Organophosphorus compounds are widely used as pesticides and were also developed as nerve agents. They work by inhibiting the enzyme acetylcholinesterase, leading to excess acetylcholine in the body and cholinergic toxicity. Management of organophosphate poisoning involves atropinization to counteract effects, with incremental atropine dosing shown to be better than bolus dosing. While pralidoxime is recommended to reactivate acetylcholinesterase, clinical trials show no clear benefit and potential for harm. Three types of paralysis can occur - acute cholinergic crisis, intermediate syndrome, and organophosphate-induced delayed polyneuropathy. Further research is still needed on many aspects of management

1. ORGANOPHOSPHORUS
POISONING
TO X I D R O M E A N D C U R R E N T C O N C E P T S O F
M A N A G E M E N T
Dr. Anoop James
DNB Trainee, Emergency Medicine
PIMS & RC

2. THE BEGINNING • Lassaigne - first synthesized in the early
1800s by reaction of alcohol with
phosphoric acid.
• Gerhard Schrader - December 23, 1936 –
accidental discovery of Tabun.
• 1938 – Sarin - Schrader, Ambrose,
Rüdiger and van der Linde
• 1944 - Soman - discovered by Richard
Kuhn
• 4th nerve agent – VX

3. ORGANOPHOSPHATES
• Organic compounds containing phosphorus group
• Widely used in agricultural sector as PESTICIDES.
• Toxic and lethal effects in humans
• Leading agent for poisoning in the developing world

4. AGENTS OF
POISONING
0
200
400
600
800
1000
1200
1400
1600
Death Cases
Dr. Bishan Rajapakse – OP Update (Port Hedland – Jan 31st ,
2012)

5. LIST OF COMMON OP POISONS
Dimethylated Diethylated S - ALKYL Others
Mononchrotophos
(TATA MONO)
Methyleparathion
(METACIL)
Duchlorvos (DDVP)
Dimethoate
(ROGORIN)
Phorate (THIMATE)
Parachion/diethylepar
athion
Chlorpyruphos
(LETHAL)
Propanofos 50%
(BANJO/PARABAL)
Acephate (ASATOP)
Trimethoate
Thiamate
Propophenos
Monochlorphos
Triazophos
Malathion
• Acetylcholinesterase ageing is much faster for dimethyl poisoning (shorter half life) than for
diethyl poisoning (longer half life), so management would have to occur sooner for
dimethyl poisoning
(Eddleston et al., 2008)

6. NORMAL
PHYSIOLOGY

8. MOA:
• Bind to acetylcholinesterase (AChE)
rendering enzyme non-functional
• Overabundance of ACh at neuronal
synapses
• Resultant cholinergic toxicity
• Over time (dependent on OP
agent), AChE-OP compound
undergoes conformational change
(‘aging’) rendering enzyme
irreversibly resistant to reactivation
by antidotal oximes

9. HOW DO ORGANOPHOSPHATES
WORK?
COVALENT
BOND
AGING

10. FATE OF ACETYL CHOLINESTERASE
Once bound, AChE has 1 of 3 possible fates:
– Endogenous hydrolysis of the phosphorylated enzyme by esterases or
paraoxonases
OR
– Reactivation by a strong nucleophile such as pralidoxime (2-PAM)
OR
– Irreversible binding and permanent enzyme inactivation (aging)

11. TOXIDROME
From time of ingestion, when would you expect clinical features of OP
poisoning to manifest?
• Great variability in toxicity and treatment response depending on OP agent
• Generally, oral/respiratory exposures result in clinical manifestations within
3 hours
• Dermal routes can take up to 12 hours

12. CLINICAL FEATURES
What are the types of paralysis that OP poisoning can cause?
 Type I – acute cholinergic crisis
 Type II – intermediate syndrome
 Type III – organophosphate induced delayed
polyneuropathy (OPIDP)

13. TYPE 1 (ACUTE CHOLINERGIC CRISIS)
• Seen in initial stages and due to persistent depolarisation
SLUDGE/BBB
Salivation
Lacrimation
Urination
Defecation, diaphoresis
Gastric Emesis
/
Bronchorrhea
Bronchospasm
Bradycardia*
DUMBELS
Defecation, diaphoresis
Urination
Miosis*
Bronchorrhea/Bronchospasm/Bradycardia*
Emesis
Lacrimation
Salivation
* Sometimes mydriasis and tachycardia observed as sympathetic
ganglia also contain nicotinic receptors
Nicotinic effects – fasciculations, muscle weakness, paralysis
CNS effects – central respiratory depression, lethargy, seizures, coma

