Acute Variceal Hemorrhage

Overview and Recommendations

Background

● Acute variceal hemorrhage usually arises from gastrointestinal varices which are collateral porto-
systemic vascular channels formed in response to portal hypertension, which is often caused by
cirrhosis of the liver.
⚬ Varices may bleed when the hepatic vein portal venous pressure gradient (HVPG) is greater than 12
mm Hg.
⚬ 10%-15% of patients with cirrhosis will have varices.

● Gastric varices can be secondary to splenic vein thrombosis.

● Common ndings in patients who present with acute variceal hemorrhage include:

⚬ hematemesis, melena, or hematochezia

⚬ lightheadedness, weakness, or cold hands/feet due to hypovolemia or anemia
⚬ signs of cirrhosis such as jaundice, ascites, encephalopathy, or spider angiomata due to liver
disease

● Variceal bleeding can be severe, di cult to control, and is associated with a mortality rate of 10%-20%
for each episode, with a high rate of recurrent bleeding.

Evaluation

● Esophagogastroduodenoscopy (EGD) is the gold standard for diagnosing gastrointestinal varices, and
should be performed once a patient with suspected variceal hemorrhage is hemodynamically stable.

● Diagnosis of variceal hemorrhage is con rmed if the EGD shows a varix or varices with any of the
following:
⚬ active bleeding from varix
⚬ "white nipple" overlying a varix
⚬ varices and no other potential source of bleeding when blood is present in stomach or endoscopy
is performed after 24 hours of hemorrhage

Management

● Admit to the intensive care unit and begin immediate volume resuscitation with crystalloids.

⚬ Provide red blood cell transfusions conservatively to maintain hemoglobin at about 8 g/dL (80 g/L)
(Strong recommendation).
⚬ Consider checking for and correcting clotting factor de ciencies and thrombocytopenia (Weak
recommendation).

● Start vasoactive medication as soon as a variceal hemorrhage is suspected (Strong recommendation)

and consider continuing vasoactive medication for 5 days. Options and usual doses include:
⚬ terlipressin - 2 mg IV every 4 hours initially, then decrease to 1 mg IV every 4 hours once bleeding is
controlled (terlipressin not available in United States and Canada)
⚬ somatostatin analogs (octreotide, vapreotide) - 50 mcg IV bolus, followed by a continuous infusion
of 50 mcg/hour IV
● In patients with cirrhosis and gastrointestinal bleeding, start antibiotic prophylaxis and continue for a
maximum of 7 days (Strong recommendation); options include:
⚬ nor oxacin 400 mg orally twice daily, or cipro oxacin IV if the oral route is not possible
⚬ ceftriaxone 1 g/day IV (may be preferred in patients with advanced cirrhosis)

● Perform esophagogastroduodenoscopy (EGD) within 12 hours to con rm the diagnosis and to treat
varices with endoscopic ligation or sclerotherapy (Strong recommendation); usual options include:
⚬ band ligation for esophageal varices (Strong recommendation)
⚬ variceal obturation using a tissue adhesive such as cyanoacrylate for gastric varices (Strong
recommendation)

● Perform transjugular intrahepatic porto-caval shunt (TIPS) procedure if variceal bleeding is refractory
to or recurs despite the combination of pharmacologic and endoscopic therapies (Strong
recommendation).

● Consider transcatheter sclerotherapy, such as balloon-occluded retrograde transvenous obliteration

(BRTO), as an alternative to TIPS for treating gastric varices (Weak recommendation).

● For uncontrollable bleeding, balloon tamponade can be used temporarily (≤ 24 hours) until more
de nitive treatment (an endoscopic or shunting procedure) is possible (Strong recommendation).

● Recurrence is common after acute variceal hemorrhage, so all patients should receive secondary
prophylaxis with a combination of nonselective beta blockers (such as nadolol or propranolol) plus
endoscopic variceal ligation (EVL) (Strong recommendation).

Related Summaries

● Acute Variceal Hemorrhage - Treatment

● Esophageal Variceal Hemorrhage - Prevention of Rebleeding

● Esophageal Varices

● Gastric Varices

● Portal Hypertension

● Transjugular Intrahepatic Portosystemic Shunts (TIPS)

General Information

Description

● gastrointestinal bleeding due to rupture of collateral porto-systemic vascular channels (varices,

especially gastrointestinal) usually formed in response to portal hypertension 1 , 2

● severe complication of cirrhosis or portal hypertension associated with high mortality 1 , 2

● rupture of gastrointestinal varices is the most common lethal complication of cirrhosis 1 , 2

Also called

● acute variceal bleed

● variceal rupture

Definitions

● Baveno VI international workshop consensus criteria for 5-day treatment failure (Baveno Level 1b,
Grade A)
⚬ follow criteria outlined in Baveno V (J Hepatol 2010 Oct;53(4):762 ) de ning failure as death or
need to change therapy by any 1 of following criteria
– fresh hematemesis (or aspiration of > 100 mL fresh blood in patient with nasogastric tube) ≥ 2
hours after start of speci c drug treatment or therapeutic endoscopy
– development of hypovolemic shock
– 3 gram drop in hemoglobin (about 9% drop in hematocrit) within any 24 hour period in patient
who has not received transfusion (time frame needs further validation)
⚬ use clear de nition of hypovolemic shock
⚬ does not include adjusted blood requirement index values
⚬ Reference - J Hepatol 2015 Sep;63(3):743 full-text , commentary can be found in J Hepatol
2015 Sep;63(3):543 , J Hepatol 2015 Oct;63(4):1048 , J Hepatol 2015 Oct;63(4):1049 , andAnn
Hepatol 2016 Mar-Apr;15(2):289

● Child-Pugh score for grading liver disease severity

⚬ Child-Pugh-Turcotte or Child-Pugh score assesses severity of liver disease using ascites,

encephalopathy, albumin, bilirubin, and prothrombin time as variables in formula
⚬ see DynaMed calculators for

– Child-Pugh-Turcotte Classi cation for Severity of Liver Disease

– Child-Pugh Classi cation for Severity of Liver Disease (SI units)

Types

● esophageal varices 1 , 2

● gastric varices classi ed based on relationship with esophageal varices and location in stomach 1 , 2

⚬ gastrointestinal varices (GOV)

