Fahim Mohamed

Publications of Fahim Mohamed

• Effects of a provincial ban of two toxic organophosphorus insecticides on pesticide poisoning hospital admissions.

  Authors: Michael Eddleston, Sriyantha Adhikari, Samitha Egodage, Hasantha Ranganath, Fahim Mohamed, Gamini Manuweera, Shifa Azher, Shaluka Jayamanne, Edmund Juzczak, Mh Rezvi Sheriff, Andrew H Dawson, Nick A Buckley

  Clinical toxicology (Philadelphia, Pa.). 03/2012; 50(3):202-9.

  Pesticide self-poisoning causes one third of global suicides. Sri Lanka halved its suicide rate by banning WHO Class I organophosphorus (OP) insecticides and then endosulfan. However, poisoning withPesticide self-poisoning causes one third of global suicides. Sri Lanka halved its suicide rate by banning WHO Class I organophosphorus (OP) insecticides and then endosulfan. However, poisoning with Class II toxicity OPs, particularly dimethoate and fenthion, remains a problem. We aimed to determine the effect and feasibility of a ban of the two insecticides in one Sri Lankan district. Sale was banned in June 2003 in most of Polonnaruwa District, but not Anuradhapura District. Admissions with pesticide poisoning to the district general hospitals was prospectively recorded from 2002. Hospital admissions for dimethoate and fenthion poisoning fell by 43% after the ban in Polonnaruwa, while increasing by 23% in Anuradhapura. The pesticide case fatality fell from 14.4% to 9.0% in Polonnaruwa (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.41-0.84) and 11.3% to 10.6% in Anuradhapura (OR 0.93, 95%CI 0.70-1.25; p = 0.051). This reduction was not sustained, with case fatality in Polonnaruwa rising to 12.1% in 2006-2007. Further data analysis indicated that the fall in case fatality had actually been due to a coincidental reduction in case fatality for pesticide poisoning overall, in particular for paraquat poisoning. We found that the insecticides could be effectively banned from agricultural practice, as shown by the fall in hospital admissions, with few negative consequences. However, the ban had only a minor effect on pesticide poisoning deaths because it was too narrow. A study assessing the agricultural and health effects of a more comprehensive ban of highly toxic pesticides is necessary to determine the balance between increased costs of agriculture and reduced health care costs and fewer deaths.

• A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol.

  Authors: Melissa Pearson, Flemming Konradsen, David Gunnell, Andrew H Dawson, Ravi Pieris, Manjula Weerasinghe, Duleeka W Knipe, Shaluka Jayamanne, Chris Metcalfe, Keith Hawton, A Rajitha Wickramasinghe, W Atapattu, Palitha Bandara, Dhammika de Silva, Asanga Ranasinghe, Fahim Mohamed, Nicholas A Buckley, Indika Gawarammana, Michael Eddleston

  BMC public health. 11/2011; 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 hasThe 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.

• Changes in the concentrations of creatinine, cystatin C and NGAL in patients with acute paraquat self-poisoning.

  Authors: Darren M Roberts, Martin F Wilks, Michael S Roberts, Ramasamyiyer Swaminathan, Fahim Mohamed, Andrew H Dawson, Nick A Buckley

  Toxicology letters. 02/2011; 202(1):69-74.

  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 beenAn 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.

• Toxicokinetics, including saturable protein binding, of 4-chloro-2-methyl phenoxyacetic acid (MCPA) in patients with acute poisoning.

  Authors: Darren M Roberts, Andrew H Dawson, Lalith Senarathna, Fahim Mohamed, Ron Cheng, Geoffrey Eaglesham, Nick A Buckley

  Toxicology letters. 01/2011; 201(3):270-6.

  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 unboundHuman 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 239mg/L (95% confidence interval 198-274mg/L). Nonlinear regression using a two-site binding hyperbola model estimated saturation of the high affinity binding site at 115mg/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 (184mg/L and 167mg/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 200mg/L, the half-life of MCPA at higher concentrations was 25.5h (95%CI 15.0-83.0h; n=16 patients) compared to 16.8h (95%CI 13.6-22.2h; n=10 patients) at lower concentrations. MCPA is subject to saturable protein binding but the influence on half-life appears marginal.

• The prevalence of previous self-harm amongst self-poisoning patients in Sri Lanka.

  Authors: Fahim Mohamed, Aravinda Perera, Kusal Wijayaweera, Keerthi Kularatne, Shaluka Jayamanne, Michael Eddleston, Andrew Dawson, Flemming Konradsen, David Gunnell

  Social psychiatry and psychiatric epidemiology. 04/2010; 46(6):517-20.

