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 Abstract
Background
Organophosphate poisoning
continues to be one of the important
problems of poisoning presenting to the
intensive care unit.
Objectives
To describe the clinical
course, diagnosis, out come of acute
organophosphate (OP) insecticide
poisoning and to review the management
measures taken in intensive care unit
(ICU).
Design
Descriptive prospective
observational study. SETTING: Intensive
Care Unit of Hamad General Hospital,
State of Qatar.
Patients
Patients with acute OP
poisoning admitted to the ICU from 1st
January to 31st December 2005.
Results
Eight patients were admitted to
the ICU; six males and two females.
Seven had accidental exposure, while one
was attempted suicide. The majority of
patients exhibited the classic clinical
features of parasympathetic overactivity.
No patient had features of intermediate
syndrome or Organophosphate Induced
Delayed Neuropathy (OPIDN). All patients
received atropine, while pralidoxime was
given to only 6 patients. Mechanical
ventilation was required in 3 patients
for respiratory failure, with mean
ventilation duration of 2.3 ± 1.5 days.
No mortalities were recorded.
Conclusions
The widespread use
of organophosphates as a household and
agricultural pesticide, in the absence
of adequate regulations and education in
their use is probably the most important
reason for OP poisoning in a
non-agricultural country like Qatar.
Despite severe toxicity in most of our
cases, there were no fatalities. This
reflects the necessity of early
diagnosis, treatment and the
implementation of advanced supportive
care in ICU.
Keywords
atropine,
organophosphate poisoning, pralidoxime.
Introduction
Pesticides comprise a wide range of compounds
including insecticides, herbicides,
fungicides and others. Thus,far more
than 1,000 active substances have been
incorporated in approximately 35,000
preparations of pesticides used in
agriculture(1). Use of pesticides has
increased food production in parallel
with the population growth in many parts
of the world. Many insect-borne diseases
have been eliminated or controlled by
the use of insecticides. Organophosphate
Compounds (OPCs) are used as
insecticides worldwide including a
non-agricultural country like Qatar. In
some countries they are used as chemical
agents of warfare. OPCs may cause acute
or chronic poisonings after accidental
or suicidal exposure. Worldwide, an
estimated 3,000,000 people are exposed
to insecticides each year, with up to
300,000 fatalities(2,3). Toxicity
generally results from accidental,
intentional ingestion or from exposure
to agricultural pesticides(2,4). Other
potential causes of organophosphate
toxicity include ingestion of
contaminated fruit, flour, or cooking
oil, and wearing contaminated clothing
(4,5). In the State of Qatar,
approximately 27 patients with OP
poisoning were admitted to the medical
ICU of Hamad General Hospital from
2003-2005. The causes of toxicity were
mostly because of the improper use of
insecticides by farmers, due to lack of
adequate regulations, instructions and
educations in the use of these
compounds. The current study was aimed
to evaluate our patients' clinical
features, characteristics, and
management modalities and compare them
to other studies elsewhere in the world.
Methods
Design & setting: A prospective descriptive
study was performed on the patients with
acute OP poison ing admitted to
our medical intensive care unit of Hamad
General Hospital between 1st January
2005 and 31st December 2005.
Criteria for diagnosis: The diagnosis of
OP poisoning was based on:
1. History of exposure.
2. Clinical manifestations of OP poisoning.
3. Low serum pseudocholinesterase activity, as the more sensitive
acetylcholinesterase is not available in
our laboratory.
Treatment with Atropine and / or
pralodixime sulfate was administered as
soon as the diagnosis of OP insecticide
poisoning was suspected. Atropine was
given as a continuous infusion at a dose
of 0.02-0.08 mg/kg per hour until
atropinisation was achieved.
Criteria to discontinue atropine:
1. Clinical recovery; usually 1-3 days after all
signs of atropinisation occurred and
drying of secretions was achieved.
2. Atropine intoxication evidenced by confusion or
tachycardia. Pralidoxime sulfate was
administered as a continuous infusion at
a dose of 0.5 gm per hour.
Criteria to discontinue pralidoxime:
1. Enzyme
activity has reached maximum and the
organophosphorous compound has been
eliminated.
2. Pralidoxime intoxication evidenced
by circumoral paraesthaesias,
convulsions, neuromuscular blockade.
