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1.  Effect of the UK’s revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment 
In September 2012 the UK’s Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single ‘100 mg l−1’ nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning.
Data were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90 000 patients/annum with paracetamol overdose.
There were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15 min 87/323 [26.9%], 60 min 145/514 [28.2%]; increase: 1.3% [95% CI –4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is £8.3 million (6.4 million–10.2 million) annually, with a cost-per-life saved of £17.4 million (13.4 million–21.5 million).
The changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.
PMCID: PMC4243911  PMID: 24666324
acetylcysteine; adverse effects; paracetamol; poisoning; regulation
2.  Suicide in Sri Lanka 1975–2012: age, period and cohort analysis of police and hospital data 
BMC Public Health  2014;14(1):839.
Sri Lanka has experienced major changes in its suicide rates since the 1970s, and in 1995 it had one of the highest rates in the world. Subsequent reductions in Sri Lanka’s suicide rates have been attributed to the introduction of restrictions on the availability of highly toxic pesticides. We investigate these changes in suicide rates in relation to age, gender, method specific trends and birth-cohort and period effects, with the aim of informing preventative strategies.
Secular trends of suicide in relation to age, sex, method, birth-cohort and period effects were investigated graphically using police data (1975–2012). Poisoning case-fatality was investigated using national hospital admission data (2004–2010).
There were marked changes to the age-, gender- and method-specific incidence of suicide over the study period. Year on year declines in rates began in 17–25 year olds in the early 1980s. Reduction in older age groups followed and falls in all age groups occurred after all class I (the most toxic) pesticides were banned. Distinct changes in the age/gender pattern of suicide are observed: in the 1980s suicide rates were highest in 21–35 year old men; by the 2000s, this pattern had reversed with a stepwise increase in male rates with increasing age. Throughout the study period female rates were highest in 17–25 year olds. There has been a rise in suicide by hanging, though this rise is relatively small in relation to the marked decline in self-poisoning deaths. The patterns of suicides are more consistent with a period rather than birth-cohort effect.
The epidemiology of suicide in Sri Lanka has changed noticeably in the last 30 years. The introduction of pesticide regulations in Sri Lanka coincides with a reduction in suicide rates, with evidence of limited method substitution.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-839) contains supplementary material, which is available to authorized users.
PMCID: PMC4148962  PMID: 25118074
Sri Lanka; Pesticide poisoning; Suicide; Period effects; Birth-cohort effects
3.  Challenges and opportunities of a paperless baseline survey in Sri Lanka 
BMC Research Notes  2014;7:452.
Personal digital assistants (PDAs) have been shown to reduce costs associated with survey implementation and digitisation, and to improve data quality when compared to traditional paper based data collection. Few studies, however, have shared their experiences of the use of these devices in rural settings in Asia. This paper reports on our experiences of using a PDA device for data collection in Sri Lanka as part of a large cluster randomised control trial.
We found that PDAs were useful for collecting data for a baseline survey of a large randomised control trial (54,000 households). We found that the PDA device and survey format was easy to use by inexperienced field staff, even though the survey was programmed in English. The device enabled the rapid digitisation of survey data, providing a good basis for continuous data quality assurance, supervision of staff and survey implementation. An unexpected advantage was the improved community opinion of the research project as a result of the device, because the use of the technology gave data collectors an elevated status amongst the community. In addition the global positioning system (GPS) functionality of the device allowed precise mapping of households, and hence distinct settlements to be identified as randomisation clusters. Future users should be mindful that to save costs the piloting should be completed before programming. In addition consideration of a local after-care service is important to avoid costs and time delays associated with sending devices back to overseas providers.
Since the start of this study, PDA devices have rapidly developed and are increasingly used. The use of PDA or similar devices for research is not without its problems; however we believe that the universal lessons learnt as part of this study are even more important for the effective utilisation of these rapidly developing technologies in resource poor settings.
PMCID: PMC4118630  PMID: 25027231
Sri Lanka; Computer; Handheld; Data collection; Randomised control trial; Epidemiology
4.  Protein tyrosine adduct in humans self-poisoned by chlorpyrifos 
Toxicology and applied pharmacology  2013;269(3):215-225.
