Treatment of portal hypertension - World Journal of Gastroenterology

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World J Gastroenterol 2012 March 21; 18(11): 1166-1175
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
Online Submissions: http://www.wjgnet.com/1007-9327office
[email protected]
doi:10.3748/wjg.v18.i11.1166
© 2012 Baishideng. All rights reserved.
TOPIC HIGHLIGHT
Ahmed Mahmoud El-Tawil, MSc, MRCS, PhD, Series Editor
Treatment of portal hypertension
Khurram Bari, Guadalupe Garcia-Tsao
care for acute variceal hemorrhage consists of vasoactive drugs, endoscopic band ligation and antibiotics
prophylaxis. Transjugular intrahepatic portosystemic
shunt (TIPS) is reserved for those who fail standard of
care or for patients who are likely to fail (“early TIPS”).
Prevention of recurrent variceal hemorrhage consists
of the combination of b-blockers and endoscopic band
ligation.
Khurram Bari, Guadalupe Garcia-Tsao, Section of Digestive
Diseases, Yale University School of Medicine, New Haven, CT
and VA-Connecticut Healthcare System, West Haven, CT 06520,
United States
Author contributions: Bari K performed the literature review
and wrote the article; Garcia-Tsao G was responsible for reviewing and revising the article for important intellectual content;
Garcia-Tsao G was responsible for final approval for publication.
Correspondence to: Guadalupe
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Garcia-Tsao, MD,
���� Section of
Digestive Diseases, Yale University School of Medicine, New
Haven, CT and VA-Connecticut Healthcare System, West Haven, CT 06520, United States. [email protected]
Telephone: +1-203-7376063 Fax: +1-203-7857273
Received: July 2, 2011
Revised: November 15, 2011
Accepted: December 31, 2011
Published online: March 21, 2012
© 2012 Baishideng. All rights reserved.
Key words: Cirrhosis; Portal hypertension; Varices; Variceal
hemorrhage; Primary prophylaxis; Secondary prophylaxis
Peer reviewers: Marek Hartleb, Professor, Department of
Gastroenterology, Silesian Medical School, ul. Medyków 14,
Katowice 40-752, Poland; Philip Rosenthal, MD, Professor of
Pediatrics and Surgery, UCSF, 500 Parnassus Avenue, Box 0136,
MU 4-East, San Francisco, CA 94143-0136, United States
Abstract
Bari K, Garcia-Tsao G. Treatment of portal hypertension. World
J Gastroenterol 2012; 18(11): 1166-1175 Available from: URL:
http://www.wjgnet.com/1007-9327/full/v18/i11/1166.htm DOI:
http://dx.doi.org/10.3748/wjg.v18.i11.1166
Portal hypertension is the main complication of cirrhosis
and is defined as an hepatic venous pressure gradient
(HVPG) of more than 5 mmHg. Clinically significant
portal hypertension is defined as HVPG of 10 mmHg or
more. Development of gastroesophageal varices and
variceal hemorrhage are the most direct consequence
of portal hypertension. Over the last decades significant
advancements in the field have led to standard treatment options. These clinical recommendations have
evolved mostly as a result of randomized controlled trials and consensus conferences among experts where
existing evidence has been reviewed and future goals
for research and practice guidelines have been proposed. Management of varices/variceal hemorrhage is
based on the clinical stage of portal hypertension. No
specific treatment has shown to prevent the formation of varices. Prevention of first variceal hemorrhage
depends on the size/characteristics of varices. In patients with small varices and high risk of bleeding, nonselective b-blockers are recommended, while patients
with medium/large varices can be treated with either
b-blockers or esophageal band ligation. Standard of
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INTRODUCTION
Portal hypertension is the increase in porto-systemic pressure gradient in any portion of the portal venous system.
Although portal hypertension could result from pre-hepatic abnormalities (e.g., portal or splenic vein thrombosis),
post-hepatic abnormalities (e.g., Budd-Chiari syndrome)
or intrahepatic non-cirrhotic causes (e.g., schistosomiasis, sinusoidal obstruction syndrome), cirrhosis is by far
the most common cause of portal hypertension and, as
such, has been the most widely investigated. In cirrhosis,
the portosystemic gradient is assessed by measuring the
wedged hepatic venous pressure (a measure of sinusoidal
hepatic pressure) and subtracting the free hepatic venous
pressure (systemic pressure) thus obtaining the hepatic
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venous pressure gradient (HVPG). A normal HVPG is
3-5 mmHg. An HVPG above 5 mmHg defines portal
hypertension, however an HVPG of 10 mmHg or greater
defines clinically significant portal hypertension as this
pressure gradient predicts clinical course in patients with
cirrhosis including development of varices[1], clinical decompensation (i.e., development of ascites, variceal hemorrhage and encephalopathy)[2], decompensation or death
after liver resection[3], and hepatocellular carcinoma[4].