Gastric lavage followed by
administration of activated charcoal via
nasogastric tube, and cleansing of the
patient's body with soap and water were
performed as needed. All patients were
admitted to the intensive care unit
regardless of the severity of the
clinical signs and symptoms. Blood gas
and routine biochemistry were performed
daily. The indications for endotracheal
intubation and mechanical ventilation
were as follows: Excessive secretions;
inability to protect the airway because
of depressed level of consciousness;
poor gas exchange, unresponsive to
oxygen treatment; cardio-respiratory
arrest; and severe metabolic acidosis
with hemodynamic instability (systolic
blood pressure < 90 mmHg).
Severity of intoxication
Mild
intoxications were defined by symptoms
of miosis, rhinorrhea, lacrimation, and
mild abdominal pain. Moderate cases were
defined as having aggravation of the
latter symptoms with additional
complaints of the respiratory and
gastrointestinal systems. Severe cases
were defined as having, in addition to
the previous symptoms, loss of
consciousness, convulsions or
respiratory depression.
Data collection and statistical analysis:
Data was collected on a standard form,
including demographic characteristics,
clinical presentation, and history of
previous disease, coexisting medical
conditions, drug history, physical
examination findings,
electrocardiography, radiography
results, and laboratory findings. All
the collected data from each
questionnaire were fed into a software
program for epidemiological analysis (Epi
info 2000).
Results
Eight patients were admitted to the ICU of Hamad
General Hospital between 1st January and
31st December 2005. Six were males and
two were females. The mean age was 30.6
± 14.3 years (range 14 to 61 years).
Three (37.5 %) patients were from India,
one (12.5%) was from Indonesia, one
(12.5 %) was from Pakistan, one (12.5 %)
was from Sudan, one (12.5 %) was from
Nepal and one (12.5 %) was from Qatar.
Seven patients were exposed to OP
accidentally, while one attempted
suicide. Six (75%) patients had
inhalational poisoning; one (12.5%)
patient was poisoned through the
gastrointestinal route while one (12.5%)
patient was poisoned through the skin.
The source of poisoning was Diazinon (O,O-diethyl
0-2-isopropyl-6-methyl(pyrimidine-4-yl)
phosphorothioate) in 3 patients, and
Malathion
(0,0-dimethyl-S-(1,2-dicarbethoxyethyl)
dithiophosphate) in one patient, but was
unknown in 4 patients.
Clinical features
( Table 1):
The most common presenting symptoms were excessive salivation (100%),
agitation (87.5%), disturbance of consciousness (75%), abdominal pain (62.5%)
and abdominal cramps (50%). The most common physical findings were miosis
(100%), weakness (75%), bradycardia (62.5) and fasciculations (62.5%). Five
patients (62.5%) were categorized as having moderate severity, while three
patients (37.5%) had severe poisoning and developed respiratory failure
evidenced by severe hypoxemia that required mechanical ventilation with a mean
ventilation duration of 2.3 ± 1.5 days. Of these patients; one had convulsion,
and two had aspiration pneumonia. The mean length of stay in the ICU was 5.8 ±
2.2 days, with a range of 3-9 days. No patient had intermediate syndrome or
OPIDN. There were no mortalities.
Investigations and treatment:
Except for low pseudocholinesterase levels
(Table 2),
no other significant abnormal laboratory results were found.
Treatment was started from 5 to 10 hours after exposure, even when a reliable
history could not be confirmed. All patients received atropine, which was
administered for 5.6 ± 2.4 days; the mean daily dose was144 ± 179.6 mg, while
the total dose was 969 ± 1710.9 mg. A total of 6 (75%) patients also received pralidoxime. Pralidoxime was given for 4.6 ± 3.5 days and the mean total dose
was 54 ± 41.6 g.
Discussion
Organophosphates are widely used in agriculture worldwide and are common causes
of poisoning that continue to result in
significant fatalities. Qatar is a
desert country where agriculture is
limited to few products in restricted
areas. But, similar to other countries,
OP and in particular Diazinon, Malathion
and other products are widely available
and are used as insecticides in
agriculture and in the household. Some
products in the market are not
registered or licensed and are not under
the supervision of health authorities.
Public perception of toxicity of OP is
low and many are unaware that even
minute quantities of OP are readily
absorbed through the skin and can be
lethal. Many people who work in farms
are simple people who lack experience in
dealing with these products. This has
been reflected in this study where most
of the poisoning occurred because of
inhalation due to lack of the
appropriate protection and safety
measures. Worldwide, the main route of
intoxication reported was the oral route
in the vast majority of cases, possibly
due to the high frequency of accidental
exposure, especially in children (6,7).
