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1.  Effect of a Brief Outreach Educational Intervention on the Translation of Acute Poisoning Treatment Guidelines to Practice in Rural Sri Lankan Hospitals: A Cluster Randomized Controlled Trial 
PLoS ONE  2013;8(8):e71787.
In developing countries, including Sri Lanka, a high proportion of acute poisoning and other medical emergencies are initially treated in rural peripheral hospitals. Patients are then usually transferred to referral hospitals for further treatment. Guidelines are often used to promote better patient care in these emergencies. We conducted a cluster randomized controlled trial (ISRCTN73983810) which aimed to assess the effect of a brief educational outreach (‘academic detailing’) intervention to promote the utilization of treatment guidelines for acute poisoning.
Methods and Findings
This cluster RCT was conducted in the North Central Province of Sri Lanka. All peripheral hospitals in the province were randomized to either intervention or control. All hospitals received a copy of the guidelines. The intervention hospitals received a brief out-reach academic detailing workshop which explained poisoning treatment guidelines and guideline promotional items designed to be used in daily care. Data were collected on all patients admitted due to poisoning for 12 months post-intervention in all study hospitals. Information collected included type of poison exposure, initial investigations, treatments and hospital outcome. Patients transferred from peripheral hospitals to referral hospitals had their clinical outcomes recorded. There were 23 intervention and 23 control hospitals. There were no significant differences in the patient characteristics, such as age, gender and the poisons ingested. The intervention hospitals showed a significant improvement in administration of activated charcoal [OR 2.95 (95% CI 1.28–6.80)]. There was no difference between hospitals in use of other decontamination methods.
This study shows that an educational intervention consisting of brief out-reach academic detailing was effective in changing treatment behavior in rural Sri Lankan hospitals. The intervention was only effective for treatments with direct clinician involvement, such as administering activated charcoal. It was not successful for treatments usually administered by non-professional staff such as forced emesis for poisoning.
Trial Registration ISRCTN73983810 ISRCTN73983810
PMCID: PMC3747188  PMID: 23990989
2.  Comparative in-vivo toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Crotalinae: Hypnale) 
BMC Research Notes  2012;5:471.
Envenoming by south Asian hump-nosed pit vipers (Genus: Hypnale) is a significant health issue in Sri Lanka and in peninsular India. Bites by these snakes frequently lead to local envenoming, coagulopathy and acute renal failure even resulting in death. Recently the genus was revised and the existence of three species viz H. hypnale, H. nepa and H. zara were recognized. There is, however, a paucity of information on the toxicity of the venoms of these species. Hence, we compared the toxic effects of the three Hypnale venoms using BALB/c mice.
Intraperitoneal median lethal doses (LD50) for H. hypnale, H. zara and H. nepa venoms were 1.6, 6.0 and 9.5 μg protein/g respectively. Minimum haemorrhagic doses for venoms of H. hypnale, H. zara and H. nepa were 3.4, 11.0 and 16.6 μg protein/mouse respectively. The minimum necrotic doses for the same venoms were 15.0, 55.1 and 68.2 μg protein/mouse respectively. Severe congestion and petecheal haemorrhages were observed in lungs, kidneys, liver and the alimentary tract. Histopathogical examination of kidneys revealed proximal tubular cell injury and acute tubular necrosis with intact basement membrane indicating possible direct nephrotoxicity. Hypnale venoms caused pulmonary oedema, hepatocellular degeneration and necrosis, focal neuronal degeneration in brain and extramedullary haemopoiesis in spleen. H. hypnale venom caused all above histopathological alterations at lower doses compared to the other two.
Hypnale venoms cause similar pathological changes with marked differences in the severity of the toxic effects in vivo. Therefore, differences in the severity of the clinical manifestations could possibly be seen among bite victims of the three Hypnale species.
PMCID: PMC3494509  PMID: 22932058
Hypnale; Nepa; Zara; Venom; Toxicity; Histopathology
3.  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
4.  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
6.  The in vitro toxicity of venoms from South Asian Hump-nosed pit vipers (Viperidae: Hypnale) 
Hump-nosed pit vipers (Genus Hypnale) are venomous snakes from South India and Sri Lanka. Envenoming by Hypnale species may cause significant morbidity and is characterized by local envenoming and less commonly coagulopathy and acute renal failure. Currently there are three nominal species of this genus: H. hypnale, H. zara and H. nepa. This study investigates the biochemical and pharmacological properties of the venoms from the three Hypnale species in Sri Lanka. The three Hypnale venoms had similar chromatographic profiles using reverse phase high performance liquid chromatography and fractions with procoagulant activity were identified. Hypnale venoms had potent cytotoxicity in cultured rat aorta smooth muscle cells with similar IC50 values. The venoms had weak neurotoxic and myotoxic activity in the isolated chick biventer muscle preparation. They had mild procoagulant activity with close MCC5 values and also phospholipase activity. Locally available polyvalent antivenom did not neutralise any venom effects. The study demonstrates that the three Hypnale venoms are similar and cytotoxicity appears to be the most potent effect, although they have mild procoagulant activity. These findings are consistent with clinical reports.
