Nicholas A Buckley

Publications of Nicholas A Buckley

• Evaluation of the Test-mate ChE (cholinesterase) field kit in acute organophosphorus poisoning.

  Authors: Bishan N Rajapakse, Horst Thiermann, Peter Eyer, Franz Worek, Steven J Bowe, Andrew H Dawson, Nicholas A Buckley

  Annals of emergency medicine. 12/2011; 58(6):559-564.e6.

  Measurement of acetylcholinesterase (AChE) is recommended in the management of organophosphorus poisoning, which results in 200,000 deaths worldwide annually. The Test-mate ChE 400 is a portableMeasurement of acetylcholinesterase (AChE) is recommended in the management of organophosphorus poisoning, which results in 200,000 deaths worldwide annually. The Test-mate ChE 400 is a portable field kit designed for detecting occupational organophosphorus exposure that measures RBC AChE and plasma cholinesterase (PChE) within 4 minutes. We evaluate Test-mate against a reference laboratory test in patients with acute organophosphorus self-poisoning. This was a cross-sectional comparison study of 14 patients with acute organophosphorus poisoning between May 2007 and June 2008. RBC AChE and PChE were measured in 96 and 91 samples, respectively, with the Test-mate ChE field kit and compared with a reference laboratory, using the limits of agreement method (Bland and Altman), κ statistics, and Spearman's correlation coefficients. There was good agreement between the Test-mate ChE and the reference laboratory for RBC AChE. The mean difference (Test-mate-reference) was -0.62 U/g hemoglobin, 95% limits of agreement -10.84 to 9.59 U/g hemoglobin. Good agreement was also observed between the categories of mild, moderate, and severe RBC AChE inhibition (weighted κ 0.85; 95% confidence interval [CI] 0.83 to 0.87). Measurement of PChE also showed good agreement, with a mean difference (Test-mate-reference) of +0.06 U/mL blood, 95% limits of agreement -0.41 to 0.53 U/mL blood. Spearman's correlation coefficients were 0.87 (95% CI 0.81 to 0.91) for RBC AChE and 0.76 (95% CI 0.66 to 0.84) for PChE. Analysis for within-subject correlation of subjects did not change the limits of agreement. The Test-mate ChE field kit reliably provides rapid measurement of RBC AChE in acute organophosphorus poisoning.

• 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.

• Delayed psychological morbidity associated with snakebite envenoming.

  Authors: Shehan S Williams, Chamara A Wijesinghe, Shaluka F Jayamanne, Nicholas A Buckley, Andrew H Dawson, David G Lalloo, H Janaka de Silva

  PLoS neglected tropical diseases. 08/2011; 5(8):e1255.

  The psychological impact of snakebite on its victims, especially possible late effects, has not been systematically studied. To assess delayed somatic symptoms, depressive disorder, post-traumaticThe psychological impact of snakebite on its victims, especially possible late effects, has not been systematically studied. To assess delayed somatic symptoms, depressive disorder, post-traumatic stress disorder (PTSD), and impairment in functioning, among snakebite victims. The study had qualitative and quantitative arms. In the quantitative arm, 88 persons who had systemic envenoming following snakebite from the North Central Province of Sri Lanka were randomly identified from an established research database and interviewed 12 to 48 months (mean 30) after the incident. Persons with no history of snakebite, matched for age, sex, geograpical location and occupation, acted as controls. A modified version of the Beck Depression Inventory, Post-Traumatic Stress Symptom Scale, Hopkins Somatic Symptoms Checklist, Sheehan Disability Inventory and a structured questionnaire were administered. In the qualitative arm, focus group discussions among snakebite victims explored common somatic symptoms attributed to envenoming. Previous snakebite victims (cases) had more symptoms than controls as measured by the modified Beck Depression Scale (mean 19.1 Vs 14.4; p<0.001) and Hopkins Symptoms Checklist (38.9 vs. 28.2; p<0.001). 48 (54%) cases met criteria for depressive disorder compared to 13 (15%) controls. 19 (21.6%) cases also met criteria for PTSD. 24 (27%) claimed that the snakebite caused a negative change in their employment; nine (10.2%) had stopped working and 15 (17%) claimed residual physical disability. The themes identified in the qualitative arm included blindness, tooth decay, body aches, headaches, tiredness and weakness. Snakebite causes significant ongoing psychological morbidity, a complication not previously documented. The economic and social impacts of this problem need further investigation.

