Background Diseases- Neither Preventable Nor Curable. e.g., MS Preventable but Not Curable e.g., Lung cancer Preventable and Curable e.g. OPC poisoning More than 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

Some OP available in Bangladesh Dimethyl compounds ( ageing 3.7 hours) Malathion Dichlorvos Dimethoat Fenthion Diethyl compounds ( 31 hrs) Chlorpyrifos Diazinon Parathion Quinalphos

Pathogenesis Inhibition 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 Ach Acetyl Cholinesterase Breakdown products OPCOPC OXIMESOXIMES CNSCNS NICNIC MUSMUS 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.Miosis 2.Fasciculation 3.Respiratory Rate 4.Bradycardia 5.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/ ICU 1.Initial stabilization 2.Reduction of exposure 3.Administration of specific antidote 4.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 pointes Oxygen saturation Blood gas analysis Renal and hepatic function Electrolytes Glucose Amylase

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 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 immediately 1.8–3 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 administration record 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 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 insufficiency 2.Maintenance of circulation 3.Treatment of convulsion and other complications 4.Fluid and electrolyte balance 5.Control of infections (aspiration pneumonia) 6.Maintenance of nutrition 7.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 0 2 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 ( mg/kg/dose), lorazepam 2-4 mg ( mg/kg/dose), or midazolam 5-10 mg ( mg/kg/dose)

Follow up of the patient 1.Vital signs 2.Signs of Atropinisation 3.Effect of oxime 4.Toxicity of atropine and oxime 5.RBC and plasma AChE level 6.Recurrence of symptoms on withdrawal of antidote 7.Restart the treatment promptly if recurrence occurs 8.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

Target end-points for atropine therapy 1.Clear chest on auscultation with no wheeze 2.Heart rate >80 beats/min 3.Pupils no longer pinpoint 4.Dry axilla 5.Systolic blood pressure >80 mmHg

Signs of Atropinisation: 1.Mydriasis 2.Tachycardia. 3.Flushing 4.Dry mouth & nose 5.Anhydrosis 6.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 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 signs 3.Denervation changes (shown by electromyography). 4.Reasonable exclusion of other causes.

Extra pyramidal manifestations 1.Atypical ocular bobbing 2.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.

Muscarinic  Gastrointestinal  Respiratory  Cardiovascular  Pupils  Urinary  Other Nausea, vomiting, abdominal cramps, diarrhoea, faecal incontinence Pulmonary oedema, hypotension Bradycardia, hypotension Blurring of vision, miosis Frequency, incontinence Increased sweating, salivation and lacrimation Nicotinic  Skeletal muscle  Sympathetic ganglion Muscle twitching, fasciculation, cramps, weakness including respiratory muscles Pallor tachycardia, hypertension CNSGiddiness, 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