INTRODUCTION

Clinical VignetteYou are posted as a CMO, casualty in the month of June. A 30 year old housewife from a nearby village is brought in the afternoon in an unconscious state. There is h/o domestic violence. Patients clothes are wet and are soiled with urine and feces.O/E pupils are constricted with BP= 80/60mmHg. You check patients blood sugar level which is 480 mg%. You order an ABG which is s/o metabolic acidosis. ECG is done and it shows bradycardia. Routine blood workup reveals normal serum electrolytes with a raised amylase level of 300.Diagnosis ??? ??

Organophosphorus Poisoning

Presenters: Dr Lohit Chauhan : Dr Dhananjay GuptaModerator : Dr. Gurmeet Kaur

INTRODUCTIONOP are a group of insecticides or nerve-agents which act at acetyl-cholinesterase

Have been used as insecticides, petroleum additives and chemical warfare agents

Carbamates are another group of insecticides which act at the same site, with a slight different MOA

WHO CLASSIFICATION (simplified)HIGHLY TOXICMODERATELY TOXIC1. Phosphamidon (Dimecron)1. Malathion2. Ethyl parathion2. Fenthion (Baytex)3. Methyl parathion3. Temephos (abate)4. Chloro-thiophos 4. Fenitrothin (tik-20)5. Carbo-phenothion5. Diazinon (spectacide)

* Shivakumar S, Ishaq RM. Management of Organophosphorus compounds (OPC) Poisoning : Current Status 2008. taken from drshivkumar.org

Epidemiology (WHO)Acute OP poisoning is one of the common and serious medical emergencies

Asia : 3 million cases/ year of acute pesticide poisoning

3 lakh deaths per year (CFR =10-15 %)

99% cases are seen in developing world

Indian DataPoisoning is 4th MC cause of deaths annually

OP poisoning is the MC poisoning

Pattern of poisoning is region-dependant

OP poisoning is more common in south India

North India- aluminium phosphide > OP

RML Data

Why is OP poisoning common ??India is an agarian countryroutinely used in farming

CAUSES OF HIGH MORTALITYHigh toxicity of available compoundsTime gap in transporting patientsPaucity of Health care personnelLack of training facilitiesLack of antidotes

Why is OP poisoning common ??

Limited resources and infrastructure for health care delivery

1. Mode of poisoning* Banerjee I, Tripathi SK, Roy AS. Clinico-Epidemiological Characteristics of Patients Presenting with Organophosphorus Poisoning. N Am J Med Sc. Vol 4(3), JMarch 2012

2. Occupation* Maharani B, Vijayakumari M. Profile of poisoning cases in a tertiary care hospital in Tamil Nadu, India. J of App Pharma Sc. Vol 3(01), Jan 2013

3. Seasonal distribution* Maharani B, Vijayakumari M. Profile of poisoning cases in a tertiary care hospital in Tamil Nadu, India. J of App Pharma Sc. Vol 3(01), Jan 2013

4. Type of Poison* Banerjee I, Tripathi SK, Roy AS. Clinico-Epidemiological Characteristics of Patients Presenting with Organophosphorus Poisoning. N Am J Med Sc. Vol 4(3), JMarch 2012

5. Relative human Toxicity

Eddleston M et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9

Mechanism Of Action

Clinical Features1. Acute O-P poisoning- Muscarinic features Resp distress- Nicotinic features Death- CNS features

2. Intermediate Syndrome

3. Delayed neuropathy (OPIDP)

4. Neuro-psychiatric disorder (COPIND)

1. Acute O-P poisoningMUSCARININC FEATURESNICOTINIC FEATURESCNS FEATURES D iarrhoeaMuscle weaknessFatigue U rinationMuscle fasiculationsConfusion M iosisMuscle paralysisUnconsciousness B ronchorrhea B ronchospasmSeizues E mesisHypertensionAtaxia L acrimationTachycardiaResp. depression S alivation S weating

