Chapter 12: Managing Effects of Organophosphates and Carbamates

Introduction
Organophosphates (OPs) and carbamates are widely used usually as insecticides. They are one of the
commonest causes of poisoning in agricultural communities. In Asia alone 200,000 deaths per year result
from intentional ingestion of OP compounds They can cause life-threatening poisoning after accidental or
suicidal exposure. Sometimes they may be used as agents of terrorism as have occurred with the use of
sarin in Japan (1995)

They are extremely toxic chemicals which can result in a variety of clinical presentations. The exposure
dose varies depending on the cause of the accident. When used as an agent of deliberate self-harm
patients may ingest doses 100-1000 times greater than what is encountered during occupational exposure
such as during swing fogging. However, there is no clear relationship between reported levels of exposure
and clinical toxicity. In clinical practice, it would be prudent to consider all oral poisonings with
anticholinesterase agents as significant.

Some OP agents have been developed as chemical warfare agents (eg. GA [Tabun], GB [Sarin], and GD
[Soman]). These are extremely toxic to humans. They have a very rapid onset of action with
predominantly central nervous system effects. They have been used in warfare such as during the Iran-
Iraq wars and during terrorist incidents, especially in Japan.

Carbamates are similar to OP in their effects on humans and have similar treatment approaches. They are
usually said to be less toxic than organophosphates because of their reversible binding to acetyl-choline
esterase (AChe), an enzyme found at nerve endings and that play a vital role in transmission of nervous
impulses from one nerve to the next and also across neuro-muscular junctions. However, if not well
managed, they can have a similar morbidity and mortality profile to organophosphates.

Mechanism of action of organophosphates

Organophosphates inhibit the acetylcholinesterase enzyme in nerve synapses (AChE), on red blood cell
membranes (RBC-AChE), and butyrylcholinesterase in plasma (PChE).

Figure 1: Mechanism of Action of Organophosphates

The transmission of nerve impulses across nerve-nerve and nerve-muscle endings depends on the release
of a transmitter chemical substance from the nerve ending. This chemical substance is called acetylcholine
(ACh). ACh acts on ACH receptors across the junction and this leads to transmission of the nerve impulse
to the next nerve fibre. This process allows nerve impulses to be conducted across all such junctions in the
body. To prevent the ACh from acting continuously and indefinitely, an enzyme called acetylcholine
esterase (AChE) that circulates in the blood stream attaches to the ACh and breaks it down. This cuts off
that nerve impulse and allows the next nerve impulse to pass through and activate the receptor on the far
side of the nerve junction.

Organophosphates exert their toxic effect by neutralizing the AChE enzyme (Figure 1). This allows the
accumulation of acetylcholine at nerve endings resulting in continuous stimulation of the neuro-effector
junctions, skeletal neuro-muscular junctions, autonomic ganglia and in the brain. This results in
overstimulation of the muscarinic( nerve organ junctions of skin, intestines, lungs, brain and spinal cord)
and nicotinic receptors (nerve-organ receptors in skeletal muscle, autonomic ganglia and nerve-nerve
junctions in the brain). Some nerve agents when combined with AChE form a permanent bond after some
time, a process known as ‘ageing’. When ageing occurs, antidotes for the organophosphate may no more
be effective.

Clinical Effects of Organophosphates and Carbamates

Poisoning by organophosphates may follow ingestion, inhalation or dermal absorption. A person exposed
to organophosphates has the following clinical effects:

1. The person initially feels sick and complains of headache, general weakness and tiredness
2. He then begins to sweat and salivate and may also develop vomiting and diarrhoea with
abdominal cramps.
3. He then develops blurring of vision and his pupils become very small.
4. With continuing exposure his muscles begin to twitch and his hands shake. His breathing becomes
very bubbly
5. He may then throw a seizure and become unconscious

A simpler way to remember the effects of organophosphates and carbamates would include the following
three mnemonics:
A: SLUDGE (M) -- Salivation, Lacrimation, Urination, Defecation, gastrointestinal Upset, Emesis
B: DUMBBELSS – Diarrhoea, Urination, Miosis / Muscle Weakness, Bronchorrhoea, Bradycardia, Emesis,
Lacrimation, Salivation / Sweating
C: 3D – Dark, Drenched, Disabled

The rapidity of progression of symptoms and possible death depends on the dose, the route of exposure,
the agent involved and the degree of protection taken by the patient. Death has been known to result
within five minutes or sometimes up to 24 hours after exposure. Death, if occurs, is usually contributed to
by respiratory depression, blockage of airways by secretions, uncontrolled seizures and cardiovascular
collapse.

