INTRODUCTION

• Organophosphorus compounds are chemical agents in wide-spread use throughout the world, mainly in agriculture.
• Exposure to organophosphates in an attempt to commit suicide is a key problem, particularly in the developing countries
• Estimates from the WHO indicate that each year, 1 million accidental poisonings and 2 million suicide attempts involving pesticides occur worldwide.
• Early diagnosis and prompt treatment is required to save the patient’s life.

Classification of op compounds

• Highly toxic organophosphates:

    e.g. tetra-ethyl pyrophosphates, parathion.
These are mainly used as agricultural insecticides.

•  Intermediately toxic organophosphates:

    e.g. coumaphos, clorpyrifos, trichlorfon.
These are used as animal insecticides.

•  Low toxicity:

    e.g. diazinon, malathion, dichlorvos.
These are used for household application and as field sprays.

 

Mechanism of action of op comp

ABOUT ACETYLCHOLINE.

• Acetylcholine (ACh) is the neurotransmitter released at all postganglionic parasympathetic nerve endings and at the synapses of both sympathetic and parasympathetic ganglia.
• It is also released at the skeletal muscle myoneural junction, and serves as a neurotransmitter in the central nervous system.

ABOUT ACETYLCHOLINESTERASE
They are present in two forms:

• True acetylcholinesterase-found primarily in the tissues and erythrocytes.
• Pseudocholinesterase -found in the serum and liver
• Cleavage of the carbon-enzyme bond from ACh is complete in a few microseconds.
• Organophosphorus compounds are acid-transferring inhibitors of Acetyl cholinesterase, to become firmly (and sometimes irreversibly) phosphorylated.
• Breaking of the phosphorus-enzyme bond requires a period varying from 60 minutes to several weeks, depending on the organophosphorus compound involved.
• Reactivation may be enhanced by hydrolysis of the acid-radical-enzyme through the use of oximes (i.e. reactivating agents).
• Accumulation of acetylcholine causes overstimulation of both muscarinic and nicotinic receptors, and subsequently disrupts the transmission of nerve impulses in both the peripheral and central nervous system.

 

• Muscarinic signs and symptoms: seizures, excessive secretions (lacrimation, salivation, bronchorrhea and wheezing, diaphoresis), and increased bowel and bladder activity with nausea, vomiting, diarrhea, abdominal cramps, and incontinence of feces and urine.

• Nicotinic signs and symptoms: hypertension, tachycardia, muscle cramps, fasciculations, weakness, and paralysis.

 

• Grading Severity of OrganophosphatePoisoning

         Normal serum acetylcholinesterase / RBC Cholinesterase level is 8.0-20.0 u/l
MILD
Walks and talks
Headache, dizzy
Nausea, Vomiting
Abdominal pain
Sweating, salivation
Rhinorrhoea
serum acetylcholinesterase enzyme (AChE) Results: 1.6-4.0 u/l

MODERATE
Cannot walk
Soft voice
Muscle twitching
(fasciculations)
Anxiety, restlessness
Small pupils (miosis)
serum acetylcholinesterase enzyme (AChE) Results: 0.8-2.0 u/l

SEVERE
Unconscious, no
papillary reflex. Muscle
twitching, flaccid paralysis.
Increased bronchial
secretions. Dyspnoea
crackles / wheeze. Possible
convulsions
Respiratory failure
serum acetylcholinesterase enzyme (AChE) Results: < 0.8 u/l

MANAGEMENT

• Treatment is initiated immediately on clinical suspicion, without waiting for blood investigations.
• Decontamination
• Airway and respiration
• Anticholinergics: Atropine for muscarinic signs and symptoms.
• Cholinesterase reactivator: Pralidoxime (2-PAM) for nicotinic signs and symptoms due to organophosphates, nerve gases, or an unknown anticholinesterase.

DECONTAMINATION

• Skin decontamination is very important step that should never be neglected or hurried.
• The patient should be removed from the site of exposure and their clothes removed.
• The patient’s body should then be thoroughly washed with soap and water to prevent further absorption from the skin.
• Gastric lavage is the only means of emptying the stomach in unconscious patients in which case the airway needs to be protected.

AIRWAY AND RESPIRATION

• The airway should be secured and adequate oxygenation ensured.
• This is important as atropine can precipitate ventricular fibrillation in hypoxic patients.
• Paradoxically, the early use of adequate atropine will dry respiratory secretions, improve muscle weakness and thereby improve oxygenation.
• Careful observation of the respiratory status is required as these patients are prone to develop respiratory failure during both the acute phase and the intermediate syndrome.

Guidelines for ventilator support
I. Respiratory Gas Tensions
i Direct Indices
Arterial Oxygen Tension < 50 mm Hg on room air
Arterial Co2 Tension > 50 mm Hg in the absence of metabolic alkalosis
ii Derived Indices
P a o2/ Fio2 < 250 mm of Hg
PA-aOo2 ( Pulmonary arterial-alveolar O2 gradient) > 350 mm of Hg
Vd/Vt> 0.6
II. Clinical - Respiratory Rate (RR)> 35 breaths/min
III. Mechanical Indices
Tidal Volume 5 ml/kg
Vital capacity < 15 ml/kg
Maximum inspiratory force <- 25 cm of H2O

ANTICHOLINERGICS
Atropine-

• Treatment with anticholinergics (to antagonize the muscarinic effects of the organophosphate on the CNS, CVS and gastrointestinal tract), is still the mainstay of treatment, and should be started as soon as the airway is secured.
• The recommended starting dose of atropine is a 2mg IV bolus. Subsequent doses of 2-5mg every 5-15 minutes should be administered until atropinization is achieved.

