Background

Following acute organophosphorus (OP) poisoning patients complain of numbness without objective sensory abnormalities or other features of OP induced delayed polyneuropathy. The aim of this study was to measure peripheral nerve function after acute exposure to OP.

Methods

A cohort study was conducted with age, gender and occupation matched controls. Motor nerve conduction velocity (MNCV), amplitude and area of compound muscle action potential (CMAP), sensory nerve conduction velocity (SNCV), F- waves and electromyography (EMG) on the deltoid and the first dorsal interosseous muscles on the dominant side were performed, following acute OP poisoning. All neurophysiological assessments except EMG were performed on the controls.

Assessments were performed on the day of discharge from the hospital (the first assessment) and six weeks (the second assessment) after the exposure. The controls were assessed only once.

Results

There were 70 patients (50 males) and 70 controls. Fifty-three patients attended for the second assessment.

In the first assessment MNCV of all the motor nerves examined, CMAP amplitude and SNCV of ulnar nerve, median and ulnar F-wave occurrence in the patients were significantly reduced compared to the controls.

In the second assessment significant reduction was found in SNCV of both sensory nerves examined, MNCV of ulnar nerve, CMAP amplitude of common peroneal nerve, F-wave occurrence of median and ulnar nerves.

No abnormalities were detected in the patients when compared to the standard cut-off values of nerve conduction studies except F-wave occurrence.

EMG studies did not show any abnormality.

Conclusion

There was no strong evidence of irreversible peripheral nerve damage following acute OP poisoning, however further studies are required.

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.

Objectives:

Acute paracetamol poisoning is an emerging problem in Sri Lanka. Management guidelines recommend ingested dose and serum paracetamol concentrations to assess the risk. Our aim was to determine the usefulness of the patient's history of an ingested dose of >150 mg/kg and paracetamol concentration obtained by a simple colorimetric method to assess risk in patients with acute paracetamol poisoning.

Materials and Methods:

Serum paracetamol concentrations were determined in 100 patients with a history of paracetamol overdose using High Performance Liquid Chromatography (HPLC); (reference method). The results were compared to those obtained with a colorimetric method. The utility of risk assessment by reported dose ingested and colorimetric analysis were compared.

Results:

The area under the receiver operating characteristic curve for the history of ingested dose was 0.578 and there was no dose cut-off providing useful risk categorization. Both analytical methods had less than 5% intra- and inter-batch variation and were accurate on spiked samples. The time from blood collection to result was six times faster and ten times cheaper for colorimetry (30 minutes, US$2) than for HPLC (180 minutes, US$20). The correlation coefficient between the paracetamol levels by the two methods was 0.85. The agreement on clinical risk categorization on the standard nomogram was also good (Kappa = 0.62, sensitivity 81%, specificity 89%).

Conclusions:

History of dose ingested alone greatly over-estimated the number of patients who need antidotes and it was a poor predictor of risk. Paracetamol concentrations by colorimetry are rapid and inexpensive. The use of these would greatly improve the assessment of risk and greatly reduce unnecessary expenditure on antidotes.

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.

BACKGROUND

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.

METHOD

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.

RESULTS

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%.

CONCLUSION

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

An increase in creatinine >3 μmol/L/h has been suggested to predict death in patients with paraquat self-poisoning and the value of other plasma biomarkers of acute kidney injury has not been assessed. The aim of this study was to validate the predictive value of serial creatinine concentrations and to study the utility of cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) as predictors of outcome in patients with acute paraquat poisoning. The rate of change of creatinine (dCr/dt) and cystatin C (dCyC/dt) concentrations were compared between survivors and deaths. Receiver-operating characteristic (ROC) curves were constructed to determine the best threshold for predicting death. Paraquat was detected in 20 patients and 7 of these died between 18 h and 20 days post-ingestion. The dCr/dt ROC curve had an area of 0.93 and the cut-off was >4.3 μmol/L/h (sensitivity 100%, specificity 85%, likelihood ratio 7). The dCyC/dt ROC curve had an area of 0.97 and the cutoff was >0.009 mg/L/h (sensitivity 100%, specificity 91%, likelihood ratio 11). NGAL did not separate survivors from deaths. Death due to acute paraquat poisoning is associated with changes in creatinine and cystatin concentrations. Further validation of these measurements is needed before they can be adopted in guiding intensive treatments.

