The relative lethal toxicity of pharmaceutical and illicit substances: A 16-year study of the Greater Newcastle Hunter Area, Australia.

AIMS: We aim to calculate 2 metrics of relative lethal toxicity; the fatal toxicity index (FTI; number of deaths per year of a daily dose) and the case fatality (CF; number of deaths per overdose) with a focus on opioids, antidepressants, antipsychotics, benzodiazepines and illicit drugs. METHODS: This descriptive cohort study used the Australian National Coronial Information System (NCIS) to identify a population of individuals with drug-associated deaths in the Greater Newcastle Hunter Area between January 2002 and December 2016. This was combined with Australian medicine dispensing data and corresponding data from the Hunter Area Toxicology Service to calculate FTI and CF. RESULTS: There were 444 drug-related deaths and 21,296 overdoses during the study period. FTI and CF were well correlated (Spearman's rho 0.64, P < .001). Of the classes of interest, opioids had the highest FTI (40.3 95% confidence interval [CI] 35.2-45.4 deaths per 100 years of use at the defined daily dose or deaths/DDD/100 years) and CF (12.4% 95%CI 11.0-13.9). Fentanyl, methadone and morphine had the highest relative fatal toxicity within this class. Tricyclic antidepressants had the highest relative fatal toxicity of all antidepressants (FTI 14.5 95%CI 9.7-19.3 deaths/DDD/100 years and CF 7.1% [95%CI 4.8-9.3]) and benzodiazepines appeared to be more associated with multiple agent deaths than single. Of the illicit drugs, heroin had the highest CF (26.4%, 95%CI 19.1-33.7). CONCLUSION: Knowledge of relative lethal toxicity is useful to prescribers and medicines and public health policy makers in restricting access to more toxic drugs and may also assist coroners in determining cause of death.

Interventions for paracetamol (acetaminophen) overdose.

BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites. OBJECTIVES: To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews. SELECTION CRITERIA: Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software. MAIN RESULTS: We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults. AUTHORS' CONCLUSIONS: These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.

Snake antivenom for snake venom induced consumption coagulopathy.

BACKGROUND: Snake venom induced consumption coagulopathy is a major systemic effect of envenoming. Observational studies suggest that antivenom improves outcomes for venom induced consumption coagulopathy in some snakebites and not others. However, the effectiveness of snake antivenom in all cases of venom induced consumption coagulopathy is controversial. OBJECTIVES: To assess the effect of snake antivenom as a treatment for venom induced consumption coagulopathy in people with snake bite. SEARCH METHODS: The search was done on 30 January 2015. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), three other sources, clinical trials registers, and we also screened reference lists. SELECTION CRITERIA: All completed, published or unpublished, randomised, controlled trials with a placebo or no treatment arm, where snake antivenom was administered for venom induced consumption coagulopathy in humans with snake bites. DATA COLLECTION AND ANALYSIS: Two authors reviewed the identified trials and independently applied the selection criteria. MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: Randomised placebo-controlled trials are required to investigate the effectiveness of snake antivenom for clinically relevant outcomes in patients with venom induced consumption coagulopathy resulting from snake bite. Although ethically difficult, the routine administration of a treatment that has a significant risk of anaphylaxis cannot continue without strong evidence of benefit.

Trials and tribulations in the removal of dextropropoxyphene from the Australian Register of Therapeutic Goods.

• The Therapeutic Goods Administration determined in November 2011 that dextropropoxyphene should be removed from the Australian Register of Therapeutic Goods. This is consistent with this drug's removal from the market in many other developed countries. • However, dextropropoxyphene is still on the market in Australia owing to a series of appeals made to the Administrative Appeals Tribunal (AAT) by the drug's manufacturer. • There is a difference between the standards by which the AAT judges the safety and efficacy of medicines and the standards used for registering therapeutic goods by regulatory agencies worldwide. • This raises the question as to whether the appeal process against TGA decisions appropriately serves the Australian public interest.

Amanita phalloides poisoning and treatment with silibinin in the Australian Capital Territory and New South Wales.

