Endoscopic Management of Variceal Haemorrhage

Endoscopic Management of Variceal Haemorrhage



ABSTRACT
One of the most important complications of portal hypertension, in the setting of liver cirrhosis or of non-cirrhotic portal hypertension, is upper gastrointestinal bleeding from ruptured gastroesophageal varices and portal hypertensive gastropathy. The management of the acute variceal bleeding is a multidisciplinary process that includes the initial assessment of the patient, effective resuscitation, timely diagnosis, control of bleeding and prevention of early rebleeding and complications such as infection, hepatorenal syndrome, or hepatic encephalopathy. Antibiotic prophylaxis, conservative targets for blood transfusions and combination therapy with vasoactive drugs and endoscopic treatments are the first-line measures in the management of acute variceal bleeding; transjugular intrahepatic portosystemic shunts should be proposed early to high-risk patients or as a rescue therapy for those who fail first-line treatment.



INTRODUCTION 
Portal hypertension, as a complication of liver cirrhosis or in the setting of non-cirrhotic portal hypertension, leads to different complications ranging from the development of varices to upper gastrointestinal bleeding from ruptured gastroesophageal varices and portal hypertensive gastropathy, to ascites, hepatorenal syndrome and hepatic encephalopathy[1]. Portal hypertension is defined as an increase in the portal venous pressure above the normal values of 1-5 mmHg. Nowadays we dont usually measure directly the portal pressure but estimate it using the hepatic venous pressure gradient (HVPG), measured as the difference between the wedged (portal vein) and the free hepatic venous pressures (inferior vena cava). The HVPG value of 10 mmHg is used to define clinically significant portal hypertension, the level of portal pressure above which complications can arise[2-5].
    The prevalence of varices in cirrhotic patients ranges from 30 to 60%, according to the presence of decompensation[6] and prospective studies have shown that more than 90% of patients will develop esophageal varices during their lifetime (Figure 1). The expected incidence of newly developed varices is about 5% per year[7,8]. Once varices develop their rate of progression in size is 5-30% per year according to the study population and follow-up endoscopic schedule[8-12]. The main prognostic factors associated to progression of small to large varices are decompensated cirrhosis (Child B/C), alcoholic etiology of cirrhosis, HVPG and the presence of red wale markings on the esophageal varices at the time of baseline endoscopy[9,11,13].


Acute variceal bleeding in patients with cirrhosis indicates decompensation and a high-risk of death[6]. The annual rate of bleeding, in absence of treatment, is 10%-15%[14,15]. The most important predictors are variceal size[8,10,16], presence of red signs on varices[17,18], and severity of liver dysfunction defined by the Child-Pugh classification[15]. These risk indicators have been combined in the North Italian Endoscopy Club (NIEC) index, which allows the classification of patients into different groups with a predicted 1-year bleeding risk ranging between 6 and 60%. The risk of bleeding is very low (1%-2%) in patients without varices at the first examination, and increases to 5% per year in those with small varices, and to 15% per year in those with medium or large varices at diagnosis. Another important determinant of variceal bleeding is the degree of portal pressure: variceal bleeding only occurs if the HVPG reaches a threshold value of 12 mmHg, if the HVPG is reduced below 12 mmHg or by more than 20% of the baseline levels the risk of bleeding is substantially reduced[19].
    In patients with cirrhosis, ruptured esophageal varices cause approximately 70% of all upper digestive bleeding[20] and are the second most common cause of mortality for cirrhotic patients[21]. Mortality from variceal bleeding has greatly decreased during the last decades to the current rates of 6-12%[6,10,22-24]. Causes of bleeding related death (i.e. any death occurring within 6 weeks from hospital admission for variceal bleeding)[25] are uncontrolled bleeding in 4-8% of cases[26-28], rebleeding and infection, renal failure, hepatic encephalopathy (these are also prognostic indicators of morbidity and mortality after the first bleeding)[29]. Other factors independently associated with a higher mortality are severe liver dysfunction,  HVPG >20 mmHg and active bleeding at endoscopy[30,31].

