Organophosphate and

C a r b a m a t e Po i s o n i n g
Andrew M. King, MD*, Cynthia K. Aaron, MD

KEYWORDS
 Organophosphate  Carbamate  Pesticides  Insecticides  Nerve agents
 Chemical warfare  Atropine  Oxime

KEY POINTS
 Organophosphates (OPs) and carbamates have a variety of applications, but are primarily
used agriculturally as pesticides.
 OPs and carbamates are responsible for the deaths of hundreds of thousands of people
every year.
 Acute toxicity results from acetylcholinesterase (AChE) enzyme inhibition and subsequent
excessive nicotinic and muscarinic stimulation in the central and autonomic nervous sys-
tems and the neuromuscular junction.
 Good supportive care, decontamination, aggressive antimuscarinic therapy, early seizure
control, and early antidotal oxime therapy are the keys to good outcomes.

INTRODUCTION
Epidemiology
Experts believe that acute poisoning from acetylcholinesterase (AChE)-inhibiting in-
secticides is responsible for more deaths than any other class of drug or chemical.1
They are a particular problem in the developing world, where highly toxic pesticides
are readily available and are used in the suicides of hundreds of thousands of people
every year.2 With an estimated case fatality rate of 10% to 20%, the subsequent health
care burden of those who do not die after a suicidal ingestion is an order of magnitude
higher.3,4 The disease burden of OP and carbamate toxicity is much less in developed
countries. In contrast with the 25,288 people who committed suicide with pesticides in
India in 2010,5 the American Association of Poison Control Centers in 2012 received a
combined 4150 calls for OP and carbamate exposures, resulting in a total of 3 deaths.6
Although unintentional agricultural poisonings do occur, they are generally less
severe.7,8

Disclosure Statement: The authors of this paper have no disclosures.

Department of Emergency Medicine, Children’s Hospital of Michigan Regional Poison Control
Center, Detroit Medical Center, Wayne State University School of Medicine, 4707 Street
Antoine, Suite 302, Detroit, MI 48201, USA
* Corresponding author.
E-mail address: [email protected]

Emerg Med Clin N Am 33 (2015) 133–151

http://dx.doi.org/10.1016/j.emc.2014.09.010 emed.theclinics.com
0733-8627/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
134 King & Aaron

Uses
Commercially, organophosphorus chemicals have a number of applications, but are
mostly employed as pesticides in a variety of settings (Box 1 from9). They protect
commercial and food crops from damaging insect vectors. They also control insect in-
festations in commercial and residential settings. It should be noted that the Environ-
mental Protection Agency has banned or plans to remove many OPs from the United
States and thus OP use for many of these applications has been sharply curtailed.
Some medical indications for organophosphates (OPs) include the eradication of
corporeal insect infestations in humans and animals. One organic phosphorus chem-
ical is used for glaucoma (diisopropyl phosphorofluorodate).
Militarized OPs (also known as nerve agents) are classified as chemical weapons
and weapons of mass destruction. Despite the manufacture of hundreds of thousands
of tons of these chemicals by various countries during the 20th century, only small
amounts have been deployed in a number of clandestine situations, including the
Iran–Iraq war, the Iranian attack on the Kurds, and more recently in the Syrian Civil
war in August 2013, resulting in more than 1400 deaths.10 Before this, the most
notable use of nerve agents was the 1995 terrorist attack in Tokyo, Japan, which
left 11 dead and more than 5000 victims seeking medical attention.11 These recent ep-
isodes are tragic reminders of the persistent threat posed by nerve agents.
By volume, carbamates are used most frequently as pesticides. However, they do
have number of interesting medical indications (Table 1).

History
OPs are of particular historical interest given their development and use as chemical
weapons. The early part of the 20th century saw the development of the G-series of
nerve agents (tabun, sarin, and soman) by the Germans, the V-series (VE, VG, VM,

Box 1
Sources of organophosphorus pesticides

Domestic
 Garden sheds—in particular insecticidal preparations but also other products that are
marketed as fertilizers but contain some organophosphorus pesticides, available as solid
or liquid formulations
 Surface and room sprays
 Baits for cockroaches and other insects (eg, chlorpyrifos)
 Shampoos against head lice (eg, malathion)
 Pet preparations (eg, 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 subway attack, and both tabun and sarin were used
during the Iraq–Iran conflict; although nerve agents share a similar mechanism of toxicity
with organophosphorus pesticides, their treatment is a specialized topic and not dealt with
in this review

From Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning.
BMJ 2007;334(7594):629-34; with permission.
 Organophosphate and Carbamate Poisoning 135

