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I. Background
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Cirrhosis
represents the
end stage of any
chronic liver
disease.
Hepatitis C and
alcohol are
currently the
main causes of
cirrhosis
in the United
States. Two
major syndromes
result from
cirrhosis:
portal
hypertension
and hepatic
insufficiency.
Additionally,
peripheral and
splanchnic
vasodilatation
with the
resulting
hyperdynamic
circulatory
state is typical
of cirrhosis
and portal
hypertension. In
a patient with
chronic
hepatitis C, a
low platelet
count
(<100,000/mm3)
may be
indicative of
progression to
cirrhosis.(1)
Cirrhosis
can remain
compensated for
many years
before the
development of a
decompensating
event.
Decompensated
cirrhosis is
marked by the
development of
any of the
following
complications:
jaundice,
variceal
hemorrhage,
ascites, or
encephalopathy.
Jaundice results
from hepatic
insufficiency
and, other than
liver
transplantation,
there is no
specific therapy
for this
complication. It
is, however,
important to
recognize and
treat
superimposed
entities (e.g.,
alcoholic
hepatitis, drug
hepatotoxicity)
that may
contribute to
the development
of jaundice.
The other
complications of
cirrhosis
occur mainly as
a consequence of
portal
hypertension and
the hyperdynamic
circulation.
Gastroesophageal
varices result
almost solely
from portal
hypertension,
although the
hyperdynamic
circulation
contributes to
variceal growth
and hemorrhage.
Ascites results
from sinusoidal
hypertension and
sodium
retention, which
is, in turn,
secondary to
vasodilatation
and activation
of neurohumoral
systems. The
hepatorenal
syndrome results
from severe
peripheral
vasodilatation
that leads to
renal
vasoconstriction.
Hepatic
encephalopathy
is a consequence
of shunting of
blood through
portosystemic
collaterals (as
a result of
portal
hypertension),
brain edema
(cerebral
vasodilatation),
and hepatic
insufficiency.
The following
treatment
recommendations
for cirrhosis
are divided
according to the
status--compensated
or
decompensated--of
the cirrhotic
patient and are
based on
evidence in the
literature,
mainly from
randomized
clinical trials
and
meta-analyses of
these trials, as
well as on the
results of the
most recent
consensus
conferences.
When little or
no data exist
from
well-designed
prospective
trials, emphasis
is given to
results from
large series and
reports from
recognized
experts. Further
controlled
clinical studies
are needed to
clarify aspects
of these
recommendations,
and revision may
be necessary as
new data appear.
Clinical
considerations
may justify a
course of action
that differs
from these
recommendations.
Recommendations
are summarized
at the end of
this document in
the Appendix.
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II. Management
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A.
Compensated
Cirrhosis
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As
mentioned
previously,
patients
with
compensated
cirrhosis
are not
jaundiced
and have
not yet
developed
ascites,
encephalopathy,
or
variceal
hemorrhage.
Median
survival
of
patients
with
compensated
cirrhosis
is
around
10
years.(2)
At this
point in
the
natural
history
of
cirrhosis,
management
is
essentially
preventive
and
consists
of
routine
monitoring
for the
development
of liver
insufficiency
and/or
the
development
of
complications
of
portal
hypertension/cirrhosis.
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Assessments in patients with compensated cirrhosis
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The following assessments are recommended:
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| The following recommendations are based on expert opinion or formal consensus development processes: |
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Liver synthetic function tests every 3 to 6 months |
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EGD
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If no varices, repeat endoscopy in 2 years |
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If small varices, repeat endoscopy in 1 year |
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If large varices, therapy to prevent first variceal hemorrhage |
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Alphafetoprotein serum levels and liver ultrasound every 6 months |
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Vaccination against hepatitis A and B in susceptible individuals |
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1. Prevention of first variceal hemorrhage
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Gastroesophageal varices are present in approximately 50 percent of cirrhotic patients. Their presence correlates with the severity of liver disease; while only 40 percent of Child A patients have varices, they are present in 85 percent of Child C patients.(6) Patients with gastroesophageal varices develop variceal hemorrhage at a rate of around 25 to 30 percent in 2 years. Mortality following variceal hemorrhage is around 30 percent. Therefore, one of the main preventive measures in the compensated cirrhotic is the prevention of first variceal hemorrhage.
