RECENT ADVANCES in CLINICAL MEDICINE Intensive Care Managament of Acute Organophosphate Poisoning: Clinical Experience and the Review of the Literature VUČINIĆ SLAVICA1, ANTONIJEVIĆ BILJANA2, BOŠKOVIĆ BOGDAN1, ĆURČIC MARIJANA2 National Poison Control Centre, Crnotravska 17, 11000 Belgrade1 Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade 2 SERBIA [email protected] Abstract:- Current therapeutic scheme for management of acute poisoning with anticholinesterase pesticides includes general supportive measures (decontamination, respiratory support) and specific pharmacological treatment (atropine, oxime, diazepam). Antidote therapy is aimed to competitively antagonise overstimulation of muscarinic receptors with atropine and to reactivate inhibited AChE with oximes. Rectivation and clinical improvement of neuromuscular function are limited by aging of acetylcholinesterase and high concentrations of organophosphates. Results of our longitudinal clinical experience confirm benefitial effect of oxime administration in OP poisoning. Key words: acute organophosphate poisoning, oxime, intensive care management 1 Introduction endogenous anticholinergic effect in normal Organophosphate (OP) insectide poisoning doses. While these effects have been results from occupational, accidental and conclusively demonstrated in experimental intentional exposure. According to the World settings the general clinical benefit in OP Health Organization, about 1 million accidental poisoning is not clear yet, and the mortality is and 2 million suicidal poisonings with high despite the use of atropine and oxime. organophosphorus insecticides are reported per There are several reasons for the contradictory year, with more than 300 000 fatalities [1]. reports: 1) The type and dose of poison are The greatest share of poisonings comes often unknown and may vary widely. 2) The from the developing countries of the Asia- extent of decontamination may greatly differ. Pacific region, but OP insecticide poisonings 3) Different oxime regimen. 4) Patients may are also a problem for countries in the differ with respect to enzyme polymorphisms developed world, although their primary in toxifying phosphorothioates (CYP concern is defense against terrorist use of these superfamily) and hydrolytic detoxication chemicals [2]. (PON1) [3]. In this paper we present our experience related to clinical management of 2 Problem formulation acute poisoning with OPs at National Poison Besides general supportive therapy, curent Control Centre (NPCC), Belgrade, that were therapeutic protocols include atropine, oxime collected during the 10 years period (1998 and benzodiazepine. Atropine is the mainstay 2007). Treatment of acute poisoning caused by of treatment of muscarinic effects in OP this class of substances will be considered poisoning worldwide. This physiologic antidote through a correlation of our experience and the effectively antagonizes muscarinic receptor review of the literature. mediated effects of excessive acetylcholine, it is somewhat effective at central m-receptors, 2.1 Mechanisms of acute toxicity of but it fails at nicotine sensitive synapses. Here, organophosphate insecticides reactivating oximes can act as specific The primary molecular mechanism of action of antidotes. Three actions have been attributed to the OP ompounds is inhibition of oximes: 1) rectivation of cholinesterase by acetylcholinesterase (EC 3.1.1.7, AChE) cleavage of phosphorylated active sites; 2) producing excessive acetylcholine (ACh) direct reaction and detoxification of unbounded accumulation and overstimulation of organophosphorus molecules, and 3) ISSN: 1790-5125 74 ISBN: 978-960-474-165-6 RECENT ADVANCES in CLINICAL MEDICINE cholinergic neurons. The variations in the acute registered in 83 (26.2%) and acute toxicity of OP are the result of their different cardiocirculatory failure in 15 (4.7%) patients. chemical structures and rates of spontaneous This is consistent with the results of other reactivation and aging. Even though aging studies with acute organophosphate occurs slowly and reactivation relatively poisoning[13]. rapidly in the case of OP insecticides, early Clinical diagnosis is relatively simple oxime administration is clinically important in and is based on medical history, circumstances patients poisoned with these agents. In addition of exposure, clinical presentation, and to reaction with AChE, OPs also react with laboratory tests. Confirmation of diagnosis can serum cholinesterase (EC 3.1.1.8, ChE), a be made by measurement of erythrocyte AChE circulating plasma glycoprotein synthetized in or serum ChE [1-4]. Many OP insecticides (e.g. the liver, in the same manner as with AChE chlorpyrifos, demethon, diazinon, dichlorvos, [3,4]. malathion, trichlorphon) appear