There are more than a hundred organophosphate compounds used regularly. Obtaining even clinically relevant data such as the lipid solubility, the half life, the conversion to active metabolites, binding to antidotes and whether they are associated with delayed neuropathy or neuropsychiatric effects is difficult or impossible for many of these compounds. There are significant clinically important differences between compounds within the class:probably the most important being the faster aging of enzyme inhibition seen with dimethyl compounds compared with diethyl compounds

Some available include

Chlorpyrifos
Coumaphos
Diazinon
Dichlorvos
Dimethoate
Famphur
Fenthion
Malathion
Mevinphos
Parathion

OVERVIEW

The organophosphate insecticides are an extremely toxic group of compounds which are rapidly absorbed by the dermal, oral and pulmonary routes. Following significant exposure symptoms of toxicity generally occur within 4 hours. The exception to this is extremely lipid soluble organophosphate (e.g. fenthion and dichlofenthion) which are rapidly taken into fat stores and subsequently slowly and intermittently released and metabolised to more active compounds. In this situation the symptoms of toxicity may not occur for up to 48 hours and may continue for weeks.

Deaths from dermal or occupational exposure are very rare. Oral ingestion of organophosphate concentrates may involve doses 100-1000 fold greater and requires an entirely different approach to management.

MECHANISM OF TOXIC EFFECTS

The organophosphate compounds phosphorylate and inactivate acetylcholinesterases. This causes an increase and accumulation of acetylcholine at nerve endings,stimulating neuro-effector junctions, skeletal neuro-muscular junctions, autonomic ganglia and in the brain. Overstimulation causes a depolarising block of neuromuscular junction receptors.
This gives rise to a large number of clinical effects in the central nervous system, autonomic nervous system and leads to paralysis.
After the initial organophosphate acetylcholinesterase bonds are formed a conformational change in the molecular structure of the organophosphate occurs which increases the binding and subsequently makes the organophosphate-acetylcholinesterase complex irreversibly bound. This process is called ageing and is highly dependent upon the type of organophosphate such that significant aging varies between, 2-36 hours after intial binding.
In addition to acetylcholinesterase inactivation and subsequent acetylcholine accumulation there is also central nervous system antagonism of GABA and dopaminergic neurons. Neurocognitive effects and late onset peripheral neuropathy is well described

KINETICS IN OVERDOSE

Absorption

All organophosphates are rapidly absorbed from the small intestine or dermal exposure. Peak concentrations may occur within a few hours.

Distribution

This is a diverse group of compounds with a wide range of lipid/water solubility characteristics and variable, but usually large, volumes of distribution.

Metabolism - Elimination

Some organophosphates (-thions) are metabolised in the liver to much more active metabolites (-oxons). These poisons (e.g. parathion, fenthion, chlorpyrifos) are also usually highly lipid soluble. Thus the slow conversion of these substances, which are widely distributed into fat, may lead to delayed and/or prolonged cholinesterase inhibition and toxic effects. This slow redistribution and/or activation may have implications for treatment: longer treatment and late commencement may be of benefit in these patients

The major route of elimination is paraoxonase. This is an enzyme which is present in serum bound to lipoproteins (HDL).

CLINICAL EFFECTS

Four clinical syndromes have been described

acute cholinergic symptoms and paralysis (most common)
subacute proximal weakness (Intermediate syndrome)
organophosphate induced delayed neuropathy (OPIDN)
chronic organophosphate induced neuropsychiatric disorder (COPIND)

The long term neuropsychological sequelae may result from both acute & chronic exposure (see also clinical grading of toxicity).

Acute cholinergic syndrome and paralysis

The clinical effects and symptomatology in acute poisoning results from muscarinic, nicotinic and central nervous system effects.

Muscarinic effects
Muscarinic effects are those mediated by stimulation of the parasympathetic nervous system.
This results in

contraction of intestinal & bronchial smooth muscles
decreased pupil size
increased secretions from all secretory glands
decreased sinus node activity (bradycardia), AV conduction defects and occasionally ventricular arrhythmias

The mnemonic DUMBELS describes most of the significant muscarinic features
Diarrhoea
Urination
Miosis
Bronchospasm
Emesis
Lachrymation
Salivation

Nicotinic effects
Nicotinic effects are due to the accumulation of acetylcholine both at the neuromuscular junction and at the preganglionic synapses of the autonomic nervous system. The accumulation of acetylcholine at the neuromuscular junction causes initial stimulation (fasciculations in muscle groups including the tounge) followed by depolarisation and paralysis.
Stimulation of the sympathetic nervous system may produce sweating, hypertension and tachycardia.