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Candidates
Three factors identify patients at a high risk of bleeding from varices: large variceal size, red wale markings on the varices, and severe liver failure.(7) Most trials on primary prevention of variceal hemorrhage have included patients with large varices. Patients with small varices have a low risk of bleeding, estimated at 7 percent over 2 years, so specific therapy is not recommended. Patients with gastric varices (with or without esophageal varices) should be treated prophylactically. |
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Accepted therapy
The results of a meta-analysis of 11 trials evaluating nonselective beta-blockers (i.e., propranolol, nadolol, and timolol) in the prevention of first variceal hemorrhage have been reported recently.(8) Overall, the bleeding rate in controls is 25 percent after a median followup of 24 months and is significantly reduced to 15 percent in beta-blocker-treated patients. Mortality is also lower in the beta-blocker group (23 percent) compared with the control group (27 percent); however, this difference is not statistically significant. This meta-analysis also analyzes the effect of beta-blockers as a function of variceal size.
The risk of first variceal bleeding in patients with large or medium-sized varices is significantly reduced by beta-blockers (30 percent in controls and 14 percent in beta-blocker-treated patients). However, in patients with small varices, the number of patients and the rate of first bleeding were too small to achieve statistical significance. In another meta-analysis based on individual patient data,(9) the beneficial effect of nonselective beta-blockers was present in patients both with and without ascites and in patients with and without poor liver function and was associated with a significant reduction in bleeding-related deaths. Additionally, a cost-effectiveness study comparing nonselective beta-blockers, sclerotherapy, and shunt surgery showed that beta-blockers were the only cost-effective form of prophylactic therapy.(10) |
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Recommended treatment schedule
The recommended dose of nonselective beta-blockers (propranolol, nadolol, or timolol) is the one that will reduce heart rate to 55-60 beats/minute. Propranolol is given twice a day and is usually started at a dose of 20 milligrams (mg) twice a day (BID). Nadolol and timolol are given once a day (QD). Nadolol is started at a dose of 40 mg QD and timolol at a dose of 10 mg QD. The nonselective beta-blocker on the Department of Veterans Affairs (VA) National Formulary is propranolol (10, 20, 40, and 80 mg tablets).
Based on data from a recent study,(11) it is recommended that prophylactic therapy be continued indefinitely. |
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Contraindications/side effects
Approximately 15 percent of patients have contraindications to the use of beta-blockers, such as asthma, insulin-dependent diabetes (with episodes of hypoglycemia), and peripheral vascular disease. The most common side effects related to beta-blockers in cirrhosis are lightheadedness, fatigue, and cold extremities.
Some of these side effects disappear with time or after a reduction in the dose of the beta-blocker. Side effects have led around 15 percent of patients to withdraw from clinical trials. The rate of side effects in trials in which nadolol was used (~10 percent) appears to be lower than in trials in which propranolol was used (~17 percent); however, direct comparisons have not been performed. |
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Alternative therapies
Because endoscopic variceal ligation (EVL) has been shown to be more useful and safe than sclerotherapy in preventing variceal rebleeding, its usefulness in preventing first variceal hemorrhage has also been examined. A meta-analysis comprising 283 patients included in four trials (two published articles, two abstracts) of EVL versus beta-blocker therapy shows that EVL reduced the risk of first hemorrhage from 16 percent in beta-blocker-treated patients to 8 percent in EVL-treated patients with no change in bleeding or overall mortality.(12)
This meta-analysis is largely based on a trial of 90 patients with large varices in which the rate of first variceal hemorrhage was significantly lower in the EVL-treated group (9 percent) compared with the propranolol-treated group (27 percent).(13) However, the rate of first hemorrhage in the propranolol-treated group is unusually high and is comparable to the rate of first hemorrhage in placebo-treated patients, including placebo-treated patients from a prior study by the same group of investigators.(14)
This suggests that patients in the EVL study were not compliant and/or were not adequately beta-blocked. Furthermore, a recent randomized trial, not included in the meta-analysis, showed that EVL was equivalent to propranolol in preventing first variceal bleed.(15) Further studies need to be performed in a larger number of patients before EVL can be widely recommended. |
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Therapies under investigation
The combination of a nonselective beta-blocker and isosorbide mononitrate (ISMN) has a synergistic portal pressure-reducing effect and could theoretically be more effective than beta-blockers alone in preventing first variceal hemorrhage.(16)
In fact, a nonblinded trial comparing nadolol alone with nadolol plus ISMN demonstrated a significantly lower rate of first hemorrhage in the group treated with combination therapy.(17) These results were maintained after 55 months of followup, without differences in survival.(18) However, two more recent double-blind placebo-controlled trials were unable to confirm these favorable results (19; 20) and a greater number of side effects (mainly headache) were noted in the combination therapy group.(19) Therefore, the use of a combination of a beta-blocker and ISMN cannot be recommended currently for primary prophylaxis until there is further proof of efficacy.
