Pediatr Transplantation 2006: 10: 893907.

Copyright 2006 Blackwell Munksgaard

Pediatric Transplantation
DOI: 10.1111/j.1399-3046.2006.00597.x

Expert pediatric opinion on the Report of the Baveno IV Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension
Shneider B, Emre S, Groszmann R, Karani J, McKiernan P, Sarin S, Shashidhar H, Squires R, Superina R, de Ville de Goyet J, de Franchis R. Expert pediatric opinion on the Report of the Baveno IV Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension. Pediatr Transplantation 2006: 10: 893907. 2006 Blackwell Munksgaard Abstract: Portal hypertension leads to a wide variety of complications, which lead to signicant morbidity and mortality and are some of the leading reasons for liver transplantation in children with chronic liver disease. Evidence-based approaches to the management of adults with portal hypertension exist and have been comprehensively reviewed in a series of international meetings, including the Baveno meetings. Similar evidence-based approaches for the management of portal hypertension in children do not exist and as such international meetings on portal hypertension have not focused on this problem in children. On October 7, 2005 at The Mount Sinai School of Medicine, a panel of pediatric experts reviewed the most recent Baveno statement and crafted a statement modied with their opinions vis a vis approaches to the management of portal hypertension in children. Benjamin Shneider1, Sukru Emre1, Roberto Groszmann2, John Karani3, Patrick McKiernan4, Shiv Sarin5, Harohalli Shashidhar6, Robert Squires7, Riccardo Superina8, Jean de Ville de Goyet9 and Roberto de Franchis10
Mount Sinai School of Medicine, New York, NY, USA, 2Yale University, New Haven, CT, USA, 3King's College Hospital, London, UK, 4Children's Hospital, Birmingham, UK, 5GB Pant Hospital, New Delhi, India, 6 University of Kentucky, Lexington, KY, USA, 7 Children's Hospital of Pittsburgh, Pittsburgh, PA, USA, 8Northwestern University Feinberg School of Medicine, Evanston, IL, USA, 9Cliniques Universitaires de Saint-Luc, Brussels, Belgium, 10 Universita degli Studi di Milano, Milan, Italy
1

Benjamin Shneider, Division of Pediatric Hepatology/ Department of Pediatrics, Mount Sinai School of Medicine, Box 1656, One Gustave L. Levy Place, New York, NY 10029, USA Tel.: 212 659 8060 Fax: 212 241 8991 E-mail: benjamin.shneider@mssm.edu The pediatric commentary on this published statement will be in italics (note bold italics are used for the headings in the original publication and have been changed to underlined nonitalic text for this commentary). Commentary was elicited on selected topics from Baveno IV. The remainder is reproduced with permission from the original publication (1). Not all topics in the Baveno IV statement were reviewed at this 1-day symposium. Those that were not reviewed have no supplementary pediatric commentary and are in a smaller font. Some sections were agreed upon in total as indicated by the use of the comment ``agreed.'' Accepted for publication 3 August 2006

Abbreviations: ABRI, adjusted blood transfusion requirement index; ALT, alanine anainotransferase; BCS, Budd-Chiari syndrome; CONSORT; CT, computerized tomography; EBL, endoscopic band ligation; EHPVO, extra-hepatic portal vein obstruction; FTT, failure to thrive; HCC, hepatocellular carcinoma; HVOTO, hepatic venous outow tract obstruction; HVPG, hepatic vein pressure gradient; ITT, intention to treat; MELD, Mayo End-Stage Liver Disease Scoring System; MRI, magnetic resonance imaging; NIEC, Northern Italian Endoscopic Club; OLT, orthotopic liver transplantation; PP, per protocol; PRBC, packed red blood cells; PTFE, polytetrauoroethylene; RCT, randomized controlled trial; rFVIIa, recombinant factor VIIa; TIPSS, transjugular intrahepatic portosystemic shunt.

893

Shneider et al.

Approaches to the management of portal hypertension in children are anecdotal and there are few if any generally agreed upon approaches (2). There have only been two randomized controlled trials of therapeutic interventions for portal hypertension in children (3, 4). Therefore, pediatricians typically have diculty in deciding how to manage this important clinical problem in children. Portal hypertension is the hemodynamic abnormality associated with the most severe complications of cirrhosis, including ascites, hepatic encephalopathy and bleeding from gastroesophageal varices. Variceal bleeding is a medical emergency associated with a mortality that, in spite of recent progress, is still in the order of 20% at six wk. The evaluation of diagnostic tools and the design and conduct of good clinical trials for the treatment of portal hypertension have always been dicult. Awareness of these diculties has led to the organization of a series of meetings aimed at reaching consensus on the denitions of some key events related to portal hypertension and variceal bleeding, and at producing guidelines for the management of patients and for the conduct of trials in this eld. Such meetings took place in Groningen, the Netherlands in 1986 (1), in Baveno, Italy in 1990 (Baveno I) (2) and in 1995 (Baveno II) (3,4), in Milan, Italy in 1992 (5), in Reston, USA in 1996 (6), and in Stresa, Italy in 2000 (Baveno III) (7, 8) All these meetings were successful and produced consensus statements on some important points, although several issues remained unsettled. To continue the work of the previous meetings, a Baveno IV workshop was held on April 2829, 2005. The workshop was attended by many of the experts responsible for most of the major achievements of the last years in this eld. The majority of them had attended the Groningen, Baveno I, Baveno II, Reston, and Baveno III meetings as well. The Baveno meetings have been directed at approaches for adults and there has been no focused attention on the same issues in children. The purpose of the 1-day seminar held on October 7, 2005 at the Mount Sinai School of Medicine was to provide expert commentary on the Baveno IV statement as it relates to pediatrics. The conference faculty were chosen in light of their record of publication in specic areas related to portal hypertension in children. This commentary is not a consensus statement, but instead reects the opinions of the faculty in light of their personal experiences and their review of the pediatric specic literature.

