This document summarizes organophosphorus insecticides and nerve gas agents poisoning. It discusses the mechanisms, clinical manifestations and management of organophosphorus poisoning, which can cause acute cholinergic crisis, intermediate syndrome and organophosphate-induced delayed polyneuropathy. Treatment involves decontamination, atropine to block muscarinic effects, oximes like pralidoxime to reactivate acetylcholinesterase, and ventilatory support for respiratory failure and intermediate syndrome. Prognosis depends on dose, toxicity of agent and timeliness of treatment.

1. Organophosphorus Insecticides and Nerve Gas Agents Poisoning Mentor: Dr A M V R Narendra MD DM Presenter: Dr Bhavanadhar P (MD) Jr Resident Dept of General Medicine, NIMS, Hyd. 18-AUG-2009

2. Introduction Organophosphorus (OP) compounds - pesticides, herbicides, and chemical warfare agents i.e., nerve gases. OP pesticide intoxications are estimated at 3 million per year worldwide with approximately 300 000 deaths. Most of the OP pesticide poisoning and subsequent deaths occur in developing countries following a deliberate self ingestion. The fatality rate following deliberate ingestion of OP pesticides in developing countries in Asia is approx 20% and may reach upto 70%.

3. Compounds OP compounds were first developed by Schrader shortly before and during the Second World War. These compounds are normally esters, thiol esters, or acid anhydride derivatives of phosphorus containing acids. Of the more than 100 OP pesticides used worldwide, the majority are either dimethyl phosphoryl or diethyl phosphoryl compounds

4. Others: Acephate Dimethoate Ethion Fentrothion Moncrotofos Phenthoate Phorate Phosphamidon Profenofos

5. Nerve gas compounds are highly potent synthetic toxic agents. G agents like Tabun, sarin, and soman are absorbed by inhalation or percutaneously; they are volatile and disappear rapidly after use. V agents are contact poisons unless aerosolised, and contaminate ground for weeks or months. They are related to OP pesticides but have much higher acute toxicity, particularly percutaneously. The toxicology and management of nerve agent and pesticide poisoning are similar

6. Mechanism of Toxicity OP’s inactivate acetylcholinesterase (AChE) by phosphorylation leading to the accumulation of acetylcholine (ACh) at cholinergic synapses And subsequent over-activation of cholinergic receptors at the NMJ and in the autonomic and CNS. The rate and degree of AChE inhibition differs according to the structure of the OP compounds and the nature of their metabolite.

7. In general, pure thion compounds are not significant inhibitors in their original form and need metabolic activation (oxidation) in vivo to oxon form. E.g., parathion has to be metabolized to paraxon in the body so as to actively inhibit AChE. Carbamates differ in mechanism, that the same enzyme is reversibly inhibited and are sometimes useful as medicines (neostigmine, pyridostigmine) as well as insecticides (carbaryl)

8. Diagrammatic representation of the possible reactivation & ageing reactions of AChE after inhibition by OP compounds

9. After the initial inhibition and formation of AChEOP complex two further reactions are possible: (1) Spontaneous reactivation of the enzyme - this may occur at a slow pace, much slower than the enzyme inhibition and requiring hours to days to occur. - the rate solely depends on the type of OP compound, - spontaneous reactivation t 1/2 of 0.7 hrs for dimethyl and 31 hrs for diethyl compounds. - the spontaneous reactivation can be hastened by reagents like oximes. These agents thereby act as an antidote in OP poisoning

10. (2) Ageing - with time, the enzyme-OP complex loses one alkyl group making it no longer responsive to reactivating agents. - ageing depends on - pH, temp, and type of OP compound; - dimethyl OP’s have ageing t ½ of 3.7 hours whereas it is 33 hours for diethyl OP’s. - hence, oximes are hypothetically useful before 12 hours in dimethyl OP’s poisoning. - However, in diethyl OP intoxication they may be useful for many days. - Nerve agents (especially soman) undergo ageing within minutes

11. Clinical Manifestations The onset, severity and duration of poisoning depend on the route of exposure and agent involved. Sequential triphasic illness follows OP intoxication : Acute Cholinergic Crisis Intermediate Syndrome (IMS) Organophosphate-Induced Delayed Polyneuropathy (OPIDN ).