– GOV type 1 - most common

● extend along lesser curvature of the stomach

● considered an extension of esophageal varices and managed similarly

– GOV type 2 - extend along fundus

⚬ isolated gastric varices (IGV) occur in absence of esophageal varices

– IGV type 1

● located in fundus
● may develop secondary to splenic vein thrombosis

– IGV type 2 - located in body, antrum or around pylorus

● ectopic varices (1%-5% of all variceal bleeding) - portosystemic shunts that occur at any site in

gastrointestinal tract or abdomen except esophageal region, including 2 , 5

 ⚬ duodenum
⚬ jejunum
⚬ ileum
⚬ colon
⚬ rectum
⚬ gall bladder
⚬ ostomy sites

Epidemiology

Who is most affected

● patients with cirrhosis 2 , 4

● patients with primary biliary cirrhosis (PBC) may develop varices and variceal hemorrhage early in
disease, even without established cirrhosis (Lancet 2015 Oct 17;386(10003):1565 )

● patients with non-cirrhotic portal hypertension (non-cirrhotic portal brosis, extrahepatic portal vein

obstruction, splenic vein thrombosis) also at risk of developing varices that may bleed 2

Incidence/Prevalence

● estimated annual incidence of acute massive gastrointestinal (GI) hemorrhage 4

⚬ upper GI bleed 40-150 episodes per 100,000 persons

⚬ lower GI bleed 20-27 episodes per 100,000 persons

● prevalence of variceal hemorrhage in patients with acute GI bleeding 4

⚬ up to 30% in patients with acute upper GI hemorrhage

⚬ up to 90% in patients with cirrhosis

● 10%-15% annual rate of variceal hemorrhage in patients with cirrhosis 1

● gastric varices

⚬ 20% prevalence in patients with variceal bleeding 2

⚬ higher bleeding incidence for fundal varices 1

Risk factors

● risk factors for variceal hemorrhage include 1 , 2

⚬ hepatic vein pressure gradient (HVPG) > 12 mm Hg (measurement requires catheterization)

⚬ varix size and location

– large esophageal varices (highest risk for rst hemorrhage)

– small varices in patients with advanced liver failure
– isolated cluster of varices in fundus of stomach

⚬ red wale marks in variceal appearance on endoscopy (indicating areas of thinning of variceal walls)
⚬ tense ascites
⚬ degree of liver failure - Child-Pugh class C cirrhosis
⚬ bacterial infection
 ⚬ coagulopathy

● bacterial infection associated with failure to control bleeding in patients with cirrhosis and variceal
hemorrhage, especially
⚬ bacterial peritonitis
⚬ urinary tract infection
⚬ pneumonia
⚬ Reference - Dig Dis 2016;34(4):382 full-text

STUDY
● SUMMARY
nonsteroidal anti-inflammatory drugs (NSAIDs) may increase risk of bleeding in patients with
esophageal varices

CASE-CONTROL STUDY: Gut 1999 Feb;44(2):270 | PDF

Details
⚬ based on case-control study
⚬ 125 cirrhotic patients admitted for bleeding related to portal hypertension compared to 75 cirrhotic
controls with esophageal varices that never bled
⚬ comparing cases vs. controls

– 25% vs. 11% used NSAIDs during prior week (odds ratio 2.8, p = 0.016)
– 17% vs. 4% used aspirin (odds ratio 4.9, p = 0.007)

⚬ Reference - Gut 1999 Feb;44(2):270 PDF

Associated conditions

● patients with primary biliary cirrhosis (PBC) may develop varices and variceal hemorrhage early in
disease before cirrhosis established(Lancet 2015 Oct 17;386(10003):1565 )

● patients with non-cirrhotic portal hypertension (such as non-cirrhotic portal brosis, extrahepatic

portal vein thrombosis, splenic vein thrombosis) also at risk of developing varices that may bleed 2

● esophageal varices reported in patients with hepatitis C with advanced brosis (Gastrointest Endosc
2006 Dec;64(6):855 )

Etiology and Pathogenesis

Causes

● gastrointestinal varices caused by 1 , 2

⚬ portal hypertension, for example due to

– cirrhosis, including alcoholic cirrhosis, cirrhosis secondary to viral hepatitis (B and C), and
primary biliary cholangitis (PBC)
– schistosomiasis
– sarcoidosis
– Budd-Chiari syndrome (BCS)
– hemochromatosis

⚬ splenic vein thrombosis - varices may occur with or without portal hypertension
Pathogenesis

● variceal wall tension is important determinant of rupture 2

● factors a ecting variceal wall tension 1 , 2

⚬ hepatic vein pressure gradient (HVPG) > 12 mm Hg

⚬ diameter of varix - a large diameter vessel will rupture at lower pressure than a small diameter
vessel
⚬ location of varix - greater risk of rupture if large varix with limited soft tissue support, such as
gastrointestinal junction

● varices bleed only if HVPG > 12 mm Hg, but not all patients with HVPG > 12 mm Hg will bleed 2

● rupture of varices occurs due to following sequence 2

⚬ variceal wall thins

⚬ varix has increased pressure and increases in diameter
⚬ tolerated wall tension is exceeded

History and Physical

History

Chief concern (CC)

● presentation of acute gastrointestinal (GI) bleeding varies depending on rate of blood loss and

includes 4
⚬ hematemesis - vomiting of fresh blood
⚬ co ee ground emesis - vomiting of altered black blood
⚬ melena - black tarry stools
⚬ hematochezia - red blood via rectum (usually from lower GI tract but sometimes from brisk
bleeding in upper GI tract)

● anemia - lethargy, fatigue, syncope, angina 4

Medication history

● ask about history of nonsteroidal anti-in ammatory drug (NSAID) use 4

Past medical history (PMH)

● ask about history of portal hypertension, cirrhosis or schistosomiasis 1 , 2

● ask about history of obesity that may predispose to nonalcoholic fatty liver disease 3

Social history (SH)

● ask about alcohol use 1 , 2

● ask about residence in schistosomiasis endemic areas (Dig Dis Sci 2000 May;45(5):1013 )

● ask about residence in hepatitis B endemic areas 2

● ask about injection drug use as risk factor for hepatitis C cirrhosis

Physical

General physical

● evaluate volume status (blood pressure, pulse, orthostatics)

● physical ndings of cirrhosis or portal hypertension may be evident

STUDY
● SUMMARY
some physical findings are specific for cirrhosis but no physical finding is sensitive for cirrhosis
in patients with liver disease

SYSTEMATIC REVIEW: JAMA 2012 Feb 22;307(8):832

Details
⚬ based on systematic review
⚬ systematic review of 86 diagnostic studies evaluating clinical indicators for detecting cirrhosis in
19,533 adult patients with liver disease
⚬ diagnostic accuracy of physical ndings for cirrhosis in patients with liver disease

