Correlation of Serum Amylase, Lipase and Creatine Kinase in Predicting the severity of Organophosphorus Poisoning

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CORRELATION OF SERUM AMYLASE, LIPASE AND CREATINE KINASE IN PREDICTING THE

SEVERITY OF ORGANOPHOSPHORUS

Submitted in partial fulfilment of requirements for

THE TAMILNADU DR.M.G.R.

INSTITUTE OF INTERNAL MEDICINE MADRAS MEDICAL COLLEGE

DISSERTATION on

CORRELATION OF SERUM AMYLASE, LIPASE AND CREATINE KINASE IN PREDICTING THE

SEVERITY OF ORGANOPHOSPHORUS POISONING

Submitted in partial fulfilment of requirements for

M.D. DEGREE BRANCH I GENERAL MEDICINE

OF

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY CHENNAI

INSTITUTE OF INTERNAL MEDICINE MADRAS MEDICAL COLLEGE

CHENNAI - 600 003 2016 - 2019

CORRELATION OF SERUM AMYLASE, LIPASE AND CREATINE KINASE IN PREDICTING THE

SEVERITY OF ORGANOPHOSPHORUS

Submitted in partial fulfilment of requirements for

MEDICAL UNIVERSITY

INSTITUTE OF INTERNAL MEDICINE

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CERTIFICATE

This is to certify that this dissertation entitled “CORRELATION

OF SERUM AMYLASE, LIPASE AND CREATINE KINASE IN PREDICTING THE SEVERITY OF ORGANOPHOSPHORUS POISONING” submitted by Dr.M.SHIVANATHAN appearing for

M.D. Branch I - General Medicine Degree examination in MAY-2019 is a bonafide record of work done by him under my direct guidance and supervision in partial fulfilment of regulations of the TamilNadu Dr. M.G.R. Medical University, Chennai. I forward this to the TamilNadu Dr.M.G.R. Medical University, Chennai, Tamil Nadu, India.

Prof.Dr.R.PENCHALAIAH, M.D., Prof.Dr.S.TITO, M.D.,

Professor of Medicine, Professor and Director Incharge, Institute of Internal medicine, Institute of Internal medicine, MMC & RGGGH, MMC & RGGGH,

Chennai- 600 003. Chennai- 600 003.

Prof.Dr.S.RAGUNANTHANAN, M.D., Prof.Dr.R.JAYANTHI, M.D.,

Professor of Medicine, The Dean,

Chief of IMCU and Toxicology, MMC & RGGGH, Institute of Internal medicine, Chennai- 600003.

MMC & RGGGH,

Chennai- 600 003.

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DECLARATION

I solemnly declare that the dissertation titled “CORRELATION

OF SERUM AMYLASE, LIPASE AND CREATINE KINASE IN PREDICTING THE SEVERITY OF ORGANOPHOSPHORUS POISONING ” is done by me at Madras Medical College & Rajiv

Gandhi Govt. General Hospital, Chennai during 2018 under the guidance and supervision of Prof.Dr.R.PENCHALAIAH., M.D, Prof.Dr.K.S.CHENTHIL., M.D. and Prof.Dr.S.RAGUNANATHANAN., M.D. The dissertation is submitted to TheTamilnaduDr.M.G.R. Medical University towards the partial fulfilment of requirements for the award of M.D. Degree (Branch I) in General Medicine.

DR. M.SHIVANATHAN,

Place: M.D.General Medicine,

Date: Postgraduate student,

Institute of Internal Medicine,

Madras Medical College,

Chennai.

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ACKNOWLEDGEMENT

At the outset, I would like to thank our beloved Dean, Madras Medical College, Prof.Dr.R.JAYANTHI, M.D., for her kind permission to use the hospital resources for this study.

I would like to express my gratitude to my Professor and Director (I/C), Institute of Internal Medicine Prof.Dr.S.TITO, M.D., for his guidance.

With extreme gratitude, I express my indebtedness to my Chief’s Prof.Dr.R.PENCHALIAH M.D., Prof. Dr.K.S.CHENTHIL M.D., and Prof.Dr.S.RAGUNANTHANAN M.D., for his motivation, advice and valuable criticism, which enabled me to complete this dissertation.

I am extremely thankful to Assistant Professors of Medicine Dr.B.PRIYADARSINI, M.D., and Dr.BIJIN OLIVER JOHN, M.D., for their guidance. I thank all the Assistant Professors of IMCU &

Toxicology for their extreme cooperation extended to me without whom the study would not have been possible.

I would also be thankful for the co-operation and criticism shown by my Postgraduate colleagues.

I am immensely grateful to the generosity shown by the patients who participated in this study.

Above all I thank the Almighty for the immense blessings and

support.

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ABBREVIATIONS

OPC - Organophosphate compounds Ach - Acetylcholine

Ch - Choline

S.AchE - Serum Acetylcholinesterase S.Amy - Serum Amylase

S.Lipa - Serum Lipase

S.CK - Serum Creatine Kinase BchE - Butryl cholinesterase

POP - PeradeniyaOrganophosphorus Poisoning U/L - Units per Litre

CNS - Central nervous system EChe - Erythrocyte Cholinesterase IMS - Intermediate syndrome P2AM - Pralidoxime

OPIDP - Organophosphate Induced Delayed Polyneuropathy COPIND - Chronic Organophosphate Induced Neuropsychiatric

Disorder

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CONTENTS Serial

no. TITLE PAGE

NO.

1. INTRODUCTION 1

2. AIMS AND OBJECTIVES 3

3. REVIEW OF LITERATURE 4

4. MATERIALS AND METHODS 40

5. OBSERVATION AND RESULTS 43

6. DISCUSSION 78

7. CONCLUSION 81

8. LIMITATIONS OF STUDY 83

9. BIBLIOGRAPHY 84

10. ANNEXURES PROFORMA

ETHICAL COMMITTEE PLAGIARISM SCREENSHOT PLAGIARISM CERTIFICATE INFORMATION SHEET CONSENT FORM

MASTER CHART

90

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INTRODUCTION

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1

INTRODUCTION

Agriculture constitutes the major component of Indian economy.

Incidence of poisoning by pesticides and consequent admission to the hospital has been increasing in recent decades. OPC ranks the foremost in the list of agents which cause pesticide poisoning. OPC are widely used insecticides in agricultural industry and are common causes of morbidity and mortality due to poisoning worldwide especially in developing countries like India.

Due to easy availability and low cost OP compounds poisoning are becoming a major source of health hazard hence it is important to recognize the entire spectrum of symptoms. Causes of poisoning are suicidal, accidental and homicidal. Suicidal poisoning is the most common cause in developing countries because of its cheapness and easy availability in the market.

