Review article published in APICON UPDATE, Assam 2009

Management of acute organophosphorus pesticide poisoning

Dr. L.J.Basumatary MD, DM (Neuro) trainee
GMCH, Guwahati
drbasumatary@gmail.com

INTRODUCTION

Organophosphate (OP) based pesticides are widely used and have emerged
as 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 the
main occupation in Assam and due to easy availability of OP pesticides they
are commonly consumed for the purpose of suicide.

Total Pesticide suicides Plausible range of

Region
suicides (% of all suicides) pesticide 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
Eastern
34,000 5,629 (16.5) 4,501 to 7,022
Mediterranean
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
233,997 (27%) to
Global 873,000 258,234 (30%)
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 art
of a systematic review conducted by Gunnell et al 2007). 3

Brief History:

OP compound were first synthesized in the early 1800s when Lassaigne

reacted alcohol with phosphoric acid. Shortly thereafter in 1854, Philip de
Clermount described the synthesis of tetraethyl pyrophosphate at a meeting
of the French Academy of Sciences. Eighty years later, Lange, in Berlin, and,
Schrader, a chemist at Bayer AG, Germany, investigated the use of
organophosphates as insecticides. However, the German military prevented
the use of organophosphates as insecticides and instead developed an
arsenal 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, as
originally intended.4

Massive organophosphate intoxication from suicidal and accidental events,

such as the Jamaican ginger palsy incident when an OP derivative

1
contaminated bootleg whisky and caused a neurological syndrome “Ginger
Jake Paralysis” which crippled as many as 50,000 persons in the USA in
1930, led to the discovery of the mechanism of action of organophosphates5.
In 1995, a religious sect, Aum Shinrikyo, used sarin to poison people on a
Tokyo subway. In 2005, 15 victims were poisoned after accidentally ingesting
ethion-contaminated food in a social ceremony in Magrawa, India. Nerve
agents have also been used in various battles, notably in Iraq in the 1980s.

Pathophysiology

Organophosphate (OP) compounds are a diverse group of chemicals that

include: insecticides (malathion, parathion, diazinon, fenthion, dichlorvos,
chlorpyrifos, ethion), nerve gases (soman, sarin, tabun, VX), ophthalmic
agents (echothiophate, isoflurophate), and antihelmintics (trichlorfon).
Herbicides (tribufos [DEF], merphos) are tricresyl phosphate–containing
industrial chemicals.

The primary mechanism of action of organophosphate pesticides is inhibition

of carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). AChE
is an enzyme that degrades the neurotransmitter acetylcholine (ACh) into
choline and acetic acid. ACh is found in the central and peripheral nervous
system, neuromuscular junctions, and red blood cells (RBCs). The two
principal human cholinesterases are acetylcholinesterase (AChE) found
primarily in nervous tissue and erythrocytes and butyrylcholinesterase
(BChE) found in liver and plasma. Both enzymes are of pharmacological and
toxicological importance, BChE is used to detect the early, acute effects of OP
poisoning while AChE is used to evaluate long-term or chronic exposure

Organophosphates inactivate AChE by phosphorylating the serine hydroxyl

group located at the active site of AChE. The phosphorylation occurs by loss
of an organophosphate leaving group and establishment of a covalent bond
with AChE.

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

Once an organophosphate binds to AChE, the enzyme can undergo 1 of the

following 3 processes:
1. Endogenous hydrolysis of the phosphorylated enzyme by esterases or
paraoxonases
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 after

exposer, within minutes to hours, depending on the mode of contact. Exposer

2
by inhalation results in the fastest appearance of toxic symptoms,followed by
the gastrointestinal route and finally dermal route.

Signs and symptoms of organophosphate poisoning can be divided into 3

broad categories, including (1) muscarinic effects, (2) nicotinic effects, and (3)
CNS effects.10

(a) Muscarinic Effects

Respiratory: Rhinorrhea, bronchorrhea, bronchospasm, cough,
severe respiratory distress
Cardiovascular : Bradycardia, hypotension
Gastrointestinal: Hypersalivation, nausea,vomiting, abdominal pain,
diarrhea, fecal incontinence
Genitourinary : Incontinence
Ocular : Blurred vision, miosis
Glands : Increased lacrimation, diaphoresis

(b) Nicotinic Effects : Muscle fasciculations,

cramping, weakness, and
diaphragmatic failure.
Autonomic nicotinic effects:Hypertension, tachycardia,
mydriasis,and
pallor.

(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 continued
depolarization at the neuromuscular junction during acute cholinergic crisis.
The Acute cholinergic phase usually passes off within 48-72 hours but
complete 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 temporal

appearance between the early type I syndrome and the later OPIDP, occurs
12-96 hours after exposure of organophosphate and associated with cranial,
proximal limb and respiratory muscle weakness with relative sparing of distal
muscle groups. Intermediate syndrome persists for 4-18 days, symptoms do
not respond well to oximes and atropine therefore treatment is mainly
supportive. The incidence of IMS in different studies has been reported to be
between 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 of
IMS, early diagnosis and prediction have remained elusive. Commonly used

3
tests such as levels of plasma cholinesterase correlate poorly with the onset
of 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 underlie
the development of IS. Electrophysiological studies of De Bleecker
demonstrated both pre- and post-synaptic defects in OPP while Avasthi and
Singh suggested desensitization of acetylcholine receptors being responsible
for IS.

