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Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Organophosphate Pesticide Poisoning Bishan Rajapakse MBChB Otago Emergency.

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Presentation on theme: "Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Organophosphate Pesticide Poisoning Bishan Rajapakse MBChB Otago Emergency."— Presentation transcript:

1 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Organophosphate Pesticide Poisoning Bishan Rajapakse MBChB Otago Emergency Medicine Advanced Trainee Registrar, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration (SACTRC)

2 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration OP Poisoning - Overview Epidemiology Mechanism Clinical features Management Current developments in Oxime therapy

3 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration CASE 36 yo female Ingestion of Dimethoate (Severely Toxic OP) Village Drunk 100mls after dispute Found by family vomiting Taken to nearest peripheral hospital (1 doctor, 2 nurses) Sent by Ambulance (no paramedics) to nearest General hospital 0930 hrs 1000 hrs0900 hrs (village) 1115 hrs

4 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration

5 Management Initial Management? –ABC’s –Atropine Ongoing Assessment & Management –Oximes (Pralidoxime, Obidoxime) -yes/no? –Dose? Duration? –Acetylcholinesterase assays?

6 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Organophosphorus (OP) Pesticide Poisoning

7 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Organophosphate Poisoning in Sri Lanka Organophosphorus poisoning –High acuity and fatality –12,000 admissions –800 deaths –Mostly self-ingestion in Young adults South Asian Clinical Toxicology Research Colaboration (SACTRC) 5 Hospitals

8 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Organophosphate Poisoning in Sri Lanka Case Fatality rates (CFR) –10-30% for most OP’s In west CFR –0.3% from all poisons Multifactorial –Toxicity of OP’s –Patient transport –Lack of resources –Training Although less common OP Poisoning is still a problem in West –Occupational exposure –Threat of Chemical warfare

9 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Mechanism of OP toxicity

10 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Inhibition of Acetycholinesterase

11 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Nicotinic, Muscurinic & Central Syndrome

12 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Simplified Acute OP Toxicity OP’s are Cholinomimetics Organophosphate

13 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration + Death Acute Cholinergic Syndrome: –Central –Peripheral Muscarinic –Peripheral Nicotinic Intermediate Syndrome OPIDN: Delayed peripheral neuropathy Neurocognitive dysfunction Clinical Features Respiratory failure } }

14 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Cholinergic Effects – “DUMBELS” D iarrhoea U rination M iosis B radycardia, Bronchorrhoea, Bronchospasm E mesis L acrimation S alivation

15 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Nicotinic Effects Muscle Weakness Respiratory difficulty –diaphragmatic weakness –respiratory arrest Stimulation of sympathetic nervous system

16 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration CNS effects Serious Effects –Coma –Respiratory centre depression –Seizures Other effects –Confusion –Memory loss –Disorientation –Delirium

17 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Case 2 24 yo female ingested 50 mls of Chlorpyrifos after an argument with her husband Forced emesis at the local hospital Arrived at the district hospital 4 hours later

18 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration A- Airway threatened, secretions present B - RR 20, O2 sats 79-90% on oxygen –Widespread creps and poor air entry C- P80 BP 100/70 D- Pupils 2mm –GCS 10/15 (M5 V2 E3) about V on the A V P U scale

19 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration

20 Fasiculations

21 Intermediate Syndrome Delayed Respiratory Failure –Proximal muscle weakness and CN lesions –Typically 1-4 days after cholinergic crisis has resolved Prolonged Effects on Nicotinic receptors Primary motor end plate degeneration Clinical importance –Delayed respiratory failure leads to death if not aware of it or prepared for it Wadia et. al 1974 : “Type II Paralysis, Senanayake and Karalliedde 1987”

22 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Chronic Effects Organophosphate induced delayed neuropathy (OPIDN) 1-3weeks Peripheral neuropathy Axonopathy due to Neuropathy Target Esterases (NTE) Chronic organophosphate induced neuropsychiatric disorder (COPIND)

23 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration

24 Difference in OPs - Toxicity 3 most common OP’s ingested in NCP –Chlorpyrifos (Diethly OP) –Dimethoate & Fenthion (Dimethly OP) Higher case fatality and intubation rates –in Dimethoate (CFR 23%, Intu 35%) and Fenthion (CFR 16%, Intu 31%) –compared with Chlorpyrifos (CFR 8%, Intu 15%)

25 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Clinical Variation Risk: Relative human toxicity of pesticides in self-poisoning chlorpyrifos fenthion dimethoate Case fatality ratio (95% CI) Eddleston M et al Differences between organophosphorus insecticides in human self- poisoning: a prospective cohort study. Lancet X symptomatic X X X Di ethyl Di methyl

26 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration AChE inhibition responded poorly to oxime therapy in the 2 Dimethyl OP’s Short half life of Ageing –(Dimethly vs Diethyl) Difference in OPs - Toxicity