The morbidity and mortality depends on the time lag between the exposure and the onset of management. Identification, risk stratification, early diagnosis and prompt treatment of OP poisoning victims are equally vital.

World Health Organization (WHO) estimates that around 0.3 million people die every year globally due to various poisonings and pesticide poisonings causes more than 2,20,000 deaths in developing countries like India because of cheap and easy availability of highly hazardous pesticides. In many Indian reports, the rates of poisoning as suicidal method range from 20.6%

(10.3% organophosphorus) to 56.3% (43.8% organophosphorus).

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2

Laboratory evaluation play a crucial role in confirmation and assessing severity of OPC poisoning. Serum acetylcholinesteraselevel is measured in OPC poisoning. It is not specific and does not correlate with the severity of poisoning and cannot be used as a prognostic indicator.

Estimation of serum amylase, lipase and creatine kinase is useful biomarkers in organophosporous poisoning. This study is undertaken to know the efficacy of newer biochemical markers like amylase, lipase and creatine kinase as indicators in assessing the severity of organophosphorus poisoning.

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AIMS AND OBJECTIVES

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3

AIM AND OBJECTIVES AIM OF THE STUDY

Correlate the Serum Amylase, Lipase and Creatine kinase in predicting the severity of Organophosphorous poisoning.

OBJECTIVES OF THE STUDY

To estimate the serum levels of amylase, lipase and creatinekinase in acute OPC poisoning and to correlate the same with clinical severity score by PeradeniyaOrganophosphorouspoisoning (POP) scale on admission and measured serially till discharge or death of the patient.

To correlate the serum levels of Amylase, Lipase and Creatine kinase with complications, intermediate syndrome and need for mechanical ventilation and outcome of the patient.

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REVIEW OF LITERATURE

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4

REVIEW OF LITERATURE HISTORY

OPC are the most commonly used pesticides in agriculture. They have been first synthesized by Lassaigne during early 1800s who observed the alcohol reaction with phosphoric acid. The synthesis of a highly potent compound Tetra Ethyl Pyrophosphate(TEPP) by Phillipe de Clerment in 1854 gave him the honour of conceiving the idea of organophosphorous compound.In 1932 Lange and kreuger, discovered the biological activity of OP esters producing a strong cholinergic effect in human beings and succeeded in the synthesis of dimethyl diethyl phosphor fluoridates . In 1936-1937, Gerhard Schrader, German scientist also noticed similar effects. This made Schrader to synthesis around 2000 compounds like parathion, tabun, sarinetc.The German military used it as a chemical warfare agents. In 1941, during World War II, the OPC were reintroduced as Insecticides.It was Davies who introduced oximesin the year 1955 and its effectiveness in OPC poisoning. The word

“cholinesterase” was introduced by Stedman and his co-workers in 1932.

Extensive research lead to find that there are two main type of cholinesterase namely AChE (True ChE) and Pseudocholinesterase.

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5 CHEMICAL STRUCTURE

The structure of OPC compound is O (S)

R1 P R2

X

OPC are esters of phosphoric acid in which the central compound is phosphorous atom with a double bond to either oxygen (P=O) or sulfur (P=S) and three side chains, one x group,R1 and R2 may be alkyl, alkoxy, amidomercapten or other groups. X group is the principal metabolite for species identification. The effectiveness as insecticides and the lack of persistence in the environment made the OPC a great popularity. Due to their unstable structure these compounds disintegrate into harmless radicals within days of application. The OPC are used as insecticides in agriculture. Some compounds are used as lubricants, plasticizers and flame retardens. Usage of some of these compounds as very potent agents of warfare is of global significance.

Anatomy and Physiology of Autonomic Nervous System

The autonomic nervous system controls the visceral function of the body.Autonomic nervous system centers are located in the hypothalamus,brainstem and spinalcord. Anatomicaly this system is divided into sympathetic and parasympathetic system. Under sympathetic nervous

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6

system preganglionic fibers exits from spinal cord between first thoracic and second lumbar segments. A parasympathetic fiber leaves CNS through cranial nerves III, VII, IX, X and second to fourth sacral spinal nerves.

Acetylcholine (Ach) is a neurotransmitter found throughout the central nervous system, the sympathetic and parasympathetic autonomic ganglia, postganglionic parasympathetic nervous system, most sympathetic glands and at the skeletal musclemotor endplate.

Ach is first synthesized by BAYER in 1867. The Ach is synthesized in the motor nerve terminal from choline and co-enzyme A (CoA) by a process facilitated by the enzyme choline acetyl transferase.

Choline+Acetyl-CoA Acetycholine

(Choline Acetyl Transferase)

Acetylcholine: 20% of Ach is Present as free Ach in axoplasm and 80%

is contained within the vesicles.

When a nerve impulse arrives at the nerve terminal causing release of acetylcholine into the synaptic space. Ach binds to and activates muscarinic and nicotinic receptors. Duration of Ach is curtailed as it is hydrolysed by the enzyme acetylcholinesterase.

Acetyl choline Acetate ion + choline (AChE)

The choline is reabsorbed actively into the neural terminal and reused in forming new acetylcholine. These events takes less than 5-10

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milliseconds and within about 20 seconds new vesicles will be formed and within another few seconds acetylcholin

these vesicles and they are ready for a new cycle of acetylcholinesterase. The actions of acetylcholine in the body depend on the receptors involved and the site.

Activation of the muscarinic receptors stimulates or

function through G protein at visceral smooth muscle, cardiac muscle and secretory glands. Nicot

membrane and in

regulates the activity of acetylcholine within the synaptic cleft.

There are two types of cholin Pseudocholinesterase

True Cholinesterase-

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milliseconds and within about 20 seconds new vesicles will be formed and within another few seconds acetylcholine is transported into the interior of these vesicles and they are ready for a new cycle of acetylcholinesterase. The actions of acetylcholine in the body depend on the receptors involved and the

Activation of the muscarinic receptors stimulates or

function through G protein at visceral smooth muscle, cardiac muscle and secretory glands. Nicotinic receptors are Na channels present in post synaptic membrane and in skeletal muscle motor endplates. Th

ity of acetylcholine within the synaptic cleft.

There are two types of cholinesterase in human body. One is docholinesterase (PChE) and other is true cholinesterase (True ChE)

- (RBC Cholinesterase)

milliseconds and within about 20 seconds new vesicles will be formed and e is transported into the interior of these vesicles and they are ready for a new cycle of acetylcholinesterase. The actions of acetylcholine in the body depend on the receptors involved and the

Activation of the muscarinic receptors stimulates or inhibits cellular function through G protein at visceral smooth muscle, cardiac muscle and inic receptors are Na channels present in post synaptic skeletal muscle motor endplates. The enzyme AchE ity of acetylcholine within the synaptic cleft.

esterase in human body. One is (True ChE).