OBJECTIVES: To report the frequency and clinical outcomes of Amanita phalloides poisoning in the Australian Capital Territory and New South Wales, and the treatments used (including silibinin). DESIGN, SETTING AND PATIENTS: Retrospective case series of patients admitted to public hospitals in Canberra and Sydney for suspected A. phalloides poisoning between 1999 and 2012 (identified from hospital records and calls to the New South Wales Poisons Information Centre). MAIN OUTCOME MEASURES: Frequency of poisoning and the clinical outcomes. RESULTS: Twelve patients presented with a history suggesting A. phalloides poisoning, 10 with probable poisoning and two with possible poisoning. Eight of those with probable poisoning developed significant hepatotoxicity and four died. Silibinin was administered to nine of those with probable poisoning (the other presented before 2005). Maintaining silibinin supply became a challenge during two clusters of poisoning. Eight of the patients with probable poisoning were not long-term residents of the ACT, and six were immigrants from Asia. CONCLUSIONS: The mortality rate due to A. phalloides poisoning in this case series was high despite treatment according to current standards, including use of silibinin, and the frequency of hepatotoxicity was more than double that for the previous decade. Ongoing public health campaigns are required.

A cost effectiveness analysis of the preferred antidotes for acute paracetamol poisoning patients in Sri Lanka.

BACKGROUND: Acute paracetamol poisoning is a rapidly increasing problem in Sri Lanka. The antidotes are expensive and yet no health economic evaluation has been done on the therapy for acute paracetamol poisoning in the developing world. The aim of this study is to determine the cost effectiveness of using N-acetylcysteine over methionine in the management of acute paracetamol poisoning in Sri Lanka. METHODS: Economic analysis was applied using public healthcare system payer perspective. Costs were obtained from a series of patients admitted to the National Hospital of Sri Lanka with a history of acute paracetamol overdose. Evidence on effectiveness was obtained from a systematic review of the literature. Death due to hepatotoxicity was used as the primary outcome of interest. Analysis and development of decision tree models was done using Tree Age Pro 2008. RESULTS: An affordable treatment threshold of Sri Lankan rupees 1,537,120/death prevented was set from the expected years of productive life gained and the average contribution to GDP. A cost-minimisation analysis was appropriate for patients presenting within 10 hours and methionine was the least costly antidote. For patients presenting 10-24 hours after poisoning, n-acetylcysteine was more effective and the incremental cost effectiveness ratio of Sri Lankan rupees 316,182/life saved was well under the threshold. One-way and multi-way sensitivity analysis also supported methionine for patients treated within 10 hours and n-acetylcysteine for patients treated within 10-24 hours as preferred antidotes. CONCLUSIONS: Post ingestion time is an important determinant of preferred antidotal therapy for acute paracetamol poisoning patients in Sri Lanka. Using n-acetylcysteine in all patients is not cost effective. On economic grounds, methionine should become the preferred antidote for Sri Lankan patients treated within 10 hours of the acute ingestion and n-acetylcysteine should continue to be given to patients treated within 10-24 hours.

Changing epidemiologic patterns of deliberate self poisoning in a rural district of Sri Lanka.

BACKGROUND: Acute poisoning is a major public health issue in many parts of the world. The epidemiology and the mortality rate is higher in low and middle income countries, including Sri Lanka. The aim of this study was to provide details about the epidemiology of acute poisoning in a rural Sri Lankan district and to identify the changing patterns and epidemiology of poisoning. METHODS: A prospective study was conducted from September 2008 to January 2010 in all hospitals with inpatient facilities in Anuradhapura district of North Central Province of Sri Lanka. Acute poisoning data was extracted from patient charts. Selected data were compared to the data collected from a 2005 study in 28 hospitals. RESULTS: There were 3813 poisoned patients admitted to the hospitals in the Anuradhapura district over 17 months. The annual population incidence was 447 poisoning cases per 100,000 population. The total number of male and female patients was approximately similar, but the age distribution differed by gender. There was a very high incidence of poisoning in females aged 15-19, with an estimated cumulative incidence of 6% over these five years. Although, pesticides are still the most common type of poison, medicinal drug poisonings are now 21% of the total and have increased 1.6 fold since 2005. CONCLUSIONS: Acute poisoning remains a major public health problem in rural Sri Lanka and pesticide poisoning remains the most important poison. However, cases of medicinal drug poisoning have recently dramatically increased. Youth in these rural communities remain very vulnerable to acute poisoning and the problem is so common that school-based primary prevention programs may be worthwhile.Lalith Senarathna, Shaluka F Jayamanna, Patrick J Kelly, Nick A Buckley,michael J Dibley, Andrew H Dawson. These authors contributed equally to this work.