A diagnosis of organophosphate poisoning may be made either by recognition of physical signs as above,
or by use of hand-held manually operated chemical agent monitors (CAM) that may be used either by
rescue personnel or even by trained persons in the hospitals. Once detected by CAM, The symbol ‘G’ will
be shown on the screen of these monitors. In hospitals red blood cell (RBC) cholinesterase activity may be
tested. Reduced levels below 75% of the lower limit of normal range would be indicative of poisoning with
organophosphate substances. RBC-AChE correlates well with synaptic AChE function and is thus a
reasonably good marker of severity.

Despite the above total reliance on cholinesterase levels may not always be possible. In most situations
the management of anticholinesterase poisoning is based primarily on clinical features. Blood
investigations should play a secondary role in aiding clinical decisions.

Triage of casualties exposed to Organophosphates.

Casualties reporting from a locality exposed to nerve agents may be categorized into four groups
depending on the level of severity of exposure. These are:
• Priority 1 (Severe casualties):
o Acute severe or life threatening effects after short exposure to effects interval of seconds
to minutes
o Distressed with breathlessness or wheeze culminating in apnoeic respiratory arrest
o Agitation, altered level of consciousness, coma, seizures, exhaustion, cyanosis, autonomic
dysfunction or flaccid Paralysis
o Abnormal vital signs : Bradycardia, Hypotension, Tachypnoea / Respiratory insufficiency
with inability to complete a sentence between breaths
o May be using accessory muscles of respiration with intercostal recession with a
respiratory rate of more than 25 in adults or more than 40 children.
o Presence of crepitations and / or wheezes on lung auscultation
o A pulse oximetry (SpO2) level of less than 92%
o RBC acetylcholinesterase levels below 10% of lower limit of normal.

• Priority 2 (Moderate Casualties)

o DUMBBELSS
o Presence of tremors and fasciculations
o Profound weakness of skeletal muscles
o Patient appears confused
o Complains of chest tightness and noted to be coughing and wheezing
o A pulse oximetry (SpO2) reading in excess of 92 %
o Vital signs : Bradycardia, Normotension, Tachypnoea
o RBC acetylcholinesterase levels between 10 – 50 % of lower limit of normal

• Priority 3 (Mild casualties)

o Suspected exposure to chemical agent
o The patient presents with eye pain and / or blurred Vision
o He is often noted to be tearing and having rhinorrhoea
o His conjunctiva are injected, sometimes with sub-conjunctival haemorrhage
o The pupils are small (miosis) and occurs with visual blurring symptoms.
o The patient complains of nausea and may vomit occasionally
o He feels very lethargic and tires easily. Muscle weakness is only mild on physical
examination.
o He would complain of abdominal cramps without diarrhoea and may not appear
distressed.
o His vital signs indicate mild tachycardia and sometimes mild hypertension
o RBC acetylcholinesterase levels would usually be more than 50% of the lower range of
nornmal.
 • Priority 4 (Non-emergency)
o Such patients would usually have been physically away from the chemical incident site
o They appear anxious, but otherwise have no significant symptoms
o They would have no eye pain, tearing or rhinorrhoea
o They are not tachypnoeic and have no wheezing on auscultation
o Pulse oximetry levels and vital signs would be normal
o RBC acetylcholinesterase levels would be within the normal range

Triage Tags used during management of organophosphate poisoning should be waterproof as would be
relevant in the management of other chemical disasters. An example of such a triage tag is shown below
(Figure 2).

Figure 2: Triage Tag used for chemical disaster casualties.