  One of the most important components of suicide prevention strategies is to target people who repeat self-harm as they are a high risk group. However, there is some evidence that the incidence ofOne of the most important components of suicide prevention strategies is to target people who repeat self-harm as they are a high risk group. However, there is some evidence that the incidence of repeat self-harm is lower in Asia than in the West. The objective of this study was to investigate the prevalence of previous self-harm among a consecutive series of self-harm patients presenting to hospitals in rural Sri Lanka. Six hundred and ninety-eight self-poisoning patients presenting to medical wards at two hospitals in Sri Lanka were interviewed about their previous episodes of self-harm. Sixty-one (8.7%, 95% CI 6.7-11%) patients reported at least one previous episode of self-harm [37 (10.7%) male, 24 (6.8%) female]; only 19 (2.7%, 95% CI 1.6-4.2%) patients had made more than one previous attempt. The low prevalence of previous self-harm is consistent with previous Asian research and is considerably lower than that seen in the West. Explanations for these low levels of repeat self-harm require investigation. Our data indicate that a focus on the aftercare of those who attempt suicide in Sri Lanka may have a smaller impact on suicide incidence than may be possible in the West.

• Acute human self-poisoning with bispyribac-containing herbicide Nominee: a prospective observational study.

  Authors: Indika Bandara Gawarammana, Darren M Roberts, Fahim Mohamed, Michael S Roberts, Gregory Medley, Shaluka Jayamanne, Andrew Dawson

  Clinical toxicology (Philadelphia, Pa.). 03/2010; 48(3):198-202.

  Self-poisoning with herbicides is an important reason for hospital admission and death in Asia. Although some herbicides have a well-described toxicity profile in humans, many of the newer compoundsSelf-poisoning with herbicides is an important reason for hospital admission and death in Asia. Although 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 400 g/L with a solvent and the other the surfactant, polyethylene glycol. We present the first case series of acute human self-poisoning with an 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 to January 2009 were collected prospectively. Admission and serial blood samples were collected from consenting patients to confirm exposure and to study the toxicokinetics of bispyribac, respectively. One hundred ten patients with a history of bispyribac ingestion presented after a median time of 4 h post-ingestion. There were three deaths at 15, 6, and 5 h post-ingestion because of asystolic cardiac arrest. All three patients had reduced Glasgow Coma Score (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 h 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% confidence interval 0.32-5.8) can be made. The majority of the remaining patients had self-limiting upper gastrointestinal symptoms and eight patients had an abnormal GCS 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 50.55 microg/mL (interquartile range 1.28-116.5; n=32). The peak concentration was noted around 3 h 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 h and plasma bispyribac concentrations did not appear to predict mortality. The lack of correlation between bispyribac outcomes and the available plasma concentrations may be because of exposure to nonbispyribac components or other undefined factors. Clinical outcomes from acute self-poisoning with bispyribac-containing herbicides appear to be relatively more favorable than other commonly used herbicides.

• A prospective observational study of the clinical toxicology of glyphosate-containing herbicides in adults with acute self-poisoning.

  Authors: Darren M Roberts, Nick A Buckley, Fahim Mohamed, Michael Eddleston, Daniel A Goldstein, Akbar Mehrsheikh, Marian S Bleeke, Andrew H Dawson

  Clinical toxicology (Philadelphia, Pa.). 02/2010; 48(2):129-36.

  The case fatality from acute poisoning with glyphosate-containing herbicides is approximately 7.7% from the available studies but these have major limitations. Large prospective studies of patientsThe case fatality from acute poisoning with glyphosate-containing herbicides is approximately 7.7% from the 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. Furthermore, the clinical utility of the glyphosate plasma concentration for predicting clinical outcomes and guiding treatment has not been determined. To describe the clinical outcomes, dose-response, and glyphosate kinetics following self-poisoning with glyphosate-containing herbicides. This prospective observational case series was conducted in two hospitals in Sri Lanka between 2002 and 2007. We included patients with a history of acute poisoning. Clinical observations were recorded until discharge or death. During a specified time period, we collected admission (n = 216, including five deaths) and serial (n = 26) blood samples in patients. Severity of poisoning was graded using simple clinical criteria. Six hundred one patients were identified; the majority ingested a concentrated formulation (36%, w/v glyphosate). Twenty-seven percent were asymptomatic, 63.7% 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 h. 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 (>734 microg/mL). The apparent elimination half-life of glyphosate was 3.1 h (95% CI = 2.7-3.6 h). Despite treatment in rural hospitals with limited resources, the mortality was 3.2%, which is lower than that 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.

