Carbamate Toxicity

Etiology

Toxic exposures to carbamates can occur via dermal, inhalational, and gastrointestinal (GI) exposures. The World Health Organization (WHO) Classification of Pesticides identifies five groups based on rat oral LD50 data. Symptom severity depends on the classification of the pesticide as well as the exposure dose.

Carbamate poisoning cases are most often related to intentional oral ingestion or dermal occupational exposure. In the developing world, cases of large outbreaks from contaminated food and crops have been reported. Based on the pharmacokinetics of various carbamates encountered, rapid symptom onset secondary to dermal exposure is possible. Exposure can result from combined dermal and inhalational exposures after working in areas recently sprayed or fogged with insecticides. Pediatric cases caused by playing on a sporting field after insecticide spraying have been reported. 

Epidemiology

American Association of Poison Control Centers (AAPCC) data, collected between 2002 and 2006, showed carbamate poisonings accounted for 14,000 reported exposures and carried a case fatality rate of 10 to 20%.[2] In 2008, the United States reported 8,000 cases to the AAPCC, accounting for 14 fatalities. 

In developing areas of the world, the lack of industry control of pesticides enables local agricultural practices to freely use highly toxic pesticides, leading to the risk of severe, unintentional work exposures and toxicity after acts of self-harm. In rural Asia, carbamate and organophosphates are often used for intentional self-injurious behaviors and account for an estimated combined 200,000 fatalities per year. Modeling data estimate 1 million to 2 million cases in rural Asia per year and expect 20% to 30% of patients to develop respiratory failure secondary to carbamate and OP intentional exposures. Combined, these two classes of insecticides are calculated to require between 1 million and 2 million ventilator days every year and account for a large burden of morbidity, mortality, and medical expenses worldwide.[3]

Pathophysiology

Acetylcholinesterase (AChE) normally hydrolyzes acetylcholine to acetic acid and choline, leading to the cessation of neurotransmitter signaling. Carbamates cause reversible inhibition of the acetylcholinesterase enzyme, which is present at parasympathetic and sympathetic ganglia, parasympathetic muscarinic terminal junctions, sympathetic fibers located in sweat glands, and nicotinic receptors at the skeletal neuromuscular junction. Persistently elevated acetylcholine levels due to AChE inhibition lead to increased neurotransmitter signaling. Central nervous system symptoms from increased acetylcholine include confusion, delirium, hallucinations, tremor, and seizures. Increased acetylcholine levels in the autonomic nervous system increase sympathetic and parasympathetic activity. Classic mnemonics emphasize the parasympathetic symptoms from carbamate and OP toxicity. For example, "DUMBBELS" stands for defecation, urination, miosis, bronchospasm or bronchorrhea, emesis, lacrimation, salivation.[4]

It is important to remember that the adrenergic symptoms of tachycardia, hypertension, and mydriasis also may be present due to acetylcholine-dependent activation of nicotinic receptors in sympathetic ganglia. Cases of carbamate poisoning may have predominate parasympathetic symptoms. However, mixed autonomic presentations are common. Nicotinic receptors at the neuromuscular junction lead to muscle fasciculations similar to the effects of depolarizing neuromuscular blocker medications (i.e., succinylcholine), and severe poisonings result in flaccid paralysis. Carbamates can also produce the intermediate syndrome seen in OP poisonings but do not lead to chronic toxicity or delayed syndromes, as carbamate bonds are hydrolyzed from acetylcholine spontaneously and rarely cause symptoms after 24 to 48 hours. 

Toxicokinetics

Exposure may be chronic or acute and absorbed from the skin, lungs, conjunctiva, mucous membranes, lungs, and GI tract. Dermal absorption appears to be low with increasing absorption in cases of disruption in the skin and exposure to highly toxic carbamates. Rat data shows peak inhibition of cholinesterases by 30 minutes after oral administration.

After massive exposures, patients may become symptomatic within 5 minutes. The time to symptom onset is dependent on the exposure dose and the toxicity of the given carbamate. Highly lipophilic carbamates will redistribute into fat stores from the extracellular fluid quickly and have decreased clinical effects initially.  