The complications that most directly result from
portal hypertension are the development of varices and
variceal hemorrhage. This review summarizes the current
standard management for varices and variceal hemorrhage in the context of cirrhotic portal hypertension.
Over the last decades, research on animal models and
clinical trials have evolved and have led to our current
management recommendations. The field has moved forward in large part through consensus conference among
experts where events and endpoints have been defined
and the existing evidence has been carefully reviewed
leading to practice recommendations. The first such con­
ference took place in 1986 in Groningen, the Netherlands and since then consensus conferences have been
alternating between Europe (Baveno conference) and the
United States [American association for the study of liver
diseases (AASLD) or AASLD single topic conference
(STC)], and are briefly summarized below (Table 1).
did not tolerate b-blockers. Endoscopic sclerotherapy was
not recommended in the prevention of first hemorrhage.
Treatment of acute hemorrhage was mainly based on endoscopic therapy, terlipressin was deemed the most effective of the vasoactive agents, with somatostatin showing
some efficacy. The transjugular intrahepatic portosystemic
shunt (TIPS) was recommended in case of treatment failure of endoscopic and pharmacologic therapy. The recommendations to prevent recurrent hemorrhage included
b-blockers or endoscopic variceal ligation (EVL) that had
been shown to be better than sclerotherapy[7]. TIPS and
surgical shunts were to be used only for patients with frequent repeated episodes of variceal hemorrhage.
In June 1996, the AASLD STC took place in Reston,
Virginia, United States, with the objective of identifying important areas in the treatment of variceal hemorrhage and future research[8]. Guidelines for initial variceal
screening and follow-up endoscopy were described in detail depending on severity of liver disease and the size of
varices on first endoscopy. Areas of further research were
identified as the role of sequential portal pressure measurements and their timing, and defining new predictors
of first hemorrhage. Primary prophylaxis recommendations were the same as in the Baveno Ⅱ conference, with
b-blockers as the mainstay of treatment and EVL requiring further studies. Vasoactive drugs in combination with
endoscopic treatment (sclerotherapy or EVL) became the
established treatment for acute hemorrhage, recognizing
the advantage of initiating vasoactive therapy prior to diagnostic endoscopy[9]. For secondary prophylaxis EVL or
b-blockers were recommended. TIPS or surgical shunts
were considered acceptable therapies for failure to control acute hemorrhage or recurrent hemorrhage despite
standard treatments.
The Baveno Ⅲ conference was held in April 2000[10],
and introduced the concept of clinically significant portal hypertension (CSPH) which was defined as HVPG
of 10 mmHg or more. The presence of varices, variceal
hemorrhage or ascites is indicative of the presence of
CSPH. Non-selective b-blockers remained the treatment
of choice to prevent first hemorrhage from large/medium varices, while EVL required further assessment.
The goals of therapy with b-blockers were defined (25%
reduction in baseline heart rate or a heart rate of 55 beats/
min). ISMN, previously recommended as an alternative
to b-blockers, was no longer recommended[11]. For treatment of acute hemorrhage, the early administration of
vasoactive drugs and continued use for up to 5 d along
with endoscopic therapy (EVL or sclerotherapy) were
considered standard. Additional measures included use of
antibiotics to prevent bacterial infection[12], and lactulose
to treat hepatic encephalopathy. With regard to prevention of rebleeding, b-blockers were considered first-line
therapy[13] as was EVL, with TIPS reserved for treatment
failures. The complications of treatment of portal hypertension were also defined for use in clinical settings and
in research trials.
The Baveno Ⅳ conference was held in April 2005[14],
and some of the key criteria (failure to control bleeding,
HISTORY OF CONSENSUS CONFERENCES
ON PORTAL HYPERTENSION
Baveno is a small town in Northern Italy located on the
west shore of Lake Maggiore. It has become the epicenter of the portal hypertension consensus workshops
aimed to reach a consensus on the definitions of key events
related to portal hypertension and variceal bleeding and
to provide guidelines for future research as well as reviewing the evidence, eventually leading to clinical practice guidelines. The first Baveno consensus workshop was
held in April 1990[5] in which significant advances in diagnosis and management of varices and variceal bleeding
including vasoactive drugs and endoscopic sclerotherapy
were reviewed. In addition to defining certain terms including size of varices, clinically significant bleeding and
rebleeding; this workshop also provided recommendations on diagnostic modalities, imaging and directions for
future clinical trials. The therapeutic recommendations
included b-blockers for primary prophylaxis of large
varices, sclerotherapy and vasoactive drugs for acute
hemorrhage and endoscopic sclerotherapy, b-blockers or
surgical shunt to prevent recurrent hemorrhage.