PMCID: PMC3114463  PMID: 21677795
7.  Deep coma and hypokalaemia of unknown aetiology following Bungarus caeruleus bites: Exploration of pathophysiological mechanisms with two case studies 
Bungarotoxin present in Bungarus caeruleus (BC) causes life threatening respiratory muscle paralysis. Deep coma and hypokalaemia have been observed in a significant proportion of patients, but the cause is unknown. We postulate the likely mechanism behind these two phenomena. We studied clinical details of two patients admitted with deep coma and performed electroencephalograms (EEG) and brain stem auditory and visual evoked potentials (BAEP and VEP). Daily serum potassium was measured along with urinary potassium excretion as a marker of total extracellular body potassium. Both patients had no brain stem reflexes on admission and the EEG revealed absent alpha and delta activity and presence of dominant theta activity. Alpha rhythm returned on the 3rd day in one patient, while in the other it did not, and the latter patient died on the 13th day due to disseminated intravascular coagulation. BAEP were delayed and VEP were absent in the deceased patient. Both had low serum potassium and low urinary potassium excretion. Replacement of potassium (up to 1.5mmol/kg/day) did not improve serum potassium and urinary potassium excretion. Absent alpha and delta activity in EEG and delayed BAEP and absent VEP are suggestive of a central action of the venom on both the cortical and brain stem neurones. Persistently low serum potassium and reduced urinary potassium excretion are suggestive of intracellular shift as the causative mechanism of hypokalaemia.
PMCID: PMC3086184  PMID: 21544185
Deep coma; hypokalaemia; Bungarus caeruleus; EEG; evoked potentials
8.  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
9.  Acute human self-poisoning with bispyribac-containing herbicide Nominee®: A prospective observational study 
Self poisoning with herbicides is an important reason for hospital admission and death in Asia. Whilst some herbicides have a well described toxicity profile in humans, many of the newer compounds rely on extrapolation from animal results as no published literature on clinical outcomes of human self poisoning has been described. One example of these compounds is bispyribac, a selective herbicide used in rice and wheat cultivation that is marketed in two containers, one containing bispyribac 400g/L with a solvent and the other the surfactant, polyethylene glycol. We present the first case series of acute human self-poisoning with a herbicide product containing bispyribac.
Clinical data for all patients who presented with acute poisoning from a bispyribac-containing herbicide (Nominee®) to two General Hospitals in Sri Lanka from June 2002 until January 2009 were collected prospectively. Admission and serial blood samples were collected from consenting patients to confirm exposure and study the toxicokinetics of bispyribac, respectively.
110 patients with a history of bispyribac ingestion presented after a median time of 4 hours post ingestion. There were three deaths at 15, 6 and 5 hours post-ingestion due to asystolic cardiac arrest. All three patients had reduced GCS (3, 12 and 13 respectively) of whom the former two had co-ingested ethanol and developed tonic clonic seizures. Admission blood sample was obtained from the former two of these patients but bispyribac was detected in only one of these patients. The other patient presented 2.5 hours post-ingestion with a GCS of 12 but bispyribac was not detected. Excluding the patient with undetectable bispyribac, a conservative estimate of the case fatality ratio at 1.81% (95% CI 0.32- 5.8) can be made. The majority of the remaining patients had self-limiting upper gastrointestinal symptoms and 8 patients had an abnormal Glasgow Coma Score on presentation to hospital. The overall median hospital stay was 3 days. Bispyribac was not detectable on admission in 21 patients; in the remaining patients, the median plasma concentration was 50.55μg/mL (IQR 1.28- 116.5; n=32). The peak concentration was noted around 3 hours post-ingestion and plasma bispyribac concentration did not predict the severity of poisoning.
The majority of patients developed self-resolving symptoms and were successfully managed in rural general hospitals without transfer to larger tertiary hospitals. Patients who died developed significant poisoning within 6 hours and plasma bispyribac concentrations did not appear to predict mortality. The lack of correlation between bispyribac outcomes and available plasma concentrations may be due to exposure to non-bispyribac components or other undefined factors. Clinical outcomes from acute self-poisoning with bispyribac-containing herbicides appear to be relatively more favourable than other commonly used herbicides.
PMCID: PMC2875159  PMID: 20397802
10.  Fructose-1, 6-diphosphate (FDP) as a novel antidote for yellow oleander-induced cardiac toxicity: A randomized controlled double blind study 
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.
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.
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
PMCID: PMC2912827  PMID: 20587052
11.  Acute Human Self-Poisoning with Imidacloprid Compound: A Neonicotinoid Insecticide 
PLoS ONE  2009;4(4):e5127.
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.
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.
PMCID: PMC2662424  PMID: 19352499

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