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CALL US...TM
The
Official Newsletter of the
Volume
6, Number 2
Summer 2008
Anticholinesterase
(Organic Phosphorus and Carbamate) Pesticide Poisoning
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Introduction
Organic phosphorus (OP) and carbamate
compounds are some of the most widely utilized pesticides in the world. Globally,
these agents may kill more people each year than acute poisoning by any other
chemical. These pesticides contribute to
thousands of deaths annually in
Case presentation
A 30
year old suicidal man was brought by
relatives to the emergency department (ED) after drinking two cups of 50% parathion
about 3 hours earlier. The patient was awake but confused and extremely
diaphoretic. His initial vital signs in the ED were: blood pressure 200/110 mm
Hg; pulse 105 beats/min; respiratory rate 24 breaths/min;
temperature 98.6°F; and oxygen saturation 94% on room air. Physical examination
showed mid-sized pupils, minimal crackles in all lung fields, and copious
vomiting and diarrhea. The patient was drooling between episodes of vomiting.
On initial
evaluation his airway was patent and he was not in immediate respiratory
distress. He was placed on oxygen by face mask, put on a cardiac monitor, an
intravenous (IV) line was inserted and 2 mg atropine administered. Even with supplemental oxygen and atropine
given, the patient's oxygen saturation began to fall soon after arrival in the
ED. His heart rate also rapidly increased to 120 beats/min,
and an ECG demonstrated a prolonged QTc interval. A portable chest radiograph
showed bilateral pulmonary edema. The poison center was contacted and
recommended administration of more atropine and pralidoxime. After an
additional 4 mg atropine and pralidoxime 1 g IV, his breath sounds improved. His
oxygenation continued to fall, and he began coughing up pink-tinged, frothy
sputum. He continued to have large amounts of vomiting and diarrhea. A
pralidoxime bolus of 1 g was administered IV over 15 minutes and an infusion at
500 mg/h was initiated. The poison center also advised giving additional 2 mg
atropine doses every 5–15 minutes as needed to control his secretions.
Although the
emesis, diarrhea, and bronchorrhea diminished after a total of 25 mg of
atropine, the clinicians elected to intubate the patient. His oxygen saturation
following intubation was 98% on 100% FIO2. He was transferred to the
intensive care unit (ICU). Toxicology
screening including acetaminophen and salicylate
concentrations was negative.
In the ICU, the
pralidoxime infusion was continued at 500 mg/h, and atropine was administered
intermittently throughout the first 24 hours of admission for a total dose of 30
mg. The chest radiograph improved over the first 24 hours. His ECG gradually improved by the second day,
with a heart rate of 105, and normalization of his QTc interval.
On hospital day 2,
his sedation was terminated and he was extubated. His nausea and vomiting had
largely improved, and no further frothy sputum was observed. Cholinesterase
measurements sent initially showed virtually no detectable red blood cell (RBC)
or butyrylcholinesterase (plasma) activity.
He was transferred to a step-down unit for observation, and did not
require any further atropine that day. The pralidoxime infusion was maintained
at 500 mg/h.
On hospital day 3,
the patient reported feeling much better. His pralidoxime infusion was stopped
and he was evaluated by psychiatry and transferred to the inpatient psychiatric
service the following afternoon.
.
Questions:
1.
What
is the mechanism of toxicity of OP and carbamate
pesticides?
2. What are the most common life-threatening
effects of OP and carbamate pesticides?
3. What treatments are most important in
managing poisonings by these agents?
Epidemiology
In 2007, Californians reported over 700 exposures to
OP and carbamate pesticides to the CPCS. Nationally, more than 15,000 poisonings with
these chemicals are reported to poison control centers each year, with five or
six fatalities. The World Health Organization (WHO) estimates that at
least one million unintentional poisonings and two million suicide attempts
occur annually worldwide from these insecticides. However, these figures undoubtedly omit
numerous unreported and possibly unrecognized illnesses resulting from lower
level environmental exposure to these chemicals.
Most often patients
present following unintentional or suicidal ingestion of cholinesterase
inhibiting insecticides or after working in areas recently treated with these
compounds. Children and adults can develop toxicity while playing in or
inhabiting a residence recently sprayed or fogged with OP or carbamate insecticides. Direct dermal contact with certain
types of these insecticides may be rapidly poisonous. Outbreaks of mass
poisoning have occurred from contamination of crops or food. OP agents have
also been used for homicide.