The main elds of discussion of the Baveno IV workshop were the same as in Baveno IIII, i.e., the denitions of key events concerning the bleeding episode, the therapeutic options in patients with portal hypertension, and the methodological requirements for future studies in this eld. For each of these topics, a series of consensus statements were discussed and agreed upon. Whenever applicable, the level of existing evidence was evaluated and the recommendations were ranked according to the Oxford System (9) (i.e., level of evidence from 1 highest to 5 lowest; grade of recommendation from A strongest, to D weakest). In light of the very limited amount of evidenced based approaches in pediatrics, this scoring system was simplied for this commentary; Grade 1 randomized controlled trial, 2 cohort studies, 3 case controlled studies, 4 case series, 5 expert opinion. The presentations given during the workshop are reported in extenso in the Baveno IV proceedings (10). A summary of the most important conclusions is reported here.
Definition of key events regarding the bleeding episode

Denitions and criteria to evaluate failure to control bleeding and failure to prevent rebleeding were introduced at Baveno II (3, 4) and reviewed at Baveno III (7, 8). Since then, these denitions and criteria have been extensively applied in trials; it has been found that some of them are rather dicult to apply and do not reect adequately the situation in clinical practice; therefore, new denitions and criteria were proposed at Baveno IV. Given the lack of validated parameters to dene failure, these new criteria are necessarily arbitrary (level of evidence 5; grade of recommendation D) (9), and must be validated in future studies, in particular as surrogate markers of outcome. It is proposed that current and future studies should incorporate both Baveno II-III and Baveno IV criteria, and evaluate failure to control bleeding using both sets of criteria. A judgment of the validity of the new criteria will be possible only after their extensive application in such studies. The Baveno IIIII and the Baveno IV denitions and criteria are reported below.
Baveno IIIII definitions and criteria for failure to control bleeding

1. The denition of failure to control bleeding is divided into two time frames:

894

Portal hypertension in children

(a) Within six h: any of the following factors: (i) transfusion of four units of blood or more, and inability to achieve an increase in systolic blood pressure of 20 mmHg or to 70 mmHg or more, and/or (ii) pulse reduction to less than 100/min or a reduction of 20/min from baseline pulse rate. (b) After six h: any of the following factors: (i) the occurrence of hematemesis, (ii) reduction in blood pressure of more than 20 mmHg from the six-h point, and/or (iii) increase of pulse rate of more than 20/min from the six-h point on two consecutive readings one h apart, (iv) transfusion of two units of blood or more (over and above the previous transfusions) required to increase the hematocrit to above 27% or hemoglobin to above 9 g/dL.
Baveno IV definitions and criteria for failure to control bleeding

ABRI ABRI Blood units transfused (Final Htinitial Ht) + 0.1 Hematocrit (or hemoglobin) is measured at least every  Six h for the first 2 days  Twelve h for days 35 The transfusion target should be an hematocrit of 24% or a hemoglobin of 8 g/dL

Notes for the Baveno IV definitions and criteria

For the purposes of analysis the following criteria should be adopted: Time to failure rst occurrence of any of the above criteria for failure (cumulative hazard plots and Cox regression analysis). Failure occurring at 120 h is considered as yes or no. The use of both time to failure and nal evaluation at 120 h is encouraged. All specic therapeutic procedures should be documented with time-points. Intention to use further specic therapy should be documented even if not used. Transfusion requirements should be recorded as a function of time for the whole interval of acute bleeding if no failure has occurred, e.g., units transfused/120 h or units transfused up to time of failure.
Baveno IIIII definitions and criteria for failure of secondary prophylaxis

1. The time frame for the acute bleeding episode should be 120 h (ve days). Agreed 2. Failure signies need to change therapy: one criterion denes failure, whichever occurs rst these are proposed criteria to be assessed prospectively as there are almost no prospective data collected that describes acute variceal hemorrhage in children. In the absence of either retrospective or prospective data of these parameters in children with variceal hemorrhage it is dicult to determine what values are clinically signicant. (a) Fresh hematemesis 2 h after start of specic drug treatment or therapeutic endoscopy. In the minority of patients who have a nasogastric tube in place, aspiration of greater than 100 mL of fresh blood represents failure volume of bleeding will need to be adjusted for weight no consensus was achieved on the amount. (b) Three gram drop in hemoglobin ( 9% drop in hematocrit) if no transfusion is administered the possibility of hemodynamic criteria would be valuable if prospective data can be collected. (c) Death. (d) ABRI (see below) 0.75 at any time point. (The threshold of ABRI dening failure requires validation.) ABRI needs to be modied to size of child (i.e., mL/kg of blood transfused) it needs to be prospectively assessed to determine validity.

Failure to prevent rebleeding is dened as a single episode of clinically signicant rebleeding from portal hypertensive sources Clinically signicant rebleeding: (a) transfusion requirement of two units of blood or more within 24 h of time zero (the time of admission of a patient to the rst hospital he is taken to) (2) (b) together with a systolic blood pressure <100 mmHg or (c) a postural change of >20 mmHg and/or (d) pulse rate >100/min at time zero.
Baveno IV definitions and criteria for failure of secondary prophylaxis

Failure to prevent rebleeding is dened as a single episode of clinically signicant rebleeding from portal hypertensive sources. The same issues raised in the section on failure to control bleeding (previous section) apply to failure of secondary prophylaxis.

895

Shneider et al.

Clinically signicant rebleeding: (a) Hematemesis/melaena. In the minority of patients who have a naso-gastric tube in place, aspiration of greater than 100 mL of fresh blood represents failure plus (b) ABRI 0.5 (The threshold of ABRI dening failure requires validation.) or (c) Decrease 3 g of hemoglobin if no transfusion is given.
Predictive models for portal hypertension

In children presinusoidal disease may diminish the applicability of this approach. (Grade 5) Children will likely require anesthesia to achieve these measurements. (Grade 4) The only current literature for these measurements is from the experience with TIPSS. (Grade 4) Alternative techniques (e.g., splenic pulp or variceal pressure measurement) for measuring portal pressure may be necessary for presinusoidal disease; EHPVO may be distinct from other forms of presinusoidal disease. (Grade 4)
Outcome prediction in compensated patients

Because of the growing importance of prognostic models in hepatology, and particularly in portal hypertension, a session devoted to this topic was introduced in Baveno IV, to replace the session that was dedicated to the diagnosis of portal hypertension in Baveno III.
Status classification of cirrhosis

Varices, ascites and bleeding in patients with cirrhosis identify four clinical statuses of increasing severity: stage 1: no varices, no ascites; stage 2: varices, no ascites; stage 3: ascites varices; stage 4: bleeding ascites (11). The outcome of a clinical status is transition to another status, death or OLT. Prognostic models specic to each clinical status should be developed. FTT, ascites and variceal bleeding in children with cirrhosis identify 4 clinical statuses of increasing severity: stage 1: evidence of uncomplicated portal hypertension; stage 2: FTT and uncomplicated portal hypertension, stage 3: FTT and (ascites or bleeding); stage 4: FTT, ascites and bleeding (Grade 5). The exact criteria to dene FTT will need to be delineated, although current criteria in use for the Pediatric End-Stage Liver Disease scoring system (i.e., <2 SD below mean) may be appropriate. The pattern of progression is determined in part based upon whether there is primarily biliary or hepatocellular disease. The pattern for EHPVO needs to be determined. (Grade 5)
Indicators of varices, and predictors of their development