In contrary, the vast majority of our
patients had inhalational poisoning. OP
poisoning due to suicidal attempt
accounts for at least 40-68% of all
cases in some countries(8, 9, 10), while
in our study suicidal attempt accounted
for only 12.5 %. There have been
occasions in previous admissions to our
hospital where exposure occurred when
people used bare hands to spread
insecticides on the body of camels to
kill insects resulting in serious
toxicities. In agreement with other
reports(11,12), the insecticide agent
was unknown in almost half the patients
in our study, and the diagnosis was
based on a history of exposure to an
unknown agent, clinical findings and low
pseudocholinesterase levels. This may be
due to the fact that those agents are
unknown or not licensed for use in the
country. In the remaining half, Diazinon
and Malathion were the cause of
toxicity. The primary mechanism of
action of OPCs is inhibition of
acetylcholinesterase (AChE). OPCs
inactivate AChE by phosphorylating the
serine hydroxyl group located at the
active site of AChE. They inhibit both
cholinesterase (known as red blood cell
acetylcholinesterase) and
pseudocholinesterase (known as plasma
cholinesterase) activity(13). The
inhibition of acetylcholinesterase
causes accumulation of acetylcholine at
synapses with resultant over-stimulation
and disruption of neurotransmission in
both central and peripheral nervous
systems(13). After some period of time
(dependent on the chemical structure of
the or ganophosphorous agent), the
acetylcholinesterase-organophosphorous
compound undergoes a conformational
change, known as "aging," which renders
the enzyme irreversibly resistant to
reactivation by an antidotal oxime(14).
The clinical features of OP poisoning
are due to excess acetylcholine at the
muscarinic and nicotinic receptors which
leads to initial stimulation and
eventual exhaustion of cholinergic
synapses(15). Following classical OP
poisoning, three well defined clinical
phases are seen: initial acute
cholinergic crisis, the intermediate
syndrome and delayed polyneuropathy (OPIDN)(16).
Symptoms of cholinergic crisis are due
to stimulation of the muscarinic and
nicotinic receptors: Nicotinic
manifestations include increased or
decreased muscle power and skeletal
muscle fasciculations. Muscarinic
manifestations include excessive
salivation, miosis, diarrhea,
bronchorrhoea, bronchospasm, Bradycardia
and urination. Other signs include
vomiting, respiratory distress,
abdominal pain and depressed level of
consciousness. In agreement with other
reports(15) the most frequent symptoms
in our study were excessive salivation,
agitation, disturbance of consciousness,
abdominal pain and abdominal cramps,
while the most common physical findings
were miosis, weakness, bradycardia and
fasciculation (Table 1). The cholinergic
phase is a medical emergency that
requires treatment in an ICU. Death is
likely during this initial cholinergic
phase due to the effects on the heart (bradycardia
and other arrhythmias), respiration
(central or peripheral ventilatory
failure) and on the brain (depression of
vital centers). The 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. Oximes (effective in
the early phase) are clinically
important reactivators of
acetylcholinesterase, which can prevent
degenerative effects of insecticide
intoxication. It is a policy in our
center to admit all patients with OP
poisoning to ICU regardless of the
severity of the clinical signs and
symptoms. The cholinergic phase is
treated as soon as the diagnosis of OP
insecticide poisoning is suspected.
Atropine and/or pralidoxime sulfate are
the standard treatments administered.
Atropine competes with acetylcholine at
muscarinic receptors, preventing
cholinergic activation. Muscarinic signs
such as miosis, diarrhea, vomiting,
sweating, bronchial secretions are
usually first to appear, and are treated
with atropine. Nicotinic signs usually
appear later, and do not respond to
atropine. Atropine is given as a
continuous infusion started as 0.02-0.08
mg/kg per hour (17),dosing should be
titrated to the therapeutic end point of
the clearing of respiratory secretions
and the cessation of
bronchoconstriction(18). Atropinization
is assessed by a combination of signs
including pupils, pulse rate, pulmonary
secretions and mental state. It is not
desirable to use any one criterion
alone, because cases are seen where the
pupils do not dilate or pulse does not
become fast inspite of adequate doses.