OP
and carbamate pesticides are collectively known as anticholinesterase agents due to their activity at
cholinergic nerve terminals in the body.
Although the term “organophosphate”
is traditionally used in clinical practice and in the literature to refer to
all phosphorus-containing pesticides that inhibit cholinesterase, phosphates (or
phosphoric acids) include compounds in which a P atom is bound covalently to
four O atoms; non-phosphate derivatives of phosphoric and phosphonic acids such
as phosphonates can also exhibit cholinesterase inhibition. Thus the term organic phosphorus compound may
be more inclusive and less misleading.
Pathophysiology
Acetylcholine
(ACh) is a neurotransmitter found at both parasympathetic and sympathetic ganglia, skeletal
neuromuscular junctions, terminal junctions of all postganglionic
parasympathetic nerves, post-ganglionic sympathetic fibers to most sweat
glands, and at some nerve endings within the central nervous system. As the axon terminal is depolarized, vesicles
containing ACh fuse with the nerve terminal,
releasing ACh into the synapse or neuro-muscular
junction. Acetylcholinesterase (AChE) is
an enzyme that hydrolyzes ACh into two inert fragments: acetic acid and
choline. Under normal circumstances, virtually all ACh released by the axon is
hydrolyzed almost immediately. Organic phosphorus insecticides and carbamates
inhibit numerous carboxylic ester hydrolases within the body, including AChE, plasma or butyrylcholinesterase (pseudocholinesterase),
and other nonspecific proteases. AChE is found in human nervous tissue and skeletal muscle,
and on erythrocyte (RBC) cell membranes. The end result of cholinesterase inhibition is
a build up of ACh in nerve terminals leading to excessive
stimulation of cholinergic neurons in the autonomic, peripheral and central
nervous systems. Chemical weapons known
as “nerve agents” are volatile, rapidly acting cholinesterase
inhibiting agents that work similarly to organic phosphorus and carbamate pesticides.
The OP and carbamate pesticides bind to a hydroxyl group at the active
site of the AChE enzyme. Part of the OP insecticide is split off during its
bonding to AChE, and a stable but slowly reversible
bond results between the remaining OP moiety and the enzyme, effectively
inactivating the enzyme in a process called “aging.” The aged OP-enzyme bond can take days to sever,
and de-novo synthesis of the enzyme is usually required for a return of
function. The carbamate-enzyme bond does
not undergo aging and resolution of clinical toxicity is generally more rapid than
with organic phosphorus poisoning.
Clinical presentation
Clinical
findings of toxicity from OP and carbamate compounds
derive from excessive stimulation of muscarinic and
nicotinic cholinergic receptors by ACh in the central and autonomic nervous
systems, and at skeletal neuromuscular junctions. A patient with anticholinesterase insecticide poisoning is classically
described as unresponsive with pinpoint pupils, muscle fasciculations,
diaphoresis, emesis, diarrhea, salivation, lacrimation, urinary incontinence,
and an odor of garlic or solvents; however, most clinical presentations are not
so typical. The onset of symptoms varies according to the compound, the route,
and the degree of exposure. Patients suffering massive ingestions can become
symptomatic as quickly as 5 minutes following ingestion, and deaths have
occurred within 15 minutes of ingestion. Most victims of acute poisonings
become symptomatic within 8 hours of exposure, and nearly all are symptomatic
within 24 hours. The longest delays may occur with compounds requiring
metabolic activation, such as malathion, or very lipid-soluble agents such as
fenthion. Symptoms may last for variable lengths of time, again based on the
agent and the circumstances of the exposure. The more lipophilic
compounds can cause cholinergic effects for days following oral ingestion.
The effects of
excessive ACh on the autonomic nervous system may vary because cholinergic
receptors are found in both the sympathetic and parasympathetic nervous
systems. Excessive muscarinic activity can be characterized by several
mnemonics, including "SLUD" (salivation, lacrimation, urination,
defecation) and "DUMBBBELS" (defecation, urination, miosis, bradycardia, bronchospasm,
bronchorrhea, emesis, lacrimation, salivation). Of these, miosis may be the
most consistently encountered sign, but multiple clinical variations can occur.
Bronchorrhea can be so profuse that it mimics
pulmonary edema.