The combination of a nonselective beta-blocker and spironolactone (that has been shown to lower portal pressure by reducing plasma volume and splanchnic blood flow) has been recently examined in a preliminary double-blind placebo-controlled trial.(21) The results suggest that nadolol plus spironolactone does not increase the efficacy of nadolol alone in the prophylaxis of first variceal bleed. However, when bleeding and ascites were considered together, combination therapy significantly reduced the development of either of these complications. |
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Therapies of proven inefficacy
ISMN alone has been shown in one study to be as effective as propranolol in preventing first variceal hemorrhage.(22) However, long-term followup of patients enrolled in this study showed higher mortality in a subgroup of patients.(23) ISMN, a potent venodilator, may lead to a higher mortality in these patients by aggravating the vasodilatory state of the cirrhotic patient.(24) In a recent multicenter trial, 133 cirrhotic patients with varices and contraindications or intolerance to beta-blockers were randomized to ISMN (n=67) or to placebo (n=66).(25)
Surprisingly, there was a greater 1- and 2-year probability of first variceal hemorrhage in the ISMN group (p=0.056), with no differences in survival. Side effects were more frequent in patients receiving ISMN. These results were further supported in another randomized trial of cirrhotic patients with ascites.(26) Therefore, the use of nitrates alone should be discouraged.
Shunt surgery trials have shown conclusively that, although very effective in preventing first variceal hemorrhage, shunt surgery is accompanied by more frequent encephalopathy and higher mortality.(27) Because the physiology of the transjugular intrahepatic portosystemic shunt (TIPS) is the same as that of surgical shunts (i.e., diversion of blood away from the liver), these results can be extrapolated to TIPS. Therefore, shunt therapy (surgery or TIPS) not only is not recommended but should not be used in the primary prevention of variceal hemorrhage.
Endoscopic sclerotherapy trials have yielded controversial results. While early studies showed promising results, later studies showed no benefit.(27; 28) In fact, a VA prospective randomized cooperative trial comparing prophylactic sclerotherapy and sham therapy had to be terminated 22.5 months after it began, because the mortality rate was significantly higher in the sclerotherapy group than in the sham-therapy group.(29) Sclerotherapy should therefore not be used for the primary prevention of variceal hemorrhage. |
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Recommendation: Nonselective beta-blockers (propranolol, nadolol, and timolol) are the therapy of choice in patients with medium-sized and large varices that have not yet bled. The dose of beta-blockers should be adjusted to achieve a maximal tolerable decrease in heart rate to a minimum of 55 beats/minute and should be continued indefinitely. Propranolol, the nonselective beta-blocker on the VA National Formulary, should be administered twice a day. Once a patient is on beta-blockers, followup EGD is unnecessary. In patients with contraindications to beta-blockers, or who develop severe side effects and in whom the risk of variceal hemorrhage is very high, EVL should be contemplated. In patients with small varices, the risk of hemorrhage is so small that treatment would not appear to be cost-effective. In these patients, followup EGD should be performed every 1 to 2 years.(3)
| The following interventions are recommended based on randomized clinical trials demonstrating delay in time to first variceal hemorrhage: |
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Nonselective beta-blockers (propranolol, nadolol, timolol) |
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EVL in noncandidates for beta-blockers |
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| The following interventions are not recommended based on randomized clinical trials demonstrating that other interventions are either more effective or safer: |
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Nitrates alone |
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Endoscopic sclerotherapy |
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Shunt surgery/TIPS |
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| The following interventions are under evaluation and cannot be recommended until additional information is available: |
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Combination beta-blocker/nitrates |
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Combination beta-blocker/diuretics |
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B.
Decompensated
Cirrhosis
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The
following
sections
deal
with the
management
of the
cirrhotic
patient
who has
developed
decompensation.
Complications
are
listed
in order
of
severity
of the
complication
and,
therefore,
in order
of their
management
priority.
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1. Treatment of acute variceal hemorrhage
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Although bleeding from esophageal varices ceases spontaneously in up to 40 percent of patients, the mortality of an episode of variceal hemorrhage is about 30 percent and occurs mostly in patients with severe liver disease and in those with early rebleeding. Rebleeding occurs in approximately 60 percent of untreated patients within 1 to 2 years of the index hemorrhage.(8) In addition to general measures, the treatment of acute variceal hemorrhage includes the control of hemorrhage (including prevention of early rebleeding) and the prevention of recurrence.
