1. Organophosphate poisoning
Dr.rawal mahendra

2. INTRODUCTION:
Pesticide poisonings are among the most common modes of poisoning fatalities.
In countries such as India organophosphates are easily accessible and, therefore, a source of both intentional and unintentional poisonings.
Worldwide mortality studies report mortality rates from 3-25%
Respiratory failure is the most common cause of death.

3. Indian data Poisoning is 4th MC cause of deaths annually.
Op is MC poisoning
Op poisoning is more common in south india.
North india- aluminium phosphide> OP

4. Common OP compounds:parathion, malathion, chlorpyrofos dichlorvos,fenthion.
Fenthoin (Dalf) seems the most dangerous among OP available as insecticides in India. These patients have more frequent paralysis and the mortality is significantly greater(32%)
Organophosphonate compounds exist in a military setting :sarin, tabun, soman.
Carbamate: carbaryl,propoxur

5. Dimethyl compound
Diethyl compound
Dichlorvas
parathion
Fenthion
chlorpyrifos
Malathion
diazinon
ethion

6. Organophosphate are irreversible inhibitor because half life of phophorylated enzyme is more than that of synthesis of fresh enzyme.
Carbamate are reversible inhibitor because half life of carbamylted enzyme is less than that of synthesis of fresh enzyme.

7. mechanism of action of OP and CRB is inhibition of ester hydrolases ache and pche.
OP inactivates AChE by phosphorylating the serine hydroxyl group located at the catalytic site of AChE.
ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors

8. Once an organophosphate binds to AChE, the enzyme can undergo one of the following:
Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases
Reactivation by a strong nucleophile such as pralidoxime (2-PAM)
Irreversible binding and permanent enzyme inactivation (aging)

9. aging
OP-AChE bond becomes irreversible only after a second side reaction called “aging”, in which one of the R groups leaves the phosphate molecule and become resistant to hydrolysis.
Different OP compounds have various aging times ranging from 2 minutes for the nerve agent soman to 72 hours for certain insecticides

10. Route of absorption Cutaneously Ingested inhaled or injected.
most patients rapidly become symptomatic, the onset and severity of symptoms depend on the specific compound, amount, route of exposure, and rate of metabolic degradation.

11. Clinical features 1.acute OP poisoning 4.neuro-psychiatric disorder.
-muscarinic features
- nicotinic features
- CNS features
2.Intermediate syndrome
3.Delayed neuropathy
4.neuro-psychiatric disorder.

12. Clinical feature
Expression of muscarinic overstimulation: bradycardia, bronchospasm, diarrhea, hypotension, lacrymation,miosis, salivation, urination and vomiting.
Expression of nicotinic overstimulation in the CNS: agitation, coma, confusion and respiratory failure.
Expression of nicotinic overstimulation at the Nm junction: fasciculations, muscle weakness and paralysis.

15. Cardiac issues — Cardiac arrhythmias, including heart block and QTc prolongation, are occasionally observed in organophosphorus agent poisoning . It is unclear whether these arrhythmias are due to direct toxicity or secondary hypoxemia.
Case reports and small case series suggest that up to one-third of patients with severe OP poisoning manifest signs of myocardial ischemia, such as an elevated troponin or changes in the electrocardiogram .
Peak troponin concentrations occur at presentation in most cases. Risk appears to be greatest in older patients and those with severe poisoning, but low in patients with mild poisoning

16. GRADING OF SEVERITY
Bardin et al validated a 3-grade system for poisoning at the time of admission:
a) Mild, shows normal consciousness with mild increase in secretions, and fasciculations.
b) Severe, shows impaired consciousness with copious secretions and multiple fasciculations.
c) Life-threatening, shows stupor with abnormal chest X-ray and PaO2 < 60 mmHg. These patients need ventilator support if initial suction, clearing of the airway and atropine do not change the picture.

17. INTERMEDIATE SYNDROME
Frist discribed in 1987 (karalliedde and senanayke)
Occurs 1-4 day after resolution of acute cholinergic crisis.
Risk factor:highly fat soluble op agent or inadequate dose of oximes

18. Incidence 10-50%
Prolonged effect on nicotinic receptor
Leads to muscle weakness
Main cause of morbidity and mortality in indian patient

19. Early signs: tremors and pharyngeal weakness( difficult deglutination,pooling of secretions)
Later: inability to flex neck,DTR’s lost,prximal muscle weakness,respiratory muscle paralysis.
Not all pt required intubation but pt with tremor and pharyngeal weakness are at increased risk.
Tratment : totally symptomatic .ventilatory support.
Wadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde 1987

20. Op induced delayed polyneuropathy(OPIND)
1-3 weeks after acute exposure due to slow release of OP from body fat
degeneration of long myelinated nerve fibres.
Pure motor or sensor-motor
Recovery is incomplete

21. CLINICAL FEATURES MOTOR sharp cramp like pain in calf
high stepping gait
shuffling gait in severe case
quadriplegia/paraplegia
wrist and foot drop
mild pyramidal sign
SENSORY
glove and stocking anaesthesia
cerebellar sign +/-

22. Chronic op induced neuro-psychiatric disorder(COPIND)
Chronic low dose exposure to OP.
40hours/week or 9month/year
No cholinergic symptoms
Plasma cholinesterase level are normal.