1. In compensated patients the development of ascites and portal hypertensive bleeding are the most relevant outcomes In children with dierent categories of disease there are specic parameters that are predictive of outcome and development of portal hypertensive bleeding is not necessarily the most relevant outcome. (Grade 5) For instance in biliary atresia total bilirubin at the time of bleeding may be most relevant (Grade 4). Persistent ascites is often a harbinger of poor prognosis. (Grade 5) Diminished hepatic synthetic capacity is also an important prognostic feature. (Grade 5) 2. HVPG is the only known predictor of the development of ascites; other potential predictors should be investigated 3. The NIEC score is presently the most reliable predictor of variceal rupture; the contribution of HVPG and other predictors should be investigated The NIEC score has not been prospectively evaluated in childhood. (Grade 5) Variceal size and red color signs are the only established endoscopic predictors of variceal hemorrhage in children. (Grade 4) There is a need for prospective studies of the risk of variceal hemorrhage controlled for variceal size, red color signs, other clinical features and underlying diagnosis. (Grade 5)
Outcome prediction in decompensated patients

There are no satisfactory non endoscopic indicators of the presence of varices. Agreed (Grade 4) While further studies are awaited, endoscopic screening is still the best practice to detect varices. Agreed (Grade 4) The hepatic vein pressure gradient (HVPG) is presently the most reliable predictor of variceal development. 896

1. Child-Pugh and MELD predict overall mortality Child-Pugh has not been prospectively examined in its ability to predict outcome in children. (Grade 5) The ability of PELD to predict near-term outcome is unclear. (Grade 4) Diverse etiologies of disease and small numbers of deaths make development of robust predictive models for pediatrics dicult. (Grade 5)

Portal hypertension in children

2. The additional role of HVPG and other potential predictors (sodium, spontaneous bacterial peritonitis, hepatorenal syndrome, others) should be assessed.
Therapeutic options in patients with portal hypertension Pre-primary prophylaxis (prevention of the formation/growth of varices)

Treatment to decrease or prevent the progression and/or prevent the development of varices. Biliary atresia (a very interesting entity of pediatric portal hypertension with rapid rate of progression). Noninvasive tests: Noninvasive tests might be useful to identify patients at risk of having or prone to develop varices (HVPG > 12 mmHg), but prospective studies are required. (4; C) Noninvasive tests are desperately needed in pediatrics as means of identifying patients at risk of having or prone to develop varices. (Grade 5) HVPG measurement may be problematic in children. (Grade 5) Gold standards for children need to be developed and prospective studies are required. (Grade 5)
Prevention of the first bleeding episode

Background: Pre-primary prophylaxis (prevention of the formation/growth of varices) Prevention of the development of complications of portal hypertension is clearly an important area for future research. Portal-systemic collaterals may develop before the appearance of varices, and can be diagnosed non invasively. However, their clinical importance is uncertain. (5; D) HVPG is predictive of varices formation. (1b; A) Recommendations for management: All cirrhotic patients should be screened for varices at diagnosis. (5; D) This is a contentious issue. There are not well established approaches to pre-primary and primary prophylaxis in children. (Grade 5) Currently it is dicult to recommend screening for varices, either when children present with portal hypertension or as part of routine surveillance. (Grade 5) Surveillance endoscopy in a formal prospective protocol of portal hypertension is strongly encouraged. (Grade 5) Despite some pharmaco-economical analysis, it is not indicated to treat cirrhotic patients with beta-blockers without prior assessment of the presence of esophageal varices. (5; D) Agreed (Grade 5) There is no indication, at this time, to treat patients to prevent the formation of varices. (1b; A) Agreed (Grade 5) Areas requiring further study: Basic mechanisms in the development and progression of portal hypertension. Natural history of low-risk varices (epidemiology and predictive factors of progression). Routine use of HVPG in clinical trials involved in investigating the complications of portal hypertension.

Use of HVPG measurements: HVPG monitoring identies patients with cirrhosis who will benet from non selective betablocker therapy in primary prophylaxis. (1b; A) ` la carte treatment using HVPG response in a primary prophylaxis needs to be evaluated, especially in high risk patients. Until then, routine use of HVPG cannot be recommended. (5; D) Patients with small varices: Patients with small varices could be treated with non-selective beta-blockers to prevent progression of varices and bleeding, but further studies, especially as relates to prevention of bleeding, are required before a formal recommendation on their use can be made. (5; D) Pediatric studies which assess variceal size progression and risk of bleeding are necessary before use of non selective b blockers are recommended for prophylaxis in small varices Prophylaxis using nonselective b-blocker prophylaxis for small varices should be only carried out as part of a clinical study. There may be possible increased risk with use of beta blockers in young children in whom cardiac output is predominantly dependent upon heart rate. (Grade 5) Patients with small varices with red wale signs or of Child C class have an increased risk of

897

Shneider et al.

bleeding and may benet from treatment. (5; D) Children with (small) varices with red wale signs have an increased risk of bleeding and may benet from treatment. (Grade 4) Prophylactic intervention may be more eective in larger varices as it relates to risk reduction in bleeding. (Grade 4) The intervention should preferably be used in a structured clinical protocol or study. (Grade 5) Pharmacological treatments: Nonselective b-blockers reduce the risk of rst variceal bleeding. (1a; A) Use of nonselective b-blockers reduces the risk of rst variceal bleeding in adults and is recommended standard therapy in clinical practice in adults. Data is insucient to recommend this as standard clinical practice in children, alternatively by analogy use in children may be considered. (Grade 4) The hemodynamic parameters/targets of b-blocker therapy in children are not clear. (Grade 5) Multi-center RCTs for primary prophylaxis are required. (Grade 5) Isosorbide mononitrate administered alone must not be used (1a; A) There is not enough data to recommend the use of the combination of b-blockers plus ISMN or spironolactone plus b-blockers for primary prophylaxis. (1b; A) (9) Other pharmacological agents able to reduce portal pressure must be adequately tested before their clinical use. (5; D) Endoscopic treatment: Prophylactic EBL is useful in preventing variceal bleeding in patients with medium and large esophageal varices. (1a; A) Primary prophylactic endoscopic sclerotherapy (Grade 1) and band ligation (Grade 4) are safe in preventing variceal bleeding in children with large or growing esophageal varices. No studies have demonstrated diminished mortality in children undergoing prophylactic endoscopic therapy for portal hypertension. Band ligation therapy in children appears to be superior to sclerotherapy in children. (Grades 1 and 4) Primary prophylactic EBL therapy should only be used in the context of a dened protocol or as part of a clinical trial. (Grade 5) There is an urgent need for a randomized controlled trial of prophylactic variceal band ligation in children. (Grade 5) 898