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8

It is present in erythrocytes, nervous tissue, spleen, lungs and grey matter. It is decreased in pernicious anemia and after antimalarial therapy. Ach is inactivated by combination with two sites on the enzyme RBC cholinesterase anionic site and esteratic site.

Plasma cholinesterase (Pseudocholinesterase)

It is found in plasma, pancreas, liver and intestinal mucosa.

NEUROCHEMISTRY OF ANS PATHWAY

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9

THE ORGAN SPECIFIC ARRANGEMENT OF ANS

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Plasma cholinesterase deficiency could be due to physiological variation , disease, iatrogenic causes and genetic defects.

1) Physiological variations:- a. Age:

• A newborn has about 50% of normal PchE activity.

• PchE activity reaches normal level at puberty.

• In old age (75-80years) the activity is 75% of normal.

b. During pregnancy PchE activity decreases 20 -30%.

2. Diseases

a. Liver disease:PchE activity decreases upto 50% in acute hepatitis, cirrhosis and liver metastasis.

b. Renal disease: PchE activity decreases to 30% normal in renal disease.

3.Drugs: OPC &Organocarbamate compounds, Anticancer drugs, Ecothiophate eye drops and Bombuteral.

4. Genetic :Patients with atypical PchE have low PchE activity.

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11 CLASSIFICATION OF OPC

I) BASED ON GROUPS PHOSPHORYLCHOLI

NES

FLOUROPHOSPHA TES

CYANOPHOSPHA TES

&HALOPHOSPHA TES

MULTIPLE CONSTITUEN

TS

Echothiopate Dimefox

Sarin Mipafox

Tabun Dimethoxy

Diethoxy Dialkoxy Diamino Trithioalkyl Triphenyl Chlorinated Mixed substituent

II) BASED ON CHEMICAL STRUCTURE A) Alkyl phosphates:

1. HETP (Hexaethyl tetra phosphate)

2. TEPP (tetraethyl pyrophosphate) tetron,fosvex

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12

3. OMPA (octamethylpyrophoramide) schardan13 4. Dimefox (bis[dimethyl amino] flurophosphine oxide)

5. Isopestox (bis[isopropylamino] flurophosphine oxide)pestox 6. Malathion(5,[1,2dicarbethoxyethyl]0,o dimethyl

dithiophosphate)

7. Sulfoteppa(tetra ethyl 0,dithiopyrophosphate)-dithione Asp-47

8. Systox,demeton(0,0 diethyl 10-2 ethylmercapto ethyl thionophosphate) 9. Dipterex(0,0 dimethyl 2-2-2 trichloro hydroxyl ethyl phosphate-tug orbait

B) Aryl phosphate 1) Paroxon

2) Parathion

3) EPN-o, ethyl-o-p nitropheyyl benzene thionophosphate, EPN 300

4) Methylparathiono, o-dimethyl o-p nitrophenylthiophosphate III) BASED ON TOXICITY:

A) Highly toxic(<D

50<50 mg/kg)

1. Azinophos-methyl 7. Cyanofenphos 2. Bomyl 8. Demeton 3. Carbophenthion 9. Dialifor 4. Chlorfenvinphos 10. Dicrotophos

11.Disulfoton 12.EPN

13.Famphur15 22.Monocrotophos 14.Phenamiphos 23.Parathio-ethyl

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13

15. Fenophosphan 24. Parathion methyl 16. Isophenfos 25. Phorate

17. Isofluorphate 26. Phostolan 18. Mephosfolan 27. Phosphomidan 19. Methmidophos 28. Prothoate 20. Methidathion 29. Sulfotep

21. Mevinphos 30. Tetraethylpyrophosphate (TEPP) B) Moderate Toxicity (D

50=50-1000mg/kg)

1) Acephate 16) IPB

2) Bensulide 17) Leptophos

3) Chloropyrofos 18) Merphos

4) Crotoxyphos 19) Naled 5) Cythioate 20)Phosalone 6) DEF 21) Phosmet 7) Deneton-s-methyl 22)Pirimiphos-ethyl 8) Diazinon 23) Profenofos

9) Dichlorvos 24)Propetaamphos

10) Dimethoate 25) Pyrazophos

11) Edifenphos 26) Quinalphos

12) Ethion17 27) Sulprofos

13) Ethoprop 28) Thiometon 18

14) Fenitrothion 29) Triazophos

15) Fenthion 30)Tribufos

31)Trichlorfon

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14 C) Low Toxicity(D

50=>1000mg/kg)

1) Bromophos 5) Phoxim

2) Etrimfos 6)Prophylthiopyrophosphate 3) Iodofenphos 7) Temephos

4) Malathion 8) Tetrachlorrinphos.

PHARMACOKINETICS OPC is absorbed by ingestion, inhalation, percutaneusly or injection. Most OPCs are lipophilic – adipose tissue accumulation is highest. The pharmacokinetics depends on certain factors such as :

1)Route of administration 2) Distance from target organs

3) Local vs Systemic metabolism and activation 4) Route of elimination

5) Endogenous hydrolysis by non-specific esterase Metabolism occurs either by hydrolysis by esterases, oxidation or by

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glutathione transfer. Around majority of compound is eliminated within 48 hours of exposure by urinary and fecal excretion.Cholinergic crisis may occur when unmetabolized OPC are mobilized from fat store – Fenthion ,Chlorfenthion.Prolonged absorption from intestine & reabsorption from fat store may allow the insecticide concentration for up to 48

hrs.MECHANISM OF ACTIONOPC inhibit enzyme AChE. The

mechanism of inhibition of the enzyme is by reacting with the esteratic site on the acetyl cholinesterase molecule. The bond formed between

phosphorus atom and the esteratic site of enzyme is stable and requires hours to weeks to reverse depending on the type of OP compounds.

Phosphorylated enzyme is inhibited because of occupation of its active site.

It is incapable of carrying out its normal function of hydrolyzing

acetylcholine. The effect of the OPC poisoning is therefore the result of continuing increased production of acetylcholine at the neuromuscular junction, resulting in depolarisation block.

This phosphorylated enzyme can undergo spontaneous hydrolysis or dealkylation. Due to spontaneous hydrolysis active enzyme cholinesterase is released and this is called reactivation. The phosphorylated enzyme can also undergo dealkylation. Once this occurs, reactivation is impossible. This process is called ageing.

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16 AGING OF ENZYME

• OPC -- Ach E - is irreversibly bound for 24 – 72 hours

• When one of the R group leaves the phosphate molecule this step is called aging .

• Denovo synthesis of Ach E is required to replenish the supply once aging has occurred

• Aging can not occur in carbamates.

• Ach E spontaneously hydrolysed in 24 hrs.