Management of Organophosphate Poisoning

Field management at the disaster site:

1. At disaster sites, casualties rescued from sites exposed to organophosphates or suspected to be

exposed to these agents would undergo an initial triage by the rescue services. All casualties
suspected to have been exposed would first need to be given one dose of the antidote. The
antidotes to be used at disaster sites come in the form of an autoinjector.
2. After a quick assessment by the rescue personnel, the severity of poisoning is determined.
3. If there is a need to protect the airway in casualties who are not fully conscious, procedures for
these would be carried out. If needed ventilator support in the form of bag mask ventilation or
oxygen or both may be given.
4. Antidote will then be administered in the form of autoinjectors. The various types of autoinjectors
available would be discussed later in the chapter
5. Following administration of the first dose of the antidote, the casualty will undergo the
decontamination process as described in Chapter 6 above.
6. Following decontamination the casualty would be re-triaged into the clean zone where the first-aid
post will be situated.
7. At the First Aid Post the priorities in management are as follows:
a. Ensure that the ABCs are secured (i.e. casualty is having an open airway, is breathing,
provided with oxygen and has vascular access instituted.
b. The patient should be placed on ECG and vital signs monitoring. Documentation of level of
consciousness, heart rate, respiratory rate, oxygen saturation and pupil size would be
important.
c. The antidotes that must be considered at the first aid post include intravenous atropine
and intravenous pralidoxime
d. If the casualty is having seizures, intravenous diazepam would be the drug of first choice
to abort these seizures.
e. If it is felt that the casualty may not be able to maintain an open airway, endotracheal
intubation should be institution with positive pressure ventilation.
8. Staff managing the casualties at the first-aid posts should be using at least a basic standard of
personal protective equipment, such as gowns, gloves and N95 masks.
9. Once the initial treatment has been provided, a disposition decision will need to be made and
arrangements for evacuation to the appropriate hospital set in motion.
10. Evacuation by ambulance must be with the presence of crew who are trained to manage the
airway, ventilation and to give further dose of autoinjectors if there were to be delays in the
evacuation process.
Autoinjectors and Antidotes used in Organophosphatre poisoning

In the initial phase of organophosphate poisoning, when the casualty is either in the contaminated zone or
the decontamination area or just sent to the first aid post, time may not be available for intravenous
administration of antidotes. In such situations the use of autoinjectors will be useful for teams attending
to these casualties so that relevant antidotes may be made available to the casualties as early as possible.
The autoinjectors that are available for organophosphate poisoning include the following:

1. AtroPen® Auto-Injector (atropine injection): Each prefilled auto-injector provides a dose of the
antidote atropine in a self-contained unit, specially designed for self or caregiver administration.
Four strengths of AtroPen® are available; they are AtroPen® 0.25 mg, AtroPen® 0.5 mg,
AtroPen® 1 mg, and AtroPen® 2 mg. When activated the AtroPen® 0.25 mg dispenses 0.25 mg
atropine sulfate. The AtroPen® 0.5 mg dispenses 0.5 mg atropine sulfate, the AtroPen® 1 mg
dispenses 1 mg atropine sulfate, and the AtroPen® 2 mg dispenses 2 mg atropine sulfate. Each
0.5 mg, 1 mg and 2 mg AtroPen® delivers atropine in 0.7 mL of sterile pyrogen-free solution
containing glycerin, phenol, citrate buffer and Water for Injection. The pH range is 4.0–5.0. After
the AtroPen® Auto-Injector has been activated, the empty container should be disposed of
properly. It cannot be refilled, nor can the protruding needle be retracted.

2. Pralidoxime Chloride Auto-Injector: When 3. Diazepam Auto-Injector C-IV : This

activated, each auto-injector dispenses 600 is a sterile solution packaged within
mg of pralidoxime chloride in 2 mL of a sterile a device that delivers its entire 2
mL contents automatically upon
solution containing 20 mg/mL benzyl alcohol,
activation. Each mL contains 5 mg
11.26 mg/mL glycine in Water for Injection,
diazepam compounded with 40%
USP. The pH is adjusted with hydrochloric propylene glycol, 10% ethyl
acid. The pH range is 2.0-3.0. The product is alcohol, 5% sodium benzoate and
pyrogen free. After an auto-injector has been benzoic acid as buffers, and 1.5%
activated, the empty container should be benzyl alcohol as preservative.
disposed of properly. It cannot be refilled nor
can the protruding needle be retracted.