The design of these studies will be complex. (Grade 5) EBL is more eective than non-selective bblockers in preventing rst variceal bleeding but does not improve survival. However the longterm benets of EBL are uncertain because of the short duration of follow-up. (1a; A) Neither EBL or b-blockade can be universally recommended for preventing rst variceal bleeding in children with portal hypertension except as part of a clinical trial. (Grade 5) EBL should be oered to patients with medium/large varices and contraindications or intolerance to b-blockers. (5; D) Gastric varices: In the absence of specic data on prophylactic studies, RCTs should be performed in patients with gastric varices. Cost-eectiveness analysis: Markov models are not a substitute for well designed clinical trials. However, welldesigned Markov models are complementary to clinical studies and should be pursued for exploratory purposes and to establish the costeectiveness of various strategies. Markov models may ll in a void where clinical trials are simply not feasible. Areas requiring further study (5; D): Comparison of EBL and b-blockers with respect to cost-eectiveness and quality of life to determine the treatment of choice. Studies to clarify whether the combined use of EBL and b-blockers is better than each treatment alone.
Treatment of acute bleeding from varices

Blood volume restitution: Blood volume restitution should be done cautiously and conservatively, using plasma expanders to maintain hemodynamic stability and PRBC to maintain the hemoglobin at approximately 8 g/dL, depending on other factors such as patients co-morbidities, age, hemodynamic status, and presence of ongoing bleeding clinically. (1b; A) Agreed (Grade 5) Recommendations regarding management of coagulopathy and thrombocytopenia cannot be made on the basis of currently available data. (5; D) Agreed (Grade 5)

Portal hypertension in children

Use of antibiotics for preventing bacterial infections/spontaneous bacterial peritonitis: Antibiotic prophylaxis is an integral part of therapy for patients presenting with variceal bleeding and should be instituted from admission. (1a; A) Antibiotic prophylaxis has not been formally studied in children with variceal hemorrhage in all forms of portal hypertension in children. (Grade 5) Prospective RCT of this question in children is not feasible. (Grade 5) Comprehensive collection of cultures (blood, urine and ascites) at presentation should be performed in children with variceal hemorrhage. (Grade 5) From a risk benet perspective and based upon adult data, antibiotic prophylaxis directed at intestinal ora (such as ceftriaxone) is an integral part of therapy for children presenting with variceal bleeding and should be instituted from admission. (Grade 5) Prevention of hepatic encephalopathy: In patients who present or develop encephalopathy, this should be treated with lactulose/ lactitol or other drugs. (5; D) There are no studies evaluating the usefulness of lactulose/lactitol for the prevention of hepatic encephalopathy. (5; D) Assessment of prognosis: No adequate prognostic model has been developed to predict outcomes. (2b; B) No individual characteristic suciently predicts prognosis. (2b; B) Child-Pugh class, active bleeding at endoscopy, HVPG, infection, renal failure, severity of initial bleeding, presence of portal vein thrombosis or of HCC, and ALT have been identied as indicators of poor prognosis. (2b; B) Timing of endoscopy: Endoscopy should be performed as soon as possible after admission (within 12 h), especially in patients with clinically signicant bleeding or in patients with features suggesting cirrhosis (5; D) Endoscopy should be carried out as soon as practical in a stable patient (within 1224 h, preferably in a shorter time period). (Grade 5)

Immediate endoscopy should be undertaken if there is early failure to control bleeding. (Grade 5) There is no evidence mandating the use of nasogastric tube aspiration or continuous drainage. (Grade 5) Use of balloon tamponade: Balloon tamponade should only be used in massive bleeding as a temporary bridge until denitive treatment can be instituted. (for a maximum of 24 h, preferably in an intensive care facility). (5; D) Balloon tamponade is rarely used in children. (Grade 4) Experience is very limited. (Grade 4) If there is local experience with this approach in children it can be a useful bridge. (Grade 4) It is dicult for any center to have signicant experience with this technique. (Grade 5) It is generally only recommended as a therapy of last resort. (Grade 5) Pharmacological treatment: In suspected variceal bleeding, vasoactive drugs should be started as soon as possible before diagnostic endoscopy. (1b, A) The data in adults are compelling and the medication is safe, there are limited uncontrolled experiences in children, in the absence of a controlled trial it is reasonable to use vasoactive drugs as soon as possible before diagnostic endoscopy. (Grade 4) Vasoactive drug therapy (terlipressin, somatostatin, vapreotide, octreotide) should be maintained in patients with esophageal variceal bleeding for 25 days. (1a; A) Duration of therapy varies, but is guided by the presence of ongoing hemorrhage. (Grade 5) Prospective studies, especially a randomized trial of duration of therapy will be needed and treatment populations clearly dened. (Grade 5) Endoscopic treatment: 1. Endoscopic therapy is recommended in any patient who presents with documented upper GI bleeding and in whom esophageal varices are the cause of bleeding. (1a; A) 2. Endoscopic therapy is recommended in any patient who presents with documented upper GI bleeding and in whom esophageal varices are the cause of bleeding. (Grade 2) 3. Ligation is the recommended form of endoscopic therapy for acute esophageal variceal 899

Shneider et al.

bleeding although sclerotherapy may be used in the acute setting if ligation is technically dicult. (1b; A) Both band ligation (for size appropriate patients) and sclerotherapy are highly eective in acute esophageal variceal bleeding. The choice of which endotherapy to use should be determined by local expertise and technical considerations. (Grade 4) Endoscopic therapy with tissue adhesive (e.g., N-butyl-cyanoacrylate) is recommended for acute gastric variceal bleeding. (1b; A) Endoscopic treatments are best used in association with pharmacological therapy, which preferably should be started before endoscopy. (1a; A) Agreed (Grade 4) Management of treatment failures: Failures of initial therapy with combined pharmacological and endoscopic therapy are best managed by a second attempt at endoscopic therapy or TIPPS (preferably with PTFE covered stents). (2b; B) Failures of initial therapy with combined pharmacological and endoscopic therapy are best managed by a second attempt at endoscopic therapy with potential use of alternative agents (by experienced individuals) for variceal obliteration. (Grade 5) There are limited experiences with TIPS in children and this can be technically challenging in biliary atresia. (Grade 4) TIPS should only be attempted at centers with experience in this procedure in children. (Grade 5) TIPS should not be used in EHPVO. (Grade 5) There is limited experience with PTFE covered stents in children. (Grade 5) Emergent shunt, nonshunt (devascularization) or transplantation is indicated in children with failure of the above therapy. (Grade 4) Areas requiring further study (5; D): Optimal duration of vasoactive drug therapy. Eectiveness of early TIPS placement and of covered stents. Best treatment for gastric varices (especially glue vs. TIPS). The potential of rFVIIa. The best treatment of patients with no active bleeding at time of endoscopy on drug therapy. Prognostic factors/models for acute bleeding (MELD score, variceal size, age, etiology of portal hypertension and other comorbidities). 900