Human data on protein binding and dose-dependent changes in toxicokinetics for MCPA are very limited. 128 blood samples were obtained in 49 patients with acute MCPA poisoning and total and unbound concentrations of MCPA were determined. The Scatchard plot was biphasic suggesting protein binding to two sites. The free MCPA concentration increased when the total concentration exceeded 239 mg/L (95% confidence interval 198–274 mg/L). Nonlinear regression using a two-site binding hyperbola model estimated saturation of the high affinity binding site at 115 mg/L (95%CI 0–304). Further analyses using global fitting of serial data and adjusting for the concentration of albumin predicted similar concentrations for saturable binding (184 mg/L and 167 mg/L, respectively) without narrowing the 95%CI. In 25 patients, the plasma concentration–time curves for both bound and unbound MCPA were approximately log-linear which may suggest first order elimination, although sampling was infrequent so zero order elimination cannot be excluded. Using a cut-off concentration of 200 mg/L, the half-life of MCPA at higher concentrations was 25.5 h (95%CI 15.0–83.0 h; n = 16 patients) compared to 16.8 h (95%CI 13.6–22.2 h; n = 10 patients) at lower concentrations. MCPA is subject to saturable protein binding but the influence on half-life appears marginal.

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

Context

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.

Objective

To describe the clinical outcomes, dose-response and glyphosate kinetics following self-poisoning with glyphosate-containing herbicides.

Methods

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.

Results

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).

Conclusions

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.

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.

Introduction

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).

Results

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.

Conclusions

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.

Background

An estimated 2–3 million people are acutely poisoned by organophosphorus pesticides each year, mostly in the developing world. There is a pressing need for new affordable antidotes and clonidine has been shown to be effective in animal studies. Our aim was to determine the safety of clonidine given as an antidote in adult patients presenting with signs or symptoms of acute organophosphate ingestion.

Methods

This study was a dose finding, open-label, multicentre, phase II trial. Forty eight patients with acute organophosphate poisoning were randomized to receive either clonidine or placebo: Four to receive placebo and twelve to receive clonidine at each dose level. The first dose level was an initial loading dose of 0.15 mg followed by an infusion of 0.5 mg of clonidine over 24 hours. The initial loading dose was increased to 0.3 mg, 0.45 and 0.6 mg. at all dosing levels however the subsequent infusion remained at 0.5 mg of clonidine over 24 hours.

Results

The baseline characteristics of both groups were similar. The trial was stopped after completion of the 3rd dosing level. At the 1st and 2nd dosing level there were no reported adverse drug reactions. At the 3rd dosing level 5 patients (42%) developed significant hypotension during clonidine treatment that responded to intravenous fluids. There were no statistical differences in ventilation rate, pre and post GCS, and mortality rates over all levels.

Conclusion

Our findings suggest use of moderate doses of clonidine in acute organophosphate poisoning can be used without causing frequent clinical problems but that higher doses are associated with a high incidence of hypotension requiring intervention. Further studies are needed to study the efficacy of clonidine as an antidote in organophosphate poisoning.

Trial registration

Current Controlled Trial ISRCTN89917816.

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.

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.

Trial Registration

Controlled-trials.com ISRCTN55264358

Please see later in the article for Editors' Summary

Editors' Summary

Background

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 http://dx.doi.org/10.1371/journal.pmed.1000104.

The US Environmental Protection Agency provides information about all aspects of insecticides (in English and Spanish)

Toxtown, an interactive site from the US National Library of Medicine provides information on exposure to pesticides and other environmental health concerns (in English and Spanish)

The US National Pesticide Information Center provides objective, science-based information about pesticides (in English and Spanish)

MedlinePlus also provides links to information on pesticides (in English and Spanish)

For more on Poisoning Prevention and Management see WHO's International Programme on Chemical Safety (IPCS)

WikiTox, a clinical toxicology teaching resource project, has detailed information on organophosphates

Background

Deliberate self-poisoning with older pesticides such as organophosphorus compounds are commonly fatal and a serious public health problem in the developing world. The clinical consequences of self-poisoning with newer pesticides are not well described. Such information may help to improve clinical management and inform pesticide regulators of their relative toxicity. This study reports the clinical outcomes and toxicokinetics of the neonicotinoid insecticide imidacloprid following acute self-poisoning in humans.