The Baveno Ⅱ workshop was held in April 1995[6].
Definitions of key clinical events were revised and new
definitions were proposed. Based on multiple randomized
controlled trials, non-selective b-blockers (NSBB) were
recommended to be the treatment of choice for primary
prophylaxis of variceal hemorrhage, while isosorbide-5
mononitrate (ISMN) was recommended in patients who
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Table 1 Portal hypertension consensus conferences in the last two decades
Title
Year
Venue
21st meeting of the European association for the study of liver
Definitions, methodology and therapeutic strategies in portal hypertension. A consensus development workshop
Developing consensus in portal hypertension
Portal hypertension and variceal bleeding. AASLD single topic symposium
Updating consensus in portal hypertension. Reports of the Baveno Ⅲ consensus workshop on definitions,
methodology and therapeutic strategies in portal hypertension
Evolving consensus in portal hypertension. Report of the Baveno Ⅳ consensus workshop on methodology of
diagnosis and therapy in portal hypertension
Portal hypertension and variceal bleeding-unresolved issues. Summary of an AASLD and European association
for the study of the liver single-topic conference
Revising consensus in portal hypertension: Report of the Baveno V consensus workshop on methodology of
diagnosis and therapy in portal hypertension
1986
1990
1995
1996
2000
Groningen, The Netherlands
Baveno, Italy
Baveno, Italy
Virginia, United States
Baveno, Italy
2005
Baveno, Italy
2007
Atlanta, United States
2010
Baveno, Italy
AASLD: American association for the study of liver diseases.
ure of secondary prophylaxis[26]. Primary prophylaxis for
small varices was the same as recommended in the 2007
AASLD STC. There was no significant change in the
recommendations for primary prophylaxis of medium
to large varices (b-blockers or EVL) with the choice of
therapy dictated by local resources, expertise and patient
preference[27]. The recommendations on the treatment
of acute variceal bleeding were unchanged except that
a stronger recommendation was made to consider early
TIPS (within 72 h) in patients with high risk of treatment
failure[28]. Recommendations for the prevention of recurrent hemorrhage, as in the AASLD STC, consisted of the
combination of b-blockers and EVL.
Evidence-based guidelines endorsed by the AASLD[29]
and the American College of Gastroenterology[30] as well
as a recent comprehensive review[31] on the treatment of
portal hypertension have been heavily based on these
consensus conferences. These guidelines and review form
the bases of the current recommendations that are described in the following section in which the advantages
(pros) and disadvantages (cons) of these therapies are
also discussed.
failure of secondary prophylaxis) were revised. For primary prophylaxis, b-blockers remained the treatment of
choice but endoscopic band ligation emerged as an excellent alternative for patients with medium or large varices,
and contraindications or intolerance to b-blockers[15,16].
Isosorbide mononitrate as a single agent therapy was not
recommended even in a combination of pharmacological
therapies[17]. Primary prophylaxis of small varices could
only be considered if they were high risk (red wale sign
or Child C)[18]. There was no significant change in the
recommendations of acute variceal hemorrhage from
Baveno Ⅲ. Small changes included the use of vasoactive
drugs for at least 5 d, and the use of balloon tamponade
only in massive bleeding as a temporary bridge until definitive treatment could be instituted. EVL was declared
superior to sclerotherapy and as the endoscopic procedure of choice in the control of acute hemorrhage[16,19].
Secondary prophylaxis should be initiated 6 d after the
index variceal bleed, and included the combination of
EVL and b-blockers[20,21]. TIPS or surgical shunts were reserved for patients with failure of secondary prophylaxis.
The second AASLD STC was held in 2007 in Atlanta,
Georgia[22]. The objective of this conference was to make
clinical recommendations in areas that did not require
further investigation and to identify research directions
for the remaining areas. Compensated and decompensated cirrhosis were identified as separate entities to be
studied separately both in clinical practice and in research[23]. The main differences compared with Baveno
Ⅳ included the emergence of capsule endoscopy as a
non-invasive alternative to esophagogastroduodenoscopy
(EGD) for assessment of varices, a firm recommendation
regarding use of b-blockers for primary prophylaxis of
small varices with high-risk features, and consideration of
[24]
b-blockers for small varices and no high-risk features .
