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, Ox-Col Poisoning Study collaborators
Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial.
Lancet. 2008 Feb 16;371(9612):579-87. doi: 10.1016/S0140-6736(08)60270-6.
Abstract/Text
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 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.
J H McDonough, L D Zoeffel, J McMonagle, T L Copeland, C D Smith, T M Shih
Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea pigs.
Epilepsy Res. 2000 Jan;38(1):1-14.
Abstract/Text
A total of eight anticholinergic drugs (aprophen, atropine, azaprophen, benactyzine, biperiden, procyclidine, scopolamine, trihexyphenidyl) were tested in parallel with diazepam for the ability to terminate seizure activity induced by the nerve agent soman. Guinea pigs, implanted with electrodes to record cortical electroencephalographic (EEG) activity, were pretreated with pyridostigmine Br (0.026 mg/kg, i.m.) and 30 min later challenged with 2 x LD50 soman (56 microg/kg, s.c.) followed 1 min later by treatment with atropine SO4 (2 mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All guinea pigs developed sustained seizure activity following this treatment. Dose-effect curves were determined for the ability of each drug to terminate seizure activity when anticonvulsant treatment was given either 5 or 40 min after seizure onset. Body weight gain and recovery of behavioral performance of a previously trained one-way avoidance task were measured after exposure. With the exception of atropine, all anticholinergic drugs were effective at lower doses than diazepam in terminating seizures when given 5 min after seizure onset; benactyzine, procyclidine and aprophen terminated seizures most rapidly while scopolamine, trihexyphenidyl, biperiden, and diazepam were significantly slower. When given 40 min after seizure onset, diazepam was the most potent compound tested, followed by scopolamine, benactyzine and biperiden; atropine was not effective when tested 40 min after seizure onset. For diazepam, the time to terminate the seizure was the same whether it was given at the 5- or 40-min delay. In contrast, most anticholinergics were significantly slower in terminating seizure activity when
Benedict R Capacio, C E Byers, K A Merk, J R Smith, J H McDonough
Pharmacokinetic studies of intramuscular midazolam in guinea pigs challenged with soman.
Drug Chem Toxicol. 2004 May;27(2):95-110.
Abstract/Text
Studies have demonstrated that benzodiazepine compounds are effective at antagonizing seizure activity produced by the organophosphate (OP) cholinesterase inhibitor soman. In this present study we have investigated the pharmacokinetics of midazolam and its associated effects on electroencephalographic (EEG) activity following intramuscular (i.m.) injection to soman-exposed guinea pigs (Crl:(HA)BR). Prior to experiments, the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered the following pretreatment/OP/treatment regimen. Pyridostigmine bromide (0.026 mg/kg, i.m.) was given 30 min prior to soman (56 micrograms/kg, 2 x LD50; subcutaneously, s.c.), followed in one minute by atropine sulfate (2 mg/kg, i.m.) and pralidoxime chloride (25 mg/kg, i.m.). All animals receiving this regimen developed seizure activity. Midazolam 0.8 mg/kg, i.m., was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure-terminated or seizure not-terminated at 30 min following anticonvulsant administration. Serial blood samples were collected for the plasma midazolam analysis; the assay was accomplished with a gas chromatograph/mass spectrometer. The mean time to seizure termination was 8.8 +/- 1.6 min. The mean time-plasma concentration data were fit to standard pharmacokinetic models. The following parameter estimates were determined from the model-fit for seizure terminated and not-terminated animals respectively: apparent volumes of distribution (Vd) were 1.4 and 1.7 l/kg; area under the time-concentration curves (AUC), 15,990 and 15,120 ng.min/ml; times to maximal plasma concentration (Tmax), 1.66 and 2.91 min and maximal plasma concentrations (Cmax) 535.1 and 436.6 ng/ml. These data indicate that i.m. injection of midazolam is effective at terminating ongoing soman-induced seizure activity. Additionally, the relatively short Tmax and latency to seizure termination demonstrate the rapidity of drug absorption and action respectively.
Eric W Dickson, Steven B Bird, Romolo J Gaspari, Edward W Boyer, Craig F Ferris
Diazepam inhibits organophosphate-induced central respiratory depression.
Acad Emerg Med. 2003 Dec;10(12):1303-6.
Abstract/Text
OBJECTIVES: Current evidence suggests that mortality from acute organophosphate (OP) poisoning is partially mediated through central nervous system (CNS) respiratory center depression (CRD). However, the exact mechanism of OP-induced CRD is unknown. In these studies, the authors investigated the hypothesis that OP-induced CRD is the result of overstimulation of CNS respiratory centers.
