Managing Acute Org a No Phosphorus

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CLINICAL REVIEW

Managing acute organophosphoruspesticide poisoningDarren M Roberts,1 Cynthia K Aaron2

Organophosphorus pesticides are usedwidely for agri-culture, vector control, and domestic purposes.Despite the apparent benefits of these uses acuteorganophosphorus pesticidepoisoning is an increasing

worldwide problem, particularly in rural areas.Organophosphorus pesticides are the most importantcause of severe toxicity and death from acute poison-ing worldwide, with more than 200 000 deaths eachyear in developing countries.1 Although the incidenceof severe acute organophosphorus pesticide poisoningis much less in developed countries, many patientswith low dose acute unintentional or occupationalexposures present to health facilities.23 We providean evidence based review of the management ofacute organophosphorus pesticide poisoning.

Why do I need to know about acute organophosphorus

poisoning?

Household and agricultural products containingorganophosphorus pesticides are prevalent (box 1),allowing many opportunities for acute poisoning.Sincethecorrelationbetweenintent,dose,andseverityof toxicity after acute poisoning is poor, each exposurerequires a thorough review.2 A structured approach torisk assessment of exposed patients is necessary.5 Longterm complications occasionally occur so a rigorousassessment is required given potential legal implica-tions in unintentional, criminal, or occupational expo-sures.

Patients with moderate to severe organophosphoruspesticide poisoning usually require management in an

intensivecareunit.26 7 Mortalityfrom severe poisoningis high (10%)1 compared with the overall mortalityfrom pharmaceuticals (0.5%).w1 Current evidence sug-gests that prompt and appropriate managementoptimises outcomes (LB).

What is the pathophysiology of acute

organophosphorus poisoning?

The effects of organophosphorus compounds onhuman physiology are multipleand complex.Organo-phosphoruscompounds inhibit numerousenzymes,ofwhich esterases seem to be the most clinically impor-tant. Inhibition of acetylcholinesterase leads to the

accumulation of acetylcholine at cholinergic synapses,interfering with normal function of the autonomic,

somatic, and central nervous systems. This producesa range of clinical manifestations, known as the acutecholinergic crisis (box 2).8 9 The organophosphorus-esterase complex subsequently undergoes multiplespontaneous reactions (fig 1).

Although clinicians commonly think of organo-phosphorus compounds as an interchangeable class,

noticeable differences are observed between them inthe clinical manifestations of acute poisoning.89 11-13

This may result from differences inpharmacokinetics,81314 additional mechanisms of toxi-city such as oxidative stress,w3 dynamic physiologicaladaptations after prolonged stimulation,81214 differ-ences between patients,1315 or potency of enzymeinhibition.8 16

How is organophosphorus poisoning diagnosed?

A history of acute exposure to an organophosphoruspesticide and development of characteristic clinicaleffects (box 2) is diagnostic of organophosphorus

poisoning. When the history is not forthcoming, how-ever, the differential diagnosis is broad and may

This article is an abridgedversion; the full version is on

bmj.com: doi=10.1136/bmj.39134.566979.BE.

Box 1 | Sources of organophosphoruspesticides

Domestic Garden shedsin particular insecticidal preparations

butalso other products that aremarketed as fertilisers

but contain some organophosphorus pesticides,available as solid or liquid formulations

Surface and room sprays

Baits for cockroaches and other insects (for example,chlorpyrifos)

Shampoos against head lice (for example, malathion)

Pet preparations (for example, pet washes, collars)

Industrial or occupational Crop protection and livestock dipping

Large scale internal control, including fumigation

Terrorism or warfare (nerve agents)

Sarin, for example, was used in the Tokyo subwayattack, and both tabun and sarin were used during the

Iraq-Iran conflict. Although nerve agents share a similarmechanism of toxicity with organophosphoruspesticides, their treatment is a specialised topic andnot dealt with in this review

