In a randomized controlled trial of individuals who had taken organophosphorus insecticides, Michael Eddleston and colleagues find that there is no evidence that the addition of the antidote pralidoxime offers benefit over atropine and supportive care.
Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit.
Methods and Findings
We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 0.88–3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 [21.5%], placebo 24/114 [21.1%], adjusted HR 1.27 [95% CI 0.71–2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit.
Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required.
Please see later in the article for Editors' Summary
Each year, about 200,000 people worldwide die from poisoning with organophosphorous insecticides, toxic chemicals that are widely used in agriculture, particularly in developing countries. Organophosphates disrupt communication between the brain and the body in both insects and people. The brain controls the body by sending electrical impulses along nerve cells (neurons) to the body's muscle cells. At the end of the neurons, these impulses are converted into chemical messages (neurotransmitters), which cross the gap between neurons and muscle cells (the neuromuscular junction) and bind to proteins (receptors) on the muscle cells that pass on the brain's message. One important neurotransmitter is acetylcholine. This is used at neuromuscular junctions, in the part of the nervous system that controls breathing and other automatic vital functions, and in parts of the central nervous system. Normally, the enzyme acetylcholinesterase quickly breaks down acetylcholine after it has delivered its message, but organophosphates inhibit acetylcholinesterase and, as a result, disrupt the transmission of nerve impulses at nerve endings. Symptoms of organophosphate poisoning include excessive sweating, diarrhea, muscle weakness, and breathing problems. Most deaths from organophosphate poisoning are caused by respiratory failure.
Why Was This Study Done?
Treatment for organophosphorous insecticide poisoning includes resuscitation and assistance with breathing (intubation) if necessary and the rapid administration of atropine. This antidote binds to “muscarinic” acetylcholine receptors and blocks the effects of acetylcholine at this type of receptor. Atropine can only reverse some of the effects of organophosphate poisoning, however, because it does not block the activity of acetylcholine at its other receptors. Consequently, the World Health Organization (WHO) recommends that a second type of antidote called an oxime acetylcholinesterase reactivator be given after atropine. But, although the beneficial effects of atropine are clear, controversy surrounds the role of oximes in treating organophosphate poisoning. There is even some evidence that the oxime pralidoxime can be harmful. In this study, the researchers try to resolve this controversy by studying the effects of pralidoxime treatment on patients poisoned by organophosphorous insecticides in Sri Lanka in a randomized controlled trial (a study in which groups of patients are randomly chosen to receive different treatments).
What Did the Researchers Do and Find?
The researchers enrolled 235 adults who had been admitted to two Sri Lankan district hospitals with organophosphorous insecticide self-poisoning (in Sri Lanka, more than 70% of fatal suicide attempts are the result of pesticide poisoning). The patients, all of whom had been given atropine, were randomized to receive either the WHO recommended regimen of pralidoxime or saline. The researchers determined how much and which pesticide each patient had been exposed to, measured the levels of pralidoxime and acetylcholinesterase activity in the patients' blood, and monitored the patients' progress during their hospital stay. Overall, 48 patients died—30 of the 121 patients who received pralidoxime and 18 of the 114 control patients. After adjusting for the baseline characteristics of the two treatment groups and for intubation at baseline, pralidoxime treatment increased the patients' risk of dying by two-thirds, although this increased risk of death was not statistically significant. In other words, this result does not prove that pralidoxime treatment was bad for the patients in this trial. However, in further analyses that adjusted for the ingestion of different insecticides, the baseline levels of insecticides in patients' blood, and other prespecified variables, pralidoxime treatment always increased the patients' risk of death.
What Do These Findings Mean?
These findings provide no evidence that the WHO recommended regimen of pralidoxime improves survival after organophosphorous pesticide poisoning even though other results from the trial show that the treatment reactivated acetylcholinesterase. Indeed, although limited by the small number of patients enrolled into this study (the trial recruited fewer patients than expected because results from another trial had a deleterious effect on recruitment), these findings actually suggest that pralidoxime treatment may be harmful at least in self-poisoned patients. This suspicion now needs be confirmed in trials that more fully assess the risks/benefits of oximes and that explore the effects of different dosing regimens and/or different oximes.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000104.
The US Environmental Protection Agency provides information about all aspects of insecticides (in English and Spanish)
Toxtown, an interactive site from the US National Library of Medicine provides information on exposure to pesticides and other environmental health concerns (in English and Spanish)
The US National Pesticide Information Center provides objective, science-based information about pesticides (in English and Spanish)
MedlinePlus also provides links to information on pesticides (in English and Spanish)
For more on Poisoning Prevention and Management see WHO's International Programme on Chemical Safety (IPCS)
WikiTox, a clinical toxicology teaching resource project, has detailed information on organophosphates