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Candidates
Candidates include patients with cirrhosis who present with upper gastrointestinal (GI) hemorrhage and in whom diagnostic endoscopy shows one of the following: active bleeding from a varix, a "white nipple" overlying a varix, clots overlying a varix, or varices with no other potential source of bleeding.(30) |
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1.a. General measures specific for variceal hemorrhage
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A general measure that is currently considered standard in the care of patients with variceal hemorrhage is the use of short-term antibiotic prophylaxis.(31) Cirrhotic patients with upper GI bleeding are at a high risk of developing severe bacterial infections (spontaneous bacterial peritonitis and other infections) associated with early recurrence of variceal hemorrhage and a greater mortality.(32; 33) Although even patients with less severe liver disease (i.e., Child A) are at an increased risk of developing bacterial infections, this risk is highest in those with more severe liver disease (i.e., Child B and C).(34; 35) The use of prophylactic antibiotics in cirrhotic patients with GI hemorrhage has been shown by meta-analysis of controlled clinical trials not only to decrease the rate of bacterial infections but also to increase survival.(36; 37)
Therefore, the use of antibiotic prophylaxis for acute variceal hemorrhage should be considered standard practice in all cirrhotic patients, particularly in those with ascites and more severe liver disease. Antibiotics used in these trials include a combination of orally administered nonabsorbable antibiotics,(38) oral norfloxacin,(39) oral ciprofloxacin,(40) intravenous (i.v.) ofloxacin followed by oral ofloxacin, and i.v. followed by oral amoxicillin clavulanate plus i.v. ciprofloxacin.(34)
The antibiotic schedule recommended by consensus (31) is norfloxacin administered orally at a dose of 400 mg BID for 7 days.(31) The rationale behind the oral administration of norfloxacin, a poorly absorbed quinolone, is the selective elimination of gram-negative bacteria in the gut, minimizing a systemic effect. However, quinolone antibiotics with similar spectrum of activity, such as ciprofloxacin or levofloxacin, could also be recommended. In the majority of patients, administration by mouth or through a nasogastric tube is possible. In cases in which this is not possible, quinolones can be administered intravenously.
Another general measure, which is recommended in the setting of acute variceal hemorrhage, is the cautious transfusion of blood products. Because restitution of lost blood has been shown in experimental animals to lead to increases in portal pressure greater than baseline (41) and to more bleeding,(42) transfusion should aim to maintain the hematocrit between 25 and 30 percent. Intravascular volume overexpansion should also be avoided as this too can precipitate variceal rebleeding. |
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1.b. Control of acute hemorrhage and prevention of early recurrence
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Accepted therapies
Pharmacological therapy has the advantages of being generally applicable and capable of being initiated as soon as a diagnosis of variceal hemorrhage is suspected, even prior to diagnostic EGD. A recent meta-analysis of 15 trials comparing emergency sclerotherapy and pharmacologic treatment (vasopressin alone or in combination with nitroglycerin, terlipressin, somatostatin, or octreotide) suggests that pharmacological therapy should be considered the first-line treatment of variceal bleeding.(43) However, the most effective, safe, and widely accepted drugs are somatostatin and terlipressin, neither of which is available in the United States.
Vasopressin and the somatostatin analogue, octreotide, are available in the United States (and are on the VA formulary). The use of vasopressin is limited by the presence of side effects. Its efficacy and safety are significantly improved by the addition of nitrates.(44) Nevertheless, side effects of combination therapy are still higher than those associated with terlipressin or somatostatin.(8) Vasopressin is administered at a continuous infusion of 0.2--0.4 units/minute, and can be increased to a maximum of 0.8 units/minute. It should always be accompanied by intravenous nitroglycerin at a starting dose of 40 mg/minute that can be increased to a maximum of 400 mg/minute, adjusted to maintain a systolic blood pressure >90 millimeters/hectogram (mm/Hg). Continuous infusion of vasopressin/nitroglycerin cannot be recommended for more than 24 hours because of an increased incidence of adverse effects.
Results of trials of octreotide have been controversial, with two recent meta-analyses showing contradictory results. One of them suggests that octreotide has little or no effect when used alone,(8) while the other shows that octreotide improves control of variceal hemorrhage compared with all alternative therapies.(45) Its side-effect profile was similar to placebo or no therapy; however, it did not show a survival benefit. There are two significant flaws of this meta-analysis.
The first is comparing octreotide to other therapies that are not comparable among themselves (no treatment, vasopressin, glipressin, balloon tamponade, and sclerotherapy). The second flaw is excluding the only double-blind placebo-controlled study of octreotide, which showed that octreotide had no effect.(46) Therefore, the efficacy of octreotide in acute variceal hemorrhage remains unclear. Octreotide is probably not useful as a single first-line therapy of acute variceal hemorrhage, but it may be of use as an adjunct to endoscopic therapy.