Type III: Organophosphate-induced delayed polyneuropathy (OPIDP) is an

uncommon clinical condition occurs 2-3 weeks after exposure to large doses
of certain OPs and is due to inhibition of neuropathy target esterase. Distal
muscle 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 symptoms
appearing after a latent period of 7-21 days. Recovery can take up to 12
months.

Neuropsychiatric effects: Impaired memory, confusion, irritability, lethargy,

psychosis, and chronic organophosphate-induced neuropsychiatric disorders
have been reported. Although the mechanism is not proven.

Extrapyramidal effects: These are characterized by dystonia, cogwheel

rigidity, and parkinsonian features (basal ganglia impairment after recovery
from acute toxicity).

Other neurological and/or psychological effects: Guillain-Barré–like syndrome

and isolated bilateral recurrent laryngeal nerve palsy are possible.

Treatment:

Diagnosis is most often possible by a detailed history and clinical

examination. If poisoning is probable, treatment should be initiated
immediately without waiting for laboratory confirmation.

Blood sample should be drawn to measure plasma pseudocholinesterase and

red blood cell AchE levels. Depressions of plasma pseudocholinesterase
and/or RBC acetylcholinesterase enzyme activities are generally available
biochemical indicators of excessive organophosphate absorption.

Initial assessment of the poisoned patient

This follows standard practice with preservation of the airway, provision of

oxygen and resuscitation.

Atropine Sulfate: Since the only life-saving antidotes for pesticide poisoning
are oxygen and atropine, and oxygen has already been given, the most
important issue after resuscitation is to decide whether the patient has taken a

4
cholinergic pesticide and requires atropine.14 Atropine can be administered by
intravenous,intramuscular or through endotracheal tube if initial IV access is
difficult to obtain. The best regimen for the administration of atropine has not
been established 15. Depending on the severity of poisoning, doses of atropine
ranging from very low to as high as 300 mg per day may be required or even
continuous infusion.16
The objective of atropine therapy is to reverse the effects of excessive
concentrations of acetylcholine at the end organs having Muscarinic receptors.
Atropine does not reactivate the cholinesterase enzyme or accelerate disposal of
organophosphate. Recrudescence of poisoning may occur if tissue concentration
remains high when the effect of atropine wears off. Atropine is effective against
Muscarinic features but it is ineffective against nicotinic actions, specifically
muscle weakness and twitching and respiratory depression.
Despite these limitations, atropine is often a life saving agent in organophosphate
poisoning.Favorable response to a test dose of atropin can help differentiate
poisoning by anti-cholinesterase agent from other conditions. However, lack of
response, with no evidence of atropinization (atropine refractoriness) is typical of
more severe poisoning.The adjunctive use of nebulized atropine has been
reported to improve respiratory distress, decrease brochial secretions and
improve oxygenation.17

Giving atropine before oxygen

Many textbooks state that atropine should not be given to a cyanosed patient
until oxygen has been given - to reduce the risk of atropine inducing ventricular
tachy-cardias. While apparently sensible, such advice risks preventing doctors
working in small rural hospitals from giving life-saving atropine treatment, since
many do not have oxygen. Furthermore, in our treatment of more than 800
patients receiving atropine, many of whom received atropine before oxygen, no
patient had a cardiac arrest within minutes of giving atropine (Eddleston,
unpublished).
The primary evidence for an increased risk of a ventricular dysrhythmia from
giving atropine to a cyanosed patient consists of very few patients. Since atropine
dries secretions and reduces bronchospasm, its administration should reduce
cyanosis.

Dosage of Atropine:
Moderately severe poisoning:

Adults and children over 12 years: 2-4 mg, repeated every 15 minutes until
pulmonary secretions are controlled, which may be accompanied by other signs
of atropinization,including flushing,dry mouth,dilated pupils and
tachycardia.severely poisoned patients may exhibit marked tolerance to atropine
and in these situation dose requirement many escalate. The desired end point is
the reversal of Muscarinic symptoms and signs with improvement in pulmonary
status and oxygenation, without an arbitrary dose limit. Person with minimal
organophosphate poisoning may develop atropine toxicity from such large doses.
Fever, muscle fibrillation and delirium are the main signs of atropine toxicity. If
these appear while the patient is fully atripinized,administration should be
discontinued, at least temporarily, while the severity of poisoning is reevaluated.

