Carbamates are common insecticides found in a variety of commercial products widely used in agriculture and household insect sprays. In Australia, at least the following carbamate insecticides are found.
Although carbamates may be listed according to their lethal dose in animals as above, these compounds are usually prepared in concentrations that account for this relative potency. Therefore, these lists do not give any useful indication of the likelihood of developing clinical consequences from an exposure. In deliberate ingestions of the concentrate, the carbamates can vary from being very poisonous to extremely poisonous and deaths are common in rural Asia (Case Fatality Rate 8%).
Carbamates are toxic chemicals which, present with similar clinical effects to organophosphates. As with organophosphates, much written in textbooks relates to dermal or occupational exposure to carbamates. Oral ingestion of carbamate concentrates may involve doses many fold greater and require a different approach to management with aggressive atropinisation.
The carbamate insecticides are rapidly absorbed by the oral and pulmonary routes although (with the exception of aldicarb) most carbamates are relatively poorly absorbed through the skin compared with organophosphates. Following significant exposure, symptoms of toxicity generally occur early, within 30 minutes, but may not develop until 1-2 hours after exposure. Clinical manifestations are the same as those seen with organophosphates but the duration of toxicity is usually shorter (less than 24 hours) however large ingestion can lead to symptoms for days.
The carbamates, like organophosphates, inhibit acetylcholinesterase. Unlike organophosphates, however, this inhibition is reversible and relatively short-lived. The inhibition of acetylcholinesterase causes an increase in acetylcholine with stimulation of autonomic receptors and depolarising block of neuromuscular junction receptors. This can give rise to a large number of clinical effects in the central nervous system, autonomic nervous system and may lead to paralysis.
All carbamates are rapidly absorbed from the small intestine or on inhalation. Peak concentrations occur rapidly.
There is a wide range of lipid/water solubility characteristics resulting in variable, but usually large, volumes of distribution.
Aldicarb undergoes extensive enterohepatic recirculation. Most of the carbamates are metabolised in the liver and then excreted in the urine within several days.
The most common clinical syndrome is one of acute cholinergic symptoms with or without paralysis. Respiratory failure because of bronchorrhoea and/or respiratory muscle weakness is the most common mode of death. Case reports of late axonal degeneration exist. There does not appear to be an intermediate syndrome as is reported with organophosphates.
These are similar to organophosphate poisoning
Severe carbamate poisoning may be complicated by hypotension and tachycardia. Vascular effects of the excess acetylcholine are mediated mainly through muscarinic receptors in the endothelium evoking release of nitric oxide and vasodilatation. Acetylcholine also acts on nicotinic receptors in the sympathetic ganglia, and muscarinic receptors in the muscle layer of medium size arteries to cause vasoconstriction. Thus, the hypotension and tachycardia that occur may be due to a low total peripheral resistance with a partially compensating high cardiac output. In these circumstances, the hypotension and vasodilatation are likely to be reversible with atropine. Symptoms and signs vary between individuals and within the same individual at different points in time depending on the varying balance of muscarinic and nicotinic effects.
The clinical effects and symptomatology in acute poisoning result from muscarinic and nicotinic effects. The clinical picture is similar to that of the organophosphates but may be more rapid at onset and shorter in duration. Symptoms beyond 24 hours probably do occur with large carbamate intoxication. Penetration of the blood brain barrier by carbamates is low and for this reason CNS symptoms are less frequent.
Muscarinic effects are those mediated by stimulation of the parasympathetic nervous system:
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. Stimulation of the sympathetic nervous system via the preganglionic synapse may produce sweating, hypertension and tachycardia. The accumulation of acetylcholine at the neuromuscular junction can, uncommonly, cause initial depolarisation and subsequent paralysis.