MANAGEMENT OF VARICEAL BLEEDING
The management of the acute variceal bleeding is a multidisciplinary process[25] that includes the initial assessment of the patient, effective resuscitation, timely diagnosis, control of bleeding, and prevention of early rebleeding and complications such as infection, hepatorenal syndrome, or hepatic encephalopathy. Blood volume restitution should be performed to maintain hemodynamic stability; packed red blood cells should be transfused conservatively aiming at hemoglobin levels between 7-8 g/dL[25,32] avoiding over transfusion which could be the cause of rebleeding[33,34]. Transfusion policy, however, should also consider the presence of co-morbidities, age, hemodynamic status and ongoing bleeding. Definitive recommendations regarding management of coagulopathy and thrombocytopenia cannot be made on the basis of currently available data[25]Antibiotic prophylaxis should be instituted from admission. It should consist of oral quinolones for most patients considering intravenous ceftriazone in patients with advanced cirrhosis, in hospital settings with high prevalence of quinolone-resistant bacterial infections and in patients on previous quinolone prophylaxis[25,35,36]. Vasoactive drugs (terlipressin, somatostatin, octreotide, vapreotide) should be started as soon as possible, even before endoscopy[37]. Vasoactive drugs used in combination with endoscopic therapy allow a better control of hemorrhage than drug therapy or endoscopy alone[38]. No significant differences have been found in several studies between different vasoactive drugs in the control of the index bleeding and in the prevention of recurrence. Terlipressin is the only vasoactive drug that has a positive effect on survival[14]. In clinical practice the choice of the vasoactive drug is based on its availability and on its cost. Vasoactive drugs therapy should be prolonged for 2-5 days according to control of bleeding and can be stopped after 24 hours free from bleeding. A post hoc analysis of a trial suggested that with higher dose of somatostatin (500 g/h) control of bleeding and better survival can be achieved in significantly higher proportion of patients[39], but this finding has never been confirmed in other trials.
    Endotracheal intubation may be needed in selected cases[37]Balloon tamponade can also be used as a bridge therapy to obtain temporary hemostasis (maximum 24 hours)[40]. Recently preliminary studies have shown that the placement of self-expanding metallic stents as an alternative to balloon tamponade for the control of refractory variceal hemorrhage may be beneficial[41,42] but these findings must be confirmed in other trials before their use can be introduced in clinical practice.
    Emergency EGD may be at the same time diagnostic and therapeutic. When it is performed early, 39-44% of patients present with active bleeding, 33-44% with signs of recent bleeding (clots or white nipple on varices)[43] and 12-28% have no sign of active or recent hemorrhage[28].

ESOPHAGEAL VARICEAL BLEEDING
Endoscopic treatment of EV may be performed by endoscopic sclerotherapy (ES) and endoscopic variceal ligation (EVL).

Endoscopic Sclerotherapy (ES)
ES, first described in 1939 by Crafford and Frenckner[44] is currently performed using flexible catheters with a short needle tip (23 or 25 gauge). Different sclerosant agents (e.g. sodium morrhuate, podidocanol, ethanolamine, alcohol, and sodium tetradecyl sulphate) have been used in controlled trials[45] and nowadays the most commonly used agents are ethanolamine oleate (5%) or polidocanol (1%-2%) in Europe, and sodium morrhuate (5%) in the United States[46,47]. The injection of the sclerosant agent may be performed into the variceal lumen (intravariceal) or adjacent to it (paravariceal) inducing thrombosis of the vessel and inflammation of the surrounding tissues[48,49] leading to fibrosis and resulting in variceal obliteration[50]. Paravariceal injection forms a fibrotic layer around varices while intravariceal injection, directly induces variceal thrombosis. Injection of sclerosant should be first made immediately below the bleeding point (1-3 mL) and then in the remaining varices near the bleeding one (2-3 mL injections). The total amount of sclerosant per session is usually 10-15 mL. Both intravariceal and paravariceal injections have been associated with good outcomes[51] and no differences have been found with different sclerosants[52], the volume injected, or frequency of sessions[53].
    Compared to EVL, ES is easier to use since it does not require to withdraw and reinsert the endoscope.
    Complications of ES are more frequent than those of EVL[47,54-60]. The complications can be classified as local: esophageal ulcers, ulcer bleeding, and esophageal stricture; cardiovascular and respiratory: pleural effusion, acute respiratory distress syndrome, and pericarditis; and systemic: fever, bacteremia, spontaneous bacterial peritonitis, distant embolism or abscess[61]. Frequent minor complications that do not require treatment occur within the first 24-48 hours: retrosternal chest pain, low grade fever, dysphagia, asymptomatic pleural effusions, nonspecific chest radiographic changes[48]. Esophageal ulcers occur in up to 90% of patients and may cause bleeding in 20% of patients[59,62]. They should be prevented and treated with proton pump inhibitors; the efficacy of sucralfate in treating these ulcers and preventing rebleeding is not clear[63]. Bacteremia may occur in up to 35% of patients and may be responsible for the development of abscesses and spontaneous bacterial peritonitis[64,65]. Less frequent complications are esophageal stenoses (2-10% of cases) and esophageal perforation[48]. Death for post-ES complications may occur in 2% of patients[66].
    In a Cochrane meta-analysis ES was not shown to be superior to the vasoactive drug therapy for the control of bleeding, rebleeding, and mortality[67].