Endoscopic therapy is highly effective in controlling active hemorrhage and in preventing early rebleeding and has become the gold standard in the management of acute variceal hemorrhage.(27) However, as mentioned above, a recent meta-analysis of 15 trials comparing sclerotherapy with vasoactive drugs (vasopressin, terlipressin, somatostatin, and octreotide) showed no differences in failure to control bleeding, rebleeding, mortality, or transfused blood units.(43) Another meta-analysis (47) compared sclerotherapy and EVL and concluded that both endoscopic therapies appear equally effective in an emergency. One study that specifically addressed the issue of endoscopic therapy in the control of acute variceal hemorrhage showed in fact that EVL was associated with greater efficacy and fewer complications than sclerotherapy.(48)
Combination of pharmacological therapy and endoscopic therapy appears to be the most promising approach in the treatment of acute variceal hemorrhage. The use of pharmacological agents with few side effects allows prolonging therapy to 5 days, the period during which the risk of rebleeding is the highest. In this way, rather than controlling the acute episode (which is achieved by endoscopic therapy), the goal of pharmacological therapy is the prevention of early rebleeding. A recent meta-analysis of eight trials involving 939 patients showed that combined treatment (vasoactive drugs plus sclerotherapy or EVL) improved the initial control of bleeding and 5-day hemostasis (RR, 1.28; 95 percent CI, 1.18-1.39) without differences in mortality or severe adverse events.(49) |
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Side effects
Vasopressin is a potent vasoconstrictor with significant side effects related to its vasoconstrictive effect. These include cardiac and peripheral ischemia, arrhythmias, hypertension, and bowel ischemia. As mentioned above, the addition of nitrates reduces the rate of adverse events; however, the combination can only be used continuously for a maximum of 24 to 48 hours to minimize the development of side effects. Octreotide and other somatostatin analogues are safe and can be used continuously for many days (5 days in most trials). |
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Other therapies
Despite urgent sclerotherapy and/or pharmacological therapy, bleeding cannot be controlled or has an early recurrence in about 10 to 20 percent of patients. Shunt therapy, either shunt surgery (in Child A patients) or TIPS, has proven clinical efficacy as salvage therapy for patients that fail to respond to endoscopic or pharmacological therapy.(50; 51) Although it had been suggested that bleeding from gastric varices was more difficult to control with TIPS than bleeding from esophageal varices, a recent study showed equal effectiveness of TIPS in both situations.(52)
Sclerotherapy is not optimal for patients bleeding from gastric fundal varices. A recent randomized study compared EVL to obliteration with butyl cyanoacrylate in patients actively bleeding from gastric varices.(53) Initial control of hemorrhage, rebleeding rate, treatment-induced ulcers, and survival were all significantly better in patients treated with cyanoacrylate obliteration. Unfortunately, cyanoacrylate is not licensed for use in the United States.
Balloon tamponade is very effective in controlling bleeding temporarily. However, its use is associated with potentially lethal complications and should be limited to patients with uncontrollable bleeding for whom a more definitive therapy (e.g., TIPS) is planned. |
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Therapies under investigation
Results of ongoing large trials of another somatostatin analogue, lanreotide, should be helpful in establishing the value of somatostatin analogues as adjuncts to endoscopic therapy in the management of acute variceal hemorrhage. Therapies aimed at improving hemostasis (e.g., activated factor VII, antifibrinolytic agents) are ongoing, and results of a recent pilot randomized, placebo-controlled trial using activated recombinant factor VII (rFVIIa) showed a benefit in Child B and C cirrhotic patients.(54) |
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Recommendation: Short (7-day) antibiotic prophylaxis is recommended in all cirrhotic patients admitted with GI hemorrhage, particularly in those with ascites and a poor liver synthetic function. Although the antibiotic most commonly used in published reports is norfloxacin (not available on the VA National Formulary) administered by mouth (PO) at a dose of 400 mg BID, equal efficacy has been observed with ciprofloxacin at a dose of 500 mg PO BID. This efficacy can most likely be extended to other quinolones, such as levofloxacin.
For patients in whom antibiotics cannot be administered by mouth or by nasogastric tube, quinolones can be administered intravenously. In the United States, endoscopic therapy (either sclerotherapy or EVL) is the therapy of choice in the control of acute variceal hemorrhage. The association of pharmacological therapy, used as soon as the diagnosis is suspected (even prior to endoscopy) and continued for 5 days after the diagnosis is established, may represent the best approach to treatment. Octreotide, the only somatostatin analogue available in the United States, is a reasonable option; however, the efficacy of somatostatin analogues remains to be established definitively in ongoing trials.