Acute fungicide self-poisoning - a prospective case series.

BACKGROUND: Pesticide self-poisoning is a global clinical and public health problem. While self-poisoning with insecticides and herbicides has been extensively studied, there is minimal literature on acute fungicide self-poisoning. We aimed to study the clinical course and outcome of fungicide self-poisoned patients recruited to a prospective cohort in Sri Lanka. METHODS: We conducted a prospective study of patients presenting with fungicide self-poisoning to nine hospitals in Sri Lanka between 2002 and 2020. Patients were enrolled by clinical research assistants, with clinical outcomes being recorded at regular review for each patient. RESULTS: We identified 337 cases of self-poisoning with fungicides (alcohol as only co-ingestant), including 28 different fungicides across 5 different fungicide classes. Median time from ingestion to examination was 3.1 (1.8-5.7) h. Nearly all presented to hospital fully conscious (GCS 15, 15-15)- only 27 patients (8.0%) presented with reduced GCS (<15) and only 2 (0.6%) had GCS 3/15. Most patients (333/337, 98.8%) made a full recovery, of whom only eight (2.37%) required intubation and ventilation. Four patients died (case fatality rate: 1.2%; 95% CI 0.0-23.4) after ingestion of edifenphos (n = 2), propamocarb and pyraclostrobin. CONCLUSION: Fungicide self-poisoning appears to be less hazardous than insecticide or herbicide self-poisoning, with a substantially lower case fatality in the same cohort. Edifenphos is an exception to this 'less toxic' rule; as a WHO Class Ib highly hazardous pesticide, we recommend its withdrawal from, and replacement in, global agricultural practice. Propamocarb should be listed in the WHO hazard classification as propamocarb hydrochloride to reflect the higher toxicity of the common agricultural formulation. Pyraclostrobin currently has no WHO classification; one is urgently required now that its ingestion has now been linked the death of a patient. Additional prospective clinical data on fungicide self-poisoning is required to expand knowledge on the effects of these diverse compounds.

Oximes for acute organophosphate pesticide poisoning.

BACKGROUND: Acute organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the developing world. Standard treatment involves administration of intravenous atropine and oxime to reactivate inhibited acetylcholinesterase. The clinical usefulness of oximes, such as pralidoxime and obidoxime, has been challenged over the past 20 years by physicians in many parts of the world. OBJECTIVES: To quantify the effectiveness and safety of the administration of oximes in acute organophosphorus pesticide-poisoned patients. SEARCH STRATEGY: We searched both English and Chinese databases: Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE (Ovid SP), EMBASE (Ovid SP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) and the Chinese language databases CNKI and WANGFANG. All searches were run in September 2009. SELECTION CRITERIA: Articles that could possibly be RCTs were retrieved to determine if they were randomised. DATA COLLECTION AND ANALYSIS: The published methodology of three RCTs was not clear. We contacted the principal authors of these, but did not obtain further information. MAIN RESULTS: Seven pralidoxime RCTs were found. Three RCTs including 366 patients studied pralidoxime vs placebo and four RCTs including 479 patients compared two or more different doses. These trials found quite disparate results with treatment effects ranging from benefit to harm. However, many studies did not take into account several issues important for outcomes. In particular, baseline characteristics were not balanced, oxime doses varied widely, there were substantial delays to treatment, and the type of organophosphate was not taken into account. Only one RCT compared the World Health Organization (WHO) recommended doses with placebo. This trial showed no clinical benefits and a trend towards harm in all sub-groups, despite clear evidence that these doses reactivated acetylcholinesterase in the blood. AUTHORS' CONCLUSIONS: Current evidence is insufficient to indicate whether oximes are harmful or beneficial. The WHO recommended regimen (30 mg/kg pralidoxime chloride bolus followed by 8 mg/kg/hr infusion) is not supported. Further RCTs are required to examine other strategies and regimens. There are many theoretical and practical reasons why oximes may not be useful, particularly for late presentations of dimethyl OP and those with a large excess of OP that simply re-inhibits reactivated enzymes. Future studies should screen for patient sub-groups that may benefit and may need flexible dosing strategies as clinical effectiveness and doses may depend on the type of OP.

