Organophosphate Toxicity

Overview
Practice Essentials
Organophosphate (OP) compounds are a diverse group of chemicals used in
both domestic and industrial settings. Examples of organophosphates include
the following:
 Insecticides – Malathion, parathion, diazinon, fenthion, dichlorvos,
chlorpyrifos, ethion
 Nerve gases – Soman, sarin, tabun, VX
 Ophthalmic agents – Echothiophate, isoflurophate
 Antihelmintics – Trichlorfon
 Herbicides – Tribufos (DEF), merphos
 Industrial chemical (plasticizer) – Tricresyl phosphate

Thus, organophosphate toxicity can result from household or occupational

exposure, military or terrorist action, or iatrogenic mishap. Exposure to
organophosphates is also possible via intentional or unintentional
contamination of food sources. Although no clinical effects of chronic, low-
level organophosphate exposure from a food source have been shown,
advancements in risk assessment and preparedness are ongoing. [1, 2]

SIGN AND SYMPTOMS

Signs and symptoms of organophosphate poisoning can be divided into three
broad categories: (1) muscarinic effects, (2) nicotinic effects, and (3) central
nervous system (CNS) effects. See Presentation.
History
Signs and symptoms of organophosphate poisoning can be divided into the
following three broad categories:
 Muscarinic effects
 Nicotinic effects
 Central nervous system (CNS) effects
Muscarinic effects
Mnemonic devices used to remember the muscarinic effects of
organophosphates are SLUDGE (salivation, lacrimation, urination, diarrhea,
GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis;
bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and
salivation). Muscarinic effects by organ system include the following:
  Cardiovascular - Bradycardia, hypotension
 Respiratory - Rhinorrhea, bronchorrhea, bronchospasm, cough, severe
respiratory distress
 Gastrointestinal - Hypersalivation, nausea and vomiting,
abdominal pain, diarrhea, fecal incontinence
 Genitourinary - Incontinence
 Ocular - Blurred vision, miosis
 Glands - Increased lacrimation, diaphoresis
Nicotinic effects
Nicotinic signs and symptoms include muscle fasciculations, cramping,
weakness, and diaphragmatic failure. Autonomic nicotinic effects include
hypertension, tachycardia, mydriasis, and pallor.
CNS effects
CNS effects include the following:
 Anxiety
 Emotional lability
 Restlessness
 Confusion
 Ataxia
 Tremors
 Seizures
 Coma
 Apnea

Organophosphate toxicity is a clinical diagnosis. Confirmation of

organophosphate poisoning is based on the measurement of cholinesterase
activity; but typically, these results are not readily available. See Workup.
Treatment begins with decontamination. Airway control and oxygenation are
paramount. The mainstays of pharmacological therapy include atropine,
pralidoxime (2-PAM), and benzodiazepines (eg, diazepam). Initial
management must focus on adequate use of atropine. Optimizing oxygenation
prior to the use of atropine is recommended to minimize the potential for
dysrhythmias. See Treatment and Medication.
 
Background
Organophosphate compounds 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.
Severe organophosphate intoxication from suicide attempts and outbreaks of
unintentional poisoning, such as the Jamaican ginger palsy incident in 1930,
led to the discovery of the mechanisms of acute and chronic toxicity of
organophosphates. In 1995, a religious sect, Aum Shinrikyo, used sarin to
poison people on a Tokyo subway. Mass poisonings still occur today; 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 battle, notably in Iraq in the 1980s.
Sarin, delivered by rockets, was used in the chemical warfare attack in
Damascus, Syria in 2013. [3] Additionally, chemical weapons still pose a very
real concern in this age of terrorist activity.
In farm workers, chronic occupational exposure to organophosphate
insecticides has been linked to neuropsychological effects in some studies.
These have included difficulties in executive functions, psychomotor speed,
verbal, memory, attention, processing speed, visual-spatial functioning, and
coordination. [4]

Pathophysiology
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).
Organophosphates inactivate AChE by phosphorylating the serine hydroxyl
group located at the active site of AChE. Over a period of time,
phosphorylation is followed by loss of an organophosphate leaving group and
the bond with AChE becomes irreversible, a process known as aging.