12. Acute Cholinergic Crisis Accumulation of acetylcholine (ACh) causing excessive stimulation of cholinergic receptors at various organs. Ach is the principle neurotransmitter in various synapses: parasympathetic system, autonomic ganglia, NMJ and central nervous system. These acute manifestations can be broadly divided into muscarinic, nicotinic, and central nervous system (CNS) effects. Practical significance of this classification is that atropine only blocks muscarinic effects whereas oximes reverse both the nicotinic and muscarinic effects

13. Summary of clinical features and antidotes in Acute Cholinergic Crisis

14. SLUDGE Salivation Lacrimation Urine incontinence Diarrhoea, Gastrointestinal cramps Emesis) DUMBELS Diarrhoea Urination Miosis Bronchospasm,Bronchorrhea Emesis Lacrimation Salivation Various mnemonics have been used to describe the muscarinic signs of OP poisoning:

15. Heart rate and blood pressure can be potentially misleading findings as increase or decrease can occur in both vital signs. Dose dependent effects : Muscarinic < Nicotinic < CNS Tachycardia/Hypertension – s/o severe poisoning Patients can also develop pancreatitis, hypo or hyperglycaemia and acute renal failure during this phase

16. Depending on the severity of the exposure, the spectrum of the clinical presentation varies Mild Small or pinpoint pupils Painful, blurred vision Runny nose and eyes Excess saliva Eyes look &quot;glassy&quot; Headache, Nausea Mild muscle weakness Localized muscle twitching Moderate Pinpoint pupils, conjunctival injection Dizziness, disorientation Coughing, wheezing, sneezing Drooling, bronchorrhoea, bronchospasm Breathing difficulty Marked muscle twitching, tremors Muscle weakness, fatigue Severe Pinpoint pupils Confusion Agitation Convulsions Copious secretions Cardiac arrhythmias, Collapse Respiratory depression, Respiratory arrest Coma Death

17. Prognosis in acute poisoning may depend -> dose and toxicity of the ingested OP (e.g., neurotoxicity potential, half life, rate of ageing, pro-poison or poison), and whether dimethyl or diethyl compound. The time of death after exposure may range from <5 min to nearly 24 hours -> dose, route of administration, agent and availability of treatment. Respiratory failure and hypotension are the immediate causes of death in acute stage. Delay in discovery and transport, insufficient respiratory management, aspiration pneumonia and sepsis are common causes of leading to death. Prognosis

18. Intermediate syndrome The intermediate syndrome is a distinct clinical entity that occurs 24 to 96 hours after the ingestion of an OP compound; Approximately 10-40% of patients treated for acute poisoning develop this illness. The onset of the IMS is often rapid, with progression of muscle weakness from the ocular muscles to the neck (the patient cannot raise their head from the pillow) proximal limbs, to the respiratory muscles (intercostals and diaphragm) over the course of 24 hours.

19. Increasing respiratory difficulty causes anxiety, sweating and use of accessory muscles of respiration. If endotracheal intubation and ventilation are not instituted early, cyanosis, coma and death follow rapidly. Paralysis may continue for 2-18 days. Proposed mechanisms include persistent inhibition of AChE leading to functional paralysis of neuromuscular transmission, muscle necrosis, and oxidative free radical damage to the receptors

20. Organophosphate-induced delayed polyneuropathy (OPIDN) This occurs about 1-3 weeks after acute exposure and an uncertain period following chronic exposure, due to degeneration of long myelinated nerve fibres. Mechanism is inhibition of neuropathy target esterase (NTE) enzyme in nervous tissues by certain OP compounds (chloropyriphos) A distinct acute or intermediate phase may not always precede its development

21. Symptoms Cramping muscle pains in the legs numbness and paraesthesiae in the distal upper and lower limbs. Acute weakness of the lower limbs follows and spreads to the hands, causing a shuffling gait, and footand wrist-drop. Muscle wasting and deformity, such as clawing of the hands, follow. Sensory loss is variable and is often mild and inconspicuous.

22. Signs Physical examination reveals symmetrical flaccid weakness of the distal muscles, especially in the legs. Tendon reflexes are reduced or lost, absent ankle reflexes being a constant feature. Later, mild pyramidal tract signs (spasticity, hypertonicity, hyper-reflexia and clonus) may develop.

23. Figure showing effects of OP poisoning

24. Diagnosis Diagnosis of OP poisoning depends on the H/o exposure to OP compounds, characteristic manifestations of toxicity and improvements of the signs and symptoms after administration of atropine. This may be aided by insisting that the pt’s party to search for a possible poison container in the vicinity of the pt. Garlic-like smell is an added clinical sign especially if the patient has ingested sulphur containing OP compound.

25. Cholinesterase (ChE) estimations (plasma butyryl cholinesterase and red cell AChE) are the only useful biochemical tool for confirming exposure to OPs, but are a poor guide to management and prognosis. Clinical severity graded on the basis of the pseudocholinesterase level mild 20-50% enzyme activity, moderate 10-20% enzyme activity severe <10% enzyme activity though the enzyme activity does not correlate well with clinical severity

26. BuChE activity Easily assayed Response to antidotal therapy less Does not correlate well with neuronal effects Levels altered in malnutrition, chronic illness, cirrhosis, infections RBC AChE activity More difficult to assay Increased activity after pralidoxime therapy Correlates well with predictable neuronal effects and severity as well Levels altered in hemoglobinopathies, thalassemia On the other hand, true or erythrocyte cholinesterase correlates well with clinical severity but is not available in most centres, especially in developing countries

