Nick A Buckley

Publications of Nick A Buckley

• Electrophysiological correlates of respiratory failure in acute organophosphate poisoning: Evidence for differential roles of muscarinic and nicotinic stimulation.

  Authors: Pradeepa Jayawardane, Nimal Senanayake, Nick A Buckley, Andrew H Dawson

  Clinical toxicology (Philadelphia, Pa.). 04/2012; 50(4):250-3.

  Background. Respiratory failure in acute organophosphate (OP) poisoning can occur early and also relatively late in the clinical course, and the pathophysiology of respiratory failure at theseBackground. Respiratory failure in acute organophosphate (OP) poisoning can occur early and also relatively late in the clinical course, and the pathophysiology of respiratory failure at these different phases may have important clinical implications. Objective. To compare the electrophysiological findings in patients with early and late respiratory failure following acute OP poisoning. Methods. A prospective observational case series of consenting symptomatic patients with acute OP poisoning were assessed with daily physical examinations and repetitive nerve stimulation (RNS) studies. RNS was done on right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. Outcomes such as need for ventilation and development of intermediate syndrome (IMS) were noted. Early respiratory failure was defined as occurring within 24 hours of ingestion. Results. Seventy-eight patients were recruited for the clinical and electrophysiological study and of those 59 (75.6%) patients had ingested chlorpyrifos. Seven patients developed respiratory failure within 24 hours of ingestion with overt muscarinic signs. They had no electrophysiological abnormalities at median and ulnar nerves before intubation. Three of them later developed "forme fruste" IMS. Five other patients developed late respiratory failure after 24 hours of ingestion, and all of them showed progressive RNS changes indicating severe IMS prior to intubation. Conclusion. The normal RNS in all patients developing early respiratory failure suggests that it is due to a central nervous system (CNS) and muscarinic effect. This emphasizes the need for early rapid atropinisation as a priority, combating the nicotinic effects being less urgent. This is in contrast with the late respiratory failure, which has been shown to be associated with neuromuscular dysfunction. Further studies are needed to quantify CNS and muscarinic dysfunction to assist in the development of better treatments for the severe and early OP poisoning.

• 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.

• Bringing greater transparency to "black box" warnings.

  Authors: Nick A Buckley, Simone Rossi

  Clinical toxicology (Philadelphia, Pa.). 07/2011; 49(6):448-51.

  The number of drugs with boxed warnings and the detail in the box are much greater in the USA than Australia. US warnings are up to ten times longer and often include a great deal of detail andThe number of drugs with boxed warnings and the detail in the box are much greater in the USA than Australia. US warnings are up to ten times longer and often include a great deal of detail and qualified advice. Australian warnings are usually just a few sentences long and the expected response unequivocal. Other details are relegated to the relevant section within the product information. The restriction of warnings such that they are succinct and used sparingly are explicitly highlighted in the guidelines for boxed warnings in Australia. In addition, the range of other risk management strategies used may be broader. Widespread prescription drug subsidies and mechanisms set up to implement the "Quality Use of Medicines" policy provide a complementary range of options. Withdrawal of registration, removal of subsidies for all or selected indications, changed product information and labels, consumer-targeted information, prescriber mail outs, education programmes, restriction to authorised prescribers, and changed pack size and packaging have all been applied at some time in response to safety concerns. The diversity of approaches around the world provides an opportunity for a systematic approach to look at the effects of boxed warnings on prescribing practices so that we might discover what works best. While there are many studies on the effect of warnings from the USA, there are few comparable studies done where different approaches are used. Further, it is not possible to easily examine the total number and purpose of boxed warnings via any government websites. If there were always explicit and potentially verifiable changes in practice as the stated goal for each boxed warning in each jurisdiction and a requirement that the effectiveness of the intervention was measured against these goals, then we might have the evidence base for better policy around boxed warnings.

• 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.

• Hyperbaric oxygen for carbon monoxide poisoning.

  Authors: Nick A Buckley, David N Juurlink, Geoff Isbister, Michael H Bennett, Eric J Lavonas

  Cochrane database of systematic reviews (Online). 01/2011;

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

• 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.

• Enhanced elimination in acute barbiturate poisoning - a systematic review.

