Gattini Daniela, Cifuentes Lorena I, Torres-Robles Romina, Gana Juan Cristóbal
Escuela de Medicina, Pontificia Universidad Católica de Chile, Gastroenterology and Nutrition Department, Division of Paediatrics, Santiago, Chile.
Escuela de Medicina, Pontificia Universidad Católica de Chile, Division of Paediatrics, Evidence-based Health Care Programme, Lira 85, 5º piso, Santiago, Metroplitana, Chile, 833-0074.
Cochrane Database Syst Rev. 2020 Mar 5;3(3):CD011573. doi: 10.1002/14651858.CD011573.pub2.
Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including bleeding (haemorrhage) from oesophageal and gastrointestinal varices. Variceal bleeding commonly occurs in children with chronic liver disease or portal vein obstruction. Therefore, prevention is important. Primary prophylaxis of variceal bleeding in adults is the established standard of care because of the results of numerous randomised clinical trials demonstrating the efficacy of non-selective beta-blockers or endoscopic variceal ligation in decreasing the incidence of variceal bleeding. In children, band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding. However, it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children.
To assess the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase Elsevier, and two other registers in February 2019. We scrutinised the reference lists of the retrieved publications, and performed a manual search of the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstracts from January 2008 to December 2018. We searched four registries for ongoing clinical trials. There were no language or document type restrictions.
We included randomised clinical trials irrespective of blinding, language, or publication status assessing sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.
We used standard Cochrane methodology to perform this systematic review. We used the intention-to-treat principle to analyse outcome data, and GRADE to assess the certainty of evidence per outcome.
We found only one randomised clinical trial that fulfilled our inclusion criteria. The trial was at high risk of bias. The trial included 108 Brazilian children with median age of 4.3 years (range 11 months to 13 years). Fifty-six children were randomised to prophylactic sclerotherapy (ethanolamine oleate 2%) and 52 children to no intervention (control). Children were followed up for a median of 4.5 years. Eight children (six from the sclerotherapy group versus two from the control group) dropped out before the end of the trial. The follow-up was from 18 months to eight years. Mortality was 16% (9/56 children) in the sclerotherapy group versus 15% (8/52 children) in the control group (risk ration (RR) 1.04, 95% confidence interval (CI) 0.44 to 2.50; very low-certainty evidence). Upper gastrointestinal bleeding occurred in 21% (12/56) of the children in the sclerotherapy group versus 46% (24/52) in the control group (RR 0.46, 95% CI 0.26 to 0.83; very low-certainty evidence). There were more children with congestive hypertensive gastropathy in the sclerotherapy group than in the control group (14% (8/56) versus 6% (3/52); RR 2.48, 95% CI 0.69 to 8.84; very low-certainty evidence). The incidence of gastric varices was similar between the sclerotherapy group and the control group (11% (6/56) versus 10% (5/52); RR 1.11, 95% CI 0.36 to 3.43; very low-certainty evidence). The incidence of bleeding from gastric varices was higher in the sclerotherapy group than in the control group (4% (3/56) versus 0% (0/52); RR 6.51, 95% CI 0.34 to 123.06; very low-certainty evidence). The study did not assess health-related quality of life. Oesophageal variceal bleeding occurred in 5% (3/56) of the children in the sclerotherapy group versus 40% (21/52) of the children in the control group (RR 0.13, 95% CI 0.04 to 0.42; very low-certainty evidence). The most prevalent complications (defined as non-serious) were pain and fever after the procedure, which promptly resolved with analgesics. However, numerical data on the frequency of these adverse events and their occurrences in the two groups were lacking. No funding information was provided. We found no ongoing trials.
AUTHORS' CONCLUSIONS: The evidence, obtained from one randomised clinical trial at high risk of bias, is very uncertain on whether sclerotherapy has an influence on mortality and if it may decrease first upper gastrointestinal or oesophageal variceal bleeding in children. The evidence is very uncertain on whether sclerotherapy has an influence on congestive hypertensive gastropathy, incidence on gastric varices, and incidence of bleeding from gastric varices. Health-related quality of life was not measured. There were no serious events caused by sclerotherapy, and analysis of non-serious adverse events could not be performed due to lack of numerical data. The GRADE assessment of each outcome showed a very low-certainty evidence. The results of the trial need to be interpreted with caution. Larger randomised clinical trials, following the SPIRIT and CONSORT statements, assessing the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are needed. The trials should include important clinical outcomes such as death, failure to control bleeding, and adverse events.
