Pesticide toxic condition is a major wellness job worldwide. Harmonizing to WHO, yearly one million inadvertent and two million self-destructive toxic condition instances are due to insect powders. Since 3rd universe states account for about one-quarter of entire ingestion of insect powders, the state of affairs is worse in these regions.1 Organophosphate compounds are often used as toxicants due to their easy handiness. Furthermore, with usage of OP compounds every bit chemical warfare agents ( e.g. Sarin, Tabun ) ; these compounds have gained much more attending instead than merely being insect powders. In India, it is the most common toxic condition and about 50 % of instances are accounted by them.2 Most of the instances are with self-destructive purpose while poisoning due to inadvertent exposure include disregard of protective steps in agricultural and industrial workers ( e.g. usage of vinyl made baseball mitts alternatively of gum elastic ) , contaminated nutrient and H2O etc. Food borne exposures have resulted in epidemics such as “ Ginger Jake palsy ” ( delayed neuropathy ) due to taint of an alcoholic drink with triorthocresylphosphate ( TOCP ) 3 and with mild to chair symptoms with usage of insecticide aldicarb on watermelons.4 In a prospective survey, OP compounds were the 2nd most common used toxicants, accounting for 13.9 % of cases.5 A decennary subsequently, in a survey uncovering tendencies of poisoning in Haryana, 355 instances were admitted in twelvemonth with alleged history of poisoning with OP compounds in PGIMS, Rohtak and continued to be 2nd most normally used toxicant substance ( 29.17 % ) .6
Organophosphate compounds are diverse group of chemicals consisting of esters, amides or thiol derived functions of phosphorous acid derivatives.7 They were foremost synthesized in 1850 ‘s with the modern merchandises following back to development in Germany in 1930’s.They are widely used as insect powders and antifungals and are normally known among Indians as sprays. However, they are found to hold clinical usage in intervention of glaucoma, myasthenia gravis and Alzheimer ‘s disease. The rapid debasement by hydrolysis on exposure to sunlight, air and later acute toxicity make them favorites among pesticides. The assorted types of organophosphate compounds and the utilizations are given in Table I:
TableI: OP compounds and their utilizations
Malathion, Parathion, Diazinon, Fenthion, Dichlorovas, Chlorpyrifos
Soman, Sarin, Tabun, VX
Mechanism of action: Organophosphates inactivate the enzyme Acetylcholinesterase ( AchE ) by responding at the esteratic site and organizing a covalent phosphate linkage at the enzyme active site. AchE suppression allows the Ach ( Acetylcholine ) to roll up and stay active in synapse therefore ensuing in sustained depolarisation of the postsynaptic nerve cells in cardinal nervous system, muscarinic sites, nicotinic site in the sympathetic and parasympathetic ganglia, and nicotinic sites at neuromuscular junction. In general, effects of muscarinic sites are sustained, whereas nicotinic sites are stimulated and so depressed ( hyperpolarisation block ) .8
The profound toxicity of these compounds is attributed to non reversible binding to enzyme Acetylcholinesterase ( AchE ) . Enzyme regeneration depends upon de novo synthesis, hydrolysis of the serine – phosphate compound or oxime ( described in front ) regeneration nevertheless over a period of 24-48 hours most of phosphyralated compounds become immune to reactivation or travel under aging ( a procedure in which the bond between organophosphate and AchE become irreverisble with clip due to separation of one of alkyl groups from OPs ) ensuing in terrible and irreverisible toxic effects.
Manners of toxic condition: Organophosphate compounds can be absorbed through tegument, conjunctiva by direct contact, GIT and unwritten mucous membrane by consumption and respiratory path through inspiration. The patients become diagnostic depending upon the nature of compound, sum, path of exposure and rate of metabolic debasement. Onset of symptoms is every bit early as 3-4 hour by inhalation/ unwritten path to 10-12 hour through cuticular path. They are distributed quickly in all organic structure tissues after soaking up and the high lipid solubility of these compounds makes their entree easy in CNS and fat tissues. Onset may be delayed for lipotropic compounds ( e.g. fenthion, diclofenthion ) 9 or compounds necessitating transition to more toxic metabolite ( e.g. hepatic metamorphosis of parathion to paraoxon ) .10 The intermittent release of toxin from the fat tissues histories for the impairment of the stable patient.
Clinical characteristics ( Fig.1 )
The clinical characteristics are due to stimulation of muscarinic, nicotinic and cardinal receptors and delayed neurotoxicity.