1South Asian Clinical ToxicologyResearch Collaboration, AustralianNational University2Regional Poison Center,Childrens Hospital of Michigan,

Detroit, MI 48201, USACorrespondence to: C K Aaron

[email protected]

BMJ 2007;334:629-34

doi: 10.1136/bmj.39134.566979.BE

Reviewerscommentsandauthorsresponses are on bmj.com

BMJ | 24 MARCH 2007 | VOLUME 334 629

For the full versions of these articles see bmj.com


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weakness so oximes are used clinically to reverse neu-romuscular blockade by reactivating the inhibitedacetylcholinesterase before ageing. Oximes should be

given as early as possible to limit the degree of ageing(fig1).8 The evidencesupportingthe efficacy of oximesand the dosing regimen is limited (UE).20 A recent ran-domised controlled trialusing pralidoxime iodide con-cludedthathighdosesweremoreeffectivethanalowerdose although further studies were recommended.21

Despite limitations in the current data and based onclinical experience, we recommend oxime use inpatients with moderate to severe organophosphoruspoisoning (UE)4 8 and benzodiazepines for patientswith agitation and seizures (LB).4 The table listsorganophosphorus triggered signs and symptoms andsomesuggested therapies in conjunction withantidotaltreatment (also see box 3 and figure 2).

Other antidotes and treatments have been proposedfor acute organophosphorus poisoning, but data sup-porting their efficacy are currently too limited torecommend their routine use.4 Several clinical trialsare in progress in Asia to tackle the limited evidenceon the efficacy of treatments for organophosphoruspoisoning.22

Auto-injectors, developed for use in exposures toorganophosphorus nerve agents, are available with afixed dose of muscarinic antagonist and oxime. Therole for these auto-injectors in the management ofacute organophosphorus pesticide poisoning is lim-ited, but they can be utilised when other forms of anti-

dotes are not available. Clinical experience suggeststhat the dose of atropine must be carefully titrated,and doses higher than those included in these formula-tions are usually required.7 HI-6 is an oxime that isincreasingly being included in auto-injectors becauseit is a more effective reactivator of acetylcholinesteraseinhibited by nerve agents compared with pralidoximeand obidoxime.

What considerations are needed for patients with mild

or no clinical toxicity, including skin exposures?

Patients who present with a history of unintentionalpoisoning who are asymptomatic or have mild symp-

toms, often do not require hospital admission (fig 2).Management priorities for these patients are rapid

triage, a detailed risk assessment, and considerationof forensic implications. If the exposure is consideredtrivial, the patient does not need medical review andcan be observed at home or in the workplace. Otherpatients should be decontaminated and monitoredclinically for a minimum of 6-12 hours. If possible,

cholinesterase activity should be measured to confirmwhether the exposureis significant. A normal cholines-terase activity six hours after exposure may be suffi-cient to exclude a major ingestion, although thisapproach has not been sufficiently assessed.

Patients with a single acute skin exposure rarelydevelop major clinical effects and probably do notrequire medical assessment. Volunteer studies docu-ment the risk of a skin exposure leading to significantclinical toxicity to be far below that of ingestion.Although the rate of organophosphorus absorptionacross the skin is slower than across the gut, patientswho are asymptomatic at 12 hours are unlikely to

develop toxicity. Such patients should be giveninstructions to present for medical review if there is anoticeable worseningof signs andsymptoms. If there isconcern about a skin exposure, testing for changes incholinesterase activity is recommended.