Central nervous system effects

These include initial cerebral stimulation followed by increasing central nervous system depression leading to coma and occasional seizure activity. Impaired level of consciousness is an important predicto of poor outcome
One element of respiratory failure in OP poisoning appears to be due to dysfunction of central respiratory control mediated by muscurinic receptors.For this reason it is important to atropinise the patient quickly.

Cardiac effects

QTc prolongation is often noted but its clinical significance is uncertain.
Tachycardia is common and may be due to various combination of nicotinic and pulmonary muscurinic effects (causing hypoxia), patients who have lung crepts or rhonchi should receive atropine even in the presence of tachycardia.
Bradycardia is normally a muscurinic effect, in this setting most clinicians in the acute phase of poisoning aim to atropinse the patient until their chest is clear and the pulse is 100 /minute

Severe organophosphate poisoning is can also be complicated by hypotension and tachycardia.

Ischaemic sequelae may develop in patients with pre-existing vascular disease. The vascular effects of the excess ACh are mediated mainly through muscarinic receptors of the endothelium evoking release of nitric oxide and vasodilatation. ACh also acts on nicotinic receptors in the sympathetic ganglia and muscarinic receptors in the muscle layer of medium size arteries to cause vasoconstriction and on CNS muscarinic receptors which have less predictable effects on blood vessels.

Thus the hypotension with tachycardia may be due to a low total peripheral resistance with a partially compensating high cardiac output. In this case the hypotension and vasodilatation are reversed by atropine (Buckley et al, 1994). Ischaemic complications may be due to unopposed vasoconstriction by acetylcholine at sites of endothelial injury (Buckley et al, 1994). Symptomatology varies between individuals and within the same individual at different points of time. This relates to a varying balance of muscarinic and nicotinic effects.

Inflamatroy infiltrates have been noted in some myocardial samples raising the possibility of an inflamatory myocarditis

Other effects

In addition to the neurologically related complications, the patients may also develop non-cardiogenic pulmonary oedema, pancreatitis and the adult respiratory distress syndrome.

Subacute proximal weakness (Intermediate syndrome IMS)

A subacute syndrome has been described in which patients develop proximal muscle weakness and cranial nerve lesions after recovery from cholinergic effects. This has been thought to be due to primary motor end plate degeneration due to prolonged inhibition of acetylcholinesterase.
Patients who develop weakness of proximal muscles,neck flexion of MRC score of 3/5 or less are at risk of late respiratory failure. A forme fruste of IMS is described with less severe weakness. Repeative nerve stimulation shows initial decrement increment progressing to severe decrement.
In Asia a common clinical screen is to check neck flexion power

Organophosphate induced delayed neuropathy (OPIDN)

Chronic organophosphate induced neuropsychiatric disorder (COPIND)

Long term neuropsychiatric sequelae have been described for all degrees of exposure. Formal neuropsychological testing and regular follow up should be performed. Use of benzodiazepines during the acute poisoning may reduce the severity of long term neuropsychiatric sequelae.

INVESTIGATIONS

Cholinesterase

If cholinesterase assay are not done immediately the sample should be diluted by a factor of 20 at the bedside (see Eddleston et al Lancet 200*)

Plasma cholinesterase

Plasma cholinesterase (PChE) is a sensitive marker of exposure but on its own gives little idea of severity of exposure. The normal range is 3000-7000 U/L. Its sensitivity varies depending upon the type of oganophosphate. There have been a number of suggested uses (Dawson et al, 1997)

Documentation of exposure in mild poisoning

The test can be done sequentially to confirm exposure in patients whose results fall within the low part of the normal range. Repeating the test a few weeks later will show whether the concentrations rebound to a higher concentration.

Determining if sufficient pralidoxime is being given (mixed cholinesterase test)

PChE is measured in the patient's plasma and in a normal plasma sample and in a 50-50 mixture of the two samples. If there is an adequate concentration of pralidoxime then the mixed sample will have a PChE value equal to the mean of the other two measures. Lower values indicate insufficient pralidoxime has been given.

Red blood cell cholinesterase

Acutely this correlates well with neuronal cholinesterase and therefore with severity and prognosis.

ECG

Should be done in moderate to severe poisonings as brady- and tachyarrhythmias may occur.