Late neurological sequelae including a peripheral neuropathy due to axonal degeneration have been recorded
Plasma cholinesterase (pseudocholinesterase) and red cell cholinesterase activities are not reliable indicators of carbamate poisoning because the carbamate-cholinesterase complex spontaneously hydrolyses in vivo within several minutes or hours. Thus, normal concentrations do not rule out intoxication. In a similar fashion to organophosphates, intoxication may also be present despite normal activity because of the wide range of normal enzyme activity and marked individual variability. If a depression of 25% or more from an individual's baseline concentration of plasma cholinesterase activity occurs that would be indicative of exposure. Samples need to be analysed immediately as in vitro hydrolysis of the carbamate-cholinesterase complex also occurs.
CXR and arterial blood gases are indicated in all poisonings. The presence of respiratory failure is a marker of severity and is most commonly due to bronchorrhoea and respiratory muscle weakness. A relatively common additional problem is hydrocarbon solvent aspiration pneumonia.
ECG should be done in moderate to severe poisonings as brady- and tachyarrhythmias may occur.
Plasma carbamate concentrations do not help in management
Difficulties in diagnosis usually arise when an unconscious or delirious patient is known to have ingested a chemical from the garden shed but the identity of the chemical is unclear.
The absence of miosis does not exclude significant carbamate poisoning. The presence of muscle fasciculation and associated weakness suggests an organophosphate more than a carbamate. The absence of significant reduction in plasma cholinesterase in the presence of a typical cholinergic syndrome suggests carbamate rather than organophosphate poisoning.
Patients with moderate or severe poisoning should be transferred to an Intensive Care facility. Asymptomatic patients who have ingested carbamate concentrate should also be considered for management in the Intensive Care Unit.
Maintenance of airway, ventilation, intravenous access, and fluids are an early priority. Mild acidosis is common in significant poisonings. Correction of serum bicarbonate to normal concentrations with sodium bicarbonate has been suggested to be clinically useful in organophosphate poisonings. Whether this is a value in carbamate poisonings is unclear.
Oral activated charcoal should be given to all patients ingesting carbamates. Patients with any history, signs, or investigation indicating severe poisoning should have elective intubation, consideration of gastric lavage, and activated charcoal, as well as the specific treatment outlined below. In addition, some carbamates have enterohepatic circulation and therefore repeated doses of activated charcoal may be of value. Specific elimination enhancement is not useful.
Atropine is used to block muscarinic effects due to excess acetylcholine. Initial treatment is to give a test dose of 1-2 mg of atropine over 10 minutes (in adults). If the patient exhibits signs of atropinisation after this test, it is likely they have had a mild poisoning. In more severe poisonings, this dose should be repeated at 5 minute intervals until the patient is atropinised.
The endpoint of atropinisation is traditionally in the absence of oropharyngeal secretions. Pupil size can only be used as an endpoint if miosis is present on admission. Patients will often require an atropine infusion to maintain atropinisation and infusions of 10-20 mg /hr or more may be required although this is very rare with carbamate poisoning.
In severe poisoning, measurement of peripheral vascular resistance may be a better measure of atropinisation as in some circumstances cholinergic features may be surprisingly minimal and hypotension/tachycardia due to circulating acetylcholine is the dominant clinical feature. Most patients with carbamate poisoning require approximately 6-12 hours of atropine treatment but should be observed for a further 24 hours after the last atropine dose.
Pralidoxime binds to organophosphates but does not bind particularly well to carbamates. In animal work, it is suggested that with carbaryl poisoning, pralidoxime may actually increase acetylcholinesterase inactivation. However, if a combination of carbamate and organophosphate poisoning has occurred pralidoxime should be given as per organophosphate poisoning section.
Seizures with carbamate poisoning are very rare but if they occur should be treated with diazepam 10-20 mg intravenously and if that is unsuccessful followed by phenobarbitone 15 mg/kg intravenously with elective intubation and ventilation (without paralysis).
Patients should be reviewed for evidence of late neurological sequelae although the evidence for this is much weaker than for organophosphates
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