Table 1
Human disease treated with carbamates

Indication Carbamate
Myasthenia gravis Edrophonium, pyridostigmine
Antimuscarinic poisoning Physostigmine
Alzheimer’s disease Rivastigmine, donepezil, galantamine, tacrine
Glaucoma Physostigmine, ecthiopate
Neuromuscular blockade reversal Pyridostigmine, neostigmine
Elapid envenomation Neostigmine
Adynamic ileus Neostigmine

and VX) by the allies, and, more recently, the ultratoxic group of agents called the Nov-
ichok or newcomer agents by the Russians.12 Many tens of thousands of tons of nerve
agents were produced and stockpiled by various countries during World War II. Since
then, most countries, in compliance with the Chemical Weapons Convention of 1997,
have destroyed or scuttled more than 80% of their declared stockpiles.13 However, as
the incidents in Tokyo and Syria have reminded us, nerve agents continue to be a
threat in the hands of terrorists and other militant groups.
The delayed peripheral neuropathy caused by certain OPs (also known as
OP-induced delayed peripheral neuropathy [OPIDN]) has led to many well-known,
toxin-induced epidemics throughout the world. The Ginger Jake paralysis that
affected thousands of Americans during prohibition was caused by an organic phos-
phorus adulterant (triorthocresyl phosphate, added to Jamaican Ginger [“jake”]
extract) to pass US Department of Agriculture inspections. Consumption of this adul-
terated extract resulted in lower extremity weakness, paraparesis, paralysis, and
impotence.14,15 Similar outbreaks of OPIDN have subsequently been reported in Sri
Lanka, Vietnam, and other developing countries.16,17
Physostigmine and its carbamate derivates have an interesting and tragic past as
well. Physostigmine is the ordeal bean of Old Calabar (Physostigma venenosum Bal-
four), and was the first carbamate isolated by Westerners.18 Since then, a number of
carbamates have been synthesized and employed as fungicides and insecticides. Un-
fortunately, it was this synthesis that led to the largest industrial accident in history19 in
1984 during production of the carbamate carbaryl at The Union Carbide Corporation’s
factory in Bhopal, India. Methyl isocyanate accidentally leaked, immediately killing
more than 3800 people and leaving thousands more suffering health effects and pre-
mature death.

AGENTS OF TOXICITY
Biochemistry
The general structures of carbamates and OPs are shown below (Fig. 1). N-Methyl
carbamate compounds are the only carbamate derivatives that inhibit AChE. Other
derivatives, such as thiocarbamates, do not inhibit AChE and are be discussed in
this article. The major carbamates and their relative toxicities are found in
Table 2.20 A number of these are not available commercially in the United States.
The structure–function relationship of organic phosphorus compounds is clinically
relevant in that each derivative’s chemical properties relates to its toxic potential.
The general structure includes a phosphoryl group (O 5 P) or a thiophosphoryl group
(P 5 S), 2 lipophilic R groups, and the leaving group (X; see Fig. 1). The X group or leav-
ing group serves as a means of classifying the various OPs.1 These groups tend to
136 King & Aaron

Fig. 1. N-Methyl carbamates contain a common NCOO structure with various side chains
R1-R3 (left). The basic structure of an organophosphate (OP) is shown on the right. Each
OP contains a phosphoryl or thiophosphoryl group, 2 side chains, and a leaving group (X).

share certain physical and pharmacodynamic characteristics, but generally do not

affect acute management.

Pharmacokinetics
A number of pharmacokinetic properties are important with respect to onset and dura-
tion of toxicity. These include route of exposure, lipophilicity, and volume of distribu-
tion, whether the agent requires metabolism before it can exert its toxic effects, serum
paraoxonase activity (an intrinsic enzyme capable of hydrolyzing certain OPs), and
elimination. Important pharmacodynamic properties include potency, rate of AChE
inhibition, and rate of aging.

Route
 OPs and carbamates are absorbed through all routes
 Ingestion and inhalation lead to immediate onset of symptoms if vaporized or
misted.
 Dermal exposure may have immediate local effects (local diaphoresis and fascic-
ulations) and delayed systemic effects.21

Table 2
The main carbamate insecticides in use and their relative toxic potency (estimated human
values)