23. Diagnosis
History of exposure and clinical features suggest OP/Carbamate poisoning. Measurement of ChE in serum and RBC assist in diagnosis. .

24. Organophosphates depress both the true CHE enzyme of red blood cells and of the myoneural junction and also the pseudocholinesterase present in plasma. The latter is easier to measure.
Clinical signs are absent if serum CHE is above 50% of normal.
clinically poisoned patients usually have levels 25% below normal.

25. The level may stay low for days, treatment should therefore be adjusted not to the CHE level but to the clinical picture.
CHE levels can also be low in liver disease, alcoholism, malnutrition and as a familial disorder, but except in the last usually does not reach 25% below the normal range, which is nearly universal in significantly poisoned individuals

26. manegment Management of organophosphate poisoning
1. check airway, breathing, circulation.
2. monitor arterial oxygen saturation, cardiac rhythms, BP, Pulse rate.
3. look for signs & symptoms.
4. obtain IV access.
5. remove the contaminated clothes&wash the skin thoroughly with soap & water .

27. 6. give atropine intravenously as soon as possible for symptomatic patient
7. perform gastric decontamination with gastric lavage once the patient is stabilised & within two hours of ingestion.
8. give activated charcoal (50 g in 200 ml)
9. maintainance atropine infusion
10. give pralidoxime

28. ????

29. Gastric lavage
• Gastric lavage decreases absorption by 42% if done at 20 minutes and by 16% if performed at 60 minutes .
Performed by first aspirating the stomach and then repetitively instilling and aspirating fluid.
Choice of fluid is tap water: 5–10 mL/kg .
No human studies in OP poisoning showing benefit of gastric lavage.

30. atropinization
Atropinisation-start with mg fast iv bolus-after 3-5minutes check the five parameters of cholinergic poisoning .
1. Poor air entry into the lungs due to bronchorroea & bronchospasm
2.excessive sweating
3. bradycardia ( <60 )
4. hypotension
5. miosis-
If above parameters are not corrected double the dose of atropine every 5 minutes until atleast 3/5 of below parameters corrected -clear chest with no wheeze -dry axillae -heart rate bpm -systolic BP > 90 mmhg -pupils no longer pinpoint

31. Mandatory targets:
– SBP greater than 90 mm Hg
– Heart rate about 110/minute
– Clear lung fields.
• Other targets:
– Pupils mid position
– Bowel sounds just present
• Targets on subsequent days:
– Day 2: HR greater than 100/minute
– Day 3: HR greater than 90/minute
– Subsequent days: At least 80/minute

32. Start atropine infusion when atropinisation achieved – 0
Start atropine infusion when atropinisation achieved – 0.05mg/kg/hour or 10-20% of loading dose.
Monitor patient ever 15 minutes. If the dose of atropine is too low cholinergic features will re occur. If the dose of atropine is too high agitation, pyrexia, reduced bowel sounds and urinary retention will occur – then reduce atropine infusion.

33. Cholinesterase Reactivators:
Pralidoxime
Obidoxime
Trimedoxime
Pralidoxime most widely used.
Oximes are only for organophosphate
who recommend that oxime is givent to all symptomatic patients who needs atropine.

34. oximes
Pralidoxime attach to the other half (the unblocked, anionic site) of the acetylcholinesterase enzyme.then binds to the organophosphate, the organophosphate changes conformation, and loses its binding to the acetylcholinesterase enzyme.
the conjoined poison / antidote then unbinds from the site, and thus regenerates the enzyme, which is now able to function again.

35. Cherian et al 1996, 1997 showed no benefit from use of oximes, with use of 12 gm over 3 days increase the risk of death, intermediate syndrome & need for ventilation.
Singh et al, 2002, trial of 16 pts. with OPP, PAM 2 gm bolus then 7.5 mg/kg/hr with continuous atropine infusion. Improved outcome but no improvement in duration of MV.

