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

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.

Current treatment for anticholinesterase poisoning is often ineffective, resulting in tens of thousands of deaths. Presynaptic acetylcholine (ACh) release is controlled by Ca2+ flow into the terminus. Reduction of the pre-synaptic Ca2+ load, using Mg2+ or calcium channel blockers, may reduce ACh release and overstimulation that causes acute toxicity and delayed respiratory failure. Eight small clinical studies, of varying quality, have suggested that MgSO4 may reduce mortality and intubation/ventilation (meta-analysis odds ratios: 0.55 [95%CI 0.32-0.94] and 0.52 [0.34-0.79], respectively).

We aim to set up an open pragmatic RCT in four Bangladeshi hospitals to determine whether addition of intravenous MgSO4 or nimodipine to standard therapy (supportive care, atropine and for OPs pralidoxime) reduces deaths after acute OP or carbamate poisoning. Primary outcome will be in-hospital all-cause mortality; secondary outcomes will include % intubated and duration of ventilation.

In these hospitals, 11% of patients die under usual care. The anticipated treatment effect is a reduction to 7% i.e. an absolute decrease of 4% with either MgSO4 or nimodipine. This reduction would be sufficient to have either treatment adopted as the new standard of care. The study would have 80% power at 2.5% level of significance to detect a 4% reduction from 11% with 1,022/arm. We will use group sequential design to conduct formal interim analysis, increasing the sample size to 1,033/arm. The hospitals admit 1800 patients/year; we expect to recruit around 70% as in our previous trials.

The RCT will provide definitive data concerning the effectiveness of these affordable, widely available therapies and potentially introduce the first new treatment for OP anticholinesterase poisoning for 50 years. Improved therapy offers the opportunity to save tens of thousands of lives amongst some of the world's poorest populations and reduce the familial and community heartbreak of suicide.

The main potential beneficiaries from this research will be patients with pesticide self-poisoning presenting to hospital in rural communities across the world, their families and communities who suffer the effects of suicide, the clinicians who currently have only moderately effective treatments, the overstretched health care systems that must care for these patients, and the government that sets up and funds hospitals.

Pesticide self-poisoning is the second most important cause of suicide worldwide, after hanging. Every year at least one million people drink agricultural pesticides and 150,000 die, many of them from the anticholinesterase insecticides under study here. Importantly, unlike hanging, many patients reach hospital alive. Therefore, improving medical therapy has a real chance of preventing deaths and allowing people to survive long enough to receive community and medical/social support.

Globally, case fatality for OP and carbamate insecticide self-poisoning is around 10%, depending on the particular insecticides ingested, despite best current therapy with supportive care, atropine and oxime drugs. A novel, affordable, and widely available therapy such as magnesium sulfate or nimodipine, if effective, would prevent thousands of deaths each year.

Every suicide is estimated to affect at least six other people - family and friends. An effective antidote that saves lives would dramatically improve the situation of these relatives and the community.

Clinicians caring for these patients have been using the same medicines for the last 50 years. Recent research from our collaboration has clearly shown how atropine can best be used. This research offers the opportunity to finally add another treatment option to standard care that will complement the effect of atropine.

We have shown that the main cost to Asian healthcare services for self-poisoning is that of intensive care for OP and carbamate insecticide poisoning. An antidote that reduced the need for intubation, ventilation, and intensive care, and the duration of mechanical ventilation, would offer marked benefits to hospitals and governments.