Therapy of portal hypertension is primarily directed at the management of its most dramatic manifestation, variceal hemorrhage. Variceal bleeding is a life threatening medical emergency, and patients with chronic liver disease should be instructed to seek immediate medical attention for any signs or symptoms of bleeding. The management can be divided into preprimary prophylaxis, prophylaxis (primary) of the first episode of bleeding, emergency therapy, and prophylaxis (secondary) of subsequent bleeding episodes. As with many other aspects of portal hypertension, almost all the modes of therapy are based on adult trials (Figure ). Many of the trials are well-controlled randomized double-blinded studies, and comprehensive meta-analysis of these trials have been performed[27-30
]. The literature on the management of variceal hemorrhage in children is predominantly descriptive and anecdotal. There have been few randomized trials of therapy for portal hypertension in children[31,32
Portal hypertension. EST: Endoscopic sclerotherapy; EVL: Endoscopic variceal band ligation; TIPS: Transjugular intrahepatic portosystemic shunt.
The concept is that early treatment of portal hypertension has the potential to delay or prevent the development of esophageal varices or other manifestations of portal hypertension. In a S. mansoni
mouse model of portal hypertension, the administration of propranolol 5 wk into the infection resulted in a significant reduction in the development of portal hypertension, portosystemic shunting, and portal venous inflow[34
]. A randomized controlled trial of timolol, a non-selective beta blocker, on the development of varices in adults did not show a significant benefit[35
]. Currently, preprimary prophylaxis remains an interesting concept that is not applicable in clinical practice.
The issue of prophylaxis of the first episode of variceal bleeding in children is controversial and is predicated on experience with adults who primarily have alcoholic cirrhosis. Surveillance endoscopy in children with liver disease and stigmata of portal hypertension is justified if the clinician anticipates recommending a prophylactic regimen. Prophylaxis may also be valuable in patients who live in remote areas far from emergency medical care. Given the unpredictable timing of the first episode of variceal bleeding, primary prophylaxis regimens need to be associated with relatively low morbidity and mortality. As such, beta blockade has been more extensively used in this setting. The improved risk-benefit ratio of endoscopic ligation therapy relative to sclerotherapy has led to reassessment of its role in primary prophylaxis[36,37
]. Uncontrolled preliminary pediatric experience of variceal hemorrhage using beta blockade has recently been reported[38-40
]. Beta blocker use in children has reduced the frequency of bleeding episodes, and in some trials has improved long-term survival in patients with esophageal varices. Initial randomized trials demonstrated efficacy in patients who had a previous bleeding episode[41
]. Subsequently, propranolol was shown to be effective in patients with varices who had never bled. In a study of 230 subjects randomized to propranolol or placebo, the incidence of bleeding and mortality over a 14 mo period was reduced by almost 50%[42
]. Several meta-analyses have demonstrated the success of propranolol[43-50
]. It is clear that a goal of at least 25% reduction in resting heart rate needs to be achieved to realize these effects. In patients in whom HVPG drops below 12 mmHg, subsequent variceal bleeding is unlikely. Achieving such a large reduction in resting heart rate and achieving a HVPG below 12 mmHg may be problematic in children in whom baseline measurements may be difficult. A wide range of dosing (0.6-0.8 mg/kg per day) divided into two to four doses of propranolol has been required in children in order to observe a “therapeutic effect”.
Unfortunately, propranolol often does not reduce HVPG below 12 mmHg, therefore a combination of beta blockade and vasodilatation therapies are now under investigation. Isosorbide-5-mononitrate, a long-acting vasodilator, may potentiate the effects of propranolol on the HVPG[51
]. Combination pharmacologic agents, such as carvedilol, may have enhanced efficacy[52
]. Unfortunately, there is little if any prospective data in children on the safety and effectiveness of beta blockade with or without vasodilators in patients with portal hypertension.