Hyperbaric oxygen for carbon monoxide poisoning.

BACKGROUND: Poisoning with carbon monoxide (CO) remains an important cause of accidental and intentional injury worldwide. Several unblinded non-randomized trials have suggested that the use of hyperbaric oxygen (HBO) prevents the development of neurological sequelae. This has led to the widespread use of HBO in the management of patients with carbon monoxide poisoning. OBJECTIVES: To examine randomised trials of the efficacy of hyperbaric oxygen (HBO) compared to normobaric oxygen (NBO) for the prevention of neurologic sequelae in patients with acute carbon monoxide poisoning. SEARCH STRATEGY: We searched the following electronic databases; Cochrane Injuries Group Specialised Register (searched June 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE (Ovid SP) 1950 to June 2010, EMBASE (Ovid SP) 1980 to June 2010, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to June 2010, ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) 1990 to June 2010. SELECTION CRITERIA: All randomised controlled trials of HBO compared to NBO, involving non-pregnant adults who are acutely poisoned with carbon monoxide (regardless of severity). DATA COLLECTION AND ANALYSIS: Two authors independently extracted from each trial information on: the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurologic symptoms at follow-up. MAIN RESULTS: Seven randomised controlled trials of varying quality were identified; one was excluded because it did not evaluate clinical outcomes. Of the six remaining trials involving 1361 participants, two found a beneficial effect of HBO for the reduction of neurologic sequelae at one month, while four others did not. One of these is an incomplete publication (an abstract of an interim analysis). Although pooled random effects meta-analysis does not suggest a significant benefit from HBOT (OR for neurological deficits 0.78, 95%CI 0.54 to 1.12), significant methodologic and statistical heterogeneity was apparent among the trials, and this result should be interpreted cautiously. Moreover, design or analysis flaws were evident in all trials. Importantly, the conclusions of one positive trial may have been influenced by failure to adjust for multiple hypothesis testing, while interpretation of the other positive trial is hampered by a high risk of bias introduced during the analysis including an apparent change in the primary outcome. Both were also stopped early 'for benefit', which is likely to have inflated the observed effect. In contrast three negative trials had low power to detect a benefit of HBO due to exclusion of severely poisoned patients in two and very poor follow-up in the other. One trial that was said to be finished around eight years ago has not reported the final analysis in any forum. AUTHORS' CONCLUSIONS: Existing randomised trials do not establish whether the administration of HBO to patients with carbon monoxide poisoning reduces the incidence of adverse neurologic outcomes. Additional research is needed to better define the role, if any, of HBO in the treatment of patients with carbon monoxide poisoning. This research question is ideally suited to a multi-center randomised controlled trial.

Macronutrient Intake in Pregnancy and Child Cognitive and Behavioural Outcomes.

Prenatal nutrient exposures can impact on brain development and disease susceptibility across the lifespan. It is well established that maternal macronutrient intake during pregnancy influences foetal and infant development. Therefore, we hypothesise that macronutrient intakes during pregnancy are correlated with cognitive development during early childhood. The current study aimed to investigate the relationship between maternal macronutrient intake during pregnancy and child cognitive and behavioural outcomes at age 4 years. We analysed prospective data from a cohort of 64 Australian mother-child dyads. Maternal macronutrient intake was assessed using a validated 74-item food frequency questionnaire at 2 timepoints during pregnancy. Child cognition and behaviour were measured at age 4 years using the validated Wechsler Preschool and Primary Scale of Intelligence, 3rd version (WPPSI-III) and the Child Behaviour Checklist (CBC). Linear regression models were used to quantify statistical relationships and were adjusted for maternal age, education, pre-pregnancy BMI, breastfeeding duration and birthweight. Child Performance IQ was inversely associated with maternal starch intake (b = -11.02, p = 0.03). However, no other associations were found. Further research is needed to explore the association between different types of starch consumed during pregnancy and child cognitive development.

Fructose-1, 6-diphosphate (FDP) as a novel antidote for yellow oleander-induced cardiac toxicity: a randomized controlled double blind study.