to be more potent inhibitors of ChE than AChE and, as the 3 Results consequence, ChE inhibition might occur to a During the ten year period, 29723 patients were greater extent than AChE inhibition. treated at the NPCC, 11174 were hospitalized, Erythrocyte AChE is identical to the enzyme and among them 526 patients were poisoned present in the target synapses, thus, it is with pesticides. OP compounds were detected regarded as biomarker of toxicity of these in 296 patients. Poisoning with dimethyl OP compounds [3-5]. was confirmed in 246 patients (malathion 153, The majority of patients exposed to OP dimethoate 69, dichlorvos 4, fenitrothion 6, pesticides (46.6%) had their AChE activity monocrotophos 8), with diethyl OP in 38 between 20 and 50% (compared to mean patients (diazinon 21, parathion 9, phorate 1, population controls) indicating mild poisoning, phoxim 1, phosalone 3, chlorpyriphos 2, about 9% patients had 10-20% of AChE quinalphos 1) and in 12 patients OP could not activity (moderate poisoning), and there were be fully identified. Majority of poisonings only 2.7% patients with AChE activity lower (92%) were due to deliberate ingestion of than 10% (severe poisoning). Additional cholinesterase inhibitors. confirmation of OP poisoning was obtained after detection of these compounds and/or their metabolites in biological samples (blood, urine, 3.1 Clinical features and diagnosis of lavate) by gas chromatography in 161 poisoned acute anticholinesterase poisoning patients. The highest registered concentration Acute cholinergic crisis is a medical emergency of malathion in blood was 61.0 mg/L in a that often requires treatment in Intensive Care severely poisoned patient who had AChE Unit. It consists of muscarinic, nicotinic and activity lower than 10%. central nervous system effects. Muscarinic features include bronchorrhoea, broncho 3.2 Assessment of the poisoning severity constriction, miotic pupils, abdominal cramps, The assessment of the severity of poisoning is involuntary defecation and urination, essential for adequate management of patients bradycardia, QT prolongation, hypotension. with anticholinesterase poisonings. At the Nicotinic features include twiching of fine NPCC for many years for this purpose we use muscles, fasciculation and hyperreflexia which the Poisoning Severity Score (PSS) [6]. PSS may progressively lead to flaccid paralysis. The considers the overall clinical course where PSS most prominent CNS symptoms are: headache, 0 designates no symptoms of poisoning, PSS 1 dizziness, drowsiness, nausea, confusion, minor (mild) poisoning, PSS 2 moderate anxiety, slurred speech, ataxia, tremor, poisoning, PSS 3 severe poisoning and PSS 4 psychosis, convulsions, coma and respiratory fatal poisoning. In addition, we take into depression [14]. consideration other relevant data available such The most common clinical signs of as the activity of AChE in erythrocytes and poisoning in patients exposed to OPs observed ChE in serum as well as good tolerance of high at Clinic of Toxicology of the NPCC were atropine doses. miosis (61.8%), bronchorrhoea (51.7%), OP were the cause of severe and fatal vomiting and diarrhea (50.8%), hypotension poisoning (PSS 3 and 4) in 129 (43.5%), and (27.8%). Acute respiratory insufficiency was mild poisoning (PSS 1) in 70 (23.7 %) patients. ISSN: 1790-5125 75 ISBN: 978-960-474-165-6 RECENT ADVANCES in CLINICAL MEDICINE The majority of clinical manifestations resolve includes careful titration of atropine until within a few days or weeks, but appearance of signs of hyperatropinization, and neurophysiological symptoms may remain for individualization of dosage. The highest total months. Fourty seven patients (15.9%) died. administered dose of atropine at NPCC was This is consistent with the findings of other 6400 mg. However, the most patients received authors who reported case fatality generally total doses of atropine up to 500 mg (32%), more than 15%. Acute respiratory while about 13% patients received atropine insufficiency, due to weakness of respiratory 500-1000 mg or up to 50 mg. muscles and central respiratory depression, was the major cause of lethal outcome in OP 3.3.3 Oxime therapy poisoning. Another cause of death was Oximes reactivate phosphorylated AChE by cardiocirculatory insufficiency which was even displacing the phosphoryl moiety from the more difficult do cope with since it is often enzyme by virtue of their high affinity for the refractory to treatment [7]. enzyme and their powerful nucleophilicity. The rate of reactivation depends on the structure of 3.3 Management of acute poisoning with the phosphoryl moiety bound to the enzyme, OP pesticides the source of the enzyme, the structure and concentration of oxime which