EVL was considered as effective and safe as b-blockers
for primary prophylaxis of medium to large sized varices.
Early TIPS emerged as an option in patients at high risk
of rebleeding[25], but required further investigation.
The Baveno Ⅴ conference in May 2010 revised the
definitions of failure to control variceal bleeding, and fail-
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CURRENT STANDARD TREATMENT OF
PORTAL HYPERTENSION IN ADULTS
Therapy of varices and variceal hemorrhage in the adult
patient with cirrhosis needs to be stratified depending on
the different clinical stages in the natural history of portal hypertension: (1) the patient with cirrhosis and portal
hypertension who has not yet developed varices and in
whom the goal is to prevent the formation of varices
(pre-primary prophylaxis); (2) the patient with gastroesophageal varices who has never had bleeding from
them, and in whom the goal is to prevent their rupture
(primary prophylaxis); (3) the patient with acute variceal
hemorrhage in whom the goal is to stop the hemorrhage
and prevent its early recurrence; and (4) the patient who
has survived an episode of acute variceal hemorrhage, in
whom the goal of therapy is to prevent late recurrence
of hemorrhage (secondary prophylaxis).
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Prevention of formation of varices (pre-primary
prophylaxis)
Every patient with a new diagnosis of cirrhosis should
have an EGD to look for the presence and size of varices. In patients who do not have gastroesophageal varices,
a large multicenter, randomized, controlled trial showed
no differences between placebo and b-blockers in the
prevention of varices[1]. Therefore, no specific treatment
for portal hypertension is recommended in this setting.
The main focus at this stage is to treat the underlying
cause of cirrhosis which will reduce portal hypertension
and may therefore prevent the development of clinical
complications.
important effect and therefore it is essential that NSBB
(as opposed to selective b-blockers) be used. Advantages
of NSBB include low cost, ease of administration and no
requirement for specific expertise. As they act by decreasing portal pressure, NSBB may also reduce other complications of cirrhosis such as bleeding from portal gastropathy, ascites and spontaneous bacterial peritonitis[37,38].
In fact, a significant reduction in portal pressure has been
related to an improvement in survival[38,39]. Additionally,
once the patient is on NSBB there is no need for repeat
EGD.
EVL has the advantage that the procedure can be
done at the same time as screening endoscopy, although
in some centers a screening EGD time slot will not allow
for the performance of EVL, and a separate therapeutic
EGD time slot is required. Also, there are relatively few
contraindications to EVL and it has been associated with
a lower incidence of side-effects compared with NSBB[15].
Prevention of first variceal hemorrhage (primary
prophylaxis)
First variceal hemorrhage occurs at an annual rate of
about 15% and although current mortality from an episode of variceal hemorrhage is lower than in the past
two decades, it still carries a significant mortality of
7%-15%[32-34], and is still associated with significant morbidity and healthcare costs. Prevention of first hemorrhage, therefore, is an important part of treatment of
portal hypertension. The size of varices, red wale signs
on varices (visualized on EGD), and severity of liver disease (Child class C) identify the patients with highest risk
of variceal hemorrhage[18]. Therefore, within this stage,
patients need to be stratified by the risk of hemorrhage
into (1) high-risk patients, i.e. ,those with medium/large
varices or those with small varices that have red wale
signs, or a Child C patient; and (2) low risk patients, i.e.,
those with small varices without red wale signs or occurring in a Child A or B patient.
In patients with medium/large varices, quality trials
have shown that non-selective b-blockers (propranolol,
nadolol) are as effective as EVL in preventing first variceal hemorrhage[35,36], and the recommendation is to use
therapy based on local resources, expertise and patient
preference.
In patients with high-risk small varices the mainstay
of treatment is NSBB because technically performing
EVL in these varices may be challenging (although there
is no clear evidence for this).
In patients with low-risk small varices, there is limited
evidence that shows that their growth may be slowed by
the use of NSBB[24]. Therefore, the use of NSBB in this
setting is considered optional and should be discussed
with the patient.
The doses are shown in Table 2, with therapeutic
goals and follow-up procedures for each of the recommended therapies.
Cons
The main inconvenience of NSBB is that approximately
15% of patients may have absolute or relative contraindications to therapy, and that another 15% require dosereduction or discontinuation due to its common sideeffects (e.g., fatigue, weakness, shortness of breath) that
resolve upon discontinuation but discourage patients
from using these drugs[27].