Endoscopic band ligation therapy has been used with greater frequency in adults with high risk varices[53,54
]. As with beta blockade, endoscopic band ligation therapy cannot be recommended for routine use in children with varices. In fact, a small randomized trial of prophylactic endoscopic sclerotherapy in children showed no survival benefit[55
Emergency therapy of variceal bleeding
The initial management of variceal bleeding is stabilization of the patient. Vital signs, particularly tachycardia or hypotension, can be especially helpful in assessing blood loss. Patients on beta blocker therapy may not manifest the usual compensatory tachycardia and are at higher risk of developing significant hypotension. Fluid resuscitation in the form of crystalloid initially, followed by red blood cell transfusion, is critical. One needs to administer these carefully to avoid overfilling the intravascular space and increasing portal pressure. Optimal hemoglobin levels in adults with variceal hemorrhage are between 7 and 9 g/dL[56
]. Nasogastric tube placement is safe and may be an essential part of the management of these patients. It allows documentation of the rate of ongoing bleeding and removal of blood, a protein source that may precipitate encephalopathy. In addition, blood in the stomach increases splanchnic blood flow and could aggravate portal hypertension and ongoing bleeding. Platelets should be administered for levels less than 50 × 109
/L, and coagulopathy corrected with vitamin K and fresh frozen plasma. There may be a value to the use of recombinant factor VIIa in severe coagulopathy as the fluid requirements may be diminished[57
]. Intravenous antibiotic therapy should be considered for all patients with variceal bleeding in light of the high risk of potentially fatal infectious complications[58,59
]. Once the patient is stabilized, endoscopy should be performed to document that hemorrhage is indeed from variceal rupture. Continued bleeding at the time of endoscopy is a finding that portends poor prognosis. A significant percentage of both adults and children with chronic liver disease will have a source of bleeding other that varices, including duodenal or gastric ulceration[58
]. Pharmacotherapy of acute hemorrhage should not be withheld until endoscopy can be performed. In fact, it may facilitate the procedure. At the time of initial endoscopy, management can begin in the form of sclerotherapy or band ligation. Bleeding that lasts more than 6 h or requires more than one red blood cell transfusion necessitates further investigation. A wide variety of therapeutic options exist in adults. Documentation of their efficacy in adults is fairly convincing, but data in children is scarce
The pharmacologic therapy of variceal bleeding usually consists of vasopressin or somatostatin (or their analogs) infusions. Vasopressin has the longest history of usage and acts by increasing splanchnic vascular tone and thus decreasing portal blood flow. Its use is often limited by the side effects of vasoconstriction, which include left ventricular failure,, bowel ischemia, angina, and chest/abdominal pain[53
]. In a study of 215 children with acute variceal hemorrhage, 184 had bleeding arrested by the combined use of fluid support and vasopressin. Vasopressin has a half-life of 30 min and is usually given as a bolus followed by continuous infusion. The recommended dose for children is 0.33 U/kg as a bolus over 20 min, followed by an infusion of 0.2 U/1.73 m2
per minute (may be increased up to 3 times the initial rate). These recommendations are empiric, based on clinical practice, and derived from extrapolation of adult dosages. Terlipressin, a long-acting synthetic analogue of vasopressin, has shown similar effects and does not require continuous infusion[57
]. Side effects appear to be reduced compared to vasopressin, but prospective data in children are lacking.
Alternatives to vasopressin have been investigated because of its poor side effect profile. Somatostatin and its synthetic homologue octreotide also have been shown to decrease splanchnic blood flow. Their effects on acute variceal hemorrhage appear to be similar to those of vasopressin, with fewer side effects[58,59
]. Continuous infusion of 1-5 μg/kg per hour of octreotide appears to be effective but may need to be initiated by the administration of a bolus. New longer-acting somatostatin analogues are currently under investigation[59
Approximately 15% of children will have persistent hemorrhage despite conservative management plus some form of splanchnic vasoconstriction. The most common secondary approach is endoscopic sclerotherapy or endoscopic band ligation. Endoscopic therapy is very effective in controlling bleeding, although it may be technically challenging. An extensive experience with emergency sclerotherapy exists in children, and it’s rare for additional therapy to be required. A variety of agents have been used (sclerosants, chemically irritating compounds such as ethanolamine/tetradecyl sulfate). These sclerosants are injected either intra-or para-variceal, until bleeding has stopped. In the setting of emergency sclerotherapy it is important to be aware of the significant incidence of associated bacteremia and to consider antibiotic prophylaxis in most patients.
