7/23/2019 1-s2.0-S0140673607612021-main (1)

1/14

Review

Management of acute organophosphorus pesticide poisoning

Michael Eddleston, Nick A Buckley, Peter Eyer, Andrew H Dawson

Organophosphorus pesticide self-poisoning is an important clinical problem in ruralregions of the developing world, and kills an estimated 200 000 people every year.Unintentional poisoning kills far fewer people but is a problem in places where highlytoxic organophosphorus pesticides are available. edical management is di!cult,with case fatality generally more than "#$. %e describe the limited evidence thatcan guide therapy and the factors that should be considered when designing furtherclinical studies. #0 years after &rst use, we still do not know how the core treatments'atropine, oximes, and dia(epam'should best be given. )mportant constraints in thecollection of useful data have included the late recognition of great variability inactivity and action of the individual pesticides, and the care needed cholinesteraseassays for results to be comparable between studies. *owever, consensus suggeststhat early resuscitation with atropine, oxygen, respiratory support, and +uids isneeded to improve oxygen delivery to tissues. he role of oximes is not completelyclear they might bene&t only patients poisoned by speci&c pesticides or patientswith moderate poisoning. mall studies suggest bene&t from new treatments such as

magnesium sulphate, but much larger trials are needed. /astric lavage could have arole but should only be undertaken once the patient is stable. andomised controlledtrials are underway in rural 1sia to assess the eectiveness of these therapies.*owever, some organophosphorus pesticides might prove very di!cult to treat withcurrent therapies, such that bans on particular pesticides could be the only methodto substantially reduce the case fatality after poisoning. )mproved medicalmanagement of organophosphorus poisoning should result in a reduction inworldwide deaths from suicide.

Lance t 2003 45"6#758905Published Online

August 15, 2007

DOI:10.1016/S0140-

6736(0761202-1

See :omment!"ge53# See 1rticles!"ge57$ See :ase eport!"ge 622

:entre for ropicaledicine, ;u!eld, >'g"'!h's!h"te>, '

>'g"i+ !h's!h'us> "d >!'is'ig> ' >t'?i+it>. e did 't

li8it the se"+h b l"gu"ge@ h'ee, e h"d li8ited "bilit t'

t"sl"te !"!es '8 hi" hee 8" studies h"e bee

d'e. "sl"ti' ' hiese !"!es "s thee'e 'deed

"++'dig t' ele"+e, est"blished b eie ' &glish

"bst"+ts. e "ls' used i'8"ti' '8 'u +'tiuig studies

i Si B"" th"t h"e e+uited 8'e th" 2000 !"tiets

!'is'ed ith 'g"'!h's!h"te, "d '8 dis+ussi's ith

+lii+i"s seeig su+h !"tiets "+'ss Asi".

Figure 1: Management of a patient with severe organophosphorus poisoning in a Sri Lankan district hospital

he "bse+e ' itesie-+"e beds "d etil"t's 8e"s th"t u+'s+i'us !"tiets "e eCuetl itub"ted "d

etil"ted ' the '!e "d. his igue is e!'du+ed ith !e8issi' '8 the +'es!'dig "uth'.

.thel"+et.+'8 Vol 371 Feruary 1!" #$$% &'7

7/23/2019 1-s2.0-S0140673607612021-main (1)

2/14

Review

'es!'de+e t': %i+h"el

&ddlest', S+'ttish P'is's

I'8"ti' *ue"u, )e

'"l Ii8", &dibugh

&16 4SA, 9

eddlestonm(yahoo)com

*athophysiologyOrganophosphorus pesticides inhibit esteraseen8ymes, especially acetylcholinesterase /(2...9* in synapses and on red-cellmembranes, and butyrylcholines-terase /(2...:* in plasma.17 Although acutebutyrylcholinesterase inhibition does not seemto cause clinical features, acetylcholinesteraseinhibition results in accumulation ofacetylcholine and o+erstimulation ofacetylcholine receptors in synapses of theautonomic ner+ous system, (;, andneuromuscular junctions.17 ronchorrhoea Miosis achrymation 3rination #iarrhoea

'ypotension >radycardia ?omiting ali+ation

Features due to overstimulation of nicotinic

acetylcholine receptors in the sympathetic system

7/23/2019 1-s2.0-S0140673607612021-main (1)

3/14

Review

(ontinued from pre+ious page*

Red cell acetylcholinesterase assays

utyrylcholinesterase

400$00

300

200600

%3H-*

100300

0 0

6 1500

5 1200>utyrylcholinesterase

7enthion%KM*

4$00

3

2600

%3H-*

1300

0

0 24 4# 72 $6 120 144

i8e (h'us

Figure 2: 2se of utyrylcholinesterase recovery as a marker of organophosphorus pesticide elimination in

04 dimethoate and 4 fenthion poisoning

Di8eth'"te is hd'!hili+ "d "!idl e?+eted '8 the b'd. Pl"s8" butl+h'lieste"se "+tiitthee'e begis t' ise "g"i ithi t' d"s ' igesti'. * +'t"st, ethi' is "t s'luble "d sl'l

edistibutes it' the bl''d "te iiti"l distibuti' it' the "t. As " esult, ethi' is dete+t"ble i the

bl''d ' 8" d"s "d butl+h'lieste"se "+tiit e8"is ihibited.

