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Review article published in APICON UPDATE, Assam 2009Management of acute organophosphorus pesticide poisoningDr. L.J.Basumatary MD, DM (Neuro) trainee

GMCH, Guwahati

drbasumatary@gmail.com

INTRODUCTION

Organophosphate (OP) based pesticides are widely used and have emergedas the major contributor to ill health associated with pesticides worldwide.1

Though accidental poisoning can occur following exposure or inhalation,serious poisoning often follows suicidal ingestion.2 Since agriculture is themain occupation in Assam and due to easy availability of OP pesticides theyare commonly consumed for the purpose of suicide.

RegionTotalsuicides

Pesticide suicides(% of all suicides)

Plausible range ofpesticide suicides

Africa 34,000 7,800 (22.9) 5,200 to 21,910

Americas 63,000 3,105 (4.9) 1,974 to 8,715

EasternMediterranean

34,000 5,629 (16.5) 4,501 to 7,022

Europe 163,000 6,080 (3.7) 1,872 to 9,170

South East Asia 246,000 51,050 (20.7) 47,720 to 82,680

Western Pacific 331,000 184,570 (55.8) 172,730 to 196,410

Global 873,000 258,234 (30%)

233,997 (27%) to

325,907 (37%)

Table 1:Global and regional estimates of pesticide suicides each year

(The global and regional estimates of pesticide suicides were calculated as artof a systematic review conducted by Gunnell et al 2007). 3

Brief History:

OP compound were first synthesized in the early 1800s when Lassaignereacted alcohol with phosphoric acid. Shortly thereafter in 1854, Philip deClermount described the synthesis of tetraethyl pyrophosphate at a meetingof the French Academy of Sciences. Eighty years later, Lange, in Berlin, and,Schrader, a chemist at Bayer AG, Germany, investigated the use oforganophosphates as insecticides. However, the German military preventedthe use of organophosphates as insecticides and instead developed anarsenal of chemical warfare agents (ie, tabun, sarin, soman). A fourth agent,VX, was synthesized in England a decade later. During World War II, in 1941,organophosphates were reintroduced worldwide for pesticide use, asoriginally intended.4

Massive organophosphate intoxication from suicidal and accidental events,such as the Jamaican ginger palsy incident when an OP derivative

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contaminated bootleg whisky and caused a neurological syndrome GingerJake Paralysis which crippled as many as 50,000 persons in the USA in1930, led to the discovery of the mechanism of action of organophosphates5.In 1995, a religious sect, Aum Shinrikyo, used sarin to poison people on aTokyo subway. In 2005, 15 victims were poisoned after accidentally ingesting

ethion-contaminated food in a social ceremony in Magrawa, India. Nerveagents have also been used in various battles, notably in Iraq in the 1980s.

Pathophysiology

Organophosphate (OP) compounds are a diverse group of chemicals thatinclude: insecticides (malathion, parathion, diazinon, fenthion, dichlorvos,chlorpyrifos, ethion), nerve gases (soman, sarin, tabun, VX), ophthalmicagents (echothiophate, isoflurophate), and antihelmintics (trichlorfon).Herbicides (tribufos [DEF], merphos) are tricresyl phosphatecontainingindustrial chemicals.

The primary mechanism of action of organophosphate pesticides is inhibitionof carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). AChEis an enzyme that degrades the neurotransmitter acetylcholine (ACh) intocholine and acetic acid. ACh is found in the central and peripheral nervoussystem, neuromuscular junctions, and red blood cells (RBCs). The twoprincipal human cholinesterases are acetylcholinesterase (AChE) foundprimarily in nervous tissue and erythrocytes and butyrylcholinesterase(BChE) found in liver and plasma. Both enzymes are of pharmacological andtoxicological importance, BChE is used to detect the early, acute effects of OPpoisoning while AChE is used to evaluate long-term or chronic exposure

Organophosphates inactivate AChE by phosphorylating the serine hydroxylgroup located at the active site of AChE. The phosphorylation occurs by lossof an organophosphate leaving group and establishment of a covalent bondwith AChE.