• AchE aging is particularly rapid with dimethyl phosphoryl compounds such as Malathion, fenthion, metyl parathion, dichlorvos , dicrotophosdicaphon , dimethoate, temephos , crotoxyphos,

• Diethyl OPC low propensity for aging benefit from P2AM.- parathion, chlorpyriphos , phorate , phosfolan, TEPP, coumaphos, diazinon , ehion , chlorothion, demeton.

• Permanent binding to the acetylcholinesterase enzyme (“aging”) may occur after a variable delay unless antidotal treatment with an enzyme reactivator is given.

• Reactivation of inhibited AChE occurs more quickly with dimethylatedOrganophosphatescompared with diethylated OPs.

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Antidotal treatment with an oxime may prolong the half early administration of oximes is therefore likely to be valuable.

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Antidotal treatment with an oxime may prolong the half early administration of oximes is therefore likely to be valuable.

Antidotal treatment with an oxime may prolong the half-life of aging;

early administration of oximes is therefore likely to be valuable.

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Hence the three independent reactions determine the speed of onset and severity of poisoning i.e.,

1. Phosphorylation of ChE by OPC2. Reactivation 3. Ageing

In acute poisoning clinical manifestations occur after more than 50% of serum cholinesterase is inhibited and severity of manifestations correlates with the degree of inhibition of serum cholinesterase activity.

• Mild poisoning - cholinesterase level reduces to 20-50%

• Moderate poisoning - cholinesterase level reduces to 10-20%

• Severe poisoning - cholinesterase level reduces to lessthan10%.

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CLINICAL FEATURES

The clinical manifestations of OP poisoning depends on the agent, quantity and route of entry. Ingestion and inhalation result in more rapid development of symptoms than dermal exposure. After ingestion symptoms appear within 30-90 minutes and a maximum of

which are highly lipophilic and which require metabolic bioactivation.

19 CLINICAL FEATURES

The clinical manifestations of OP poisoning depends on the agent, quantity and route of entry. Ingestion and inhalation result in more rapid development of symptoms than dermal exposure. After ingestion symptoms 90 minutes and a maximum of 24 hrs in case of compounds which are highly lipophilic and which require metabolic bioactivation.

The clinical manifestations of OP poisoning depends on the agent, quantity and route of entry. Ingestion and inhalation result in more rapid development of symptoms than dermal exposure. After ingestion symptoms 24 hrs in case of compounds which are highly lipophilic and which require metabolic bioactivation.

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20 LOCAL EFFECTS:

GI symptoms appear first before the onset of systemic symptoms. In inhalation typically exhibit respiratory effects. After ocular exposure symptoms generally begins in the eyes.

Systemic effects: Three well defined clinical phases are observed:

1. Initial cholinergic phase.

2. The intermediate syndrome (IMS)

3. Organophosphate Induced Delayed Polyneuropathy.

4. Chronic Organophosphate Induced Neuropsychiatric Disorder

1. The cholinergic phase is mainly due to accumulation of Ach at the cholinergic synapses and may be classified into A) Muscarinic(all postganglionic nerve endings) B) Nicotinic (Autonomic ganglia and skeletal muscle end plate) C)CNS manifestations(synapses in CNS )

A) Muscuranic manifestation:

Gastro intestinal System Nausea, vomiting, increased salivation, diarrhea, abdominal cramps, tenesmus, fecal incontinence.

Respiratory System Bronchorrhoea, Rhinorrhea, dyspnoea, wheeze, cough, pulmonary edema, cyanosis.

Sweat glands & Lacrimal glands Increased sweating & lacrimation

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Cardiovascular system Bradycardia, hypotension and arrythmias.

Genitourinary Urinary Incontinence

Eyes Miosis,Diplopia and Lacrimation

B)Nicotinic manifestations:

Striated muscle Muscle twitching, cramps, fasciculation, respiratory

muscle weakness.

Sympathetic ganglia Pallor,tachycardia, hypertension.

C) Central nervous system manifestations:

Anxiety, restlessness, giddiness, emotional liability, slurred speech, ataxia, seizure, drowsiness, confusion, difficulty in concentration, headache, nightmare, insomnia, excessive dreaming, apathy, tremor, depression, generalized weakness, coma, absence of reflexes, cheyne-stokes respiration,

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depression of respiratory and circulatory centres with Dyspnea, Hypotension and Cyanosis.

2. The Intermediate Syndrome (IMS)

After apparent recovery from cholinergic crisis muscle paralysis occurs, but before the expected onset of the delayed polyneuropathy has been identified as “Intermediatesyndrome(IMS)”. This is type II paralysis first described by Wadia et al. In 1974 and later christened as “Intermediate syndrome(IMS)” by Senanayake,Karalliedde L. The syndrome is of Acute onset, seen within 24-96 hrs(1-4days) after poisoing, affecting conscious patients without fasciculations or other cholinergic manifestations. The cardinal features of this syndrome is muscle weakness affecting predominantly proximal limb muscles and neck flexors.The muscles innervated by motor cranial nerves III,VII and X are affected in different combinations. These patients were conscious and showed marked anxiety, sweating, dyspnoeic and restlessness caused by progressive hypoxia.

The neck muscle weakness was a constant feature. Patients were unable to raise head above the pillows. Weakness of shoulder abduction and hip flexion was also noted. However normal strength in the distal muscle gives a false impression that the limbs are spared. Tendon reflexes are diminished or in most patients with no sensory impairment. Complete recovery occurs within 4- 18 days if adequate ventilator support is given. But altered function at neuromuscular junction may persistupto 2 yrs after its occurrence.

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The syndrome carries great mortality if not recognized in time and treated. The agents commonly responsible are fenthion, monochrotophos and Dimethoate. Respiratory insufficiency develops over 6 hrs approximately.

Initially patient uses accessory muscles of ventilation. There is increase in ventilator rate, sweating, restlessness and later cyanosis if not recognized patient soon becomes unconscious and death follows. A consensus from literature search appears that IMS may result from inadequate therapy with oximes.

IMS is likely to result from post synaptic neuromuscular dysfunction.

The symptom complex begins at a time when the cholinesterase function is very low and the OP compounds is still detectable in the body. As blood levels of OPC’s fall and OPC’s tissue redistribution occurs the motor end plates may be rechallenged by the cholinesterase inhibitor in the presence of inadequate circulatory oximes.