2. Muscarinic / Wadia type 1 syndrome

1. Excessive Sweating2. Miosis3. Bronchorrhoea / spasm4. Bradycardia

5. Hypotension

3. BronchorrhoeaEarly cause of morbidity and mortality

Excess fluid is from airway secretions

Obstruction of upper and lower airways

Pulmonary edema - - hypoxia - - death

The Grading of Clinical severity

4. Intermediate syndromeDescribed in 1987 (Karalliedde and Senanayake)

Occurs 24-96 hours after resolution of acute cholinergic crisis

Most imp. factor responsible is quantum of exposure of OPC

May occur from inadequate oxime therapy

IMS - pathophysiology Incidence = 10-50 %

Prolonged effects on Nicotinic receptors

Primary motor end plate degeneration

Leads to muscle weakness

IMS- muscle weakness ofMuscles innervated by cranial nerves : III-VII and X

Neck flexors- a constant feature- one of the earliest signs - inability of patients to raise heads off pillow

Proximal limb muscle weakness- typically involve shoulder abductors, hip flexors

Respiratory muscles - death

IMS other featuresDeep tendon Reflexes :Usually absent / decreased Sensory system usually intact

Muscarinic symptoms :absentrarely short relapses may occur

IMS- complicationsWeakness -- Frank paralysis

Respiratory distress -- Death

Main cause of morbidity and mortality in Indian patients.

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5. OPIDPOP induced Delayed Polyneuropathy

Delayed, rare, neurotoxic effect

1-5 weeks after severe acute poisoning, due to slow release of OP from body fat

symmetrical sensory-motor axonal degeneration of the peripheral nerves and SC

5. OPIDP - C/fMotorSharp cramp like pain in calfHigh stepping gait (initially)Shuffling gate in severe casesQuadriplegia / paraplegiaWrist and foot dropMild pyramidal signs

SensoryGlove-stocking anesthesiaCerebellar signs +/-

6. COPINDChronic OP induced Neuro-psychiatric disorder

Chronic low-dose exposure to OP compounds

40 hours/week, 9 months/ year

No cholinergic symptoms

Non responsive to levodopa

Plasma cholinesterase levels are normal

6. COPIND c/fNeurological SymptomsPsychiatric Symptoms1. Impairment in memoryAnxiety2. Impairment in concentrationDysthymia3. Impairment in leaningDepression4. Chronic fatigue5. EPS : dystonia6. Resting tremor, bradykinesia7. Rigidity of face Parkinson-like8. Postural instability

Non responsive to levodopa

Diagnosis and Management

Diagnosis of OP poisoningDiagnosis is mainly clinical, Based on :

H/o Ingestion of poisonCharacteristic clinical featuresClinical improvement after atropine/ oximeInhibition of cholinesterase activity

1. Inhibition of cholinesteraseDemonstrating a decrease in cholinesterase

Definitive or gold standard method

Theoretically RBC/ true cholinesterase is more accurate than plasma/ pseudo

But plasma / pseudo-cholinesterase is more easily available test

Diagnosis :Plasma / SChE : - easy to measure- easily available- more useful in acute exposure

50 % reduction in normal values : diagnostic (baseline values usually NA)

Progressive increase in SChE with treatment

2. Cholinesterase levelsUseful in monitoring clinical course of illness

persistent Low levels are a predictor of IMS (Intermediate syndrome)

SChE activity is < 20 % during onset of IMS* Tajune J, Robert J. Organophosphoric poisoning. Ann Emerg Med 1987 ; 16:193.

3. Electro-neuro-myogram (ENMG)

30 Hz rapid nerve stimulation - decremental responses correlate best with clinical weakness

Most useful diagnostic test of IMS ** Senanayake N et al. Neurotoxic effects of OP insecticides : an intermediate syndrome. NEJM. 1987 ; 316 :761-63.