Carbamates are hepatically metabolized via hydrolysis, hydroxylation, and conjugation, and 90% are renally excreted in a matter of days. Data are conflicting on CNS and cerebrospinal fluid penetration of carbamates. Adults tend to have less CNS toxicity, whereas, in pediatric exposures, CNS depression is often a predominant symptom.  Importantly, carbamates do not undergo the “aging” that occurs during the phosphorylation of organophosphates to acetylcholinesterase, and the carbamate-cholinesterase bond hydrolyzes spontaneously within hours.[5]

History and Physical

A high degree of suspicion based on historical features and the presence of a clinical toxidrome is important to detect carbamate toxicity. Patients with CNS toxicity can present with altered mental status and may be unable to provide a detailed history on presentation. Initially, treatment for carbamate and OP toxicity is going to be the same, as the manifestations of acute poisoning are similar. If additional historians are available, identification of what compounds were either intentionally ingested or were involved in the unintentional exposures by checking a Material Safety and Data Sheet may help identify to which class of insecticide the patient was exposed. This will help guide decisions for pralidoxime therapy, as discussed in later sections.

Evidence of hypersalivation, lacrimation, GI distress, bronchorrhea, and diaphoresis on examination support the diagnosis. Patients may be bradycardic or tachycardic, and their pupil exam may show miosis or mydriasis due to the mixed stimulation of the parasympathetic and sympathetic nervous systems. OP and carbamate toxicity should be considered for the differential diagnosis in patients presenting with pinpoint pupils, excessive sweating, and difficulty breathing. Chronic neuropathy may develop.[6]

Evaluation

Waiting for laboratory testing can delay potentially lifesaving treatments and are often unhelpful, as symptoms of carbamate toxicity likely will improve before the results of laboratory testing are available. Levels of butyrylcholinesterase (BuChE) and red cell acetylcholinesterase (RBC AChE) can be obtained in the evaluation of potential OP and carbamate toxicity. BuChE is produced in the liver and secreted into the blood. RBC AChE is expressed at neuronal synapses. RBC AChE levels readily return to normal in carbamate poisoning. RBC AChE levels also can be falsely low in cases with clinically severe cholinergic symptoms if the assay is not quickly obtained or if the sample is not rapidly cooled or frozen. Due to a wide variation in the mean values of BuChE activity, results are difficult to interpret without baseline values from a given patient.[7]

Treatment / Management

Decontamination [2][8][9](B3)

Due to the continued cutaneous absorption of carbamate pesticides, decontamination should take place as soon as possible. Medical providers should avoid self-contamination by wearing personal protective equipment (PPE). Neoprene or nitrile gloves provide adequate protection from cutaneous exposures, and the provider should wear full PPE with a minimum of a gown, mask, and face shield. Latex gloves do not provide adequate protection for insecticides. All clothing should be removed from the patients, and the skin should be triple-washed with water, then soap and water, and then rinsed again with water. Vomitus and diarrhea may cause cutaneous absorption in providers in cases of GI ingestions.

In massive, life-threatening ingestions, GI decontamination may be considered if (1) the patient has not had bouts of emesis, (2) the ingestion occurred within 1 hour, and (3) if the patient is protecting their airway. In this instance, nasogastric lavage can be instituted. In severe toxicity, patients may have seizures, respiratory paralysis, and coma. Airway protection should take place before GI decontamination if any of these features are present. Data is disputed regarding carbamate toxicity's adequate adsorption by activated charcoal. Some experts recommend administering 1 g/kg of single-dose activated charcoal if the patient presents within 1 hour of a massive life-threatening GI ingestion. Consultation with the poison center or regional toxicologist before GI decontamination may be a reasonable approach given the risk of aspiration of activated charcoal and the questionable benefit of this therapy.

