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. Is it a thione ( ie contains sulphur moitey) which is metabolised to the more activate oxone.
Some available include
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 organophosphates most frequently involves high concentrations causing exposures 100-10000 fold greater than dermal exposure and requires an entirely different approach to management to occupational exposure. All oral exposure should be considered high risk and should be admitted.
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. This gives rise to a large number of clinical effects in those systems
Initially overstimulation causes a depolarising block of neuromuscular junction receptors with subsequent paralysis. Postsynaptic receptors may downregulate (decrease in numbers) causing late neuromuscular junction failure (also termed intermediate syndrome)
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 initial 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.
All organophosphates are rapidly absorbed from the small intestine or dermal exposure. Peak concentrations may occur within a few hours.
This is a diverse group of compounds with a wide range of lipid/water solubility characteristics and variable, but usually large, volumes of distribution.
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).
The major clinical syndromes described:
The long term neuropsychological sequelae may result from both acute & chronic exposure (see also clinical grading of toxicity).
Muscarinic effects are those mediated by stimulation of the parasympathetic nervous system. This results in:
The mnemonic DUMBELS describes most of the significant muscarinic features
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 tongue) followed by depolarisation and paralysis due to failure of the neuromuscular junction.
Stimulation of the sympathetic nervous system may produce sweating, hypertension and tachycardia.
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 predictor 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.
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.
Inflammatory infiltrates have been noted in some myocardial samples raising the possibility of an inflammatory myocarditis. This injury may be related to other components of the pesticide such as solvents
In addition to the neurologically related complications, the patients may also develop non-cardiogenic pulmonary oedema, pancreatitis and the adult respiratory distress syndrome.
Original descriptions of this syndrome described in which patients who develop proximal muscle weakness and cranial nerve lesions after recovery or control from cholinergic effects. It is apparent that all patients who develop such weakness have progressive neuromuscular junction dysfunction from the time of the acute exposure and that careful clinical examination will show continued symptoms or need for treatment. This has been thought to be due to primary motor end plate dysfunction due to prolonged inhibition of acetylcholinesterase, it involves both presynaptic and postsynaptic failure.
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. Repeated nerve stimulation shows initial decrement increment progressing to severe decrement. These studies suggest that IMS is part of the continuum of acute nicotinic syndrome. In Asia a common clinical screen is to check neck flexion power.
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. Use of benzodiazepines during the acute poisoning may reduce the severity of long term neuropsychiatric sequelae.
If the cholinesterase assay is not done immediately the sample should be diluted by a factor of 20 at the bedside (see Eddleston et al Lancet 200*)
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.
Acutely this correlates well with neuronal cholinesterase and therefore with severity and prognosis.
Should be done in moderate to severe poisonings as brady- and tachyarrhythmias may occur.
CXR is indicated in all severe poisonings as aspiration pneumonia (contributed to by hydrocarbon diluents) may occur.
Metabolic acidosis may occur and probably worsens prognosis an should be actively treated
Measurement of the organophosphate is unhelpful in aiding management.
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
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.
Any patient who has ingested a concentrated preparation, is likely to develop significant toxicity irrespective of other initial signs.
Impaired GCS at presentations the strongest predictor of death and has a similar predictive value to the Poison Severity Score. (See Davies et al)
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; muscurinic syndrome, nicotinic syndrome, CNS-impaired GCS)
See Eddleston et al
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.
Organophosphates used in agriculture have low volatility and do not off gas (unlike organophosphates used as chemical weapons such as Sarin which are a gas).
Staff should also:
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.
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.
Competitive non-depolarising neuromuscular blockers should be considered in patients who require ventilation as these may protect the neuromuscular junction from subsequent NMJ failure as a consequence of over stimulation
Oral activated charcoal should be given to all patients ingesting organophosphates who present within 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.
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 children.the starting dose could range from 0.01 to 0.03 mg/kg:
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.
The exact role of oximes and dose is not established. Its use is controversial, In many institutions it is not used at all, A randomised control trial of the WHO recommended protocol of 2 grams loading followed by 500mg constant infusion did not show any survival benefit and suggested harm.( Eddleston et al)
Reactivation is much more likely in diethyl organophosphates which age slowly than dimethyl organophosphates which age rapidly.
Treatment should be tailored to the individual patient by ideally assessing for objective evidence of response following the initial dose. The best intermediat outcome would be improvement in power or in NMJ function, improvement in red cell cholinestersase is another intermetidate outcome often used.
In children higher doses are required to achieve 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.
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.
Initially, diazepam 10-20 mg IV followed by phenobarbitone 15 mg/kg IV and elective intubation and ventilation (without paralysis).
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).
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 is not useful.
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.
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