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Portal Hypertensive Bleeding
Introduction
Portal hypertension is defined by a pathologic increase in portal pressure in which the pressure gradient between the portal vein and inferior vena cava (the portal pressure gradient, PPG) is increased above the upper normal limit of 5 mm Hg. Portal hypertension becomes clinically significant when the PPG increases above the threshold of 10 mm Hg (formation of varices) or 12 mm Hg (variceal bleeding, ascites).
Acute variceal bleeding (AVB) is the most dreaded complication of portal hypertension because, even though mortality rates have decreased due to improvement in general management, medical treatment, and endoscopic therapy, mortality is still approximately 15%. Moreover, variceal bleeding leads to deterioration in liver function and can trigger other complications of cirrhosis such as bacterial infections, hepatic encephalopathy (HE), or hepatorenal syndrome. Therapy to prevent rebleeding (secondary prophylaxis) is mandatory given that patients surviving a variceal bleeding episode have a very high risk of rebleeding, which is associated with mortality as high as that of the first bleed.
Natural History of Varices in Cirrhosis
The natural history of cirrhosis is considered to be a progression from compensated cirrhosis to decompensated cirrhosis. Compensated cirrhosis is defined as the absence of jaundice, variceal hemorrhage (VH), ascites, and HE. On the other hand, decompensated cirrhosis is defined as the presence of one of these features. The transition from compensated to decompensated cirrhosis occurs at a rate of 5% to 7% per year. The development of portal hypertension directly leads to the formation of portal-systemic collaterals such as esophageal and gastric varices and represents a key stage in this natural history of cirrhosis.
When cirrhosis is diagnosed, varices are present in approximately 30% to 40% of compensated patients and in 60% of those with decompensated cirrhosis. The annual incidence of new varices is approximately 5% to 10% ; these initially develop as small varices and gradually dilate at a rate of 5% per year. The factor that has been most consistently associated with variceal progression is baseline Child-Pugh or its worsening during follow-up. Variceal bleeding usually occurs late in the natural history of portal hypertension and in order for varices to bleed the hepatic venous pressure gradient (HVPG) must rise above 12 mm Hg. Certain characteristics, such as the severity of liver disease, the size of the varix, and the presence of red wale marks (specially on thin areas of the variceal wall), place the varices at higher risk of bleeding, which can occur with an incidence of 4% to 15% per year. The risk of bleeding is very low (between 1% and 2%) in patients without varices at the first examination, and increases to approximately 5% per year in those with small varices and to 15% per year if medium or large varices are present at diagnosis.
Prevention of First Bleeding From Esophageal Varices
Screening for Esophageal Varices
Until recently, the current consensus was that every cirrhotic patient should be endoscopically screened for varices at the time of diagnosis to detect those requiring prophylactic treatment. However, the introduction of transient elastography (Fibroscan) of the liver has changed this scenario in some patients. Fibroscan is used to estimate the degree of liver fibrosis but also to determine if patients are at risk of having varices and portal hypertension. This has been extensively studied and validated in patients with cirrhosis due to hepatitis C (HCV); current guidelines suggest that patients with HCV and elastography values of stiffness less than 20 kPa and a platelet count over 150,000 could avoid screening endoscopy because the risk of having varices is extremely low.
In patients without varices on initial endoscopy, follow-up evaluation should be performed after 2 to 3 years (2 if there is a deterioration in liver function). In patients with small varices, a follow-up endoscopy should be performed every 1 to 2 years to check for a possible increase in size, based on an expected 10% to 15% per year rate of progression of small to large varices. This time interval should be shortened in cases of clinical decompensation. Primary prophylaxis with nonselective β-blockers (NSBBs, propranolol, nadolol, carvedilol) or endoscopic band ligation (EBL) must be initiated when the patient develops medium to large varices or small varices with red wale signs in those with Child-Pugh class C cirrhosis. No follow-up endoscopy is needed once NSBBs are started, but once initiated, NSBBs should be maintained through the patient's life. Although still not discussed in guidelines, there is recent evidence (2016) suggesting that carvedilol might delay the progression of small to large esophageal varices (EVs).
Nonselective β-Blockers Versus Endoscopic Banding Ligation for Primary Prophylaxis
NSBBs are effective in the prevention of variceal bleeding. These drugs reduce portal pressure by decreasing portal venous inflow through vasoconstriction of the splanchnic circulation and by decreasing cardiac output. A reduction in HVPG to 12 mm Hg or less, or 20% or less from baseline, protects from VH and also decreases the incidence of clinical decompensation. NSBB side effects (hypotension, fatigue, weakness) can be managed by adjusting the dose. However, up to 20% of patients may have absolute or relative contraindications.
Propranolol is typically started at 20 mg twice daily and nadolol at 40 mg once a day. These drugs are given in a stepwise fashion, increasing the dose until it is maximally tolerated or the resting heart rate is between 50 and 60 beats/min. Carvedilol is more effective than propranolol in reducing HVPG through an anti α-adrenergic activity and a mildly vasodilating effect. Carvedilol is started with 6.25 mg once a day and afterwards the dose is increased to 6.5 mg twice a day (higher doses may not further decrease portal pressure, yet may increase the risk of arterial hypotension). Indirect data suggests that carvedilol is more effective than propranolol/nadolol in primary prophylaxis, although this has not been adequately studied in head-to-head clinical trials.
