What Is Known
- Primary prophylactic treatment is recommended in adults with portal hypertension and a high risk of variceal bleeding.
- There are few studies in the paediatric population, and therefore no guidelines to advise appropriate management.
What Is New
- All centres surveyed agree on the need to screen every child with clinical signs of portal hypertension by gastroscopy.
- All endoscopists surveyed use the definition of high-risk varices developed by Duché et al for biliary atresia.
- All centres surveyed perform primary prophylaxis in cases of high-risk varices.
See “Tacit Consensus” by Shneider on page 497.
Children with portal hypertension are at risk of bleeding and have a poor prognosis (1,2). Primary prophylaxis in children could play a role as a bridge to liver transplantation (in cases of liver cirrhosis mainly biliary atresia) and providing time for patients awaiting portal derivation surgery such as a meso-Rex bypass (in cases of portal cavernoma).
In the adult population, it has been well documented that primary prophylaxis decreases the bleeding risk from 30% to 15% and improves survival (3–5). Noncardioselective beta-blockers (NCSBB) remain the preferred primary prophylactic treatment for small varices with a high risk of bleeding (Child Pugh B or C or red wale marks) (4). Endoscopic variceal ligation (EVL) is employed in cases of grade 2 or 3 varices, with equivalent efficacy to NCSBB, but with less contraindications and better clinical tolerance (5). Sclerotherapy is no longer used in adults because of its more frequent and serious adverse effects as compared to EVL (6,7).
In the paediatric population, EVL and sclerotherapy are considered the methods of choice in the treatment of oesophageal variceal haemorrhage and prevention of rebleeding (8)—sclerotherapy being reserved for small children in whom it is not anatomically possible to use the equipment for EVL. Nevertheless, the use of sclerotherapy, EVL, and NCSBB in primary prophylaxis remains controversial because of the lack of data about the efficacy and safety of these treatments, and of the lack of a large consensus on the definition of the endoscopic patterns of high-risk varices predictive of the bleeding risk. There are currently no clear recommendations to guide clinical management in these patients (9).
The aim of the present study is to assess the clinical practice of endoscopic and pharmacological primary prophylaxis for portal hypertension in children with a high risk of bleeding in France and French-speaking Belgium, Switzerland, and Quebec.
MATERIALS AND METHODS
A total of 38 French-speaking hospitals were contacted by mail or by telephone from March to June 2015 (all 35 French University and Regional Paediatric Hospitals, Sainte Justine in Montreal Quebec, Saint Luc in Brussels Belgium, and The University Hospital in Geneva Switzerland).
The centres were each sent a questionnaire regarding their management of children suspected of having portal hypertension and a high risk of bleeding (Table 1). The diagnosis of portal hypertension was considered in patients with palpable splenomegaly, thrombocytopenia (platelets <149 × 109/L) or specific findings on ultrasound (thickening of the small omentum, flow reversal of the portal vein, or bypass veins).
Oesophageal varices were graded according to Cales’ classification developed for adults (10) and oesogastric varices type 1 or 2 (OGV1 or OGV2) according to Sarin and Kumar's (11) classification.
The data were collected and analysed using Microsoft Excel spreadsheet (2010 version). Frequencies (in absolute numbers) and averages (in percentages) were calculated.
The study was conducted according to the principles of the Declaration of Helsinki.
Twenty-eight out of 38 centres returned a completed questionnaire, and thus a 74% of response rate.
Among these 28 centres, 20 (71%) perform primary prophylaxis for portal hypertension within their institution, 1 (4%) does so only for patients with cystic fibrosis because of its particular medical recruitment, and 7 (25%) refer their patients to a tertiary centre.
The number of patients followed each year is shown in Figure 1, and the proportion of centres practicing screening endoscopy and primary prophylaxis is shown in Figure 2.
The prophylactic techniques used for each grade of varices are reported Figure 3.
Twenty out of 21 centres stated that their method of choice is EVL when possible.
In order to be suitable for EVL, 17 centres reported a minimum age range of 8 to 12 months and a minimum weight of at least 8 to 10 kg. One centre reported the successful use of EVL in a 5-month-old child weighing 6.5 kg.
Regarding primary prophylaxis with NCSBB, 8 centres reported the occasional use of this therapy, with a wide range of dosages being employed, typically an initial dose of 1 to 3 mg/kg with an incremental dose augmentation over time. Clinical endpoints varied across sites: a decrease in heart rate of 10% to 25%, a resting heart rate <80 beats per minute, and a decrease in the clinical grade of oesophageal varices.
Finally, there were no death, no cases of immediate haemorrhage, and no severe adverse events reported. Nevertheless 2 centres reported rare cases of perforation after sclerotherapy (see Supplemental Digital Content, http://links.lww.com/MPG/A826).
This epidemiological observational study focuses on the current practice of primary prophylactic treatment of portal hypertension in children with high risk of bleeding, in France, Quebec, Belgium, and Switzerland.
In respect to the potential benefit of endoscopic screening, the results show that despite the absence of high-level evidence, 85% of responding centres perform screening gastroscopy to follow-up children deemed to be at risk of portal hypertension in cases of biliary atresia and all of them do so (100%) in cases of portal cavernoma. The use of screening gastroscopy in cases of cystic fibrosis is less common, probably due to chronic lung disease conferring a higher risk for general anaesthesia. It is also less common in cases of other chronic fibrotic liver diseases, in which portal hypertension often occurs later.