Table 1. Results in Order of Decreasing Positive Likelihood Ratio

Finding Sensitivit Speci cit Positive Negative Number

y y Likelihoo Likelihoo of
d Ratio d Ratio Studies

Leukonyc 43%-44% 97%-98% 16-22 0.57-0.58 2

hia (white
discolorat
ion on
nails)

Gynecom 18%-58% 97%-98% 5.8-35 0.43-0.84 2

astia

Distende 31% 98% 11 0.72 4

d
abdomin
al veins
(caput
medusae)
 Finding Sensitivit Speci cit Positive Negative Number
y y Likelihoo Likelihoo of
d Ratio d Ratio Studies

Encephal 16% 98% 10 0.86 5

opathy

Decrease 36% 97% 9 0.65 3

d body
hair

Ascites 35% 95% 7.2 0.69 11

Facial 73%-82% 88%-92% 5.9-10 0.2-0.31 2

telangiect
asia

Testicular 18% 97% 5.8 0.84 1

atrophy

Palmar 46% 91% 5 0.59 7

erythema

Spider 46% 89% 4.3 0.61 13

nevi

Jaundice 28% 93% 3.8 0.82 5

Splenome 34% 90% 3.5 0.74 13

galy

Firm liver 73% 81% 3.3 0.37 4

Periphera 37% 90% 3 0.71 3

l edema

Hepatom 74% 69% 2.4 0.37 10

egaly

⚬ Reference - JAMA 2012 Feb 22;307(8):832

Skin
● jaundice may be present 1

● spider nevi may occur with portal hypertension 1

Abdomen

● signs of portal hypertension may include 1

⚬ ascites
⚬ visible abdominal portosystemic collaterals
⚬ splenomegaly

Extremities

● palmar erythema may occur with portal hypertension

Rectal

● rectal varices may occur with portal hypertension 2

Diagnosis

Making the diagnosis

● variceal hemorrhage diagnosed when esophagogastroduodenoscopy (EGD) shows any of 1

⚬ active bleeding from varix

⚬ "white nipple" overlying a varix
⚬ varices and no other potential source of bleeding when blood is present in stomach or endoscopy
is performed after 24 hours of hemorrhage

Differential diagnosis

● other causes of acute gastrointestinal bleeding 4

⚬ peptic ulcer disease

⚬ gastritis (duodenitis)
⚬ Mallory-Weiss tear
⚬ esophagitis
⚬ gastric carcinoma
⚬ Dieulafoy lesion - gastrointestinal submucosal artery that can rupture into lumen causing massive
hemorrhage (J Clin Gastroenterol 2015 Aug;49(7):541 )
⚬ angiodysplasia
⚬ portal hypertensive gastropathy or portal hypertensive enteropathy (see Portal Hypertension for
additional information)

Testing overview

● esophagogastroduodenoscopy (EGD) is gold standard for diagnosis of gastrointestinal varices;

recommended within 12 hours in hemodynamically stable patients to make diagnosis and treat
variceal hemorrhage

● consider capsule endoscopy for high-risk patients when EGD is contraindicated or negative, or patient
is unwilling to have EGD
● cross-sectional computed tomography is preferred imaging in patients with bleeding cardiofundal

varices (GOV2 and IGV1) to guide management 1 , 2 , 4

● colonoscopy or angiography may be useful to identify ectopic varices if endoscopy fails to reveal
source of upper gastrointestinal hemorrhage

● blood tests

⚬ blood type and cross-match for transfusion

⚬ complete blood count including platelets
⚬ coagulation studies (prothrombin time/INR, partial thromboplastin time [PTT]) in patients without
cirrhosis
⚬ electrolytes, glucose, blood urea nitrogen (BUN), creatinine
⚬ liver function tests

Blood tests

● blood tests include

⚬ blood type and cross-match for transfusion

⚬ complete blood count, including platelets, to con rm blood loss
⚬ coagulation studies (prothrombin time/INR, partial thromboplastin time [PTT]) in patients without
cirrhosis
⚬ electrolytes, glucose, blood urea nitrogen (BUN), creatinine
⚬ liver function tests
⚬ Reference - Curr Health Sci J 2017 Jul;43(3):191

● prothrombin time/INR not reliable measure of coagulation status in patients with cirrhosis (Baveno

Grade 1b, Level A) 3

Imaging studies

Endoscopy

● esophagogastroduodenoscopy (EGD)

⚬ gold standard for diagnosis of gastrointestinal varices 1 , 2

⚬ usually requires sedation 2

⚬ American Association for the Study of Liver Diseases (AASLD) recommendations

– performing EGD within 12 hours in hemodynamically stable patients to make diagnosis of

variceal hemorrhage, and to treat it with endoscopic variceal ligation or sclerotherapy 1

– diagnosis of variceal hemorrhage based on presence of 1

● active bleeding from varix

● "white nipple" overlying a varix
● varices and no other potential source of bleeding when blood is present in stomach or
endoscopy is performed after 24 hours of hemorrhage
– grading gastrointestinal varices at time of EGD

● ≤ 5 mm - small
● > 5 mm - large (includes medium grade in practice settings using 3-grade morphologic
assessment)
● Reference - Hepatology 2007 Sep;46(3):922
 ⚬ Baveno VI workshop on portal hypertension recommendations on endoscopy include 3

– if not contraindicated (QT prolongation) consider infusion of erythromycin (250 mg IV) 30-120
minutes before endoscopy (Baveno Grade A, Level 1b)
– protection of the airway should be used for endoscopy of patients with altered consciousness
(Baveno Grade D, Level 5)
⚬ bene t of elective endotracheal intubation prior to EGD in acute variceal bleeding remains unclear
(Therap Adv Gastroenterol 2014 Sep;7(5):206 )
⚬ picture of bleeding esophageal varix can be found in Lancet 2001 Jul 28;358(9278):293

● esophageal capsule endoscopy 2

⚬ minimally invasive alternative to EGD for detecting and grading esophageal varices
⚬ consider for high-risk patients when EGD is contraindicated or negative, or patient unwilling to
have EGD

● see Esophageal Varices and Gastric Varices for additional information

Cross-sectional computed tomography

● cross-sectional computed tomography is preferred imaging in patients with bleeding cardiofundal

varices (GOV2 and IGV1) to guide management 1

● may reveal anatomic derivation of collaterals as well as presence of thrombosis

