ORGANOPHOSPHOROUS ORGANOPHOSPHOROUS POISONINGPOISONING

PRESENTOR Dr. S.PRIYAPRESENTOR Dr. S.PRIYA MODERATOR Lt.Col A.K. GHOSH MODERATOR Lt.Col A.K. GHOSH

(Classified specialist Medicine & (Classified specialist Medicine & Cardiology)Cardiology)

INTRODUCTIONINTRODUCTION

Acute organic insecticide poisoning is Acute organic insecticide poisoning is a major health problem all over the a major health problem all over the world, particularly in the developing world, particularly in the developing countries, where organophosphates countries, where organophosphates (OPs) are the most common suicidal (OPs) are the most common suicidal poisons with high morbidity and poisons with high morbidity and mortalitymortality

The OP compounds are popular The OP compounds are popular insecticides because of their effectiveness insecticides because of their effectiveness and nonpersistence in the environment and nonpersistence in the environment owing to their unstable chemical nature.owing to their unstable chemical nature.

They do not persist in the body or They do not persist in the body or environment as do organochlorides and environment as do organochlorides and have become the insecticide group of have become the insecticide group of choice replacing DDT, an organochloride choice replacing DDT, an organochloride compound compound

PHARMACOLOGYPHARMACOLOGY

CLASSIFICATION1. Agricultural insecticides (high toxicity) Paration phorate mevinphos disulfoton.

2. Animal insecticides (intermediate toxicity) chlorpyrifos.

3. Household use or use in golf courses (low toxicity) malathion dichlorvos.

PHARMACOKINETICSPHARMACOKINETICS SkinSkin Oral mucosaOral mucosa Conjunctival mucosaConjunctival mucosa G.I.TG.I.T Respiratory routes Respiratory routes Organophosphate compounds block Organophosphate compounds block

ACETYLCHOLINEACETYLCHOLINEACETICACID & ACETICACID & CHOLINE CHOLINE

Increased acetylcholine at synapses Increased acetylcholine at synapses Most common cause of toxic effect of Most common cause of toxic effect of

o.p.poisoning o.p.poisoning

PATHOPHYSIOLOGYPATHOPHYSIOLOGY OPs bind to the active serine residue

of acetyl cholinesterase irreversibly Convert the enzyme into an inactive

protein complex Result in accumulation of acetyl

choline at the receptors

  Etiology of OP Poisoning Etiology of OP Poisoning 

Suicidal Suicidal Accidental poisoning Accidental poisoning Occupational exposure such as Occupational exposure such as

farming farming Large proportion(68%) suicidal Large proportion(68%) suicidal

attemptsattempts Young patients <30 yrs with male Young patients <30 yrs with male

preponderancepreponderance

CLINICAL FEATURESCLINICAL FEATURES CardiovascularCardiovascular: Bradycardia, hypotension.: Bradycardia, hypotension.

RespiratoryRespiratory Rhinorrhea, bronchorrhea, Rhinorrhea, bronchorrhea, bronchospasm, cough. bronchospasm, cough.

Gastrointestinal:Gastrointestinal: Increased salivation, nausea Increased salivation, nausea and vomiting, abdominal pain, diarrhea, fecal and vomiting, abdominal pain, diarrhea, fecal incontinence.incontinence.

Ocular:Ocular: Blurred vision, increased lacrimation, Blurred vision, increased lacrimation, miosis. miosis.

CLINICAL FEATURES(CONTD..)CLINICAL FEATURES(CONTD..)

Nicotinic EffectsNicotinic Effects

Cardiovascular: Tachycardia, Cardiovascular: Tachycardia, hypotension.hypotension.

MMusculoskeletal:usculoskeletal: Weakness, Weakness, fasciculations, cramps, paralysisfasciculations, cramps, paralysis

Central Receptor StimulationCentral Receptor Stimulation

  Anxiety, restlessness, ataxia, absent Anxiety, restlessness, ataxia, absent reflexes, convulsions, insomnia, reflexes, convulsions, insomnia, tremors, dysarthria, coma, tremors, dysarthria, coma, hyperreflexia, Cheyne Stokes hyperreflexia, Cheyne Stokes breathing, respiratory depression, breathing, respiratory depression, and circulatory collapse come under and circulatory collapse come under thisthis

Multisystem ManifestationsMultisystem Manifestations

The end-result may be involving the The end-result may be involving the gastrointestinal tract, respiratory gastrointestinal tract, respiratory system, cardiovascular system, system, cardiovascular system, nervous system, skeletal muscles, as nervous system, skeletal muscles, as well as metabolic effects such as well as metabolic effects such as hypo- or hyperglycemia.hypo- or hyperglycemia.

