Transfusion and Treatment of severe Anaemia in African Children: a randomised controlled trial (TRACT)

在撒哈拉以南非洲，严重贫血是儿童最终住院的最常见原因之一。它可以直接杀死儿童，也间接导致每年80万儿童疟疾死亡。对于因严重贫血（定义为血红蛋白低于6 g/dl）住院的儿童，结局仍然很差，9-10%在住院期间死亡，另有12%在入院后6个月内死亡-另有6%的严重贫血需要额外治疗和再次住院。高6个月的病死率和慢性持续健康问题的儿童与这种情况表明，目前的建议和/管理策略是不工作的实践。由于严重贫血非常常见，在初步诊断后出现的高“隐性”疾病和死亡率可能会导致5岁以下儿童的总体死亡率。因此，如果不加以适当解决，严重贫血可能成为实现关于非洲儿童生存的千年发展目标4的障碍。这项试验的研究者包括儿童健康、传染病、输血医学和贫血研究方面的专家。他们在非洲资源有限的医院进行大型临床试验方面经验丰富。通过对现有数据和文献的广泛审查，该小组确定了需要在临床试验中解决的重度贫血管理的关键领域，即1/哪些儿童应该接受输血？目前的世卫组织指南旨在避免过度输血，建议仅在血红蛋白（Hb）<4g/dl（或<6 g/dl，如果伴有并发症）的儿童中输血。这些具体建议尚未在临床试验中进行评估，因此非洲各国的做法各不相同。我们不知道给所有Hb <6 g/dl的孩子输血是否会有帮助。2、一次输血应该输多少血？根据目前的建议，四分之一接受输血的儿童仍然严重贫血，多达三分之一的儿童在一次住院期间接受两次或两次以上的输血。我们不知道提供更大的初始血量是否会有帮助-这也可以减少额外输血的风险（包括血液匹配不良或血液感染），以及卫生人员准备血液所花费的时间。3/儿童入院后应获得哪些长期支持？与长期结果不佳相关的主要因素是多种维生素和矿物质缺乏以及细菌引起的血液感染--我们不知道服用维生素补充剂或抗生素来预防感染是否会改善结果。TRACT旨在回答这些问题。这是一项随机对照试验，涉及马拉维和乌干达3700名患有严重贫血的2个月至12岁儿童。该试验将持续2年，儿童将接受6个月的随访，以确保获得长期结果。该试验将同时研究三种可能改善严重贫血管理的方法-旨在减少早期和晚期死亡，以及贫血复发或再次入院。该试验将比较（i）目前保守的WHO输血建议与更自由的方法，在谁获得血液和他们获得多少血液方面（iii）与WHO推荐的标准叶酸盐/铁相比，额外的多种维生素多种矿物质补充剂和（iii）抗生素复方新诺明，以预防新的细菌感染3个月与无抗生素相比。该设计具有广泛的实用性，主要是临床纳入标准，因此可以在入院时快速识别和招募儿童。干预措施切实可行;许多已经用于其他疾病，因此在试验结束时，可以在非洲资源不足的儿科卫生设施中实施。

In sub-Saharan Africa severe anaemia is one of the most common reasons why children end up in hospital. It can kill children directly - and also contributes indirectly to the 800,000 child malaria deaths/year. For children hospitalised with severe anaemia (defined as a haemoglobin below 6g/dl) outcomes remain poor, with 9-10% dying in-hospital and an additional 12% dying in the 6 months following admission - and a further 6% having another episode of severe anaemia requiring additional treatment and re-hospitalisation. The high 6-month case fatality and chronic ongoing health issues of children with this condition indicate that the current recommendations and/ management strategies are not working in practice. Because severe anaemia is very common, the high 'hidden' sickness and mortality occurring after the initial diagnosis is likely to contribute to overall under-five mortality. If not adequately addressed, severe anaemia may therefore be an obstacle to achievement of the Millennium Development Goal No.4 on child survival in Africa. The investigators in this trial include specialists in child health, infectious diseases, transfusion medicine, and anaemia research. They have considerable experience in doing large clinical trials in hospitals with limited resources in Africa. Through extensive review of the available data and literature, the group have identified key areas of severe anaemia management which need to be addressed in a clinical trial, namely1/Which children should receive a transfusion? Current WHO guidelines, designed to avoid overuse of blood, recommend transfusions only in children with a haemoglobin (Hb) <4g/dl (or <6g/dl if accompanied by complications). These specific recommendations have not been evaluated in clinical trials and thus practice varies across African countries. We don't know if giving blood to all children with Hb <6g/dl would help. 2/ How much blood should be given in a transfusion? On current recommendations a quarter of children receiving transfusions remain severely anaemic and up to one third get two or more blood transfusions during a single hospital admission. We don't know if giving larger initial volumes of blood would help - this could also reduce risks from additional transfusion (which include bad blood matching or blood infections), and the amount of time health personnel spend getting blood ready. 3/ What, if any, longer-term support should children get after hospital admission? The major factors related to poor longer term outcome are multiple vitamin and mineral deficiencies and blood infections caused by bacteria - we don't know if giving vitamin supplements or antibiotics to prevent infections would improve outcomes. TRACT is designed to answer these questions. It is a randomised controlled trial involving 3700 children aged 2 months to 12 years admitted to hospitals with severe anaemia in Malawi and Uganda. The trial will take place over 2 years and children will be followed up for 6 months to make sure longer-term outcomes are captured. The trial will simultaneously look at three ways management of severe anaemia might be improved - with the aim of reducing early and late deaths, and anaemia recurrence or readmission to hospital. The trial will compare (i) current conservative WHO recommendations for transfusion against a more liberal approach, in terms of who gets blood and how much blood they get (iii) additional multi-vitamin multi-mineral supplements compared with the standard folate/iron recommended by WHO and (iii) an antibiotic, cotrimoxazole, to prevent new bacterial infections for 3 months compared with no antibiotic. The design is practical with broad, largely clinical inclusion criteria, so that children can be rapidly identified and recruited at hospital admission. The interventions are practical; many are already in use for other diseases so could be implemented in under-resourced paediatric health facilities across Africa at the end of the trial.