Methodology/Principal Findings

Demographic and clinical data were prospectively recorded in patients with imidacloprid exposure in three hospitals in Sri Lanka. Blood samples were collected when possible for quantification of imidacloprid concentration. There were 68 patients (61 self-ingestions and 7 dermal exposures) with exposure to imidacloprid. Of the self-poisoning patients, the median time to presentation was 4 hours (IQR 2.3–6.0) and median amount ingested was 15 mL (IQR 10–50 mL). Most patients only developed mild symptoms such as nausea, vomiting, headache and diarrhoea. One patient developed respiratory failure needing mechanical ventilation while another was admitted to intensive care due to prolonged sedation. There were no deaths. Median admission imidacloprid concentration was 10.58 ng/L; IQR: 3.84–15.58 ng/L, Range: 0.02–51.25 ng/L. Changes in the concentration of imidacloprid in serial blood samples were consistent with prolonged absorption and/or saturable elimination.

Conclusions

Imidacloprid generally demonstrates low human lethality even in large ingestions. Respiratory failure and reduced level of consciousness were the most serious complications, but these were uncommon. Substitution of imidacloprid for organophosphorus compounds in areas where the incidence of self-poisoning is high may help reduce deaths from self-poisoning.

Key Points

Acetylcholinesterase inhibition by organophosphorus pesticides or nerve gases can cause acute parasympathetic system dysfunction, muscle weakness, seizures, coma, and respiratory failure. Prognosis depends on the dose and relative toxicity of the specific compound, as well as pharmacokinetic factors.

Initial resuscitation, then atropine and oxygen, are considered to be the mainstays of treatment, although good quality studies to show benefit have not been found. We don't know the optimum dose of atropine to give, but common clinical practice is to administer sufficient to keep the heart rate greater than 80 beats per minute, systolic blood pressure above 80mmHg, and the lungs clear. Glycopyrronium bromide may be as effective as atropine in preventing death, with fewer adverse effects, although no adequately powered studies have been done.

Washing the poisoned person and removing contaminated clothes is a sensible approach, but no studies have been done to evaluate benefit. Healthcare workers should ensure that washing does not distract them from other treatment priorities, and should protect themselves from contamination.

Benzodiazepines are considered to be standard treatment to control organophosphorus induced seizures, although no studies have been found.

We don't know whether activated charcoal, alpha2 adrenergic receptor agonists (clonidine), butyrylcholinesterase replacement therapy using fresh frozen plasma or plasmapheresis, magnesium sulphate, N-methyl-D-aspartate receptor antagonists, organophosphorus hydrolases, sodium bicarbonate, milk and other "home remedies" taken soon after ingestion, cathartics, or extracorporeal clearance improve outcomes. Oximes have not been shown to improve outcomes, but studies have been of poor quality so a definite conclusion cannot be made.Potential benefits from gastric lavage or ipecacuanha are likely to be outweighed by the risks of harm, such as aspiration.

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.

Background

The usefulness of a low butyrylcholinesterase activity on admission for predicting severity in acute organophosphorus insecticide poisoning has long been debated. Previous studies have been confounded by the inclusion of multiple insecticides with differing inhibitory kinetics.

Aim

We aimed to assess the usefulness of admission butyrylcholinesterase activity, together with plasma organophosphorus concentration, for predicting death with identified organophosphorus insecticides.

Design

A prospective cohort of self-poisoned patients

Methods

We prospectively studied 91 and 208 patients with proven dimethoate or chlorpyrifos self-poisoning treated using a standard protocol. Plasma butyrylcholinesterase activity and organophosphorus concentration were measured on admission and clinical outcomes recorded.

Results

The usefulness of a plasma butyrylcholinesterase activity <600mU/ml on admission varied markedly - while highly sensitive in chlorpyrifos poisoning (sensitivity 11/11 deaths; 100%, 95%CI 71.5-100), its specificity was only 17.7% (95%CI 12.6-23.7). In contrast, while poorly sensitive for deaths in dimethoate poisoning (12/25 patients; 48%, 95%CI 27.9-68.7) it was reasonably specific (86.4%, 95%CI 75.7-93.6). A high organophosphorus concentration on admission was associated with worse outcome; however, a clear threshold concentration was only present for dimethoate poisoning.

Conclusions

Plasma butyrylcholinesterase activity on admission can provide useful information; however, it must be interpreted carefully. It can only be used to predict need for critical care and death when the insecticide ingested is known and its sensitivity and specificity for that insecticide has been studied. Plasma concentration of some organophosphorus insecticides predicts outcome. The development of rapid bedside tests for organophosphorus detection may aid early assessment of severity.