27 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Different rates of OP - AChE inhibition, reactivation and ageing t 1/2 inhibition –Milliseconds for both diMethyl and diEthyl OPs Eddleston M, Eyer P, Worek F, Mohamed F, et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet Oct 22-28;366(9495): t1/2 Spontaneous reactivation –0.7 hr for diMethyl –31 hrs for diEthyl t1/2 of Ageing –3.7 hrs for diMethyl –33 hrs for diEthyl

28 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Time to Death Eddleston M, Eyer P, Worek F, Mohamed F, et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet Oct 22-28;366(9495):1452-9

29 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration ChlorpyrifosDimethoate Fenthion Median (IQR) Hours to Adm 4 (2 to 5) 3 (2 to 5) 4 (2 to 7) Admission values Mean [OP] (uM) Median PChE (mU/ml) Median AChE (mU/  mol Hb) MedianAged AChE 19.4%71.9%70.3% Eddleston M, Eyer P, Worek F, Mohamed F, et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet Oct 22-28;366(9495):1452-9

30 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Effectiveness of 1 gram pralidoxime treatment Chlorpyrifos Dimethoate

31 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Dimethyl OPs - specific features Oximes less effective Dimethoate patients died sooner –Hypotensive shock Fenthion patients had higher incidence of delayed respiratory failure –Initially few symptoms –Later required intubation

32 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Management ?

33 Management The priorities in management are : Resuscitation! –A,B,C,D,E Atropinisation of symptomatic patients Decontamination Other Treatments - Oximes

34 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Resuscitation of OP poisoned patients ABCDE – Careful attention to management of “airway + breathing” ATROPINE is part of A, B, and C and –administer simultaneously to resuscitation GI Decontamination is NOT a life saving procedure! –Should not be performed before resuscitation

35 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Respiratory Failure in OP patients Review of 376 OP poisoned patients in NCP 1 –90pts (24%) required intubation 52 (58%) intubated within 2 hours 46 (51%) died –29 (32%) Well on admission but required intubation >24hrs 1 Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH et al. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 2006;99(8):

36 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration When OP Patients were intubated in NCP Eddleston et al. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 2006;99(8): Fenthion <2hours All OP’s 2-24hours >24hours

37 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Atropine administration in OP poisoning Indications How fast to give For how long Toxicity of Atropine

38 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Indications for AtropineSpeed of intial Atropinisation Indications Atropinisation – Endpoint Poor air entry in lungs caused bronchospasm and bronchorrhoea Hypotension Bradycardia Excessive sweating (Miosis) Chest Clear Systolic BP >80mmHg Heart rate >80/min Dry Axillae Pupils no longer pinpoint Atropine

39 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Speed of intial Atropinisation Study looked at severely poisoned OP patients in Sri Lanka –22 patients, all required intubation, but survived to discharge –Mean dose of atropine required 23.4mg (range 1- 75mg) Eddleston et al. Speed of initial atropinisation in significant organophosphorus pesticide poisoning--a systematic comparison of recommended regimens. J.Toxicol.Clin.Toxicol. 2004;42(6): Text book recommendations for atropinisation varied markedly –Average patient 23.4mg – (8 to 1380 mins) –Severely ill patient 75mg – (25 to 4440 mins)

40 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Suggested Atropine Regimen Loading –Doubling dose regime e.g mgs every 5 minutes Maintenance –Continuous infusion < 3mg/hr –10-20% of loading dose/hour Endpoints –Clear chest on auscultation with no wheeze –Heart rate >80 beats/min

41 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration What if you give too much Atropine ? Anticholinergic Syndrome: –Hot as hell –Blind as a bat –Red as a beet –Dry as a bone –Mad as a hatter CVS - Severe Tachycardia (eg HR >120) Risk of ischaemia in elderly patients CNS - Confusion, Agitation Hyperthemia

42 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Gastrointestinal Decontamination ?

43 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Risks Aspiration Trauma Electrolyte Imbalances Cardiac Arrest Cost Benefits Removal of poison load Prevention of ongoing poison absorption More beneficial in Toxic OP’s Gastrointestinal Decontamination

44 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Gastrointestinal Decontamination Options: Nothing Emesis Gastric Lavage Activated Charcoal

45 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Risk of Intervention Aspiration Trauma –Oesphageal Injury –Nasopharyngeal injury 1. Eddleston M, Haggalla S, Reginald K, Sudarshan K, Senthilkumaran M, Karalliedde L, et al. The hazards of gastric lavage for intentional self-poisoning in a resource poor location. Clin Toxicol (Phila) 2007;45(2):

46 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Risk of Intervention Electrolyte Abnormalities Cardiac Arrest –Increased Vagal Tone especially with toxin induced bradycardia Induced emesis, Lavage Cost

47 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Summary of Experimental Evidence GI decontamination should be done in ideal settings –Means to protect airway –Expertise to carry out procedure safely Little benefit in outcomes after 1 hour Position statement: single-dose activated charcoal. J Toxicol Clin Toxicol 1997;35: Position statement and practice guidelines on the use of multi- dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:

48 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Decontamination for OPs Within 1 hour –Gastric lavage if no contraindications Able to protect airway GCS >12 –Followed by single dose AC 1-2 hours – debatable –In some centres the above treatment is acceptable > 2 hours ingestion –No place for Gastric Lavage or AC

49 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Oximes ?