7/23/2019 1-s2.0-S0140673607612021-main (1)

4/14

&''

7/23/2019 1-s2.0-S0140673607612021-main (1)

5/14

Review

Panel 3: Summary of treatment#$"31"3#

(hec airay, breathing, and circulation. =lace patient in theleft lateral position, preferably ith head loer than the feet, toreduce ris of aspiration of stomach contents. =ro+ide high Loo$ygen, if a+ailable. )ntubate the patient if their airay orbreathing is compromised

Obtain intra+enous access and gi+e 12 mg of atropine as a bolus,depending on se+erity. et up an infusion of 0I% normal salineaim to eep the systolic blood pressure abo+e :0 mm 'g and urineoutput abo+e 0I5 mHgHh

@ecord pulse rate, blood pressure, pupil si8e, presence of seat, andauscultatory ndings at time of rst atropine dose

Ni+e pralido$ime chloride " g or obido$ime "50 mg*intra+enously o+er "0120 min into a second cannula follo ithan infusion of pralido$ime 0I51 gHh or obido$ime 20 mgHhr* in0I% normal saline

5 min after gi+ing atropine, chec pulse, blood pressure, pupil si8e,seat, and chest sounds. )f no impro+ement has taen place, gi+edouble the original dose of atropine

(ontinue to re+ie e+ery 5 min gi+e doubling doses ofatropine if response is still absent. Once parameters ha+ebegun to impro+e, cease dose doubling. imilar or smallerdoses can be used

Ni+e atropine boluses until the heart rate is more than :0 beatsper minute, the systolic blood pressure is more than :0 mm 'g,and the chest is clear appreciating that atropine ill not clearfocal areas of aspiration*. eating stops in most cases. Atachycardia is not a contraindication to atropine since it can becaused by many factors panel *.

7/23/2019 1-s2.0-S0140673607612021-main (1)

6/14

Review

patient has a patent airay and ade4uatebreathing and circulation. )deally, o$ygenshould be pro+ided at the rst opportunity.'oe+er, little e+idence supports the commonad+ice that atropine must not be gi+en untilo$ygen is a+ailable.17,1$,4$,50 )n hospitals thatha+e no access to o$ygen, atropine should begi+en early to patients ith pesticide poisoningto reduce secretions and impro+e respiratoryfunction.32actors aecting outcome in organophosphoruspesticide self-poisoning

urma, but as a 2% poder in ri ana

Alyl sub-groups most pesticides ha+e either to methyl groupsattached +ia o$ygen atoms to the phosphate dimethylorganophosphorus* or to ethyl groups diethylorganophosphates* gure 2*. Acetylcholinesterase ageing ismuch faster for dimethyl poisoning than for diethyl poisoning,therefore to be eecti+e, o$imes must be gi+en 4uicly topatients ith dimethyl poisoning panel 5*. A fe pesticidesha+e atypical structures, ith another alyl group eg, propyl inprofenofos* attached to the phosphate group +ia a sulphuratom.

7/23/2019 1-s2.0-S0140673607612021-main (1)

7/14

Review

0 P"."thi'( P"'?' + ui"l!h'sO 40

O 4 0 O 4 0 )5 2 5

5 5O P O 4 0

5

)O5 2

0 )O5 2

0, 2

2O P O 4

5 2O P O 4

5

S, 2 , 2

S O )

/ %'('+.'t'!h's 6 P.'/e('/'s F P.'thi'!h's

0 0 O 40 * I

3 S 40 S 405 5 543 ) 4 4E 4 O P O 4 3 5

3 7 5 3 7

O P O 425 O P O 4205,O 403 ,O , ,

I O I S

Figure 3: +hemical classes of organophosphorus pesticidesStu+tues ' 'g"'!h's!h'us !esti+ides '8 diethl (A, *, , di8ethl (D, "d S-"ll (&, +l"sses. %'st

'g"'!h's!h'us !esti+ides "e thi'"tes, ith " d'uble-b'ded sul!hu "t'8 lied t' the !h's!h"te (A, , th"t eeds t' be +'eted t' the "+tie '?' (eg, A t' *. A e 'g"'!h's!h'us !esti+ides "e '?'s (eg, D,

& "d d' 't eed "+ti"ti'@ the "e "ble t' ihibit "+etl+h'lieste"se die+tl "s s'' "s the "e "bs'bed.

atropine for control of sei8ures induced byinhaled organophosphorus ner+e agents.60'oe+er, e$tra-pyramidal eects and sei8uresare not common features of organophosphoruspoisoning.$,21

Atropine ill probably remain theantimuscarinic agent of choice until high-4uality randomised trials sho anothermuscarinic antagonist to ha+e a better benet-to-harm ratio because it is a+ailable idely,aordable, and moderately able to penetrateinto the (;. ;o non randomised controlled

trials ha+e compared dierent regimens ofatropine for either loading or continuationtherapy. As a result, many dierentrecommendations ha+e been made!a "00Cre+ie noted more than 20 dosing regimens,some of hich ould tae many hours to gi+ethe full loading dose of atropine.15

7/23/2019 1-s2.0-S0140673607612021-main (1)

8/14

Review

0 600 A+et-l+h'li(este."se "+tiit- i( it.'