Muscarinic Features: The accretion of Ach at postganglionic muscarinic receptors leads to increased parasympathetic activity of smooth musculus in lungs, GIT, bosom, eyes, vesica, secretory secretory organs and increased sympathetic discharge for perspiration secretory organs and the attendant manifestations can be easy remembered by pneumonic SLUDGE/BBB ( Salivation, Lacrimation, Urination, Defecation, GI symptoms, Emesis, Bronchorrhea, Bronchospasm, Bradycardia ) or DUMBELS ( Diarrhea, Diaphoresis, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Salivation ) . Meiosis may be most sensitive marker amongst lachrymation, rhinorrhea and profuse perspiration in moderate to severe poisoning whereas abdominal spasms, diarrhea and purging are more common in terrible toxic condition.
Nicotinic Effectss: Fasciculations, progressive failing and hypotonus are due to inordinate Ach at nicotinic musculus terminal plates doing relentless depolarisation of skeletal musculus. Respiratory failure due to bronchial cramp, noncardiogenic pneumonic hydrops and respiratory musculus palsy is a common cause of decease due to OP toxicants. Cardiac toxicity comprises of stages including a brief period of intense adrenergic tone, a period of enhanced parasympathetic activity, and protraction of QTc.8 Other cardiovascular effects include high blood pressure, tachycardia, re-entrant arrhythmias and torsade de pointes etc.
CNS Effectss: Organophosphate compounds transverse blood encephalon barrier, they may do ictuss, choreoathetoid motions, ataxy, dysarthrias, shudders, absent or overdone physiological reactions, anxiousness, agitation, emotional labilities, slurred address etc.
Delayed Neurotoxicity: Altered witting province after 4-5 yearss taking to deep coma, encephalopathy11, dystonia, gear rigidness and parkinsonian features12,13 ( radical ganglia damage after recovery from acute toxicity ) has besides been reported.
The clinical manifestations seen with OP poisoning can be seen as in Fig.2.
Rating of organophosphate toxic condition has been formulated harmonizing to badness on assorted clinical and biochemical parametric quantities and is shown in table II.
Table II. Grading of Organophosphate Poisoning14
Organophosphate toxic condition: Badness Grade
Walks and negotiations
Can non walk
No pupillary physiological reaction
Muscle vellication, Fasciculations
Flaccid palsy, Fasciculations
Increased bronchial secernment
Dyspnoea, cracklings, wheeze
SERUM AchE LEVELS
1.6-4 U/L ( AchE 20-50 % of normal* )
0.8-2 U/L ( AchE 10-20 % of normal )
& lt ; 0.8 U/L ( AchE & lt ; 10 % of normal )
*Normal value of serum AchE is 8-20 U/L.
Diagnosis of organophosphate toxic condition
History of exposure to organophosphate compound in the presence of marks and symptoms normally clinches the diagnosing which is confirmed by low AchE degrees. The compounds inhibit both plasma cholinesterase ( besides called butyrylcholineesterase or pseudocholineesterase ) and RBC cholinesterase. RBC AchE degrees are more specific than plasma AchE degrees since RBC AchE has similar construction to synapyic AchE.15 AchE degrees & lt ; 10 % of normal indicate terrible toxicity whereas degrees 20-50 % and 10-20 % history for mild and moderate toxicity severally.
Several OP compounds are metabolized to p-nitrophenol which can be easy detected in urine.16 Serum degrees of OP compounds, though of small relevancy in patient direction yet assist in finding the residuary OP residue in patients with drawn-out marks of toxicity. Auxiliary surveies include serum electrolyte, blood urea N, creatinine, glucose, Ca, Mg, electrocardiography and thorax skiagraphy.
Differential diagnosing includes toxicity due to carbamates, nicotine, carbachol, bethanechol, pilocarpine, mushrooms and cholinergic crisis like in myasthenia gravis and Eaton-Lambert ‘s syndrome. Signs and symptoms of carbamate toxic condition closely resembles that of OP toxic condition, nevertheless the oximes are non recommended owing to early hydrolysis of carbamylated enzyme, therefore easy reverisibility and non ripening of the carbamylated enzymes ( c.f. Phosphyralated enzymes- may undergo ageing by losing one of the alkyl group, therefore going resistant to hydrolysis ) .