4. Other tests of prognostic valueHyperglycemia Neutrophilic leucocytosisProteinuria / glycosuriaECG changes (QTc prolongation)Blood pH (acidosis)Hyper amylasemiaSerum CPK levels

5. Hyperglycemia in OP-poisonOxidative stressRenal tubular damage Stimulation of adrenalsRelease of catecholamines

Transient hyperglycemia and glycosuria are often seen in acute OP-poisoning * Namba T, Nolte CT, Jackrel J, Grob D. Poisoning due to organophosphate insecticides: Acute and chronic manifestations.Am J Med.1971;50:47592.

6. Blood pHMetabolic Acidosis develops in patients of OP poisoning, more common with hypotension*1.

Unknown mechanism. If pH < 7.20, treatment with sodium bicarbonate beneficial*2.

*Prakash O.et al. Low ph predicts mortality in OPP and carbamates poisoning, JAPI 2002; 50:857.*Roberts DM, Buckley NA. Alkalinisation for treating organophosphorus pesticide poisoning. Cochrane Database of Systematic Reviews 2005;1:CD004897.pub2.

7. QTc prolongationIndicates poor prognosis in OP- poisoning

1. Cholinergic stimulation of heart : M2a. negative ionotropyb. negative chronotropy

2. Oxidative stress causes conduction problems

* Shadnia S, Okazi A, et al. Prognostic value of long QTc interval in acute and severe OP poisoning. J of Med Toxico 2009 ; 5(4).

8. Hyper- amylasemiaCholinergic stimulation of salivary glandsCholinergic stimulation of pancreasAcute pancreatitis (rare)

Raised amylase levels correlate with severity and presence of shock in acute OP poisoning *

* Lin CL, Yang CT, Pan KY, Huang CC. Most common intoxication in nephrology ward organophosphate poisoning. Ren Fail 2004 ;26:349-54..

9. Acute Pancreatitisd/t Excessive cholinergic stimulation and ductular hypertension

Painless Ac. Pancreatitis has been reported

Amylase (>300) : low Sn, low SpLipase (>300) : useful for diagnosis* Hsiao CT, Yang CC, Deng JF, Bullard MJ, Liaw SJ. Acute Pancreatitis following Organohosphate Intoxication. J Toxicol Clin Toxicol. 1996 ;34(3):343-7.

Management

What to do ??Call AIIMS poison cell : (NPIC)

- National Poisons Information Cell - Toll free no. 1800 116 117- Other : 011 - 26589391- Open 24 X 7 , 365 days a year

The Paradox of Poisoning.

The only thing I know is that I dont know anything

- Socrates

1. Identification of poisonHistory by patient/ attendantClinical presentation.By showing photographs.WHO colour code on container.

Poison :Identification

WHO colour code on container.Red labelExtremely toxicMonocrotophos,zinc phosphide,ethyl mercury acetate, and others.Yellow labelHighly toxicEndosulfan,carbaryl,quinalphos,and others.Blue labelModerately toxicMalathion,thiram,glyphosate,and others.Green labelSlightly toxicMancozeb,oxyfluorfen, mosquito repellant oils and liquids, and most other household insecticides.

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Identification of poisonSigns of cholinergic excess or developing intermediate syndrome Disparity between history and clinical presentation, follow, clinical judgment.After identification classify as Organophosphorus and non-Organophosphorus.

Organophosphosphate

Management :Immediate, Protocol

When not sure about the poison..??Atropine test : Inject 0.6- 1 mg IV atropine.If pulse rate goes up by 25 per minute or skin flushing develops patient has mild or no toxicity for OPs.

Management : SpecificGeneral Principles of Therapy :

Decontamination, Resuscitation, Stablization.Muscarinic antagonistsFluids.Acetylcholinesterase reactivators.Gastric Decontamination.Miscellaneous.

DecontaminationHealthcare workers and OP Poisoning.Few western hospitals, reported such poisoning.None shows inhibition of Acetyl/Butyryl cholinesterases.Cases from Asia : Health-care workers take no special precautions , No cases of secondary poisoning reported.