Once AChE has been inactivated, ACh accumulates throughout the nervoussystem, resulting in overstimulation of muscarinic and nicotinic receptors.Clinical effects are manifested via activation of the autonomic and centralnervous systems and at nicotinic receptors on skeletal muscle.

Once an organophosphate binds to AChE, the enzyme can undergo 1 of thefollowing 3 processes:

1. Endogenous hydrolysis of the phosphorylated enzyme by esterases orparaoxonases

2. Reactivation by a strong nucleophile such as pralidoxime (2-PAM)3. Complete binding and inactivation (aging) 6-9

Clinical Features:

Symptoms of acute organophosphate poisoning develop during or afterexposer, within minutes to hours, depending on the mode of contact. Exposer

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by inhalation results in the fastest appearance of toxic symptoms,followed bythe gastrointestinal route and finally dermal route.

Signs and symptoms of organophosphate poisoning can be divided into 3broad categories, including (1) muscarinic effects, (2) nicotinic effects, and (3)

CNS effects.10

(a) Muscarinic EffectsRespiratory: Rhinorrhea, bronchorrhea, bronchospasm, cough,

severe respiratory distressCardiovascular : Bradycardia, hypotensionGastrointestinal: Hypersalivation, nausea,vomiting, abdominal pain,

diarrhea, fecal incontinenceGenitourinary : IncontinenceOcular : Blurred vision, miosisGlands : Increased lacrimation, diaphoresis

(b) Nicotinic Effects : Muscle fasciculations,cramping, weakness, anddiaphragmatic failure.

Autonomic nicotinic effects:Hypertension, tachycardia,mydriasis,andpallor.

(c) CNS effects: anxiety, emotional lability,restlessness, confusion,ataxia, tremors,seizures, and coma.

Paralysis:

Acute organophosphate poisoning (OPP) can result in three types of paralysis.11-13

Type I: This condition is described as acute paralysis due to continueddepolarization at the neuromuscular junction during acute cholinergic crisis.The Acute cholinergic phase usually passes off within 48-72 hours butcomplete clinical recovery from all the effects may take up to a week.Treatment is supportive with oximes, atropine and mechanical ventilation, in

addition to gastric lavage and decontamination.

Type II (intermediate syndrome): So named because of its temporalappearance between the early type I syndrome and the later OPIDP, occurs12-96 hours after exposure of organophosphate and associated with cranial,proximal limb and respiratory muscle weakness with relative sparing of distalmuscle groups. Intermediate syndrome persists for 4-18 days, symptoms donot respond well to oximes and atropine therefore treatment is mainlysupportive. The incidence of IMS in different studies has been reported to bebetween 20-68%. It has been commonly associated with OPCs like diazinon,dimethoate, methylparathion, methamidaphos, monocrotophos, fenthion and

ethylparathion. Despite its common occurrence, data on the risk factors ofIMS, early diagnosis and prediction have remained elusive. Commonly used

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tests such as levels of plasma cholinesterase correlate poorly with the onsetof IMS

The pathogenic mechanisms that lead to IS have not been clearly elucidated.De Bleecker et al suggested that the slow release of organophosphates from

deep tissues and the persistent inhibition of acetylcholinesterase may underliethe development of IS. Electrophysiological studies of De Bleeckerdemonstrated both pre- and post-synaptic defects in OPP while Avasthi andSingh suggested desensitization of acetylcholine receptors being responsiblefor IS.

Type III: Organophosphate-induced delayed polyneuropathy (OPIDP) is anuncommon clinical condition occurs 2-3 weeks after exposure to large dosesof certain OPs and is due to inhibition of neuropathy target esterase. Distalmuscle weakness with relative sparing of the neck muscles, cranial nerves,and proximal muscle groups characterizes OPIDP. The underlying pathology

of OPIDP is central-peripheral axonal degeneration with clinical symptomsappearing after a latent period of 7-21 days. Recovery can take up to 12months.