⚬ multidetector triphasic contrast computed tomography parameters

– consider using iomeprol (iodinated IV contrast medium) via antecubital vein

– acquiring unenhanced, and, following contrast injection, arterial, portal venous, and equilibrium
phases obtained at 40, 70, and 150 seconds
– z-axis from diaphragm to cover below left renal vein for unenhanced, arterial, and equilibrium
images
– z-axis from apex of lung to ischial tuberosities (include rectum) for portal phase images

⚬ Reference - Radiographics 2013 Jan-Feb;33(1):87

Other imaging

● colonoscopy or angiography may be useful to identify ectopic varices if endoscopy fails to reveal
source of upper gastrointestinal hemorrhage (Med Clin North Am 2008 May;92(3):551 )

IMAGE 1 OF 1

Acute variceal hemorrhage

Angiographic study in patient presenting with third variceal

bleed following transjugular intrahepatic portosystemic
shunting. Large varices remain despite placement of
multiple coils (open arrow). Laminated thrombus is visible
within lumen of stent. Distal splenorenal shunting was
performed subsequently (solid arrow).

Management
Management overview

● acute variceal hemorrhage usually arises from varices located in the esophagus or cardiofundal
region of the stomach formed in response to portal hypertension, which is often caused by cirrhosis
of the liver

● admit to intensive care

⚬ assess for cirrhosis and need for airway protection

⚬ provide prompt intravascular volume support and conservative blood transfusions as needed,
starting transfusion when hemoglobin reaches about 7 g/dL (70 g/L) and maintaining hemoglobin
between 7 g/dL (70 g/L) and 9 g/dL (90 g/L)
⚬ blood volume restitution should be conservative (Baveno Level 1b, Grade A)

● start pharmacologic therapy (using terlipressin, somatostatin or somatostatin analogs [octreotide,

vapreotide]) as soon as variceal hemorrhage suspected and continue for up to 5 days after
con rmation of diagnosis
⚬ vasopressin (Pitressin)

– not FDA approved for use in acute gastrointestinal hemorrhage and not recommended by
professional organizations
– associated with high risk of adverse e ects, which may be reduced by addition of nitroglycerin
to vasopressin treatment
⚬ terlipressin (not currently available in United States) - initial dose 2 mg IV every 4 hours, may be
decreased to 1 mg IV every 4 hours once bleeding controlled
⚬ somatostatin or somatostatin analogs (octreotide, vapreotide) (only octreotide available in United
States)
– usual doses

● octreotide/vapreotide - 50 mcg IV bolus, then continuous infusion 50 mcg/hour

● somatostatin - 250 mcg IV bolus, then continuous infusion 250 mcg/hour

● start short-term antibiotic prophylaxis (maximum 7 days) in any patient with cirrhosis and
gastrointestinal hemorrhage (Baveno Level 1a, Grade A)
⚬ ceftriaxone 1 g/day IV is preferred, especially for patients with advanced cirrhosis, patients on
quinolone prophylaxis, and in hospitals with high prevalence of quinolone-resistant organisms
⚬ consider individual patient risks and local antimicrobial susceptibility patterns to determine
appropriate rst line antibiotic for prophylaxis at each treatment center (Baveno Level 5, Grade D)

● perform esophagogastroduodenoscopy (EGD) within 12 hours of admission (in hemodynamically

stable patients) to diagnose and treat variceal hemorrhages with endoscopic variceal ligation or
sclerotherapy

● balloon-occluded retrograde transvenous obliteration (BRTO) may be used to treat gastric varices

● bridge therapies may help control bleeding in unstable patients

⚬ balloon tamponade be used temporarily (≤ 24 hours) for uncontrollable bleeding until more
de nitive therapy (such as transjugular intrahepatic portosystemic shunt [TIPS] or endoscopic
therapy) can be performed
⚬ self-expanding covered esophageal metal stents may be as e ective as and safer than balloon
tamponade for refractory esophageal variceal bleeding (Baveno Level 4, Grade C)
● shunting procedures

⚬ TIPS may be used as salvage therapy in patients with

– esophageal or gastric variceal bleeding not adequately controlled by medical or endoscopic

therapy
– recurrent esophageal variceal bleeding after 2 endoscopic treatment
– recurrent gastric variceal bleeding after 1 endoscopic treatment

⚬ portal-systemic shunts have been used infrequently to control variceal bleeding or prevent
rebleeding due to concerns of increased risk of portal-systemic encephalopathy and liver failure
with their use, but evidence may not support these concerns
– portacaval shunts for emergency treatment of bleeding esophageal varices associated with
prompt control of bleeding and increased survival compared to transjugular intrahepatic
portosystemic shunt (TIPS) or endoscopic therapy, and not associated with increased
encephalopathy
– portacaval shunts also associated high rates of lifelong shunt patency

Follow-up

● preventive therapy for variceal rebleed critically important

⚬ high risk of rebleeding in patients who survive episode of acute variceal hemorrhage
⚬ start secondary prophylaxis as soon as possible from day 6 of index variceal bleeding episode
(Baveno Grade D, Level 5)

● combination of nonselective beta blockers (NSBBs) plus endoscopic variceal ligation (EVL) considered
best option for secondary prophylaxis of variceal hemorrhage in multiple guidelines (AASLD/ACG
Class I, Level A; Baveno Grade A, Level 1a)
⚬ combination of EVL plus medical therapy may reduce risk for rebleeding from esophageal varices
compared to either monotherapy but not associated with e ect on overall mortality
DynaMed Level 2

⚬ repeat EVL every 1-2 weeks until obliteration (AASLD/ACG Class I, Level C)
⚬ NSBBs may reduce rebleeding rate and mortality in patients who survive rst episode of variceal
bleeding DynaMed Level 2

– adjust NSBB to maximum tolerated dose (AASLD/ACG Class I, Level C)

– contraindications for NSBB usage may be absent at therapy initiation but should be monitored
during disease evolution (Baveno Grade D, Level 5)
– in patients with refractory ascites, close monitoring indicated and consideration of
discontinuation or reduction of dose in patients that develop (Baveno Grade C, Level 4)
● low blood pressure
● impairment of renal function