4. DuoDote® Auto-Injector (atropine and pralidoxime chloride injection): Each prefilled DuoDote®
Auto-Injector provides a single intramuscular dose of atropine and pralidoxime chloride in a self-
contained unit, specifically designed for administration by emergency medical services personnel.
When activated, each DuoDote® Auto-Injector delivers the following:
• 2.1 mg of atropine in 0.7 mL of sterile, pyrogen-free solution containing 12.47 mg glycerin and
not more than 2.8 mg phenol, citrate buffer, and Water for Injection. The pH range is 4.0 – 5.0.
• 600 mg of pralidoxime chloride in 2 mL of sterile, pyrogen-free solution containing 40 mg
benzyl alcohol, 22.5 mg glycine, and Water for Injection. The pH is adjusted with hydrochloric
acid. The pH range is 2.0 to 3.0.
 INSTRUCTIONS FOR THE USE OF THE DUODOTE AUTO-INJECTOR
(IMPORTANT: Do Not Remove Gray Safety Release until ready to use)
CAUTION: Never touch the Green Tip (Needle End)!

1) Tear open the plastic pouch at any of the notches. Remove

the DuoDote Auto-Injector from the pouch.

2) Place the DuoDote Auto-Injector in your

dominant hand. (If you are right-handed, your
right hand is dominant.) Firmly grasp the center of
the DuoDote Auto-Injector with the Green Tip
(needle end) pointing down.

3) With your other hand, pull off the Gray Safety

Release. The DuoDote Auto-Injector is now ready to
be administered.

4) The injection site is the mid-outer

thigh area. The DuoDote Auto-
Injector can inject through clothing.
However, make sure pockets at the
injection site are empty.

5) Swing and firmly push the Green

Tip straight down (a 90° angle)
against the mid-outer thigh.
IMPORTANT: After the auto-injector triggers, hold the DuoDote Auto-Injector firmly in
place against the injection site for approximately 10 seconds.

6) Remove the DuoDote Auto-Injector from the thigh

and look at Green Tip. If the needle is visible, the
drug has been administered. If the needle is not
visible, check to be sure the Gray Safety Release has
been removed, and then repeat above steps
beginning with Step 4, but push harder in Step 5.

7) After the drug has been administered, push

the needle against a hard surface to bend the
needle back against the DuoDote Auto-Injector.

8) Put the used DuoDote Auto-Injector back into the plastic pouch, if available. Leave
used DuoDote Auto-lnjector(s) with the patient to allow other medical personnel to see
the number of DuoDote Auto-lnjector(s) administered.

9) Immediately move yourself and the patient away from the contaminated area and seek
definitive medical care for the patient.

Clinical management of Organophosphate Poisoning

The principles of medical management of organophosphate casualties, depending on level of acuity would
be as follows:

Priority 1 casualties (severe):

a. Remove from toxic exposure. This must be done as quickly as possible to minimize further
exposure. Removal from the contaminated environment must be followed by initial
decontamination before the casualty is handed over to the medical teams at the first aid post or
sent to hospital.

b. Maintain open airway: The airway may get occluded by the tongue falling backwards in the case of
the unconscious casualty and also by the excessive secretions from the airways that are
characteristic of nerve agent poisoning. Initially the head-tilt, chin-life technique may be employed
for the unconscious casualty. Unconscious casualties would require early intubation to better
ensure that the airway stays protected and that adequate ventilation may be instituted.

c. Restore adequate breathing: this would usually be by use of the bag-valve mask ventilator or by
an automated ventilator. The use of 100% oxygen is encouraged in the initial phases. This can also
help to wash out any residual organophosphate vapour present in the airways. One should aim to
achieve a breathing rate of 10 – 12 breaths per minute with an average tidal volume of 500 ml. As
an alternative in the casualty who is breathing spontaneously, 100% O2 with non-rebreather mask
and reservoir bag at > 10 l/min may be instituted.

