Management of OPC Poisoning: Current

Vs Evidence-Based Practice

Background

Diseases-Neither Preventable Nor Curable. e.g., MSPreventable but Not Curable e.g., Lung cancerPreventable and Curable e.g. OPC poisoning• More than 200 000 deaths each year in

developing countries• Mortality from severe poisoning is high (>10%)

BMJ 2007;334:629-34

Acetylcholinesterase (AChE)

AChE is an enzyme that degrades the neurotransmitter acetylcholine

↗AChE

Mechanism of toxicity of organophosphorus compounds

Mechanism of toxicity of organophosphorus compounds

Some OP available in Bangladesh

Dimethyl compounds ( ageing 3.7 hours)• Malathion• Dichlorvos • Dimethoat• Fenthion Diethyl compounds ( 31 hrs)• Chlorpyrifos• Diazinon• Parathion• Quinalphos

PathogenesisInhibition of acetyl cholinesterase leads to the accumulation of acetylcholine at cholinergic synapses, interfering with normal function of the autonomic, somatic, and central nervous systems. This produces a range of clinical manifestations, known as the acute cholinergic crisis

AchAcetyl Cholinesterase Breakdown

products

OPC

OXIMES

CNS

NIC

MUS Atropine

Signs and symptoms of OPC poisoning

Four clinical syndromes have been described:

1. Acute cholinergic syndrome (most common)2. Sub acute proximal weakness (Intermediate

syndrome)3. Organophosphate induced delayed neuropathy

(OPIDN)4. Chronic organophosphate induced neuropsychiatric

disorder (COPIND)

Grading of severity of poisoning

• Clinical Grading• Biochemical Grading

Grading of severity of poisoning

Clinical grading: based on-1.Miosis2.Fasciculation3.Respiratory Rate4.Bradycardia5.Level of consciousness

*Mild(0-3), * Moderate(4-7), *Severe(8-11)

Grading of severity of poisoning

Biochemical Grading:Red cell cholinesterase activity (% normal) Grade• 20-50% Mild• 10-20%

Moderate• <10% Severe

Management of OPC Poisoning

Hospitalization/ ICU1. Initial stabilization2. Reduction of exposure3. Administration of specific antidote4. Supportive treatment

Initial Stabilization of the patient

• Clear airway and • Adequate ventilation because the patient with

acute organophosphate poisoning (ACC) commonly presents with respiratory distress.

• Oxygen- high flow?? Prior to atropinization

• Circulation- iv access

Decontamination• Dermal spills—wash pesticide spills from the patient

with soap and water and remove and discard contaminated clothes, shoes and any other material made from leather

• Gastric lavage—consider for presentations within 1 or 2 hours, when the airway is protected. A single aspiration of the gastric contents may be as useful as lavage

• Activated charcoal without cathartic—50 g may be given orally or nasogastrically to patients who are cooperative or intubated, particularly if they are admitted within one or two hours or have sever toxicity

Investigations

ECG: torsades de pointesOxygen saturationBlood gas analysisRenal and hepatic functionElectrolytesGlucoseAmylase

Antidotes in the treatment of OPC poisoning

• Atropine- Reverses the muscarinic features.

• Oxime- Reactivate cholinesterase and reverses the nicotinic features.

Dosage regimens of Atropine• Repeated doses of atropine should be

administered until signs of atropinisation appear.

• Conventional Vs Evidence-Based Practice

• Try test dose of atropine

Dosage regimens of Atropine

Test dose of Atropine: It is preferable to initiate the antidote therapy with

a 'test dose' of parenteral atropine-sulphate (1.2 mg in adults and 0.01 mg/kg in children IV)

This therapeutic test provides a measure of severity of organophosphate poisoning.

If the signs of atropinisation occur rapidly, it is unlikely that the poisoning is severe or it may not be OPC poisoning.

Dosage regimens of Atropine: Conventional Practice

• Dosage regimens are usually designed according to the severity of poisoning and to the signs of atropinisation

• 2-5 mg every 5-10-15 minutes. After initial atropinization, maintain the atropinization by reducing the dose or increasing the duration between doses of atropine

• 1 ampoule contains 0.6 mg atropine sulphate

Dosage regimens of Atropine: Alternative regimen: ??? Evidence-Based

• Give first dose atropine immediately1.8–3 mg (three to five 0.6 mg ampoules) rapidly IV into a fast-flowing IV drip

• Don’t delay starting atropine if oxygen is unavailable

BMJ 2007;334:629-34, J Med Toxicol 2012 Feb17 online

Assess – is the patient atropinised?