27. Analytical identification of OP compound in gastric aspirate or in the body fluids gives the clue that pt has been exposed to OP compound. However in doubtful cases and especially if laboratory facilities are not available, 1mg atropine can be given intravenously. If this does not produce marked anticholinergic manifestations, anticholinesterase poisoning should be strongly suspected

28. Treatment: Acute Cholinergic crisis Decontamination and Supportive therapy Blockade of Muscarinic activity with ATROPINE Reversal of cholinesterase inhibition with OXIME nucleophiles Correction of Metabolic abnormalities

29. Decontamination and Supportive therapy Protection of the health care staff ABC(Airway, Breathing & Circulation) Comatose or vomiting patients should be kept in lateral, preferably head down position with neck extension to reduce the risk of aspiration. Patent airway should be secured with placement of Guedel’s airway or with endotracheal intubation especially if the patient is unconscious, fitting, or vomiting. Frequent suctioning is essential as excessive oropharyngeal and respiratory secretions may occlude the airway. Need for o2 therapy this can be assessed by frequent assessment of arterial oxygen saturation

30. Decontamination: Skin decontamination. The skin and clothes of these patients are frequently contaminated with poison and vomiting. Hence should be removed and the skin vigorously washed with soap and water Gastric lavage. Gastric lavage should be considered in patients presenting within 1-2 hours of ingestion of poison. Risks of gastric lavage include aspiration, hypoxia, and laryngeal spasm, and these can be reduced with proper management of airway

31. Activated charcoal Activated charcoal helps to reduce the poison load by adsorbing it; Though its efficacy has not been conclusively proven in humans, single to multiple dose activated charcoal is routinely used in clinical practice. AVOID cathartics and induced emesis

33. Specific antidote for muscarinic effects ; no effect on nicotinic symptoms. It reverses life threatening features that can result in death -> central respiratory depression, bronchospasm, excessive bronchosecretion, severe bradycardia, and hypotension Current guidelines recommend the use of bolus doses to attain target endpoints, followed by setting up an infusion to maintain these end-points. Atropine

34. Target end-points for Atropine therapy Heart rate >80/ min Dilated pupils Dry axillae Systolic blood pressure >80 mm Hg Clear chest on auscultation with resolution of bronchorrhea (absence of wheeze and crepts) Recommended dose is an initial iv bolus of 1.8-3mg with subsequent doses doubled every 5 minutes until atropinization is achieved.(0.05mg/kg in children) Maintenance dose: 20% of initial atropinizing dose per hour for first 48 hours and gradually taper over 5 -10 days, continuously monitoring the adequacy of therapy.(0.02-0.08mg/kg/hr)

35. Look for atropine TOXICITY Agitation, confusion, hyperthermia, urinary retention and severe tachycardia that can precipitate ischaemic events in patients with underlying coronary artery disease. Close observation and dose adjustment is essential to avoid the features of both under- and over-atropinization. Anticholinergic agent glycopyrrolate along with atropine can be used in order to limit the central stimulation produced by atropine

36. Oximes Oximes work by reactivating acetylcholinesterase that has been bound to the OP molecule. Pralidoxime is the most frequently used oxime worldwide; other members include obidoxime, and experimental HI 6 and HLO 7. They can be highly effective in restoring skeletal muscle strength and improving diaphragmatic weakness where atropine has virtually no effect. The therapeutic window for oximes is limited by the time taken for ‘ageing’ of the enzyme-OP complex, because ‘aged’ enzyme can no longer be reactivated by oximes

37. WHO recommends pralidoxime dose of 30 mg/kg bolus iv followed by continuous infusion of 8mg/kg/hour Infusion continued until recovery : 12 hrs after atropine has been stopped. BChE noted to increase. Dizziness, headache, blurred vision, and diplopia, are common side effects of oxime therapy. Rapid administration may lead to tachycardia, laryngospasm, muscle spasm, and transient neuromuscular blockade.

38. Intermediate syndrome Ventilatory support should be instituted before a pt develops resp failure to maintain a PaO2 > 97 mmHg (>13kPa), PaCO2 of 30-45 mmHg (4-6 kPa) and pH > 7.3. Diazepam or midazolam may be used for sedation during ventilation. Weaning from respiratory support should be initiated as early as possible. Parenteral nutrition is often required. Unless OPIDN develops, recovery from IMS is complete with adequate ventilatory care

39. OPIDN There are no specific therapeutic measures. Regular physiotherapy may reduce deformity caused by muscle-wasting. Recovery from OPIDN is incomplete and may be limited to the hands and feet, although substantial functional recovery after 1-2 years may occur in younger patients .

40. Figure showing effects of OP poisoning

41. 30 mg / kg bolus 8 mg / kg / hr 4 mg / kg bolus 0.5 mg / kg / hr