Moderate Toxicity
High Toxicity (LD50 <50 mg/kg) (LD50 5 50–200 mg/kg) Low Toxicity (LD50 >200 mg/kg)
Aldicarb (Temik) Bufencarb (Bux) BPMC (Fenocarb)
Aldoxycarb (Standak) Carbosulfan Carbaryl (Sevin)
Aminocarb (Metacil) Pirimicarb (Pirimor) Isoprocarb (Etrofolan)
Bendiocarb (Ficam) Promecarb MPMC (Meobal)
Carbofuran (Furadan) Thiodicarb (Larvin) MTMC (Metacrate, Tsumacide)
Dimetan (Dimetan) Trimethacarb (Broot) XMC (Cosban)
Dimetilan (Snip)
Dioxacarb (Eleocron, Famid)
Formetanate (Carzol)
Methiocarb (Mesurol)
Methomyl (Lannate, Nudrin)
Oxamyl (Vydate)
Propoxur (Baygon)

Data from National Crime Records Bureau. Accidental Deaths and Suicides in India - 2010. Available
at: http://ncrb.nic.in/ADSI2010/home.htm. Accessed June 4, 2014.
 Organophosphate and Carbamate Poisoning 137

Pharmacokinetic Properties
 OPs are lipophilic compounds with some sequestering in fat stores.
 Highly lipophilic agents may have a delay in symptoms development.22,23
 Highly lipophilic agents cause protracted toxicity.24,25
 Redistribution of lipid soluble OPs from fat stores can “repoison” a patient.
 Carbamates are inactivated more quickly and generally do not cause prolonged
toxicity.

Metabolism and Subsequent Activation

 OPs are either “oxons” (which can directly inhibit AChE) or “thions” (which
require desulfuration to the oxon form to become maximally active).
 Once “thions” (P 5 S) are oxidized to “oxons”(P 5 O), they have enhanced
toxicity.
 Carbamates do not require metabolism to become active.

Toxicodynamics
OPs and carbamates both inhibit synaptic AChE. Synaptic AChE normally prevents
further downstream neurotransmission by hydrolyzing acetylcholine to acetic acid
and choline. Acetic acid feeds into the Krebs cycle, whereas choline is taken back
up by the neuron and resynthesized to new acetylcholine. Subsequently, acetylcholine
accumulates in the nerve or myoneuronal synapse, which leads to characteristic toxic
manifestations (cholinergic toxidrome). True AChE is found not only in nervous tissue,
but also on the surface of erythrocytes (erythrocyte or red blood cell cholinesterase).
Butyrylcholinesterase (also known as pseudocholinesterase or plasma cholinesterase)
is found primarily in the liver and is responsible for xenobiotic metabolism (eg, cocaine,
succinylcholine). It is important to note that erythrocyte AChE activity more closely
mirrors neuronal AChE activity than does butyrylcholinesterase, and is a better marker
for neuronal physiologic status.26–28

Toxicodynamic Differences Between Organophosphates and Carbamates

The unique pharmacodynamics of organosphosphates and carbamates and their dif-
ferences in interaction with AChE play a role in the clinical toxicity differences as well
as implications for antidotal therapy.
Within the anticholinesterase protein catalytic site lays a serine hydroxyl group
(–OH). The serine group becomes phosphorylated once the leaving group (X) is
released. At this point, the OP–serine bond can spontaneously hydrolyze and the
enzyme regains its function, or, an R group leaves (ages), it becomes irreversibly phos-
phorylated, and the enzyme is permanently inhibited (Fig. 2). The relative speeds of
these processes have major implications with respect to administration of the anti-
dotal oximes.
Antidotal oximes increase the rate of hydrolysis and reactivation and prevent irre-
versible aging. Although those OPs with shorter R-group side chains age more
quickly, they also reactivate more quickly and are theoretically more responsive to
oxime therapy, provided it is administered early. In contrast, although there is more
time to administer oximes to patients poisoned with long-R chain OPs, a greater
amount of oxime administered over a longer period of time is required.21 The reverse
can be argued as well; administration of oximes to dimethyl phosphoryl–poisoned pa-
tients is less likely to benefit precisely because of those OPs propensity to age
quickly.29 In other words, by the time the oxime is available to facilitate hydrolysis
and reactivate AChE, the OP has already aged. Unfortunately, once aged, oximes
138 King & Aaron

Fig. 2. Phosphonyl (1) and phosphinyl (2) organophosphate molecules bind to the acetyl-
cholinesterase enzyme with resultant loss of the leaving group (X). The acetylcholinesterase
(AChE) enzyme is now inhibited in both cases and cholinergic toxicity ensues. Before the loss
of the R group in (1), both complexes are treatable with atropine and oximes. However,
after the loss of the R group (1), the OP has “aged” and the AChE enzyme is irreversibly
inhibited.