Neurological ManifestationsNeurological Manifestations

THREE types of paralyses recognized TYPE I TYPE II TYPE III

Type-I Paralysis or Acute Paralysis Type-I Paralysis or Acute Paralysis

Initial cholinergic crisis Initial cholinergic crisis Persistent depolarization at NMJPersistent depolarization at NMJ Blockade of acetylcholinesterase Blockade of acetylcholinesterase Develops within 24-48 h. Develops within 24-48 h. FEATURES- muscle fasciculations, FEATURES- muscle fasciculations,

cramps, twitching, and weakness cramps, twitching, and weakness Respond to atropine Respond to atropine

Type IType I (Contd…) (Contd…)

Muscle paralysis Muscle paralysis Upper motor neuron lesionUpper motor neuron lesion Muscle paralysis - respiratory Muscle paralysis - respiratory

muscles--->respiratory failuremuscles--->respiratory failure requiring ventilation requiring ventilation

Acute respiratory failure in 33% of Acute respiratory failure in 33% of patients who presented with OP patients who presented with OP poisoningpoisoning

Type-II Paralysis or Intermediate Type-II Paralysis or Intermediate SyndromeSyndrome

Wadia as Type-II paralysis Wadia as Type-II paralysis Senanayake as intermediate Senanayake as intermediate

syndromesyndrome 24-96 h after the poisoning24-96 h after the poisoning Majority of patients, respiratory Majority of patients, respiratory

insufficiency insufficiency Cranial nerve palsiesCranial nerve palsies Proximal muscle weakness Proximal muscle weakness

TYPETYPE II(CONTD..) II(CONTD..)

Relative sparing of the distal muscle Relative sparing of the distal muscle groupsgroups

Incidence varies - 8% and 49% Incidence varies - 8% and 49% Earliest manifestations Earliest manifestations Weakness of neck flexionWeakness of neck flexion Inability to lift the head from the pillow Inability to lift the head from the pillow Test to assess if patient is likely to develop Test to assess if patient is likely to develop

respiratory muscle weaknessrespiratory muscle weakness Cranial nerves involved are those Cranial nerves involved are those

supplying the extraocular muscles supplying the extraocular muscles

TYPETYPE II(CONTD..) II(CONTD..)

VII and X are less frequent. VII and X are less frequent. Syndrome persists for approx 4-18 Syndrome persists for approx 4-18

days days Most patients survive this with Most patients survive this with

ventilatory support unless infections ventilatory support unless infections complicate the coursecomplicate the course

There is a myopathy evidenced by There is a myopathy evidenced by significant elevation of muscle significant elevation of muscle enzymes enzymes

TYPE III PARALYSISTYPE III PARALYSIS

OP-induced delayed polyneuropathy OP-induced delayed polyneuropathy (OPIDP) is a sensory-motor distal (OPIDP) is a sensory-motor distal axonopathyaxonopathy

Occurs after the ingestion of large doses , Occurs after the ingestion of large doses , chronic exposure chronic exposure

One being pure motor polyneuropathy One being pure motor polyneuropathy Other having a mild sensory component Other having a mild sensory component

with a more prominent motor component. with a more prominent motor component.

Other Neurologic Manifestations Other Neurologic Manifestations 

Impaired memory, confusion, Impaired memory, confusion, irritability, lethargy irritability, lethargy

Extrapyramidal manifestations Extrapyramidal manifestations Developing for 4-40 days following Developing for 4-40 days following

poisoning and lasting for approx 1-4 poisoning and lasting for approx 1-4 weeks, including dystonias, resting weeks, including dystonias, resting tremor, cog-wheel rigidity tremor, cog-wheel rigidity

Other Neurologic Other Neurologic Manifestations(contd…)Manifestations(contd…)

optic atrophy, degeneration of retina, optic atrophy, degeneration of retina, defective vertical smooth pursuit defective vertical smooth pursuit movements, myopia owing to spasm, movements, myopia owing to spasm, or paresis of accommodation.or paresis of accommodation.