• Medical management of paraquat ingestion.

  Authors: Indika B Gawarammana, Nicholas A Buckley

  British journal of clinical pharmacology. 05/2011; 72(5):745-57.

  Poisoning by paraquat herbicide is a major medical problem in parts of Asia while sporadic cases occur elsewhere. The very high case fatality of paraquat is due to inherent toxicity and lack ofPoisoning by paraquat herbicide is a major medical problem in parts of Asia while sporadic cases occur elsewhere. The very high case fatality of paraquat is due to inherent toxicity and lack of effective treatments. We conducted a systematic search for human studies that report toxicokinetics, mechanisms, clinical features, prognosis and treatment. Paraquat is rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12-24 h. Clinical features are largely due to intracellular effects. Paraquat generates reactive oxygen species which cause cellular damage via lipid peroxidation, activation of NF-κB, mitochondrial damage and apoptosis in many organs. Kinetics of distribution into these target tissues can be described by a two-compartment model. Paraquat is actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis. Paraquat also causes renal and liver injury. Plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis. Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed. Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course. Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti-inflammatory and NF-κB inhibitory actions. However, there are no published human trials. The case fatality is very high in all centres despite large variations in treatment.

• A strategy for changing plasma pralidoxime kinetics and, perhaps, effect in organophosphorus insecticide poisoning.

  Authors: Michael Eddleston, Nicholas A Buckley

  Critical care medicine. 04/2011; 39(4):908-9.

• Toxicologists in public health--Following the path of Louis Roche (based on the Louis Roche lecture "An accidental toxicologist in public health", Bordeaux, 2010).

  Authors: Andrew H Dawson, Nicholas A Buckley

  Clinical toxicology (Philadelphia, Pa.). 02/2011; 49(2):94-101.

  The global burden of clinical toxicology suggests a natural partnership with public health. This article reflects the content of a Louis Roche lecture given in 2010. HISTORICAL CONTEXT: Our practiceThe global burden of clinical toxicology suggests a natural partnership with public health. This article reflects the content of a Louis Roche lecture given in 2010. HISTORICAL CONTEXT: Our practice and research in clinical toxicology has evolved from clinical cases to toxico-epidemiology to public health. This evolution in practice was initially unplanned but gained momentum and impact as we placed it more formally in a public health framework. This perspective is implicit in Louis Roche's call to "examine all aspects of the poisoning problem" and still provides a valuable starting point for any clinical toxicologist. Clinical toxicology has always had a patient centered focus but its greatest successes have been related to public health interventions. Our early failures and later success in pubic health toxicology correlated with our understanding of the importance of partnerships outside our field. The most rapid dissemination and implementation of information derived from research occur through apriori partnerships with other agencies and international partners. Addressing both local and global need has a number of bilateral synergies. Repositioning clinical toxicology into a public health framework increases access to strategic partnerships, research funds, and policy implementation while still addressing questions that are important to clinical practice.

• Formulation changes and time trends in outcome following paraquat ingestion in Sri Lanka.

  Authors: Martin F Wilks, John A Tomenson, Ravindra Fernando, P L Ariyananda, David J Berry, Nicholas A Buckley, Indika Bandara Gawarammana, Shaluka Jayamanne, David Gunnell, Andrew Dawson

  Clinical toxicology (Philadelphia, Pa.). 01/2011; 49(1):21-8.

  Deliberate self-harm with pesticides is a significant public health problem in rural Asia. We have previously shown an improved survival of patients with paraquat self-poisoning following theDeliberate self-harm with pesticides is a significant public health problem in rural Asia. We have previously shown an improved survival of patients with paraquat self-poisoning following the introduction of a new formulation with an increased emetic concentration, an alginate and a purgative in Sri Lanka. Further, formulation changes were introduced in October 2006; this study was designed to assess the impact of these changes on 6-week mortality following paraquat ingestion. Prospective, cohort study of patients admitted with paraquat poisoning to 10 hospitals across Sri Lanka between September 2006 and September 2008. Overall, there was a significant (p < 0.001) increase in survival in the 533 patients included in this study compared to previous data (44.5 vs. 35.2% before September 2006 and 27.1% before October 2004). Patients ingesting the new INTEON formulation had a higher survival rate than those ingesting standard formulation (40.2 vs. 31.0%), but this effect was not statistically significant in Cox's proportional hazards model (hazard ratio 0.81, 95% CI 0.61?1.08 (unadjusted) and 1.17, 95% CI 0.82?1.68 (fully adjusted), respectively). This study has confirmed a continued improvement in survival of patients following self-harm with paraquat in Sri Lanka in recent years; however, in contrast to previous investigations, a beneficial effect associated with the INTEON formulation could not be substantiated. This may be partly due to the large number of patients in whom paraquat concentrations were too low for analytical confirmation of the formulation (n = 105) and who had a very high survival rate (86.7%).

