Effectiveness and safety of calcium channel blockade for organophosphorus and carbamate anticholinesterase insecticide poisoning (CCBOC study)

通过饮用农业中使用的农药企图自杀（称为“农药自毒”）是全球第二大自杀方式，每年造成超过15万人死亡，其中大部分在贫困的亚洲农村社区。使用的杀虫剂通常储存在家中，在压力或愤怒的时刻很容易获得。重要的是，自我中毒后的生存使家庭，社区和医疗/社会服务能够支持这个人，帮助他们找到不再这样做的理由。被称为有机磷（OP）和氨基甲酸酯杀虫剂的杀虫剂是造成全球约三分之二死亡的原因。它们都能抑制一种叫做乙酰胆碱酯酶的酶，这种酶通常能分解大脑和神经中的化学物质乙酰胆碱。因为它的分解现在停止了，乙酰胆碱积累并导致呼吸问题，即使使用最好的治疗，也可能严重到足以致命。不幸的是，50年来，尽管进行了数千项研究，数百万人死亡，但没有一种新药被引入医疗实践。目前的治疗方法并不总是有效;迫切需要新的治疗方法。钙盐流入神经细胞是使神经工作并与体内其他细胞交流的必要条件。用部分阻断神经细胞通道的药物--钙通道阻断药物[CCB]或镁盐--小心地减少钙的流动，可能会减少杀虫剂的影响，防止死亡。已经在中毒患者中进行了八项镁的研究;有些人认为这种治疗有益，但总体而言，研究规模太小，结果好坏参半。目前还没有关于这些药物是否有效的明确信息，我们建议对孟加拉国4家大型医院收治的OP或氨基甲酸酯中毒患者进行一项大型研究（或随机对照试验，RCT），这些医院的中毒是一个主要问题，每年造成数千人死亡。我们将在3年半的时间里招募大约3,100名患者参加这项研究。随机选择的三分之一的患者将接受常规治疗，而1/3将获得额外的CCB药物，1/3将获得额外的镁。额外治疗将持续2天。我们将检查三组中有多少患者死亡（目前约有11%的患者在正常治疗下死亡），以及有多少患者需要去重症监护病房寻求呼吸帮助（称为机械通气，机器为他们呼吸）。我们将观察这些额外的治疗是否会减少死亡或需要机械通气的患者数量。我们的团队在治疗和研究中毒患者方面拥有丰富的经验，曾在斯里兰卡和孟加拉国进行过类似的农药中毒研究，并领导了最近全球治疗的改善。这项研究将证明这些相对便宜，广泛可用的治疗方法是否有助于中毒患者。这可能会导致50年来第一个针对这些形式的中毒的新治疗方法被引入世界各地的常规医院实践。研究结果将与世界卫生组织和我们在亚洲中毒中心和医院的同事分享。更好的治疗为挽救亚洲农村一些最贫困社区的数万人的生命提供了机会，并减少了儿童，家庭和社区自杀的心碎。它将在孟加拉国建立高质量的基础设施，其他医生和研究人员将能够利用这些基础设施为患有其他疾病和问题的患者开展研究。这项研究将为临床研究人员提供有用的经验，他们将能够用于自己的研究。我们也会与学术实验室合作，进行研究，帮助我们更好地了解这些毒物对人体的影响。

Attempted suicide by drinking pesticides used in farming (called 'pesticide self-poisoning') is the second most important global means of suicide, killing over 150,000 people each year, mostly in poor rural Asian communities. The pesticide used is often stored in the home and easily available at moments of stress or anger. Importantly, survival after self-poisoning allows families, community, and medical/social services to support the person, to help them find reasons not do it again.Pesticides called organophosphorus (OP) and carbamate insecticides are responsible for about two thirds of these deaths across the world. They both inhibit an enzyme called acetylcholinesterase, which usually breaks down the chemical acetylcholine found in the brain and nerves. Because its breakdown is now stopped, acetylcholine accumulates and causes problems with breathing which may be severe enough to kill, even with best available treatment. Unfortunately, no new medicine has been introduced into medical practice for 50 years, despite thousands of studies and millions of deaths. Current treatment does not always work; new treatments are urgently required.Flow of calcium salt into the nerve cells is essential for allowing nerves to work and communicate with other cells in the body. Carefully reducing this flow of calcium with medicines that partially block channels in the nerve cell - calcium channel blocking medicines [CCB] or the magnesium salt - may reduce the pesticides' effects and prevent deaths. Eight studies of magnesium have already been done in poisoned patients; some have suggested benefit from this treatment but overall the studies have been too small and the results mixed. There is no clear information on whether these medicines work.We propose to set up a big study (or randomised controlled trial, RCT) of patients with OP or carbamate poisoning admitted to 4 large Bangladeshi hospitals where this poisoning is a major problem, killing thousands of people each year. We will recruit around 3,100 patients to the study over 3 1/2 years. One third of the patients selected at random will receive routine treatment, while 1/3 will get additional CCB medicines and 1/3 will get the additional magnesium. The extra treatments will be given for 2 days. We will check how many patients die (currently about 11% die with normal treatment) and how many need to go to the intensive care ward for help with their breathing (called mechanical ventilation where a machine breathes for them) across the three groups. We will look to see whether these additional treatments reduce the number of patients dying or needing mechanical ventilation.Our group has a great deal of experience treating and studying poisoned patients, having done similar studies of pesticide poisoning in Sri Lanka and Bangladesh and led recent global improvements in treatment.The study will provide proof about whether these relatively cheap, widely available treatments help the poisoned patients. It potentially will result in the first new treatment for these forms of poisoning for 50 years being introduced in routine hospital practice across the world. The results will be shared with the World Health Organisation and our colleagues in poison centres and hospitals across Asia. Better treatment offers the opportunity to save tens of thousands of lives amongst some of the poorest communities in rural Asia and reduce the heartbreak of suicide amongst children, families, and communities.There will be other benefits from the study. It will set up high-quality infrastructure in Bangladesh that other doctors and researchers will be able to use to set up studies for patients with other diseases and problems. The study will offer useful experience to clinical researchers that they will be able to use for their own research. We will also work with academic laboratories to do studies that will help us better understand the effects of these poisons on human bodies.