Rare neurological Guillian-Barrι Rare neurological Guillian-Barrι syndrome, sphincter involvement, syndrome, sphincter involvement, isolated bilateral recurrent laryngeal isolated bilateral recurrent laryngeal nerve paralysis, and ototoxicity nerve paralysis, and ototoxicity

Cadiovascular ManifestationsCadiovascular Manifestations Prolonged Q-T corrected (QTc) interval (67%);Prolonged Q-T corrected (QTc) interval (67%); Elevated ST segment (24%);Elevated ST segment (24%); Inverted T-waves (17%); Inverted T-waves (17%); Prolonged PR interval (9%);Prolonged PR interval (9%); Rhythm abnormalities such as sinus tachycardia Rhythm abnormalities such as sinus tachycardia

(35%), sinus bradycardia (28%), extra systoles , (35%), sinus bradycardia (28%), extra systoles , atrial fibrillation, ventricular tachycardia ;atrial fibrillation, ventricular tachycardia ;

Other manifestations noncardiogenic pulmonary Other manifestations noncardiogenic pulmonary edema (43%), hypertension (22%), and edema (43%), hypertension (22%), and hypotension (17%). hypotension (17%).

CARDIAC TOXICITYCARDIAC TOXICITY

Phase 1:Phase 1: A brief period of increased A brief period of increased sympathetic tone sympathetic tone

Phase 2:Phase 2: Prolonged periodof increased Prolonged periodof increased parasympathetic activity, including parasympathetic activity, including atrioventricular block. atrioventricular block.

Phase 3:Phase 3: QT prolongation followed by QT prolongation followed by torsade de pointstorsade de points , ventricular tachycardia, , ventricular tachycardia, and development of ventricular fibrillation.and development of ventricular fibrillation.

CARDIAC TOXICITY (contd..)CARDIAC TOXICITY (contd..)

Recent study QTc prolongation at Recent study QTc prolongation at admissionadmission respiratory failure and respiratory failure and higher mortalityhigher mortality

Mech of toxicityMech of toxicitydirect toxic effect direct toxic effect on the myocardium, overactivity of on the myocardium, overactivity of cholinergic or nicotinic receptors, cholinergic or nicotinic receptors, hypoxemia, acidosis, electrolyte hypoxemia, acidosis, electrolyte abnormalities abnormalities

  Respiratory Manifestations Respiratory Manifestations

Muscarinic effects of bronchorrhea, Muscarinic effects of bronchorrhea, bronchospasm and laryngeal spasm result bronchospasm and laryngeal spasm result in airway obstruction.in airway obstruction.

The nicotinic effects ->weakness and The nicotinic effects ->weakness and paralysis of respiratory and oropharyngeal paralysis of respiratory and oropharyngeal muscles muscles

Central depression ->respiratory arrest Central depression ->respiratory arrest Intermediate syndrome develop Intermediate syndrome develop

respiratory failure- mechanical ventilation respiratory failure- mechanical ventilation

Gastrointestinal Manifestations Gastrointestinal Manifestations

GI manifestations are the first to GI manifestations are the first to appearappear

They respond well to atropine They respond well to atropine therapy therapy

  Management Management Decontamination of the skin is very Decontamination of the skin is very

important. The patient should be stripped important. The patient should be stripped and washed with soap and waterand washed with soap and water

Forced emesis if the patient is fully awake Forced emesis if the patient is fully awake or through a gastric lavage or through a gastric lavage

0.5-1 g/kg activated charcoal every 4 h 0.5-1 g/kg activated charcoal every 4 h Serotonin adipinate that enhances the Serotonin adipinate that enhances the

propulsive function of git resulted in propulsive function of git resulted in shortening of the toxicogenic phase and a shortening of the toxicogenic phase and a

3.5-fold reduction of mortality.3.5-fold reduction of mortality.

Airway and RespirationAirway and Respiration

Adequate oxygenation should be ensured Adequate oxygenation should be ensured (a) Symptoms of ocular muscle (a) Symptoms of ocular muscle

involvement (e.g.; diplopia), (b) neck involvement (e.g.; diplopia), (b) neck muscle weakness, (c) respiratory rate, (d) muscle weakness, (c) respiratory rate, (d) tidal volume or vital capacitytidal volume or vital capacity

(e) Single breath count, and (f) arterial (e) Single breath count, and (f) arterial blood gas estimation or pulse oximetry. blood gas estimation or pulse oximetry. Respiratory infections should be Respiratory infections should be anticipated and treated appropriately anticipated and treated appropriately

Cardiac MonitoringCardiac Monitoring Hemodynamic and electrocardiographic Hemodynamic and electrocardiographic

monitoring monitoring Hypoxemia and electrolyte abnormalities Hypoxemia and electrolyte abnormalities

contribute to cardiac complications. Some contribute to cardiac complications. Some of these may revert with atropine.of these may revert with atropine.