Endoscopic band ligation of varices may be a preferable approach because it is easier and safer. A randomized trial of band ligation versus sclerotherapy in adults demonstrated similar control of active bleeding and recurrence of hemorrhage with significantly lower overall complications and mortality). A potential concern of this technique in children (whose esophageal wall is thinner than adults), is entrapment of the full thickness of the esophageal wall by the rubber band with subsequent ischemic necrosis and perforation.
The Sengstaken-Blackmore tube (SSBT) was designed to stop hemorrhage by mechanically compressing esophageal and gastric varices. The device consists of a rubber tube with at least two balloons. It is passed into the stomach, where the first balloon is inflated and pulled up snug against the gastroesophageal junction. Once the tube is secured in place, the second balloon is inflated in the esophagus at a pressure (60-70 mmHg) that compresses the varices without necrosing the esophagus. A channel in the rubber tube allows gastric contents to be sampled for evidence of bleeding. This therapy is very effective in controlling acute bleeding. Unfortunately, it is associated with significant number of complications and high incidence of re-bleeding when the tube is removed. Most patients find the treatment uncomfortable, and its use in children requires significant sedation. Use of the SSBT increases the risk of aspiration pneumonia, which can be a life threatening complication in a patient with liver failure. Re-bleeding has been reported in 33%-60% of patients. Given these problems it is reserved for severe uncontrollable hemorrhage and generally serves as a temporizing measure until a more definite procedure can be performed.
Surgical and interventional radiology
Surgical therapy is usually a last resort approach to acute variceal hemorrhage. The reluctance to perform emergency surgery partly stems from its associated high mortality but also from concerns of an increased incidence of encephalopathy and greater difficulty for subsequent liver transplantation. The surgical procedures available can be divided into transection, devascularization, and portosystemic shunting. The first two techniques are rarely used and work by interrupting blood flow through the esophagus. Liver transplantation may be an effective means of treating esophageal variceal bleeding if an acceptable organ can be procured quickly enough. Variceal embolization via a percutaneous transhepatic or transsplenic approach has been advocated by some hepatologists as another method of controlling acute hemorrhage. Transjugular intrahepatic portosystemic shunt (TIPS) placement may be the optimal approach for intractable bleeding since it does not require surgery or puncture of an organ that is predisposed to hemorrhage. A catheter is inserted into the jugular vein and is advanced into the hepatic vein where a needle is used to form a tract between the portal vein and the hepatic vein. This tract is expanded with a balloon angioplasty catheter, and a stent is then placed forming a permanent portosystemic shunt. The experience in children is limited. Size limitations and local expertise may be limiting factors in some cases, but given the high risk associated with emergency surgery or the use of SSBT, TIPS may be the treatment of choice in the emergent setting, especially when liver transplantation is imminent.
Secondary prophylaxis: The long term management of portal hypertension in children with a previous episode of variceal bleeding is complex. One must take into consideration several factors; first the natural history; as discussed earlier, there are significant differences in the setting of minimal and inactive versus active and progressive hepatic disease. As a result, certain individuals may have the possibility of outgrowing their portal hypertension through the development of spontaneous portosystemic shunts, whereas other might be expected to develop end-stage liver disease and ultimately be candidates for liver transplantation. The second issue stems from the great diversity in therapeutic modalities. The physiologic goal of pharmacologic therapy varies from program to program (i.e, change in heart rate, hepatic portal venous gradient pressures, etc). Sclerotherapy may be administered with a wide variety of agents and by two different techniques (i.e, intra or para variceal). Endoscopic band ligation offers an important and generally safer alternative. Finally, at least six different portosystemic shunting procedures have been described, all with their own advantages and disadvantages.
Sclerotherapy and ligation therapy: Sclerotherapy and band ligation therapy work by physical obliteration of esophageal varices. Bleeding may occur during the several weeks required to complete the obliteration. Most importantly the principal problem of portal hypertension is not addressed. Despite these problems, endoscopic therapy has been a mainstay of the treatment of esophageal varices, and there is significant amount of clinical experience with these therapies in children.