Decontamination

Guidelines : Universal Precautions, Maximum Ventilation, Frequent rotation of staff to keep exposure minimum.PPE should not consist Latex / Vinyl.Patient : All clothing to be removed, discard in ventilated area.Thorough irrigation with water.Wash with soap and water.Soaps containing 30% ethanol advocated.Ocular decontamination : water only.

Initial Stabilisation

Patent Airway, adequate Breathing and Circulation.Oxygen at first opportunity.Little evidence, Atropine not to be given until oxygen availability*1. However, in hospitals where oxygen not available, Atropine to be started early*2.Patient Position : Left Lateral, Neck Extended.Reduce aspiration risk.Keeps airway patent.Decrease pyloric emptying and absorption of poison.*1Erdman AR. Insecticides. In: Dart RC, Caravati EM, McGuigan MA, et al, eds. Medical toxicology, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 2004: 147596.

*2Aaron CK. Organophosphates and carbamates. In: Shannon MS,Borron SW, Burns M, eds. Clinical management of poisoning and drug overdose, 4th edn. New York, Elsevier Science, 2006.

Initial Stabilisation

Gastrointestinal decontamination

Often first intervention

To be considered only after stabilization, oxygen, atropine and oximes.Lavage only if patient arrives within 1 hour.Only consider if patient intubated or conscious and willing to cooperate.* The Hazards of Gastric Lavage for Intentional Self Poisoning in a Resource Poor Location Clin Tox 2007;45(2):136-43

Not beneficial, rather increases chances of Aspiration Pneumonia & Deaths*

Gastrointestinal decontaminationInduced emesis : Ipecacuanha induced , Contraindicated.Activated charcoal : Studies failed to find any benefit ( Why..??)It binds in vitro, but not in gut due to rapid absorption.Ingested dose too large for the amount of charcoal. NO evidence suggests that patients with pesticide poisoning benefit with activated charcoal.** Eddleston M, Juszczak E, Buckley NA, et al. Randomised controlled trial of routine single or multiple dose superactivated charcoal for self-poisoning in a region with high mortality. Clin Toxicol 2005; 43: 44243.

Muscarinic antagonist

Muscarinic antagonist

A small RCT found no difference in mortality or ventilator rates, comparing Atropine and Glycopyrrolate.Hyoscine : best for severe Extra-pyramidal features with few peripheral signsIn animal studies, found more effective than Atropine for control of seizures induced by inhaled nerve gas agents.However, Atropine remains mainstay of therapy.Easy and wide availability.Affordability .Moderate ability to penetrate CNS.

Muscarinic antagonist

AIM OF THERAPY : ATROPINETo reverse cholinergic features.To improve Cardiac and Respiratory functions.Target Endpoints of Atropinization.Drying of Pulmonary secretions, ie. Clear lung fields on auscultation. (Most reliable)Heart rate > 80 beats / min.SBP > 80 mmHg.Pupils : No longer pinpoint.Dry Axillae.Bowel sounds : just present.

End points of atropinisation

Lung secretionsHypotensionBradycardiaSweatingMiosisBowels : Hyperactive

ATROPINEClear ChestSBP > 80mmHgHR > 80/minDry AxillaePupils no longer pinpoint.Bowel sounds : Just present

Atropine Dosing

Incremental Dosing

1.8 to 3 mg Atropine (i/v)Repeat every 5 minutes with doubling the dose each time.Endpoint : Atropinization.Followed by : 10 to 20 % of total dose required for atropinization every hour via i/v infusionTo be held once anticholinergic effects occur.(Absent bowel sounds, urinary retention, agitation).Bolus DosingV/S2-5 mg Atropine every 10 to 15 min.

Endpoint : Atropinization.Followed by maintenance using reduced doses or increasing time duration in b/w doses.