The conventional representation refering to diagnosing is given in Fig.3
Organophosphate toxic condition is a medical exigency. Life can be saved by early diagnosing and effectual intervention. Patients should be admitted and observed carefully. The individuals involved in pull offing these patients should sooner have on masks, aprons, and rubber baseball mitts to avoid secondary taint. Treatment includes decontamination, general supportive steps and specific intervention.
Decontamination and methods to retard the soaking up of toxicant: In instance of contact with toxicant, the remotion of apparels and thorough lavation of organic structure with soap and H2O should be done ( organophosphate compounds get hydrolysed in aqueous solution at high pH ) . Skin creases, hair and nails should be exhaustively cleaned. Ocular decontamination should be done with water/ normal saline. Gastric decontamination in signifier of stomachic lavage should be carried out with KMnO4. The slurry of activated wood coal can be left in tummy to absorb the residuary toxicant. Gastric lavage should be repeated every 3-4 hour to take any residuary toxicant secreted in tummy due to let go of from fat stores.17 Forced vomit and sirup ipecac have no role.18
General supportive steps: it includes the basic rules of resuscitation i.e.
A- Airway should be secured to forestall aspiration by oropharyngeal suction, endotracheal cannulation.
B- Breathing by ambubag or mechanical airing.
C- Circulation- hydrate the patient by procuring broad dullard IV lines.
D- Detoxification by counterpoisons
Anticholinergic drugs: These agents are the pillar of intervention. These act as competitory adversaries of Ach at muscarinic receptors taking to reversal of muscarinic effects of organophosphate compounds both in CNS and fringe.
Atropine: It is life salvaging antidote taking to reversal of muscarinic effects but has no consequence on musculus weakness/paralysis and regeneration of AchE. Early disposal of drug in appropriate dosage is an indispensable portion of direction. Atropine has been shown to hold secondary function in commanding ictuss and CNS manifestations in add-on to primary function in glade of secernments and bronchospasm.19
Intermittent regimen – Atropine has to be started at 1-3 milligram four bolus dosage with increase of the dosage to be doubled every 5 proceedingss till the mark terminal points of atropine therapy ( pupils no longer pinpointed, clear thorax on auscultation with no wheeze, dry armpit, systolic blood force per unit area & gt ; 80 millimeter Hg and bosom rate & gt ; 80 beats per minute ) are achieved.20 However, tachycardia is non a good indexs of atropinisation since the status can happen due to nicotinic symptoms, hypoxia or due to sympathetic over responsiveness. Similarly, pupil distension may ensue due to hypoxic harm to the encephalon instead than being a mark of atropinisation.
Continuous extract therapy – Continuous extract of atropine at the rate of 0.02-0.08 mg/kg/hr following bolus injection has been besides investigated and proven to be utile as it requires less observation, produces less fluctuation in plasma atropine concentration which makes ablactating easier.21 In add-on, atropine extract at a rate of 10-20 % of atropine required for atropinization every hr by I/V extract has besides been found to be utile in pull offing the patients.22 If really big doses ( more than 30 milligrams ) were ab initio required, so less can be used. It is rare that an extract rate greater than 3-5 mg/ hr is necessary nevertheless, larger doses may be required if oximes are non available.20
Atropine tapering – The atropine dosages has to be maintained by increasing the dosage interval bit by bit from 5- 15 min to a period of 2-3 hour over a period of 3-5 yearss and subsequent backdown of atropine on 5th-7th twenty-four hours.
The assorted atropine regimens can be described by simple algorithm as in fig.4
Atropine toxicity: It includes confusion, agitation, hyperthermy, intestinal obstruction and tachycardia.23 The drug should be stopped instantly till the marks of over atropinisation remain. The drug can be restarted at rate of 70-80 % of old dosage when the characteristics of toxicity settle down. The patient should so be seen often to guarantee that the new extract rate has reduced the marks of atropine toxicity without allowing the reappearance of cholinergic marks.
Glycopyrrolate: It is an alternate to atropine. It does non traverse the blood encephalon barrier, therefore the CNS symptoms like coma and confusion do non react. It is used as an adjunct to atropine in instance of voluminous secernments, in atropine toxicity or if atropine is non available. It is given as 0.05mg/kg organic structure weight and is titrated till the coveted consequence of dry mucose membranes is achieved. The extra advantage of glycopyrrolate studied is the less opportunities of respiratory infections.24
Cholinesterase reactivators: These agents, normally known as oximes ( pralidoxime, obidoxime ) acquire attached to liberate anionic site of enzyme AchE. The oximes so respond with phosphorus atom of organophosphate attached at the esteratic site of the enzyme, therefore organizing oxime phosphate which gets easy diffused go forthing AchE intact. In add-on, they slow the ripening of phosphorylated enzyme composite and besides convert the organophosphate compound to a harmless one.25 Oximes do non traverse the blood encephalon barrier ; hence the action is limited to the skeletal musculus and autonomic sites ( reverses nicotinic symptoms ) .