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 one of
the following:
 Endogenous hydrolysis of the phosphorylated enzyme by esterases or
paraoxonases
 Reactivation by a strong nucleophile such as pralidoxime (2-PAM)
 Irreversible binding and permanent enzyme inactivation (aging)
Organophosphates can be absorbed cutaneously, ingested, inhaled, or
injected. Although most patients rapidly become symptomatic, the onset and
severity of symptoms depend on the specific compound, amount, route of
exposure, and rate of metabolic degradation. [5]

Epidemiology
Frequency
United States
In 2016, the American Association of Poison Control Centers reported 1994
single exposures to organophosphate insecticides alone, with 17 major
outcomes and one death. In addition, 537 single exposures to
organophosphate insecticides in combination with carbamate or non-
carbarbamate insecticides were reported, with two major outcomes and no
deaths. [6]
International
Pesticide poisonings are among the most common modes of poisoning
fatalities. In countries such as India and Nicaragua, organophosphates are
easily accessible and, therefore, a source of both intentional and unintentional
poisonings. The incidence of international organophosphate-related human
exposures appears to be underestimated. [7]
Mortality/Morbidity
Worldwide mortality studies report mortality rates from 3-25%. [8] The
compounds most frequently involved include malathion, dichlorvos, trichlorfon,
and fenitrothion/malathion.
Mortality rates depend on the type of compound used, amount ingested,
general health of the patient, delay in discovery and transport, insufficient
respiratory management, delay in intubation, and failure in weaning off
ventilatory support.
Complications include severe bronchorrhea, seizures, weakness, and
neuropathy. Respiratory failure is the most common cause of death.
Age
Organophosphates (OPs) may affect children or other at-risk populations
differently. The increased susceptibility has not been elucidated but may
involve delayed or persistent effects. More work in this area is in progress and
should help identify the true risk potential.

WORKUP

Laboratory Studies
Organophosphate (OP) toxicity is a clinical diagnosis. Confirmation of
organophosphate poisoning is based on the measurement of cholinesterase
activity; typically, these results are not readily available in a clinically relevant
timeframe. Although red blood cell (RBC) and plasma (pseudo) cholinesterase
(PChE) levels can both be used, RBC cholinesterase correlates better with
central nervous system (CNS) acetylcholinesterase (AChE) and is, therefore,
a more useful marker of organophosphate poisoning.
The portable Test-mate ChE field test measures RBC AChE and PChE within
4 minutes. A study of patients with acute organophosphorus poisoning
compared Test-mate ChE results with those of a reference laboratory test and
found good agreement between the two. Results show the Test-mate ChE
field kit is a reliable test that provides rapid measurement of RBC AChE in
acute organophosphorus poisoning. [13]
If possible, draw blood for measurement of RBC and plasma cholinesterase
levels prior to treatment with pralidoxime (2-PAM). Monitoring serial levels can
be used to determine a response to therapy.
RBC AChE represents the AChE found on RBC membranes, similar to that
found in neuronal tissue. Therefore, measurement more accurately reflects
nervous system OP AChE inhibition.
Plasma cholinesterase is a liver acute-phase protein that circulates in the
blood plasma. It is found in CNS white matter, the pancreas, and the heart. It
can be affected by many factors, including pregnancy, infection, and medical
illness. Additionally, a patient's levels can vary up to 50% with repeated
testing.
RBC cholinesterase is the more accurate of the two measurements, but
plasma cholinesterase is easier to assay and is more readily available.
Cholinesterase levels do not always correlate with severity of clinical illness.
Moreover, a variety of conditions can result in falsely lowered cholinesterase
levels (see Diagnostic Considerations).
The level of cholinesterase activity is relative and is based on population
estimates. Neonates and infants have baseline levels that are lower than
adults. Because an individual patient's baseline levels are rarely available, the
diagnosis can be confirmed by observing a progressive increase in the
cholinesterase value until the values plateau over time.

Other laboratory findings include the following:

 Leukocytosis
 Hemoconcentration
 Metabolic and/or respiratory acidosis
 Hyperglycemia
 Hypokalemia
 Hypomagnesemia
 Elevated troponin levels [14]
 Elevated amylase levels
 Elevated liver function test results
A retrospective analysis of OP-poisoned patients by Liu et al found a direct correlation
between the severity of poisoning and mortality and the presence of pretreatment
metabolic and respiratory acidosis. [15]

Imaging Studies
A chest radiograph may reveal pulmonary edema but typically adds little to the
clinical management of a poisoned patient.

Electrocardiography
ECG findings include prolonged QTc interval, elevated ST segments, and
inverted T waves. [14] Although sinus tachycardia is the most common finding in
the poisoned patient, sinus bradycardia with PR prolongation can develop with
increasing toxicity due to excessive parasympathetic activation.