– addition of isosorbide-5-mononitrate to beta blockers has been suggested to improve e ciency

of treatment in hemodynamic nonresponders (Baveno Grade D, Level 5) but isosorbide
mononitrate (alone or in addition to beta blockers or endoscopic therapy) does not appear to
reduce bleeding or mortality in patients with esophageal varices DynaMed Level 2
– carvedilol may be as e ective as nadolol plus isosorbide mononitrate for prevention of
gastrointestinal variceal rebleeding with fewer adverse events DynaMed Level 2

● endoscopic sclerotherapy not recommended - nadolol plus isosorbide mononitrate is safer and more
e ective than sclerotherapy for prevention of variceal rebleeding DynaMed Level 1
● for gastric varices endoscopic cyanoacrylate injection is recommended (Baveno Grade A, Level 1b) and
associated with decreased rebleeding and mortality compared to beta blocker DynaMed Level 2 and
compared to endoscopic band ligation DynaMed Level 2

● shunt procedures used for recurrent variceal bleeding despite combination pharmacologic and
endoscopic therapy (AASLD/ACG Class I, Level A; Baveno Grade B, Level 2b)
⚬ transjugular intrahepatic portosystemic shunt (TIPS) reduces rebleeding rates but increases risk for
hepatic encephalopathy compared to
– drug therapy for secondary prophylaxis of variceal bleeding DynaMed Level 1

– tissue adhesive (cyanoacrylate) injection in patients with bleeding of gastric varices

DynaMed Level 2

⚬ portosystemic shunting associated with less rebleeding but more encephalopathy than endoscopic
therapy following variceal hemorrhage DynaMed Level 2

⚬ distal splenorenal shunt may be as e ective as TIPS for prevention of recurrence in patients with
refractory variceal bleeding DynaMed Level 2

⚬ small-diameter prosthetic H-graft portacaval shunt associated with longer time to shunt failure
than TIPS in patients with portal hypertension due to cirrhosis and longer survival in patients with
Child-Pugh class A or B cirrhosis DynaMed Level 2

Prognosis

Treatment failure

● esophageal variceal bleeding stops spontaneously in ≤ 40% patients 1

● variceal bleeding cannot be controlled, or recurs early, in about 10%-20% patients, even with urgent

endoscopic and/or pharmacologic therapy 3

● patients with Child-Turcotte-Pugh Class C or Class B with active bleeding have high risk of treatment

failure and rebleeding 1 , 2 )

● factors associated with 5-day failure based on retrospective cohort of 117 patients with cirrhosis and
acute variceal bleeding with hepatic venous pressure (HPVG) measurement
⚬ 15% had 5-day failure de ned as uncontrolled bleeding, re-bleeding or death
⚬ factors associated with 5-day failure include

– HVPG > 20 mmHg

– systolic blood pressure at admission < 100 mmHg
– non-alcoholic cause of cirrhosis

⚬ Reference - J Hepatol 2008 Feb;48(2):229

Mortality

● overall mortality from variceal bleeding about 15%-20% 3

⚬ mortality has greatly decreased since 1980s

⚬ any death occurring within 6 weeks from hospital admission usually considered a bleeding-related
death (vs. other related causes such as liver failure)
⚬ immediate mortality from uncontrolled bleeding about 4%-8%
⚬ pre-hospital mortality about 3%
 ⚬ risk for mortality

– peaks in rst days after bleeding, then slowly decreases

– after 6 weeks equalizes to risk before bleeding

● variable mortality in patients with cirrhosis and acute variceal hemorrhage 1

⚬ 20% 5-year mortality when acute variceal hemorrhage is sole complication

⚬ > 80% 5-year mortality when presenting with other complications

● mortality associated with gastric variceal hemorrhage about 30%-53%, with 30% rebleed rate 2

● early rebleeding a strong predictor of death from variceal bleeding 3

⚬ incidence of early rebleeding about 30%-40% in rst 6 weeks

⚬ about 40% of all rebleeding episodes occur in rst 5 days

● factors associated with 6-week mortality

⚬ Child-Pugh Class C
⚬ MELD score ≥ 18
⚬ failure to control bleeding or early rebleeding
⚬ Reference - Baveno VI international workshop consensus on assessing prognosis (J Hepatol 2015
Sep;63(3):743 full-text ), commentary can be found in J Hepatol 2015 Sep;63(3):543 ,J
Hepatol 2015 Oct;63(4):1048 , J Hepatol 2015 Oct;63(4):1049 , andAnn Hepatol 2016 Mar-
Apr;15(2):289

● risk of death indicators 3

⚬ Child-Pugh classi cation or its components

⚬ blood urea nitrogen or creatinine
⚬ active bleeding on endoscopy
⚬ hepatocellular carcinoma

STUDY
● SUMMARY
Child-Pugh score appears better able to predict 6-week mortality than model for end-stage
liver disease (MELD) score in patients with acute variceal hemorrhage treated with vapreotide
and endoscopic band ligation

COHORT STUDY: J Clin Gastroenterol 2017 May/Jun;51(5):446

Details
⚬ based on prospective cohort study derived from subgroup of vapreotide trial (DEBV-VAP/EVP-301)
⚬ 70 patients with acute variceal hemorrhage treated with vapreotide (50 mcg IV bolus and 50
mcg/hour continuous infusion for 5 days) and endoscopic variceal band ligation (EVL) or
scleropathy if EVL unfeasible were followed for 6 weeks
⚬ 5-day treatment failure de ned as composite endpoint comprising hemostasis failure, rebleeding,
or death that occur within 5 days of patient admission
⚬ 5-day mortality 10% and 6-week mortality 26%
⚬ both CTP and MELD scores were signi cant independent predictors of 5-day treatment failure (p <
0.05) and 6-week mortality (p < 0.02)
⚬ calibration plot analysis of mortality risk predicted by CTP and MELD scores with observed risk
rates may indicate
 – signi cant disagreement between MELD and modi ed MELD predicted mortality risk and
observed risk (p < 0.05)
– no signi cant disagreement between CTP predicted mortality risk and observed risk

⚬ mortality predicted by CTP score

Table 2. 6-week Mortality Predicted by Child-Pugh Score

Child-Pugh Score Predicted Mortality Child-Pugh Class

5 4.4% A

6 7%

7 10.8% B

8 16.5%

9 24.3%

10 34.4% C

11 46%

12 58.1%

13 69.3%

⚬ Reference - J Clin Gastroenterol 2017 May/Jun;51(5):446

⚬
DynaMed Commentary

Results of this study suggest that while the MELD and CTP scores have similar general ability
to discriminate between patients with greater risk of mortality (represented by the area under
curve), the lack of disagreement between observed and expected mortality risk reported for
the CTP score may indicate it has greater utility in practice for predicting mortality risk for
individual patients.