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

  Authors: Indika Gawarammana, Fahim Mohamed, Steven Bowe, Ashoka Rathnathilake, Shantha Narangoda, Shifa Azher, Andrew Dawson, Nick Buckley

  BMC Emergency Medicine. 01/2010;

  Abstract 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 poisoningAbstract 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

• Acute human lethal toxicity of agricultural pesticides: a prospective cohort study.

  Authors: Andrew H Dawson, Michael Eddleston, Lalith Senarathna, Fahim Mohamed, Indika Gawarammana, Steven J Bowe, Gamini Manuweera, Nicholas A Buckley

  PLoS medicine. 01/2010; 7(10):e1000357.

  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 theagricultural 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. 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.

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

  Authors: Indika Gawarammana, Fahim Mohamed, Steven J Bowe, Ashoka Rathnathilake, Shantha K Narangoda, Shifa Azher, Andrew H Dawson, Nick A Buckley

  BMC emergency medicine. 01/2010; 10:15.

  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%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. Current Controlled trial ISRCTN71018309.

• Pattern of pesticide storage before pesticide self-poisoning in rural Sri Lanka.

  Authors: Fahim Mohamed, Gamini Manuweera, David Gunnell, Shifa Azher, Michael Eddleston, Andrew Dawson, Flemming Konradsen

  BMC public health. 11/2009; 9(1):405.

  ABSTRACT: BACKGROUND: Deliberate self-poisoning with agricultural pesticides is the commonest means of suicide in rural Asia. It is mostly impulsive and facilitated by easy access to pesticides. TheABSTRACT: BACKGROUND: Deliberate self-poisoning with agricultural pesticides is the commonest means of suicide in rural Asia. It is mostly impulsive and facilitated by easy access to pesticides. The aim of this large observational study was to investigate the immediate source of pesticides used for self-harm to help inform suicide prevention strategies such as reducing domestic access to pesticides. METHODS: The study was conducted in a district hospital serving an agricultural region of Sri Lanka. Patients who had self-poisoned with pesticides and were admitted to the adult medical wards were interviewed by study doctors following initial resuscitation to identify the source of pesticides they have ingested. RESULTS: Of the 669 patients included in the analysis, 425 (63.5%) were male; the median age was 26 (IQR 20-36). In 511 (76%) cases, the pesticides had been stored either inside or immediately outside the house; among this group only eight patients obtained pesticides that were kept in a locked container. Ten percent (n = 67) of the patients used pesticides stored in the field while 14% (n=91) purchased pesticides from shops within a few hours of the episode. The most common reasons for choosing the particular pesticide for self-harm were its easy accessibility (n=311, 46%) or its popularity as a suicide agent in their village (n= 290, 43%). CONCLUSIONS: Three quarters of people who ingested pesticides in acts of self-harm used products that were available within the home or in close proximity; relatively few patients purchased the pesticide for the act. The study highlights the importance of reducing the accessibility of toxic pesticides in the domestic environment.

• Factors influencing variability in clinical outcomes from imidacloprid self-poisoning.

  Authors: Fahim Mohamed, Andrew H Dawson, Darren Roberts

  Clinical toxicology (Philadelphia, Pa.). 10/2009;

• Acute intentional self-poisoning with a herbicide product containing fenoxaprop-P-ethyl, ethoxysulfuron, and isoxadifen ethyl: a prospective observational study.

  Authors: Shukry Zawahir, Darren M Roberts, Chathura Palangasinghe, Fahim Mohamed, Michael Eddleston, Andrew H Dawson, Nick A Buckley, Lingling Ren, Gregory A Medley, Indika Gawarammana

  Clinical toxicology (Philadelphia, Pa.). 08/2009;

  Background. Herbicides are commonly ingested for self-harm, but relatively little has been published on poisoning with herbicides other than paraquat and glyphosate. We report here a case series ofBackground. Herbicides are commonly ingested for self-harm, but 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 product containing the selective phenoxy herbicide compounds fenoxaprop-P-ethyl and ethoxysulfuron and a safener isoxadifen ethyl. Method. Clinical data on all patients presenting with Tiller Gold or Whip Super poisoning to two General Hospitals 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 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 (Glasgow coma scale 9-14) that resolved without intervention over several hours. Only symptomatic and supportive care was required. The median hospital stay was 1 day (IQR: 1-2) and the case fatality was zero (95% confidence interval: 0-4.2%). 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 > 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.