Studies of human cases of self-inflicted poisoning suggest that chlorpyrifos oxon reacts not only with acetylcholinesterase and butyrylcholinesterase but also with other blood proteins. A favored candidate is albumin because in vitro and animal studies have identified tyrosine 411 of albumin as a site covalently modified by organophosphorus poisons. Our goal was to test this proposal in humans by determining whether plasma from humans poisoned by chlorpyrifos has adducts on tyrosine. Plasma samples from 5 self-poisoned humans were drawn at various time intervals after ingestion of chlorpyrifos for a total of 34 samples. All 34 samples were analyzed for plasma levels of chlorpyrifos and chlorpyrifos oxon (CPO) as a function of time post-ingestion. Eleven samples were analyzed for the presence of diethoxyphosphorylated tyrosine by mass spectrometry. Six samples yielded diethoxyphosphorylated tyrosine in pronase digests. Blood collected as late as 5 days after chlorpyrifos ingestion was positive for CPO-tyrosine, consistent with the 20-day half-life of albumin. High plasma CPO levels did not predict detectable levels of CPO-tyrosine. CPO-tyrosine was identified in pralidoxime treated patients as well as in patients not treated with pralidoxime, indicating that pralidoxime does not reverse CPO binding to tyrosine in humans. Plasma butyrylcholinesterase was a more sensitive biomarker of exposure than adducts on tyrosine. In conclusion, chlorpyrifos oxon makes a stable covalent adduct on the tyrosine residue of blood proteins in humans who ingested chlorpyrifos.
PMCID: PMC3677773  PMID: 23566956
chlorpyrifos; diethoxyphosphorylated tyrosine; butyrylcholinesterase; albumin; poisoned patients; mass spectrometry
5.  The construction and evaluation of a device for mechanomyography in anaesthetized Göttingen minipigs 
To devise a method for assessing evoked muscle strength on nerve stimulation [mechanomyography (MMG)] in the anaesthetized minipig.
Study design
Prospective observational.
Sixty male Göttingen minipigs weighing 10.5–26.0 kg.
After cadaveric studies, a limb fixation device was constructed which allowed the twitch responses of the pelvic limb digital extensor muscles to be measured by force-displacement transduction in response to supramaximal train-of-four (TOF) stimulation of the common peroneal nerve. The device was tested in 60 minipigs weighing 10.5–26.0 kg positioned in dorsal recumbency.
The technique recorded the MMG of the common peroneal-pelvic limb digital extensor nerve-muscle unit for up to 12 hours during which twitch height remained constant in 18 animals in which single twitch duration was <300–500 ms. In 42, in which twitch duration was >300–500 ms, 2 Hz nerve stimulation caused progressive baseline elevation (reverse fade) necessitating a modified signal capture method for TOF ratio (TOFR) computation. However, T1 was unaffected. The mean (range) of the TOFR in pigs with reverse fade was 1.2 (1.1–1.3).
Conclusions and clinical relevance
The technique allowed MMG recording in unparalysed pigs in response to TOF nerve stimulation and revealed a hitherto unreported complication of MMG monitoring using TOF in animals: reverse fade. This complicated TOFR calculation.
PMCID: PMC4017097  PMID: 22788355
anaesthesia; minipigs; mechanomyography; reverse fade
6.  Diurnal variation in probability of death following self-poisoning in Sri Lanka—evidence for chronotoxicity in humans 
Background The absorption, distribution, metabolism and elimination of medicines are partly controlled by transporters and enzymes with diurnal variation in expression. Dose timing may be important for maximizing therapeutic and minimizing adverse effects. However, outcome data for such an effect in humans are sparse, and chronotherapeutics is consequently less practised. We examined a large prospective Sri Lankan cohort of patients with acute poisoning to seek evidence of diurnal variation in the probability of survival.
Methods In all, 14 840 patients admitted to hospital after yellow oleander (Cascabela thevetia) seed or pesticide [organophosphorus (OP), carbamate, paraquat, glyphosate] self-poisoning were investigated for variation in survival according to time of ingestion.
Results We found strong evidence that the outcome of oleander poisoning was associated with time of ingestion (P < 0.001). There was weaker evidence for OP insecticides (P = 0.041) and no evidence of diurnal variation in the outcome for carbamate, glyphosate and paraquat pesticides. Compared with ingestion in the late morning, and with confounding by age, sex, time of and delay to hospital presentation and year of admission controlled, case fatality of oleander poisoning was over 50% lower following evening ingestion (risk ratio = 0.40, 95% confidence interval 0.26–0.62). Variation in dose across the day was not responsible.
Conclusions We have shown for the first time that timing of poison ingestion affects survival in humans. This evidence for chronotoxicity suggests chronotherapeutics should be given greater attention in drug development and clinical practice.
PMCID: PMC3535746  PMID: 23179303
Circadian rhythm; self-injurious behaviour; toxicology; poisoning; Cascabela thevetia; pesticides; Sri Lanka
7.  Reactivation of Plasma Butyrylcholinesterase by Pralidoxime Chloride in Patients Poisoned by WHO Class II Toxicity Organophosphorus Insecticides 
Toxicological Sciences  2013;136(2):274-283.
Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide, and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) class II OP insecticide poisoning. Patient data were derived from 2 studies, a cohort study (using a bolus treatment of 1g pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2g pralidoxime over 20min, followed by an infusion of 0.5g/h, with placebo). Two grams of pralidoxime variably reactivated BuChE in patients poisoned by 2 diethyl OP insecticides, chlorpyrifos and quinalphos; however, unlike acetylcholinesterase reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1-g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO class II OP-poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful.
PMCID: PMC3858199  PMID: 24052565
organophosphorus insecticides; butyrylcholinest erase; pralidoxime; marker; human poisoning.
8.  Scottish and Newcastle Antiemetic Pre-treatment for paracetamol poisoning study (SNAP) 
Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.
This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.
Trial registration
EudraCT number 2009-017800-10, IdentifierNCT01050270
PMCID: PMC3626543  PMID: 23556549
Paracetamol; Acetylcysteine; Overdose; Antidotes; Hepatotoxicity
9.  A role for solvents in the toxicity of agricultural organophosphorus pesticides 
Toxicology  2012;294(2-3):94-103.
Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12 h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4 [0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates.
PMCID: PMC3325481  PMID: 22365945
Suicide; Organophosphorus insecticides; Solvents; Cyclohexanone
10.  The impact of pesticide suicide on the geographic distribution of suicide in Taiwan: a spatial analysis 
BMC Public Health  2012;12:260.
Pesticide self-poisoning is the most commonly used suicide method worldwide, but few studies have investigated the national epidemiology of pesticide suicide in countries where it is a major public health problem. This study aims to investigate geographic variations in pesticide suicide and their impact on the spatial distribution of suicide in Taiwan.
Smoothed standardized mortality ratios for pesticide suicide (2002-2009) were mapped across Taiwan's 358 districts (median population aged 15 or above = 27 000), and their associations with the size of agricultural workforce were investigated using Bayesian hierarchical models.
In 2002-2009 pesticide poisoning was the third most common suicide method in Taiwan, accounting for 13.6% (4913/36 110) of all suicides. Rates were higher in agricultural East and Central Taiwan and lower in major cities. Almost half (47%) of all pesticide suicides occurred in areas where only 13% of Taiwan's population lived. The geographic distribution of overall suicides was more similar to that of pesticide suicides than non-pesticide suicides. Rural-urban differences in suicide were mostly due to pesticide suicide. Areas where a higher proportion of people worked in agriculture showed higher pesticide suicide rates (adjusted rate ratio [ARR] per standard deviation increase in the proportion of agricultural workers = 1.58, 95% Credible Interval [CrI] 1.44-1.74) and overall suicide rates (ARR = 1.06, 95% CrI 1.03-1.10) but lower non-pesticide suicide rates (ARR = 0.91, 95% CrI 0.87-0.95).
Easy access to pesticides appears to influence the geographic distribution of suicide in Taiwan, highlighting the potential benefits of targeted prevention strategies such as restricting access to highly toxic pesticides.
PMCID: PMC3351735  PMID: 22471759
Suicide; Pesticide; Mapping; Ecological studies; Taiwan
11.  Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol 
Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease.
We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance.
Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials.
Trial registration
Clinical NCT00558142; EudraCT: 2006-003509-18.
PMCID: PMC3293780  PMID: 22305183
Contrast-induced nephropathy; acetylcysteine; prevention; kidney; contrast media
12.  A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol 
BMC Public Health  2011;11:879.
The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety.
A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals.
The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm.
This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence.
Trial Registritation
The trial is registered on ref: NCT1146496 (
PMCID: PMC3227631  PMID: 22104027
13.  Acute intentional self-poisoning with a herbicide product containing fenoxaprop-P-ethyl, ethoxysulfuron and isoxadifen ethyl. A prospective observational study 
Herbicides are commonly ingested for self-harm; however, relatively little has been published on poisoning with herbicides other than paraquat and glyphosate. We report here a case series of patients with acute exposure to a combination herbicide (brand name Tiller Gold or Whip Super) containing the selective phenoxy herbicide fenoxaprop-P-ethyl, the sulfonylurea herbicide ethoxysulfuron and the safener isoxadifen ethyl.
Clinical data on all patients presenting with Tiller Gold or Whip Super poisoning to two General Hospital in Sri Lanka from 2002-2008 were collected prospectively until discharge.
Eighty-six patients with a history of Tiller Gold or Whip Super ingestion were included. The median time to presentation was 4 hours post-ingestion (IQR 2 to 10 hrs) and the median volume ingested was 22.5ml (IQR: 20-60; n=64). Most patients demonstrated limited clinical signs of poisoning and none required mechanical ventilation or intensive care treatment. The main clinical features were an epigastric burning sensation and vomiting; however, most of those who vomited had received gastric lavage or forced emesis. Eight patients had a reduced level of consciousness on admission (GCS 9 -14) that resolved without intervention over several hours. Only symptomatic and supportive care was required. The median hospital stay was 1 day (IQR: 1 to 2) and the case fatality was zero (95% CI: zero to 4.2%). This low case fatality compared favorably with the case fatality of other common herbicides in our cohort: paraquat >40%, propanil >10%, 4-chloro-2-methylphenoxyacetic acid (MCPA) > 5% and glyphosate >2%.