The combination of vasopressin plus nitroglycerin is another pharmacological option in the United States, but it can only be used for a maximum of 24 hours. Shunt surgery or TIPS is indicated in patients in whom hemorrhage from esophageal varices cannot be controlled or in whom bleeding recurs in spite of two sessions of endoscopic therapy (associated or not with pharmacological therapy). In patients who bleed from gastric fundal varices, failure of one sclerotherapy session should be enough to recommend shunt therapy. Balloon tamponade should be limited to patients with uncontrollable bleeding for whom a more definitive therapy (e.g., TIPS) is planned.
| The following interventions are recommended based on randomized clinical trials, experimental studies, and meta-analyses |
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Administration of antibiotic prophylaxis such as norfloxacin (400 mg BID) or ciprofloxacin (500 mg BID) |
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Conservative blood replacement (goal: hematocrit of 25 to 30 percent) |
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Early endoscopic diagnosis and therapy (sclerotherapy or EVL) |
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Early initiation of pharmacological therapy
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Vasopressin plus nitroglycerin (for a maximum of 24 hours) |
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In case of failure to control bleeding or early rebleeding, a prompt decision for rescue therapy should be made (no more than two sessions of endoscopic therapy) |
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Recommended rescue therapies are TIPS or shunt surgery |
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| The following interventions are not recommended based on randomized clinical trials or uncontrolled studies demonstrating that other interventions are either more effective or safer: |
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Balloon tamponade should be used only as a bridge to rescue therapy |
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Emergency surgery or TIPS are not recommended as the first therapeutic option; they are recommended only as rescue therapies |
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| The following interventions are under evaluation and cannot be recommended until additional information is available: |
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Somatostatin analogues or other pharmacological therapy (use extended to 5 days |
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Agents to improve hemostasis |
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1.c. Prevention of recurrent variceal hemorrhage
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Patients who survive an episode of acute variceal hemorrhage have a very high risk of rebleeding and death. The median rebleeding rate in untreated individuals is around 60 percent within 1 to 2 years of the index hemorrhage, with a mortality of 33 percent.(8) It is therefore essential that patients who survive an episode of variceal hemorrhage be started on therapy to prevent recurrence prior to discharge from the hospital. Patients who required shunt surgery or TIPS to control the acute episode do not require further preventive measures. However, TIPS occlusion is quite frequent (see below) and reintervention may be necessary if bleeding recurs.
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Candidates
Candidates are patients who have recovered from an episode of acute variceal hemorrhage, have had no evidence of hemorrhage for at least 24 hours, and in whom pharmacological therapy for the control of acute variceal hemorrhage has been discontinued. |
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Accepted therapies
Nonselective beta-blockers and sclerotherapy have reduced variceal rebleeding and death in treated patients compared with untreated controls. In these studies, rebleeding rates of 57 to 63 percent are described in untreated controls compared with rates of 42 to 43 percent in treated patients.(8; 27; 47) A meta-analysis of 10 randomized trials comparing propranolol to sclerotherapy in the prevention of variceal rebleeding shows comparable rates of variceal rebleeding and survival for both therapies, with a significantly higher rate of side effects with sclerotherapy.(8)
Therefore, treatment with nonselective beta-blockers is preferable to sclerotherapy in the prevention of rebleeding. beta-blockers are used at the same doses recommended for prevention of first variceal hemorrhage (see above). As mentioned previously, the combination of a nonselective beta-blocker and ISMN has a synergistic portal pressure-reducing effect and could theoretically be more effective than beta-blockers alone. Only one study has performed a direct comparison between the combination of propranolol plus ISMN and propranolol alone.(55)
This study showed a benefit of combination therapy (33 percent versus 41 percent rebleeding rate), but it was not statistically significant. However, data collected from different randomized clinical trials show lower median rebleeding rates (~33 percent) in patients treated with combined pharmacological therapy compared with rebleeding rates in patients treated with nonselective beta-blockers alone (~50 percent).(8) Therefore, the pharmacological therapy of choice in the prevention of variceal rebleeding is probably the combination of a nonselective beta-blocker and a nitrate.
EVL, compared with sclerotherapy, reduces the rebleeding rate, side effects, and, importantly, mortality.(56) Therefore, EVL is considered the endoscopic treatment of choice in the prevention of variceal rebleeding. EVL sessions are repeated at 7- to 14-day intervals until variceal obliteration, which usually requires two to four sessions. Once eradicated, EGD to evaluate recurrence of varices is usually repeated at 6- to 12-month intervals.