Despite its proved efficaciousness in studies26,27, usage of oximes has been a affair of argument since early 1890ss by assorted surveies demoing small or no benefit28,29 to harmful effects.30 The disparities are accounted by differences in the lipophilicity, ability of adhering with side ironss ( O’dimethyl vs O’diethyl organophosphates ) , rate of ageing of complex and deficient continuance or dosing of intervention.
Pawar et al demonstrated decrease in morbidity and mortality in reasonably terrible instances of acute organophosphorus-pesticide toxic condition with high-dose regimen of pralidoxime, dwelling of a changeless extract of 1 g/h for 48 H after a 2 g lading dosage. They besides observed a lessening in entire needed dosage of atropine with establishment of uninterrupted infusion.27 Where as in a recent two-base hit blinded placebo controlled test by Eddleston, no improved endurance or decreased demand for cannulation was seen in patients with organophosphorus insect powder poisoning with oxime therapy despite clear reactivation of ruddy cell acetylcholinesterase in diethyl copmpound poisoned patients.30 Chugh et Al in a prospective designed survey evaluated the function of atropine or atropine plus pralidoxime and concluded that conventional doses of pralidoxime ( 2g stat followed by 1g every 6 hrly ) did non cut down mortality, infirmary stay and demand for ventilator support.31 Later on comparing the conventional doses of PAM ( 2g stat followed by 1g every 6 hrly ) with the uninterrupted extract of PAM ( 2g stat followed by uninterrupted extract at 10mg/kg/h or to a upper limit of 500mg/hr ) , they could non happen any important difference in footings of endurance benefit, demand for ventilator support and infirmary stay.
WHO recommends the usage of pralidoxime with the lading dosage of 30 mg/kg over 10-20 min followed by 8-10 mg/kg/hr until clinical recovery or 7 yearss, whichever is later.32 Singh et Al observed improved result with uninterrupted PAM therapy, when compared with historical controls, without important demand for mechanical ventilation.33 Alternatively, guidelines laid down by southern infirmary web recommends utilizing an initial bolus dosage of 2 grams four ( 30 mg/kg ) over 30 min followed by 1 gram every 8 hourly in mild to chair toxic condition and 500 mg/hr in terrible toxic condition boulder clay clinical recovery ( 12 – 24 hour after atropine no longer recommended or the patient is extubated ) or 7 yearss whichever is later.13 The later regimen appears to be more promising since rapid and uninterrupted extract has been reported with high blood pressure, respiratory failure, cardiac arrhythmias, concern and blurring of vision.30
The Cochrane reappraisal on “ Oximes for acute organophosphate pesticide poisoning ” provinces, current grounds is deficient to bespeak whether oximes are harmful or good in the direction of acute organophosphorus pesticide toxic condition, despite strong experimental grounds due to conflicting clinical surveies. Based on apprehension of the mechanism, in vitro and animate being informations, theoretically, benefita?’risk ratio is more likely to be favorable when they are given early, to patients with serious toxic condition by diethyl OPs.34 However, systemic reappraisal on oximes did non back up WHO recommendations and stated the deficiency of grounds of oximes in OP poisoning owing to late presentations of patients, usage of dimethyl compounds and big consumption of poison.The reappraisal stressed the demand of big graduated table RCTs to analyze other stratigies and regimens.35
The precise intervention protocol of oximes is non good known, but carnal surveies have shown a degree of oximes 4mg /ml to be effective.36 However in terrible toxic condition ( ensuing due to big sum of toxicant ) these oximes degrees are improbable to function the intent. Therefore, in the absence of consensus, it will be hard to oppose the recommendations of WHO.
Magnesium: It reduces the Ach release by barricading the presynaptic Ca channels. In add-on, it besides counteracts the direct repressive action of organophosphate compounds on Na+-K+ ATPase pump.37 At a dosage of 4 gm/day, it has been shown to cut down the mortality and in hospital stay.