The effectiveness of sclerotherapy has been studied for both prevention of initial and subsequent bleeding episodes. Scleroptherapy, which has in general been supplanted by band ligation, with the exception of very young or small children in which band ligation may not be feasible. Intravariceal, paravariceal, and some combination injection protocols have been used. A wide variety of sclerosing agents have been used without a clear cut difference in their efficacy or adverse side effects. A meta analysis of seven studies and 748 patients revealed mortality rates of 47% in the sclerotherapy group and 61% in the conservatively managed group. A variety of complications have been reported (Table ).
Table 2 Major complications of endoscopic sclerotherapy in children (%)
Retrosternal pain, bacteremia, and fever post treatment are common. Esophageal ulceration may occur after sclerotherapy, and the associated symptoms may be ameliorated with sucralfate slurry therapy.
The range of complications associated with sclerotherapy has prompted the development of alternative endoscopic methods such as band ligation. This technique involves suctioning of a varix into the end of an endoscope so that a rubber band can be placed around the varix leading to thrombosis. Direct comparisons of endoscopic sclerotherapy and variceal ligation in adult patients have yielded results in favor of ligation. Similar results have been reported in children by Zargar et al. The major advantage of variceal ligation is avoidance of needle injection of varices, which appears to reduce the rate of complications. In addition, variceal ligation appears to lead to obliteration in fewer sessions and is associated with lower rate of rebleeding.
Portosystemic Shunting: A variety of procedures have been used to divert portal blood flow and decrease portal blood pressure: (1) Mesocaval Shunts: formed with the insertion of a graft between the superior mesenteric vein and the inferior vena cava; (2) Portacaval Shunts: formed by side-to-side anastomosis of the portal vein and the inferior vena cava; and (3) Distal Splenorenal Shunt: formed by end-to-side anastomosis of the splenic vein and the left renal vein.
The portacaval shunt diverts nearly all the portal blood flow into the subhepatic inferior vena cava. This is very effective decompressing the portal system, but also diverts a significant amount of blood from its normal hepatic metabolism, predisposing to the development of hepatic encephalopathy. Decreased hepatic blood flow theoretically also may lead to worsening of underlying liver disease. An intermediate shunt can be made by placing a graft between the mesenteric or portal vein and the vena cava. This decompresses the portal system while allowing a greater amount of portal blood flow into the liver. The use of grafts unfortunately is associated with increased risk of thrombosis and many times with worsening retrograde flow.
Another approach involves diversion of splenic blood flow into the left renal vein, which can be done nonselectively (central) or semiselectively (distal splenorenal shunt).
A substantial pediatric experience with surgical portosystemic shunting has been accumulated over the past 20 years. The results are clearly different in patients with extra-or intrahepatic portal hypertension (Table ).
Table 3 Results of portosystemic shunting in children[63,64]
An alternative shunting procedure for children with extrahepatic portal vein thrombosis is the meso-Rex bypass, this procedure involves the placement of an autologous venous graft from the mesenteric vasculature to the left intrahepatic portal vein. One of the major advantages of this approach is the restoration of normal portal blood flow, which eliminates the risk of hepatic encephalopathy and should preserve hepatic function. The selection of patients for this procedure is not clear both from a clinical indication and surgical feasibility, and some have advocated that this procedure be considered in all children with portal vein thrombosis. Standard diagnostic imaging may not clearly indicate whether there is patency of the intrahepatic portal vein, and the potential in this group of children for hypercoagulable states must be kept in mind.
In stark contrast to the excellent results in portal vein thrombosis, there are generally poor results of portosystemic shunts in children with decompensated liver disease. The incidence of recurrent bleeding and death approaches 50%. Hepatic encephalopathy is a frequent and serious complication of portosystemic shunting in decompensated liver disease, and studies have failed to show improvement in long-term survival in patients with intrahepatic disease.
Overall, surgical portosystemic shunting is an excellent approach to the long-term management of children with intractable variceal bleeding in the setting of compensated cirrhosis. In addition, significant gastric variceal hemorrhage in children may be an indication to consider surgical shunting. TIPS may be an alternative shunting procedure for children with refractory bleeding and serves as an effective bridge to transplantation. The procedure is typically feasible, with published success in children as small as 14 kg, although special procedural modifications must be undertaken in small children. Long term shunt occlusions limit the overall application of this efficacious therapy, although newer data with coated stents may improve long-term patency rates for TIPS.