BACKGROUND: Cardiac toxicity due to ingestion of oleander plant seeds in Sri Lanka and some other South Asian countries is very common. At present symptomatic oleander seed poisoning carries a mortality of 10% in Sri Lanka and treatment of yellow oleander poisoning is limited to gastric decontamination and atropine administration. The only proven effective antidote is digoxin antibodies but these are not available for routine use because of the high cost. The main objective of this study is to investigate the effectiveness of a new and inexpensive antidote for patients with life threatening arrhythmias due oleander poisoning. METHOD/DESIGN: We set up a randomised double blind clinical trial to assess the effectiveness of Fructose 1, 6 diphosphate (FDP) in acute yellow oleander poisoning patients admitted to the adult medical wards of a tertiary hospital in Sri Lanka. Patients will be initially resuscitated following the national guidelines and eligible patients will be randomised to receive either FDP or an equal amount of normal saline. The primary outcome measure for this study is the sustained reversion to sinus rhythm with a heart rate greater than 50/min within 2 hours of completion of FDP/placebo bolus. Secondary outcomes include death, reversal of hyperkalaemia on the 6, 12, 18 and 24 hour samples and maintenance of sinus rhythm on the holter monitor. Analysis will be on intention-to-treat. DISCUSSION: This trial will provide information on the effectiveness of FDP in yellow oleander poisoning. If FDP is effective in cardiac glycoside toxicity, it would provide substantial benefit to the patients in rural Asia. The drug is inexpensive and thus could be made available at primary care hospitals if proven to be effective. TRIAL REGISTRATION: Current Controlled trial ISRCTN71018309.

Global DNA methylation and cognitive and behavioral outcomes at 4 years of age: A cross-sectional study.

BACKGROUND: Accumulating evidence suggests that breastfeeding exclusivity and duration are positively associated with child cognition. This study investigated whether DNA methylation, an epigenetic mechanism modified by nutrient intake, may contribute to the link between breastfeeding and child cognition. The aim was to quantify the relationship between global DNA methylation and cognition and behavior at 4 years of age. METHODS: Child behavior and cognition were measured at age 4 years using the Wechsler Preschool and Primary Scale of Intelligence, third version (WPPSI-III), and Child Behavior Checklist (CBC). Global DNA methylation (%5-methylcytosines (%5mC)) was measured in buccal cells at age 4 years, using an enzyme-linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. RESULTS: Data were collected from 73 children recruited from the Women and Their Children's Health (WATCH) study. No statistically significant associations were found between global DNA methylation levels and child cognition or behavior (p > .05), though the estimates of effect were consistently negative. Global DNA methylation levels in males were significantly higher than in females (median %5mC: 1.82 vs. 1.03, males and females, respectively, (p < .05)). CONCLUSION: No association was found between global DNA methylation and child cognition and behavior; however given the small sample, this study should be pooled with other cohorts in future meta-analyses.

Pralidoxime in acute organophosphorus insecticide poisoning--a randomised controlled trial.

BACKGROUND: 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. CONCLUSIONS: 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.

Management of acute organophosphorus pesticide poisoning.

Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available. Medical management is difficult, with case fatality generally more than 15%. We describe the limited evidence that can guide therapy and the factors that should be considered when designing further clinical studies. 50 years after first use, we still do not know how the core treatments--atropine, oximes, and diazepam--should best be given. Important constraints in the collection of useful data have included the late recognition of great variability in activity and action of the individual pesticides, and the care needed cholinesterase assays for results to be comparable between studies. However, consensus suggests that early resuscitation with atropine, oxygen, respiratory support, and fluids is needed to improve oxygen delivery to tissues. The role of oximes is not completely clear; they might benefit only patients poisoned by specific pesticides or patients with moderate poisoning. Small studies suggest benefit from new treatments such as magnesium sulphate, but much larger trials are needed. Gastric lavage could have a role but should only be undertaken once the patient is stable. Randomised controlled trials are underway in rural Asia to assess the effectiveness of these therapies. However, some organophosphorus pesticides might prove very difficult to treat with current therapies, such that bans on particular pesticides could be the only method to substantially reduce the case fatality after poisoning. Improved medical management of organophosphorus poisoning should result in a reduction in worldwide deaths from suicide.

Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial.