STUDY
● SUMMARY
patients with gastrointestinal varices derived from chronic portal vein thrombosis and
noncirrhotic portal hypertension may be associated with better prognosis than patients with
gastrointestinal varices derived from cirrhotic portal hypertension

COHORT STUDY: Hepatology 2016 May;63(5):1640

 Details
⚬ based on prospective cohort study
⚬ 178 patients (mean age 41 years) with chronic portal vein thrombosis and noncirrhotic portal
hypertension, treated by condition indication as for cirrhotic portal hypertension, evaluated for
outcome over median follow-up of 49 months (range 1-598 months)
⚬ baseline evaluation of varices

– variceal bleeding, seen in 15% (esophageal in 26 patients, gastric in 1 patient)

– nonhemorrhagic varices included 55.6% (99 patients)

● large esophageal varices (LEV) in 33.7% (60 patients [19 patients also had gastric varices])
● small esophageal varices (SEV, without red signs) in 15.7% (28 patients)

⚬ 24 had median of 2 (range 1-19) surveillance endoscopies

⚬ SEV grew to LEV in 42% (10 patients), with additional development of GOV2 in 2 patients,
GOV in 1 patient, and IGV1 in 1 patient
● large gastric varices (GV) in 6.2% (11 patients [4 patients also had esophageal varices])
● factors associated with presence of nonhemorrhagic varices at presentation

⚬ ascites (adjusted odds ratio 4.05, 95% CI 1.26-13.03)

⚬ splenomegaly (adjusted odds ratio 3.91, 95% CI)

– no varices in 29.2% (52 patients)

● 40 patients with no initial varices had median of 2 (range 1-9) surveillance endoscopies over
follow-up
● 10 patients developed varices as SEV (5 patients), LEV (4 patients) or isolated GV (IGV1, 1
patient) over median 37.5 months (range 7-166 months)
⚬ primary prophylaxis treatment outcomes

– in 67 patients with LEV, comparing bleeding rates by treatment

● hemorrhage in 32% of 55 patients treated with nonselective beta blockers (NSBB)

● hemorrhage in 25% of 8 patients treated with endoscopic band ligation (EBL [EBL alone in 3
patients, with NSBB in 5 patients])
– in 9 patients with gastric varices treated with NSBB, none had variceal hemorrhage over median
followup of 46 months (range 6-248 months)
– gastric variceal hemorrhage in 8.7% of 23 patients with gastric varices concurrent with LEV
treated with primary prophylaxis
⚬ outcomes for 57 patients with portal hypertensive bleeding (from LEV in 48 patients, gastric varices
in 4 patients, other causes in 5 patients)
– blood transfusion (mean 4 units packed red blood cells) required in 75%
– endoscopic therapy for hemostasis used in 51%, failure to control hemorrhage in 15.8% (9
patients)
● all 9 treated with emergency surgery, 6 achieved hemostasis
● 3 remaining patients treated with NSBB and achieved hemostasis

⚬ mortality reported in 5.1% (9 patients) over median 51-month (range 8-280 months) follow-up
⚬ Reference - Hepatology 2016 May;63(5):1640

● see Esophageal Varices and Gastric Varices for additional information

Prevention and Screening

Prevention
● preventive therapy for variceal rebleed critically important - high risk of rebleeding in patients who
survive episode of acute variceal hemorrhage

● primary prophylaxis of gastrointestinal variceal hemorrhage

⚬ identi cation of esophageal varices

– esophagogastroduodenoscopy (EGD) to diagnose esophageal and gastric varices recommended

at time of cirrhosis diagnosis (AASLD/ACG Class IIa, Level C; Baveno Grade A, Level 1b)
– transient elastography may be used to identify patients who may safely avoid endoscopy
screening
– recent American Association for the Study of Liver Diseases (AASLD) guidance suggests need for
EGD may be ruled out in patients with platelet count > 150,000/mm3 and liver sti ness
measurement < 20 kilopascals (kPa), due to very low risk (< 5%) of having high-risk varices (also
Baveno Grade A, Level 1b)(4)
– repeat EGD in patients with no varices

● in 3 years in patients with compensated cirrhosis (AASLD/ACG Class I, Level C)

● if hepatic decompensation occurs and then annually (AASLD/ACG Class I, Level C)

– platelet count to spleen diameter ratio < 909 may help diagnose (and ratio > 909 may rule out)
gastrointestinal varices in patients with cirrhosis
– in patients with cirrhosis, National Institute for Health and Care Excellence (NICE) recommends

● upper gastrointestinal endoscopy to detect gastrointestinal varices

● surveillance with upper gastrointestinal endoscopy every 3 years for patients in whom no
varices were detected
● Reference - Cirrhosis in over 16s: assessment and management. NICE 2016 Jul:NG50 PDF

⚬ non-selective beta blockers for primary prophylaxis of rst variceal bleed

– recommended for

● medium or large varices (> 5 mm) that have not bled (AASLD/ACG Class I, Level A; Baveno
Grade A, Level 1a)
● small varices (≤ 5 mm) that have not bled and if factors demonstrating increased risk of
hemorrhage present (AASLD/ACG Class IIa, Level C; Baveno Grade D, Level 5)
⚬ Child-Pugh class B or C (note: recent guidance from AASLD and Baveno VI workshop limits
this to class C)(6)
⚬ red wale marks on varices

● small varices without signs of increased risk (Baveno Grade A, Level 1b)
● patients with gastric varices, despite lack of evidence to support this treatment (Baveno
Grade D, Level 5)
– not recommended for patients with cirrhosis and no varices (AASLD/ACG Class III, Level B)
– usual starting doses propranolol 20 mg twice daily or nadolol 40 mg once daily then titrated for
hemodynamic response
– nonselective beta blockers (propranolol or nadolol) associated with reduced risk of rst bleed in
patients with esophageal varices DynaMed Level 2
– EGD follow-up not necessary in patients taking beta blockers
– hepatic venous pressure gradient (HVPG) measurement may be used as prognostic indicator in
centers with adequate expertise and equipment during treatment with beta blockers (Baveno
Grade D, Level 5)
 ● acute HVPG response to IV propranolol (10% decrease or to ≤ 12 mm Hg) may be used to
identify patients who will respond to beta blockers (Baveno Grade A, Level 1b)
● for primary prophylaxis with chronic nonselective beta blockers, a decrease in HVPG ≥ 20%
from baseline or to ≤ 12 mm Hg is clinically relevant (Baveno Grade A, Level 1a)
● HVPG ≥ 20 mm Hg, Child-Pugh class C, or active bleeding at endoscopy may predict 5-day
treatment failure (Baveno Grade B, Level 2b)
⚬ endoscopic variceal ligation (variceal band ligation)