3. Organophosphate Induced Delayed Polyneuropathy (OPIDP)

Though uncommon in India, it is a distal motor axonopathy develops following a latent period of 2-4 weeks after the cholinergic crisis. The main clinical features are distal muscle weakness especially of feet and hand. The weakness is preceded by limb pain and parasthesia. Wasting of distal muscles of particularly small muscle of the hand and those of anterior and peroneal compartments of the leg is a inevitable consequence. In some patients pyramidal tract signs appear after a few weeks or few months. Recovery is

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variable. The phosphorylation of an enzyme neuropathy target esterase in nervous tissue is considered to be responsible for the polyneuropathy. Several out breaks of OPIDP have occurred in various countries where the poison was traced in most instances to be accidental contamination or adulteration of cooking oils with mineral oils. In 1930’s more than 50000 US citizens became paralysed after drinking Jamica ginger contaminated with TOCP.

4. Chronic Organophosphate Induced Neuropsychiatric Disorder (COPIND)

These are the delayed complications due to acute exposure to high dose of OPC. The manifestations are depression, anxiety, memory disturbances, dystonic reactions, cog-wheel rigidity, schizophrenia. It is due to the sequelae of convulsions, respiratory failure, cardiacarrythmias and anoxia.

CLINICAL SEVERITY SCORING

The following grading of clinical severity are useful in OPC poisoning :- 1.Modified Dreisbach Clinical Criteria 2. Poisoning severity Scale (PSS)

3.Peradeniya Organophosphorus Poisoning Scale (POP Scale) Senanayake N.(1993) proposed ParadeniayaOrganophosphorus Poisoning

(POP) scale for grading the severity is the commonly used one.

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25 POP SCALE

The revised grading for Bardin et al (1990) for OPC poisoning severity

includes the history of intake exposure to organophosphorus, attempted suicide, clinical signs and makes use of investigations(decreased PaO2 and abnormal

chest Xray) in early assessment of respiratory failure.

Revised grading for organophosphoruspoisoning : Grade Criteria Mild poisoning : History of intake/exposure

PARAMETERS

Score 0

Score 1

Score 2 PUPIL SIZE

≥

2 mm <2mm Pinpoint RESPIRATORY

RATE

<20/min

≥

20/min

≥

20/min with central cyanosis

HEART RATE >60/min 41-60/min <40/min FASCICULATION None Present

Generalised/continuous

Both generalised and continuous

LEVEL OF

CONSCIOUSNESS

Conscious and rationale

Impaired response to verbal commands

No response to verbal commands

SEIZURE Absent Present - GRADE

(Score)

Mild (0-3)

Moderate (4-7)

Severe

(8-11)

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26 Mild signs:

Normal consciousness Secretions 1+

Fasciculations 1+

Severe poisoning : Severe signs:

Altered consciousness Secretions 3+

Fasciculations 3+

Life threatening poisoning : Suicide attempt

Stupor

PaO2<75mm Hg(<10mm Hg) Abnormal chest roentgenogram.

MANAGEMENT

DIAGNOSIS

1. History or evidence of exposure to organophosphate.

2. Signs and symptoms of poisonoing.

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3. Improvement of these signs and symptoms after the administration of Pralidoxime and atropine.

4. Inhibition of cholinesterase activity of blood.

Diagnosis is based on the history of exposure and the presence of characteristic muscarinic, nicotinic, and CNS manifestations of acetylcholine excess.There may be a solvent odor, and some agents have a strong garlicky odor.

Blood/serum chemistry :

Serum electrolytes, Random blood glucose, Serum creatinine

Hematology (including white cells count as leukocytosis is common) PlasmacholinesteraseSequential rise of plasma cholinesterase activity every few days for 14 to 28 days may confirmation of organophosphate exposure in the absence of pre exposure baseline values.

Serum Amylase Serum Lipase

Serum Creatine Kinase

Serum levels of organophosphorus compounds and their metabolites.

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28 Arterial Blood Gas :

Arterial blood gas analysis in patients with CNS or respiratory depression.

Urine analysis :

Estimation of excretory products of organophosphorus agents.

Chest radiograph : For respiratory failure

Electrophysiological studies :It is useful in neurological features Electromyography

Single fibre electromyography Train of four

Laryngoscopy : To evaluate vocal cord functions indirect laryngoscopy is useful

Ultra sound/CT scan :To evaluate pancreatic status

Positron emission tomography : To estimate cortical visual loss following respiratory failure.

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29 TREATMENT

I) ACUTE CHOLINERGIC CRISIS

All patients should be managed as emergencies in hospital.

A. First aid

B. Prevent further absorption of insecticide C. Specific antidote therapy

1. Anticholinergic medication

2. Reactivation of Aectylcholine-oximes D. Benzodiazepines

E. Other medications

Mild poisoning: Warrants admission to hospital for atleast 72 hrs for observation and treatment.

Moderate poisoning: admission in ICU.

Severe poisoning: merit immediate transfer and admission to ICU.

A. First Aid:

a) Remove patient from the contaminated environment.

b) Remove contaminated clothing.

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30

c) Wash skin with soap and water and eyes with water.

d) Assess breathing and circulation.

e) Resusciate if necessary

f) Support vital function if necessary O2 inhalation

Lung ventilation Ionotropes

g) Control of convulsion

h) Monitor ECG, blood pressure, O2 saturation,ventilation,level of consciousness.

B. Prevent further absorption of insecticide:

a) Gastric lavage: performed using largest possible oro-gastric tubes with 50-100ml of fluid/lavage, preferably within 1 hr of ingestion protect airway in patients with impaired consciousness.

b) Administer activated charcoal: dose initial 60-100 gms, followed by 0.25 gms to 0.5gms/kg every 1-4 hrs.

C. Specific antidotal therapy: Treatment aims:

a) Reversal of synaptic biochemical abnormalities.

b) Reversal of cholinesterase blockade.

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31

This is activated by administering sufficient quantity of two complimentary medications.

i) Anticholinergic medication- atropine or glycopyrrolate.

ii) Reactivation of AchE-oximes.

i) Anticholinergic medication: Atropine:

It is a tertiary amine, a competitive antagonist of acetylcholine at muscuranic post synaptic membrane and in the CNS. In symptomatic poisoned adults

Inject 1.8-3 mg (3-5 ml) of atropine, bolus. Check whether targets are achieved.

Aim for heart rate >80 beats per minute, SBP > 80 mm Hg, and a clear chest (atropine won't dry focal areas of aspiration).Double the atropine dose every five minutes if you have not achieved these Targets.

Review patient every 5 min. Once these parameters start improving.

Repeat last same or smaller dose of atropine.

If improvement in these parameters is persistent and satisfactory after 5 min, now you can plan for atropine infusion.Calculate total dose of atropine required for rapid atropinisation.

Start hourly atropine infusion at 20% of total dose of atropine required for atropinisation. Most patients do not need >3-5 mg (5-9 ml) per hour of atropine infusion.

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32

Use Targets checklist to reduce infusion rate by 20% every 4 hourly once your patient is stable

Do not use oral secretions to guide therapy in patients who are intubated, unconscious, having oropharyngeal airway in situ and with intermediate syndrome.Ignore sweating to adjust atropine dose.

