OP POISOINING

1. Organophosphate Poisoning
Dr. Rajesh K. Mandal
MBBS(KU)
MD Internal Medicine( Bir Hospital,NAMS)
Department of Medicine,Bheri Hospital,Nepalgunj

2. History
OP compounds were first synthesized in the early 1800s when
Lassaigne reacted alcohol with phosphoric acid.
80 years later, Lange, in Berlin, and, Schrader, a chemist at
Germany, investigated the use of organophosphates as insecticides.
However, the German military prevented the use of OP as
insecticides and instead developed an arsenal of chemical warfare
agents.

3. During World War II, in 1941, OP were reintroduced worldwide for
pesticide use, as originally intended.
Massive organophosphate intoxication from suicidal and accidental
events, such as the Jamaican ginger palsy incident in 1930, led to
the discovery of the mechanism of action of organophosphates.
Sarin, delivered by rockets, was used in the chemical warfare attack
in Damascus, Syria in 2013.
Additionally, chemical weapons still pose a very real concern in this
age of terrorist activity.

4. Introduction
• Organophosphates are potent cholinesterase inhibitors
capable of causing severe cholinergic toxicity following
cutaneous exposure, inhalation, or ingestion.
• case fatality rate in developing countries in Asia is 5-20%
• used as insecticides worldwide for more than 50 years
• The use of these agents has declined in the last 10 to 20
years, in part due to the development of carbamate

5. • Medical applications of organophosphates include
– reversal of neuromuscular blockade
(neostigmine , pyridostigmine , edrophonium )
– treatment of glaucoma, myasthenia gravis, and Alzheimer
disease ( echothiophate , pyridostigmine, tacrine,
and donepezil ).

6. Epidemiology
• Worldwide, an estimated 3,000,000 people are exposed
to organophosphate agents each year,
• with up to 300,000 fatalities

13. Source of Exposure
• Generally from accidental or
intentional ingestion of, or
exposure to, agricultural
pesticides
• Other potential causes:
– ingestion of contaminated
fruit, flour, or cooking oil
– wearing contaminated
clothing

14. OP
compounds
Nerve
Agents
G Agents
Sarin, Tabun,
Soman
V Agents
VX, VE
Insecticides
Dimethyl
Compounds
Dichlorvuos,
Fenthion,
Malathion,
Methamidos
Diethyl
Compounds
Chlorpyrifos,
Diazinon,
Parathion,
Quinalphos

17. • Organophosphorus pesticides inhibit esterase enzymes,
– acetylcholinesterase in synapses and on red-cell membranes,
– butyrylcholin esterase in plasma.
• butyrylcholinesterase inhibition does not seem to cause clinical
features,

19. Ageing
• After some period of time,the acetylcholinesterase organophosphorous
compound undergoes a conformational changes known as ageing
• After ageing has taken place, new enzyme needs to be synthesised before
function can be can be restored
• ageing renders the enzyme irreversibly resistant to reactivation by an
antidotal oxime
• The rate of ageing is important
– Determines toxicity
– Rapid with dimethyl compounds: 3.7 hours
– Diethyl compounds: 31 hours
– Especially more rapid with nerve agents
• Soman: within minutes

20. • In addition, plasma cholinesterase (also called
butylcholinesterase [BuChE] or pseudocholinesterase)
• and neuropathy target esterase (NTE) are inhibited by
organophosphorus agents;
• however, the clinical significance of these interactions are
less certain

21. Clinical Features
• Onset and duration varies; depends on the
– organophosphorus agent's rate of AChE inhibition,
– the route of absorption,
– enzymatic conversion to active metabolites,
– and the lipophilicity
• Oral or respiratory exposures : within three hours,
• dermal absorption: may be delayed up to 12
hours.

22. • Lipophilic agents such as dichlofenthion, fenthion,
and malathion
– delayed onset of symptoms (up to 5 days)
– prolonged illness (greater than 30 days),
– related to rapid adipose fat uptake and delayed redistribution
from the fat stores

23. Acute Cholinergic Syndrome
• presents with manifestations of cholinergic excess
• Primary toxic effects involve the
– autonomic nervous system,
– neuromuscular junction,
– central nervous system (CNS)

25. • SLUDGE/BBB –
S alivation, L acrimation, U rination,D efecation, G astric E
mesis, B ronchorrhea, B ronchospasm, B radycardia
• DUMBELS –
D efecation, U rination, M iosis, B ronchorrhea/Bronchospas
m/Bradycardia, E mesis, L acrimation,S alivation

27. • nicotinic effects
– fasciculations,
– muscle weakness,
– paralysis
• Nicotinic and muscarinic receptors also have been
identified in the brain, and may contribute to
central respiratory depression, lethargy, seizures,
and coma