After 3-5 minutes of atropine administrationrecord followings :-(1) air entry into lungs: clear chest(2) blood pressure: SBP > 80 mm Hg(3) heart rate: > 80 beats/ min(4) Pupil: no longer pinpoint(5) Dry axillae

Contd.

Assess – is the patient atropinised?

• Mark them on an OPC observation sheet

• A uniform improvement in most of the five parameters is required, not improvements in just one.

• Pupil dilatation is sometimes delayed. and the other parameters may improve more rapidly, it is reasonable to observe air entry on chest auscultation, heart rate, and blood pressure as the main parameters for adequate atropinisation.

• When all the parameters are satisfactory, the patient has received enough atropine and is “atropinised”

Giving fluids/ IV channel

Two IV drips should be set up One for fluid and drugs. Give 500–1000 ml

(10–20 ml/kg) of normal saline

Other for atropine

Continuation of bolus atropine loading to reach atropinisation

• If after 3–5 min a consistent improvement across the five parameters has not occurred.

Then• Continue to double the dose every 3-5 minutes until

atropinisation has been achieved • Do not simply repeat the initial dose of atropine

Atropinise the patient as quickly as possible

Atropine treatment after atropinization

• Once atropinized set up an infusion using one of the two IV cannulae

• In the infusion, give 10–20% of the total atropine that was required to load the patient every hour

Observation of the patient: The most important

• Follow up every 15 min with five parameter• If recurrence of bronchospasm or bradycardia, give further

boluses of atropine• Once the patient settled then follow up hourly for the first 6

hours to check that the atropine infusion rate is sufficient and that there are no signs of atropine toxicity

• As the required dose of atropine falls, observation for recurrence of cholinergic features can be done less often (every 2–3 hours)

• However, regular observation is still required to spot patients at risk of, and going into, respiratory failure

ATROPINE SHEET (tick box if true) Time/ date

Heart rate >80

Clear Lungs *

Pupil Size (C/N/D)

Dry axilla

Syst BP >80

Bowel sounds A/D/N/I

Confu-sion

Fever (>37.5)

Atropine Infusion (mg/hr)

Bolus given? Size?

22.30 52 creps+ pinpoint No 90/60 Incre’d No No 2.4mg bolus 22.35 60 creps+ pinpoint No 90/60 Incre’d No No 4.8mg bolus 22.40 82 +/- pinpoint yes 110/60 Normal No No 4mg bolus 22.50 100 wheeze 2mm yes - Decr’d No No 2mg Bolus 23.00 105 clear 3mm yes - D No No 2mg/hr infus’n 23.15 105 clear 3-4mm yes - D No No “ “ 23.32 102 clear “ yes - D No No “ “ 00.30 98 clear “ yes 110/60 D No No “ “ 01.30 85 clear “ yes - D No No “ “ 02.30 72 wheeze “ yes - N/D No No bol 2mg infus’n 02.35 96 clear “ yes - D No No 2.4mg/hr infus’n 02.45 98 clear “ yes - D No No “ 0400 102 clear “ yes - D No No “ * Beware focal chest creps secondary to aspiration pneumonia or pneumonitis. ** Beware persistently small pupils secondary to direct contact of OP with the eye. Assess patient hourly for at least the first 6 hours AND until required infusion has been stable for 3 hours. Thereafter assess every 6 hours. After changing infusion rate (either up or down), assess hourly until stable for three hours.

Atropine toxicity

Peripheral effect

• Dry mouth• Mydriasis ?

• Blurred vision• Hot dry skin• Tachycardia ?

• Look for retention of urine

Central effect• Hyperpyrexia• Restlessness

• Anxiety• Excitement

• Hallucination• Delirium• Mania

• Cerebral depression• Coma

Atropine toxicity

• Hot as a hare• Blind as a bat• Dry as a bone• Red as a beet• Mad as a hen

Management of Atropine toxicity

• Stop the atropine infusion • Check again after 30 min to see whether the features of

toxicity have settled• If not, continue to review every 30 min or so • When they do settle, restart at 70–80% of the previous

rate• The patient should then be seen frequently to ensure

that the new infusion rate has reduced the signs of atropine toxicity without permitting the reappearance of cholinergic signs

Oximes

Action of Oximes:• Oximes are the specific biochemical antidote

for OPC induced intoxication• They reactivate the inhibited cholinesterase• Oximes ameliorate the nicotinic, muscarinic &