d. IV Atropine 2 -4 mg will need to be administered every 5 to 10 minutes till drying of secretions and
mucous membranes is achieved (loading dose). Atropine is a pharmacological antidote to
organophosphates. Following this atropinization will need to be maintained with IV atropine 1
mg/hr titrated to effect for 72 hrs (3 days) and tail down over next 48 hrs (2 days)

e. Severe casualties will, in addition require IV Pralidoxime 500mg/hr for 120 hrs (5 days) This is
because a lot of the organophosphate is attached to fat tissue in the human body and is released
gradually. Pralidoxoime exerts its effect by attaching to one half of the acetylcholinesterase
enzyme. It then binds to the organophosphate which is attached to the other half. The
organophosphate changes conformation, and loses its binding to the acetylcholinesterase enzyme.
The conjoined poison / antidote then unbinds from the enzyme. This regenerates the enzyme,
which is now able to function again. The adult dose is 30 mg/kg (typically 1-2 g), administered by
intravenous therapy over 15–30 minutes or intramuscular injection or subcutaneous injection,
repeated 60 minutes later. It can also be given as a 500 mg/hour continuous IV infusion. In
children the recommended dose is 20–50 mg/kg body weight followed by a maintenance infusion
at 5–10 mg/kg body weight/hour.

f. IV Diazepam (valium) 10 mg may be given prophylactically for every serious casualty or if seizures
occur.

g. Salbutamol (Ventolin) nebuliser 10mg in 4 ml(2:2) + Ipratropium bromide (Atrovent) 0.5 mg in 2

ml. This would be important in the initial stages when bronchorrhoea is a predominant feature of
the clinical presentation. The Salbutamol nebulizer may be repeated after 30 minutes, if
necessary. Atrovent nebulization is only to be repeated after at least 4 hours. For children, the
dosage of Salbutamol is as follows:
i. < 5 years: 2.5 mg (0.5:1 solution)
ii. 5 – 10 years: 5 mg (1:1 solution)
 h. I/V hydrocortisone 200 mg stat would also be advised as an initial dose in all instances, though
there has been no randomized trial as to its effectiveness specifically for organophosphate
poisoning.

i. Adequate hydration with IV fluids will be required as atropine dries mucosal secretions and
contributes to tachycardia.

j. Admit to ICU. Serious casualties with organophosphate poisoning will require close monitoring for
at least the first five days of their care with continuous vital signs, ECG and pulse oximetry
monitoring at 30 minute intervals till stabilization of condition

k. If the patient’s condition continues to improve and remain stable he may be transferred to a
general ward for continuation of treatment and supportive care up till 1 week during which signs
of delayed neurologic sequelae should be watched for. Following accidental or suicidal exposure,
three well defined neurological syndromes have been identified:
i. initial life threatening acute cholinergic crisis which often requires management in
intensive care unit
ii. intermediate syndrome in which cranial nerve palsies, proximal muscle weakness and
respiratory muscle weakness are common and patients often require respiratory support
iii. delayed organophosphate induced polyneuropathy

In addition to these three classical neurological syndromes following acute exposure and in some
following low dose chronic exposure, several neurobehavioural changes have been observed and
these have been termed together as 'chronic organophosphate induced neuropsychiatric
disorders' (COPIND).

l. The patient may be discharged on Day 8 if RBC AchE level is >75% and the patient is
asymptomatic.

m. Other useful investigations and measurements for such patients would be

 ECG – Look for brady- and tachy-arrhythmias. All moderate to severe poisonings should be
monitored on a cardiac monitor.

 CXR – Obtain in all severe poisonings as aspiration pneumonia (contributed to by hydrocarbon

diluents) is common

 Arterial Blood Gases – Indicated in all severe poisoning as respiratory function is often
critically compromised. Arterial oxygenation can guide the severity of respiratory function

 Spirometry or Wrights respirometer readings– measurement of forced vital capacity or tidal

volume can be a useful serial measure of respiratory muscle function.

 Nerve conduction studies – Repetitive nerve stimulation studies show parallel changes with
progressive muscle weakness. A change from a decrement–increment pattern to progressive
or severe decrements indicates severe weakness and respiratory failure is usually imminent.

Carbamates
The management for carbamates is the same as above except that pralidoxime is not indicated. The
clinical course is usually shorter and delayed or prolonged respiratory failure is much less common.