36. Eddleston et al 2009 Largest Oxime Trial
• 235 patients, pralidoxime = 121, saline = 114
• 2 g loading dose over 20 minutes
• Then 0.5 g/hour for maximum 7 days
• Continued till atropine not required for 12–24 hours or death
Conclusion:
Patients with relatively low-dose occupational poisoning by diethyl organophosphorus insecticides have been shown to clinically improve after low-dose pralidoxime administration . However, for self-poisoned patients, have no consistent clinical trial evidence for the use of this regimen of pralidoxime in OP insecticide poisoning.

37. The controversies
Two RCT’s in vellore ,india in early 1990’s noted harm from low dose PAM infusion
A cochrane review included two RCT and two metaanalyasis 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 fatality ,fewer cases of pneumonia and reduced time on MV.

38. THE CONSENSUS Oximes will not be effective in very sevre OP poisoning
No role if started after 48 hour
Less effective in severe complication like aspiration pneumonia or hypoxic brain injury before tretment
Less or no effect with dimethyl compound or atypical op poisoning
Not effective in carbamate poisoning but are not contraindicated either.

39. Therapeutic end point Resolution of muscle fasciculation and weakness
Reactivation and increment in s.che level
Infusion continued until pt remain symptom free for atleast 12 hours without additional atropine
Or until extubated

40. pralidoxime
WHO guidelines recommended giving a 30 mg/kg loading dose of Pralidoxime over min followed by a continuous infusion of 8-10 mg/kg/hr until clinical recovery or seven days have elapsed whichever is later.
obidoxime:loading dose of 250 mg is followed by an infusion of 750 mg every 24 hrs

41. Other usefull therapy in organophosphate poisoning

42. Early Enteral Feeding
Early institution of enteral feeds may be associated with improved outcomes in the critically ill because it prevents enterohepatic circulation.
Current Concepts in the Management of Organophosphorus…

43. ALKALINIZATION
IV infusion of sodium bicarbonate produces moderate alkalinization (blood pH between 7.45 and 7.55) in OP pesticide poisoning
The alkalinization products of nerve agents such as soman are shown to be less toxic and hence, the IV infusion of sodium bicarbonate may even be more beneficial in nerve agents poisoning.
Roberts DM, Buckley N. (2012). Alkalinisation for organo-phosphorus pesticide poisoning

44. clonidine
Clonidine is a centrally acting alpha-2 receptor agonist. It is used as centrally acting antihypertensive drug. It inhibits presynaptic release of acetylcholine, thereby decreasing the cholinergic symptoms caused by organophosphate poisoning
An optimum dose of clonidine with clonidine bolus injection (0.15–0.30 mg) followed by an infusion at the rate of 0.5 mg/24 hours appears to be clinically acceptable in OP poisoning
Perera PM, Jayamanna SF, Hettiarachchi R, et al. A phase II clinical trial to assess the safety of clonidine in acute organophosphorus pesticide poisoning. Trials. 2009;10:73.

45. Magnesium Sulfate
Intravenous MgSO4 (4 g) given in the first day after admission have been shown to decrease hospitalization period and improve outcomes in patients with OP poisoning.
Magnesium sulfate blocks calcium channels and thus reduces acetylcholine release.
It also reduces CNS overstimulation resulting from N-methyl D-aspartate receptor (NMDAR) activation and reversed for the neuroelectrophysiological defects.
Source: Data from Blain PG 2011.

46. Hemoperfusion ::Organophosphorus pesticides are fat-soluble macromolecular substances that can bind to the proteins easily.
As hemoperfusion therapy is highly effective in clearing lipid soluble or plasma protein-bound poisons, it has been proposed that repeated hemoperfusion would rapidly attenuate the poisoning symptoms and minimize complications.
In a recent study in China found that early & repeated hemoperfusion was more efficient than single hemoperfusion in treating organophosphate poisoning.

47. Fresh frozen plasma :
Bio-scavengers such as fresh frozen plasma (FFP) or albumin have been recently suggested as a useful therapy through clearing of free organophosphates.
In a nonrandomized controlled study of 12 patients and 21 control found that FFP therapy increased the levels of 2-BuChE in OP poisoned patients and suggested that it may prevent the development of intermediate syndrome and mortality rate.
In another study, despite significant increase in BuChE concentrations with FFP, did not find considerable benefit following treatment with FFP or albumin.

48. agitation Review dose of atropine
Provide adequate sedation with benzodiazepine
Physical restraint of patient in warm condition risks severe hyperthermia which exacerbates by atropine.

49. THANK YOU

50. Other agent GACYCLIDINE: antiglutaminergic
Inhibit sezures that was induced by soman.
VITAMIN E:
In a study on rats, vitamin E was reported to have therapeutic effects in dimethoate and malathion- induced oxidative stress in rat erythrocytes.