C.N.S. effects

Pralidoxime

Praliodoxime is used in conjunction with atropine in moderate and severe poisoning. It has a strong synergistic effect with atropine and provides a dose sparing effect on the amount of atropine

Dosage regimen of pralidoxime

Loading dose 30 mg/kg of pralidoxime over 10–20 min, followed by continuous infusion of 8–10 mg/kg per hour until clinical recovery (12 hours after stopping administration of atropine or once butyrylcholinesterase is noted to increase)

Obidoxime

• Currently obidoxime has been introduced. It crosses blood brain barrier more than pralidoxime

• Where obidoxime is available, a loading dose of 250 mg is followed by an infusion giving 750 mg every 24 hours

Advantages of rapid incremental dose atropinization followed by atropine infusion

• Reduces morbidity and mortality• Shortens the length of hospital stay• Requires a shorter time to atropinization• Requires less frequent follow-up• Maintain sustain blood levels of atropine• Lower incidence of atropine toxicity• Less IMS

High Quality Supportive Care

1. Management of respiratory insufficiency2. Maintenance of circulation3. Treatment of convulsion and other

complications4. Fluid and electrolyte balance5. Control of infections (aspiration

pneumonia)6. Maintenance of nutrition7. Control of body temperature

Respiratory Failure

• Management of respiratory failure represents the corner stone of treatment.

• Artificial ventilation should be started at the first sign of respiratory failure.

• For pulmonary edema, high concentration 02 and diuretic should be used.

• Morphine and aminophyline should be avoided. • Broad spectrum antibiotic is used as prophylactic

measure for aspiration pneumonia.

Active Cooling and Sedation

• Lay a towel soaked with water over the patient's chest and place in a fan's airflow.

• Benzodiazepines Benzodiazepines are usually given intravenously as

required for agitation or seizures—with doses starting at:5-10 mg diazepam (0.05-0.3 mg/kg/dose),lorazepam 2-4 mg (0.05-0.1 mg/kg/dose), ormidazolam 5-10 mg (0.15-0.2 mg/kg/dose)

Follow up of the patient

1. Vital signs2. Signs of Atropinisation3. Effect of oxime4. Toxicity of atropine and oxime5. RBC and plasma AChE level6. Recurrence of symptoms on withdrawal of antidote7. Restart the treatment promptly if recurrence

occurs8. Patient’s general condition

Disposition

• Consider discharge from ICU to medical ward once stable for 12 hours after oxime

• Stable for 48 hours after discharge from intensive care unit- consider disposition and psychiatric review

Cause of Death in OPC poisoning

1. Immediate death:– Seizures.– Complex ventricular arrhythmias.

2. Death within 24 hours: - Acute cholinergic crisis in untreated severe case -Respiratory failure.3. Death within 10 days of poisoning: - intermediate syndrome.

Contd.

Cause of Death in OPC poisoning

3. Death within 10 days of poisoning: - intermediate syndrome.

4. Late death: - Secondary to ventricular arrhythmias, including

Torsades de Pointes, which may occur up to 15 days after acute intoxication.

Prognosis of Organophosphorus Insecticide Poisoning

• Deaths usually occur within the first 24 hours in untreated cases and within 10 days in treatment failure cases.

• If there has been no anoxic brain damage, recovery will usually occur within 10 days, although there may be residual sequelae.

Factors related to death in OPC poisoning

• Amount ingested• Delay in hospitalization• Delay in starting treatment• Neglected • Lack of standardized treatment protocol• Atropine toxicity• Lack of frequent monitoring• Lack of ICU support including financial constrain• Treatment seeking behavior

Should We Let Her Die?

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Target end-points for atropine therapy

1. Clear chest on auscultation with no wheeze2. Heart rate >80 beats/min3. Pupils no longer pinpoint4. Dry axilla5. Systolic blood pressure >80 mmHg

Signs of Atropinisation:

1.Mydriasis2.Tachycardia.3.Flushing4.Dry mouth & nose5.Anhydrosis6.Bronchodilation

Special circumstances with atropine therapy

• As atropine can induce VT & VF in a severely hypoxic patient, hypoxia should be corrected before administration of atropine

• As severely poisoning patients exhibit marked atropine resistance, they may require up to 2-3 times the standard dose of atropine.

Side effect of pralidoxime

• Mild biochemical signs of liver toxicity. • Too rapid administration will result in vomiting,

tachycardia and hypertension (especially diastolic hypertension).