Prevention of rebleeding

Time to start secondary prophylaxis: Secondary prophylaxis should start as soon as possible from day 6 of the index variceal bleeding episode. (5; D) Agreed (Grade 5) The start time of secondary prophylaxis should be documented. Patients with cirrhosis who have not received primary prophylaxis: 1. Beta-blockers (1a; A), band ligation (1a; A) or both (1b; A) should be used for prevention of recurrent bleeding. 2. Band ligation therapy has been shown to be eective in children with portal hypertension secondary to cirrhosis (Grade 2) and may be superior to sclerotherapy when feasible. (Grade 1) 3. There is very limited data for b-blocker therapy in children. (Grade 4) 4. At present, band ligation therapy is recommended for secondary prophylaxis. (Grade 4) The use of b-blockade as either replacement or additional therapy for band ligation in children requires further investigation. (Grade 5) 5. Combination of b-blockers and band ligation is probably the best treatment (1b; A) but more trials are needed. There is no evidence to support the addition of b-blockers to variceal band ligation. (Grade 5) Controlled trials of this combination is needed. (Grade 5) 6. Assessment of hemodynamic response to drug therapy provides prognostic information about rebleeding risk. (2b; B) Patients with cirrhosis who are on beta blockers for primary prevention and bleed: Band ligation should be added. (5; D) Agreed (Grade 5) Patients who have contraindications or intolerance to b-blockers: Band ligation is the preferred treatment for prevention of rebleeding. (5; D) Agreed (Grade 5) Patients who fail endoscopic and pharmacological treatment for prevention of rebleeding: TIPS or surgical shunts (distal splenorenal shunt or 8 mm H-graft) are eective for those with Child class A/B cirrhosis and should be used. (2b; B)

Portal hypertension in children

Surgical shunts (preferably a distal splenorenal shunt) and nonshunts (when a shunt is precluded) are the preferred approach for children with compensated cirrhosis and a good near term prognosis. (Grade 4) TIPS can be considered as a bridge to transplantation in children with a near term need for liver transplantation. (Grade 4) PTFE stents may change the utility of TIPS as a more longterm therapy for refractory variceal hemorrhage. (Grade 5) In non surgical candidates, TIPS is the only option. (5; D) Transplantation provides good long-term outcomes in Child class B/C cirrhosis and should be considered. (2b; B) TIPS may be used as a bridge to transplantation. (4; C) Transplantation provides good long-term outcomes in children with a life expectancy of less than two years (e.g. in a child with biliary atresia and total bilirubin >4 mg/dL or a child with hepatic synthetic failure). (Grade 3) The exact parameters that predict poor shortterm prognosis need to be dened. (Grade 5) Patients who have bled from isolated gastric varices, type 1 (12) or gastroesophageal varices, type 2 (12): N-butyl-cyanoacrylate (1b; A), TIPS (2b; B) or b-blockers (2b; B) are recommended. Patients who have bled from gastro-esophageal varices, type 1: May be treated with N-butyl-cyanoacrylate, band ligation of esophageal varices or bblockers. (2b; B) Patients who have bled from portal hypertensive gastropathy: Beta-blockers (1b; A) should be used for prevention of recurrent bleeding. Patients in whom b-blockers are contraindicated or fail and who cannot be managed by non-shunt therapy: TIPS (4; C) or surgical shunts (4; C) should be considered. Areas requiring further study (5; D): Combination of b-blockers plus nitrates. Use of HVPG monitoring for decision making and its eect on patients outcome.

Non-cirrhotic portal hypertension

A session devoted to non-cirrhotic portal hypertension was introduced at Baveno IV, in view of the increasing recognition and growing interest of this clinical entity. Due to time constraints, the discussion was limited to the BCS HVOTO and to EHPVO. This session replaced the session that in Baveno III was devoted to portal hypertensive gastropathy and gastric varices.
BCS HVOTO

Denition: BCS is an eponym for HVOTO which can be located from the level of the small hepatic veins to the level of the termination of inferior vena cava into the right atrium. BCS is an heterogeneous condition with regard to causes and pathogenesis. BCS is considered secondary when the mechanism for HVOTO is compression/invasion by a benign or malignant tumor, abscess or cyst. BCS is considered primary otherwise. Hepatic congestion secondary to heart failure and pericardial disease are excluded from the denition of BCS. Obstruction conned to small hepatic veins or sinusoids in the context of liver irradiation, chemotherapy, stem cell transplantation or exposure to toxic agents is excluded from the denition of BCS. The terms veno-occlusive disease and sinusoidal obstruction syndrome require further denition. Etiology: Primary BCS is frequently associated with one or several risk factors for thrombosis. These underlying disorders are often occult at presentation with BCS. Myeloproliferative disorders should be investigated in any patient with BCS, irrespective of the peripheral blood picture. When liver synthetic function is impaired, low plasma levels of antithrombin, protein C, and protein S are not specic for an inherited defect. Diagnosis: BCS is diagnosed by the demonstration of an obstruction of the venous lumen, or by the presence of hepatic vein collaterals. Liver biopsy is not necessary to make a diagnosis of BCS when vascular imaging has 901

Shneider et al.

demonstrated obstruction of the hepatic venous outow tract. Liver biopsy is the only means to make a diagnosis of BCS of the small intrahepatic veins. Clinical trials for therapy of BCS have not been performed so that current therapy is based on less rigorous information. Treatment: On the basis of current expert opinion (5; D) Anticoagulation should be recommended to all patients, in the absence of major contra-indications. However, there is no consensus on the optimal duration of anticoagulation. Previous bleeding related to portal hypertension is not considered a major contra-indication for anticoagulation, provided appropriate prophylaxis for recurrent bleeding is initiated. Complications of portal hypertension may be treated as recommended for the other types of liver diseases. Stenoses that are amenable to percutaneous angioplasty/stenting should be actively looked for, and treated accordingly. TIPS insertion should be attempted when angioplasty/stenting is not feasible, and when the patient does not improve on medical therapy. Liver transplantation should be considered in patients with manifestations refractory to the above procedures. Areas requiring further studies (5; D): Accurate diagnostic tests for myeloproliferative disorder and antiphospholipid syndrome. Benet and risk of prolonged anticoagulation therapy. Benet and risk of pharmacological therapy for portal hypertension. Optimal timing of angioplasty and TIPS with respect to severity of symptoms. Indications for thrombolysis.
EHPVO (13)