cannot reactivate the enzyme and any further AChE activity requires the de novo syn-
thesis of additional AChE enzyme30
Carbamates also inhibit AChE enzyme in an identical fashion; however, the carba-
mate–AChE bond is weaker than that formed by OPs. Thus, carbamate–AChE bonds
spontaneously hydrolyze more rapidly and AChE function returns typically within 24 to
48 hours. In contrast with OPs, carbamates cannot age and prolonged toxicity is
uncommon.
Pathophysiology
The 2 acetylcholine receptor subtypes found in humans and animals are the musca-
rinic and nicotinic receptors. These receptors are further subclassified according to
their locations in the body and what occurs after acetylcholine binds to the receptor.
In general, muscarinic receptors are found in the central nervous system (CNS),
exocrine glands, and the hollow end-organs innervated by the parasympathetic sys-
tem, and nicotinic receptors are located in the postganglionic neurons of both the
parasympathetic and sympathetic chains, the adrenal medulla, and the neuromus-
cular junction (Fig. 3).31 Both are found in the brain.

Fig. 3. Graphic representation of the acetylcholine-relevant physiology and anatomy. (From

Cannard K. The acute treatment of nerve agent exposure. J Neurol Sci 2006;249(1):86–94;
with permission.)
 Organophosphate and Carbamate Poisoning 139

Excess acetylcholine at the 2 receptor subtypes results in different end-organ ef-

fects. When poisoned by OP and carbamate xenobiotics, toxicity varies and may man-
ifest with primarily nicotinic effects (hypertension, tachycardia, fasciculations,
weakness, mydriasis), muscarinic effects (miosis, bradycardia, bronchospasm, bron-
chorrhea), or a combination of the two. Acetylcholine excess at the neuromuscular
junction results in a type II paralysis in the same way succinylcholine depolarizes
and paralyzes skeletal muscle. Additionally, cholinergic neurons interact with other
neurotransmitter systems ultimately leading to g-aminobutyric acid (GABA) inhibition
and N-methyl-D-aspartate activation, which may in part be responsible for
CNS-mediated respiratory depression and seizure activity.32–35 Table 3 summarizes
the clinical effects of cholinergic toxicity.

CLINICAL MANIFESTATIONS

Onset and severity of toxicity depend on a variety of factors, including agent, route,
formulation, amount, and duration of exposure. For example, death may occur within
minutes of inhalational exposure to nerve agents, whereas symptoms from dermal ex-
posures of highly lipophilic agents requiring activation may be delayed by up to
48 hours.36 Time to onset of symptoms after ingestion tends to be slightly delayed
compared with inhalation, with clinical effects expected to begin within 30 to
90 minutes.
Similarly, initial and presenting symptoms depend on the route of exposure. Inges-
tion often presents with vomiting and other gastrointestinal symptoms, whereas aero-
sol exposure causes ocular and respiratory symptoms. Dermal exposure may present
with localized sweating and fasciculations. Both dermal and inhalational exposures
are recognized occupational hazards and exposure can occur during formulation

Table 3
Clinical effects of organophosphate poisoning (acetylcholine excess)

Anatomic Site of Action Signs and Symptoms

Muscarinic effects
Sweat glands Sweating
Pupils Constricted pupils
Lacrimal glands Lacrimation
Salivary glands Excessive salivation
Bronchial tree Wheezing
Gastrointestinal Cramps, vomiting, diarrhea, tenesmus
Cardiovascular Bradycardia, decrease in blood pressure
Ciliary body Blurred vision
Bladder Urinary incontinence
Nicotinic effects
Striated muscle Fasciculations, cramps, weakness, twitching, paralysis,
respiratory embarrassment, cyanosis, arrest
Sympathetic ganglia Tachycardia, elevated blood pressure
Central nervous system Anxiety, restlessness, ataxia, convulsions, insomnia, coma,
effects absent reflexes, Cheyne-Stokes respirations, respiratory and
circulatory depression

From Bradberry SM, Vale J. Organophosphorus and carbamate insecticides. In: Wallece K, Brent J,
Burkhart KK, editors. Critical care toxicology: diagnosis and management of the critically poisoned
patient. Philadelphia: Elsevier Mosby; 2005. p. 940; with permission.
140 King & Aaron

manufacture, mixing, or spraying. Nonsuicidal ingestion can occur when workers do