Imaging

CXR is indicated in all severe poisonings as aspiration pneumonia (contributed to by hydrocarbon diluents) may occur.

Blood gases

Metabolic acidosis may occur and probably worsens prognosis an should be actively treated

Blood concentrations

Measurement of the organophosphate is unhelpful in aiding management.

DIFFERENTIAL DIAGNOSIS

Difficulties in diagnosis usually arise when an unconscious or delirious patient is known to have ingested an unknown chemical from the garden shed (see differential diagnosis of garden shed poisoning). The absence of miosis does not exclude significant organophosphate poisoning. The presence of muscle fasciculations and associated weakness strongly supports the diagnosis.

Organophosphates often have an odour similar to garlic though this may be masked by hydrocarbon diluents. Significant (i.e. not mild) poisoning will almost invariably be associated with a low plasma cholinesterase. Similar but usually milder clinical features may occur with poisoning with carbamate insecticides.

At a practical level if there are signs that could be cholinergic then the patient should be given a test dose of atropine of 0.6 to1.2mgs. Patients who become atropinised on that dose do nothave a significant cholinergic poisoning (at that point in time) however some OPs do have a delayed onset of clinical signs

DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS

Often, organophosphates are listed according to their lethal dose in animals as being low, moderate or high toxicity. As the compounds are usually prepared in concentrations that account for their relative potency, these lists do not give any indication of the likelihood of developing clinical consequences from an exposure. In deliberate ingestions of concentrates, these poisons vary from being very poisonous to extremely poisonous. The major differences are that a number of these poisons require metabolic activation and thus may have a delayed or prolonged course.

DETERMINATION OF SEVERITY

The following table has been suggested as a guide to determining severity by . However if a patient has any CNS signs or paralysis or has ingested a concentrated preparation, the poisoning is likely to be severe irrespective of other initial signs.

MILD	MODERATE	SEVERE
Walks & talks Headache & dizzy Nausea & vomiting Abdominal pain Sweating Salivating Pl. Cholinesterase 20%-50% of normal	Can't walk, Soft voice Muscle fasciculations, Small pupils, Pl. Cholinesterase 10%-20% of normal	Unconscious, No pupillary reflex, Muscle fasciculations, Flaccid paralysis Increased bronchial secretions, Dyspnoea, Crackles or wheeze Respiratory failure, Pl. Cholinesterase < 10% of normal

An alternate system used successfully in parts of asia is to simply score the patient out of 3 (1 point for each of the following; muscurinc syndrome, nicotinic syndrome, CNS-impaired GCS)

TREATMENT

See Eddleston et al

Supportive

Maintenance of airway, ventilation, IV access and fluids are the early and major priority as patients may deteriorate rapidly. Early and aggressive atropinisation (see below) should be commenced early during this time.
Mild acidosis is common in significant poisonings, the correction of the serum bicarbonate to normal concentrations with sodium bicarbonate has been suggested to be clinically useful.

Staff health issues

Staff should also

Gown and glove
Remove (and destroy) patient's clothes
Wash the patient a number of times (soap, alcohol and soap)

While staff will often notice eye and upper respiratory symptoms while looking after these patients we (unpublished data) and others (Butera et al, 2002) have shown that plasma cholinesterase concentrations in healthcare workers do not change indicating the symptoms are most likely from exposure to the irritant hydrocarbon solvent rather than to the organophosphate itself.

Intensive Care admission

Patients with moderate or severe poisoning should be transferred to an Intensive Care facility. Asymptomatic patients who have ingested organophosphate concentrate should also be managed in ICU.

GI Decontamination

Activated charcoal
Oral activated charcoal should be given to all patients ingesting organophosphates who present within 1-2 hours. Evidence did not demonstrate benefit after 2 hours. Patients with any history, signs or investigation indicating severe poisoning should have elective intubation, consideration of gastric lavage and activated charcoal and the specific treatment outlined below.

Antidotes

Atropine
Atropine is used to block muscarinic effects due to excessive acetylcholine (it has no effect on nicotinic induced paralysis)
Initial treatment is to give a stat test dose of 1-2 mg of atropine (in adults). If the patient exhibits signs of atropinisation after this test dose it is likely that they have mild poisoning.
In other patients, subsequent doses should be doubled and repeated every 5 minutes intervals until the patient is atropinised. The primary end point of atropinisation is drying of bronchial secretions (manifest as crepts and wheeze) Pupil size can only be used as an end point if miosis is present on admission also the dilation of pupils often lags behind other signs of atropinsiation.
Patients will often require an atropine infusion to maintain atropinisation and infusions of 10-20 mg/h are commonly required with severe poisonings. A good starting point is to give 10-20% of the total loading dose per hour of atropine needed for atropinisation. See Eddleston et al for further guidance and for an example of an atropine monitoring sheet.

