic therapy should made depending on the local

resources, availability of experienced endoscopists and

cost of endoscopic therapy [74]. Most authors recommend

starting with beta-blockers if there are no contraindications

because they are inexpensive, easy to use and relatively safe

[71–74].

Active variceal bleeding is a medical emergency and its

management ideally should be performed in an intensive

care setting by a team of experienced nurses, gastroenter-

ologists or hepatologists, endoscopists, interventional radi-

ologists, and surgeons. If these are not available, patients

should be referred to an appropriate institution, preferably

with a liver transplant program. Initial therapy must be

aimed at correcting hypovolemia, achieving hemostasis and

preventing complications (such as renal failure, infection

and hepatic encephalopathy) that increase the risk of

rebleeding [64,68]. Pharmacotherapy must be started as

soon as possible; if available even during transfer to the

hospital. Blood volume replacement is important, but

increased transfusion may lead to a further rise in portal

pressure and additional variceal bleeding, accordingly

the goal is to maintain the hematocrit between 25 and

30% [64,69]. Early administration of antibiotics (norflox-

acin 400 mg/day for 7 days) has been shown to improve

survival [75]. In some cases endotracheal intubation maybe

necessary as these patients have a high risk of aspiration due

to either underlying hepatic encephalopathy and/or the

sedation required for the endoscopy. A recent study

addressing management of coagulopathy showed that the

administration recombinant factor VII by correcting pro-

thrombin time significantly decreased the proportion of

patients who failed to control variceal bleeding [76].

Specific hemostatic treatments for variceal bleeding include

vasoactive drugs that decrease portal pressure, endoscopic

band ligation and surgical portosystemic shunts or TIPS.

Pharmacotherapy for acute variceal bleeding depends on

what is available locally. If available, terlipressin (2 mg/4 h

for the first 48 h, then 1 mg/4 h for up to 5 days) should be the

first choice, as it is superior to placebo in reducing mortality

[77,78]. This medication controls variceal bleeding in

75–80% of cases in 2 days and around 70% at 5 days [79].

Somatostatin (bolus of 250 mg, followed by an infusion of

250 mg/h for 5 days) or octreotide (100 mg bolus followed by

50 mg/h for 5 days) are good options if terlipressin is not

available [80,81]. In the United States octreotide is widely

used as terlipressin is not available. The recommended

treatment for acute variceal bleeding is to begin a vasoactive

drug (within 1 or 2 h if possible) to be continued for 5 days

and therapeutic endoscopy (Fig. 4) [64,68]. This approach

controls bleeding in 75% of cases [77,82]. Although this

combination improves the results of endoscopy and

decreases rebleeding; combination therapy does not improve

6-week mortality compared with endoscopic or drug therapy

alone [83,84].

If the patient has a recurrent bleeding episode a single

endoscopic re-treatment is reasonable if the patient is stable

[64,85]. In hemodynamically unstable patients other defini-

tive measures such as TIPS or surgery need to be considered.

If there is massive bleeding, balloon tamponade may

temporarily aid in controlling the hemorrhage, however, it

has a high incidence of rebleeding when the balloon is

deflated and may cause pressure necrosis of the esophageal

mucosa with prolonged use [85,86]. TIPS is very effective

with control rates around 95%, but since these patients are

very sick mortality rates remain high [64,85,87]. TIPS is

preferred over shunt surgery because it is associated with

less operative morbidity and mortality [17,88]. Moreover, in

patients awaiting liver transplantation, TIPS appears to be a

better option than surgery [88]. In selected cases shunt

surgery, an H—graft mesocaval shunt, for Child A patients

is a viable option if an experienced surgeon is available.

After patients have bled the risk of a repeat episode is

around 60% and mortality from each rebleeding episode is

near 20% [67]. Therefore, these patients need to be treated

very aggressively. Both beta-blockade and endoscopic band

ligation can be used. If possible the effect of beta-blockers

should be monitored with the use of HVPG. The goal is

reduction below 12 mmHg otherwise a goal of reduction of

heart by 25% is acceptable [64,68]. If one of these fails, the

best approach is a combination of beta-blockers plus

endoscopic band ligation, however, information is limited.

Those patients with recurrent bleeding despite the above


measures should be offered a TIPS or shunt surgery if they

are Child A.

8. Summary

As the demand for OLT increases, patients with advanced

cirrhosis will end up spending a longer time waiting in the list

with an increased risk of developing further decompensation

and dying. Only the expansion of the donor pool will have a

major impact on the survival of patients; however, this seems

to be extremely challenging given that use of marginal

donors and living related liver transplantation has not made a

significant impact on waiting times. Therefore, both preven-

tion and effective treatment of complications such as ascites,

dilutional hyponatremia, hepatorenal syndrome, spon-

taneous bacterial peritonitis, hepatic encephalopathy and

variceal bleeding may improve the likelihood of a patient

surviving until OLT.

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Management of complications of cirrhosis in patients awaiting liver transplantation

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