Pralidoxime Toxicity

• Very few cases of pralidoxime toxicity have been reported.

• Dizziness, blurred vision, diplopia, headache, nausea and tachycardia have been reported if the rate of administration exceeds 0.5 gm. per minute.

Fig: Nicotinic, muscarinic and central syndrome

Intermediate Syndrome (IMS)• IMS occurs due to dysfunction of the post-synaptic

neuromuscular junction• Pathogenesis unclear. But thought to be due to persistent

inhibition of acetyl cholinesterase• IMS develop about 24-96 hours after OPC induced intoxication • Respiratory insufficiency may herald the onset of IMS. • The patient is usually conscious. • Muscles innervated by cranial nerves show varying degree of

weakness. External ocular muscles are most commonly affected

• Weakness is bilateral and symmetrical• Patient cannot raise the head from bed.• There is no sensory impairment.

• Respiratory insufficiency develops over approximately 6 hours. • There is increased in respiratory rate, sweating, restlessness and

later cyanosis. • If untreated the patient may soon become unconscious and die.• The paralytic signs are 2 types. Type 1 (present on admission) and

Type 2 (appearing subsequently and not responding to atropine).• Management – in the line of respiratory failure.

Intermediate Syndrome (IMS)

Delayed Polyneuropathy

• Organophosphorus induced delayed polyneuropathy (OPIDP) occurs following a latent period of 2-4 weeks after exposure by any route.

• The cardinal symptoms are distal weakness and in some cases paraesthesia in the distal parts of the limbs, foot drops, wrist drop and claw hands are inevitable consequences.

• Pyramidal signs may appear after a few weeks or few months.

• Recovery is variable and the condition may be permanent. Severe cases progress to complete paralysis, impaired respiration and death.

Delayed Polyneuropathy

Suggested diagnostic criteria include: 1. Symptoms and signs of polyneuropathy.2. Sometimes later pyramidal tract signs3. Denervation changes (shown by

electromyography).4. Reasonable exclusion of other causes.

Extra pyramidal manifestations

1. Atypical ocular bobbing2. Cerebellar ataxia 3. Choreo athetosis 4. Chorea with psychiatric changes and 5. Parkinsonism .

• All patients and their attendants should be repeatedly encouraged to bring the sample to the health facility for diagnosis and management.

Toxic effects

• The first is the acute toxicity is due to the irreversible inhibition of acetylcholinesterase (AChE),which subsequently led to accumulation of acetylcholine at

* Muscarinic receptors- in cholinergic receptor cell.

*Nicotinic receptors - in skeletal neuromuscular junction and autonomic ganglia.

* Central Nerves System.

Toxic effects

The second effect is arising from single or repeated exposure to OPC.

Is a delayed onset of ataxia.

With degeneration of the axon and the myelin both central and peripheral nervous system,which is known as oganophosphate-induced delayed polyneuropathy.

Clinical Features

• Acute poisoning: Result from substantial intake of the toxicant in a single

occasion.

• Sub-acute poisoning: Due to repeated smaller doses through penetration into the

system over a short period of time.

• Chronic poisoning: Refers to cumulative effect occurring from repeated exposure

to small amount of pesticides over a long period of time.

MuscarinicGastrointestinalRespiratoryCardiovascularPupilsUrinary Other

Nausea, vomiting, abdominal cramps, diarrhoea, faecal incontinencePulmonary oedema, hypotension Bradycardia, hypotension Blurring of vision, miosis Frequency, incontinenceIncreased sweating, salivation and lacrimation

NicotinicSkeletal muscle Sympathetic ganglion

Muscle twitching, fasciculation, cramps, weakness including respiratory musclesPallor tachycardia, hypertension

CNS Giddiness, tension, anxiety, restlessness, difficulty in concentration, confusion, slurred speech, insomnia, headache, tremor, apathy, withdrawal and depression, drowsiness, nightmares, ataxia, generalized weakness, coma, cheyne-stokes respiration, convulsion, depression of respiratory and circulatory centres.

Acute cholinergic crisis (ACC)

Note: The mnemonic “DUMBELS” describes most of the significant muscarinic features

Diarrhoea Urination Miosis Bronchospasm Emesis Lacrimation Salivation

Note: The mnemonic “DUMBELS” describes most of the significant muscarinic features

Diarrhoea Urination Miosis Bronchospasm Emesis Lacrimation Salivation