In severe poisonings, measurement of peripheral vascular resistance may be a better method of measuring adequate atropinisation as, in some circumstances, cholinergic features may be surprisingly minimal (perhaps due to a depolarising block of the muscarinic receptors) and hypotension/tachycardia due to circulating acetylcholine are dominant clinical features (Buckley et al, 1994)

In children.the starting dose could range from 0.01 to 0.03 mg/kg:

an unclear history or minimal symptoms is 0.01 mg/kg and then proceed with a doubling dose every 5 minutes titrated against response (predominately clearing the chest and drying secretions)
if the child is clearly symptomatic then start with 0.03 mg/kg and then titrate using a doubling dose

Pralidoxime
Pralidoxime binds to organophosphates and removes them from acetylcholinesterase if ageing has not occurred. The pralidoxime-organophosphate complex is water soluble and rapidly excreted by the kidneys.

Patients with mild to moderate poisoning should receive pralidoxime with an initial dose of 2 g (30 mg/kg) intravenously over 15 minutes followed by 1 gm 8th hourly for a minimum of 48 hours.

Severe poisonings or oral exposures should have an infusion of 500 mg/hour (8 mg/kg/h) after the initial dose.

The success of pralidoxime binding to available organophosphate may be determined by the mixed plasma cholinesterase test and the infusion adjusted accordingly. For the majority of organophosphate poisonings this treatment is only of use in the first 36 hours but pralidoxime should be used in severe poisonings regardless of the time of exposure.

For poisonings with highly lipid soluble organophosphates this treatment should be used even in late presentations and may need to be continued for up to 2-3 weeks.

In children a loading dose of 25-50 mg/kg is recommended followed by a continuous infusion of 10-20 mg/kg/h. A loading dose of 50 mg/kg may be appropriate in more severely poisoned patients (Schexnayder S et al)

Pralidoxime undergoes renal excretion, in patients with renal failure the dose may need to be reduced.

Benzodiazepines
All patients with significant exposure should receive adjunctive treatment with benzodiazepines. There are no clinical trials to define the appropriate dose. In the absence of any other indications for benzodiazepines the authors aim for a daily dose that is equivalent to 40 mg diazepam.

Treatment of specific complications

Seizures
Initially, diazepam 10-20 mg IV followed by phenobarbitone 15 mg/kg IV and elective intubation and ventilation (without paralysis).

Haemodynamic collapse and ischaemia

Patients who become hypotensive often have extremely low peripheral vascular resistance which responds to very large doses of atropine. These patients should have a Swan-Ganz catheter inserted to monitor the effects of therapy. These patients may seem to be adequately atropinised using the normal clinical criteria. Paradoxical vasoconstriction can occur at atheromatous sites due to endothelial dysfunction at these sites and unopposed action of acetylcholine receptors in the arterial smooth muscle. In theory this vasoconstriction should respond to atropine and be exacerbated by adrenaline and dopamine. Also, most patients have high rather than low cardiac output. Thus atropine, rather than inotropic drugs, should be used for the treatment of hypotension (Buckley et al, 1994).

Ventricular tachycardia

Isoprenaline or overdrive pacing (rate 120-140) are indicated for torsade de pointes and should be considered for all tachyarrhythmias. Magnesium is normally the drug of choice for treating torsade de pointes.

Elimination enhancement

Elimination enhancement is not useful.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP

Late neurological sequelae include a peripheral neuropathy which is due to axonal degeneration. This may be due to the inhibition of the enzyme neurotoxic (target) esterase (reported in occupational exposures). It is much more common with (though not limited to) certain compounds with a higher affinity for this enzyme. Long term neuropsychiatric sequelae have been described for all degrees of exposure. Formal neuropsychological testing and regular follow up should be performed.

REFERENCES

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Thompson DF, Thompson GD, Greenwood RB, Trammel HL. Therapeutic dosing of pralidoxime chloride. Drug Intelligence & Clinical Pharmacy 1987; 21(7-8):590-3.
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