– recommended as an option for prevention of rst variceal hemorrhage in patients with medium
or large varices (> 5 mm) that have not bled (AASLD/ACG Class I, Level A; Baveno Grade A, Level
1a)
– beta blockers preferred instead for patients with varices not at highest risk of hemorrhage
(Child-Pugh class A, no red signs)
– endoscopic variceal ligation for primary prevention of esophageal variceal bleeding may reduce
bleeding rate and mortality DynaMed Level 2

– placement of > 6 rubber bands per endoscopic treatment session for esophageal varices not
associated with better patient outcomes DynaMed Level 2

⚬ prophylactic sclerotherapy not recommended (AASLD/ACG Class III, Level A; Baveno Grade A, Level
1a) and does not appear to reduce incidence of rst variceal bleed or overall mortality in patients
with esophageal varices DynaMed Level 2

⚬ cyanoacrylate injection may reduce mortality and variceal bleeding in patients with cirrhosis and
large gastric varices with no prior bleeding DynaMed Level 2

⚬ limited evidence comparing variceal banding and beta blockers for primary prophylaxis in
esophageal varices
– endoscopic variceal ligation may be more e ective than nonselective beta blockers for primary
prevention of esophageal bleeding but not bleed-related mortality DynaMed Level 2

– carvedilol might be more e ective than variceal band ligation for preventing rst variceal bleed
DynaMed Level 2

⚬ combination of beta blocker plus endoscopic band ligation does not appear to improve e cacy of
primary prevention of variceal bleeding compared to either monotherapy DynaMed Level 2

⚬ see Esophageal Variceal Hemorrhage - Primary Prophylaxis for details

Screening

● not applicable

Guidelines and Resources

Guidelines

International guidelines

● Baveno VI consensus workshop recommendations on stratifying risk and individualizing care for
portal hypertension can be found in J Hepatol 2015 Sep;63(3):743 full-text , editorial can be found
in J Hepatol 2015 Sep;63(3):543

● World Gastroenterology Organization (WGO) practice guideline on esophageal varices can be found at
WGO 2014 Jan PDF

United States guidelines

● American Association for the Study of Liver Diseases (AASLD) practice guidance on portal hypertensive
bleeding in cirrhosis can be found in Hepatology 2017 Jan;65(1):310 , correction can be found in
Hepatology 2017 Jul;66(1):304, commentary can be found in Hepatology 2017 Jul;66(1):301

● American Society for Gastrointestinal Endoscopy (ASGE) guideline on modi cations in endoscopic
practice for elderly can be found in Gastrointest Endosc 2013 Jul;78(1):1 , correction can be found in
Gastrointest Endosc 2013 Sep;78(3):559

● American Society for Gastrointestinal Endoscopy (ASGE) guideline on role of endoscopy in

management of variceal hemorrhage can be found in Gastrointest Endosc 2014 Aug;80(2):221 ,
commentary can be found in Gastrointest Endosc 2015 Mar;81(3):774

● American College of Radiology (ACR) Appropriateness Criteria for radiologic management of gastric
varices can be found at ACR 2019 PDF

United Kingdom guidelines

● British Society of Gastroenterology (BSG) guidelines on prevention and management of variceal

hemorrhage in patients with cirrhosis can be found in Gut 2015 Nov;64(11):1680 full-text

● National Institute for Health and Clinical Excellence (NICE)

⚬ NICE guidance on stent insertion for bleeding esophageal varices can be found at NICE 2011 Apr
27:IPG392 PDF
⚬ NICE guideline on management of acute upper gastrointestinal bleeding in patients aged > 16
years can be found at NICE 2016 Aug:CG141 PDF

European guidelines

● Czech expert quality improvement guideline on transjugular intrahepatic portosystemic shunt (TIPS)
can be found in Cardiovasc Intervent Radiol 2012 Dec;35(6):1295 full-text

Mexican guidelines

● Mexican consensus on portal hypertension can be found in Rev Gastroenterol Mex 2013 Apr-
Jun;78(2):92 full-text [Spanish]

Central and South American guidelines

● Brazilian Society of Hepatology (SBH) updated 2017 recommendations on variceal bleeding can be
found in Arq Gastroenterol 2017 Dec;54(4):349 full-text

● Peruvian Social Security (EsSalud) clinical practice guideline on evaluation and management of upper
gastrointestinal bleeding can be found in Rev Gastroenterol Peru 2018 Jan;38(1):89 [Spanish]

● Catalan Society of Gastroenterology and Hepatology expert position paper on evaluation and
treatment of critically ill cirrhotic patients can be found in Gastroenterol Hepatol 2016 Nov;39(9):607
[Spanish]

Review articles

● review can be found in Dis Mon 2018 Jul;64(7):312

● review can be found in Semin Respir Crit Care Med 2012 Feb;33(1):46
● reviews of management of acute variceal bleeding can be found in

⚬ F1000Res 2019;8. doi: 10.12688/f1000research.18807.1 full-text

⚬ Clin Liver Dis 2014 May;18(2):347
⚬ Clin Endosc 2014 Jul;47(4):308 full-text

● review of advances in management of acute variceal bleeding can be found in Gastroenterology 2018
May;154(7):1964

● review of management of gastrointestinal varices can be found in World J Gastrointest Pharmacol

Ther 2019 Jan 21;10(1):1 full-text

● review of prevention and treatment of variceal hemorrhage can be found in Liver Int 2017 Jan;37
Suppl 1:104

● review of risk strati cation and management of acute variceal bleeding can be found in Hepatol Int
2018 Feb;12(Suppl 1):81

● review of diagnosis and management of gastrointestinal bleeding can be found in Acta Biomed 2018
Dec 17;89(8-S):12 full-text

● review of etiologies and management of upper gastrointestinal bleeding can be found in Mayo Clin
Proc 2019 Apr;94(4):697

● review of radiological evaluation of gastrointestinal bleeding can be found in World J Gastrointest

Pharmacol Ther 2014 Nov 6;5(4):200 full-text

● review of portal hypertension and gastrointestinal bleeding can be found in World J Gastroenterol
2013 Aug 21;19(31):5035 full-text