Although parasympathetic
or muscarinic findings are emphasized in these
mnemonics, muscarinic signs may not be clinically evident, except in very
severe poisonings. In many cases, parasympathetic findings are offset by
excessive autonomic activity from stimulation of nicotinic adrenal receptors
(resulting in catecholamine release) and postganglionic sympathetic fibers.
Mydriasis is reported in many cases. Sympathetic
stimulation may result in hyperglycemia, leukocytosis
and urinary retention.
Cardiopulmonary
effects are also common with severe poisonings from cholinesterase
inhibitors. Increased sympathetic tone
is often initially present, and most patients present with a sinus tachycardia,
with or without hypertension. Bradycardia with a
prolonged PR interval and atrioventricular blocks of various degrees occur as
toxicity becomes more severe. QT
interval prolongation has been reported in severe cases. The most common pulmonary complications of
these compounds are bronchorrhea and bronchoconstriction. Liquid pesticide preparations
are usually dissolved in a hydrocarbon-based solvent, frequently resulting in aspiration
leading to hydrocarbon-induced pneumonitis.
Acetylcholine
stimulation of nicotinic receptors also governs skeletal muscle activity. The
effects of excessive cholinergic stimulation at these sites are similar to that
of a depolarizing neuro-muscular blocking agent (succinylcholine)
initially resulting in fasciculations or weakness. As the severity of poisoning progresses,
paralysis ensues. Paralysis of the respiratory muscles in combination with
bronchorrhea, bronchoconstriction, and CNS depression leads to hypoxemia and
respiratory arrest, which is the most common cause of death.
Diagnosis
When a patient
presents in cholinergic crisis with a history of acute excessive exposure to a
cholinesterase inhibitor insecticide, the diagnosis is usually straightforward.
However, when the history is unreliable or does not suggest poisoning, the
physician must turn to other means to confirm the diagnosis of OP or carbamate insecticide poisoning.
The most reliable
laboratory test for confirming cholinesterase inhibition by insecticides
measures specific insecticides or active metabolites in biologic tissues.
Unfortunately, urine and serum assays for organic phosphorus compounds and
their metabolites are available but are rarely obtainable within a reasonable
period of time to guide clinical management. Therefore, the most accurate and
readily obtainable laboratory testing for these agents relies on surrogate
markers for neuronal ACh found in the red blood cell
(RBC) and plasma. Butyrylcholinesterase
(plasma cholinesterase) is able to metabolize various compounds, including
succinylcholine and cocaine. RBCs contain a form of AChE that is structurally similar to the enzyme found in nerve
tissue. Inhibition of either RBC cholinesterase or butyrylcholinesterase does
not contribute to signs or symptoms of poisoning. Testing the activity of these enzymes only
serves as a marker of systemic cholinesterase inhibitor poisoning.
After a significant
exposure, butyrylcholinesterase activity usually falls first, followed rapidly
by a decrease in RBC cholinesterase activity. The sequence may be highly
variable, but by the time patients present with acute symptoms, levels of both
cholinesterase activities have usually fallen well below baseline values, and
often have fallen below detectable limits.
Butyrylcholinesterase
activity usually recovers before RBC cholinesterase activity, often returning
to normal within a few days in the absence of a repeat or ongoing exposure.
However, butyrylcholinesterase activity is less specific for exposure than is
red cell cholinesterase activity. Low butyrylcholinesterase activity can be
found in patients with a number of disorders, including malnutrition, hepatic
disease, metastatic cancer, and iron deficiency anemia. Oral contraceptives can
also cause a measurable decrease in butyrylcholinesterase
activity. Additionally, day-to-day variation in the activity of this enzyme in
healthy individuals may be as high as 20%.
RBC cholinesterase
activity is thought to reflect nervous tissue AChE activity more accurately than
butyrylcholinesterase. Because these
blood tests are only markers of neuronal enzyme inhibition, individual variation
may lead to some patients presenting highly symptomatic after minimal
reductions in RBC or butyrylcholinesterase, while others may be asymptomatic
after losing 50% activity. The wide range of normal RBC and butyrylcholinesterase
activity also allows for patients with high-normal values to suffer significant
falls in cholinesterase activity, yet still register near normal levels of
cholinesterase activity on laboratory assay.
The most important aspect to consider when interpreting the
cholinesterase activity is the comparison of reported laboratory values with
baseline values in that individual. Because baseline values are usually
unavailable in most cases, laboratories report out a "reference
range" of activity. This range is based on the central 95% of values of
cholinesterase activity for the general population.