Stable Patients with clear chest but heart rate just below target do not need further more atropine.

Bronchorrhoea is the most important sign for titrating dose of atropine once patient is stable.

Atropine toxicity= absent bowel sounds + fever + confusion.

Stop atropine infusion for 60 min, if patient has developed atropine toxicity.

Re-start infusion at 80% of initial rate, once the temperature comes down and the patient gets calm.

PRALIDOXIME For whom ?

Only to treat Organophosphorus poisoned patients.

How much ?

Bolus dose: 30 mg/kg PAM over 30 minutes. Adults-2g Obidoxime @ 4mg/kg over 20 min

Maintenance dose: continuous infusion of 8 mg/kg per hour. Adults- 500mg/hr

Obidoxime- 0.5mg/kg/hr infusion

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33 How ?

PAM must be given by Infusion. Go slow, both for bolus and maintenance. A fast infusion can cause vomiting, hypertension, cardiac arrhythmia or a cardiac arrest.

Effectiveness of pralidoxime differs according to the class of Organophosphorus compounds. In Profenofos P2AM is not effective.

In dimethyl Organophosphorus compound PAM is effective upto 12 hours. And in diethyl Organophosphorus compound upto 5 days.

Pralidoxime is not generally recommended for carbamate intoxication, because in such cases the cholinesterase inhibition is spontaneously reversible and short-lived.

However, if the exact agent is not identified and the patient has significant toxicity, pralidoxime may be be given empirically.

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34

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35 D) BENZODIAZEPINES

They are used when the patients are agitated and who develop seizures.

Diazepam appears to counteract some aspects of CNS derived symptoms which are not affected by atropine.Diazepam 10 mg slow IV push, repeated as necessary.Up to 30-40 mg diazepam per 24 hours can be given.

E) OTHER MEDICATIONS

a) Magnesium :It was thought to be counteracting the direct toxi inhibitory effect of OPC’c on N.K.Atase.Singh et al administered magnesium sulphate 4mg IV to patients intoxicated with OP and observed that the neuroeletrophysiological effects that had been observed earlier were reversed.

b) Clonidine:

o Protective effects of clonidine or likely to involve multiple effects including

o Blockade of acetylcholine release and post synaptic muscarinic receptors.

o Transient inhibition of acetylcholinesterase

o Inhibits the release of acetylcholine from central and peripheral cholinergic neurons.

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36

MANAGEMENT OF INTERMEDIATE SYNDROME

It usually presents 12 to 96 hours after exposure. Early signs of intermediate syndrome are action tremors and pharyngeal weakness (difficulty in deglutition or pooling of secretions in pharynx).Later patient develops inability to flex neck, deep tendon jerks are lost, develop cranial neuropathies, proximal muscle weakness and respiratory muscle paralysis. Not all patients will develop the full intermediate syndrome requiring intubation and ventilation, but patients with tremors and pharyngeal weakness are at risk.

Later patient develops inability to flex neck, deep tendon jerks are lost, develop cranial neuropathies, proximal muscle weakness and respiratory muscle paralysis. Treatment of intermediate syndrome totally symptomatic.

PAM should be continued and provide adequate ventilator support.

Patient should be kept in hospital upto 5 days because patient may develop respiratory difficulty during the recovery phase of cholinergic crisis. During the intermediate syndrome patient may develop profuse diarrhea. They should be managed with fluids and electrolytes.

Patient will require ventilator support if he develops respiratory muscle paralysis. Do not use atropine unless signs of cholinergic excess are present.

Common cause of death in Organophosphorus poisoning is respiratory failure and complication in management of respiratory failure.

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37

MANAGEMENT OF DELAYED POLYNEUROPATHY

Physiotherapy and exercise done regularly may improve the muscle weakness. No drugs are available for treatment of this condition.

MORTALITY:

Mortality rate in India and other developing countries ranges from 4- 38%.Mortality depends upon the poison used, quantity ,duration after exposure and atropinisation of all the toxins.

Malathion has the lowest toxicity because of rapid hydrolyzation of carboxy ester group to products with little or no anticholinesterase activity.

Fenthion has the maximum mortality.

Early death is due to

1) CNS depression 2) Seizures

3) Ventricular arrhythmias 4) Respiratory failure due to

Excessive bronchial secretions Bronchospasms

Pulmonary oedema

Paralysis of respiratory muscles

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38

Apnea due to depression of medullary respiratory center.

Late death is due to

1. Respiratory failure associated with Infection

Pneumonia Septicaemia

2. Complication due to mechanical ventilation 3. Ventricular arrythymias ,sudden collapse.

PATHOPHYSIOLOGY OF SERUM CREATINE PHOSPHOKINASE

Experimental study done in rats with an OP showed decrease in tissues ChE activity accompanied by increase in serum CPK activity. The CPK activity was significantly elevated in poisoning cases and more significant changes in the patients who died due to poisoning. Significant increase in serum creatine phosphokinase coincides with the appearance of myonecrosis , destruction of musclemembrane. The initial changes are in the mitochondria, which swell and then show lysis of the central cristae.

Though there is difference in structures of these AChEIs, the imyopathic changes which is induced is same, suggesting that it is a common mechanism.

This mechanism is due to an excess of Ach and its interactions with nAChRs and it is not a direct action of these inhibitors on muscle. The common denominator is muscle hyperactivity, such as fasciculations.

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39

Carbofuran cause fasciculations and myopathy produces a significant increase in serum total CK activity that was seen as early as half an hour after carbofuran injection and persistedly increasing for 3hrs. Under influenceof acute carbofuran poisoning , examination of the serum and diaphragm revealed several characteristic changesin CK isoenzymes. Theisoezyme CK-MM type was elevated >2 fold in the diaphragm within half an hour and remained significantly higher than control at 24hr. The leakage of CK decreased following restoration of normal muscle activity.

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MATERIALS AND METHODS

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40

MATERIALS AND METHODS

Study centre : Toxicology ward, Institute of Internal Medicine MMC, RGGGH

Duration of study : 6 months (From November 2017 to April 2018)

Study design : Observational study Sample Size : 100 patients

Analysis Plan : SPSS, Epi info Inclusion Criteria

All cases of acute organophosphorus poisoning admitted to our hospital within 24 hours with clinical features and physical evidence of consumption of the poison irrespective of age and gender.