This combination herbicide product appears to be safe in patients with acute self-poisoning, particularly in comparison with other herbicides, and causing few clinical features
PMCID: PMC3145122  PMID: 19663557
14.  Prolonged Refractory Hypotension following Combined Amlodipine and Losartan Ingestion Responsive to Metaraminol 
Case Reports in Medicine  2011;2011:283672.
Introduction. Overdose with the calcium channel blocker amlodipine can cause profound hypotension that may be exacerbated by the concurrent ingestion of an angiotensin II receptor antagonist. Best management of such overdoses is uncertain although the use of hyperinsulinaemia-euglycaemia (HIE) has been recommended. Case report. We report a case of mixed amlodipine and losartan overdose in a 50-year-old lady. Severe hypotension was resistant to conventional vasopressors and high-dose insulin/euglycaemia, but did respond to a metaraminol infusion. Conclusion. A trial of metaraminol early in severe cases of calcium channel blocker and angiotensin II receptor antagonist toxicity may be of benefit, especially when conventional ionotropic treatment measures are failing.
PMCID: PMC3099204  PMID: 21629799
15.  Relationship between blood alcohol concentration on admission and outcome in dimethoate organophosphorus self-poisoning 
Many patients acutely poisoned with organophosphorus insecticides have co-ingested alcohol. Although clinical experience suggests that this makes management more difficult, the relationship between plasma concentration of alcohol and insecticide is unknown. We aimed to determine whether acute intoxication results in ingestion of larger quantities of insecticide in dimethoate self-poisoning and a worse clinical outcome.
We set up a prospective study of acute dimethoate self-poisoning in Sri Lankan district hospitals. An admission plasma sample was analysed to identify the ingested insecticide; in patients with detectable dimethoate, plasma alcohol was measured.
Plasma from 37 of 72 (51.4%) dimethoate-poisoned patients had detectable alcohol {median concentration 1.10 g l−1[110 mg dl−1][interquartile range (IQR) 0.78–1.65]} a median of 3 h post ingestion. The median plasma dimethoate concentration was higher in patients who had ingested alcohol [479 µmol l−1 (IQR 268–701) vs. 145 µmol l−1 (IQR 25–337); P < 0.001]. Plasma dimethoate concentration was positively correlated with plasma alcohol (Spearman's ρ= 0.34; P= 0.0032). The median alcohol concentration was higher in the 21 patients who died compared with survivors (0.94 vs. 0.0 g l−1, P= 0.018). Risk of death was greater amongst individuals who consumed alcohol [odds ratio (OR) 4.3, 95% confidence interval (CI) 1.2, 16.4]; this risk was abolished by controlling for dimethoate concentration (OR 0.3, 95% CI 0.0, 8.8), indicating that deaths were not due to the direct toxic effects of alcohol.
Alcohol co-ingestion is associated with higher plasma concentrations of dimethoate and increased risk of death. Larger studies are required to assess this finding's generalizability, since efforts to reduce deaths from self-poisoning may benefit from concurrent efforts to reduce alcohol consumption.
PMCID: PMC2805864  PMID: 20002086
ethanol; insecticide; metabolism; organophosphorus; poisoning; suicide
16.  Acute Human Lethal Toxicity of Agricultural Pesticides: A Prospective Cohort Study 
PLoS Medicine  2010;7(10):e1000357.
In a prospective cohort study of patients presenting with pesticide self-poisoning, Andrew Dawson and colleagues investigate the relative human toxicity of agricultural pesticides and contrast it with WHO toxicity classifications, which are based on toxicity in rats.
Agricultural pesticide poisoning is a major public health problem in the developing world, killing at least 250,000–370,000 people each year. Targeted pesticide restrictions in Sri Lanka over the last 20 years have reduced pesticide deaths by 50% without decreasing agricultural output. However, regulatory decisions have thus far not been based on the human toxicity of formulated agricultural pesticides but on the surrogate of rat toxicity using pure unformulated pesticides. We aimed to determine the relative human toxicity of formulated agricultural pesticides to improve the effectiveness of regulatory policy.
Methods and Findings
We examined the case fatality of different agricultural pesticides in a prospective cohort of patients presenting with pesticide self-poisoning to two clinical trial centers from April 2002 to November 2008. Identification of the pesticide ingested was based on history or positive identification of the container. A single pesticide was ingested by 9,302 patients. A specific pesticide was identified in 7,461 patients; 1,841 ingested an unknown pesticide. In a subset of 808 patients, the history of ingestion was confirmed by laboratory analysis in 95% of patients. There was a large variation in case fatality between pesticides—from 0% to 42%. This marked variation in lethality was observed for compounds within the same chemical and/or WHO toxicity classification of pesticides and for those used for similar agricultural indications.