Introduction

Acute self-poisoning with the organophosphorus (OP) pesticide dimethoate has a human case fatality three-fold higher than poisoning with chlorpyrifos despite similar animal toxicity. The typical clinical presentation of severe dimethoate poisoning is quite distinct from that of chlorpyrifos and other OP pesticides: many patients present with hypotension that progresses to shock and death within 12–48 h post-ingestion. The pathophysiology of this syndrome is not clear.

Case reports

We present here three patients with proven severe dimethoate poisoning. Clinically, all had inappropriate peripheral vasodilatation and profound hypotension on presentation, which progressed despite treatment with atropine, i.v. fluids, pralidoxime chloride, and inotropes. All died 2.5–32 h post-admission. Continuous cardiac monitoring and quantification of troponin T provided little evidence for a primary cardiotoxic effect of dimethoate.

Conclusion

Severe dimethoate self-poisoning causes a syndrome characterized by marked hypotension with progression to distributive shock and death despite standard treatments. A lack of cardiotoxicity until just before death suggests that the mechanism is of OP-induced low systemic vascular resistance (SVR). Further invasive studies of cardiac function and SVR, and post-mortem histology, are required to better describe this syndrome and to establish the role of vasopressors and high-dose atropine in therapy.

Background

Deliberate self-poisoning is a major public heath issue in developing countries. In rural Sri Lanka deliberate self-poisoning is one of the leading causes of hospital death. The majority of patients with poisoning present to rural hospitals for initial treatment that are staffed by non-specialist and often relatively junior doctors. The treatment of self-poisoning patients poses numerous clinical challenges and further difficulties are experienced if patients are uncooperative and aggressive, intoxicated with alcohol or suffering mental illness. Previous research in developed countries has examined self-poisoning patients and their treatment but little is know about self-poisoning patient care in the context of rural health provision in developing countries. This study provides the first focused exploration of the experiences and perceptions of primary care rural hospital doctors in Sri Lanka toward the treatment of self-poisoning patients.

Methods

Semi-structured in-depth interviews were conducted with fifteen doctors from rural hospitals in the North Central Province, Sri Lanka. All interviews were recorded and transcribed and subject to thematic analysis.

Results

Participating doctors did perceive that treating self-poisoning patients in a primary care rural hospital as potentially confidence-building. However, resource issues such as the lack of medication, equipment and staffing were seen as important challenges to treating self-poisoning patients. Other challenges identified included disparity with community and other staff members regarding expectations of care, a sense of professional isolation and a lack of continuing education programs.

Conclusion

Addressing professional isolation through educational and trainee programs for doctors and reducing the variance in expectations between professional groups and the community has the potential to improve delivery of care for self-poisoning patients.

Organophosphorus (OP) pesticide self-poisoning is a major clinical problem across the rural developing world, killing an estimated 200,000 people every year. Medical management is difficult, with case fatality often over 20%. In this review, we describe the limited evidence base that should guide therapy. Fifty years after first being used, we still do not know how the core treatment - atropine, oximes, and diazepam - should best be administered. Major constraints in collecting useful data have been the late recognition of great variety among OPs and the care that cholinesterase assays require for their results to be interpreted or compared between studies. However, consensus exists that early resuscitation with atropine, oxygen, respiratory support, and fluids is required to improve oxygenation of patients. The role of oximes is unclear - they may only benefit patients poisoned by some OPs or patients with moderate poisoning. Small studies have suggested possible benefit from new treatments, eg. magnesium sulphate, but much larger trials are needed. Gastric lavage may have a role but should only be considered once the patient is stable. RCTs are now underway in rural Asia to address particular aspects of therapy. However, some specific OP pesticides may ultimately prove very difficult to treat with current treatments such that focused bans may be the only method to substantially bring down the case fatality for OP poisoning. Improved medical management of OP poisoning will result in a marked reduction in the global number of deaths from suicide.

Background:

Organophosphorus pesticide poisoning kills around 200,000 people each year, principally due to self poisoning in the Asia-Pacific region.

Aim:

We wished to assess whether patients at high risk of death could be identified accurately using clinical parameters soon after hospital admission.