Box 2 | Clinicalfeatures of acute organophosphoruspoisoning8-10

Acute cholinergic crisis

The acute cholinergic crisis is caused by theaccumulation of acetylcholine at cholinergic synapses.The particular clinical features depends on the type ofreceptors stimulated and their location:

Muscarinic receptors: diarrhoea, urinary frequency,miosis, bradycardia, bronchorrhoea andbronchoconstriction, emesis, lacrimation, salivation(DUMBELS), and hypotension. Cardiac arrhythmiashave also been reported

Nicotinic receptors: fasciculations and muscleweakness, which may progress to paralysis andrespiratory failure,* mydriasis, tachycardia, andhypertension

Central nervous system: altered level ofconsciousness, respiratory failure,* and seizures; therelative contribution of cholinergic and otherneurotransmitters is not well characterised

*Respiratory failure occurs as a result of centrally or

peripherally mediated mechanisms. It may manifesteither during the acute cholinergic crisis (type Iparalysis) or during an apparent recovery phase(intermediate syndrome, or type II paralysis). Weaknessof neck flexors is an early sign of significant muscleweakness and may be useful for predicting the onset ofrespiratory failure.1112

Organophosphorus induced delayed polyneuropathy

Unrelated to acetylcholinesterase inhibition, thisoccurs because of inhibition of other enzymes, inparticular neurotoxic target esterase.Organophosphorus induced delayed polyneuropathy ischaracterised by demyelination of long nerves, whenneurological dysfunction occurs 1-3 weeks after anacute exposure, particularly motordysfunction but also

sensory dysfunction, which may be chronicor recurrent

Suggested symptom basedtreatment recommendations for

organophosphorus poisoning

Sign or symptom Recommended therapy

Excessive salivation,

lacrimation,nausea andvomiting, diarrhoea

Atropine, glycopyrrolate

Bronchorrhoea,bronchospasm

Atropine, ipratropium, glycopyrrolate

Hypotensi on Flui ds, atropine, v asopressors,inotropes

B radycardia Atropine, glycopyrrolate

Eye pain Mydriatics, c ycloplegics

Muscle weakness Oximes

Respiratory failure Intubationand ventilation,oximes

Seizures Benzodiazepines

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What considerations are needed for patients with

moderate and severe poisoning?

Patients with moderate or severe organophosphoruspoisoning should be admitted to an intensive careunit after resuscitation to allow careful titration of anti-dotes (fig 2), intubation, ventilation, and inotropes orvasopressors if required.7 Specialist advice from aclinical or medical toxicologist is recommended; onecan be contactedthrough thelocal poisons information

centre in many regions. Close observations are alsorequired because rapid clinical deterioration and

death are reported in patients who seemed to be reco-vering from the acute cholinergic crisis.6 11 High qual-ity general medical and nursing care is a priority forpatients given that the duration of admission may be

long and that secondary complications are an impor-tant cause of morbidity and mortality. If the facility is

Patient with history of acute exposure to organophosphorus compound

Detailed history, including typeof organophosphorus compound, route,

amount of exposure, and time

Unintentionalexposure(including skin)

Intentionalselfpoisoning

Regular reviews with or withoutquantification of cholinesterase

activity if available (UE)

Medically clear - consider disposition andpsychiatric review (LB)

Admit to intensive care unit for continuousclinical monitoring and ongoing titration

(including weaning) of atropine (LB).Oximes can be stopped either 12 hours

after atropine is stopped, or oncebutyrylcholinesterase is increasing (UE)

Universal precautions (LB). Discard and destroy all clothing

Minor toxicity*Asymptomatic or mild clinical symptomsNormal clinical observations (heart rate,blood pressure, respiratory rate, pulseoximetry), and

Acetylcholinesterase >80% of lowerreference range (butyrylcholinesteraseactivity may be completely inhibited)

Major toxicity*Central nervous system signs includingaltered mental status, or

Respiratory signs, orMuscle fasciculations or weakness, orHeart rate 100 beats/min or hypotension

Resuscitation (assessment and management of airway, breathing, circulation)and targeted clinical review (box 2) (LB)

Administer atropine (LB),oxime (UE), and

benzodiazepines (LB) as per box 3

Consider discharge to medical wardonce stable for 12 hours after oxime (UE)

Stable for 48 hoursafter discharge

from intensivecare unit (UE)