门静脉高压常伴随晚期肝病出现，且常引发危及生命的并发症，包括食管和胃肠道静脉曲张破裂出血（大出血）。静脉曲张破裂出血常见于患有慢性肝病或门静脉阻塞的儿童。因此，预防至关重要。鉴于众多随机临床试验结果表明非选择性β受体阻滞剂或内镜下静脉曲张结扎术在降低静脉曲张破裂出血发生率方面的有效性，成人静脉曲张破裂出血的一级预防已成为既定的标准治疗方法。在儿童中，已提出套扎术、β受体阻滞剂和硬化疗法作为食管静脉曲张破裂出血一级预防的替代方法。然而，这些治疗方法用于儿童一级预防时是有益还是有害尚不清楚。
评估硬化疗法与假手术或不干预相比，对患有慢性肝病或门静脉血栓形成的儿童食管静脉曲张破裂出血一级预防的益处和危害。
我们于2019年2月检索了Cochrane肝胆疾病组对照试验注册库、Cochrane系统评价数据库、PubMed、Embase Elsevier以及另外两个注册库。我们仔细查阅了检索到的出版物的参考文献列表，并对2008年1月至2018年12月期间主要的儿科胃肠病学和肝病学会议（NASPGHAN和ESPGHAN）的摘要进行了手工检索。我们在四个注册库中检索了正在进行的临床试验。没有语言或文献类型限制。
我们纳入了随机临床试验，无论是否采用盲法、语言或发表状态，评估硬化疗法与假手术或不干预相比，对患有慢性肝病或门静脉血栓形成的儿童食管静脉曲张破裂出血一级预防的效果。
我们采用标准的Cochrane方法进行这项系统评价。我们采用意向性分析原则分析结局数据，并使用GRADE评估每个结局的证据确定性。
我们仅发现一项符合纳入标准的随机临床试验。该试验存在较高的偏倚风险。该试验纳入了108名巴西儿童，中位年龄为4.3岁（范围为11个月至13岁）。56名儿童被随机分配至预防性硬化疗法组（2%油酸乙醇胺），52名儿童被分配至不干预组（对照组）。儿童的中位随访时间为4.5年。8名儿童（硬化疗法组6名，对照组2名）在试验结束前退出。随访时间为18个月至8年。硬化疗法组的死亡率为16%（9/56名儿童），对照组为15%（8/52名儿童）（风险比（RR）1.04，95%置信区间（CI）0.44至2.50；极低确定性证据）。硬化疗法组21%（12/56）的儿童发生上消化道出血，对照组为46%（24/52）（RR 0.46，95%CI 0.26至0.83；极低确定性证据）。硬化疗法组充血性高血压性胃病的儿童多于对照组（14%（8/56）对6%（3/52）；RR 2.48，95%CI 0.69至8.84；极低确定性证据）。硬化疗法组和对照组胃静脉曲张的发生率相似（11%（6/56）对10%（5/52）；RR 1.11，95%CI 0.36至3.43；极低确定性证据）。硬化疗法组胃静脉曲张出血的发生率高于对照组（4%（3/56）对0%（0/52）；RR 6.51，95%CI 0.34至123.06；极低确定性证据）。该研究未评估健康相关生活质量。硬化疗法组5%（3/56）的儿童发生食管静脉曲张破裂出血，对照组为40%（21/52）（RR 0.13，95%CI 0.04至0.42；极低确定性证据）。最常见的并发症（定义为非严重并发症）是术后疼痛和发热，使用镇痛药后可迅速缓解。然而，缺乏关于这些不良事件发生频率及其在两组中发生情况的数值数据。未提供资金信息。我们未发现正在进行的试验。
从一项存在较高偏倚风险的随机临床试验获得的证据非常不确定硬化疗法是否会影响死亡率，以及是否会降低儿童首次上消化道或食管静脉曲张破裂出血的发生率。关于硬化疗法是否会影响充血性高血压性胃病、胃静脉曲张发生率以及胃静脉曲张出血发生率的证据也非常不确定。未测量健康相关生活质量。硬化疗法未导致严重事件，且由于缺乏数值数据，无法对非严重不良事件进行分析。对每个结局的GRADE评估显示证据确定性极低。该试验结果需谨慎解读。需要按照SPIRIT和CONSORT声明进行更大规模的随机临床试验，评估硬化疗法与假手术或不干预相比，对患有慢性肝病或门静脉血栓形成的儿童食管静脉曲张破裂出血一级预防的益处和危害。这些试验应包括重要的临床结局，如死亡、出血控制失败和不良事件。