EVL requires specific expertise. The risks include
that of the endoscopic procedure and conscious sedation
(bleeding, aspiration, perforation and reaction to medications), plus the risk of bleeding from ligation-induced
ulcers. In fact, although the quantity of side-effects is
greater with NSBB than with EVL[15], the severity of
side-effects is greater with EVL. While no lethal side-effects have been reported with the use of NSBB[16], three
deaths resulting from EVL-induced bleeding ulcers have
been reported[15,16].
Recommendation
The issue of which is the best treatment for primary pro­
phylaxis (NSBB or EVL) has not yet been settled, and
there are centers that perform predominantly EVL while
others prefer the more rational approach of starting with
NSBB and switching to EVL if there is intolerance to
NSBB. Carvedilol is a NSBB with an added vasodilatory
effect through anti-a-1 adrenergic activity that has recently been shown to be more effective than EVL in preventing first variceal hemorrhage[40]. Although considered a
promising alternative, further research is necessary before
it can be widely recommended.
MANAGEMENT OF ACUTE VARICEAL
HEMORRHAGE
Pros
NSBB decrease portal pressure through a reduction in
portal blood flow. Their mechanism of action involves
decreasing cardiac output via b-1 receptors and causing
splanchnic vasoconstriction by blocking b-2 receptors,
resulting in unopposed a-1 activity. The latter is the most
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Acute variceal hemorrhage is a medical emergency requiring intensive care. The basic medical principles of airway,
breathing and circulation are followed to achieve hemodynamic stability. Blood transfusion is done conservative­
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Table 2 Primary prophylaxis and secondary prophylaxis of variceal hemorrhage
Therapy
Starting dose
Therapy goals
Propranolol (1) 20 mg orally twice a day;
(2) Adjust every 2-3 d until treatment goal is achieved;
(3) Maximal daily dose should not exceed 320 mg
Nadolol
EVL
Maintenance/follow-up
(1) Maximum tolerated dose; (1) At every outpatient visit make sure
(2) Aim for resting heart rate that patientis appropriately b-blocked;
of 50-55 beats per minute
(2) Continue indefinitely;
(3) No need for follow-up EGD
As for propranolol
As for propranolol
(1) 40 mg orally once a day;
(2) Adjust every 2-3 d until treatment goal is achieved;
(3) Maximal daily dose should not exceed 160 mg
Every 2-4 wk until the obliteration of varices
Propranolol (1) 20 mg orally twice a day;
(2) Adjust every 2-3 d until treatment goal is achieved;
(3) Maximal daily dose should not exceed 320 mg
Nadolol
(1) 40 mg orally once a day;
(2) Adjust every 2-3 d until treatment goal is achieved;
(3) Maximal daily dose should not exceed 160 mg
ISMN
(1) Only to be used in conjunction with propranolol or nadolol;
(2) 10 mg orally at night every day;
(3) Adjust every 2-3 d by adding 10 mg in am and then pm;
(4) Maximal dose is 20 mg twice a day
EVL
Every 2-4 wk until the obliteration of varices
Obliteration of varices;
Eradication of new varices
following initial obliteration
(1) Maximum tolerated dose;
(2) Aim for resting heart rate
of 50-55 beats per minute
As for propranolol
First EGD performed 1-3 mo after obliteration and every 6-12 mo thereafter
(1) Maximal tolerated dose;
(2) Systolic blood pressure
remains over 95 mmHg
Continue indefinitely
Obliteration of varices;
Eradication of new varices
following initial obliteration
First EGD performed 1-3 mo after obliteration and every 6-12 mo thereafter
(1) At every outpatient visit make sure
that patient is appropriately b-blocked;
(2) Continue indefinitely
As for propranolol
Either one of the three therapies shown in the table are recommended. EGD: Esophagogastroduodenoscopy; EVL: Endoscopic variceal ligation; ISMN:
Isosorbide-5-mononitrate.
ly for a target hemoglobin level between 7-8 g/dL[41],
because excessive blood volume restitution can increase
portal pressure[42,43]. There are no definite recommendations on management of coagulopathy and thrombocytopenia, as randomized controlled trials of recombinant
factor Ⅶa have not shown any advantages[44,45]. Antibiotic
prophylaxis is provided by quinolones with consideration
of iv ceftriaxone in patients with advanced cirrhosis or
previous therapy with quinolones[12,46]. Safe vasoactive
drugs are started as soon as possible, prior to diagnostic endoscopy. Endoscopy is done as soon as possible
and not more than 12 h after presentation. If a variceal
source is confirmed, EVL is the procedure of choice, but
sclerotherapy is an option when EVL is technically difficult. TIPS is recommended in patients who fail standard
combination therapy with endoscopic and pharmacological therapy, however salvage TIPS is accompanied by a
very high mortality. Predictors of failure are Child class C,
HVPG > 20 mmHg and active bleeding at endoscopy[47].