• Changes in serial laboratory test results in snakebite patients: when can we safely exclude envenoming?

  Authors: Graham Ireland, Simon G A Brown, Nicholas A Buckley, Jeff Stormer, Bart J Currie, Julian White, David Spain, Geoffrey K Isbister

  The Medical journal of Australia. 09/2010; 193(5):285-90.

  To determine which laboratory tests are first associated with severe envenoming after a snakebite, when (ie, how long after the bite) the test results become abnormal, and whether this can determineTo determine which laboratory tests are first associated with severe envenoming after a snakebite, when (ie, how long after the bite) the test results become abnormal, and whether this can determine a safe observation period after suspected snakebite. Prospective cohort study of 478 patients with suspected or confirmed snakebite recruited to the Australian Snakebite Project from January 2002 to April 2009, who had at least three sets of laboratory test results and at least 12 hours of observation in hospital after the bite. Severe envenoming was defined as venom-induced consumption coagulopathy (VICC), myotoxicity, neurotoxicity or thrombotic microangiopathy. International normalised ratio (INR), activated partial thromboplastin time (aPTT), creatine kinase (CK) level, and neurological examination. There were 240 patients with severe envenoming, 75 with minor envenoming and 163 non-envenomed patients. Of 206 patients with VICC, 178 had an INR > 1.2 (abnormal) on admission, and the remaining 28 had an INR > 1.2 within 12 hours of the bite. Of 33 patients with myotoxicity, a combination of CK > 250 U/L and an abnormal aPTT identified all but two cases by 12 hours; one of these two was identified within 12 hours by leukocytosis. Nine cases of isolated neurotoxicity had a median time of onset after the bite of 4 hours (range, 35 min - 12 h). The combination of serial INR, aPTT and CK tests and repeated neurological examination identified 213 of 222 severe envenoming cases (96%) by 6 hours and 238 of 240 (99%) by 12 hours. Laboratory parameters (INR, aPTT and CK) and neurological reassessments identified nearly all severe envenoming cases within 12 hours of the bite, even in this conservative analysis that assumed normal test results if the test was not done.

• 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.

• Prospective policy analysis: how an epistemic community informed policymaking on intentional self poisoning in Sri Lanka.

  Authors: Melissa Pearson, Zwi B Anthony, Nicholas A Buckley

  Health research policy and systems / BioMed Central. 01/2010; 8:19.

  Policy analysis is often retrospective and not well suited to helping policy makers decide what to do; in contrast prospective policy analysis seeks to assist in formulating responses to challengingPolicy analysis is often retrospective and not well suited to helping policy makers decide what to do; in contrast prospective policy analysis seeks to assist in formulating responses to challenging public policy questions. Suicide in Sri Lanka is a major public health problem, with ingestion of pesticides being the primary method. Previous policy interventions have been associated with reduced mortality through restricting access to the most toxic pesticides. Additional means of reducing access are still needed. The prospective policy analysis comprised two stages. The first used a consensus activity within a well defined policy community to generate and frame policy options. The second broadened the analysis to include other stakeholders. We report the consensus activity with seven actors from agriculture, health, and academia. Policy options were identified through two rounds of discussion along with ratings by each participant on their degree of support for each option. Data were analysed quantitatively and discussions analysed with Nvivo 8 to code prominent and recurrent themes. The main finding was the strong support and consensus for two proposals: further regulation of pesticides and the novel idea of repackaging pesticides into non-lethal doses. Participants identified several factors that were supportive of future policy change including a strong legislative framework, good links between agriculture, health and academia, and a collaborative relationship with industry. Identified barriers and potential threats to policy change included political interference, difficulties of intersectoral collaboration, acceptability of options to the community, difficulty of implementation in rural communities and the challenge of reducing mortality. The development and consideration of policy options within this epistemic community reflected an appreciation and understanding of many of the factors that can facilitate or thwart policy change. The understanding of context, evidence and ideas, implementation and impact influenced how the participants considered and rated the options. Use of epistemic community actors identified the level of support for each option, helped elaborate the particularities of context, as well as the power and influence of ideas. Further examination of the potential barriers and opportunities for these options will determine if broader consensus, involving a wider range of stakeholders, can be achieved and policy change promoted.