not adhere to appropriate industrial hygiene.
Clinical effects are owing to stimulation of the muscarinic and nicotinic receptors
(see Table 3). Muscarinic stimulation causes defecation, urination, miosis, brady-
cardia, bronchorrhea, bronchospasm, emesis, lacrimation, and salivation (remem-
bered by the mnemonic DUMBBBELS). Stimulation of the nicotinic receptors in the
sympathetic ganglia and neuromuscular junction will cause mydriasis, tachycardia,
weakness, hypertension, and fasciculations (Monday–Tuesday–Wednesday–
Thursday–Friday).37 The “mixed” nicotinic and muscarinic clinical effects can be
confusing and lead to misdiagnosis.38 Clinical effects owing to nicotinic receptor stim-
ulation tend to occur first in more severe poisonings.39
CNS effects are varied and can be both nonspecific and severe. These effects
include headache, dizziness, restless, anxiety, insomnia, confusion, tremor, dysar-
thria, ataxia, seizures, coma, and central respiratory depression.40 Finally, given the
balance needed between the dopamine and cholinergic systems, it is not surprising
that both acute and delayed extrapyramidal symptoms occur.41–43
Muscle weakness and paralysis is of particular importance, which contributes to res-
piratory arrest and death. Severe OP poisoning results in depolarizing paralysis, pre-
ceded by muscle twitching and fasciculations. Mechanical ventilation is often
necessary because striated intercostal and diaphragmatic muscles become paralyzed.
Additionally troubling is the “intermediate syndrome,” which develops after acute
exposure to certain highly lipophilic OPs.44 This syndrome, which occurs a few days
after a well-defined cholinergic phase, is defined by the development of diffuse weak-
ness, often leading to respiratory failure requiring ventilatory assistance.45 It is so
named because it typically occurs after the initial cholinergic phase and before the
delayed-neuropathic phase (see Intermediate syndrome, elsewhere in this article).
Inhibition of neuropathy target esterase by certain OPs leads to a syndrome known
as OPIDN. OPIDN typically develops weeks after an acute exposure. A characteristic
progression of symptoms occurs, starting with paresthesias in the hands and feet
leading to sensory loss, weakness, ataxia, and distal muscle flaccidity. Those who
develop OPIDN may recover after a few months; however, in some cases, the effects
are permanent (see Organic Phosphorus-Induced Delayed Neuropathy, elsewhere in
this article). OPs and carbamates affect a number of additional organ systems. The
various cardiac effects are shown in Box 2.
Ventricular dysrhythmias occur a few days after admission and may be related to
direct myocardial damage from interstitial inflammation, myocarditis, or patchy peri-
carditis, which has been described in post mortem histopathology.46–49 The prog-
nostic utility of the QTc interval with respect to respiratory failure and mortality has
been described in at least 3 studies,50–52 but this is not a consistent finding.53,54 QT
prolongation and Torsades de pointes is reported with relative frequency.49,55 Pancre-
atitis and hyperamylasemia have been reported56 and has a reported incidence of
12% of OP-poisoned patients in 1 case series.57 Hyperglycemia and hypokalemia
are the most common metabolic abnormalities.58
Hypotension can occur in up to 17% of OP-poisoned patients based on 1 case se-
ries and may have a variety of etiologies.59 OP- and carbamate-poisoned patients are
invariably volume depleted (emesis, diaphoresis, urination, etc), which indicates a
need for fluid resuscitation during atropinization. Additionally, OPs may cause addi-
tional hypotension by a generalized decrease in the sympathetic outflow from the me-
dulla (“sympatholysis”).60–62 This has been a particular issue with dimethoate.
Hypotension refractory to fluid resuscitation should be managed with direct-acting va-
sopressors, the choice of agent depending on the physiologic parameters of the
 Organophosphate and Carbamate Poisoning 141

Box 2
Cardiac manifestations of organophosphorus insecticide poisoning

Bradycardia, tachycardia
Ventricular arrhythmias
Torsades de pointes
Ventricular fibrillation
Asystole
ECG changes
ST-segment changes
Peaked T waves
AV block
QT interval prolongation
Histopathologic changes
Lysis of myofibrils
Z-band abnormalities

Abbreviations: AV, atrioventricular; ECG, electrocardiogram.

Adapted from Bradberry SM, Vale J. Organophosphorus and carbamate insecticides. In:
Wallece K, Brent J, Burkhart KK, editors. Critical care toxicology: diagnosis and management
of the critically poisoned patient. Philadelphia: Elsevier Mosby; 2005. p. 940. Table 91–2; with
permission.

individual patient. Other medications or therapies that can be considered for refractory
shock include methylene blue or lipid emulsion therapy.63 Neither of these treatments
has been evaluated in the setting of OP or carbamate poisoning and should be consid-
ered off-label indications.