Exclusion Criteria

1. Consumption of Organophosphorous poison with alcohol . 2. Other pesticide poisoning.

3. Mixed poisoning.

4. Other routes of ingestion (skin, ear and eye)

5. Known medical illness like chronic liver disease, malignancy, renal failure, myopathy, autoimmune disorder, coronary artery disease

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41

6. Patients on drugs like aspirin, statins, steroids, analgesics, ocps.

7. Patients with lipid disorders and gall stone diseases Methodology :

After obtaining the informed consent details of history and clinical examination were recorded. Peradeniya OP poisoning scale was applied to all study subjects and the severity of OP poisoning was graded as mild, moderate, severe. In all study subjects blood was collected on admission, day 2, day of discharge for estimation of serum amylase, lipase, acetyl cholinesterase and creatine phosphokinase. Other routine investigations were done.

Statistical analysis:

1. Continuous variables are represented in mean, median, mode and standard deviation.

2. Categorical variables are represented in frequencies and percentages.

3. When a Categorical Variable is associated with a categorical variable, the variables are represented in both by tables and bar diagrams. For test of significance, chi-square test is used. Fisher’s exact test is used when more than 20% of the cell values have expected cell value less than 5.

4. When a continuous variable is associated with continuous variable, correlation tests are used.

5. When the paired samples variable such as variable at admission, day one and at discharge is associated with the categorical variables such

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42

as outcome, clinical severity, and then repeated measures ANOVA is used.

6. P-value less than 0.05 is considered statistically significant.

7. Data was analysed using SPSS software version 16.

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RESULTS

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43

OBSERVATION AND RESULTS

RESULTS

1) Population Characteristics:

A) Age:

The mean age of the study population was 38.49 and standard deviation of 16.17. This is represented in the following table.

Mean 38.49

Median 35.00

Mode 50

Std. Deviation 16.179

Minimum 14

Maximum 85

The Following Histogram shows the distribution of age in the study population:

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44 B) Gender:

The study population comprised of 25% females and 75% males. And this is represented in the following Pie-chart.

C) Age and Sex Distribution:

Sex

Total

F M

Age category (Years)

<20 Count 4 7 11

% within Age 36.4

%

63.6

% 100.0%

21-30 Count 11 18 29

% within Age 37.9

%

62.1

% 100.0%

31-40 Count 7 13 20

% within Age 35.0

%

65.0

% 100.0%

41-50 Count 1 21 22

25. 25%

75. 75%

Gender

Female Male

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45

% within Age

4.5% 95.5

% 100.0%

51-60 Count 1 7 8

% within Age 12.5

%

87.5

% 100.0%

>60 Count 1 9 10

% within Age 10.0

%

90.0

% 100.0%

Total Count 25 75 100

% within Age 25.0

%

75.0

% 100.0%

Bar Diagram (Age in Yrs. In X axis & No. of Persons in Y axis with Males and Females in the graph)

4

11

7

1 1 1

7

18

13

21

7

9

0 5 10 15 20 25

<20 21-30 31-40 41-50 51-60 >60

Female Male

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46 2) Occupation:

Sex

Total

F M

Occupation Agri Count 5 26 31

% within

Occupation 16.1% 83.9% 100.0%

Non- Agri

Count 20 49 69

% within

Occupation 29.0% 71.0% 100.0%

% within

Occupation 25.0% 75.0% 100.0%

Bar Diagram (Frequency in X axis with Agri& Non-Agri with Male & Female in the graph with No. of Persons in Y axis)

26

49

5

20

0 10 20 30 40 50 60

Agri Non-agri

Male Female

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47 3) Types of Compound and Outcome

Outcome

Total Death Discharge

Compound Bromophos Count 0 4 4

% within Compound .0% 100.0% 100.0%

Chlormephos Count 1 0 1

% within Compound 100.0% .0% 100.0%

Chlorpyrifos Count 3 10 13

% within Compound 23.1% 76.9% 100.0%

Demeton Count 1 0 1

Diazinon Count 1 4 5

% within Compound 20.0% 80.0% 100.0%

Dichlorphos Count 0 1 1

Dicrotophos Count 1 4 5

% within Compound 20.0% 80.0% 100.0%

Dimethoate Count 0 2 2

Endosulphan Count 2 1 3

% within Compound 66.7% 33.3% 100.0%

Ethion Count 0 2 2

Femaphos Count 0 2 2

Fenthion Count 0 2 2

Fonofos Count 1 0 1

Isofluorphat Count 1 0 1

Malathion Count 0 5 5

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48

Monocrotphos Count 14 5 19

% within Compound 73.7% 26.3% 100.0%

Parathion Count 1 1 2

% within Compound 50.0% 50.0% 100.0%

Phorate Count 2 4 6

% within Compound 33.3% 66.7% 100.0%

Phosphomidon Count 4 1 5

% within Compound 80.0% 20.0% 100.0%

Phoxim Count 0 3 3

Primiphos Count 0 2 2

Profenofos Count 2 3 5

% within Compound 40.0% 60.0% 100.0%

Quinalphos Count 0 7 7

Temephos Count 0 1 1

Triazophos Count 0 2 2

% within Compound 34.0% 66.0% 100.0%

Fisher’s Exact value = 40.587 p-Value =0.001Bar Diagram (Types of Compound In X axis & No. of cases in Y axis with Discharge and Death)

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49 4) Quantity of Exposure and Outcome:

Mean 63.55

Median 50.00

Mode 25

Std. Deviation 44.006

Minimum 10

Maximum 150

Outcome

Total Death Discharge

Quantity (ml)

<25 Count 0 27 27

% within Quantcate .0% 100.0% 100.0%

26-50 Count 1 29 30

% within Quantcate 3.3% 96.7% 100.0%

0 1

3 1 1

0 1

0 2

0 0 0 1 1

0 14

1 2

4

0 0 2

0 0 0 4

0 10

0 4

1 4

2 1

2 2 2 0 0

5 5

1 4

1 3

2 3

7

1 2 0

2 4 6 8 10 12 14 16

Bromophos Chlormephos Chlorpyrifos Demeton Diazinon Dichlorphos Dicrotophos Dimethoate Endosulphan Ethion Femaphos Fenthion Fonofos Isofluorphat Malathion Monocrotphos Parathion Phorate Phosphomidon Phoxim Primiphos Profenofos Quinalphos Temephos Triazophos

Death Discharge

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50

51-75 Count 5 6 11

76-100 Count 15 3 18

>100 Count 13 1 14

Bar Diagram (Quantity in ml in X axis and No. of cases in Y axis with Death and Discharge).