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

  Authors: Michael Eddleston, Peter Eyer, Franz Worek, Edmund Juszczak, Nicola Alder, Fahim Mohamed, Lalith Senarathna, Ariyasena Hittarage, Shifa Azher, K Jeganathan, Shaluka Jayamanne, Ludwig von Meyer, Andrew H Dawson, Mohamed Hussain Rezvi Sheriff, Nick A Buckley

  PLoS medicine. 07/2009; 6(6):e1000104.

  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 recommendsBACKGROUND: 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.

• Acute human self-poisoning with imidacloprid compound: a neonicotinoid insecticide.

  Authors: Fahim Mohamed, Indika Gawarammana, Thomas A Robertson, Michael S Roberts, Chathura Palangasinghe, Shukry Zawahir, Shaluka Jayamanne, Jaganathan Kandasamy, Michael Eddleston, Nick A Buckley, Andrew H Dawson, Darren M Roberts

  PLoS ONE. 02/2009; 4(4):e5127.

  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 clinicalBACKGROUND: 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.

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

  Authors: Michael Eddleston, Edmund Juszczak, Nick A Buckley, Lalith Senarathna, Fahim Mohamed, Wasantha Dissanayake, Ariyasena Hittarage, Shifa Azher, K Jeganathan, Shaluka Jayamanne, MH Rezvi Sheriff, David A Warrell

  Lancet. 03/2008; 371(9612):579-87.

  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 toxicBACKGROUND: 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.

• Compliance for single and multiple dose regimens of superactivated charcoal: a prospective study of patients in a clinical trial.

  Authors: Fahim Mohamed, M Roshini Sooriyarachchi, Lalith Senarathna, Shifa Azhar, M H Rezvi Sheriff, Nick A Buckley, Michael Eddleston

  Clinical toxicology (Philadelphia, Pa.). 02/2007; 45(2):132-5.

  BACKGROUND: Although activated charcoal is widely used for the treatment of self-poisoning, its effectiveness is unknown. An important consideration is patient compliance since poor compliance willBACKGROUND: Although activated charcoal is widely used for the treatment of self-poisoning, its effectiveness is unknown. An important consideration is patient compliance since poor compliance will limit effectiveness. We aimed to describe compliance in a randomized controlled trial (RCT) performed in Sri Lanka, presuming that this would set the upper limits for compliance in routine clinical use. METHOD: 1,103 patients randomized to single or multiple (six doses q4h) 50 g doses of superactivated charcoal were prospectively observed. Charcoal was given by study doctors who recorded the amount ingested and the amount of persuasion required for the patients to drink the charcoal. RESULTS: 559 patients were randomized to receive one dose and 544 to receive six doses. Data was available for 1,071 (97%) patients. Eighty-eight were unable to complete their course; 98 required a NG tube, leaving 885 patients that received the first dose by mouth. The mean estimated amount of the prescribed dose of charcoal taken orally as a single or first dose was 83% (95% C.I. 82-84%). For patients receiving multiple doses, this amount fell over the next five doses to 66% (63-69%). While only 3.2% of patients refused the first dose, 12.3% refused the sixth. Relatively less persuasion was required for patients ingesting the first or single dose; 38% of patients required intense persuasion by the sixth dose. CONCLUSION: Compliance for a single dose of superactivated charcoal among trial patients was good. However, even in the ideal circumstances of a RCT, compliance decreased thereafter for patients taking more than one dose.

• Speed of initial atropinisation in significant organophosphorus pesticide poisoning--a systematic comparison of recommended regimens.

  Authors: Michael Eddleston, Nick A Buckley, Helaina Checketts, Lalith Senarathna, Fahim Mohamed, M H Rezvi Sheriff, Andrew Dawson

  Journal of toxicology. Clinical toxicology. 02/2004; 42(6):865-75.