MANAGEMENT
Diagnostics
The diagnosis of OP or carbamate poisoning is typically a clinical diagnosis based on
history and physical examination. In the United States, an exposure is usually known
and reported by the patient, bystanders, coworkers, or emergency medical services.
The simultaneous presence of both muscarinic and nicotinic effects should strongly
suggest OP exposure and empiric, immediate treatment is warranted. Similarly, any
multicasualty incident where multiple victims have seizures, became comatose, or
suffer cardiac arrest should raise suspicion for nerve agent release. Nevertheless,
the diagnosis can be elusive, especially in the case of mild toxicity or atypical presen-
tations; laboratory evaluation and consultation with a medical toxicologist or poison
center may help.
Exposure is typically confirmed in 1 of 2 ways. The first method involves detection of
organophosphorus metabolites (para-nitrophenol or dialkyl phosphate) in the urine.
The second approach involves the assay of AChE and is most useful when the diag-
nosis is not evident or when mild or chronic toxicity is present. Cholinesterase activity
levels are often not readily available within a practical time window for emergency cli-
nicians.64–66 However, laboratory testing can provide useful parameters to follow while
managing an intoxicated patient and can give insight into the disease course and
142 King & Aaron

response to therapy.22,27,67–69 In general, erythrocyte cholinesterase activity corre-

lates best with neuronal AChE activity at the neuromuscular junction and is the
preferred test to evaluate oxime effectiveness.70 Plasma cholinesterase activity can
also be useful, but there are a number of mitigating factors and differences with
plasma cholinesterase assays that affect their utility.22,26,27,67–69

Clinical Management
Removal from the source and patient decontamination is often performed before
health care facility arrival and ideally should be performed by health care providers
in appropriate personal protective equipment. Although secondary contamination
from exposed individuals is likely minimal, level C personal protective equipment
used by properly trained, hospital-based health care providers is recommended.71
See the article by Holland for further information on personal protective equipment
and decontamination.
Further decontamination should be addressed only after initial stabilization and
injury assessment. Removal of all clothing and equipment may substantially reduce re-
sidual exposure directly to the patient and prevent off-gassing of fumes.72 The patient
should then be washed down with soap and water. Alternative methods of decontam-
ination include dilute alkaline soap, military reactive skin decontamination lotion tow-
elettes, sponges, or lotion. Dry decontamination can be performed with talcum
powder, flour, or Fuller’s earth (73available online at http://www.bt.cdc.gov/agent/
agentlistchem.asp).74 Any agent used for decontamination is hazardous waste and
should be disposed of appropriately.
Most patients who succumb to OP or carbamate exposure die from loss of airway
and respiratory drive or from seizures. Threats to airway patency include salivation,
emesis and aspiration, bronchorrhea, bronchospasm, pulmonary edema, seizures,
CNS depression, muscular weakness, and overt paralysis. In severely poisoned pa-
tients, early control of airway and breathing is often required and may need to be per-
formed concurrently with decontamination. Rapid atropinization should be initiated
even before oxygen administration because oxygenation may be impossible until se-
cretions are controlled.75,76 The need for rapid sequence intubation depends on the
clinical situation and response to aggressive and early atropinization. If succinylcho-
line is used for rapid sequence intubation, there will be prolonged paralysis because
succinylcholine is metabolized by plasma cholinesterases.77,78 Although not contrain-
dicated, the use of succinylcholine for rapid sequence intubation is discouraged and
short-acting, nondepolarizing agents are preferred.
Because seizures can be lethal in cholinesterase-inhibiting agent intoxication,
aggressive seizure control with benzodiazepines is paramount and may increase sur-
vival, prevent CNS injury, and avoid cardiac dysrhythmias.74 Although any GABAergic
agent is likely to be effective, an initial dose of 10 mg of intravenous diazepam is sug-
gested given its rapid onset and ease of titration, although any parenteral benzodiaz-
epine may be used. If intravenous access is not immediately available, intramuscular
lorazepam or midazolam can be substituted. Other often-employed anticonvulsants
are unlikely to be effective.79 Specific therapeutic recommendations are discussed
elsewhere in this article.
Gastrointestinal decontamination after OP or carbamate ingestion is of unknown
benefit; however, emesis is common and further removal via gastric aspiration or
lavage is unlikely to have added benefit. OPs are often dissolved in various hydrocar-
bons and attempted mechanical decontamination may lead to pulmonary aspiration
and pneumonitis. It may however, be reasonable to attempt gastric aspiration under
appropriate conditions if the patient’s airway is intact or protected. Further
 Organophosphate and Carbamate Poisoning 143

decontamination with activated charcoal may be reasonable to limit agent absorption.