Neuropsychiatric effects: Impaired memory, confusion, irritability, lethargy,psychosis, and chronic organophosphate-induced neuropsychiatric disordershave been reported. Although the mechanism is not proven.

Extrapyramidal effects: These are characterized by dystonia, cogwheelrigidity, and parkinsonian features (basal ganglia impairment after recoveryfrom acute toxicity).

Other neurological and/or psychological effects: Guillain-Barrlike syndromeand isolated bilateral recurrent laryngeal nerve palsy are possible.

Treatment:

Diagnosis is most often possible by a detailed history and clinicalexamination. If poisoning is probable, treatment should be initiatedimmediately without waiting for laboratory confirmation.

Blood sample should be drawn to measure plasma pseudocholinesterase andred blood cell AchE levels. Depressions of plasma pseudocholinesteraseand/or RBC acetylcholinesterase enzyme activities are generally availablebiochemical indicators of excessive organophosphate absorption.

Initial assessment of the poisoned patient

This follows standard practice with preservation of the airway, provision ofoxygen and resuscitation.

Atropine Sulfate: Since the only life-saving antidotes for pesticide poisoning

are oxygen and atropine, and oxygen has already been given, the mostimportant issue after resuscitation is to decide whether the patient has taken a

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Glycopyrolate has been studied as an alternative to atropine and found to havesimilar outcome using continuous infusion. In a study by Bardin PG et al 1990,7.5 mg of glycopyrolate were added to 200ml of saline and infusion was titratedto the desired effects of dry mucus membranes and heart rate above 60bpm.Theapparent advantage to this regimen was a decreased number of respiratory

infections. This may represent an alternative when there is concern forrespiratory infection due to excessive and difficult to control secretions and in thepresence of altered level of consciousness where the distinction betweenatropine toxicity or relapse of organophosphate poisoning is less clear.18

OXIMES

Pralidoxime is the oxime most often used worldwide and occurs in twocommon forms: pralidoxime chloride (2-PAM) and mesylate (P2S). Itreactivates cholinesterase by removing the phosphoryl group bound to theesteratic site. The great majority of its effects are on the peripheral nervous

system, since its lipid solubility is low and entry into the central nervoussystem (CNS) limited, but may also reverse the CNS effects of OP.Pralidoxime has been shown to be effective in sarin-poisoned mice, rats,rabbits and dogs. Also, it has therapeutic efficacy against acute toxicity ofdichlorvos.This drug is not effective in soman and tabunpoisoning.Pralidoxime becomes ineffective as an antidote when administeredmore than 24 to 48 hours postexposure as a result of aging of thephosphateester bond. Pralidoxime also slows the process of aging ofphosphorylated acetylcholinesterase to a nonreactivatable form and detoxifiescertain OPs by direct chemical actions. In spite of numerous studies, themechanism of action of pralidoxime in human OP poisoning is still unknown.19

Also, further studies are required to investigate the effects of high doses ofpralidoxime in common known of OP poisoning(Table 3)

Dosage of Pralidoxime:

The dose of pralidoxime commonly recommended in the literature for thetreatment of organophosphorus poisoning in adults is a 30 mg/kg bolus,followed by a continuous infusion of 8 mg/kg/hr20. This dose is used to rapidlyachieve and maintain a concentration of pralidoxime above 4 mg/L. This issometimes referred to as the WHO recommended dose. 21

The recommended dose of pralidoxime is based on the chloride salt; doses for other

pralidoxime salts (iodide, mesilate and metilsulfate) are calculated by converting the

recommended pralidoxime chloride dose into equivalent dosing units (see Table 2).