TREATMENT

Decontamination
Remove all clothing from and gently cleanse patients suspected of
organophosphate exposure with soap and water because organophosphates
are hydrolyzed readily in aqueous solutions with a high pH. Consider clothing
as hazardous waste and discard accordingly.
Health care providers must avoid contaminating themselves while handling
patients. Use personal protective equipment, such as neoprene gloves and
gowns, when decontaminating patients because hydrocarbons can penetrate
nonpolar substances such as latex and vinyl. Use charcoal cartridge masks
for respiratory protection when decontaminating patients who are significantly
contaminated.
Irrigate the eyes of patients who have had ocular exposure using isotonic
sodium chloride solution or lactated Ringer's solution. Morgan lenses can be
used for eye irrigation.

Medical Care
Airway control and adequate oxygenation are paramount in organophosphate
(OP) poisonings. Intubation may be necessary in cases of respiratory distress
due to laryngospasm, bronchospasm, bronchorrhea, or seizures. Immediate
aggressive use of atropine may eliminate the need for intubation.
Succinylcholine should be avoided because it is degraded by plasma
cholinesterase and may result in prolonged paralysis. In addition to atropine,
pralidoxime (2-PAM) and benzodiazepines (eg, diazepam) are mainstays of
medical therapy (see Medication).
Central venous access and arterial lines may be needed to treat the patient
with organophosphate toxicity who requires multiple medications and blood-
gas measurements.
Continuous cardiac monitoring and pulse oximetry should be established; an
electrocardiogram (ECG) should be performed. Torsades de pointes should
be treated in the standard manner. The use of intravenous magnesium sulfate
has been reported as beneficial for organophosphate toxicity. The mechanism
of action may involve acetylcholine antagonism or ventricular membrane
stabilization.

Surgical Care
Patients with trauma or blast injury should be treated according to standard
advanced trauma life support (ATLS) protocol. Patient decontamination
should always be considered to prevent medical personnel poisoning.

Deterrence/Prevention
Health care providers must avoid contaminating themselves while handling
patients poisoned by organophosphates. The potential for cross-
contamination is highest in treating patients after massive dermal exposure.
Use personal protective equipment, such as neoprene or nitrile gloves and
gowns, when decontaminating patients because hydrocarbons can penetrate
nonpolar substances such as latex and vinyl. Use charcoal cartridge masks
for respiratory protection when caring for patients with significant
contamination.