Increase indegree of

clinicaltoxicity

NoYes

Yes

Considerdecontamination(LB or UE), box 3

Acutedeterioration

Clinically stablefor 12 hours after

exposure (UE)

No

Fig 2 | Decision tree for management of patients presenting with history of acute

organophosphorus poisoning57-914 *Patients may have variable degrees of miosis, salivation,

diaphoresis, urinary frequency, or lacrimation, which may assist in diagnosis of

organophosphorus poisoning. Because these manifestations are not considered to influence

outcome they are not included in this decision tree.Assessment of respiratory status includes

respiratory rate and depth, presence of adventitious sounds such as rales and rhonchi,

presence of bronchorrhoea, and objective measurements of pulse oximetry, arterial blood

gases, and forced vital capacity or forced expiratory volume in one second.Muscle weakness:

difficulty in mobilisation or reduced forced vital capacity on spirometry before development of

paralysis and respiratory failure. Caution with patients with a history of exposure to fenthion

(or highly fat soluble organophosphorus compounds). Patients with fenthion poisonings are

usually characterised by minimal or absent cholinergic symptoms for 24-48 hours, after whichthey develop increasing muscle weakness and respiratory failure

Box 3 | Specific treatments for the routine managementof acute organophosphorus poisoning2 4 7 8 w6

Atropine (LB)

For poisoning in adults initially give 1-3 mg atropineintravenously (0.02 mg/kg in children). The main endpoints of atropinisation are a clear chest onauscultation with resolution of bronchorrhea (focalcrepitations or wheeze may be noted when there hasbeen pulmonary aspiration) and a heart rate of morethan 80 beats/min. If these targets are not achieved by3-5 minutes, double the intravenous dose. Continue todouble the dose and give intravenously every3-5 minutes until atropinisation has been achieved.Large doses (hundreds of mg) may be required in somepatients.Maintain atropinisation by infusion, starting with10%-20% of the loading dose every hour. Regularclinical observations are necessary to ensure thatatropinisation is achieved without toxicity (delirium,hyperthermia, and ileus)

Oximes (UE)Several oximes have beendeveloped,but two are morecommonly used for treatment of acuteorganophosphorus poisoning. They are administeredas an infusion which shouldbe continued until recovery(12 hours after stopping administration of atropine oronce butyrylcholinesterase is noted to increase)Pralidoxime chlorideloading dose of 30 mg/kgintravenously over 20 minutes, followed by an infusionof 8 mg/kg/h. In adults it is usually given as a 2 gloading dose followed by 500 mg/h. Various salts areavailable and their dose is determined by convertingthis doseintoequivalentdosing unitsfor example,1 gpralidoxime iodide is roughly equal to 650 mgpralidoxime chloride

Obidoximeloading dose of 4 mg/kg over 20 minutes,followed by an infusion of 0.5 mg/kg/h. In adults it isusually given as 250 mg loading dose followed by750 mg every 24 hours

Benzodiazepines (LB)

Benzodiazepines are usually given intravenously asrequired for agitation or seizureswith doses startingat: 5-10 mg diazepam (0.05-0.3 mg/kg/dose),lorazepam 2-4 mg (0.05-0.1 mg/kg/dose), ormidazolam 5-10 mg (0.15-0.2 mg/kg/dose)

Decontamination

Dermal spillswash pesticide spills from the patientwith soap and water and remove and discardcontaminated clothes, shoes and any other material

made from leather (LB)Gastric lavageconsider forpresentationswithin1 or 2hours, when theairway is protected. A single aspirationof the gastric contents may be as useful as lavage (UE)Activatedcharcoal without cathartic50g may begivenorallyor nasogastrically to patients who are cooperativeor intubated, particularlyif they areadmittedwithin oneor two hours or have severe toxicity (UE)

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Contributors: DMR drafted the initial manuscript which was then improvedafter discussion between DMR and CKA. Both authors are guarantors.

Competing interests: None declared.