Some authors have expressed concern about the amount of pralidoxime iodide

required to achieve the recommended target as high levels of iodide may increase the

risk of thyroid toxicity. 22

Table 2 : Equivalent dosing units of pralidoxime salts

Salt Equivalent dose (g)

Pralidoxime chloride 1

Pralidoxime mesilate 1.34

Pralidoxime metilsulfate 1.43Pralidoxime iodide 1.53

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Table3: Results of systematic reviews assessing the comparativeeffectiveness of pralidoxime

Systematic review (year) Results/conclusions

Eddleston (2002)

Descriptive analysis of Abdollahi(1995), Samuel (1995), Cherian(1997) and Dadan (1999)

Conclusion: A generalisedstatement that pralidoxime shouldnot be used in OP poisoning is notsupported by the published results

Buckley (2005)

Descriptive analysis of Samuel(1995) and Cherian (1997)

Conclusion: Current evidence isinsufficient to indicate whetheroximes are harmful or beneficial inthe management of acuteorganophosphorus pesticidepoisoning

Bairy (2006)

Descriptive analysis of De Silva(1992), Abdollahi (1995), Samuel(1995), Cherian (1997), Balali-Mood (1998), Cherian (2005),Chugh (2005), and Dadan (1999)

Conclusion: The clinical benefits ofoximes in OP poisoning remainsunclear

Peter (2006)

Meta-analysis of Duval (1991), DeSilva (1992), Abdollahi (1995),Cherian (1997), Balali-Mood(1998), Sungur (2001) and Cherian(2005)

o Oxime therapy was notassociated with a statisticallysignificant difference in mortality

(RD 0.09, 95% CI -0.08, 0.27);need for mechanical ventilation (RD

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0.16, 95% CI -0.07, 0.38),incidence of intermediate syndrome(RD 0.16, 95% CI -0.12, 0.45)compared to standard care.

o Oxime therapy was associatedwith a statistically significantincrease in the need for intensivecare (RD 0.19, 95% CI 0.01, 0.36)compared to standard care

Conclusion: Based on the currentavailable data on humanorganophosphate poisoning, oximetherapy was associated with eithera null effect or possible harm

Rahimi (2006)

Meta-analysis of De Silva (1992),Abdollahi (1995), Cherian (1997),Balali-Mood (1998), Sungur (2001)and Cherian (2005)

Oxime therapy was associated witha statistically significant increase inmortality (RR 2.17, 95% CI 1.34,3.51); need for mechanicalventilation (RR 1.53, 95% CI 1.16,2.02), incidence of intermediatesyndrome (RR 1.57,

The systematic reviews all acknowledged the limitations of the current evidencebase (primarily the small sample size, poor methodology and inadequatereporting). Eddleston et al (2002), Buckley et al (2005) and Bairy et al (2005)indicated that the current evidence is too weak to draw conclusions.23 HoweverPeteret al(2005) ,Rahimi et al(2005) conclude that even with the limitations, the

current evidence indicates that pralidoxime is not effective in the treatment oforganophosphate poisoning.24

Blood pressure should be monitored during administration because ofoccasional occuence of hypertensive crisis.If intravenous injection is notpossible PAM may be given by deep intramuscular route.

Gastrointestinal decontamination:

The efficacy of gastric lavage falls rapidly with time since ingestion 25. By thetime most patients arrive in hospital, the majority of pesticide will have passed

into the small bowel, out of the reach of gastric lavage. Some diluted solventmay be left in the stomach this will smell of pesticide if sucked out with a

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NG tube. The volume of fluid in the stomach will appear large in cholinergicpoisoning due to the secretion of fluid into the bowel 26.There is currently no evidence that either single or multiple dose regimens ofactivated charcoal result in clinical benefit .27-28

Seizure control:The Benzodiazepines (diazepam or lorazepam) are the agents of choice asinitial therapy.