Medication Summary
The mainstays of medical therapy in organophosphate (OP) poisoning include
atropine, pralidoxime (2-PAM), and benzodiazepines (eg, diazepam). Initial
management must focus on adequate use of atropine. Optimizing oxygenation
prior to the use of atropine is recommended to minimize the potential for
dysrhythmias.
Much larger doses of atropine are often needed for OP pesticide poisoning
than when atropine is used for other indications. In order to achieve adequate
atropinization quickly, a doubling approach typically used, with escalation of
doses from 1 mg to 2 mg, 4 mg, 8 mg, 16 mg, and so on. A severe OP
pesticide poisoning case has been known to deplete a hospital’s supply of
atropine. Data from the sarin attack on the Tokyo subway suggest that
patients poisoned by nerve agents require much less atropine than those
poisoned by OP pesticides.
de Silva et al studied the treatment of OP poisoning with atropine and 2-PAM
and, later the same year, with atropine alone. [16] They found that atropine
seemed to be as effective as atropine plus 2-PAM in the treatment of acute
OP poisoning.
The controversy continued when other authors observed more respiratory
complications and higher mortality rates with use of high-dose 2-PAM. Low-
dose (1-2 g slow IV) 2-PAM is the current recommendation. Studies are under
way to assess the role of low-dose 2-PAM. Improved survival has been shown
in patients with moderately severe OP poisoning who received early,
continuous 2-PAM infusion compared with those who received intermittent
boluses. [17]
A meta-analysis and review of the literature performed by Peter et al
emphasized optimal supportive care along with discriminating use of 2-PAM,
especially early in the course of treatment of moderately to severely OP
poisoned patients, are the hallmarks of treatment. [18] More prospective data
are required.
Intraosseous administration has been found as effective as intravenous
infusion for rapid delivery of atropine and midazolam into the bloodstream, in
studies in pigs. Unlike intravenous administration, intraosseous administration
can be conveniently performed by rescuers wearing personal protective
equipment to prevent contamination. [19, 20]
Because large amounts of atropine may be required for patients with OP
poisoning, reconstitution of powdered atropine is a viable option, especially in
mass-casualty settings. [21] Rajpal et al demonstrated the clinical safety and
efficacy of sublingual atropine to healthy volunteers. This may offer another
route of administration for the OP-poisoned patient, especially in a mass-
casualty scenario. [22]
If atropine is unavailable or in limited supply, intravenous glycopyrrolate or
diphenhydramine may provide an alternative anticholinergic agent for treating
muscarinic toxicity; however, glycopyrrolate does not cross the blood-brain
barrier and cannot treat central effects of OP poisoning. Additionally, Yavuz et
al demonstrated reduced myocardial injury and troponin leak in fenthion-
poisoned rats treated with diphenhydramine. [23] Nebulized ipratropium bromide
can also be used to treat muscarinic effects in the lungs.
A single-center, randomized, single-blind study by Pajoumand et al found a
benefit to magnesium therapy in addition to standard oxime and atropine
therapy in reducing hospitalization days and mortality rate in patients with OP
poisoning. [24] The mechanisms appear to be inhibition of acetylcholine (ACh)
and OP antagonism. A phase II study of magnesium therapy in 50 patients
with acute OP poisoning reported no adverse reactions. [25] Larger randomized
studies are needed to demonstrate the efficacy of magnesium in this setting.
Possible future interventions include neuroprotective agents used to prevent
nerve damage and bioscavengers aimed to prevent AChE inhibition by nerve
agents or OP. Investigations into adjunctive and alternative therapies have
mostly used animal models and have resulted in variable
conclusions. [26, 27, 28]  In a study of rats poisoned with sarin, Lewine et al
reported that the addition of ketamine to standard countermeasures (atropine,
2-PAM, and midazolam) provides clinically relevant additional protection
against the negative neurobiological consequences of sarin, even when
initiation of treatment is delayed by almost an hour. [28]  

Anticholinergic agents
Class Summary
These agents act as competitive antagonists at the muscarinic cholinergic
receptors in both the central and the peripheral nervous system. These agents
do not treat nicotinic effects.

Atropine IV/IM (Isopto, Atropair)

 View full drug information
Initiated in patients with OP toxicity who present with muscarinic symptoms.
Competitive inhibitor at autonomic postganglionic cholinergic receptors,
including receptors found in GI and pulmonary smooth muscle, exocrine
glands, heart, and eye.
The endpoint for atropinization is dried pulmonary secretions and adequate
oxygenation. Tachycardia and mydriasis must not be used to limit or to stop
subsequent doses of atropine. The main concern with OP toxicity is
respiratory failure from excessive airway secretions.

Glycopyrrolate (Robinul)
 View full drug information
Indicated for use as an antimuscarinic agent to reduce salivary,
tracheobronchial, and pharyngeal secretions. Does not cross the blood-brain
barrier. Can be considered in patients at risk for recurrent symptoms (after
initial atropinization) but who are developing central anticholinergic delirium or
agitation.
Since glycopyrrolate does not cross BBB, it is not expected to control central
cholinergic toxicity. Bird et al suggested that atropine (rather than
glycopyrrolate) was associated with lower, early OP-induced mortality

Antidotes, OP poisoning
Class Summary
These agents prevent aging of AChE and reverse muscle paralysis with OP
poisoning.

Pralidoxime (2-PAM, Protopam)

 View full drug information
Nucleophilic agent that reactivates the phosphorylated AChE by binding to the
OP molecule. Used as an antidote to reverse muscle paralysis resulting from
OP AChE pesticide poisoning but is not effective once the OP compound has
aged. Current recommendation is administration within 48 h of OP poisoning.
Because it does not significantly relieve depression of the respiratory center or
decrease muscarinic effects of AChE poisoning, administer atropine
concomitantly to block these effects of OP poisoning.
Signs of atropinization might occur earlier with addition of 2-PAM to treatment
regimen.
Benzodiazepines
Class Summary
These agents potentiate effects of gamma-aminobutyrate (GABA) and
facilitate inhibitory GABA neurotransmission.

Diazepam (Valium, Diastat, Diazemuls)

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For treatment of seizures. Depresses all levels of CNS (eg, limbic and
reticular formation) by increasing activity of GABA.

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