Treatment
The
earliest potential causes of death in anticholinesterase poisoning are respiratory
failure and hypoxemia that may result from coma and convulsions, nicotinic
effects on skeletal muscles (weakness and paralysis) and muscarinic effects on
the cardiovascular and pulmonary system (bronchospasm, bronchorrhea,
aspiration, bradydysrhythmias, or hypotension.) Therefore primary treatment for
a patient exposed to these compounds is directed at ensuring an adequate airway
and ventilation, and at reversing excessive muscarinic effects, particularly bronchorrhea. Decontamination of the skin is important in
topical exposures but GI decontamination is unlikely to be effective in the
majority of cases. Contamination of
health care workers with these agents during decontamination procedures is
possible but very unlikely when standard barrier protection precautions are
undertaken.
Atropine
antagonizes ACh at muscarinic cholinergic receptors
to reverse excessive secretions, miosis, bronchospasm, vomiting, diarrhea,
diaphoresis, and urinary incontinence. For adults with anticholinesterase
pesticide poisoning, IV doses should begin with boluses of 1–5 mg. Recommended dosing for children is 0.05 mg/kg
up to adult doses depending on the severity of symptoms. Repeat doses of
1–2 mg should be given every 2–3 minutes or more rapidly until stabilization
occurs. A reduction in pulmonary secretions is the primary target of
atropine therapy. Large cumulative doses of atropine may be required. Tachycardia is not a contraindication to
atropine therapy. Isolated pulmonary manifestations may respond to
administration of nebulized atropine or ipratropium. If atropine-induced antimuscarinic
CNS toxicity is present, but peripheral cholinergic findings necessitate the
administration of more atropine, glycopyrrolate bromide can be substituted for
atropine because its quaternary ammonium structure limits CNS penetration.
Although pesticide-bound
AChE undergoes hydrolytic regeneration at a very slow rate, this process can be
enhanced by using an oxime medication such as pralidoxime
hydrochloride (2-PAM). Pralidoxime is
unable to rejuvenate active enzyme from the OP–AChE
complex that has undergone aging. Therefore, pralidoxime therapy is most
effective if started early in the course of toxicity. The starting dose of pralidoxime for adults
is 1–2 g IV and for children 20–40 mg/kg IV, both over 10–15
minutes. A constant infusion of pralidoxime appears to be more effective than bolus dosing
in maintaining necessary levels. For adults, a maintenance infusion of
250–500 mg/h is usually recommended, titrating
to symptoms, but infusions of up to 8 mg/kg/h or more may be required in some
cases. Reports in children suggest using a continuous infusion of 10–20
mg/kg/h after the initial bolus. Side
effects of pralidoxime are usually minimal at normal doses. The efficacy of pralidoxime
in some anticholinesterase pesticide poisonings has
been questioned in recent studies from other countries, and results may depend
on the agent involved in the exposure.
Finally, studies
suggest the administration of diazepam or other benzodiazepines may improve
outcome in anticholinesterase pesticide
poisoning. Besides decreasing the
incidence of seizure and resulting CNS damage, there is data to support
improved respiratory function and outcome when benzodiazepines are used in
conjunction with oximes in severe cases.
Discussion of case questions
1. What is
the mechanism of toxicity of OP and carbamate
pesticides?
OP and carbamate
pesticides cause toxicity by binding to cholinesterase in nerve terminals,
inhibiting the breakdown of acetylcholine.
The result is excessive stimulation of cholinergic neurons on the
autonomic, peripheral and central nervous systems.
2. What is the most common life-threatening
effect of OP and carbamate pesticides?
Extreme weakness and
paralysis due to cholinergic motor neuron stimulation leading to respiratory
arrest is the earliest cause of death in most anticholinesterase
pesticide poisonings. Copious pulmonary
secretions from muscarinic stimulation can lead to pulmonary edema, aspiration
and hypoxia that can also be fatal.
3.
What treatments are
most important in managing poisonings by these agents?
Airway support with mechanical ventilation
may be required as initial therapy in severe cases when paralysis and
respiratory arrest are imminent.
Atropine should be administered, often in large quantities, to control
muscarinic signs and symptoms.
Pralidoxime should also be given to patients with symptomatic OP
poisoning to help more quickly rejuvenate cholinesterase.
Consultation assistance
Consultation with a
specialist in poison information or with a medical toxicologist can be obtained
free of charge by calling the California Poison Control System at
1-800-222-1222.
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