28. • Cardiac arrhythmias, including heart block and QTc
prolongation: occasionally observed
• unclear whether due to direct toxicity or secondary
hypoxemia.
• acute pancreatitis may complicate poisoning

29. • Respiratory issues :
• Fatalities from acute OP poisoning results from
• respiratory failure due to a combination of
• depression of the CNS respiratory center,
• neuromuscular weakness,
• excessive respiratory secretions, and
• bronchoconstriction.
• Fatality also occurs due to cardiovascular collapse
• Survivors may have neurobehavioral deficits such
as decreased memory, abstraction, and
Parkinsonism, which may be permanent

31. Intermediate(neurologic) Syndrome
• 10 to 40 percent of patients poisoned
• develop a distinct neurologic disorder 24 to 96 hours
after exposure (1-4 days)
• consists of characteristic neurological findings
including
– Weakness that rapidly spread from the ocular muscle
– neck flexion weakness,
– decreased deep tendon reflexes,
– cranial nerve abnormalities,
– proximal muscle weakness,
– Weakness of muscles of respiration: results in respiratory
insufficiency.

32. • Risk factors for
– exposure to a highly fat-soluble organophosphorus agent
– related to inadequate doses of oximes
• Clinical deterioration and improvement appear to
correlate with red blood cell (RBC)
acetylcholinesterase levels.
• Nerve conduction studies reveal unique
postsynaptic abnormalities that differentiate this
disorder from delayed neurotoxicity

33. • No specific treatment
• Supportive care: maintenance of airway and ventilation
• With adequate supportive care, including prolonged
mechanical ventilation, most patients have complete
resolution of neurologic dysfunction within two to three
weeks.

34. Delayed and long term neuropathy/
OPIDN
• Rare complication
• typically occurs 2-3 weeks after ingestion of one of a
small number of specific organophosphorus agents,
including chlorpyrifos
• It is a mixed sensory/motor polyneuropathy
• Especially affects long myelinated neurons
• Appears to result from inhibition of neuropathy target
esterase(NTE) rather than alteration of RBC AChE

36. • Mechanism involve inhibition of
neuropathy target esterase (NTE),
– is found in the brain, peripheral nerves, and
lymphocytes,
– is responsible for the metabolism of various
esters within the cell

37. • Muscle cramps, numbness and painful "stocking-
glove" paresthesias
• Followed by symmetrical motor polyneuropathy
characterized by flaccid weakness of the lower
extremities, which ascends to involve the upper
extremities
• primarily affects distal muscle groups,
• Paralysis of the lower limb is associated with foot
drop and a high stepping gait, progressing to
paraplegia
• Upper limb: wrist drop
• Initially tendon reflexes are reduced or lost, but
later mild spasticity develops

38. • Electromyograms and nerve conduction studies of
affected patients reveal decreased firing of motor
conduction units
• Histopathologic sections of peripheral nerves reveal
Wallerian degeneration of large distal axons
• No specific therapy
• Regular Physiotherapy may limit deformitiy caused
by muscle wasting
• Recovery is often incomplete
• Substantial functional recover after 1-2 years may
occur, especialy in younger patients

39. DIAGNOSIS
• Definite history of ingestion
• clinical grounds
– In the absence of a known ingestion or exposure
– Many organophosphorus agents have a characteristic
petroleum or garlic-like odor

40. • every effort should be made to precisely identify the agent
• imperative to determine if a dimethyl or a diethyl poison
was involved
• Dimethyl compounds undergo rapid aging:
– early initiation of oxime therapy critical;
• diethyl compounds exhibit delayed toxicity,
– may require prolonged treatment

41. – Direct measurement of RBC acetylcholinesterase activity
prodes a measure of degree of toxicity
– may be used to determise effectiveness of oxime therapy in
regeneration of enzyme
– test is not available in most of the laboratories
– plasma or pseudo acetylcholinesterase actiity is more easily
performed
– but doesnot correlate well with severity of poisoning and should
not be used to guide therapy

42. • Many organophosphorus pesticides are more
potent inhibitors of butyrylcholinesterase than they
are of acetylcholinesterase
• can be used to detect exposure to an
organophosphorus or carbamate pesticide
• Daily assays can be used to monitor when
enzyme activity starts to rise again,

44. Atropine Challenge test
• if diagnosis is in doubt whether an organophosphate or
carbamate
• 1 mg IV in adults (0.01 to 0.02 mg/kgin child)
• Absence of anticholinergic signs (tachycardia, mydriasis,
decreased bowel sounds, dry skin) strongly suggests
poisoning with organophosphate