Regarding EVL versus combination pharmacological therapy (beta-blockers plus nitrates), there are three studies showing different results. One study showed a benefit of combination pharmacological therapy,(57) another showed a benefit of EVL,(58) and a third showed no difference among treatment groups, despite a clear tendency in favor of pharmacological therapy.(59) These differences probably reflect the dosage of medications used, patient population, and, ultimately, center expertise.(60) Both therapies would appear to be equivalent. Therefore, the choice between pharmacological therapy and endoscopic therapy will depend on such factors as local expertise, compliance, tolerability, and patient preference. |
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Contraindications/side effects
The side effects of pharmacological therapy are reportedly more frequent with the combination therapy (beta-blockers plus nitrates) than with beta-blockers alone, mostly in terms of headache and weakness.(8) In fact, in the trial that compared both therapies head-to-head, drug discontinuation because of side effects was significantly greater in the combination therapy group (15 percent versus 2 percent).(55)
In patients that are intolerant to combination therapy, nitrates should be discontinued and beta-blockers alone should be continued. Complications of EVL occur in about 14 percent of cases but are usually minor. The most common complication is transient dysphagia and chest discomfort. Shallow ulcers at the site of each ligation are the rule, but they rarely bleed. |
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Alternative therapies
Shunt surgery is very effective in preventing rebleeding; however, it markedly increases the risk of hepatic encephalopathy, without an effect on survival.(27; 61) Not surprisingly, recent meta-analyses of 11 trials that compared TIPS to endoscopic therapy show similar results.(62; 63) That is, even though rebleeding is significantly less frequent with TIPS, post-treatment encephalopathy occurs significantly more often after TIPS, without differences in mortality. Additionally, shunt dysfunction occurs quite frequently, with 77 percent of patients requiring balloon angioplasty or re-stenting in the first year.(64) Unfortunately, Duplex sonography is not a sensitive test in predicting the presence of a hemodynamically significant TIPS stenosis. When occlusion is suspected, shunt status should be assessed by venography and direct portal pressure measurements.(65)
Furthermore, a recent trial showed that, even though pharmacological (propranolol plus nitrates) therapy was less effective than TIPS in preventing rebleeding, it caused less encephalopathy, identical survival, and more frequent improvement in Child-Pugh class with lower costs than TIPS.(66) Therefore, TIPS should not be used as a first-line treatment, but as a rescue therapy for patients who have failed pharmacologic plus endoscopic treatment. |
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Therapies under investigation
Combining endoscopic therapy with pharmacological therapy is rational because non-selective beta-blockers theoretically will protect against rebleeding prior to variceal obliteration and would prevent variceal recurrence. A recent randomized trial demonstrates that the combination of EVL plus nadolol plus sucralfate is more effective in preventing variceal rebleeding than EVL alone,(67) with rebleeding rates of 23 percent and 47 percent, respectively. Currently, it seems reasonable to combine non-selective beta-blockers with ECL in cases where pharmacological therapy or endoscopic therapy have failed. |
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Therapies that should no longer be used
As mentioned above, EVL has been shown to be superior to sclerotherapy, and has been associated with lower rebleeding rates, a lower frequency of esophageal strictures, and the need for fewer sessions to achieve variceal obliteration.(47; 56) Therefore, sclerotherapy should no longer be considered an adequate therapy to prevent variceal rebleeding. |
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Trials suggest that EVL is followed by a higher rate of variceal recurrence in comparison with sclerotherapy. Even though meta-analysis shows no significant difference in variceal recurrence between treatments,(47) the efficacy of combination EVL plus sclerotherapy compared with EVL alone in reducing variceal recurrence has been explored. A recent meta-analysis of seven such trials showed that the combination of EVL and sclerotherapy offers no advantage over EVL alone regarding the prevention of rebleeding or reduction of mortality and is associated with a higher complication rate.(68) Therefore, evidence accumulated so far should discourage the use of combination EVL plus sclerotherapy.
Recommendation: Pharmacological therapy with a combination of nonselective beta-blockers and nitrates or endoscopic therapy with EVL are accepted therapies in the prevention of variceal rebleeding. The choice will depend on factors such as expertise, compliance, tolerance, and patient preference. In patients that rebleed on pharmacological therapy or on EVL, the combination of EVL and pharmacological therapy should be considered. TIPS is only indicated in patients in whom rebleeding recurs and in patients treated with combined endoscopic and pharmacologic therapy. In patients who are surgical candidates, shunt surgery can be considered even prior to TIPS in centers where the expertise is available.