14. TYPE 1 (ACUTE CHOLINERGIC CRISIS)
• Cardiac
• Cardiac arrhythmias – heart block, QTc prolongation
• Myocardial ischemia – elevated troponin and changes on ECG
• Respiratory
• Respiratory failure – combination of CNS resp. centre depression,
neuromuscular weakness, excessive respiratory secretions and
bronchoconstriction

15. TYPE 2 (INTERMEDIATE SYNDROME)
• 24-48 hours after poisoning, often when
acute cholinergic syndrome signs
decreased/gone
(take care!)
• 10-40% of patients
• Exact pathology not clear
• No clear association between particular
OP pesticide and development of
syndrome
• Persists for 14-20 days
• Resolution within 2-3 weeks (with
adequate supportive care eg. ventilatory
support)
• Recovery usually without sequelae
• Weakness of muscles of
respiration (diaphragm,
intercostal muscles, accessory
muscles including neck muscles)
• Weakness of proximal limb
muscles
• Others – cranial nerve
abnormalities, decreased deep
tendon reflexes
What are the characteristic clinical
findings in intermediate
syndrome?

16. TYPE 3 (ORGANOPHOSPHATE INDUCED
DELAYED POLYNEUROPATHY – OPIDP)
• 2-3 weeks after poisoning
• Distal degeneration of axons of both peripheral and CNS
• Clinical features
• Transient painful ‘stock & glove’ paraesthesias followed by a symmetrical motor polyneuropathy
characterised by flaccid weakness of lower extremities which ascends to involve upper extremities
• High-stepping gait associated with bilateral foot drop
• Predominantly distal but can involve proximal in severe neurotoxicity
• Risk of development independent of severity of acute cholinergic toxicity
• Recovery 6-12 months – spastic ataxia may be permanent outcome of OPIDP

17. DELAYED ORGANOPHOSPHATE
ENCEPHALOPATHY (DOPE)
• “CNS intermediate”
• New syndrome recognised and described in 2008
• Clinical features
• Normal sensorium then progression to coma days after poisoning (delayed coma)
• Miosed non-reacting pupils
• Extra-pyramidal signs – dystonia, resting tremor, cog-wheel rigidity, choreo-athetosis
• Investigations
• EEG – bi hemispheric slow waves (features consistent with encephalopathy)
• CT brain and CSF analysis normal
• Persistently low pseudo-cholinesterase levels and increasing atropine requirements during
coma
• Prognosis excellent with adequate supportive care

18. Current Concepts In
Management Of
Organophosphate
Poisoning

19. RESUSCITATION
• Airway – Early Intubation to secure
airway and prevent aspiration
• Breathing – Ensure adequate
ventilation
• Circulation – Obtain large bore IV
access. Start IV fluids if victim is in
hypotension
• Decontamination – Remove any
remnants of the toxin in contact with
the patient.

20. GOALS OF TREATMENT
Reduce absorption of toxin
Enhance elimination
Neutralize toxin

21. REDUCE ABSORPTION
• Removal from skin, eyes and hair
• Emesis induction
• Gastric Lavage
• Activated charcoal and cathartics
• Whole bowel irrigation
• Endoscopic or surgical removal of ingested chemical

22. ATROPINIZATION
Adequacy of atropinization
Mandatory targets:
• SBP > 90 mm Hg
• Hr > 110/min
• Clear lung fields
Other targets:
• Pupils mid position
• Bowel sounds just present

23. TARGETS ON SUBSEQUENT DAYS
• Day 2: HR > 100/min
• Day 3: HR > 90/min
• Subsequent days: At least 80/min

24. ATROPINIZATION DOSE
Two approaches:
1. Bolus Dose Adminstration: 2-5 mg Atropine every 10-15 min
followed by maintainance using reduced doses
2. Incremental dose administration with rapid
escalation:
1.8 – 3 mg Atropine by iv infusion ---- repeat every 5 min interval doubling the dose each
time ----- 10 - 20% of atropine required for atropininzation every hour by iv infusion

25. Atropine 2 – 3 mg by iv bolus
Double the dose every 5 min
until atropinization occurs
10 – 20% of atropine required for
atropinization as hourly
infusion

26. BOLUS DOSE VS INCREMENTAL DOSE
• Incremental dose clearly better in relation to the outcomes of
death and intermediate syndrome.
• Superior to Bolus Dose Regime
• Recommended as standard of care
Studies by Abedin and Blain PG

27. ATROPINE VS GLYCOPYRROLATE
• Respiratory and CNS complications less with Glycopyrrolate
• Role of Glycopyrrolate alone or in combination with Atropine is
not yet clear
• Not recommended – more evidence required

28. ROLE OF PRALIDOXIME
• Nucleophilic agents – reactivate bound acetylcholinesterase
• Pralidoxime, Obidoxime, Trimedoxime
• WHO recommendation - (30 mg/kg pralidoxime chloride
bolus followed by 8 mg/kg/hour infusion)