Endoscopic Variceal Ligation (EVL).
Endoscopic Variceal Ligation (EVL). The first reports of EVL appeared in 1988 by Stiegmann et al[68]. While ES used chemical action to obliterate varices, EVL causes a mechanical strangulation with rubber bands that induces thrombosis with ischemic necrosis of the mucosa. EVL consists in placing rubber rings on esophageal varices after sucking them into a plastic cylinder attached to the tip of the endoscope[69,70](Figure 2). In the beginning single-shot ligators were used, requiring the use of an overtube with all the complications of its use; nowadays multiple-shot (4-10 bands) devices are commonly used and the procedure is simpler and faster[46]. During an emergency EGD the bleeding varix is identified; the endoscope is then removed from the patient and the banding device is loaded. The endoscope is then reinserted into the esophagus up to the gastroesophageal junction to identify the varices. Then the tip of the endoscope is oriented toward the varix and a continuous suction is applied until the varix fills the cap. At this moment the band can be fired[70]. The bands should be placed on the varix at the point of bleeding or starting from the gastroesophageal junction in a helical fashion[48] for 6-8 cm within the palisade and perforating zones[61]. The rubber bands on the ligated varix detach in 1-10 days leaving shallow esophageal ulcers and smaller esophageal varices. The ulcers generated by EVL are bigger and shallower than those of ES and heal more rapidly[61,71]. The scars that may be generated by EVL ulcers[72], make subsequent redevelopment of varices more difficult. After band ligation patients should start with liquids at room temperature for the first 12 h and then take soft foods gradually. A recent trial has shown that proton pump inhibitor therapy is associated with smaller ulcers but the total number and the symptoms were not different[73]. Varices are considered eradicated when they have either disappeared or cannot be sucked and banded by the ligator[46]. Variceal eradication is obtained in about 90% of patients with up to 4 banding sessions[46] but recurrence is not uncommon[74].


A meta-analysis of 7 randomized controlled trials (RCTs) showed that there is a tendency toward benefit of EVL compared to ES in terms of control of bleeding, recurrent bleeding, side effects, need for fewer endoscopic treatments, and survival[60]. Therefore, EVL has become the treatment of choice for variceal bleeding but ES can be used when EVL is technically difficult[25,37].
    Compared to ES, EVL has a higher frequency of recurrent varices[75-77] but they can be treated with repeated EVL[77].
    Minor complications of EVL, that respond well to oral analgesia and antacids, include chest pain and transient dysphagia. Serious, but rare, complications include massive bleeding from untimely sloughing of bands, esophageal perforation (mostly for the use of overtube), esophageal strictures[78] and bacteremia[79] even if with a lower frequency than with ES[80]. Finally, there are reports that EVL may cause worsening of and/or appearance of PHG[81].

COMBINATION THERAPY
Vasoactive drugs and endoscopic therapy
Vasoactive drugs and endoscopic therapy. Combination of vasoactive drugs plus EVL/ES is the standard of care for variceal bleeding[25,37]. In fact, a meta-analysis of 8 trials demonstrated that combined therapy (endoscopic plus vasoactive drugs) compared to endoscopic therapy alone (ES or EVL) improved control of bleeding and 5-day hemostasis without differences in severe side effects or mortality[38].

EVL plus ES
EVL plus ES. Some studies have been performed on the combination of EVL and ES in order to achieve variceal eradication more quickly and thus reduce the likelihood of rebleeding[39]and the incidence of recurrent varices[82]. A meta-analysis of 7 RCTs by Singh et al showed that combination therapy had no advantage over EVL alone in the control of bleeding varices, prevention of rebleeding or reducing mortality[83] with a significant increase in esophageal strictures.

FAILURES OF ENDOSCOPIC THERAPY
Current guidelines define treatment failure a failure to control acute variceal bleeding within 24 hours, or failure to prevent clinically significant rebleeding or death within 5 days of treatment[25]. Approximately 10-15% of patients have a risk of treatment failure[28,37]. Child-Pugh class, shock at admission, presence of portal vein thrombosis, active bleeding at endoscopy, and elevated HVPG >20mmHg have been shown to be predictive of treatment failure[28,31]. A second attempt at endoscopic therapy can be tried, possibly changing the endoscopic technique[25,84] but if this is unsuccessful a more aggressive approach by shunt therapy (TIPS or surgical) may be needed[25,37] (Figure 3). Indeed, a recent trial showed a significant reduction in treatment failures and in mortality by early use of TIPS (within 72 hours after admission) in patients with active variceal bleeding and in Child-Pugh class B cirrhosis or class C disease[85].


GASTRIC VARICEAL BLEEDING
Bleeding from gastric varices (GV) is less frequent but more severe than bleeding from EV[20]. The treatment of GV is more difficult than that of EV because of the torrential blood outflow and their treatment modality depends on their location in the stomach and relation with EV. The Sarin classification is most widely used[20,25]. Gastroesophageal varices type 1 (GOV1) are an extension of esophageal varices along the lesser curvature of the stomach and have the same behavior of EV as far as haemostasis and rebleeding is concerned and therefore should be treated as EV[86]. Gastroesophageal varices type 2 (GOV2) located in the fundus of the stomach have been treated with different endoscopic techniques including ES, EVL, obliteration with glue and thrombin injection.