0 1

5

15

13 27

29

6

3

1 0

5 10 15 20 25 30 35

<25 26-50 51-75 76-100 >100

Death Discharge

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5) Duration of Presentation and Clinical Severity by POP score

Duration <3

% within durcat 4-6

% within durcat 7-9

% within durcat 10-12

% within durcat

>12

% within durcat Total

% within durcat Fisher’s Exact Test Value = 46

Bar diagram (No.of Hours in X axis with No. of cases in Y axis with Mild, Moderate and Severe in the graph)

0 5 10 15 20 25

<3 23

11

3

51

Duration of Presentation and Clinical Severity by POP score

POP Score Mild Moderate

Count 23 11

% within durcat 62.2% 29.7%

Count 5 9

Count 0 6

% within durcat .0% 42.9%

Count 1 0

% within durcat 20.0% .0%

Count 1 1

Count 30 27

Fisher’s Exact Test Value = 46 p-value= <0.001

Bar diagram (No.of Hours in X axis with No. of cases in Y axis with Mild, Moderate and Severe in the graph)

4to6 7to9 10to12 >12

5

0 1 1

9

6

0 1

17

8

4

11

Duration of Presentation and Clinical Severity by POP score

Total Severe

3 37

8.1% 100.0%

17 31

54.8% 100.0%

8 14

57.1% 100.0%

4 5

80.0% 100.0%

11 13

84.6% 100.0%

43 100

43.0% 100.0%

Bar diagram (No.of Hours in X axis with No. of cases in Y axis with Mild,

11 Mild

Moderate Severe

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6) Clinical Severity by

POP score Mild Moderate

Severe Total

Chi-Square test value = 68 p

Bar Diagram ( POP Score with Mild, Moderate, Severe & Total in X axis with number of cases in Y axis) :

0 5 10 15 20 25 30 35

Mild 0

52

Clinical Severity by POP Score and Outcome

Outcome

Death Discharge

Count 0

% within popscore .0% 100.0%

Count 0

% within popscore .0% 100.0%

Count 34

% within popscore 79.1% 20.9%

Count 34

% within popscore 34.0% 66.0%

Square test value = 68 p-value=<0.001

Bar Diagram ( POP Score with Mild, Moderate, Severe & Total in X axis with number of cases in Y axis) :

Death Discharge

Moderate

Severe 0

34 30

27

9

Outcome

Total Discharge

30 30

100.0% 100.0%

27 27

100.0% 100.0%

9 43

20.9% 100.0%

66 100

66.0% 100.0%

Bar Diagram ( POP Score with Mild, Moderate, Severe & Total in X axis with

Discharge

Death Discharge

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53

7) Clinical Severity and Mean Acetyl Cholinesterase (AchE) values

POP score Mean Std. Deviation N Ach

Day 1

Mild 5163.70 2141.799 30

Moderate 3990.96 2185.931 27

Severe 447.77 365.618 31

Total 3142.59 2687.519 88

Ach Day 2

Mild 3934.77 1083.934 30

Moderate 2959.89 1028.229 27

Severe 439.61 328.203 31

Total 2404.41 1738.862 88

Ach Discharge

Mild 5092.03 1138.736 30

Moderate 4833.81 801.782 27

Severe 2025.97 1290.781 31

Total 3932.72 1791.592 88

p-Value<0.001 (Repeated Measures ANOVA Used)

Line diagram ( Mild, Moderate & Severe POP score in X axis with AchE values in Y axis)

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54

8) Clinical Severity and Mean Serum Amylase:

POP score Mean Std. Deviation N

Amylase Day 1

Mild 84.73 48.225 30

Moderate 154.59 131.818 27

Severe 248.94 147.786 31

Total 164.01 135.144 88

Amylase Day 2

Mild 80.93 49.373 30

Moderate 124.00 80.139 27

Severe 396.03 309.277 31

Total 205.15 236.775 88

Amylase Discharge

Mild 65.63 18.365 30

Moderate 77.85 22.300 27

Severe 208.42 179.641 31

Total 119.68 125.479 88

p-Value<0.001 (Repeated Measures ANOVA Used)

Bar Diagram (Mild, Moderate & Severe in X axis with Values in Y axis with Amylase)

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55

9) Clinical Severity and Mean Serum Lipase:

POP score Mean Std. Deviation N

Lipase Day 1

Mild 71.53 17.716 30

Moderate 93.78 49.825 27

Severe 192.26 105.996 31

Total 120.89 87.199 88

Lipase Day 2

Mild 71.93 20.794 30

Moderate 87.48 37.286 27

Severe 300.35 242.141 31

Total 157.17 179.152 88

Lipase Discharge

Mild 66.30 14.408 30

Moderate 73.74 19.542 27

Severe 178.32 154.783 31

Total 108.05 105.691 88

p-Value = 0.007 (Repeated Measures ANOVA Used)

Line Diagram (Mild, Moderate & Severe in X axis with Values in Y axis with Lipase)

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10) Clinical Severity and Mean creatine Kinase:

Popscore Mean Std. Deviation N

CK Day 1

Mild 75.17 38.930 30

Moderate 97.44 82.926 27

Severe 302.84 211.099 31

Total 162.20 169.965 88

CK Day 2

Mild 74.30 30.005 30

Moderate 148.93 243.244 27

Severe 679.71 595.233 31

Total 310.47 464.831 88

CK Discharge

Mild 67.67 23.527 30

Moderate 73.41 27.057 27

Severe 293.16 331.573 31

Total 148.86 223.100 88

p-Value< 0.001 (Repeated Measures ANOVA Used)

Line Diagram (Mild, Moderate & Severe in X axis with Values in Y axis with Creatine Kinase)

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57

11) Correlation between Duration of Presentation and AchE values, Serum Amylase, Lipase & CK values:

duration quantity hospstay

Atropine dose Ach

Day 1

Pearson Correlation -.390^** -.692^** -.199^* -.554^**

Sig. (2-tailed) .000 .000 .047 .000

N 100 100 100 100

Ach Day 2

Pearson Correlation -.461^** -.777^** -.386^** -.620^**

Sig. (2-tailed) .000 .000 .000 .000

N 92 92 92 92

Ach Discharge

Pearson Correlation -.430^** -.733^** -.123 -.454^**

Sig. (2-tailed) .000 .000 .255 .000

N 88 88 88 88

Amylase Day 1

Pearson Correlation .192 .490^** .008 .302^**

Sig. (2-tailed) .056 .000 .941 .002

N 100 100 100 100

Amylase Day 2

Pearson Correlation .159 .426^** .343^** .435^**

Sig. (2-tailed) .131 .000 .001 .000

N 92 92 92 92

Amylase Discharge

Pearson Correlation .318^** .480^** .016 .316^**

Sig. (2-tailed) .002 .000 .882 .003

N 88 88 88 88

Lipase Day 1

Sig. (2-tailed) .008 .000 .866 .002

N 100 100 100 100

Lipase Day 2

Pearson Correlation .118 .446^** .424^** .472^**

Sig. (2-tailed) .264 .000 .000 .000

N 92 92 92 92

Lipase Discharge

Sig. (2-tailed) .003 .000 .880 .007

N 88 88 88 88

CK Day 1

Sig. (2-tailed) .001 .000 .111 .000

N 100 100 100 100