SIGNS OF ATROPINIZATION

• Increased heart rate (>100 beats/min)
• Moderately dilated pupils
• Reduction in bowel sounds
• Dry mouth
• Decrease in bronchial secretions.

Target end points for atropine therapy
Clear chest on auscultation with no wheeze
Heart rate> 80 beats/min
Pupil no longer pin point
Dry axilla
Systolic blood pressure > 80 mm of Hg

 

CHOLINESTERASE REACTIVATOR

• The use of oximes in acute organophosphorus poisoning has been a controversial subject for the last two decades as there have been very few randomized controlled trials that have addressed the role of pralidoxime (PAM).

 

• Pralidoxime should be started as early as possible to prevent permanent binding of the organophosphate to acetylcholinesterase.
• Before administering, ensure blood specimen (heparinised tube) is taken for acetylcholinesterase analysis.
• Rapid administration may result in tachycardia, laryngospasm, muscle rigidity and transient neuromuscular blockade.

Mechanism of action

• Oximes are nucleophilic agents that re-activate the phosphorylated acetylcholinesterase by binding to the organophosphate converting it into a harmless compound, this action most marked at the nicotinic skeletal neuromuscular junction.
•  A transient reaction protecting the enzyme from further inhibition.
• Reactivation of the inhibited alkyl phosphorylated enzyme to free the active unit (if given early enough)

Equivalent dosing units of pralidoxime salts.

Salt	Equivalent dose(g)
Pralidoxime chloride	1
Pralidoxime mesilate	1.34
Pralidoxime metilsulfate	1.43
Pralidoxime iodide	1.53

 

• INDICATIONS:
• Suspected exposure to nerve agent
• Organophosphate poisoning
• CONTRAINDICATIONS
• Poisonings involving: carbamate insecticide Sevin, inorganic phosphates, or organophosphates having no anticholinesterase activity.
• Asthma
• Peptic ulcer disease
• Severe cardiac disease
• ADVERSE REACTIONS
• Dizziness
• Headache
• Blurred vision
• Hypertension
• Tachycardia
• Nausea / vomiting
• DRUG INTERACTIONS: Respiratory depressants can potentiate the effects of pralidoxime . These include narcotics, phenothiazines , antihistamines, and alcohol . Should not be used with theophylline preparations.

ARTICLE’S QUOTING THE USES ( PRO’S) OF PRALIDOXIME

• 1992 Samuel, Vellore, India.

                   Compared 1g bolus pralidoxime with a 12g infusion over 4 days in 72 patients. Found non-significant increase in death and ventilation requirement in patients receiving the infusion.

• Chugh SN, Aggarwal N, Dabla S, Chhabra B (2005), Comparative evaluation of "atropine alone" and "atropine with pralidoxime (PAM)" in the management of organophosphorus poisoning, Journal of the Indian Academy of Clinical Medicine 6: 33-37

 Pralidoxime (1 g/6 hrs) vs standard treatment
No statistical difference in the risk of death or the need for ventilation     between the treatment groups 

 

• Cherian MA, Roshini C, Visalakshi J, Jeyaseelan L, Cherian AM (2005), Biochemical and clinical profile after organophosphorus poisoning--a placebo-controlled trial using pralidoxime, The Journal of the Association of Physicians of India 53: 427-431.

      Pralidoxime (12 g/day (severe) or 4 g/day (moderate) over 3 days) vs placebo (and standard care)
No statistical difference in the risk of death or the need for ventilation between the treatment groups

• Pawar KS, Bhoite RR, Pillay CP, Chavan SC, Malshikare DS, Garad SG (2006), Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial, The Lancet 368: 2136-2141.

          Results:- The results of the comparison between ‘low-dose’ pralidoxime and ‘high-dose’ pralidoxime reported by Pawar et al (2006) are summarised in Table 7. The primary outcomes of this study were: median atropine dose in the first 24 hours of admission, proportion of patients requiring intubation and the number of days on ventilation.
‘High-dose’ pralidoxime significantly reduced the number of deaths and the number of patients with pneumonia compared to the ‘low-dose’ treatment arm. Outcomes associated with the administration of supportive therapy (median atropine dose in first 24 hr of admission, proportion of patients requiring intubation and the number of days on ventilation) were also significantly improved in the ‘high-dose’ arm.
The authors of this study concluded that a high-dose regimen of pralidoxime reduces morbidity and mortality in patients with moderately severe organophosphorus poisoning.
Interpretation -A high-dose regimen of pralidoxime, consisting of a constant infusion of 1 g/h for 48 h after a 2 g loading dose, reduces morbidity and mortality in moderately severe cases of acute organophosphorus-pesticide poisoning

CONCLUSION
Current evidence suggests that the efficacy of Atropine has been proved beyond doubt; the clinical experience with pralidoxime has lead widespread doubt about its efficacy in the treatment of organophosphorus poisoning. The studies questioned the efficacy of pralidoxime in the management of op poisoning are coming from Srilanka and India and all these studies have been criticised either on the basis of noncomparable groups of selected patients, or inadequate doses of PAM.
Cochrane reviews concluded that current evidence is insufficient to indicate whether oximes are harmful or beneficial in the management of Acute OP pesticide poisoning.