The use of early (pre-emptive) TIPS (within about 48 h
of admission) in patients at high risk of failing standard
therapy has been shown to reduce mortality[28]. These
patients are specifically those who are Child C (score of
10-13 points) or are Child B with active hemorrhage (at
the time of diagnostic endoscopy), and constitute < 20%
of the patients admitted for variceal hemorrhage. In these
patients it is recommended to consider early preemptive TIPS. All others should continue standard therapy
with vasoactive drugs continued for 2-5 d depending on
control of bleeding and severity of liver disease. Vasoactive drugs can be discontinued once the patient has been
free of bleeding for at least 24 h. Balloon tamponade is
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only used as a temporary measure (inflated for 12 h or
less) to control bleeding while a definitive therapy (TIPS
or endoscopic therapy) is planned. A new self-expanding
esophageal stent is being tested that may replace balloon
tamponade[48].
Although there are pros and cons for each of these
first-line therapies (pharmacological and endoscopic),
the current recommendation is to use them jointly in the
control of acute hemorrhage.
Pros
Vasoactive agents improve the control of variceal hemorrhage when combined with endoscopic therapy and
when compared to endoscopic therapy alone[49]. However
there appears to be no significant difference among the
different vasoactive agents regarding control of hemorrhage and early rebleeding. Vasopressin, a powerful vasoconstrictor, is associated with more adverse events[50],
and should not be considered a first-line vasoactive drug.
Terlipressin is the only agent that, in small studies and
when compared to no treatment, improved survival[50]. In
practice, the choice of pharmacological agent is usually
based on availability and cost. Octreotide, a somatostatin analogue, is the only safe vasoactive drug available in
the United States. Doses and schedules for the different
vasoconstrictors are shown in Table 3. Except for vasopressin that must be administered with nitroglycerin,
the administration of these agents does not require any
special procedure or expertise and can be started in the
emergency room setting.
Endoscopic therapy in the acute setting is very effective in controlling variceal hemorrhage, particularly when
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Table 3 Vasoactive agents used in the management of acute hemorrhage
Drug
Standard dosing
Duration
Somatostatin
Initial iv bolus 250 μg (can be repeated in the first hour Up to 5 d
if ongoing bleeding); continuous iv infusion of 250 to
500 μg/h
Octreotide (somatostatin Initial iv bolus of 50 μg (can be repeated in first hour if Up to 5 d
analogue)
ongoing bleeding); continuous iv infusion of 50 μg/h
Vapreotide (somatostatin Bolus: 50 μg; continuous iv infusion of 50 μg/h
Up to 5 d
analogue)
Vasopressin +
0.2-0.4 units/min continuous iv infusion intravenously, Maximum of
nitroglycerine
may titrate to a maximum of 0.8 units/min; always use 24 h at lowest
in combination with nitroglycerine
effective dose
Terlipressin (vasopressin Initial 48 h: 2 mg iv every 4 h until control of bleeding; Up to 5 d
analogue)
maintenance: 1 mg iv every 4 h to prevent re-bleeding
a spurting varix is observed. However, in a meta-analysis
comparing sclerotherapy vs vasoactive drugs, no differences in efficacy were observed between treatments, with
more side-effects with sclerotherapy[51]. EVL has replaced
sclerotherapy as the endoscopic procedure of choice due
to more effective control of bleeding, obliteration of
varices in fewer treatment sessions, a lower rebleeding
rate, and lower mortality[19,33]. How EVL compares with
vasoactive drugs alone remains to be determined. There
is no added benefit of a combination of EVL and sclerotherapy over band ligation alone.
Inhibits vasodilator hormones like glucagon causing
splan­chnic vasoconstriction and reduced portal blood
flow
Same as somatostatin, longer duration of action
Similar to somatostatin with higher metabolic stability
Causes direct vasoconstriction on splanchnic
circulation resulting in decreased portal blood flow
Splanchnic vasoconstriction; the active metabolite
lysine-vasopressin is gradually released over several
hours thus decreasing typical vasopressin side effects
effects), however the choice is dependent on availability
and cost. Octreotide is the only vasoactive drug available
in the United States. The endoscopic therapy of choice is
EVL.