● review of endoscopic management of esophageal varices can be found in World J Gastrointest Endosc
2012 Jul 16;4(7):312 full-text

● review of gastric and ectopic varices can be found in Clin Liver Dis 2014 May;18(2):371

● review of diagnosis and management of acute variceal bleeding and hepatorenal syndrome in
cirrhosis can be found in Dig Dis Sci 2019 Jun;64(6):1419

● review of management of varices and variceal hemorrhage in cirrhosis can be found in N Engl J Med
2010 Mar 4;362(9):823 , correction can be found in N Engl J Med 2011 Feb 3;364(5):490,
commentary can be found in N Engl J Med 2010 Jun 17;362(24):2331

● review of management of acute esophageal variceal bleeding in patients with cirrhosis can be found
in Curr Med Res Opin 2016;32(3):467

● review of endoscopic treatment of esophageal varices in patients with cirrhosis can be found in World
J Gastroenterol 2014 Sep 28;20(36):13015 full-text

● review of endoscopic treatment of gastric varices can be found in Clin Liver Dis 2014 Nov;18(4):809
MEDLINE search

● to search MEDLINE for (Acute variceal hemorrhage) with targeted search (Clinical Queries), click
therapy , diagnosis , or prognosis

Patient Information

● handout on gastrointestinal bleeding from EBSCO Health Library or in Spanish

● handout on management of variceal bleeding from Canadian Liver Foundation

● handout on portal hypertension from British Liver Trust

● information on managing the intensive care unit experience from American Thoracic Society PDF

ICD Codes

ICD-10 codes

● I85.0 oesophageal varices with bleeding

● I86.4 gastric varices

● I98.2 oesophageal varices in diseases classi ed elsewhere

⚬ K70.3 alcoholic cirrhosis of liver

⚬ K71.7 toxic liver disease with brosis and cirrhosis of liver

– use additional external cause code (Chapter XX ), if desired, to identify toxic agent
⚬ K74 brosis and cirrhosis of liver

– K74.3 primary biliary cirrhosis

– K74.4 secondary biliary cirrhosis
– K74.5 biliary cirrhosis, unspeci ed
– K74.6 other and unspeci ed cirrhosis of liver

⚬ B65 schistosomiasis [bilharziasis]

– B65.0 schistosomiasis due to Schistosoma haematobium [urinary schistosomiasis]

– B65.1 schistosomiasis due to Schistosoma mansoni [intestinal schistosomiasis]
– B65.2 schistosomiasis due to Schistosoma japonicum
– B65.3 cercarial dermatitis
– B65.8 other schistosomiasis
– B65.9 schistosomiasis, unspeci ed

References

General references used

1. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk
strati cation, diagnosis, and management: 2016 practice guidance by the American Association for
the study of liver diseases. Hepatology. 2017 Jan;65(1):310-35 , correction can be found in
Hepatology 2017 Jul;66(1):304 , commentary can be found in Hepatology 2017 Sep;66(3):1009
2. Boregowda U, Umapathy C, Halim N, et al. Update on the management of gastrointestinal varices.
World J Gastrointest Pharmacol Ther. 2019 Jan 21;10(1):1-21 full-text

3. de Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno
VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol.
2015 Sep;63(3):743-52 full-text , editorial can be found in J Hepatol 2015 Sep;63(3):543 ,
commentary can be found in J Hepatol 2015 Oct;63(4):1048

4. Kim BS, Li BT, Engel A, et al. Diagnosis of gastrointestinal bleeding: A practical guide for clinicians.
World J Gastrointest Pathophysiol. 2014 Nov 15;5(4):467-78 full-text

5. Henry Z, Uppal D, Saad W, Caldwell S. Gastric and ectopic varices. Clin Liver Dis. 2014 May;18(2):371-88

Recommendation grading systems used

● American Association for the Study of Liver Diseases/American College of Gastroenterology

(AASLD/ACG) grading system for recommendations
⚬ classi cations of recommendations

– Class I - evidence and/or general agreement that a given diagnostic evaluation, procedure, or
treatment is bene cial, useful, and e ective
– Class II - con icting evidence and/or divergence of opinion about usefulness/e cacy of
diagnostic evaluation, procedure, or treatment
● IIa - weight of evidence/opinion in favor of usefulness/e cacy
● IIb - usefulness/e cacy less well-established by evidence/opinion
– Class III - evidence and/or general agreement that diagnostic evaluation, procedure, or
treatment is not useful/e ective and in some cases may be harmful
⚬ levels of evidence

– Level A - data derived from multiple randomized clinical trials or meta-analyses

– Level B - data derived from single randomized trial or nonrandomized studies
– Level C - only consensus opinion of experts, case studies, or standard-of-care

⚬ Reference - AASLD/ACG practice guideline on prevention and management of gastroesophageal

varices and variceal hemorrhage in cirrhosis (Hepatology 2007 Sep;46(3):922 ), correction can be
found in Hepatology 2007 Dec;46(6):2052, commentary can be found in Hepatology 2008
Apr;47(4):1428

● Baveno VI consensus workshop uses Oxford Centre for Evidence Based Medicine (CEBM) 2009
grading system for evidence and recommendations
⚬ grades of recommendation

– Grade A - consistent level 1 studies

– Grade B - consistent level 2 or 3 studies or extrapolations from level 1 studies
– Grade C - level 4 studies or extrapolations from level 2 or 3 studies
– Grade D - level 5 evidence or troublingly inconsistent or inconclusive studies of any level

⚬ levels of evidence

– Level 1a - systematic review with homogeneity of randomized controlled trials (RCTs)

– Level 1b - individual RCT with narrow con dence interval
– Level 1c - all or none case series
 – Level 2a - systematic review with homogeneity of cohort studies
– Level 2b - individual cohort study or low-quality RCT
– Level 2c - "outcomes" research or ecological studies
– Level 3a - systematic review with homogeneity of case-control studies
– Level 3b - individual case-control study
– Level 4 - case series, poor-quality cohort or case-control studies
– Level 5 - expert opinion without explicit critical appraisal; or based on physiology, bench
research, or " rst principles"
⚬ Reference - Baveno VI consensus workshop recommendations on stratifying risk and
individualizing care for portal hypertension (J Hepatol 2015 Sep;63(3):743 full text ), editorial
can be found in J Hepatol 2015 Sep;63(3):543 , commentary can be found in Ann Hepatol 2016
Mar-Apr;15(2):289

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