The human data provided toxicity rankings for some pesticides that contrasted strongly with the WHO toxicity classification based on rat toxicity. Basing regulation on human toxicity will make pesticide poisoning less hazardous, preventing hundreds of thousands of deaths globally without compromising agricultural needs. Ongoing monitoring of patterns of use and clinical toxicity for new pesticides is needed to identify highly toxic pesticides in a timely manner.
Please see later in the article for the Editors' Summary
Editors' Summary
Suicide is a preventable global public health problem. About 1 million people die each year from suicide and many more harm themselves but survive. Although many people who commit suicide have a mental illness, stressful events (economic hardship or relationship difficulties, for example) can sometimes make life seem too painful to bear. Suicide attempts are frequently impulsive and use methods that are conveniently accessible. Strategies to reduce suicide rates include better treatment of mental illness and programs that help people at high risk of suicide deal with stress. Suicide rates can also be reduced by limiting access to common suicide methods. The single most important means of suicide worldwide is agricultural pesticide poisoning. Every year, between 250,000 and 370,000 people die from deliberate ingestion of pesticides (chemicals that kill animal pests or unwanted plants). Most of these suicides occur in rural areas of the developing world where high levels of pesticide use in agriculture combined with pesticide storage at home facilitate this particular method of suicide.
Why Was This Study Done?
To help reduce suicides through the ingestion of agricultural pesticides, the Food and Agriculture Organization of the United Nations recommends the withdrawal of the most toxic pesticides—World Health Organization (WHO) class I pesticides—from agricultural use. This strategy has proven successful in Sri Lanka where a ban on class I pesticides in 1995 and on the class II pesticide endosulfan in 1998 has reduced pesticide deaths by 50% over the past 20 years without decreasing agricultural output. Further reductions in suicides from pesticide ingestion could be achieved if regulatory restrictions on the sale and distribution of the most toxic class II pesticides were imposed. But such restrictions must balance agricultural needs against the impact of pesticides on public health. Unfortunately, the current WHO pesticide classification is based on toxicity in rats. Because rats handle pesticides differently from people, there is no guarantee that a pesticide with low toxicity in rodents is safe in people. Here, the researchers try to determine the relative human toxicity of agricultural pesticides in a prospective cohort study (a study in which people who share a characteristic—in this case, deliberate pesticide ingestion—are enrolled and followed to see how they fare).
What Did the Researchers Do and Find?
The researchers examined the case fatality (the proportion of patients dying after hospital admission) of different agricultural pesticides among patients who presented with pesticide self-poisoning at two Sri Lankan referral hospitals. Between April 2002 and November 2008, 9,302 people were admitted to the hospitals after swallowing a single pesticide. The researchers identified the pesticide ingested in 7,461 cases by asking the patient what he/she had taken or by identifying the container brought in by the patient or relatives. 10% of the patients died but there was a large variation in case fatality between pesticides. The herbicide paraquat was the most lethal pesticide, killing 42% of patients; several other pesticides killed no one. Compounds in the same chemical class and/or the same WHO toxicity class sometimes had very different toxicities. For example, dimethoate and malathione, both class II organophosphate insecticides, had case fatalities of 20.6% and 1.9%, respectively. Similarly, pesticides used for similar agricultural purposes sometimes had very different case fatalities.
What Do These Findings Mean?
These findings provide a toxicity ranking for pesticides that deviates markedly from the WHO toxicity classification based on rat toxicity. Although the findings are based on a study undertaken at just two Sri Lankan hospitals, they are likely to be generalizable to other hospitals and to other parts of rural Asia. However, because the study only included patients who were admitted to hospital after ingesting pesticides, the actual case fatalities for some pesticides may be somewhat different. Nevertheless, these findings have several important public health implications. For example, they suggest that the decision taken in January 2008 to withdraw paraquat, dimethoate, and fenthion from the Sri Lankan market should reduce deaths from pesticide poisoning in Sri Lanka by a further 33%–65% (equivalent to about 1,000 fewer suicides per year). More generally, they suggest that basing the regulation of pesticides on human toxicity has the potential to prevent hundreds and thousands of intentional and accidental deaths globally without compromising agricultural needs.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Matt Miller and Kavi Bhalla
The World Health Organization provides information on the global burden of suicide and on suicide prevention (in several languages) and on its classification of pesticides
The US Environmental Protection Agency provides information about all aspects of pesticides (in English and Spanish)
Toxtown, an interactive site from the US National Library of Science, provides information on environmental health concerns including exposure to pesticides (in English and Spanish)
The nonprofit organization Pesticide Action Network UK provides information about all aspects of pesticides
The US National Pesticide Information Center provides objective, science-based information about pesticides (in several languages)
The Food and Agriculture Organization of the United Nations leads international efforts to reduce hunger; as part of this effort, it has introduced pesticide policy reforms (in several languages)
MedlinePlus provides links to further resources about suicide and about pesticides (in English and Spanish)
PMCID: PMC2964340  PMID: 21048990
17.  A prospective observational study of the clinical toxicology of glyphosate-containing herbicides in adults with acute self-poisoning 
The case fatality from acute poisoning with glyphosate-containing herbicides is approximately 7.7% from available studies but these have major limitations. Large prospective studies of patients with self-poisoning from known formulations who present to primary or secondary hospitals are needed to better describe the outcome from acute poisoning with glyphosate-containing herbicides. Further, the clinical utility of the glyphosate plasma concentration for predicting clinical outcomes and guiding treatment has not been determined.