Ventricular tachycardia with a prolonged Ventricular tachycardia with a prolonged QTc is best treated with electrical pacing QTc is best treated with electrical pacing

SVT can be treated with IV bolus of short-SVT can be treated with IV bolus of short-acting β-blockers.acting β-blockers.

Specific Therapy Specific Therapy Anticholinergic AgentsAnticholinergic Agents Atropine can Atropine can

be started initially as a 2-mg be started initially as a 2-mg intraventricular (IV) bolus intraventricular (IV) bolus

Then at doses of 2-5 mg IV bolus Then at doses of 2-5 mg IV bolus every 5-15 min until atropinization is every 5-15 min until atropinization is achieved.achieved.

No longer necessary to achieve total No longer necessary to achieve total atropinization i.e full mydriasis, heart atropinization i.e full mydriasis, heart rate more than 150/min, and absent rate more than 150/min, and absent bowel sounds.bowel sounds.

At approx 100/min,At approx 100/min, Pupils' midsize,Pupils' midsize, Bowel sounds just present, Bowel sounds just present,

maintains adequately atropinization maintains adequately atropinization without risks of hyperexcitability, without risks of hyperexcitability, restlessness, hyperpyrexia and restlessness, hyperpyrexia and cardiac complications that are seen cardiac complications that are seen with total atropinization. with total atropinization.

The dose of atropine required is The dose of atropine required is maximal on day 1 and tends to maximal on day 1 and tends to decrease over the next few days. decrease over the next few days.

OximesOximes

Reactivate the phosphorylated Reactivate the phosphorylated acetylcholinesterase by binding to the acetylcholinesterase by binding to the organophosphorus molecule.organophosphorus molecule.

Report by de Silva Report by de Silva et alet al found that P2AM found that P2AM did not make any difference to the did not make any difference to the outcomes.outcomes.

Reactivation has been shown to be Reactivation has been shown to be complete when oximes are given 1 hr after complete when oximes are given 1 hr after exposureexposure

r

Randomized control trials Randomized control trials

((Indian Journal of Pharmacology, Vol39, No2, Mar-Apr07)Indian Journal of Pharmacology, Vol39, No2, Mar-Apr07) TRIAL 1TRIAL 1

moderately severe group,6-> placebo arm moderately severe group,6-> placebo arm 5-> treatment group.5-> treatment group.

In the severe group, 5-> the placebo In the severe group, 5-> the placebo group 5-> treatment group.group 5-> treatment group.

While 12 g PAM infusion/day was used for While 12 g PAM infusion/day was used for severe cases for three dayssevere cases for three days

4 g/day was used for moderate cases also 4 g/day was used for moderate cases also for 3 days.for 3 days.

Placebo group was given saline infusion. Placebo group was given saline infusion.

ConclusionConclusion

Treatment with PAM did not make Treatment with PAM did not make any difference in OP poisoningany difference in OP poisoning

The more useful treatment options The more useful treatment options are anticholinergic drugs like are anticholinergic drugs like atropine and supportive ventilation. atropine and supportive ventilation.

Trial 2Trial 2

A 1 g bolus of pralidoxime (termed A 1 g bolus of pralidoxime (termed 'low dose') was compared with 12 g 'low dose') was compared with 12 g given as a reducing infusion over 4 given as a reducing infusion over 4 days without a loading dose (termed days without a loading dose (termed 'high dose').'high dose').

This RCT reported an increased This RCT reported an increased mortality rate (22% mortality rate (22% vsvs 14%; 14%;

..

ConclusionConclusion

The authors argued that 'high-dose' The authors argued that 'high-dose' pralidoxime was therefore pralidoxime was therefore 'associated with a worse outcome' 'associated with a worse outcome' and should have 'no role in op and should have 'no role in op poisoning management poisoning management

Increased requirement for ventilation Increased requirement for ventilation among patients who received the among patients who received the infusion as compared to those who infusion as compared to those who received the bolus dose.received the bolus dose.