portal veins, with or without splenic or superior mesenteric vein involvement. (Grade 4) 3. In children, the intrahepatic portal vein is more commonly preserved with infants having the highest degree of patency, and adolescents the lowest. This may be due more to a process of progressive atrophy than ongoing thrombosis. (Grade 4) 4. Some children may have diuse intrahepatic portal vein dysplasia (i.e. the process involves both the intra and extrahepatic portal venous system). (Grade 4) Vasculitis associated with moya moya disease. Post radiation venulitis. Embryological malformation of the liver. Careful delineation of anatomy is important in quantifying the possibilities for surgical correction. (Grade 4) EHPVO often manifests as portal cavernoma, which is a network of porto-porto collaterals and develops as a sequel of portal vein obstruction. EHPVO often manifests as portal hypertension and in chronic disease is characterized by portal cavernoma, which is a network of porto-porto collaterals and develops as a sequel of portal vein obstruction. (Grade 4) Isolated thrombosis of the splenic vein or superior mesenteric vein with patent portal vein is excluded. Isolated thrombosis of the splenic vein with patent portal vein is excluded. (Grade 4) Isolated thrombosis of the superior mesenteric vein is extremely rare and not part of the spectrum of EHPVO. (Grade 4) The denition should be augmented by a statement of presence or absence of cirrhosis and neoplasia. Etiology: EHPVO is a heterogeneous entity with regard to causes and pathogenesis, particularly between children and adults. The majority of children have acquired EHPVO. (Grade 4) The incidence of other associated anomalies (particularly GI and cardiac) suggests a developmental etiology. (Grade 4) A small number of children have a genetic predisposition to thrombosis. (Grade 4) EHPVO in adults is frequently associated with one or several risk factors for thrombosis which may be occult at presentation. Presence of cirrhosis, neoplasia and other intra-abdominal causes such as inammation,

Denition: 1. EHPVO is dened by obstruction of the extrahepatic portal vein with or without involvement of the intra-hepatic portal veins. 2. EHPVO is dened by obstruction of the extrahepatic portal vein, completely or in part, with or without involvement of the intra-hepatic 902

Portal hypertension in children

trauma, etc. do not exclude the presence of systemic risk factors. Clinical presentation: EHPVO can be acute or chronic. EHPVO in children is typically chronic. (Grade 4) EHPVO can be assumed to be recent when patients present with symptoms such as abdominal pain, ascites, fever or symptoms suggestive for intestinal ischemia, in the absence of portal cavernoma and porto-systemic collaterals. Chronic EHPVO is associated with portal cavernoma and may present with variceal bleed, splenomegaly, abnormal blood cell counts and occasionally jaundice. A proportion of children have growth retardation. Chronic EHPVO is associated with portal hypertension and portal cavernoma and often presents with variceal bleeding and/or splenomegaly. Abnormal blood cell counts and/or occasionally jaundice is less frequently a presenting feature. Rarely this is an incidental nding on imaging. A proportion of children have growth retardation. (Grade 4) Diagnosis: EHPVO is diagnosed by imaging techniques like Doppler ultrasound, CT or MRI which demonstrate portal vein obstruction, presence of intraluminal material or portal vein cavernoma. Chronic EHPVO is diagnosed by imaging techniques like Doppler ultrasound, CT or MRI with absence of a normal portal vein, with presence of a portal vein cavernoma, collateral veins and splenomegaly. (Grade 4) Assessing the patency of the intrahepatic portal veins may require direct portography or inspection. (Grade 4) In acute portal vein thrombosis, intraluminal thrombus within a normal portal vein with or without occlusion may be present. (Grade 5) Liver biopsy may be required to exclude cirrhosis. (Grade 5) Natural history: Most patients with EHPVO in the absence of cirrhosis and neoplasia have a relatively benign course. Morbidity is mainly related to variceal bleed, recurrent thrombosis, symptomatic portal biliopathy and hypersplenism.

Morbidity is related to variceal bleeding, symptomatic portal biliopathy, hypersplenism/ splenomegaly (associated with physical limitations and poor quality of life), progressive derangement of synthetic function of the liver, delayed physical and sexual development, FTT, rarely portopulmonary hypertension, hepatopulmonary syndrome, and possible subclinical encephalopathy. (Grade 4) The natural course of EHPVO is mainly determined by the presence or absence of associated diseases such as cirrhosis or neoplasia. Treatment [in the absence of cirrhosis and neoplasia see surgical guidelines in companion manuscript (5)]: Chronic EHPVO. For children with EHPVO and a cavernoma a meso-Rex bypass has shown promise in expert hands and can be considered as either primary or secondary therapy. There needs to be reasonable certainty that this procedure will be anatomically feasible. (Grade 4) [see practice guidelines addendum] A prospective registry of results of this procedure may be indicated. (Grade 5) For primary prophylaxis of variceal bleeding there is insucient data on whether betablockers or endoscopic therapy should be preferred. See above there is insucient evidence to recommend either b-blocker or endoscopic therapy as primary prophylaxis in children with EHPVO. (Grade 5) For the control of acute variceal bleeding, endoscopic therapy is eective. (1b; A) In the absence of specic data on patients with EHPVO it is presumed that the same treatments used in bleeding cirrhotic patients could be applied. (5; D) For the control of acute variceal bleeding, endoscopic therapy is eective. In the absence of specic data on patients with EHPVO it is presumed that the same treatments used in bleeding cirrhotic patients could be applied. (Grade 4) For secondary prophylaxis, endoscopic therapy is eective. (1b; A) There is insucient evidence to recommend b-blockers. For secondary prophylaxis meso-Rex bypass (Grade 4), endoscopic therapy (Grade 3) or distal splenorenal shunt (Grade 3) are eective. The specic therapy that is utilized is dependent upon local expertise amongst other factors. 903

Shneider et al.

(Grade 5) There is insucient evidence to recommend b-blockers. (Grade 5) There is no consensus on the indication for anticoagulant therapy. Agreed However, in those patients with a persistent documented prothrombotic state, anticoagulant therapy can be considered. Agreed There is insucient evidence in favor of interventional therapy such as TIPS and local thrombolysis. Agreed Decompressive surgery should only be considered for patients with failure of endoscopic therapy. (5; D) Meso-Rex bypass is preferred over shunting when feasible and should be utilized in cases of failure of endoscopic therapy. (Grade 4) For portal biliopathy with obstructive jaundice, endoscopic therapy is recommended. (5; D) In case of failure, shunt surgery may be considered. (5; D) For portal biliopathy with obstructive jaundice, endoscopic biliary therapy is recommended. In case of failure of endoscopic biliary therapy shunt or bypass surgery should be done. Hepaticojejunostomy may be considered to relieve obstructive jaundice. (Grade 4) Recent EHPVO. Recent EHPVO rarely resolves spontaneously. The evidence on which to base recommendations for anti-coagulant therapy is weak.