Various studies clearely found Incremental Dosing far superior to bolus dose administration

Atropine Monitoring

Patient to be assessed every 15 min to check adequacy of dosages.If clinical features recur, further increment in boluses and doubling.Once parameters reached, Monitoring hourly for atleast 6 hours to check effectiveness of infusion.

Timeheart rateClear lungPupilDry axillaSBP > 80 mm HgBowel soundsmental stateFever >37.5cSPO2Atropine infusion dose

OP / Carbamate Observation Sheet

Atropine : When to stop..??

Bronchorrhoea : most important, for titrating dose. Atropine toxicity = absent bowel sounds + fever + confusion.Stop infusion for 60 min, if toxicity.Re-start infusion at 80% of initial rate, once the temp. comes down and patient calms.Most do not need >3-5 mg (5-9 ml) / hour of atropine infusion.Reduce rate by 20% every 4 hourly once patient is stable. STOP.

OximesReactivate Acetyl cholinesterase, remove phosphoryl group.Discovered in 1950s by Wilson et al.Among various oximes (obidoxime and trimedoxime) Pralidoxime (PAM) remains, most widely used.Prevent continued toxicity by Scavenging and detoxifying enzyme.Also endogenous anticholinergic effects.Available in four Salts : chloride, iodide, metilsulfate, and mesilate.Chloride and iodide most widely used in developing countries.Chloride salt better than iodide.More active compound per gram of salt.No risk of thyroid toxicity.

OximesTherapeutic effectiveness depends onConcentration of poison consumed (Poison load).Time lapse between poisoning and administrationType of OPC. (More effective on diethyl than dimethyl). Dimethyl compound reactivate and age at slower rate.Lipid solubility of OPC.Concentration of Oxime in blood.

OximesThe ControversiesTwo RCTs in Vellore, India in early 1990s noted, Harm from low dose PAM infusion.A Cochrane review ( included two RCTs , 2005) & two other meta-analysis reported no clear benefit or harm.An RCT in Baramati, India studying very high dose of PAM in 200 patients with moderate OP poisoning showed reduced Case fatility. (1% vs 8%).

OximesThe consensusOximes will not be effective in very severe (large dose) poisoning.Treatment with oximes should be started as early as possible, no role if started after 48 hours.Less effective in severe complications such as aspiration pneumonia or hypoxic brain injury before treatment.Less or no effectiveness with dimethyl compounds and atypical organophosphates.Not effective in carbamates but are not contraindicated either.

OximesDosingPAM : 1-3 gm/day, no role after 48 hrs.Serum levels of > 4 mg/lit is necessary for effective treatment.To achieve this, administered as bolus 20-40mg/kg followed by continuous infusion at 500mg/hr.WHO recommendations : Loading dose 30mg/kg, followed by infusion of 8mg/kg/hr.

OximesTherapeutic end pointResolution of muscle fasciculation and weakness, Reactivation and Increment in SChE levels.Use longer than 24 hours indicated if unaged OPs release from fat tissue.Infusion continued until patient remains symptom free for atleast 12 hours without additional atropine.Or until extubated.

Role of BenzodiazepinesControl agitation.Sedation in ventilated patients.Many opioids, metabolized via SChE, so use for sedation in pulmonary edema can worsen CNS manifestation.Control of seizures : First line therapy in OP poisoning, phenytoin not recommended d/t membrane stabilizing effects.Seizures uncommon in oxygenated patients, more common in nerve gas agents (soman and tabum).Diazepam reduce neural damage and prevent respiratory failure (animal studies).

Role of Magnesium Sulphate

MgSO4 (4g) i/v in first day after admission, decrease hospitalization period and mortality.It blocks Calcium channels and reduce acetylecholine release from presynaptic terminals.Also reduces CNS overstimulation from NMDA receptor activation.

Role of ClonidineCentrally acting 2-adrenergic receptor agonists.Reduces acetylcholine synthesis and release from presynaptic terminalsAnimal studies, shown benefit in combination with atropine. Effect in humans unknown.