Design:

We evaluated the usefulness of the International Program on Chemical Safety Poison Severity Score (IPCS PSS) and the Glasgow Coma Score (GCS) prospectively for predicting death in patients poisoned by organophosphorus pesticides.

Methods:

Data were collected as part of a multicentre cohort study in Sri Lanka. Study doctors saw all patients on admission, collecting data on pulse, blood pressure, pupil size, need for intubation, and GCS.

Results:

1365 patients with a history of acute organophosphorus poisoning were included. Receiver operating characteristic (ROC) curves were calculated for the IPCS PSS and GCS on admission. The IPCS PSS and GCS had similar ROC area under the curves (AUC) and best cut points as determined by Youden's index (AUC/sensitivity/specificity 0.81/0.78/0.79 for IPCS PSS ≥ grade 2 and 0.84/0.79/0.79 for GCS ≤13). The predictive value varied with the pesticide ingested, being more accurate for dimethoate poisoning and less accurate for fenthion poisoning (GCS AUC 0.91 compared to 0.69).

Conclusions:

GCS and the IPCS PSS were similarly effective at predicting outcome. Patients presenting with a GCS ≤ 13 need intensive monitoring and treatment. However, the identity of the organophosphate must be taken into account since the half of all patients who died from fenthion poisoning only had mild symptoms at presentation.

Background

The case-fatality for intentional self-poisoning in the rural developing world is 10-50 fold higher than industrialised countries, due mostly to the use of highly toxic pesticides and plants. We aimed to determine whether routine therapy with multiple dose activated charcoal to interrupt enterovascular or enterohepatic circulations offers benefit, compared to no charcoal.

Methods

We conducted an open-label parallel group randomised controlled trial of six 50g doses at four hourly intervals vs no charcoal vs a single 50g dose of activated charcoal in three Sri Lankan hospitals. Mortality was the primary outcome.

Findings

4632 patients were randomised to receive no charcoal (1554), a single dose of charcoal (1545), or six doses of charcoal (1533); outcomes were available for 4629. 2338 (50.5%) had ingested pesticides whilst 1647 (35.6%) had ingested yellow oleander seeds. Mortality did not differ significantly between the groups. 97 of 1531 (6.3%) participants in the multiple dose group died, compared with 105 of 1554 (6.8%) in the no charcoal group (adjusted odds ratio [OR] 0.96, 95% confidence interval [CI] 0.70-1.33). No significant differences were noted for patients who took particular poisons, were more severely ill on admission, or who presented early. The RCT was registered as ISRCTN02920054.

Interpretation

We found no benefit from routine administration of multiple dose activated charcoal for acute self-poisoning, nor from early administration of charcoal. We cannot recommend the routine use of activated charcoal in rural Asia-Pacific; while further studies of early charcoal administration may be useful, effective affordable treatments are urgently required.

Intentional self-poisonings with seeds from the yellow oleander tree (Thevetia peruviana) are widely reported. Activated charcoal has been suggested to benefit patients with yellow oleander poisoning by reducing absorption and/or facilitating elimination. Two recent randomised controlled trials (RCTs) assessing the efficacy of activated charcoal reported conflicting outcomes in terms of mortality. The effect of activated charcoal on the pharmacokinetics of Thevetia cardenolides has not been assessed. This information may be useful for determining whether further studies are necessary. Serial blood samples were obtained from patients enrolled in a RCT assessing the relative efficacy of single dose (SDAC) and multiple doses (MDAC) of activated charcoal compared to no activated charcoal (NoAC). The concentration of Thevetia cardenolides was estimated using a digoxin immunoassay. The effect of activated charcoal on cardenolide pharmacokinetics was compared between treatment groups using the AUC24, the 24h Mean Residence Time (MRT24), and regression lines obtained from serial concentration points adjusted for exposure. Erratic and prolonged absorption patterns were noted in each patient group. The apparent terminal half-life was highly variable, with a median time of 42.9h. There was a reduction in MRT24 and the apparent terminal half-life estimated from linear regression in patients administered activated charcoal compared to the control group (NoAC). This effect was approximately equal in patients administered MDAC or SDAC. Activated charcoal appears to favourably influence the pharmacokinetic profile of Thevetia cardenolides in patients with acute self-poisoning, which may have clinical benefits. Given the conflicting clinical outcomes noted in previous RCTs, this mechanistic data supports the need for further studies to determine whether a subgroup of patients (eg. those presenting soon after poisoning) will benefit from activated charcoal.

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.