• Extreme variability in the formation of chlorpyrifos oxon (CPO) in patients poisoned by chlorpyrifos (CPF).

  Authors: Florian Eyer, Darren M Roberts, Nicholas A Buckley, Michael Eddleston, Horst Thiermann, Franz Worek, Peter Eyer

  Biochemical pharmacology. 06/2009;

  Chlorpyrifos (CPF) is a pesticide that causes tens of thousands of deaths per year worldwide. Chlorpyrifos oxon (CPO) is the active metabolite of CPF that inhibits acetylcholinesterase. However, thisChlorpyrifos (CPF) is a pesticide that causes tens of thousands of deaths per year worldwide. Chlorpyrifos oxon (CPO) is the active metabolite of CPF that inhibits acetylcholinesterase. However, this presumed metabolite has escaped detection in human samples by conventional methods (HPLC, GC-MS, LC-MS) until now. A recently developed enzyme-based assay allowed the determination of CPO in the nanomolar range and was successfully employed to detect this metabolite. CPO and CPF were analysed in consecutive plasma samples of 74 patients with intentional CPF poisoning. A wide concentration range of CPO and CPF was observed and the ratio of CPO/CPF varied considerably between individuals and over time. The ratio increased during the course of poisoning from a mean of 0.005 in the first few hours after ingestion up to an apparent steady state mean of 0.03 between 30 and 72 hrs. There was a hundred fold variation in the ratio between samples and the interquartile range (between individuals) indicated over half the samples had a 5-fold or greater variation from the mean. The ratio was independent of the CPF concentration and the pralidoxime regimen. CPO was present in sufficient quantities to explain any observed acetylcholinesterase inhibitory activity. The effectiveness of pralidoxime in reactivating the inhibited acetylcholinesterase is strongly dependent on the CPO concentration. Differences in clinical outcomes and the response to antidotes in patients with acute poisoning may occur due to inter-individual variability in metabolism.

• In reply.

  Authors: Geoffrey K Isbister, Barrie Stokes, Nicholas A Buckley, Stephen B Duffull

  Annals of emergency medicine. 08/2008; 52(1):87-88.

• The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka.

  Authors: Pradeepa Jayawardane, Andrew H Dawson, Vajira Weerasinghe, Lakshman Karalliedde, Nicholas A Buckley, Nimal Senanayake

  PLoS medicine. 07/2008; 5(7):e147.

  Intermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulationIntermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulation (RNS) predictors of IMS that would assist in patient management and clinical research. Seventy-eight consenting symptomatic patients with organophosphate poisoning were assessed prospectively with daily physical examination and RNS. RNS was done on the right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. The study was conducted as a prospective observational cohort study in the Central Province, Sri Lanka. IMS was diagnosed in ten out of 78 patients using a priori clinical diagnostic criteria, and five of them developed respiratory failure. All ten patients showed progressive RNS changes correlating with the severity of IMS. A decrement-increment was observed at intermediate and high frequencies preceding the onset of clinical signs of IMS. As the patient developed clinical signs of IMS, decrement-increment was progressively noted at low and intermediate frequencies and a combination of decrement-increment and repetitive fade or severe decrement was noted at high frequencies. Severe decrement preceded respiratory failure in four patients. Thirty patients developed forme fruste IMS with less severe weakness not progressing to respiratory failure whose RNS was characterized by decrement-increment or a combination of decrement-increment and repetitive fade but never severe decrements. Characteristic changes in RNS, preceding the development of IMS, help to identify a subgroup of patients at high risk of developing respiratory failure. The forme fruste IMS with the characteristic early changes on RNS indicates that IMS is a spectrum disorder. RNS changes are objective and precede the diagnosis and complications of IMS. Thus they may be useful in clinical management and research.