METHODS: Wistar rats received prophylaxis with either normal saline (controls), atropine, the peripherally acting anticholinergics glycopyrrolate (GLYC), ipratropium bromide (IB), or the CNS respiratory center attenuator diazepam. To determine if a dual CNS/peripheral cholinergic mechanism is responsible for animal death, two additional groups received combination treatment with diazepam plus either IB or GLYC. All treatments were completed 5 minutes before OP with subcutaneous dichlorvos. Differences in 10-minute and 24-hour mortality were assessed by the Fisher exact test.
RESULTS: Dichlorvos poisoning resulted in profound fasciculations without obvious seizure in all cohorts. In controls and animals treated with peripherally acting anticholinergics, fasciculations were followed by sedation and respiratory arrest (0% 10-minute survival in all cohorts). In contrast, pretreatment with either atropine or diazepam significantly improved 10-minute survival (100% and 44%, respectively). Although GLYC or IB afforded no protection when given alone, when delivered in conjunction with diazepam, the combination significantly improved survival (both groups 88% at 24 hours), suggesting a dual CNS/pulmonary muscarinic mechanism of lethality.
CONCLUSIONS: The central respiratory depressant diazepam paradoxically attenuates organophosphate-induced respiratory depression, and when combined with peripherally acting anticholinergic agents, reduces mortality in a rat model of severe acute OP poisoning.
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
Pralidoxime in acute organophosphorus insecticide poisoning--a randomised controlled trial.
PLoS Med. 2009 Jun 30;6(6):e1000104. doi: 10.1371/journal.pmed.1000104. Epub 2009 Jun 30.
Abstract/Text
BACKGROUND: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit.
METHODS AND FINDINGS: We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 [21.5%], placebo 24/114 [21.1%], adjusted HR 1.27 [95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit.
CONCLUSIONS: Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required.
Nick A Buckley, Michael Eddleston, Yi Li, Marc Bevan, Jane Robertson
Oximes for acute organophosphate pesticide poisoning.
Cochrane Database Syst Rev. 2011 Feb 16;(2):CD005085. doi: 10.1002/14651858.CD005085.pub2. Epub 2011 Feb 16.
Abstract/Text
BACKGROUND: 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 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.
OBJECTIVES: To quantify the effectiveness and safety of the administration of oximes in acute organophosphorus pesticide-poisoned patients.
SEARCH STRATEGY: 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.
SELECTION CRITERIA: Articles that could possibly be RCTs were retrieved to determine if they were randomised.
DATA COLLECTION AND ANALYSIS: The published methodology of three RCTs was not clear. We contacted the principal authors of these, but did not obtain further information.
MAIN RESULTS: 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.
AUTHORS' CONCLUSIONS: 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.
John V Peter, John L Moran, Petra Graham
Oxime therapy and outcomes in human organophosphate poisoning: an evaluation using meta-analytic techniques.
Crit Care Med. 2006 Feb;34(2):502-10.
Abstract/Text
OBJECTIVE: The status of oximes in human organophosphate poisoning is controversial. This analysis compares the outcomes of therapy with or without oximes.
DESIGN: Quantitative analysis using meta-analytic techniques.
METHODS: Controlled trials of oximes in human organophosphate poisoning were identified by search of MEDLINE and TOXLINE (1966 to May 2005) and review of published articles.
MEASUREMENTS AND MAIN RESULTS: Of the 3,122 articles on organophosphate poisoning identified by electronic search, 116 related to oxime use in human organophosphate poisoning. Seven trials, including two randomized controlled trials, compared oximes with standard medical care. Varying dosage schedules of pralidoxime or obidoxime were used. The effects of oxime therapy on mortality rate, mechanical ventilation, incidence of intermediate syndrome, and need for intensive care therapy were analyzed and expressed as risk difference (positive values indicating oxime harm). The random effects estimator was reported because of underlying heterogeneity of treatment effects between study types. No statistically significant association of oxime therapy was demonstrated for either mortality (risk difference 0.09, 95% confidence interval -0.08 to 0.27), ventilatory requirements (risk difference 0.16, 95% confidence interval -0.07 to 0.38), or the incidence of intermediate syndrome (risk difference 0.16, 95% confidence interval -0.12 to 0.45), although point estimates of effect suggested harm. An increased need for intensive care therapy (risk difference 0.19, 95% confidence interval 0.01 to 0.36) was apparent with oxime therapy.
CONCLUSIONS: Based on the current available data on human organophosphate poisoning, oxime was associated with either a null effect or possible harm. The lack of current prospective randomized controlled trials, with appropriate patient stratification, mandates ongoing assessment of the role of oximes in organophosphate poisoning.