Observation:Close observation for a period of at least 72 hours to ensure that Muscarinicsymptoms do not recur as atropine is withdrawn. In very severe poisoning byingested OP, particularly the more lipophilic and slowly hydrolysedcompounds, metabolic disposition may require as many as 5-14 days.In somecases, this slow elimination may combine with profound cholinesteraseinhibition to require atropinization for several days or even weeks. As dosage

is reduced, the lung bases should be checked frequently for crackles. Ifcrackles are heard, or other Muscarinic signs,atropinization must be re-established promptly.

Figure 1: Clinical pathway for the management of patients with acuteorganophosphorus poisoning(Roberts DM, Aaron CK (2007), Managing acuteorganophosphorus pesticide poisoning, British Medical Journal334: 629-634.)29

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Conclusion

Medical management of severe cholinergic pesticide poisoning is difficult, withhigh mortality. Some patients will die no matter how well managed. However,careful resuscitation with appropriate use of antidotes, followed by goodsupportive care and observation, should minimise the number of deaths in theperiod after admission to hospital.

REFERENCES:

1. Eddleston M. Patterns and problems of deliberate self poisoning in the developing

world. QJM 2000; 93:715-731.2. Dutoit PW, Maller FO, Ventonder WM, Ungerer MJ. Experience with intensive caremanagement of organophosphate insecticide poisoning. S Afr Med J 1981; 60:227-9.

3. Gunnell D, Eddleston M, Phillips MR, Konradsen F (2007), The global distribution offatal pesticide self-poisoning: systematic review, BMC Public Health 357

4. Sudakin DL, Power LE. Organophosphate exposures in the United States: alongitudinal analysis of incidents reported to poison centers.

J Toxicol Environ Health A. Jan 15 2007;70(2):141-7.5. Morgan JP, Penovich P. Jamaica ginger paralysis: fourty seven

year follow-up. Arch Neurol 1978;35:530-2.6. Mehrani H. Simplified procedures for purification and stabilization of human plasma

butylcholinesterase. Process Biochem 2004; 39: 877-882.7. Arufe MI, Romero JL, Gamero JJ, Mereno MJ. Oxidation of cholinesterase-inhibiting

pesticides: A simple experiment to illustrate the role of bioactivation in the toxicity ofchemicals. Biochem Educat2000; 28: 174-177.

8. McQueen MJ. Clinical and analytical considerations in the utilization of cholinesterasemeasurements. Clinica Chimica Acta 1995; 237: 91-105.

9. Sungur M, Guven M. Intensive care management of organophosphate nsecticidepoisoning. Crit Care 2001; 5(4): 211-215.

10. Johnson MK, Vale JA. Clinical Management of Acute Organophosphate poisoning: Anoverview in Clinical and Experimental Toxicology of Organophosphates andCarbamates. (Ballantyne B,Marrs TC, eds.) Oxford :Butterworth Heinemann,1992:528-535.

11. Wadia RS, Sadagopan C, Amin RB, Sardesai HV.Neurological manifestations oforganophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry 1974; 37 :

841-7.12. Senanayake N, Karalliedde L.Neurotoxic effects of organophosphorus insecticides.

An intermediate syndrome.N Engl J Med 1987; 316 : 761-3.13. Karalliedde L. Organophosphorus poisoning and anaesthesia. Anaesthesia 1999; 54 :

1073-88.14. B Ballantyne, TC Marrs: Overview of the biological and clinical aspects of

organophosphates and carbamates. In Clinical and experimental toxicology oforganophosphates and carbamates. Edited by Ballantyne B, Marrs TC. Oxford:Butterworth heinemann; 1992:3-14.

15. International Programme on Chemical Safety. Antidotes for poisoning byorganophosphorus pesticides. Monograph on atropine.http://www.intox.org/databank/documents/antidote/antidote/atropine.htm . 2002.

16. Goswami R, Chaudhuri A and Mahashur AA. Study of respiratory failure in

organophosphateand carbamate poisoning. heart Lung 1994;23:466-72 Roberts

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