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Glycopyrolate has been studied as an alternative to atropine and found to have
similar 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 titrated
to the desired effects of dry mucus membranes and heart rate above 60bpm.The
apparent advantage to this regimen was a decreased number of respiratory
infections. This may represent an alternative when there is concern for
respiratory infection due to excessive and difficult to control secretions and in the
presence of altered level of consciousness where the distinction between
atropine toxicity or relapse of organophosphate poisoning is less clear.18

OXIMES

Pralidoxime is the oxime most often used worldwide and occurs in two
common forms: pralidoxime chloride (2-PAM) and mesylate (P2S). It
reactivates cholinesterase by removing the phosphoryl group bound to the
esteratic site. The great majority of its effects are on the peripheral nervous
system, since its lipid solubility is low and entry into the central nervous
system (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 of
dichlorvos.This drug is not effective in soman and tabun
poisoning.Pralidoxime becomes ineffective as an antidote when administered
more than 24 to 48 hours postexposure as a result of aging of the
phosphateester bond. Pralidoxime also slows the process of aging of
phosphorylated acetylcholinesterase to a nonreactivatable form and detoxifies
certain OPs by direct chemical actions. In spite of numerous studies, the
mechanism of action of pralidoxime in human OP poisoning is still unknown.19
Also, further studies are required to investigate the effects of high doses of
pralidoxime in common known of OP poisoning(Table 3)

Dosage of Pralidoxime:

The dose of pralidoxime commonly recommended in the literature for the

treatment of organophosphorus poisoning in adults is a 30 mg/kg bolus,
followed by a continuous infusion of 8 mg/kg/hr 20. This dose is used to rapidly
achieve and maintain a concentration of pralidoxime above 4 mg/L. This is
sometimes 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 1.43
Pralidoxime iodide 1.53

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Table3: Results of systematic reviews assessing the comparative
effectiveness of pralidoxime
Systematic review (year) Results/conclusions

• Descriptive analysis of Abdollahi

(1995), Samuel (1995), Cherian
(1997) and Dadan (1999)
Eddleston (2002)
Conclusion: A generalised
statement that pralidoxime should
not be used in OP poisoning is not
supported by the published results

• Descriptive analysis of Samuel

(1995) and Cherian (1997)

Buckley (2005) Conclusion: Current evidence is

insufficient to indicate whether
oximes are harmful or beneficial in
the management of acute
organophosphorus pesticide
poisoning

• Descriptive analysis of De Silva

(1992), Abdollahi (1995), Samuel
(1995), Cherian (1997), Balali-
Bairy (2006) Mood (1998), Cherian (2005),
Chugh (2005), and Dadan (1999)

Conclusion: The clinical benefits of

oximes in OP poisoning remains
unclear
Peter (2006)

• Meta-analysis of Duval (1991), De

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

o Oxime therapy was not

associated with a statistically
significant difference in mortality
(RD 0.09, 95% CI -0.08, 0.27);
need for mechanical ventilation (RD

7
 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 associated

with a statistically significant
increase in the need for intensive
care (RD 0.19, 95% CI 0.01, 0.36)
compared to standard care

Conclusion: Based on the current

available data on human
organophosphate poisoning, oxime
therapy was associated with either
a null effect or possible harm

• Meta-analysis of De Silva (1992),

Abdollahi (1995), Cherian (1997),
Balali-Mood (1998), Sungur (2001)
and Cherian (2005)

Rahimi (2006) Oxime therapy was associated with

a statistically significant increase in
mortality (RR 2.17, 95% CI 1.34,
3.51); need for mechanical
ventilation (RR 1.53, 95% CI 1.16,
2.02), incidence of intermediate
syndrome (RR 1.57,

The systematic reviews all acknowledged the limitations of the current evidence
base (primarily the small sample size, poor methodology and inadequate
reporting). 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 However
Peter et al (2005) ,Rahimi et al (2005) conclude that even with the limitations, the
current evidence indicates that pralidoxime is not effective in the treatment of
organophosphate poisoning.24

Blood pressure should be monitored during administration because of

occasional occuence of hypertensive crisis.If intravenous injection is not
possible PAM may be given by deep intramuscular route.

Gastrointestinal decontamination:

The efficacy of gastric lavage falls rapidly with time since ingestion 25. By the
time 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 solvent
may be left in the stomach – this will smell of ‘pesticide’ if sucked out with a

8
NG tube. The volume of fluid in the stomach will appear large in cholinergic
poisoning due to the secretion of fluid into the bowel 26.
There is currently no evidence that either single or multiple dose regimens of
activated charcoal result in clinical benefit .27-28

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

Observation:
Close observation for a period of at least 72 hours to ensure that Muscarinic
symptoms do not recur as atropine is withdrawn. In very severe poisoning by
ingested OP, particularly the more lipophilic and slowly hydrolysed
compounds, metabolic disposition may require as many as 5-14 days.In some
cases, this slow elimination may combine with profound cholinesterase
inhibition to require atropinization for several days or even weeks. As dosage
is reduced, the lung bases should be checked frequently for crackles. If
crackles are heard, or other Muscarinic signs,atropinization must be re-
established promptly.

Figure 1: Clinical pathway for the management of patients with acute

organophosphorus poisoning(Roberts DM, Aaron CK (2007), Managing acute
organophosphorus pesticide poisoning, British Medical Journal 334: 629-634.)29

9
Conclusion

Medical management of severe cholinergic pesticide poisoning is difficult, with

high mortality. Some patients will die no matter how well managed. However,
careful resuscitation with appropriate use of antidotes, followed by good
supportive care and observation, should minimise the number of deaths in the
period after admission to hospital.

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