Clonidine: It inhibits the presynaptic synthesis and discharge of Ach and besides has adrenergic agonistic action. The effects are more marked at cardinal nervous system than peripheral cholinergic synapses.38
Benzodiazepines: They potentiate and facilitate repressive GABA neurotransmission and are used for agitated, hallucinating patients and to command ictuss. They besides have been reported to cut down respiratory rate in rats and cognitive shortages in Primatess but no human information is available.39
Sodium Bicarbonate: Animal surveies suggest that increasing pH with sodium hydrogen carbonate may cut down mortality rate irrespective of the acidosis40 but no randomised controlled tests are available and farther surveies are warranted in this respect.
Trihexiphenydyl: This cardinal anticholinergic compound has been tried with good consequences in instances of delayed brain disorder ( Personal communicating ) . However needs rating in tests.
Complications of organophosphate toxic condition: In add-on to early complications described above, organophosphate compounds lead to late complications which are described as:
Intermediate syndrome ( IS ) : First described in 1974, this neuropathic syndrome is characterized by the development of neuromuscular failing, after 3-4 yearss of exposure/resolution of acute cholinergic crisis and appears to ensue from a combined pre and station synaptic disfunction of the neuromuscular transmittal. Persistent suppression of nicotinic receptors & A ; structural transmutation of Ach receptors have besides been suggested as alternate mechanisms.
The characteristics include facial, cervix and proximal musculus failing, cranial nervus paralysiss, depressed sinew physiological reactions and respiratory musculus weakness/paralysis. However the primary manifestation is respiratory failure due to failing of musculuss of respiration. Tachypnoea is an of import mark & A ; must non be ignored ; CO2 keeping is a late characteristic & A ; must non be relied upon. Incidence is reported to be 15 % among Indians & A ; it may acquire complicated by respiratory infections or cardiac arrhythmia. In a retrospective analysis of patients admitted in our ICU, 27 % of the patients had IS. The status can prevail for 4-18 yearss and vary in clinical scenes from being self restricting to demand of mechanical airing. Trouble in ablactating from the ventilator, inability to raise caput and lift limbs with presence of oculogyric crisis/ excess optic musculus failing should raise intuition of intermediate syndrome. In a prospective survey, insistent nervus stimulation ( RNS ) alterations correlated with the badness of IS. Predating the oncoming of IS, decrement-increment form was observed at intermediate and high frequences whereas decrement-increment form at low frequences and terrible decrease at higher frequences with insistent slices was noted with IS onset.41 Mechanical airing remains the chief stay of intervention in intermediate syndrome.
Organophosphate induced delayed polyneuropathy ( OPIND ) : It normally occurs 2-3 hebdomads after big dosage of organophosphate toxic condition and consequences due to damage to afferent fibers of the peripheral and cardinal nervousnesss ( axonal motor neuropathy ) and suppression of the neuropathy mark esterase. The disease is characterized by distal musculus failing with sparing of cranial nervousnesss, proximal and neck musculuss ( c.f. intermediate syndrome ) and paraesthesia of appendages. OPIDN preponderantly affect the legs and may last for hebdomads to months. Treatment is chiefly supportive with no definite intervention established boulder clay day of the month.
Organophosphate compounds are powerful insect powders but are being often misused as toxicants for ego injury. The AchE suppression by these compounds leads to muscarinic, nicotinic and CNS symptoms. High index of intuition of organophosphate toxic condition, early diagnosing and prompt intervention can be life salvaging. General supportive steps include decontamination of viscera/skin in contact with toxicant, care of patent air passages with equal airing of the patient. The specific counterpoison atropine, an antimuscarinic agent is a life salvaging drug. In add-on, other antimuscarinic agents like glycopyrrolate and Benadryl besides are of proved benefit in organophosphate toxic condition. Though oximes have strong theoretical footing for their usage, yet grounds sing its public-service corporation in patients of self injury due to OP compounds is conflicting owing to amount of compound ingested, inability to cognize the chemical nature & A ; late presentation. In add-on, the inability to quantify precise doses, monitoring and possible side effects of oximes further draw the custodies of clinicians. However, inspite of constructing grounds against the ineffectualness of oximes, it seems hard to travel against the current WHO recommendations for their usage in OP poisoning for the grounds explained. The usage of newer compounds which include Mg, Catapres, Na hydrogen carbonate are assuring but surveies are missing sing the usage in organophosphate toxic condition and big graduated table tests are needed to further research their action.