ES
ES was shown to be ineffective and with a high rate of complications[87], possibly because the high volume of blood flowing through GV may wash away the sclerosant.

Gastric varices obliteration
Gastric varices obliteration consist in the injection of a tissue adhesive (polymers of cyanoacrylate) into a varix; the tissue adhesive upon contact with blood immediately polymerizes obliterating the varix. Complications of this procedure are rare but may be severe (with a mortality rate 0.5%): rebleeding due to extrusion of the glue cast (4.4%), sepsis (1.3%), pulmonary, cerebral, or splenic emboli (0.7%), gastric ulcer formation (0.1%) and mesenteric hematoma associated with hemoperitoneum and bacterial peritonitis (0.1%)[88]. Gastric varices obliteration is effective for acute fundal GV bleeding as it allows a better control of bleeding and reduces the rate of rebleeding [87,89-93] in comparison with alternative treatments. In the United States cyanoacrilate use is not approved by the Food and Drug Administration.

EVL
EVL was shown to be similar to cyanoacrylate in controlling active bleeding but with higher rebleeding rate[89]. Therefore, EVL is recommended as an alternative option, where tissue adhesives are not available[37].

Intravariceal thrombin injection
Intravariceal thrombin injection was useful in achieving initial hemostasis in GV bleeding without significant side effects in preliminary studies[87,94-96] but further evidence is needed before its use could be recommended in clinical practice.
    In case of treatment failure of pharmacological and endoscopic therapy TIPS should be considered, sometimes associated with coil embolization of GV[37].
    The actual recommendation for the treatment of GV is to use tissue adhesive (e.g. N-butyl-cyanoacrylate) for acute bleeding from isolated gastric varices (IGV) and gastroesophageal varices type 2 (GOV2) that extend beyond the cardia; in acute bleeding from gastroesophageal varices type 1 (GOV1) EVL or tissue adhesive can be used[25,37].

ECTOPIC VARICEAL BLEEDING
Portal hypertension may be responsible not only for the development and/or bleeding of esophageal and gastric varices but also of varices in other sites, e.g. in the duodenum, rectum and peristomal. Ectopic variceal bleeding is rare (less than 5% of portal-hypertensive related bleeding episodes) but mostly occurs from duodenal varices. No formal recommendation on their optimal treatment can be made because no clinical trials have been made. To date they are treated like EV or GV and the preferred treatment depends mainly on local expertise and location of the varices[97-99].

ES
ES was shown to be effective in controlling bleeding from duodenal[100,101], rectal[102,103], and stomal varices[104,105].

Ectopic varices obliteration
Ectopic varices obliteration. Cyanoacrylate glue injection has been successfully used to obliterate bleeding duodenal[106,107], jejunal[108], and rectal varices[109].

EVL
EVL for bleeding duodenal varices is challenging because of limited visibility from the banding hood. It may be useful for temporary hemostasis but rebleeding is a problem[110,111]. However, several cases of successful treatment of rectal varices using EVL have been reported[112,113].

RECOMMENDATIONS
Blood transfusion should be aimed at hemoglobin levels between 7-8 g/dL.
    Definitive recommendations regarding management of coagulopathy and thrombocytopenia cannot be made on the basis of currently available data.
    Antibiotic prophylaxis should be instituted from admission, oral quinolones for most patients considering intravenous ceftriaxone in patients with advanced cirrhosis, in hospital settings with high prevalence of quinolone-resistant bacterial infections and in patients on previous quinolone prophylaxis.
    Vasoactive drugs (terlipressin, somatostatin, octreotide, vapreotide) should be started as soon as possible, even before endoscopy, and should be maintained for 2-5 days according to control of bleeding and can be stopped after 24 hours free from bleeding.
    Vasoactive drugs should be used in combination with endoscopic therapy.
    Emergency EGD may be at the same time diagnostic and therapeutic.
    Esophageal variceal bleeding may be treated by endoscopic variceal ligation or endoscopic sclerotherapy.
    Gastric variceal bleeding: Gastroesophageal varices type 1 (GOV1) should be treated as esophageal varices; Gastroesophageal varices type 2 (GOV2) should be treated with different endoscopic techniques including ES, EVL, obliteration with glue and thrombin injection.
    Ectopic variceal bleeding: No formal recommendation on their optimal treatment can be made because no clinical trials have been made. To date they are treated like EV or GV and the preferred treatment depends mainly on local expertise and location of the varices.
    TIPS should be used as an early treatment for high-risk patients or as a rescue therapy for patients who do not respond to endoscopic and drug therapy.

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