45. POP score

46. Management
• Check airway, breathing, and circulation.
• Place patient in the left lateral position, preferably with
head lower than the feet, to reduce risk of aspiration of
stomach contents.
• Provide high flow oxygen
• Obtain intravenous access
• Intubate the patient if their airway or breathing is
compromised
• avoid succinylcholine for intubation(metabolished by
AChE)

48. Atropine
• Atropine 2 to 5 mg iv for adults and 0.05mg/kg iv for
children at begining
• Record pulse rate, blood pressure, pupil size, presence of
sweat, and auscultatory findings at time of first atropine
dose
• 5 min after giving atropine, check pulse, blood pressure,
pupil size, sweat, and chest sounds.
• If no improvement has taken place, give double the
original dose of atropine
• dose should be doubled every 3 to 5 min until pulmonary
muscarinic signs and symptoms are alleviated.

49. pralidoxime
• Cholinesterase reactivating agent
• Give pralidoxime chloride 30mg/kg intravenously over 30
min into a second cannula; (25 to 50mg/kg for children)
• rapid administration has been occasionally associated
with cardiac arrest
• follow with continous infusion of pralidoxime 8mg/kg/h in
0·9% normal saline (10 to 20 mg/kg/hr for children)

50. • Continue to review every 5 min; give doubling doses
of atropine if response is still absent.
• Once parameters have begun to improve, cease
dose doubling.
• GOAL:
– clearing of respiratory secretions and the cessation of
bronchoconstriction with
– normalised oxygen saturation
– systolic blood pressure > 80 mmHg,
– pulse > 80 beats/min
• Tachycardia and mydriasis are NOT appropriate
markers for therapeutic improvement,
– may indicate continued hypoxia, hypovolemia, or
sympathetic stimulation

51. • Clinical judgment is needed about additional
doses of atropine
– if the heart rate and blood pressure are slightly below
their targets but the chest is clear.
• Severe hypotension might benefit from
vasopressors.
• Once the patient is stable, start an infusion of
atropine giving every hour about 10–20% of the
total dose needed to stabilise the patient

52. • Check the patient often to see if too much
or too little atropine is being given.
• If too little is given, cholinergic features will
re-emerge after some time.
• If too much is given,
– patients will become agitated and pyrexia,
– and develop absent bowel sounds and urinary
retention.
– stop the infusion and wait 30–60 min for these
features to settle
– start again at a lower infusion rate

53. • Continue to review respiratory function.
• Intubate and ventilate patients
– if tidal volume is below 5 mL/kg
– or vital capacity is below 15 mL/kg,
– or if they have apnoeic spells,
– or PaO2 is less than 8 kPa (60 mm Hg)
– or FI O2 of more than 60%
• Assess flexor neck strength regularly in conscious
patients
• Any sign of weakness: risk of developing respiratory
failure (intermediate syndrome).
• Tidal volume should be checked every 4 h in such
patients.

54. • Treat agitation by reviewing the dose of atropine being
given and provide adequate sedation with
benzodiazepines.
• Physical restraint of agitated patients in warm conditions
– risks severe hyperthermia,
– exacerbated greatly by atropine because it inhibits normal
thermoregulatory responses, including sweating.

55. • Monitor frequently for recurring cholinergic crises.
• Such crises can occur for several days to weeks after
ingestion of some organophosphorus.
• Patients with recurring cholinergic features will need
retreatment with atropine and oxime

56. • Immediate endotracheal intubation
– If Moderately to severely poisoned patients with
markedly depressed mental status
– MILDLY POISONED PATIENTS may rapidly develop
respiratory failure.
– avoid the use of succinylcholine when performing
rapid sequence intubation (RSI)
– Succinylcholine is metabolized by AchE
– Nondepolarizing neuromuscular blocking agents
(eg, rocuronium ) can be used, but may be less
effective due to competitive inhibition at the
neuromuscular junction

57. Atropine
• competes with acetylcholine at muscarinic receptors,
preventing cholinergic activation
• Atropine infusion
– Once patient is stable
– With 10-20% of initial atropinisation dose per hour
– Continue same dose for 24-48 hours
– Taper dose by 20-30% daily

58. • other muscarinic antagonists have been
studied in animals
• An important difference between such
drugs is their penetration into the CNS
• Glycopyrronium bromide and hyoscine
methobromide do not enter the CNS
• hyoscine has excellent penetration
• Atropine : available widely, affordable, and
moderately able to penetrate into the CNS.