• Prolonged absorption and delayed peak paracetamol concentration following poisoning with extended-release formulation.

  Authors: Darren M Roberts, Nicholas A Buckley

  The Medical journal of Australia. 04/2008; 188(5):310-1.

  A woman with acute poisoning from extended-release paracetamol presented at 14.5 hours post-ingestion. The paracetamol's absorption phase and elimination half-life appeared prolonged, with peak bloodA woman with acute poisoning from extended-release paracetamol presented at 14.5 hours post-ingestion. The paracetamol's absorption phase and elimination half-life appeared prolonged, with peak blood concentration occurring at 20 hours post-ingestion, requiring an extended course of intravenous N-acetylcysteine. Current treatment recommendations, based on experience with a different formulation in the United States, may not be appropriate for the Australian formulation.

• Guidelines for the management of paracetamol poisoning in Australia and New Zealand--explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres.

  Authors: Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins, Nicholas A Buckley

  The Medical journal of Australia. 04/2008; 188(5):296-301.

  Paracetamol is involved in a large proportion of accidental paediatric exposures and deliberate self-poisoning cases, although subsequent hepatic failure and death are both uncommon outcomes. TheParacetamol is involved in a large proportion of accidental paediatric exposures and deliberate self-poisoning cases, although subsequent hepatic failure and death are both uncommon outcomes. The optimal management of most patients with paracetamol overdose is usually straightforward. However, several differing nomograms and varying recommendations regarding potential risk factors for hepatic injury introduce complexity. In order to reconcile management advice with current Australasian clinical toxicology practice, revised guidelines have been developed by a panel of clinical toxicologists consulting to the poisons information centres in Australia and New Zealand using a workshop and consultative process. This article summarises the rationale for the recommendations made in these new guidelines.

• Improvement in survival after paraquat ingestion following introduction of a new formulation in Sri Lanka.

  Authors: Martin F Wilks, Ravindra Fernando, P L Ariyananda, Michael Eddleston, David J Berry, John A Tomenson, Nicholas A Buckley, Shaluka Jayamanne, David Gunnell, Andrew Dawson

  PLoS medicine. 03/2008; 5(2):e49.

  BACKGROUND: Pesticide ingestion is a common method of self-harm in the rural developing world. In an attempt to reduce the high case fatality seen with the herbicide paraquat, a novel formulationBACKGROUND: Pesticide ingestion is a common method of self-harm in the rural developing world. In an attempt to reduce the high case fatality seen with the herbicide paraquat, a novel formulation (INTEON) has been developed containing an increased emetic concentration, a purgative, and an alginate that forms a gel under the acid conditions of the stomach, potentially slowing the absorption of paraquat and giving the emetic more time to be effective. We compared the outcome of paraquat self-poisoning with the standard formulation against the new INTEON formulation following its introduction into Sri Lanka. METHODS AND FINDINGS: Clinical data were prospectively collected on 586 patients with paraquat ingestion presenting to nine large hospitals across Sri Lanka with survival to 3 mo as the primary outcome. The identity of the formulation ingested after October 2004 was confirmed by assay of blood or urine samples for a marker compound present in INTEON. The proportion of known survivors increased from 76/297 with the standard formulation to 103/289 with INTEON ingestion, and estimated 3-mo survival improved from 27.1% to 36.7% (difference 9.5%; 95% confidence interval [CI] 2.0%-17.1%; p = 0.002, log rank test). Cox proportional hazards regression analyses showed an approximately 2-fold reduction in toxicity for INTEON compared to standard formulation. A higher proportion of patients ingesting INTEON vomited within 15 min (38% with the original formulation to 55% with INTEON, p < 0.001). Median survival time increased from 2.3 d (95% CI 1.2-3.4 d) with the standard formulation to 6.9 d (95% CI 3.3-10.7 d) with INTEON ingestion (p = 0.002, log rank test); however, in patients who did not survive there was a comparatively smaller increase in median time to death from 0.9 d (interquartile range [IQR] 0.5-3.4) to 1.5 d (IQR 0.5-5.5); p = 0.02. CONCLUSIONS: The survey has shown that INTEON technology significantly reduces the mortality of patients following paraquat ingestion and increases survival time, most likely by reducing absorption.