Advanced Neuroprotective Drugs

Ketamine : Noncompetitive NMDAR antagonist, within 1 hour of nerve gas agent induced seizures along with Midazolam/diazepam.Tezampanel : Glutamate receptor antagonist specific for kainate subtype Rc, useful in soman(nerve gas) induced seizures and neuropathy.Gacyclidine : Another antiglutamatergic compound found beneficial in conjunction to standard therapy in nerve gas poisoning .

Advanced Neuroprotective Drugs

For OPIDN : standard therapy plus corticosteroids.Protease inhibitors : target esterase and prevent delayed neuropathy.Intermediate syndrome resistant to standard treatment, artificial respiration.Antioxidants : lipid peroxidation and thiobarbituric formed in OP poisoning, Antioxidant beneficial. Vitamin E reported to have therapeutic effect

Intermediate syndrome : ManagementUsually presents 12 to 96 hours after exposure.Early signs : action tremors and pharyngeal weakness (difficult deglutition , pooling of secretions).Later : inability to flex neck, DTRs lost, cranial neuropathies, proximal muscle weakness and respiratory muscle paralysis.Not all require intubation and ventilation, but patients with tremors and pharyngeal weakness, at increased risk.Treatment : totally symptomatic. Ventilator support if respiratory muscle paralysis.

Ventilatory SupportIndicated in stupor / coma, Hypoxemia (PaO2 5 mL/kg at Pressure of 3-5 cm of H2O.

Parameter Weaning thresholdPaCO2 20 L/minRespiratory frequency 6 breaths/min

Role of AlkalinizationIV infusion of Soda. Bicarbonate produce moderate alkalinization (pH : 7.45 to 7.55) in OP poisoning.Infusion of higher dosages (5mEq/Kg) in 60 minutes followed by 5-6 mEq/kg/day was shown useful.(In dogs)More beneficial in Nerve agent poisoning.Cochrane review : Insufficient evidence to establish use of NaHCO3 in human OP Poisoning.

Role of Early Enteral Feeding. Early enteral feeds associated with improved outcomes in critically ill because it prevents enterohepatic circulation.Early nutritional supplementation in OP poisoning assumes importance as these patients may require prolonged ventilatory support.

Role of Fresh Frozen Plasma. FFP contains important components like clotting factors, proteins, enzymes, etc.It is hypothesized that butyrylcholinesterase present in FFP sequester free poison in blood and remove it from circulation.Two trials, both unfavourable to FFP intervention.Current evidence not strong enough to make clear conclusion regarding bioscavenger role of FFP

For the future..Removal of OPs from blood : Hemodialysis, Hemoperfusion or hemofiltration.Hemofiltration after dichlorovos poisoning revealed beneficial therapeutic effects.Military research aims at : Injecting Butyrylcholinesterase after cloning into soldiers before exposure to nerve gases.Not practical for prophylaxis in self-poisoning as one cannot predict when a person is going to ingest pesticide.Use of recombinant bacterial phosphotriesterases, or hydrolases to break down OPs enzymatically.

Take home messageEarly stabilization and resuscitation. Incremental dose Atropine.Early institution of Oximes.External decontamination, MgSO4, Clonidine, Use of benzodiazepines and NMDA receptor antagonists, Alklinization, Early Enteral feeding were found to be beneficial.FFP, forced emesis were found harmful.Activated charcoal, Gastric lavage were found to have no benefit or harm.Gastric lavage : easily performed, cheap could be used as an adjunct if performed within one hour.

Thank You

SeverityAChE

(RBC)MuscarinicNicotinicCNS

Mild> 40%nausea, vomiting, diarrhoea, salivation, bronchorrhoea and -constriction, bradycardia

headache, dizziness

Moderate 20 - 40%as above, + miosis, incontinencefasciculations (fine muscles)as above, + dysarthria, ataxia

Severe< 20%as above, + fasciculations (diaphragm, resp. muscles)as above, + coma, convulsions