29. TRIALS WITH OXIMES
• Cherian et al. JAPI 1997. No bolus. 12 g of pralidoxime chloride over
3 days
• Pawar et al. Lancet 2006. 2 g loading, then 2 g/hour pralidoxime
iodide over 48 hours (50 gm total dose)
• Eddleston M, et al. 2009. 2 g loading dose then 0.5 g/hour
pralidoxime chloride for maximum 7 days (maximum possible dose
86 g)

30. LARGEST OXIME TRIAL
• 235 patients, pralidoxime = 121, saline = 114
• 2 g loading dose over 20 minutes. Then 0.5 g/hour for
maximum 7 days
• Continued till atropine not required for 12–24 hours or
death

31. SUMMARY OF TRIALS
• Overall null effect or potential harm with oximes on meta-
analysis of trials
• The largest oxime study tend to harm
• Only one study showed a reduction in mortality

34. WHY THERE IS NO BENEFIT?

35. Oxime Dose
• Methodological flaws in study designs
• Oxime doses varied widely
• Substantial delays to treatment
• Type of OP not taken into account
• Cost of oximes.

36. Eddleston study:
– Reactivation happens with diethyl but not dimethyl
– No difference in mortality
– Median pseudocholinesterase levels were lower in survivors
who received placebo than those who died with pralidoxime.
Type of Compound

37. Toxicity of Antidote
• Oximes by themselves can cause muscle weakness
• Rapid infusion causes dizziness, flushing, numbness
• Formation of stable phosphoryl oximes with high
anticholinesterase activity.

38. Only one RCT compared the World Health Organization
(WHO) recommended doses with placebo. This trial showed
no clinical benefits and a trend toward harm in all
subgroups, despite clear evidence that these doses
reactivated acetylcholinesterase in the blood.

39. INFERENCE
• Current evidence is insufficient to indicate whether oximes are harmful
or beneficial.
• The WHO recommended regimen is not supported
• Large excess of OP reinhibits reactivated enzymes – not useful in severe
poisoning
• Further RCTs are required to examine other strategies and regimens.

40. Does fresh frozen plasma leads to
improvement in health outcomes in
organophosphate poisoning?

41. Two trials:
1. One trial compared the effect of ‘FFP versus no intervention’
2. One trial compared the effect of ‘FFP versus albumin and saline’
The meta-analysis of the results indicated that the administration
of FFP to patients with OP poisoning may be harmful with respect
to the outcome of death and duration of hospital stay.
Inference: Current research data is inconclusive regarding the role
of
bio scavenger therapy.

42. ROLE OF CLONIDINE IN OPP
 Centrally acting alpha-2 receptor agonist.
 Inhibits presynaptic release of acetylcholine – decreases the cholinergic
symptoms caused by organophosphate poisoning.
 Synergistic action with atropine.
 Sedation, hypotension, bradycardia, rebound hypertension
 Bolus injection (0.15–0.30 mg) followed by an infusion at the rate of 0.5
mg/24 hours

43. ACTIVATED CHARCOAL
• No high quality RCTs to support the benefit of activated
charcoal use in acute organophosphate poisoning.
• Also there is no evidence of harm.

44. GASTRIC LAVAGE
 Decreases absorption by 42% at 20 min
16% at 60 min
 Preferably in awake patients
 Choice of fluid is tap water: 5-10ml/kg
 No evidence that a larger tube is better
 No human studies showing benefit in OPP

45. ALKALINIZATION IN OPP
Using Sodium Bicarbonate
5 mEq/kg in 60 minutes followed by 5–6 mEq/kg/day was
shown to be useful.
Alkalinization products are shown to be less toxic.

46. MAGNESIUM SULPHATE
• Intravenous MgSO4 (4 g) given in the first day after admission have
been shown to decrease hospitalization period and improve outcomes
in patients with OP poisoning.
• Magnesium sulfate blocks calcium channels and thus reduces
acetylcholine release.
• Also reduces CNS overstimulation resulting from N-methyl D-aspartate
receptor (NMDAR) activation.

47. FORCED EMESIS
• No RCTs to address the issue
• By general consensus it is not advisable
• Interferes with life saving interventions
• Adverse effects of inducing agents

48. SUMMARIZING
• Remember there are 3 types of paralysis - do not miss any one of
them!
• Type I – ACUTE CHOLINERGIC
• Type II – INTERMEDIATE SYNDROME
• Type III – OPIDP
• DOPE
• Identify the Poison
• SLUDGE/BBB and DUMBELS (+ nicotinic and CNS effects)
• Management
• Incremental atropine doses
• MgSO4 – more research needed
• Role of oximes is controversial – more research needed

49. THANK YOU !