• Activated charcoal decreases the risk of QT prolongation after citalopram overdose.

  Authors: Geoffrey K Isbister, Lena E Friberg, Barrie Stokes, Nicholas A Buckley, Christopher Lee, Naren Gunja, Simon G Brown, Ellen MacDonald, Andis Graudins, Anna Holdgate, Stephen B Duffull

  Annals of emergency medicine. 12/2007; 50(5):593-600, 600.e1-46.

  STUDY OBJECTIVE: We determine whether single-dose activated charcoal (SDAC) administration after citalopram overdose reduces the proportion of patients developing abnormal QT prolongation. METHODS:STUDY OBJECTIVE: We determine whether single-dose activated charcoal (SDAC) administration after citalopram overdose reduces the proportion of patients developing abnormal QT prolongation. METHODS: Data were collected retrospectively for citalopram overdose patients presenting to 8 emergency departments. Demographics, dose, coingested drugs, SDAC administration, and serial ECGs were extracted from medical records. The primary outcome was the proportion of patients who had an observed QT,RR combination at any time above an abnormal threshold, established as a predictor of torsade de pointes. We compared the proportion of patients with QT prolongation who received or did not receive SDAC. These data were analyzed within a Bayesian framework, using probabilities of abnormal QT,RR combinations with and without derived from a previous single-center study. WinBUGS was used to generate posterior estimates and credible intervals of the relative risk by combining the prior probabilities and the study data. RESULTS: SDAC was administered on average 2.1 hours (range, 0.5 to 6.25 hours) after ingestion in 48 of 254 admissions, and abnormal QT,RR combinations occurred in 2 cases (4.2%), compared with 23 of 206 (11.2%) cases not receiving SDAC. There did not appear to be any clinically important difference in age, sex, dose, and cardiotoxic coingestants between the 2 groups. No cases of torsade de pointes occurred. The estimated relative risk of having an abnormal QT,RR combination for SDAC compared to no SDAC was 0.28 (0.06 to 0.70) (median with 2.5% and 97.5% credible limits). The probability that the relative risk was less than 1.0 was 0.99, which can be interpreted as very strong evidence in favor of a beneficial effect of SDAC. The absolute risk difference was estimated as 7.5% and the median number needed to treat as 13.3. CONCLUSION: SDAC may be effective in reducing the risk of a prolonged QT in patients after citalopram overdose. Current trends toward nonuse of activated charcoal should be evaluated to determine whether patients poisoned by specific agents may benefit from activated charcoal administration.

• Serotonin toxicity: a practical approach to diagnosis and treatment.

  Authors: Geoffrey K Isbister, Nicholas A Buckley, Ian M Whyte

  The Medical journal of Australia. 10/2007; 187(6):361-5.

  Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity - serotonin toxicity. SerotoninExcess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity - serotonin toxicity. Serotonin toxicity is characterised by neuromuscular excitation (clonus, hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, diaphoresis, tremor, flushing) and changed mental state (anxiety, agitation, confusion). Serotonin toxicity can be: mild (serotonergic features that may or may not concern the patient); moderate (toxicity which causes significant distress and deserves treatment, but is not life-threatening); or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure). Diagnosis of serotonin toxicity is often made on the basis of the presence of at least three of Sternbach's 10 clinical features. However, these features have very low specificity. The Hunter Serotonin Toxicity Criteria use a smaller, more specific set of clinical features for diagnosis, including clonus, which has been found to be more specific to serotonin toxicity. There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single-drug therapy in susceptible individuals. Treatment should focus on cessation of the serotonergic medication and supportive care. Some antiserotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined.

• Does restricting pack size of paracetamol (acetaminophen) reduce suicides?

  Authors: Nicholas A Buckley, David Gunnell

  PLoS medicine. 05/2007; 4(4):e152.

• Hyperbaric oxygen for carbon monoxide poisoning : a systematic review and critical analysis of the evidence.

  Authors: Nicholas A Buckley, Geoffrey K Isbister, Barrie Stokes, David N Juurlink

  Toxicological reviews. 02/2005; 24(2):75-92.

  Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce thePoisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.