Priority 2 casualties (moderate):

a. Remove from toxic exposure as for serious casualties. This must be done as quickly as possible
to minimize further exposure. Removal from the contaminated environment must be followed
by initial decontamination before the casualty is handed over to the medical teams at the first
aid post or sent to hospital.

b. IV Atropine 2 – 4 mg should be administered every 5 to 10 minutes till drying of secretions and

mucous membranes (loading dose). Maintain atropinization with IV atropine 1 mg/hr titrated
to effect for 24 hrs and tail down over next 48 hrs (2 days).

c. IV Pralidoxime 500mg/hr should be administered for the next 72 hrs (3 days)

d. IV Diazepam (valium) 10 mg is recommended for seizures. This may be repeated as necessary.

e. Salbutamol(Ventolin) nebuliser 10 mg in 4 ml(2:2) and repeat at 30 minute intervals, if

required. For children, the dosage of Salbutamol is:

• < 5 years: 2.5 mg (0.5:1 solution)

• 5 – 10 years: 5 mg (1:1 solution)

f. Adequate hydration with i.v. fluids.

g. Admit to a monitored bed. Monitor pulse, respiratory rate, blood pressure at 30 minute
intervals and continuos ECG and pulse oximetry monitoring for 24 hours. If deteriorating or no
improvement, follow the severe poisoning protocol

h. If the patient’s condition continues to remain stable he may be sent to the general ward for
continuation of treatment and supportive care for another 48 hrs

i. These patients may be discharged on Day 4 if the RBC AchE levels >75% and patient is
asymptomatic. At discharge, the patient should be advised to return if he experiences any
subjective sensation of feeling weak. The patients should also be reviewed within 1 week for
intermediate syndrome and blood cholinesterase levels and at 1 month for OPIDN and repeat
blood cholinesterase levels.
Priority 3 casualties (mild):

a. Remove from toxic exposure as for serious casualties. Again this must be done as quickly as
possible to minimize further exposure. Removal from the contaminated environment must be
followed by initial decontamination before the casualty is handed over to the medical teams
at the first aid post or sent to hospital.

b. IV Atropine 2 – 4 mg every 5 to 10 minutes till drying of secretions and mucous membranes

(loading dose)

c. IV Pralidoxime 500mg/hr for 24 hours will usually be needed.

d. Salbutamol (Ventolin) nebulizer 10 mg in 4 ml (2:2) may be given if the casualty has bronchitic
symptoms. This may be repeated as necessary. For children, the dosage of salbutamol is as
follows:
i. > 5 years: 5 mg (1:1 solution.)
ii. < 5 years: 2.5 mg (0.5:1 solution)

e. The patient may be discharged home on Day 2 if the RBC AchE level is >75% and the patient is
asymptomatic. At discharge the patient should be advised to return if any subjective sensation
of feeling weak were to occur.

f. The patient should be reviewed in 1 week for intermediate syndrome and blood
cholinesterase levels and again at 1 month for OPIDN and blood cholinesterase levels.

Priority 4 casualties (non-contaminated):

a. Reassuarance forms the cornerstone of the management of these casualties. Field medical teams
and hospital teams need to exercise patience and provide a listening ear and carefully evaluate
them for any features of organophosphate exposure.

b. Blood for RBC Cholinesterase levels should be taken in the hospital to confirm that they have not
had any significant exposure to the nerve agents. These results may be shared with them once
available.

c. If their anxiety symptoms persist, referral to the CARE (Caring Action in Response to Emergencies)
team would be useful, as the psychological support and information sharing provided may be all
that would be required. Teams attending to these patients should provide advice as appropriate.

d. It is also important to ensure that mechanisms for regular follow up are made available for this
group of patients. If the patients require further reassurance, a 1 week review for Intermediate
Syndrome (IMS) and Blood Cholinesterase and even a 1 month review for Organophosphate
Induced Delayed Neuropathy (OPIDN) may be conducted.

Conclusion

The overall in-hospital case-fatality rate has traditionally been around 15 % (2% to 30%), though the
actualk rate varies with the organophosphate used and the community where the patient is managed.
What is most important would be the need to recognize the cholinergic toxidrome of organophosphate /
carbamate poisoning, ensure that decontamination measures and antidotes are promptly administered,
triage early and ensure that patients are managed by protocol.