59. Pralidoxime
• atropine does not bind to nicotinic receptors
– ineffective in treating neuromuscular dysfunction
• Pralidoxime : cholinesterase reactivating
agents that are effective in treating both
muscarinic and nicotinic symptoms
• should NOT be administered without
concurrent atropine
– worsening symptoms due to transient oxime-
induced acetylcholinesterase inhibition
• other oximes, such obidoxime

60. • Oximes work by reactivating AChE that
has not undergone ageing
• Less effective with dimethyl compounds
and nerve agents (especially soman)
• Once the AchE bound OPs start ageing,
pralidoxime is rendered ineffective
– Importance of starting oximes early
• It also binds to some free OPs and
prevents further AChE binding
• Effective for unaged OPs that are
redistributed from fat tissue

62. • Administered to:
– all patients with evidence of cholinergic toxicity,
– patients with neuromuscular dysfunction, or
– patients with exposures to organophosphorus agents known to cause
delayed neurotoxicity
• World Health Organization recommendation for IV bolus
therapy with pralidoxime is at least 30 mg/kg
• Bolus : 2g IV over 4 mins, repeated 4-6 hourly
• Although no treatments have been shown to prevent the
intermediate syndrome or organophosphorus agent-induced
delayed neuropathy (OIDN), early oxime treatment may be of
benefit in this situation

63. • Should be administered slowly over 30 minutes
• After the bolus dose, pralidoxime given as a
continuous infusion of at least 8 mg/kg per hour
• Infusion continued until patient remains symptom
free for at least 12 hours without additional
atropine
– Or until patient is extubated
– 7 days

64. • In one large, prospective study, patients poisoned with diethyl
compounds (eg chlorpyrifos) had significantly lower mortality
and intubation rates following treatment with pralidoxime than
those poisoned with dimethyl agents (eg dimethoate, fenthion)
. Conversely, in a small, double-blinded randomized trial, no
significant benefit, and a trend towards harm, was found in the
group treated with pralidoxime compared to patients given
placebo, regardless of the type of organophosphate ingested .
• Until this variability is better understood and other treatments
become available, we believe that all patients poisoned with
organophosphorus agents should be treated with an oxime

65. Benzodiazepines
• Organophosphorus agent-induced seizures
• Prophylactic diazepam has been shown to decrease
neurocognitive dysfunction after organophosphorus agent
poisoning
• This led, in part, to the US military development of a 10
mg autoinjector of diazepam for use in the setting of
chemical attack

66. Decontamination
• In cases of topical exposure with potential dermal
absorption
• aggressive decontamination with complete removal of the
patient's clothes and vigorous irrigation of the affected
areas
• clothes and belongings should be discarded since they
absorb organophosphorus agents, and reexposure may
occur even after washing

67. Gastric Lavage
• present less than one hour following ingestion
• Following initial resuscitation and treatment
– AFTER performing endotracheal intubation and initiating
therapy with atropine and an oxime
• substantial risk of aspiration in patients with increased
secretions and decreased mental status
• activated charcoal
• The standard dose is 1 g/kg (maximum dose 50 grams).
• randomized and observational trials suggest that AC given
after the first hour provides no benefit to patients with
these ingestions

68. Other therapies
• Magnesium sulphate
– blocks ligand-gated calcium channels, resulting in reduced
acetylcholine release from pre-synaptic terminals,
– thus improving function at neuromuscular junctions,
– Reduces CNS overstimulation
• clonidine
– reduces acetylcholine synthesis and release from presynaptic
terminals

69. • Alkalisation
– Sodium bicarbonate
– Increases in blood pH (up to 7·45– 7·55) have been
reported to improve outcome in dogs through an
unknown mechanism
– in Brazil and Iran
• Haemofiltration
– Removing organophosphorus from the blood
– poor solubility in fat : dichlorvus
• recombinant bacterial phosphotriesterases,
– break down organo phosphorus pesticides
enzymatically

70. Pregnancy
• Pregnant patients who have ingested OP insecticides
during the second or third trimester of pregnancy have
been treated successfully with atropine and pralidoxime
and later delivered healthy newborns with no significant
abnormalities.
• However, foetal distress is a possible complication of
both of the poisoning as well as its treatment

71. Organophosphate vs Carbamates
• Carbamate compounds are derived from carbamic acid
• carbamates are rapidly absorbed via all routes of
exposure.
• transient cholinesterase inhibitors,
– spontaneously hydrolyze from the cholinesterase enzymatic
site within 48 hours.
• Carbamate toxicity tends to be of shorter duration than
that caused by equivalent doses of organophosphates,
• although the mortality rates associated with exposure to
these chemical classes are similar

72. References
• UpToDate
• Davidson’s Principle and Practices of Medicine, 22nd
edition
• Various Articles