1 EddlestonM. Patternsand problems of deliberate self-poisoninginthe developing world. QJMed2000;93:715-31.

2 Roberts DM,Fraser JF,Buckley NA,Venkatesh B. Experiencesofanticholinesterase pesticide poisonings in an Australian tertiary

hospital. Anaesth IntensiveCare2005;33:469-76.3 LaiMW, Klein-SchwartzW, Rodgers GC Jr, AbramskyL, Haber DA,

BronsteinAC, et al.2005 annualreport of the AmericanAssociationof Poison Control Centers national poisoning and exposuredatabase. J Toxicol Clin Toxicol 2006;44:803-932.

4 EddlestonM, Singh S, Buckley NA. Organophosphorus poisoning(acute). ClinEvid2005 Aug;(16):1744-55.

5 Daly FFS, Little M,MurrayL. A risk assessmentbased approachto themanagement of acutepoisoning.EmergMed J2006;23:396-9.

6 Sungur M, Gven M. Intensive care management oforganophosphate insecticide poisoning. Crit Care 2001;5:211-5.

7 EddlestonM, Dawson A, KarallieddeL, Dissanayake W, Hittarage A,Azher S, et al.Early managementafterself-poisoningwith anorganophosphorusor carbamatepesticidea treatment protocolforjunior doctors.Critical Care2004;8:R391-7.

8 Eyer P. The role of oximesin themanagementof organophosphoruspesticide poisoning. Toxicol Rev2003;22:165-90.

9 Namba T. Cholinesterase inhibition by organophosphoruscompounds and its clinical effects. Bull WorldHealthOrgan1971;44:289-307.

10 Lotti M, Moretto A. Organophosphate-induced delayedpolyneuropathy. Toxicol Rev2005;24:37-49.

11 Karalliedde L, Baker D, Marrs TC. Organophosphate-inducedintermediate syndrome: aetiology and relationships with myopathy.Toxicol Rev2006;25:1-14.

12 Eddleston M, Mohamed F, DaviesJOJ, Eyer P, Worek F, Sheriff MHR,et al. Respiratory failure in acute organophosphorus pesticideself-poisoning. QJMed2006;99:513-22.

13 EddlestonM, Eyer P, Worek F, Mohamed F, Senarathna L, VonMeyer L, et al. Differences between organophosphorus insecticides

in human self-poisoning: a prospective cohort study. Lancet2005;366:1452-9.

14 Lotti M. Cholinesterase inhibition: complexitiesin interpretation.ClinChem 1995;41:1814-8.

15 Eyer F,Meischner V, KiderlenD, Thiermann H,WorekF, HaberkornM,et al. Human parathion poisoning: a toxicokinetic analysis. ToxicolRev2003;22:143-63.

16 Worek F, Diepold C, Eyer P. Dimethylphosphoryl-inhibited humancholinesterases: inhibition, reactivation, and aging kinetics.Arch

Toxicol 1999;73:7-14.17 Carlock LL, Chen WL,GordonEB, Killeen JC,ManleyA, MeyerLS, etal.

Regulating and assessing risks of cholinesterase-inhibitingpesticides: divergent approaches and interpretations.J ToxicolEnviron HealthB Crit Rev1999;2:105-60.

18 Thiermann H, Szinicz L, Eyer P,Zilker T, WorekF. Correlationbetweenred blood cell acetylcholinesterase activity and neuromusculartransmission in organophosphate poisoning. ChemBiol Interact2005;157-158:345-7.

19 Nolan RJ,Rick DL,Freshour NL, Saunders JH. Chlorpyrifos:pharmacokinetics in human volunteers. Toxicol ApplPharmacol1984;73:8-15.

20 Buckley NA,Eddleston M, Szinicz L. Oximesfor acuteorganophosphate pesticide poisoning. CochraneDatabase Syst Rev2005 Jan 25;(1):CD005085.