| The following interventions are recommended based on randomized clinical trials and meta-analyses: |
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Nonselective beta-blockers (propranolol, nadolol, timolol) plus nitrates |
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Endoscopic variceal ligation |
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In case of recurrent variceal bleeding despite the above therapies, pharmacological therapy plus EVL can be recommended |
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Recommended rescue (third-line) therapies are TIPS or shunt surgery |
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| The following interventions are not recommended based on clinical trials demonstrating that other interventions are either more effective or safer: |
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Sclerotherapy |
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EVL plus sclerotherapy |
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| The following intervention is under evaluation and cannot be recommended until additional information is available: |
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EVL plus pharmacological therapy |
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2. Treatment of spontaneous bacterial peritonitis (SBP)
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SBP is an infection of ascites that occurs in the absence of a contiguous source of infection (e.g., intestinal perforation, intra-abdominal abscess). SBP occurs in 10 to 20 percent of hospitalized cirrhotic patients. When first described, its mortality exceeded 90 percent; however, with early recognition of the disease and prompt and appropriate antibiotic therapy, in-hospital mortality from an episode of SBP has been reduced to around 30 percent. Early diagnosis is a key issue in the management of SBP.
As outlined recently,(31) a diagnostic paracentesis should be performed in any patient admitted to the hospital with cirrhosis and ascites, in any cirrhotic patient who develops compatible symptoms or signs, and in any cirrhotic patient with worsening renal or liver function. The diagnosis is established with an ascites polymorphonuclear count (PMN) of > 250/mm3. Ascites and blood samples for culture should also be obtained as soon as the diagnosis of SBP is suspected as this will aid in the patient's management. In patients with hepatic hydrothorax in whom an infection is suspected and in whom SBP has been ruled out, a diagnostic thoracentesis should be performed.
Spontaneous bacterial empyema, a condition akin to SBP that is defined as a pleural fluid with a PMN count >250/mm3 in a cirrhotic patient, may occur in the absence of ascites or SBP.(69) To increase the sensitivity of the bacteriological culture, ascites and/or pleural fluid should be inoculated at the patient's bedside into blood culture bottles.(31; 70) SBP and spontaneous bacterial empyema should be managed in an identical manner. The following management recommendations in these areas are based on evidence in the literature and are the results of a consensus conference on the diagnosis and management of SBP sponsored by the International Ascites Club.(31)
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2.a. Treatment of the acute infection
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Accepted therapy
Once an ascites PMN count of >250/mm3 is detected, and before obtaining the results of ascites or blood cultures, antibiotic therapy needs to be started. The antibiotic that has been most widely used in the treatment of SBP is intravenous cefotaxime with which SBP resolves in around 90 percent of treated patients.(71-73)
Other third-generation cephalosporins, such as ceftriaxone, have been shown to be as effective as cefotaxime in uncontrolled studies.(74; 75) In a controlled randomized trial, the combination of amoxicillin and clavulanic acid administered intravenously was shown to be as effective and safe as cefotaxime in the treatment of SBP.(76) Patients who develop SBP on prophylactic quinolones (see below) have responded as well to cefotaxime as patients not on prophylaxis.(77)
Cefotaxime is on the VA National Formulary but may be restricted at the facility or Veterans Integrated Service Network (VISN) level. However, other third-generation cephalosporins with a similar spectrum of activity, such as ceftriaxone, are available and should be equally effective. The intravenous preparation of amoxicillin and clavulanic acid is not available in the United States but another beta-blocam/beta-blocamase inhibitor combination, such as ampicillin/sulbactam, would have a similar spectrum of activity. The susceptibility patterns of individual practice settings should be taken into consideration when selecting the antibiotic for SBP. |
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Dose and duration
Doses of cefotaxime used in clinical trials have ranged between 2 grams i.v. every 4 hours and 2 grams i.v. every 12 hours. One randomized study compared two different dose schedules of cefotaxime (2 grams every 6 hours versus 2 grams every 12 hours) and showed similar rates of SBP resolution and patient survival with both schedules.(73) Ceftriaxone has been used at a dose of 1 to 2 grams i.v. every 24 hours and ceftazidime at a dose of 1 gram i.v. every 12 to 24 hours. The only study assessing the combination of amoxicillin and clavulanic acid used a dose of 1 gram/0.2 gram i.v. every 8 hours.(76)
Antibiotic treatment can be safely discontinued after the ascites PMN count decreases to below 250/mm3, which was shown to occur in a period of 5 days.(78) Another study shows that 5-day therapy with cefotaxime is as effective as 10-day therapy.(72) Therefore, duration of antibiotic therapy should be for a minimum of 5 days, but given that the median time to SBP resolution in controlled trials is 8 days, this latter duration is probably preferable. A study showed that i.v. ciprofloxacin could be safely switched to oral antibiotics after 2 days of therapy and once a response to therapy is demonstrated by a decrease in ascites PMN.(79) |
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