Recommendations may vary depending on the severity
of liver disease. In patients who are Child C (or Child B
with active hemorrhage), the risk of failing recommended
treatment (vasoactive drugs and EVL) is high and therefore proceeding to a “rescue” therapy (i.e., TIPS) before
failure occurs should be considered. In patients who are
Child A, mortality with the treatment of choice is essentially nil[32,34], and these patients may respond to vasoactive
therapy alone, although this requires further exploration.
Cons
Vasoactive drugs often require placement of central lines
and require close monitoring for ischemic complications.
Vasopressin is the most potent vasoconstrictor, but its
use is limited by multiple side-effects related to splanchnic vasoconstriction (e.g., bowel ischemia) and systemic
vasoconstriction (e.g., hypertension, myocardial ischemia).
Terlipressin is an analogue of vasopressin that, although
safer, is still accompanied by more side-effects than somatostatin[52]. The main side effects of the somatostatin
analogs octreotide and vapreotide are sinus bradycardia,
hypertension, arrhythmia, and abdominal pain.
Endoscopic therapy during acute hemorrhage carries
the usual risks of endoscopic procedures, with increased
risk of aspiration due to active bleeding and the emergency nature of the procedure. In the setting of active
hemorrhage, the band ligator limits the visibility, and it
becomes technically difficult to maneuver the endoscope
back into the stomach. Elastic bands can slip or can cause
ulcers that can result in rebleeding. As mentioned previously, EVL has less side-effects than sclerotherapy and is
the endoscopic therapy of choice.
PREVENTION OF RECURRENT VARICEAL
HEMORRHAGE (SECONDARY
PROPHYLAXIS)
The risk of rebleeding in patients who survive an episode of variceal hemorrhage is high (median rebleeding
rate 60%), with a mortality of up to 33%. Prevention of
rebleeding is therefore an essential part of the management of the patient with variceal hemorrhage. Patients
who had a TIPS performed during the acute episode do
not require specific therapy for portal hypertension or
for varices but should be referred for transplant evaluation. TIPS patency should be checked through Doppler
ultrasound every 6 mo. For the majority (patients who
do not have a TIPS performed during the acute episode),
secondary prophylaxis with NSBB should be started as
soon as the intravenous vasoactive drug is discontinued.
NSBB significantly reduce the risk of recurrent hemorrhage[13]. Although the addition of ISMN to NSBB has
a greater portal pressure-reducing effect[53], in clinical trials the combination of NSBB and ISMN is no different
from NSBB alone regarding the rate of overall rebleeding or mortality, but has a higher rate of side-effects[54].
Sclerotherapy decreases rebleeding rates and mortality, but
is associated with serious complications (e.g., esophageal
strictures, bleeding from ulcers). Sclerotherapy has been
replaced by EVL, since it has significantly better outcomes
Recommendation
The specific treatment of choice for acute variceal hemorrhage is the combination of vasoactive drugs (started
prior to EGD) and emergency endoscopic therapy (at the
time of initial diagnostic EGD). The pharmacological
therapy of choice is terlipressin (lower mortality in small
placebo-controlled studies) or somatostatin (fewer side-
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Mechanism of action
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Bari K et al . Treatment of portal hypertension
(rebleeding, mortality and side-effects) compared with
sclerotherapy. Studies comparing pharmacological therapy (NSBB plus ISMN) vs EVL show no differences in
recurrent hemorrhage, but there is a suggestion of a beneficial effect on survival with pharmacological therapy in
the long term[54,55]. The combination of pharmacological
(NSBB alone or NSBB + ISMN) plus EVL is associated
with lower rebleeding rates than either therapy alone[31,56],
and constitutes the treatment of choice.
In patients who experience recurrent variceal hemorrhage despite the combination of pharmacologic and endoscopic treatment, TIPS with polytetrafluoroethylenecovered stents[57] or, where expertise is available, surgical
shunts[58] should be provided.
Table 2 presents the doses, therapeutic goals and followup procedures for the recommended therapies. The pros
and cons of each of these first-line therapies (pharmacological and endoscopic) are the same as those described
for primary prophylaxis, with some additional considerations described below.
HVPG-guided therapy would appear rational, a small trial
showed that outcomes with HVPG-guided therapy are
no different from those in patients treated with combined
pharmacological and endoscopic therapy[62]. Until the best
treatment for non-responders is settled, larger clinical
trials are performed, and HVPG measurements are standardized across centers, HVPG-guided therapy cannot be
currently recommended[63].