To describe the clinical outcomes, dose-response and glyphosate kinetics following self-poisoning with glyphosate-containing herbicides.
This prospective observational case series was conducted in two hospitals in Sri Lanka between 2002 and 2007. We included patients with a history of acute poisoning. Clinical observations were recorded until discharge or death. During a specified time period we collected admission (n=216, including 5 deaths) and serial (n=26) blood samples in patients. Severity of poisoning was graded using simple clinical criteria.
601 patients were identified; the majority ingested a concentrated formulation (36% w/v glyphosate). 27.6% were asymptomatic, 64% had minor poisoning and 5.5% of patients had moderate to severe poisoning. There were 19 deaths (case fatality 3.2%) with a median time to death of 20 hours. Gastrointestinal symptoms, respiratory distress, hypotension, altered level of consciousness and oliguria were observed in fatal cases. Death was strongly associated with greater age, larger ingestions and high plasma glyphosate concentrations on admission (>734μg/mL). The apparent elimination half life of glyphosate was 3.1 hours (95% CI 2.7 to 3.6 hours).
Despite treatment in rural hospitals with limited resources the mortality was 3.2% which is lower than reported in previous case series. More research is required to define the mechanism of toxicity, better predict the small group at risk of death and find effective treatments.
PMCID: PMC2875113  PMID: 20136481
Toxicokinetics; suicide; pesticide; mortality; prognosis
18.  The prevalence of previous self-harm amongst self-poisoning patients in Sri Lanka 
One of the most important components of suicide prevention strategies is to target people who repeat self-harm as they are a high risk group. However, there is some evidence that the incidence of repeat self-harm is lower in Asia than in the West. The objective of this study was to investigate the prevalence of previous self-harm among a consecutive series of self-harm patients presenting to hospitals in rural Sri Lanka.
Six hundred and ninety-eight self-poisoning patients presenting to medical wards at two hospitals in Sri Lanka were interviewed about their previous episodes of self-harm.
Sixty-one (8.7%, 95% CI 6.7–11%) patients reported at least one previous episode of self-harm [37 (10.7%) male, 24 (6.8%) female]; only 19 (2.7%, 95% CI 1.6–4.2%) patients had made more than one previous attempt.
The low prevalence of previous self-harm is consistent with previous Asian research and is considerably lower than that seen in the West. Explanations for these low levels of repeat self-harm require investigation. Our data indicate that a focus on the aftercare of those who attempt suicide in Sri Lanka may have a smaller impact on suicide incidence than may be possible in the West.
PMCID: PMC3092923  PMID: 20372876
Deliberate self-harm; Developing countries; Sri Lanka; Previous self-harm; Self-poisoning
19.  Hypothermia and Fever After Organophosphorus Poisoning in Humans—A Prospective Case Series 
Journal of Medical Toxicology  2010;6(4):379-385.
There have been many animal studies on the effects of organophosphorus pesticide (OP) poisoning on thermoregulation with inconsistent results. There have been no prospective human studies. Our aim was to document the changes in body temperature with OP poisoning. A prospective study was conducted in a rural hospital in Polonnaruwa, Sri Lanka. We collected data on sequential patients with OP poisoning and analyzed 12 patients selected from 53 presentations who had overt signs and symptoms of OP poisoning and who had not received atropine prior to arrival. All patients subsequently received specific management with atropine and/or pralidoxime and general supportive care. Tympanic temperature, ambient temperature, heart rate, and clinical examination and interventions were recorded prospectively throughout their hospitalization. Initial hypothermia as low as 32°C was observed in untreated patients. Tympanic temperature increased over time from an early hypothermia (<35°C in 6/12 patients) to later fever (7/12 patients >38°C at some later point). While some of the late high temperatures occurred in the setting of marked tachycardia, it was also apparent that in some cases fever was not accompanied by tachycardia, making excessive atropine or severe infection an unlikely explanation for all the fevers. In humans, OP poisoning causes an initial hypothermia, and this is followed by a period of normal to high body temperature. Atropine and respiratory complications may contribute to fever but do not account for all cases.