However, a large, prospective, randomized, clinical trial for all self-poisonings in rural
Asia utilizing therapy with multidose activated charcoal did not find improved out-
comes with multidose activated charcoal administration.80 Furthermore, the use of
activated charcoal should be balanced against atropine-induced ileus and subse-
quent risk of aspiration and charcoal pneumonitis.81

PHARMACOLOGY AND TREATMENT OPTIONS

The pharmacologic section is divided into 3 main sections based on their therapeutic
mechanisms: Antimuscarinic agents, oxime therapy, and seizure control with benzo-
diazepines. The options available to most health care facilities include antimuscar-
inics, oximes, and benzodiazepines.

Antimuscarinics
Atropine
Atropine is a competitive inhibitor of muscarinic receptors both in the CNS and
peripheral nervous systems. Atropine has no effect at nicotinic receptors and
cannot ameliorate symptoms caused by nicotinic stimulation. It is readily available
in most hospitals and easily titrated, given its quick onset of action. Atropine is indi-
cated to reverse any clinical evidence of muscarinic toxicity, especially respiratory
embarrassment from bronchorrhea, bronchospasm, and pulmonary edema. Atro-
pine has the added advantage of helping to control seizures as well as cardiac
toxicity.82–84
Rapid administration of atropine in rapidly escalating doses is recommended.
Patient should receive 1 to 2 mg of atropine initially, and the dose should be
doubled every 5 minutes until pulmonary secretions are dried and the patient has
an adequate heart rate and blood pressure.76 Once control is achieved with bolus
dosing, an atropine infusion should be initiated at 10% to 20% of the total dose
required to stabilize the patient per hour.85 Very large doses may be required and
the clinician may quickly exhaust the hospital’s supply of atropine. Early discussion
with pharmacy regarding the mobilization of hospital and regional stores is sug-
gested. See the article by elsewhere in this issue on resources for information on
mobilizing Chempacks.

Glycopyrrolate
Because atropine is able to cross the blood–brain barrier, CNS anticholinergic toxicity
may occur before adequate control of peripheral cholinergic symptoms. Atropine
treatment can be replaced with glycopyrrolate, a peripheral antimuscarinic agent
without CNS muscarinic receptor activity. Despite limited evidence, glycopyrrolate
is not inferior to atropine, and should be considered an appropriate alternative to atro-
pine if atropine supply is limited.86 Finally, if bronchorrhea and bronchoconstriction are
the primary forms of toxicity, ipratropium can be administered by inhalation with direct
effects on the target end organ.87,88 Indications for antimuscarinic pharmacologic
therapy are provided in Table 4.

Oxime Therapy
Early initiation of oxime therapy prevents OP aging by reactivating enzymes and
improving outcomes. The main goal of oxime therapy is reversal of nicotinic effects
and muscular weakness/paralysis. In vitro experiments demonstrate effective reacti-
vation of OP-poisoned AChE.
144 King & Aaron

Table 4
Recommended symptom based treatment for cholinergic poisoning

Sign/Symptom Agent
Salivation, lacrimation, nausea, Atropine, glycopyrrolate
vomiting, diarrhea
Bronchorrhea, bronchospasm Atropine, ipratropium, glycopyrrolate
Hypotension Fluids, atropine, vasopressors, inotropes
Bradycardia Atropine, glycopyrrolate
Eye pain Ophthalmic preparations that are mydriatics and
cycloplegics
Muscle weakness Oxime therapy
Respiratory failure Intubation and ventilation, oxime therapy (muscle
weakness)
Seizures Benzodiazepines (diazepam, midazolam, lorazepam)

Unfortunately, robust demonstration of clinical efficacy remains elusive.89,90 The

most recent Cochrane review evaluated the existing randomized, controlled trials
and concluded that the “current evidence was insufficient to indicate whether oximes
are harmful or beneficial”; however, study heterogeneity limited the ability to group re-
sults.89 Lower quality evidence suggests efficacy91–95 and oxime therapy continues to
be recommended by many authorities until better evidence emerges that demon-
strates a lack of benefit or harm. A recent, retrospective analysis from India found
that mortality, in combination with poisoning severity and duration of ventilation,
was dependent on delay in oxime administration.96
The most commonly utilized oximes include pralidoxime (2-PAM, Protopam), obi-
doxime (Toxigonin), P2S, and TMB-4. The various oximes are dosed differently and
optimal dosing regiments are debated. The suggested US textbook dosing of prali-
doxime (1–2 g IV, then 1 g every 6–12 hours or 500 mg/h) may be inadequate.92,97–99
The World Health Organization recommends a higher dosing regiment (30 mg/kg
bolus, then 8 mg/kg/h or 30 mg/kg every 4 hours). The recommended obidoxime
dosing regiment is 4 mg/kg, then 0.5 mg/kg/h or 2 mg/kg every 4 hours.74 In all situ-
ations, the dosing should be individualized, depending on patient response.
Administration of oximes to carbamate-poisoned patient is likewise controversial.
However, the preponderance of the data suggests that oxime therapy in the setting
of carbamate toxicity improves morbidity and mortality28,67,100; empiric oxime therapy
should be employed in any patient presenting with cholinergic symptoms.20
Adverse reactions reported with oxime administration include hypertension, vomit-
ing, and short-lived augmentation of neuromuscular block and may be dosing rate
related.91,101,102

