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Can we define severity criteria for the common cardiotropic drugs taken in overdose?
Abstracts / Toxicology Letters 196S (2010) S1–S36
impact of predefined prognostic variables. It is also important for trials to be registered and be reported using CONSORT guidelines. Further, collection of standardised observational data outside of trials may improve understanding of the epidemiology, the clinical presentation, utility of diagnostic tests, prognosis, lethal dose, and relative differences in toxicity within poison classes. Such data are also critical in planning RCTs. Regional cooperation in such efforts should be actively pursued. There have been small but significant changes over the last decade in the management of poisoning that have been the result of clinical research. There is a need for greater understanding of good clinical research practice, methodology and critical appraisal. This should lead to a commitment to provide more good quality evidence through RCTs. doi:10.1016/j.toxlet.2010.03.140
S25-2 Can we define severity criteria for the common cardiotropic drugs taken in overdose? B. Mégarbane Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Université Paris-Diderot, France Background: Drug-induced cardiovascular failure remains a leading cause of death. Our objective was to discuss the criteria of severity for poisonings involving the usual cardiotoxicants. Methods: Review of PubMed-referenced studies. Results: Following an overdose, severe cardiotoxicity rapidly appears with the sudden onset of hypotension, intra- or atrioventricular block, ventricular tachycardia fibrillation or asystole. Other subsequent critical features include mental status deterioration, seizures, hyperlactacidemia, and respiratory failure, generally due to organ hypoperfusion. Systematic cardiac monitoring in the intensive care unit is mandatory. Overdoses with calcium-channel blockers, beta-blockers, and membrane-stabilizing agents result in myocardial negative inotropic effects as well as arterial dilatation. Cardiac failure results from decreased systolic myocardial contractility, diastolic dysfunction, alteration in the geometry of heart contraction, myocarditis, or acute coronary syndrome. Initial evaluation of severity is based on the drug type, the pharmaceutical formulation, and the ingested dose. When available, the value of the plasma concentrations of the toxicant remains debated. Prognostic factors remain poorly investigated except for digitalis, colchicine, theophylline, and antidepressants. They are specific of the class of toxicant, including the mechanism of shock, the degree of QRS enlargement, the severity of renal or respiratory failure, and the response to the supportive treatments. Catecholamines represent the first-line therapy if hypotension persists despite fluids. Sodium bicarbonate is required if ventricular conduction is delayed. Despite optimal supportive and antidotal treatments, management of drug-induced cardiovascular failure may require extracorporeal life support to allow the patient’s recovery. However, clarification of prognosticators of refractoriness to pharmacological treatment remains mandatory. Conclusion: Drug-induced circulatory failure is life-threatening. Early determination of its mechanism as well as the continuous monitoring of patient’s hemodynamic conditions is essential to improve management. Poisoning severity should be continuously evaluated, based on easily available clinical, biological, ECG, and hemodynamic parameters, in order to help indicating the adequate treatments including those exceptional. doi:10.1016/j.toxlet.2010.03.141
S31
S25-3 New approaches of treatment in paraquat poisoning S.Y. Hong Soonchunhyang University Hospital, South Korea Antioxidant therapy has emerged as a new treatment modality for diseases for which the causative agents are thought to be reactive oxygen species (ROS). However, the optimal dose of antioxidant treatment has yet to be determined for acute paraquat (PQ) intoxication, which has been identified as an ROS-mediated medical condition. Based on our preliminary in vitro data from a previous study, we have proposed that 50 mg/kg glutathione (GSH) would be adequate for suppressing ROS in patients with acute PQ intoxication. This proposal was evaluated by measuring serum levels of reactive oxygen metabolites (ROMs) before and after the administration of 50 mg/kg GSH to each of five patients with acute PQ intoxication. When pretreatment levels of ROM were extremely high (as in one of our cases), they had already decreased prior to GSH administration. However, in the other four cases the ROM levels did not change significantly prior to GSH administration. ROM levels decreased significantly after GSH administration in all cases (50 mg/kg, administered intravenously over 12 h). They decreased below the levels found in the general population only in two cases, one of whom died after a cardiac arrest at 3 h after PQ ingestion (2 h after admission). ROMs in the survivor continued to decrease during the first 8 h, finally to levels lower than those found in the general population. In conclusion, 50 mg/kg GSH significantly suppressed serum ROM levels in PQ-intoxicated patients. However, this dose was not sufficient to suppress ROM levels when the PQ concentration was extremely high. doi:10.1016/j.toxlet.2010.03.142
S26 Detoxication and Susceptibility to Anticholinesterase Pesticides S26-1 Role of albumin in the detoxication of organophosphorus and carbamate pesticides M.A. Sogorb, E. Vilanova Universidad Miguel Hernández de Elche, Spain The capability of serum albumins to hydrolyze ester bonds is well-known since long time ago. We have been working in the characterization of the organophosphorus and carbamate hydrolyzing activities associated to albumins. The hydrolysis of these pesticides is an efficient detoxication route because none of the hydrolyzed pesticides are able to inhibit acetylcholinesterase. We demonstrated that mammal serum albumins are able to hydrolyze the carbamate carbaryl and the following organophosphorus pesticides: paraoxon, chlorpyrifos-oxon and diazoxon. Probably many other organophosphorus and carbamates may be also hydrolyzed in more or less extension by albumin. The hydrolysis was species-dependant because paraoxon was not hydrolyzed by chicken serum albumin. Our studies established that all these substrates were hydrolyzed through a mechanism based in the transient phosphorylation or carbamylation of the tyrosine residue located in position