  OBJECTIVE: Early deaths from organophosphorus (OP) pesticide self-poisoning result from respiratory failure and cardiovascular collapse. Therapy requires the urgent use of atropine to reverseOBJECTIVE: Early deaths from organophosphorus (OP) pesticide self-poisoning result from respiratory failure and cardiovascular collapse. Therapy requires the urgent use of atropine to reverse cholinergic excess, thereby improving respiratory function, heart rate, and blood pressure. We aimed to assess variation in textbook recommendations for early atropinisation and to see whether this variation affected time to stabilisation using model data from 22 severely poisoned patients seen in a Sri Lankan clinical trial. METHODS: We extracted prospectively recorded data on atropine requirements for 22 OP poisoned patients who required intubation but survived to discharge. We did a systematic search for textbook recommendations for initial atropinisation regimens. These regimens were then applied to data from the Sri Lankan patients. RESULTS: The patients required a mean of 23.4 mg (standard deviation 22.0, range 1-75 mg) atropine to clear the lungs, raise the pulse above 80 bpm, and restore systolic blood pressure to more than 80 mmHg. Textbook recommendations varied markedly--atropinisation of an average patient, requiring the mean dose of 23.4 mg, would have taken 8 to 1380 mins; atropinisation of a very ill patient, requiring 75 mg, would have taken 25 to 4440 mins. Atropinisation was attained most rapidly with a regimen of increasing bolus doses after failure to respond to the previous bolus. CONCLUSIONS: There is great variation in recommendations for atropinisation, with some regimens taking hours and even days to stabilise a patient. The guidelines are very flexible--possibly appropriate for experienced emergency physicians or clinical toxicologists, but completely inappropriate for the inexperienced junior doctors who see most cases worldwide. We recommend that a consensus guideline be developed by appropriate organisations to bring order to this important part of OP therapy, while acknowledging the paucity of data to drive the guidelines.

• Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil--a GABAA-gated chloride channel blocker.

  Authors: Fahim Mohamed, Lalith Senarathna, Adrian Percy, Manel Abeyewardene, Geoffrey Eaglesham, Ron Cheng, Shifa Azher, Ariyasena Hittarage, Wasantha Dissanayake, M H Rezvi Sheriff, Willie Davies, Nick A Buckley, Michael Eddleston

  Journal of toxicology. Clinical toxicology. 01/2004; 42(7):955-63.

  OBJECTIVE: Fipronil, a broad spectrum N-phenylpyrazole insecticide that inhibits GABAA-gated chloride channels, has been in use since the mid-1990s. A high affinity for insect compared to mammalianOBJECTIVE: Fipronil, a broad spectrum N-phenylpyrazole insecticide that inhibits GABAA-gated chloride channels, has been in use since the mid-1990s. A high affinity for insect compared to mammalian GABA receptors results in lower animal toxicity than other insecticides blocking this channel. To date, only two accidental cases of fipronil poisoning in humans have been published. CASE SERIES: We report seven patients with fipronil self-poisoning seen prospectively in Sri Lanka together with pharmacokinetics for four patients. Non-sustained generalized tonic-clonic seizures were seen in two patients (peak measured plasma fipronil concentrations 1600 and 3744 microg/L); both were managed with diazepam without complications. A patient with a peak measured plasma concentration of 1040 microg/L was asymptomatic throughout his stay. Plasma concentration was still high at discharge 3-4 days post-ingestion when the patients were well. Retrospective review of >1000 pesticide poisoning deaths since 1995 found only one death from fipronil-based products. In contrast to the good outcome of the above cases, this patient required intubation and ventilation and had continuous fits despite therapy with barbiturates and benzodiazepines. CONCLUSIONS: Our experience with prospectively observed patients suggests that fipronil poisoning is characterized by vomiting, agitation, and seizures, and normally has a favorable outcome. Management should concentrate on supportive care and early treatment of seizures. However, further experience is needed to determine whether increased susceptibility to fipronil or larger doses can produce status epilepticus.

• Deaths due to absence of an affordable antitoxin for plant poisoning.

  Authors: Michael Eddleston, Lalith Senarathna, Fahim Mohamed, Nick Buckley, Edmund Juszczak, M H Rezvi Sheriff, Ariaranee Ariaratnam, Senaka Rajapakse, David Warrell, K Rajakanthan

  Lancet. 10/2003; 362(9389):1041-4.

  There is a severe shortage of affordable antivenoms and antitoxins in the developing world. An anti-digoxin antitoxin for oleander poisoning was introduced in Sri Lanka in July, 2001, but because ofThere is a severe shortage of affordable antivenoms and antitoxins in the developing world. An anti-digoxin antitoxin for oleander poisoning was introduced in Sri Lanka in July, 2001, but because of its cost, stocks ran out in July, 2002. We looked at the effect of its introduction and withdrawal on case fatality, and determined its cost-effectiveness. The antitoxin strikingly reduced the case fatality; its absence resulted in a three-fold rise in deaths. At the present price of US2650 dollars per course, every life saved cost 10209 dollars and every life year cost 248 dollars. Reduction of the antitoxin's price to 400 dollars would reduce costs to 1137 dollars per life gained; a further reduction to 103 dollars would save money for every life gained. Treatments for poisoning and envenoming should be included in the present campaign to increase availability of affordable treatments in the developing world.