Trial 3Trial 3

It compared 'high-dose' pralidoxime It compared 'high-dose' pralidoxime ((i.e.,i.e., 12 g by continuous infusion 12 g by continuous infusion without loading dose) with the without loading dose) with the placebo saline infusion placebo saline infusion

'high-dose' regimen was associated 'high-dose' regimen was associated with a significantly higher risk of with a significantly higher risk of death death

Nonrandomized Clinical TrialsNonrandomized Clinical TrialsTrial 1Trial 1

One group (group I) received atropine One group (group I) received atropine alonealone

Other group (group II) received atropine Other group (group II) received atropine &PAM&PAM

PAM neither improved the atropine PAM neither improved the atropine profile in group II patients as compared to profile in group II patients as compared to group I nor did it significantly change the group I nor did it significantly change the ventilatory profile in the two groups.ventilatory profile in the two groups.

Mortality was negligible in both the Mortality was negligible in both the groups groups

Trial 2Trial 2 Atropine was given intravenously to all patients in Atropine was given intravenously to all patients in

amounts sufficient to maintain the pulse rate > amounts sufficient to maintain the pulse rate > 120/minute and to keep the pupil fully dilated. 120/minute and to keep the pupil fully dilated.

Patients in the control group were also given a Patients in the control group were also given a median of 4 g PAM intravenously during the first median of 4 g PAM intravenously during the first 24 h of treatment.24 h of treatment.

Thereafter PAM was given intravenously at a 1 g Thereafter PAM was given intravenously at a 1 g daily dose for up to five days.daily dose for up to five days.

There were no significant differences between There were no significant differences between the study and control groups with regard to any the study and control groups with regard to any of the outcomes such as median atropine of the outcomes such as median atropine requirement in first 24 hours, patient with requirement in first 24 hours, patient with intermediate syndrome and median hospital stay intermediate syndrome and median hospital stay (days) or the patient needing intensive care (days) or the patient needing intensive care treatment or ventilation,treatment or ventilation,

DiscussionDiscussion

There was no statistically significant There was no statistically significant association of oxime therapy with association of oxime therapy with mortality ventilator requirements or the mortality ventilator requirements or the incidence of intermediary syndrome incidence of intermediary syndrome

Increased need for intensive care therapyIncreased need for intensive care therapy Oximes in OP poisoning was associated Oximes in OP poisoning was associated

with either a null effect or possible harm with either a null effect or possible harm concluded that use of oximes in OP concluded that use of oximes in OP

poisoning was associated with either poisoning was associated with either a null effect or possible harm a null effect or possible harm

Discussion (contd…)Discussion (contd…)

Studies have given following resultsStudies have given following results De Silva De Silva et al:-et al:- No benefit from No benefit from

pralidoxime was found pralidoxime was found Johnson and Vale:-(a) failure of treatment Johnson and Vale:-(a) failure of treatment

is usually a function of inadequate dosing is usually a function of inadequate dosing (b) Emphasized that dosage should be (b) Emphasized that dosage should be

maintained continuously until clear, maintained continuously until clear, irreversible, clinical improvement is irreversible, clinical improvement is achieved achieved

Discussion(contd..)Discussion(contd..)

Current WHO guidelines :-Current WHO guidelines :-Recommend giving a 30 mg/kg Recommend giving a 30 mg/kg loading dose of pralidoxime over 10-loading dose of pralidoxime over 10-20 minutes followed by a continuous 20 minutes followed by a continuous infusion of 8-10 mg/kg/h until clinical infusion of 8-10 mg/kg/h until clinical recovery or seven days have recovery or seven days have elapsed, whichever is later .elapsed, whichever is later .

Toxicol Rev. 2003;22(3):165-90 Toxicol Rev. 2003;22(3):165-90

These studies impressively demonstrated These studies impressively demonstrated that any generalisation regarding an that any generalisation regarding an effective oxime concentration is effective oxime concentration is inappropriate inappropriate

pralidoxime plasma concentrations of pralidoxime plasma concentrations of around 80 mumol/L (13.8 mg/L around 80 mumol/L (13.8 mg/L pralidoxime chloride) should be attained .pralidoxime chloride) should be attained .

These concentrations should be These concentrations should be maintained as long as circulating poison is maintained as long as circulating poison is expected to be present, which may require expected to be present, which may require oxime therapy for up to 10 daysoxime therapy for up to 10 days

The most appropriate consists of a The most appropriate consists of a bolus short infusion followed by a bolus short infusion followed by a maintenance dosage. For maintenance dosage. For pralidoxime chloride, a 1 g bolus over pralidoxime chloride, a 1 g bolus over 30 minutes followed by an infusion of 30 minutes followed by an infusion of 0.5 g/h appears appropriate to 0.5 g/h appears appropriate to maintain the target concentrtion of maintain the target concentrtion of about 13 mg/L (70 kg person). about 13 mg/L (70 kg person).