'b* A+et-l+h'li(este."se "+tiit- i( i'

500

%m3HKmo

l

400

Acetylcholinesteras

e

300

200

100

0

600

'b*

500

%m3HKmo

l

400

Acetylcholinesteras

e

300

200

100

+0

600

'b*

500

%m3HKmo

l

400

Acetylcholinesteras

e

300

200

100

0

0 24 4# 72 $6

i8e (h'us

Figure 4: Bariable response to oximes ofacetylcholinesterase inhibited bydierent classes oforganophosphorus pesticides

A+etl+h'lieste"se "s e"+ti"ted ull (A Cui"l!h's, " diethl

!esti+ide@ !"ti"ll (* '?de8et'-8ethl, " di8ethl !esti+ide, ' 't "t "ll

( !'e''s, " S-"ll !esti+ide b '?i8es "te !'is'ig. he "'

sh's the ti8e ' ist d'se ' !"lid'?i8e. )'8"l "+etl+h'lieste"se

"+tiit is "b'ut 600 89/F8'l b. I-it' "+etl+h'lieste"se "+tiit

sh's h' 8u+h ' the eG8e +" be e"+ti"ted, i.e. h' 8u+h ' it

h"s 't et "ged (i these thee +"ses, ' "d8issi' he the ist d'se

' !"lid'?i8e "s gie, A: H#5, *: H50, : 5, ' the eG8e "s

't "ged. All !"tiets !eseted t' h's!it"l ithi 4 h.

acetylcholinesterase ageing panel 5* inducedby these dierent pesticides. )nterestingly, the>aramati#2 study did not nd a dierence inbenet of high-dose pralido$ime in moderatedimethyl or diethyl organophosphoruspoisoning. 7urther studies are needed toestablish hether this benet remains forse+ere poisoning.

)nterpretation of clinical e+idence regardingo$imes should tae into account this +ariability inresponse of dierent pesticides.6$

7/23/2019 1-s2.0-S0140673607612021-main (1)

9/14

Panel 5: Reactions of acetylcholinesterase after

inhiitionwith organophosphorus

)nhibited acetylcholinesterase reacti+atesspontaneously but sloly.

7/23/2019 1-s2.0-S0140673607612021-main (1)

10/14

Review

en9odia9epines

=atients poisoned ith organophosphorusfre4uently de+elop agitated delirium.

7/23/2019 1-s2.0-S0140673607612021-main (1)

11/14

Review

en8yme before e$posure to organophosphorusner+e gases.106uch a prophylactic approach isnot practical for self-poisoning ithorganophosphorus because e cannot predicthen a person is going to ingest the pesticide.

ucley ;A, Paralliedde , #ason A, enanayae ;, /ddleston M.&here is the e+idence for the management of pesticide poisoning! is clinical to$icology ddling hile the de+eloping orld burnsW

&o'icol (lin &o'icol "00C;#

7/23/2019 1-s2.0-S0140673607612021-main (1)

12/14

!$&

7/23/2019 1-s2.0-S0140673607612021-main (1)

13/14

Review

" &adia @, adagopan (, Amin @>, ardesai '?. ;eurologicalmanifestations of organophosphate insecticide poisoning. Neurol Neurosur* Psych 9C37untic A, , Marrs utterorth 'einemann, " 5C215C.

50 @eigart V@, @oberts V@. Organophosphate insecticides.)n @ecognition and management of pesticidepoisonings, 5th edn. &ashington #(, OBce of=esticide =rograms, 3 /n+ironmental =rotectionAgency, 2C1C9.

5 ?ance M?, elden >, (lar @7. Optimal patient position fortransport and initial management of to$ic ingestions.

Ann E!er* Med "#1ardin =N, +an /eden 7. Organophosphate poisoninggrading the se+erity and comparing treatment beteenatropine and glycopyrrolate. (rit (are Med0 1%ero+itch M, @eiss A, >ulostein M, Po8er/. copolamine treatment for se+ere e$tra-pyramidalsigns folloing organophosphate chlorpyrifos*ingestion. (lin &o'icol"005 ;3ucley ;A. =ralido$ime for organophosphatepoisoning. Lancet "0063!%

7/23/2019 1-s2.0-S0140673607612021-main (1)

14/14

Review

6 /ddleston M, 8inic8 , /yer =, >ucley ;. O$imes inacute organophosphorus pesticide poisoning asystematic re+ie of clinical trials. Q Med"00" '&, ary ), Altuntas 7. ouchard ;(, >ecer M, Nert8 , 'oman @. 77= inorganophosphate poisoning hatJs the secret ingredientW(lin &o'icol "005;3