Role of b-blockers and comparison with endoscopic therapy. Usefulness of long-term anticoagulants, TIPS, shunt surgery. Development of good experimental models.
Providing scientific evidence: RCTs and beyond

In previous Baveno workshops, a session was devoted to the methodological requirements for future trials in portal hypertension. At Baveno IV this session was replaced by one addressing some aspects of therapy in clinical practice that have not been or cannot be evaluated by RCTs, due to: (a) inadequate quality of trials, (b) uncommon diseases or (c) distinct features of the more common diseases. Addressing these issues should contribute to EBM when adequate information from RCTs is not possible to obtain or not yet available.
Possible use of per protocol analysis

On the basis of current expert opinion (5; D), in patients with recent EHPVO: anticoagulation should be given for at least three months in all patients. when an underlying persistent prothrombotic state has been documented, life-long anticoagulant therapy is recommended. In patients with EHPVO and associated cirrhosis, hepatocellular carcinoma should be excluded. There is insucient data on which to base recommendations for giving anticoagulant therapy to these patients. Areas requiring further studies (5; D): Natural history in children vs. adults: hepatic dysfunction, portal biliopathy, growth retardation. Etiology role of various prothrombotic states in EHPVO (in the East), identication of susceptible population. Assessment of thrombosis, progression and recurrence. Denitions of variceal bleeding and predictors of rst bleed and rebleed. 904

In superiority trials, ITT strategies are preferred and PP analysis regarded only as supportive. In non-inferiority trials, ITT and PP approaches (if appropriately pre-dened) may both contribute. When PP results dier from ITT results, the population excluded from PP analysis should be scrutinized. The applicability of the intervention may be questioned.
Assessing changes in therapeutic effects with progression of the disease

To assess how treatment eect may change with disease progression, use interaction tests between outcome predictors and the intervention(s). Both unadjusted results and results adjusted for strong outcome predictors should be provided, regardless of baseline comparisons. Any subgroup analyses should be pre-dened, have sucient power and usually be limited to primary outcome. Otherwise, they are exploratory methods that can help design further studies but should not modify the conclusions of RCTs.
Handling the heterogeneity of RCTs in meta-analysis

1. Heterogeneity can be used cautiously to suggest indications for a particular intervention. 2. This requires that: dierences in trial methodology are not present.

Portal hypertension in children

Clinical source of heterogeneity is identied. 3. Stratied analysis of pooled individual data can be done. Primary/secondary aims should be dened. Plan for statistical analysis should be predened (including multiple testing). Subsequent analysis can use the same pooled data as long as the above protocol is followed.
Identification of factors that modify therapeutic effects in a clinically significant way

Focus on complications of cirrhosis rather than portal hypertension. Selected mix of institutions. Potential interest from both government and industry for funding such a database.
``Survival analysis'' for competing end-points other than death

Physicians must learn how to identify the factors that most often modify the clinical outcome at variance with the results of RCTs. The quality of RCTs (internal and external validity) should be evaluated. The internal validity can be assessed according to the CONSORT statement. The external validity can be assessed according to a list of variables which dene the peculiarity of the trial population: dierences in demography, co-morbidities, limitations due to inclusion/exclusion criteria, variability in the schedules and dosages of drugs, usage of interfering drugs, low compliance, duration of treatment.
Approach to the diagnosis and treatment of uncommon cases where evidence from RCT is not forthcoming

The KaplanMeier plot is often used to estimate the probability of survival free of other end-points, e.g., variceal bleeding. This produces non-interpretable results that may also be biased. The cause is that analysis using censoring of patients assumes that those who die or reach other competing end-points are still at risk for the primary end-point, which is not true (14). For this type of analysis, cumulative hazard plots and Cox regression analysis are better.
Need for international collaboration on clinical trials

Almost all, if not all, RCTs in portal hypertension are underpowered. This applies to uncommon but also common types of conditions associated with portal hypertension. In cardiology and oncology, very large international multinational trials are conducted, so it is feasible! We should do the same for solving our problems in management of portal hypertension.
Conclusions

Consensus-driven, clinical protocols are required to dene the optimal methods for clinical management of uncommon conditions where RCTs cannot be performed. Treatment of uncommon manifestations of portal hypertension with evidence-based medicine awaits the identication of biologically plausible surrogate markers. Alternative study designs (clinical databases, N of 1 trials) should be adapted to identify eective treatments for uncommon manifestations of portal hypertension. Observational studies of treatment eect require statistical techniques to minimize confounding by indication.
Continuous monitoring of the clinical outcome of treatments in so-called clinical databases

1. Development of a database to monitor outcomes is desirable. 2. Goals should include monitoring outcome in: Three major clinical areas in portal hypertension. Specic subgroups. 3. Funding mechanisms should be identied.

The purpose of the consensus denitions about the variceal bleeding episode is to use them in trials and other studies on portal hypertension, as well as in clinical practice. This does not mean that authors cannot use their own denitions, but they are encouraged to use and evaluate in parallel these Baveno IV consensus denitions. This should result in some measure of standardization and increased ease of interpretation among dierent studies. Equally important, if there are uniformly dened end-points, metaanalyses will be based on more homogeneous studies, which is an essential prerequisite of this methodology. It is desirable that future studies be reported using these denitions as part of the evaluation. Change or renement can then take place, as they have at Baveno IV with respect to Baveno II, Reston and Baveno III, to ensure that the consensus denitions do have clinical relevance and are easily applied in practice. Several denitions agreed upon in Baveno I (2), II (3, 4) and III (7, 8) were taken for granted and not discussed in Baveno IV. Interested 905

Shneider et al.

readers can refer to the Baveno I, II (24) and III (7, 8) reports. The suggestions about the topics of future studies reect the opinions of the experts about the areas were new information is most needed. As long as new diagnostic tools and new treatments appear, they will have to be assessed in comparison with present-day standards. These expert opinions are in general not evidence based and do not reect the consensus opinion of the pediatric gastroenterologists/hepatologists. They should serve as the basis for future consensus conferences and for the initiation of prospective studies of portal hypertension in children. It is hoped that Baveno V will be accompanied by a satellite symposium dedicated to pediatric issues.
Acknowledgments
The Baveno IV workshop was endorsed and supported in part by an unrestricted educational grant of the European Association for the Study of the Liver (EASL). The Baveno IV workshop was also endorsed by the Italian Association for the study of the liver (AISF), the Italian Association of hospital gastroenterologists and endoscopists (AIGO), the Italian association for digestive endoscopy (SIED), and the Italian Society of Gastroenterology (SIGE) The 1-day symposium on pediatric portal hypertension was supported by unrestricted educational grants from The Kellner Family Foundation. Reprinted from The Journal of Hepatology, Vol. 43, de Franchis R.J., Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension, 167177, 2005, with permission from the European Association for the Study of the Liver and Dr. Roberto de Franchis.