50 Oximes Ineffective in some situations –Ageing –Variation between organophosphates Effective protocols not established –Variation in use Zero – 24 grams a day Expensive USA $ / gram India $6- 9 / gram Sri Lanka 55 cents / gram Unlikely to address Non-ACh effects

51 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Oxime treatment?

52 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Oxime Dose and Administration Most common Oxime dose in Asia is 1g every 4- 6hrs (ie 4-6g/day) – is this the best?? 1990’s Randomised trials compared12g infusion over 3-4 days, with 1g bolus and placeabo They concluded no benefit from pralidoxime, and increased mortality –No loading dose used – inadequate levels Johnson et al “Evaluation of two treatment regimens of pralidoxime (1gm single bolus dose vs 12gm infusion) in management of OP Poisoning. J Assoc Physicians Indi. 1996; Cherian et al “Effectiveness of oximes (PAM- Pralidoxime) in the treatment of organophosphorus poisoning (OPP) a randomised, double blind placaebo controlled clinical trial. J Assoc Physicians India. 1997;

53 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Early RCTs - Low dose Pam, NO Bolus Loading dose (0.16g/hr infusion without bolus in 50kg person) Suggested therapeutic plasma level of Oxime

54 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration More Recent Oxime Dose and Administration studies Pawar et al Lancet 2006 OP Poisoned patients treated in India 200 OP patients given 2g bolus and then, randomised either –1g “bolus” every 4 hours for 48hours (Control) –1g “continuous infusion” every hour for 48hours (Study) Pawar et al. “Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial.” Lancet 2006: 368:

55 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Results Pawar et al Lancet 2006 Study group (High dose PAM infusion) :- Required less atropine in 1 st 24hours –6mg vs 30mg (median dose) Lower intubation Rates –64% in Study Patients vs 88% in Controls Shorter duration of ventilatory support –5 days vs 10 days Lower mortality (1% vs 8%) Lower incidence of pneumonia

56 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Pralidoxime plama conc. Reproduced from - Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:

57 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Oxime Dose and Administration Pawar et al Lancet 2006 –Short time to admission (median 2h) Early PAM Results may not be reproduceable to many other South Asian settings –No measurement of acetylcholinesterase or neuromuscular function to explain a causal link of findings with dose of Oxime –Specific pesticide type not recorded (eg dimethy / diethyl) –Underpowered trial size –No reproduceable algorithm for atropine dosing or pralidoxime cessation –Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:

58 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Acetylcholinesterase Assays Biomarkers of Exposure to Organophosphorus insecticide –Plasma cholinesterase(PChE) Sensetive but Not specific –Red cell acetylcholinestersase (RBC-AChE) Correlates better with AChE at synapse Different levels of inhibition with different OP agents –Chlorpyrifos vs Dimethoate Uses –Confirmation of diagnosis –Severity

59 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Testmate ChE Designed for occupational exposure Quantitative test RBC-AChE and PChE Ellman method 4 minutes

60 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Alternate sites for antidotes Protect AChE Supply AChE Reduce ACh Protect ACh Receptor Reduce OP Load Multiple Mechanisms

61 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Other Treatments under investigation Magnesium Reduces acetylcholine release Blockage pre-synaptic calcium channels Limited human studies Clonidine Decrease the presynaptic synthesis and release of acetylcholine. Central nervous system > peripheral cholinergic synapses Diazepam Diazepam reduces respiratory failure (rats) and cognitive deficit (primates) Postulate “uncoordinated stimulation of the respiratory centres decreases phrenic nerve output”.

62 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration OP Poisoning -Summary Epidemiology Mechanism –Muscarinic, Nicotinic, CNS effects –Causing “Respiratory failure” and Death Treatment –Resucitation is the mainstay –ABCD’s include Atropine –Decontamination may be useful in certain circumstances –Oximes may be more useful in high dose regimens if administered early

63 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration With thanks to: SACTRC Associate Professor Nick Buckley Professor Andrew Dawson Dr Mark Perera Dr A Aroona Asfir Ox-Col Study Team Dr Michael Eddleston Consultant Physicians NCP Medical and Nursing Staff of: Dr S Jayamanne Polonnaruwa General Hospital Dr Hettiarachchi Peradeniya Teaching Hospital Consultant Physicians Peradeniya Dr I Gawaramanna Dr K Kularatne

64 Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration Wikitox Resource on Clinical toxicology –Upload and Download teaching and learning info Multiple sources Free acess to all

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