Roja Rahimi, Shekoufeh Nikfar, Mohammad Abdollahi
Increased morbidity and mortality in acute human organophosphate-poisoned patients treated by oximes: a meta-analysis of clinical trials.
Hum Exp Toxicol. 2006 Mar;25(3):157-62.
Abstract/Text
Organophosphates are one of the most common causes of poisoning, especially in the Third world, with high morbidity and mortality. The treatment of this type of poisoning involves the use of atropine and oximes. Atropine has been used successfully in large doses to counteract the muscarinic effects of organophosphate poisoning, but the efficacy of oximes in the management of this poisoning remains under question. In this study, we undertook a meta-analysis by reviewing all clinical trials to evaluate the efficacy of oximes in the management of organophosphate poisoning. The databases of PUBMED, EMBASE, Cochrane, SCOPUS, and the search engine of Google were searched for all clinical trials on the use of oximes in organophosphate poisoning. The inclusion criteria were death, development of intermediate syndrome, and need for ventilation. Six clinical trials met the inclusion criteria and were included in the metaanalysis. The chi2 tests for heterogeneity (P = 0.25, 0.16, and 0.33, respectively) indicated that the included studies were not significantly heterogeneous and could be combined. A significant relative risk (P = 0.0017) for death among oxime-exposed was 2.17 (95% CI of 1.34-3.51). The 'need for ventilation' in patients who received oxime was higher (P = 0.03) than those who did not receive oxime with a relative risk of 1.53 (1.16-2.02). The incidence of 'intermediate syndrome' for oxime-exposed patients was significantly higher (P = 0.01) than oxime non-exposed patients with a relative risk of 1.57 (95% CI 1.11-2.11). It can be concluded that oximes are not effective in the management of organophosphate-poisoned patients and, surprisingly, they can be dangerous and worsen the patient's clinical situation.
Kirti S Pawar, Ramesh R Bhoite, Chandrakant P Pillay, Sujata C Chavan, Dhananjay S Malshikare, Saraswati G Garad
Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial.
Lancet. 2006 Dec 16;368(9553):2136-41. doi: 10.1016/S0140-6736(06)69862-0.
Abstract/Text
BACKGROUND: The role of oximes for the treatment of organophosphorus pesticide poisoning has not been conclusively established. We aimed to assess the effectiveness of a constant pralidoxime infusion compared with repeated bolus doses to treat patients with moderately severe poisoning from organophosphorus pesticides.
METHODS: 200 patients were recruited to our single-centre, open randomised controlled trial after moderately severe poisoning by anticholinesterase pesticide. All were given a 2 g loading dose of pralidoxime over 30 min. Patients were then randomly assigned to control and study groups. Controls were given a bolus dose of 1 g pralidoxime over 1 h every 4 h for 48 h. The study group had a constant infusion of 1 g over an hour every hour for 48 h. Thereafter, all patients were given 1 g every 4 h until they could be weaned from ventilators. Analysis was by intention to treat. Primary outcome measures were median atropine dose needed within 24 h, proportion of patients who needed intubation, and number of days on ventilation. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00333944.
FINDINGS: 100 patients were assigned the high-dose regimen, and 100 the control regimen. There were no drop-outs. Patients receiving the high-dose pralidoxime regimen required less atropine during the first 24 h than controls (median 6 mg vs 30 mg; difference 24 mg [95% CI 24-26, p<0.0001]). 88 (88%) and 64 (64%) of controls and high-dose patients, respectively, needed intubation during admission to hospital (relative risk=0.72, 0.62-0.86, p=0.0001). Control patients required ventilatory support for longer (median 10 days vs 5 days; difference 5 days [5-6, p<0.0001]).
INTERPRETATION: A high-dose regimen of pralidoxime, consisting of a constant infusion of 1 g/h for 48 h after a 2 g loading dose, reduces morbidity and mortality in moderately severe cases of acute organophosphorus-pesticide poisoning.
Andrew M King, Cynthia K Aaron
Organophosphate and carbamate poisoning.
Emerg Med Clin North Am. 2015 Feb;33(1):133-51. doi: 10.1016/j.emc.2014.09.010. Epub 2014 Nov 15.
Abstract/Text
Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors. Some OP and carbamates have therapeutic indications such as physostigmine. Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents. Both classes inhibit acetylcholinesterase (AChE) enzymes, leading to excess acetylcholine accumulation at nerve terminals. In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation. The toxic effects from OPs and carbamates differ with respect to reversibility, subacute, and chronic effects. Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management.
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