BACKGROUND: The case-fatality for intentional self-poisoning in the rural developing world is 10-50-fold higher than that in industrialised countries, mostly because of the use of highly toxic pesticides and plants. We therefore aimed to assess whether routine treatment with multiple-dose activated charcoal, to interrupt enterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such an environment. METHODS: We did an open-label, parallel group, randomised, controlled trial of six 50 g doses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoal in three Sri Lankan hospitals. 4632 patients were randomised to receive no charcoal (n=1554), one dose of charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients. 2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander (Thevetia peruviana) seeds. Mortality was the primary outcome measure. Analysis was by intention to treat. The trial is registered with controlled-trials.com as ISRCTN02920054. FINDINGS: Mortality did not differ between the groups. 97 (6.3%) of 1531 participants in the multiple-dose group died, compared with 105 (6.8%) of 1554 in the no charcoal group (adjusted odds ratio 0.96, 95% CI 0.70-1.33). No differences were noted for patients who took particular poisons, were severely ill on admission, or who presented early. INTERPRETATION: We cannot recommend the routine use of multiple-dose activated charcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful, effective affordable treatments are urgently needed.

Clinical outcomes and kinetics of propanil following acute self-poisoning: a prospective case series.

BACKGROUND: Propanil is an important cause of death from acute pesticide poisoning, of which methaemoglobinaemia is an important manifestation. However, there is limited information about the clinical toxicity and kinetics. The objective of this study is to describe the clinical outcomes and kinetics of propanil following acute intentional self-poisoning. METHODS: 431 patients with a history of propanil poisoning were admitted from 2002 until 2007 in a large, multi-centre prospective cohort study in rural hospitals in Sri Lanka. 40 of these patients ingested propanil with at least one other poison and were not considered further. The remaining 391 patients were classified using a simple grading system on the basis of clinical outcomes; methaemoglobinaemia could not be quantified due to limited resources. Blood samples were obtained on admission and a subset of patients provided multiple samples for kinetic analysis of propanil and the metabolite 3,4-dichloroaniline (DCA). RESULTS: There were 42 deaths (median time to death 1.5 days) giving a case fatality of 10.7%. Death occurred despite treatment in the context of cyanosis, sedation, hypotension and severe lactic acidosis consistent with methaemoglobinaemia. Treatment consisted primarily of methylene blue (1 mg/kg for one or two doses), exchange transfusion and supportive care when methaemoglobinaemia was diagnosed clinically. Admission plasma concentrations of propanil and DCA reflected the clinical outcome. The elimination half-life of propanil was 3.2 hours (95% confidence interval 2.6 to 4.1 hours) and the concentration of DCA was generally higher, more persistent and more variable than propanil. CONCLUSION: Propanil is the most lethal herbicide in Sri Lanka after paraquat. Methylene blue was largely prescribed in low doses and administered as intermittent boluses which are expected to be suboptimal given the kinetics of methylene blue, propanil and the DCA metabolite. But in the absence of controlled studies the efficacy of these and other treatments is poorly defined. More research is required into the optimal management of acute propanil poisoning.

Do targeted bans of insecticides to prevent deaths from self-poisoning result in reduced agricultural output?

BACKGROUND: The pesticides monocrotophos, methamidophos, and endosulfan were a very common cause of severe poisoning in Sri Lanka during the 1980s and early 1990s, before they were banned in 1995 and 1998. Now, the most commonly used insecticides are the less toxic World Health Organization Class II organophosphorus pesticides and carbamates. These bans were followed by a large reduction in both fatal poisonings and suicide in Sri Lanka. OBJECTIVE: We aimed to see if these bans adversely affected agricultural production or costs. METHODS: We used data from the World Resources Institute to compare the yields of the main crop groups in Sri Lanka with those from surrounding South Asian countries for 1980-2005. We also examined data from the Sri Lankan Department of Census and Statistics to examine the yields of 13 specific vegetable crops and rice for 1990-2003, along with the costs of rice production. RESULTS: We found no drop in productivity in the years after the main bans were instituted (1995, 1998). We observed substantial annual fluctuation in estimated yields in all data sources, but these did not coincide with the bans and were no larger than the fluctuations in other countries. Also, there was no sudden change in costs of rice production coinciding with bans. CONCLUSIONS: Countries aiming to apply restrictions to reduce deaths from pesticide poisoning should evaluate agricultural needs and develop a plan that encourages substitution of less toxic pesticides. If farmers have an affordable alternative for pest control for each crop, there is no obvious adverse effect on agricultural output.