  Authors: Darren M Roberts, Nick A Buckley

  Clinical toxicology (Philadelphia, Pa.). 01/2011; 49(1):2-12.

  Despite a worldwide decline in barbiturate use, cases of acute poisoning with severe toxicity are still noted, particularly in developing countries. Severe poisonings often require prolongedDespite a worldwide decline in barbiturate use, cases of acute poisoning with severe toxicity are still noted, particularly in developing countries. Severe poisonings often require prolonged admission to an intensive care unit, so enhanced elimination might be useful to hasten recovery. Information regarding the efficacy of these techniques for individual barbiturates is not available in standard textbooks. To determine the evidence supporting the effect of enhanced elimination and its role in the management of acute barbiturate poisoning. A systematic review was conducted using broad search criteria in three databases. All potentially relevant articles were obtained, and reference lists were manually reviewed. Ninety-four publications fulfilling inclusion criteria were located. Studies were classified as controlled or uncontrolled, and clinical and pharmacokinetic end points were manually extracted. If not directly stated, standard pharmacokinetic methods were used to calculate the clearance and efficiency of enhanced elimination techniques for each barbiturate and tabulated for direct comparison. PROSPECTIVE CONTROLLED CLINICAL TRIALS: Two of the 94 publications were prospective controlled studies (only one stated that allocation was via blinded randomisation), and both assessed the effect of multiple-dose activated charcoal for acute phenobarbital poisoning. These studies demonstrated enhanced elimination with a decrease in elimination of half-life from approximately 80 to 40?h, but only one study reported clinical benefits. UNCONTROLLED SERIES AND SINGLE CASE REPORTS: Sufficient data to determine the clearance due to enhanced elimination were available in only 52 of these papers. Barbiturate clearances by enhanced elimination varied markedly among studies. While extracorporeal modalities appeared to increase the direct clearance of many barbiturates, there was insufficient information to confirm a clinical benefit. There is limited evidence to support the use of enhanced elimination in the treatment of poisoning with most barbiturates. There is no role for urine alkalinisation, while multiple-dose activated charcoal may be useful for most phenobarbital and possibly primidone poisonings. Extracorporeal techniques appear to enhance elimination, but the clinical benefits, relative to the potential complications and cost, are poorly defined. Extracorporeal techniques such as haemodialysis and haemoperfusion can be considered for patients with life-threatening barbiturate toxicity such as refractory hypotension.

• Oximes for acute organophosphate pesticide poisoning.

  Authors: Nick A Buckley, Michael Eddleston, Yi Li, Marc Bevan, Jane Robertson

  Cochrane database of systematic reviews (Online). 01/2011;

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

• IV versus oral acetylcysteine.

  Authors: Nick A Buckley, Michael Eddleston, Yi Li

  Annals of emergency medicine. 04/2010; 55(4):393-4; author reply 394-5.

• Hypothermia and Fever after organophosphorus poisoning in humans--a prospective case series.

  Authors: Alison Moffatt, Fahim Mohammed, Michael Eddleston, Shifa Azher, Peter Eyer, Nick A Buckley

  Journal of medical toxicology : official journal of the American College of Medical Toxicology. 03/2010; 6(4):379-85.

  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 aimThere 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.

• 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 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.

• 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.

• Are we using the right dose? - A tale of mole and gram.

  Authors: Peter Eyer, Michael Eddleston, Horst Thiermann, Franz Worek, Nick A Buckley

  British journal of clinical pharmacology. 07/2008;

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

  Authors: Gamini Manuweera, Michael Eddleston, Samitha Egodage, Nick A Buckley

  Environmental health perspectives. 05/2008; 116(4):492-5.

  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 andBACKGROUND: 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.

• Mild clinical toxicity and dose-dependent pharmacokinetics following acute lopinavir/ritonavir poisoning in a HIV-positive patient.

  Authors: Darren M Roberts, John E Ray, Nick A Buckley

  AIDS (London, England). 04/2008; 22(6):792-3.

• 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.

• Management of acute organophosphorus pesticide poisoning.

  Authors: Michael Eddleston, Nick A Buckley, Peter Eyer, Andrew H Dawson

  Lancet. 03/2008; 371(9612):597-607.

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