impact of predefined prognostic variables. It is also important for trials to be registered and be reported using CONSORT guidelines. Further, collection of standardised observational data outside of trials may improve understanding of the epidemiology, the clinical presentation, utility of diagnostic tests, prognosis, lethal dose, and relative differences in toxicity within poison classes. Such data are also critical in planning RCTs. Regional cooperation in such efforts should be actively pursued. There have been small but significant changes over the last decade in the management of poisoning that have been the result of clinical research. There is a need for greater understanding of good clinical research practice, methodology and critical appraisal. This should lead to a commitment to provide more good quality evidence through RCTs. doi:10.1016/j.toxlet.2010.03.140
S25-2 Can we define severity criteria for the common cardiotropic drugs taken in overdose? B. Mégarbane Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Université Paris-Diderot, France Background: Drug-induced cardiovascular failure remains a leading cause of death. Our objective was to discuss the criteria of severity for poisonings involving the usual cardiotoxicants. Methods: Review of PubMed-referenced studies. Results: Following an overdose, severe cardiotoxicity rapidly appears with the sudden onset of hypotension, intra- or atrioventricular block, ventricular tachycardia fibrillation or asystole. Other subsequent critical features include mental status deterioration, seizures, hyperlactacidemia, and respiratory failure, generally due to organ hypoperfusion. Systematic cardiac monitoring in the intensive care unit is mandatory. Overdoses with calcium-channel blockers, beta-blockers, and membrane-stabilizing agents result in myocardial negative inotropic effects as well as arterial dilatation. Cardiac failure results from decreased systolic myocardial contractility, diastolic dysfunction, alteration in the geometry of heart contraction, myocarditis, or acute coronary syndrome. Initial evaluation of severity is based on the drug type, the pharmaceutical formulation, and the ingested dose. When available, the value of the plasma concentrations of the toxicant remains debated. Prognostic factors remain poorly investigated except for digitalis, colchicine, theophylline, and antidepressants. They are specific of the class of toxicant, including the mechanism of shock, the degree of QRS enlargement, the severity of renal or respiratory failure, and the response to the supportive treatments. Catecholamines represent the first-line therapy if hypotension persists despite fluids. Sodium bicarbonate is required if ventricular conduction is delayed. Despite optimal supportive and antidotal treatments, management of drug-induced cardiovascular failure may require extracorporeal life support to allow the patient’s recovery. However, clarification of prognosticators of refractoriness to pharmacological treatment remains mandatory. Conclusion: Drug-induced circulatory failure is life-threatening. Early determination of its mechanism as well as the continuous monitoring of patient’s hemodynamic conditions is essential to improve management. Poisoning severity should be continuously evaluated, based on easily available clinical, biological, ECG, and hemodynamic parameters, in order to help indicating the adequate treatments including those exceptional. doi:10.1016/j.toxlet.2010.03.141
S31
S25-3 New approaches of treatment in paraquat poisoning S.Y. Hong Soonchunhyang University Hospital, South Korea Antioxidant therapy has emerged as a new treatment modality for diseases for which the causative agents are thought to be reactive oxygen species (ROS). However, the optimal dose of antioxidant treatment has yet to be determined for acute paraquat (PQ) intoxication, which has been identified as an ROS-mediated medical condition. Based on our preliminary in vitro data from a previous study, we have proposed that 50 mg/kg glutathione (GSH) would be adequate for suppressing ROS in patients with acute PQ intoxication. This proposal was evaluated by measuring serum levels of reactive oxygen metabolites (ROMs) before and after the administration of 50 mg/kg GSH to each of five patients with acute PQ intoxication. When pretreatment levels of ROM were extremely high (as in one of our cases), they had already decreased prior to GSH administration. However, in the other four cases the ROM levels did not change significantly prior to GSH administration. ROM levels decreased significantly after GSH administration in all cases (50 mg/kg, administered intravenously over 12 h). They decreased below the levels found in the general population only in two cases, one of whom died after a cardiac arrest at 3 h after PQ ingestion (2 h after admission). ROMs in the survivor continued to decrease during the first 8 h, finally to levels lower than those found in the general population. In conclusion, 50 mg/kg GSH significantly suppressed serum ROM levels in PQ-intoxicated patients. However, this dose was not sufficient to suppress ROM levels when the PQ concentration was extremely high. doi:10.1016/j.toxlet.2010.03.142
S26 Detoxication and Susceptibility to Anticholinesterase Pesticides S26-1 Role of albumin in the detoxication of organophosphorus and carbamate pesticides M.A. Sogorb, E. Vilanova Universidad Miguel Hernández de Elche, Spain The capability of serum albumins to hydrolyze ester bonds is well-known since long time ago. We have been working in the characterization of the organophosphorus and carbamate hydrolyzing activities associated to albumins. The hydrolysis of these pesticides is an efficient detoxication route because none of the hydrolyzed pesticides are able to inhibit acetylcholinesterase. We demonstrated that mammal serum albumins are able to hydrolyze the carbamate carbaryl and the following organophosphorus pesticides: paraoxon, chlorpyrifos-oxon and diazoxon. Probably many other organophosphorus and carbamates may be also hydrolyzed in more or less extension by albumin. The hydrolysis was species-dependant because paraoxon was not hydrolyzed by chicken serum albumin. Our studies established that all these substrates were hydrolyzed through a mechanism based in the transient phosphorylation or carbamylation of the tyrosine residue located in position