As mentioned above, EVL is associated with bleeding
from EVL-induced ulcers. Treatment with proton pump
inhibitors post ligation reduces the size of these ulcers,
with a trend towards a lower risk of bleeding[64], and can
be considered in this setting.
Recommendation
The treatment of choice to prevent rebleeding is the combination of pharmacological therapy (NSBB ± ISMN)
and EVL. Contrary to other clinical stages, risk stratification has not been tested in this setting. The main predictor of recurrent bleeding and death is the Child classification. It is conceivable that patients who are Child A
would only require one or other therapy, while patients
who have more advanced disease require the combination
therapy. Patients who fail this therapy should be considered for TIPS placement and, in centers where expertise
is available, for a surgical shunt. Patients with recurrent
variceal hemorrhage are in a category of “further decompensation” of cirrhosis and, as such, should be evaluated
for liver transplantation.
Pros
Pharmacologic agents provide protection against rebleeding during the initial phase after index hemorrhage while
esophageal varices are being obliterated by EVL. NSBB
alone or in combination with ISMN should be used. The
choice will depend on patient tolerability. Patients who
are not candidates for EVL should receive combination
NSBB + ISMN.
The lowest rates of recurrent variceal hemorrhage (ap­
proximately 10%) are observed in individuals who have a
hemodynamic response to pharmacologic therapy, defined
as a decrease in HVPG to < 12 mmHg or a de­crease of >
20% from baseline levels[39,59]. The more rational approach
would thus be to guide therapy based on hemodynamic
response and, in those who achieve a hemodynamic response, endoscopic therapy would not be necessary. However there are cons (see below) to this approach.
Patients who are intolerant or have contraindications
to pharmacological therapy should receive EVL alone.
CURRENT STANDARD TREATMENT OF
PORTAL HYPERTENSION IN CHILDREN
The most common causes of portal hypertension in children are biliary atresia and portal vein thrombosis. Data
regarding the prevalence of esophageal varices in children with portal hypertension is very limited and to date
there have been no randomized controlled trials comparing different treatments for primary and secondary prophylaxis[65].
Regarding primary prophylaxis, there is currently no
recommended treatment[22,66]. In a recent gathering of experts at the AASLD annual meeting, it was concluded that,
before a randomized trial could be performed in children,
pediatric research should focus on addressing questions
of the natural history and diagnosis of varices, prediction
of variceal bleeding, optimal approaches to b-blocker and
ligation therapy, and alternative study designs to explore
therapeutic efficacy in children[65].
Regarding acute variceal hemorrhage, management
in children is based on limited data comparing EVL and
sclerotherapy[67], and expert pediatric opinion based on
adult Baveno Ⅳ guidelines[66]. These include vasoactive
agents, antibiotic prophylaxis and endoscopic variceal ligation.
EVL is also recommended for secondary prophylaxis
of variceal hemorrhage but it has not been compared
with b-blockers[22,66]. In children with portal vein throm-
Cons
A recent study suggests that NSBB are associated with
a poorer survival in patients with refractory ascites[60], a
condition that may be present in patients in this clinical
stage. However, the study is retrospective and the groups
were disparate at baseline, with patients on NSBB having
more advanced disease as shown by a higher prevalence
of varices and variceal hemorrhage, and there is evidence
that indicates the contrary, that is, that NSBB may be
beneficial for these patients[13,61]. Therefore, unless stronger evidence arises, the use of NSBB in patients with
refractory ascites should not be contraindicated.
The combination of NSBB + ISMN has a higher incidence of side effects because of the added ones associated
with ISMN, specifically headache and lightheadedness. As
mentioned above, the lowest rebleeding rates are in patients who experience a hemodynamic response. Although
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Bari K et al . Treatment of portal hypertension
bosis, meso-rex bypass appears to be the best option for
secondary prophylaxis[22,66].
11
CONCLUSION
In the last two decades significant advances in the field
of portal hypertension have improved the clinical care
and survival of patients with cirrhosis and portal hypertension. In addition to better treatment strategies and
improved therapeutic options, the issue of risk stratification has become more important so that, within each
clinical stage, different patient subpopulations have been
identified that require a different management. Clearly,
further research is necessary to explore new pharmacological options that would allow a majority of patients to be
hemodynamic responders, thereby foregoing the need for
HVPG measurements and even the need for endoscopic
therapy. The identification of different risk populations
within each stage also requires further definition. It is expected that future trials and Baveno and AASLD conferences will continue to advance the field.
12
13
14
15
16
17
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S- Editor Gou SX
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