In cases of biliary atresia (12,13) endoscopic screening could start by the age of 6 months in patients with failed portoenterostomy when serum bilirubin concentration rises >40 μmol/L, or when clinical splenomegaly or thrombocytopenia first occur. A child affected with biliary atresia younger than 12 months of with a bilirubin concentration >100 μmol/L or with 1 or more grade 1 varix is at high risk of developing rapidly life-threatening varices. This cannot, however, be extrapolated to other causes of portal hypertension and requires further investigation because these are isolated studies.
Regarding the potential benefit of primary prophylaxis, the results also show that all centres provide primary prophylaxis when they consider that the bleeding risk is high, based on endoscopic findings: OGV1, grade 2 varices with red marks, and grade 3 varices. This correlates with the definition of high-risk varices as suggested by Duché et al (14) in cases of biliary atresia.
Scientific data in the paediatric population are lacking because of the difficulty in carrying out studies looking at primary prophylaxis. There are obvious ethical challenges, and double blinding is rarely possible (15). The few currently available retrospective studies on primary prophylaxis show that sclerotherapy and EVL are effective techniques in decreasing the risk of bleeding from oesophageal varices (16–23). Only 1 prospective study (24) compared sclerotherapy to a control group and showed a decrease in the overall incidence of bleeding; however, there was no difference in overall survival.
Schneider et al (9) stated in 2016 that prophylactic therapy with EVL may be considered only in selected children, and that NCSBB should be avoided while there is no evidence concerning the dosage, efficacy, and safety.
With respect to the reported use of primary prophylaxis, the results show that 67% of centres do not perform any primary prophylaxis in cases of grade 1 varices with red marks, or grade 2 varices without red marks. Although all centres concur with the need for primary prophylaxis in cases of grade 2 varices with red marks, this was not the case for grade 3 varices: 19 centres (90%) reported the use of primary prophylaxis in such patients, although it is not clear why the remaining 2 did not do similarly. Only 11 centres (52%) use primary prophylaxis in cases of OGV1. It is now well understood that the presence of large varices and red marks increases the risk of bleeding (25). Duché et al (14) suggest that in cases of biliary atresia primary prophylaxis is beneficial in the presence of OGV1 (irrespective of the grade of the oesophageal varices), grade 2 varices with red marks, and grade 3 varices. It is worth noting, however, that grading of varices has not yet been standardized in children. D’Antiga et al (26) recently demonstrated reasonably consistent agreement on endoscopic features of portal hypertension in children amongst experienced paediatric endoscopists.
Regarding the choice of prophylactic treatment, approximately 20% of centres report using NCSBB if deemed appropriate (predominantly in cases of OGV1 or OGV2), despite the debate about adverse effects and the absence of consensual monitoring (4). Nevertheless, a prospective Indian study conducted by Samanta et al (27) reported no adverse event with the use of propranolol or carvedilol in a cohort of 62 children, with a statistically significant decrease of varices.
The results from our study demonstrate that all centres prefer an endoscopic technique for primary prophylaxis when deemed necessary, and furthermore that EVL is preferred over sclerotherapy, which is consistent with the previously published risks of the latter (8), except for small children in whom it is not anatomically possible. Regarding OGVs, most OGV1 can be treated at the same time as oesophageal varices ligation. OGV2 are rare and treated on a case-by-case basis.
Regrettably, there are 2 major limitations of the present study: firstly one quarter (26%) of the centres approached did not respond to the questionnaire. Secondly, without direct access to the medical records we assume that the reported data accurately reflects local practice. Furthermore, we have neither the mean age of the children in whom primary prophylaxis was undertaken nor the exact number of children concerned. Nevertheless, taking into account the lower limit stated by each centre, we count a minimum of 427 children, which represents a substantial number.
In conclusion, our findings suggest that despite the absence of scientific recommendations there is a tacit consensus, regarding the need to screen children with portal hypertension with gastroscopy, the definition of the endoscopic patterns of high-risk varices, and the need to provide primary prophylaxis for these varices.
The challenge in recommending primary prophylaxis in children is 2-fold.
Firstly, an agreement has yet to be found amongst specialists about the definition of the endoscopic predictive signs of variceal bleeding; we suggest the presence of OGV1, of grade 2 varices with red marks, or of grade 3 varices.
Secondly, the benefits of primary prophylaxis with respect to morbidity and mortality are still debated as prospective studies are notably difficult to undertake because of ethical considerations. Such a study has therefore some part to play in the medical progress by collecting all clinical practice from all medical centres. And actually the results of the present study advocate the need for primary prophylaxis in cases of portal hypertension with a high bleeding risk.
The authors would like to acknowledge S. Berthet (Nice), C. Borderon (Clermont-Ferrand), L. Bridoux-Henno (Rennes), P. Broue (Toulouse), J. Cardona (Poitiers), N. Catteau (Nîmes), A. Comte (Besançon), S. Destombe (St Etienne), G. Dimitrov (Orléans), M. Duché (Paris-Bicêtre), Y. Hatchuel (Fort de France), F. Lacaille (Paris-Necker), A. Lachaux (Lyon), T. Lamireau (Bordeaux), J. Languepin (Limoges), M. Laurans (Caen), J. Lemale (Paris-Trousseau), S. Marineau (Ste Justine, Quebec), S. Mclin (Geneve, Switzerland), L. Michaud (Lille), O. Mouterde (Rouen), A. Munck (Paris-Debré), J. Rebeuh (Strasbourg), B. Roquelaure (Marseille), X. Stephenne (St Luc, Belgium), N. Thomassin (Grenoble), A. Turquet (La Réunion), and S. Willot (Tours) for completing the questionnaire. The authors also thank Matthew Aldred, MD (Queen Mary Hospital, Hong Kong) for the English revision.
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