Vinel, M.D., Toulouse; Germany: M Schepke, M.D., Bonn; India: YC Chawla, M.D., Chandigarh; Italy: G Barosi, M.D., Pavia, M. Merli, A Morabito, M.D., Milano; Massimo Primignani, M.D., Milan; F.Salerno, M.D., Milan; F Schepis, M.D., Modena; M. Zoli, M.D., Bologna; Spain: JG Abraldes, M.D., Barcelona, A Albillos, M.D., Madrid, R Ban ares, M.D., ` s, M.D., Barcelona, R Planas, M.D., Madrid, P Gine Badalona, C. Villanueva, M.D., Barcelona; Switzerland: A Hadengue, M.D., Geneva; Taiwan: HC Lin, M.D., Taipei; GH Lo, M.D. Kaohsiung; The Netherlands: H Janssen, M.D., Rotterdam; H. van Buuren, M.D., Rotterdam; United Kingdom: E Elias, M.D., Birmingham; D. Patch, M.D., London; United Kingdom: A Blei, M.D., Chicago, IL; T. Boyer, M.D., Atlanta, GA; N Chalasani, M.D., Indianapolis, IN; JM Henderson, M.D. Cleveland, OH; Y Iwakiri, M.D., New Haven, CT; WR Kim, Rochester, MN; V Shah, M.D., Rochester, MN; B Shneider, M.D., New York, NY; J Talwalkar, Rochester, MN. The following gave review lectures during the Workshop: Michael Fallon, M.D., Birmingham, AL, USA; Pere ` s, M.D., Barcelona, Spain; Christian Gluud, M.D., Gine Copenhagen, Denmark; Pier Mannuccio Mannucci, M.D., Milan, Italy; Miguel Navasa, M.D., Barcelona, Spain; Luigi Pagliaro, M.D., Palermo, Italy.

References
1. Burroughs AK, ed. Methodology and Review of Clinical Trials in Portal Hypertension. Excerpta Medical Congress Service No. 763. New York, Amsterdam: Oxford, 1987. 2. de Franchis R, Pascal JP, Ancona E, et al. Denitions, methodology and therapeutic strategies in portal hypertension. A consensus development workshop. J Hepatol 1992: 15: 256 261. 3. de Franchis R. Developing consensus in portal hypertension. J Hepatol 1996: 25: 390394. 4. de Franchis R, ed. Portal hypertension II. Proceedings of the Second Baveno International Consensus Workshop on Denitions, Methodology and Therapeutic Strategies. Oxford: Blackwell Science, 1996. 5. Spina GP, Arcidiacono R, Bosch J, et al. Gastric endoscopic features in portal hypertension: Final report of a consensus conference. J Hepatol 1994: 21: 461467. 6. Grace ND, Groszmann RJ, Garcia-Tsao G, et al. Portal hypertension and variceal bleeding: An AASLD single topic symposium. Hepatology 1998: 28: 868880. 7. de Franchis R. Updating consensus in portal hypertension: Report of the Baveno III Consensus Workshop on Denitions, Methodology and Therapeutic Strategies in Portal Hypertension. J Hepatol 2000: 33: 846852. 8. de Franchis R, ed. Portal hypertension III. Proceedings of the IIIrd Baveno International Consensus Workshop on Denitions, Methodology and Therapeutic Strategies. Oxford: Blackwell Science, 2001. 9. http://www.cebm.net/downloads/Oxford_EBM_Levels_5.rtf. 10. de Franchis R. Portal hypertension IV. Proceedings of the IVth Baveno International Consensus Workshop on Methodology of Diagnosis and Treatment in Portal Hypertension. Oxford: Blackwell Science, in press. 11. DAmico G. Esophageal varices: From appearance to rupture; natural history and prognostic indicators. In Groszmann RJ, Bosch J, eds. Portal Hypertension in the 21st Century. Dordrecht: Kluwer Academic Publishers, 2004: pp. 147154. 12. Sarin SK, Lahoti D, Saxena SP, Murthi NS, Makwane UK. Prevalence, classication and natural history of gastric varices: Long-term follow-up study in 568 patients with portal hypertension. Hepatology 1992: 16: 13431349.

Participants
The following chaired sessions during the Workshop: Jaime Bosch, M.D., Barcelona, Spain; Andrew K Burroughs, M.D., London, UK; Gennaro DAmico, M.D., ` n, M.D., BarcePalermo, Italy; Juan Carlos Garcia-Paga lona, Spain; Guadalupe Garcia-Tsao, M.D., New Haven, CT, USA; Norman D Grace, M.D., Boston, MA, USA; Roberto Groszmann, M.D., New Haven CT, USA; Patrick Kamath, M.D., Rochester, MN, USA; Loren Laine, M.D., Los Angeles, CA, USA; Didier Lebrec, M.D., Clichy, ` s, France; Carlo Merkel, M.D., Padua, Italy; Juan Rode M.D., Barcelona, Spain; Shiv K Sarin, New Delhi, India; Tilman Sauerbruch, Bonn, Germany; Thorkild I.A. Srensen, M.D., Copenhagen, Denmark; Dominique Valla, M.D., Clichy, France. The following participated in the presentations and the discussion as panellists: Argentina: J Vorobio, M.D., Rosario; Belgium: F. Nevens, M.D., Leuven; Canada: J Heathcote, M.D., Toronto; N. Marcon, M.D., Toronto; I Wanless, M.D. Toronto; Denmark: F Bendtsen, M.D., Copenhagen; E Christensen, M.D., Copenhagen; Egypt: G Shiha, M.D., al Mansoura; France: B Bernard-Chabert, ` s, M.D., Angers, R. Moreau, M.D., M.D., Reims; P. Cale Clichy, C. Silvain, M.D., Poitiers; D Thabut, M.D., Paris; JP

906

Portal hypertension in children

13. Sarin SK, Agarwal SR. Extraheptic portal vein obstruction. Semin Liver Dis 2002: 22: 4358. 14. Thomsen BL, Mller S, Srensen TIA. The Copenhagen Esophageal Varices Sclerotherapy Project. Optimised analysis of recurrent bleeding and death in patients with cirrhosis and oesophageal varices: Application of a multi-stage competing risk model. J Hepatol 1994: 21: 367375. Tygat N, Bosch J, eds. Portal Hypertension in the 21st Century. Boston, MA: Kluwer Academic Publishers, 2004. 3. Goncalves ME, Cardoso SR, Maksoud JG. Prophylactic sclerotherapy in children with esophageal varices: Long-term results of a controlled prospective randomized trial. J Pediatr Surg 2000: 35: 401405. 4. Zargar SA, Javid G, Khan BA, et al. Endoscopic ligation compared with sclerotherapy for bleeding esophageal varices in children with extrahepatic portal venous obstruction. Hepatology 2002: 36: 666672. 5. Superina R, Shneider B, Emre S, Sarin SK, de Ville de Goyet J. Surgical guidelines for the management of extra-hepatic portal vein obstruction. Pediatr Transplant 2005: (submitted).

Additional Pediatric References

1. de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005: 43: 167176. 2. Shneider B. Approaches to the management of pediatric portal hypertension: Results of an informal survey. In: Groszmann R,

907