Atropinisation, once achieved, should be
maintained for 1-3 days, depending upon
the compound involved. When muscular
paralysis supervenes, mechanical
ventilation is required. The maximum
dose of atropine in two reports was 1300
mg and 19590 mg respectively(16,17). All
of our patients received atropine for
5.6 ± 2.4 days and the mean daily dose
was 144 ± 179.6 mg, while the mean total
atropine dose was 969 ± 1710.9 mg.
Pralidoxime sulfate was administered as
a continuous infusion started as 0.5 gm
per hour. Continues infusions (500
mg/hour) have been advocated by some
authors for severe poisoning and have
been found to achieve the same
therapeutic level as intermittent
boluses(19-21). Oximes displace the
organophosphates from the acetylchoine
esterases and bind to the enzyme itself.
Later it disassociates and ACHE is
reactivated. Pralidoxime should not be
administered without concurrent
atropine, to prevent worsening symptoms
due to transient oxime-induced
acetylcholinesterase inhibition(22). It
is desirable to maintain the therapeutic
level of pralidoxime till the enzyme
activity has reached maximum and the
organophosphorous compound has been
eliminated. Toxicity of pralidoxime is
evidenced by circumoral paraesthaesias,
convulsions, neuromuscular blockade and
inhibition of acetylcholinesterase. In
this study, a total of 6 (75%) patients
received pralidoxime. Pralidoxime was
given for 4.6 ± 3.5 days and the mean
total dose was 54 ± 41.6 g. As the
poison can be absorbed from the intact
skin, it is necessary to remove any
soiled clothing and wash the skin if
there is evidence of contamination. A
gastric lavage is required for oral
ingestion and this may profitably be
repeated after 2-3 hours as the drug is
secreted back into the stomach and to
remove any residue not fully removed.
The duration of hospitalization ranged
as expected from only 3 days for the
mild cases to 9 days for the severe
cases, but prolonged durations also have
been reported(20). Mortality rate in
different studies ranged from 12 - 27.6
% (23-25). No mortalities were reported
in our patients which may be attributed
to the early diagnosis and treatment, in
the presence of facilities for advanced
supportive care like mechanical
ventilation. Organophosphates may cause
long-term morbidity after the acute
phase of the poisoning, mainly in the
cardiovascular system and in the central
nervous system(28-31). Unfortunately,
however, we lost the long-term follow-up
in our patients. After the acute
cholinergic phase, a second stage of
weakness called the Intermediate
syndrome (IMS) occurs. This syndrome was
described in 1974. It develops 24-96
hours after resolution of the acute
cholinergic poisoning symptoms and
manifests commonly as paralysis and
respiratory distress. This syndrome
involves proximal muscle groups, with
relative sparing of distal muscle
groups. Various degrees of cranial nerve
palsies are also observed. Neuromuscular
transmission defects and toxin-induced
muscular instability play a role in the
intermediate syndrome. The intermediate
syndrome persists for 4-18 days, can
require intubation and can be
complicated by infections or cardiac
arrhythmias. The incidence of IMS in
different studies has been reported to
be between 20 and 68% (32). None of our
patient developed this syndrome. Some
patients develop organophosphate induced
delayed neuropathy (OPIDN) 2-3 weeks
after exposure to large doses of certain
OPCs. OPIDN is an uncommon clinical
condition. It occurs in association with
the ingestion of large amounts of
organophosphate and manifests as limb
weakness persisting long after the acute
cholinergic symptoms have subsided. The
clinical picture is characterized by a
distal paresis in lower limbs. Affected
patients present with transient, painful
"stocking-glove" paresthesias followed
by a symmetrical motor polyneuropathy
characterized by flaccid weakness of the
lower extremities, which ascends to
involve the upper extremities. Sensory
disturbances are usually mild. Delayed
neurotoxicity primarily affects distal
muscle groups, but in severe
neurotoxicity, proximal muscles groups
may also be affected(33). Fortunately,
none of our patients develop OPIDN. In
conclusion, the widespread use of
organophosphates as household and
agricultural pesticides, absence of
adequate regulations controlling their
sale and application, and low public
perception of toxicity of
organophosphates are the major reasons
for acute OP poisoning in Qatar. The
increasing experience of the medical
staff in early diagnosis, management and
implementation of advanced supportive
care has resulted in low mortality in
this group of patients.
References
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