PMCID: PMC2996541  PMID: 20300985
Organophosphorus; Pesticide; Poisoning; Thermoregulation; Cholinergic
20.  Hypothermia and Fever After Organophosphorus Poisoning in Humans—A Prospective Case Series 
Journal of Medical Toxicology  2010;6(4):379-385.
There have been many animal studies on the effects of organophosphorus pesticide (OP) poisoning on thermoregulation with inconsistent results. There have been no prospective human studies. Our aim was to document the changes in body temperature with OP poisoning. A prospective study was conducted in a rural hospital in Polonnaruwa, Sri Lanka. We collected data on sequential patients with OP poisoning and analyzed 12 patients selected from 53 presentations who had overt signs and symptoms of OP poisoning and who had not received atropine prior to arrival. All patients subsequently received specific management with atropine and/or pralidoxime and general supportive care. Tympanic temperature, ambient temperature, heart rate, and clinical examination and interventions were recorded prospectively throughout their hospitalization. Initial hypothermia as low as 32°C was observed in untreated patients. Tympanic temperature increased over time from an early hypothermia (<35°C in 6/12 patients) to later fever (7/12 patients >38°C at some later point). While some of the late high temperatures occurred in the setting of marked tachycardia, it was also apparent that in some cases fever was not accompanied by tachycardia, making excessive atropine or severe infection an unlikely explanation for all the fevers. In humans, OP poisoning causes an initial hypothermia, and this is followed by a period of normal to high body temperature. Atropine and respiratory complications may contribute to fever but do not account for all cases.
PMCID: PMC2996541  PMID: 20300985
Organophosphorus; Pesticide; Poisoning; Thermoregulation; Cholinergic
21.  Paracetamol (acetaminophen) poisoning 
Clinical Evidence  2007;2007:2101.
Mortality from paracetamol overdose is now about 0.4%, although severe liver damage occurs without treatment in at least half of people with blood paracetamol levels above the UK standard treatment line. In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute paracetamol poisoning? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: activated charcoal (single or multiple dose), gastric lavage, ipecacuanha, liver transplant, methionine, N-acetylcysteine.
Key Points
Paracetamol (acetaminophen) is a common means of self-poisoning in Europe and North America, often taken as an impulsive act of self-harm in young people. Mortality from paracetamol overdose is now about 0.4%, although without treatment, severe liver damage occurs in at least half of people with blood paracetamol levels above the UK standard treatment line.In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage.
Standard treatment of paracetamol overdose is acetylcysteine, which based on animal studies and clinical experience, is widely believed to reduce liver damage and mortality, although few studies have been done. Adverse effects from acetylcysteine include rash, urticaria, vomiting, and anaphylaxis which can, rarely, be fatal.We don't know what the optimal dose, route, and duration of acetylcysteine treatment should be. However, liver damage is less likely to occur if treatment is started within 8 to 10 hours of ingestion.
It is possible that methionine reduces the risk of liver damage and mortality after paracetamol poisoning compared with supportive care, but we don't know for sure.
We don't know whether activated charcoal, gastric lavage, or ipecacuanha reduce the risks of liver damage after paracetamol poisoning. The rapid absorption of paracetamol suggests that a beneficial effect from treatments that reduce gastric absorption is unlikely in many cases.
Liver transplantation may increase survival rates in people with fulminant liver failure after paracetamol poisoning compared with waiting list controls, but long-term outcomes are unknown.
PMCID: PMC2943815  PMID: 19450343
22.  Pattern of pesticide storage before pesticide self-poisoning in rural Sri Lanka 
BMC Public Health  2009;9:405.
Deliberate self-poisoning with agricultural pesticides is the commonest means of suicide in rural Asia. It is mostly impulsive and facilitated by easy access to pesticides. The aim of this large observational study was to investigate the immediate source of pesticides used for self-harm to help inform suicide prevention strategies such as reducing domestic access to pesticides.
The study was conducted in a district hospital serving an agricultural region of Sri Lanka. Patients who had self-poisoned with pesticides and were admitted to the adult medical wards were interviewed by study doctors following initial resuscitation to identify the source of pesticides they have ingested.
Of the 669 patients included in the analysis, 425 (63.5%) were male; the median age was 26 (IQR 20-36). In 511 (76%) cases, the pesticides had been stored either inside or immediately outside the house; among this group only eight patients obtained pesticides that were kept in a locked container. Ten percent (n = 67) of the patients used pesticides stored in the field while 14% (n = 91) purchased pesticides from shops within a few hours of the episode. The most common reasons for choosing the particular pesticide for self-harm were its easy accessibility (n = 311, 46%) or its popularity as a suicide agent in their village (n = 290, 43%).