Benzodiazepines
In animal models, duration of seizure activity has been correlated with the extent of
neuronal damage. Benzodiazepines should be utilized as early as possible to halt
seizure activity. There are no head-to-head studies in humans that suggest 1 agent
is superior to another. Once an intravenous line is established, a benzodiazepine
can be easily titrated. A reasonable initial dose of diazepam is 5 to 10 mg IV
repeated every 5 minutes until seizure control is obtained. If an IV is not estab-
lished, diazepam has erratic intramuscular bioavailability and alternative agents
such as midazolam or lorazepam should be considered. Intranasal and buccal
 Organophosphate and Carbamate Poisoning 145

formulations of midazolam are viable alternatives if no intravenous access is avail-

able. Midazolam has a relatively short elimination half-life when compared with
other benzodiazepines owing to its relatively high water solubility and may require
redosing.

NONPHARMACOLOGIC TREATMENT OPTIONS

Good supportive care is the cornerstone of management of any poisoned patient. Pa-
tients poisoned with OPs and carbamates often develop respiratory failure and require
intubation and ventilation. Respiratory failure suggests a poor prognosis.103 The usual
care of a ventilated patient should be maintained such as elevation of the head of the
bed deep venous thrombosis prophylaxis, and lung-protective ventilatory settings.
There is no strong evidence to suggest that hemodialysis or hemoperfusion improve
outcomes in the setting of OP and carbamate toxicity.104

SPECIAL CONSIDERATIONS
The Intermediate Syndrome
Upon resolution of the acute cholinergic phase and before the development of delayed
neuropathy, the intermediate syndrome may occur. A few days after poisoning and
during resolution of the cholinergic crises, some OP-poisoned patients develop severe
weakness leading to respiratory failure with the need for (re-)intubation and mechan-
ical ventilation in otherwise seemingly improved, conscious patients.44 The amount of
weakness is variable23 and demonstrates a spectrum of findings. The first clinical
signs of intermediate syndrome are bulbar muscle insufficiency and a simple bedside
test is the inability to lift one’s head off of the bed. The intermediate syndrome may
persist for several weeks. The pathophysiology of the intermediate syndrome remains
unclear, but seems to be multifactorial74 and care remains supportive.

Organic Phosphorus-Induced Delayed Neuropathy

Delayed peripheral neurologic dysfunction, occurring weeks after an acute poisoning,
is well-documented after acute exposures (ie, OPIDN). OPIDN is a separate entity from
the intermediate syndrome with a different pathophysiologic process. OPIDN results
from phosphorylation and inhibition of neuropathy target esterase, leading to a “dying
back” neuronopathy with preservation of the cell body.105 Exposure to certain OPs,
such as triorthocresyl phosphate, can cause OPIDN in the absence of a cholinergic
toxidrome. Historically, contaminated food products and beverages have led to a
number of epidemics in the United States, Vietnam, and Sri Lanka. Onset of OPIDN
is variable, often within weeks and months of exposure. Recovery is similarly variable
and may take months or years.14,106 Interestingly, delayed neuropathy owing to the
carbamates carbaryl, carbofuran, and m-tolyl methyl carbamate has also been
described.107–110

SUMMARY

The outcomes of victims of carbamate and OP poisoning are multifactorial. In general,

outcome depends on the severity of poisoning (amount, duration, and agent), certain
individual factors including one’s intrinsic ability to metabolize certain OPs, preexisting
disease, time to receipt of medical therapy, access to specialists, and hospital capa-
bilities. Despite good supportive and antidotal care, mortality remains high, especially
in the case of OP poisoning. Therapy includes supportive care and aggressive and
early administration of antimuscarinic agents and oximes. Patients poisoned by OPs
146 King & Aaron

should be observed closely after the resolution of acute cholinergic toxicity for devel-
opment of the intermediate syndrome and OPIDN. In general, although acute carba-
mate toxicity should resolve within 24 to 48 hours, clinicians should be aware of the
potential for these patients to develop delayed neuropathy as well.

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