Variceal ligation is performed every 3 to 4 weeks until variceal eradication is achieved, which typically occurs after 2 to 4 sessions. Eradication is defined by either the disappearance of the varices or the impossibility of grasping and banding them with the ligator. Meta-analyses of randomized controlled trials (RCTs) of β-blockers versus band ligation indicate that ligation is associated with a lower incidence of first VH without differences in mortality. Nonetheless, endoscopic ligation requires several sessions and may be associated with important side effects, such as bleeding from postligation ulcers. Although the choice of β-blockers or endoscopic therapy should be made depending on the local resources, availability of experienced endoscopists, patient preference, side effects, and contraindications, a reasonable approach is to begin with β-blockers if there are no contraindications because they are inexpensive, easy to use, and relatively safe. Those patients who develop side effects or have contraindications to β-blockers should then be offered endoscopic variceal band ligation. If the patient tolerates NSBBs, no follow-up endoscopy is needed. In those that undergo EBL and for whom varices are eradicated, follow-up endoscopies approximately 3 months after the complete eradication should be performed and varices should be reeradicated upon recurrence.
All randomized studies and meta-analyses comparing the combination of NSBB plus EBL versus EBL alone in primary prophylaxis had failed to demonstrate a clear benefit from combination therapy, with a predicted higher number of adverse events in the combination therapy group not supporting the use of combination therapy for primary prophylaxis. However, a 2017 study has challenged this recommendation, suggesting that the combination therapy of NSBB and EBL may be more effective in primary prophylaxis than NSBB alone or EBL alone for the prevention of acute variceal bleeding, although with similar mortality rates at 2 years. Until more data is available, it is wise to follow the current guidelines of using either NSBB or EBL, but not in combination.
General Management of Acute Variceal Bleeding (AVB)
Ruptured EV cause 80% of all upper gastrointestinal bleeding episodes in patients with portal hypertension. Diagnosis is established at emergency endoscopy based on observing one of the following: (1) active bleeding from a varix (observation of blood spurting or oozing from the varix); (2) white nipple or clot adherent to a varix; or (3) presence of varices without other potential sources of bleeding ( Fig. 15.1 ). Endoscopy should be performed within the first 12 hours of admission, especially in patients with hematemesis or hemodynamic instability.
AVB should be managed in an intensive care setting. The initial ABCs (airway, breathing, circulation) of resuscitation should be applied with the aim of maintaining aerobic metabolism and restoring an appropriate oxygen transport to the tissues. At least two large bore venous accesses should be placed on admission, as they can be necessary for rapid administration of volume during initial resuscitation. An airway should be immediately secured, and endotracheal intubation is mandatory before endoscopy if there is any concern about the safety of the airway, especially in encephalopathic or actively bleeding patients, as they are at risk of bronchoaspiration of gastric content and blood; this risk is further exacerbated by endoscopic procedures.
Avoiding prolonged hypotension is particularly important to prevent further complications such as renal failure and ischemic hepatitis, which are associated with increased risk of rebleeding and death, and therefore blood volume replacement with plasma expanders must be used, aiming at maintaining a mean arterial pressure of at least 65 mm Hg. However, overexpansion must also be avoided as it may induce rebound increases in portal pressure and facilitate rebleeding. Therefore, a delicate fluid balance is needed. In fact, an RCT showed that a restrictive transfusion strategy in which patients were only transfused if hemoglobin levels dropped below 7 g/dL improved survival in Child-Pugh A and B patients, except in patients with shock, ongoing bleeding, or ischemic heart disease.
As mentioned earlier, the main associated complications of AVB are bacterial infections, HE, and impaired renal function. Infections may be both a consequence and a precipitating event leading to AVB. Antibiotic treatment significantly decreases the risk of rebleeding and improves survival. In most cases, either norfloxacin 400 mg by mouth twice daily for 7 days or IV ceftriaxone 1 to 2 g/day can be given, although intravenous antibiotics are preferred in those patients with hypovolemic shock and advanced cirrhosis, in hospital settings of high prevalence of quinolone-resistant bacterial infections, and in patients on previous quinolone prophylaxis. Variceal bleeding can trigger HE, mainly because of the intestinal absorption of toxic substances generated from blood proteins. Even though there is no strong data supporting the need of prophylactic treatment, both lactulose and rifaximin should be used to prevent HE.
The rapid implementation of vasoconstrictors and performance of endoscopy should be instituted within the first 12 hours of admission; however this interval can be shortened to 6 hours in those with hematemesis once they are stabilized in a monitored unit.
Finally, it is important to consider if the patient is at high risk for treatment failure, which is known to occur in approximately 15% of patients. Critically, this is the population where mortality-related bleeding concentrates. A multicenter European randomized clinical trial showed that high-risk patients (defined as Child-Pugh C up to 13 points, or Child B plus active bleeding at endoscopy) benefit from a preemptive transjugular intrahepatic portosystemic shunt (TIPS) within 72 hours of admission. This approach markedly decreased rebleeding and mortality without increasing the incidence of HE. Beneficial effects of the use of preemptive TIPS in high-risk patients were confirmed in an observational retrospective study.
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