Three quarters of people who ingested pesticides in acts of self-harm used products that were available within the home or in close proximity; relatively few patients purchased the pesticide for the act. The study highlights the importance of reducing the accessibility of toxic pesticides in the domestic environment.
PMCID: PMC2777873  PMID: 19889236
23.  Extreme variability in the formation of chlorpyrifos oxon (CPO) in patients poisoned by chlorpyrifos (CPF) 
Biochemical Pharmacology  2009;78(5):531-537.
Graphical abstract
Formation of chlorpyrifos oxon (CPO) in self-inflicted poisoning with chlorpyrifos (CPF).
Left: time course of plasma concentrations (single patient). Right: ratio of CPO/CPF 2–5 days after poisoning (n = 74).
Chlorpyrifos (CPF) is a pesticide that causes tens of thousands of deaths per year worldwide. Chlorpyrifos oxon (CPO) is the active metabolite of CPF that inhibits acetylcholinesterase. However, this presumed metabolite has escaped detection in human samples by conventional methods (HPLC, GC-MS, LC-MS) until now. A recently developed enzyme-based assay allowed the determination of CPO in the nanomolar range and was successfully employed to detect this metabolite. CPO and CPF were analysed in consecutive plasma samples of 74 patients with intentional CPF poisoning. A wide concentration range of CPO and CPF was observed and the ratio of CPO/CPF varied considerably between individuals and over time. The ratio increased during the course of poisoning from a mean of 0.005 in the first few hours after ingestion up to an apparent steady-state mean of 0.03 between 30 and 72 h. There was a hundred-fold variation in the ratio between samples and the interquartile range (between individuals) indicated over half the samples had a 5-fold or greater variation from the mean. The ratio was independent of the CPF concentration and the pralidoxime regimen. CPO was present in sufficient quantities to explain any observed acetylcholinesterase inhibitory activity. The effectiveness of pralidoxime in reactivating the inhibited acetylcholinesterase is strongly dependent on the CPO concentration. Differences in clinical outcomes and the response to antidotes in patients with acute poisoning may occur due to inter-individual variability in metabolism.
PMCID: PMC2714474  PMID: 19433070
AChE, acetylcholinesterase (EC; BChE, butyrylcholinesterase (EC; CPF, chlorpyrifos; CPO, chlorpyrifos oxon; PON 1, paraoxonase 1 (EC; RBC, red blood cells; Organophosphorus; Chlorpyrifos; Poisoning; Toxicokinetics; Pralidoxime
24.  Pralidoxime in Acute Organophosphorus Insecticide Poisoning—A Randomised Controlled Trial 
PLoS Medicine  2009;6(6):e1000104.
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.
Trial Registration ISRCTN55264358
Please see later in the article for Editors' Summary
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.
Additional Information
Please access these Web sites via the online version of this summary at
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
PMCID: PMC2696321  PMID: 19564902
25.  OpdA, a bacterial organophosphorus hydrolase, prevents lethality in rats after poisoning with highly toxic organophosphorus pesticides 
Toxicology  2008;247(2-3):88-92.
Organophosphorus (OP) pesticides poison more than 3,000,000 people every year in the developing world, mostly through intentional self-poisoning. Advances in medical therapy for OP poisoning have lagged, and current treatment is not highly effective with mortality of up to 40% in even the most advanced Western medical facilities. Administration of a broadly active bacterial OP hydrolase to patients in order to hydrolyze OPs in circulation might allow current therapies to be more effective. The objective of this work was to evaluate the efficacy of a new recombinant bacterial OP hydrolase (OpdA), cloned from Agrobacterium radiobacter, in rat models of two chemically distinct but highly toxic and rapidly acting OP pesticides: dichlorvos and parathion. Without OpdA treatment, median time to death in rats poisoned with 3 × LD50 of dichlorvos or parathion was 6 minutes and 25.5 minutes, respectively. Administration of a single dose of OpdA immediately after dichlorvos resulted in 100% survival at 24 hours, with no additional antidotal therapy. After parathion poisoning, OpdA alone caused only a delay to death. However, an additional two doses of OpdA resulted in 62.5% survival at 24 hours after parathion poisoning. In combination with pralidoxime therapy, a single dose of OpdA increased survival to 75% after parathion poisoning. Our results demonstrate that OpdA is able to improve survival after poisoning by two chemically distinct and highly toxic OP pesticides.
PMCID: PMC2408951  PMID: 18378376
Organophosphorus (OP); hydrolase; acetylcholinesterase (AChE); pralidoxime (2-PAM)

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