21 PawarKS, Bhoite RR,PillayCP, ChavanSC, MalshikareDS, GaradSG.Continuous pralidoxime infusion versus repeatedbolus injection totreat organophosphorus pesticide poisoning: a randomisedcontrolled trial.Lancet2006;368:2136-41.

22 Buckley NA,Roberts D, EddlestonM. Overcoming apathy in researchon organophosphate poisoning.BMJ2004;329:1231-3.

23 Roberts D, Senarathna L. Secondary contamination inorganophosphate poisoning. QJ Med2004;97:697-8.

24 LittleM, MurrayL. Consensus statement: risk of nosocomialorganophosphate poisoningin emergency departments.EmergMedAustralas 2004;16:456-8.

25 Eddleston M, Juszczak E, Buckley NA,SenarathnaL, Mohamed F,Sheriff MHS, et al. Randomised controlled trialof routine singleormultiple dose superactivated charcoal for self-poisoning in a regionwith high mortality. ClinToxicol 2005;43:442-3.

A spot of botherThat Easter weekend I was on four night shifts. The firstnight was busy, and I went to sleep early the next day, buttypicallyIwasawakeagainwithinanhourandahalf:afirealarm hadbeen setoff by someone cooking in the hospitalaccommodation. Good start, I thought.

I eventually got back to sleep, but when I woke up thatevening I felt the familiar scratchy throat and slight achethat generally heralds a viral illness. I went to work hop-ingitwouldpass,but,astheeveningprogressed,Irapidlygot worse. My main anxiety was that I had two morenights which would be impossible to cover.

Needless to say, that night was one of the worst I veeverhadculminating in thetransfer to Birminghamof aboywho hadcome in moribund with intussusceptionandthe resuscitation of a hypothermic baby an hour before

handover. During this time I

d been popping para-cetamol and shivering my way through.InthemorningIwasinabadstate,anditwasclearthat

I wouldnt be able to cover my last two nights. My col-league was extremely supportiveand told me to go homeand leave the rest to her, which I gratefully did.

BythistimeIwasfeverishwithtemperatureinthehigh39s and a bad sore throat. The following day there wasa rash on my forehead and nose, the fevers continued,and I developed sore and ulcerated mucous membranes.The third day, with persisting fever and an exquisitelysore throat that made it impossible to eat or drink, I vis-ited the emergency general practitioner. He gave meamoxicillin, which I gladly took (against my medicalcommon sense).

Bythefourthdaymyeyeswereverysore,andmyown

general practitioner acknowledged that I looked

extremely sick and took blood samples. I requestedmeasles serology, as I was becoming suspicious despitehaving no obvious contacts. My overall condition wasnotgood. I couldnt take anythingorally, not even water,without a big dose of Difflam. Later that day, after therash had spread all over my body and my eyes hadbecome so sore that I couldnt keep them open, thediagnosis seemed certain.

As soon as I suspected measles I informed occupa-tional health, and (as I found out later) chaos ensued. Itseemed that I had been everywhere and seen everyoneduring my infective period, including several oncologypatients, sick neonates, and transfers to two tertiary cen-tres. Patients were isolated, colleagues were sent home.Everyone had blood tests, and many received the

measles, mumps, and rubella (MMR) vaccine.ItwasonlywhenIwenttothelocalchemisttopickupaprescription that I saw the headline in the local paper:Measles shuts childrens ward. I felt guilty for thetrouble I was causing and guilty for having so much timeoff work, and I still felt systemically dreadful. Gradually,however, the symptoms settled, and the diagnosis wasconfirmed by serology.

The whole experience was hard, but enlightening. Asdoctors, we feel guilty for being ill and almost feel com-pelled to soldier on. I was touched by the supportivenessof my colleagues, and I learnt a lot about public health. Iam now even more steadfast in my views on the impor-tance of MMR.

Simon Pirie paediatric specialist registrar, Gloucester Royal Hospital

[email protected]

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Managing Acute Org a No Phosphorus