Respiratory

Respiratory failure and hypoxemia is the primary cause of death after toxic exposure to AChE inhibitors. This is multifactorial secondary to bronchorrhea, muscular weakness with potential flaccid paralysis, and depression of CNS respiratory drive. After decontamination, initial patient assessment should be directed at ensuring adequate ventilation and oxygenation. Increased respiratory secretions may be treated with atropine via competitive inhibition of the excessive muscarinic receptor excitation. Early endotracheal intubation should be performed for patients with difficulty managing their respiratory secretions, comatose or severely depressed mental status, or significant skeletal muscle weakness. Depolarizing neuromuscular blockers such as succinylcholine should be avoided, as serum cholinesterases are inactivated by AChE inhibitors, and prolonged paralysis lasting up to several hours can occur. Instead, paralysis should be induced using nondepolarizing neuromuscular blockers such as rocuronium.  

Atropine

Atropine competitively antagonizes the increased acetylcholine levels at muscarinic receptors and decreases symptoms of lacrimation, salivation, miosis, emesis, diarrhea, diaphoresis, urinary incontinence, bronchospasm, and excessive respiratory secretions. Atropine, starting at doses of 1 to 3 milligrams intravenously (IV) in adults or 0.05 mg/kg IV in pediatric patients with a minimum dose of 0.1mg, should be administered. The dose should be doubled every five minutes if the previous dose provides an inadequate response. Previous descriptions of “atropinization" (dry skin and mucous membranes, decreased bowel sounds, tachycardia, an absence of bronchospasm, and mydriasis) did not emphasize meaningful endpoints of resuscitation and treatment should be directed towards achieving cardiorespiratory stability. An adequate dose of atropine is reached when there is attenuation of tracheobronchial secretions and decreasing bronchoconstriction accompanied by adequate blood pressure and heart rate for tissue perfusion. After a stabilizing dose of atropine is reached, treatment response is maintained by a constant infusion of atropine that is usually 10% to 20% of the bolus dose per hour. Tachycardia is not a contraindication to atropine administration in patients presenting with carbamate poisoning, as tachycardia may be secondary to hypoxia and excessive bronchopulmonary secretions. Doses over 1000mg of atropine have been recorded over 24 hours to treat severe AChE inhibitor poisonings. Atropine does not reverse the skeletal muscle weakness caused by nicotinic receptor stimulation in carbamate toxicity. Patients need to have continued monitoring for potential respiratory failure, requiring mechanical ventilation after atropine administration.  

Oxime

Pralidoxime (2-PAM) is commonly given to patients with OP toxicity early in the presentation to prevent the “aging” process as OPs irreversibly bind to AChE. Carbamates will spontaneously disassociate from AChE and recover function within 24 to 48 hours. Studies have shown potentially increased AChE inactivation if pralidoxime is administered in cases of carbaryl poisoning. However, the potential benefit from oxime therapy in aldicarb poisoning has been described. In cases of known single-agent carbamate toxicity without concern for possible concomitant OP exposure, pralidoxime therapy can be withheld. However, when faced with undifferentiated insecticide toxicity, pralidoxime can be given, as administration in carbamate toxicity is unlikely to be detrimental, and the benefit for OP intoxication is well described. 

Benzodiazepines

Benzodiazepines are used for the treatment of seizures and agitation for intubated patients after carbamate toxicity. Limited data exist evaluating the efficacy of benzodiazepines for seizures secondary to insecticide poisonings, as seizures are uncommon in large case series of carbamate and OP toxicity. Due to this lack of data, standard abortive seizure therapy with benzodiazepines is commonly instituted.

Disposition

Carbamates typically have a more benign clinical course compared to OP poisonings due to transient cholinesterase inhibition and rapid reactivation of AChE enzymatic activity. Most patients will experience complete recovery within 24 hours. Patients who have depressed levels of consciousness can have significant mortality. Patients with mild initial symptoms not requiring atropine can be safely discharged after observation. Moderate poisonings will necessitate 24 hours of observation, and patients requiring atropine should be admitted to a monitored setting for continued assessment of their respiratory status.

Differential Diagnosis

When treating a patient with cholinesterase poisoning, the differential diagnosis includes three broad categories of cholinergic toxicity: (1) cholinesterase inhibitors, (2) cholinomimetics, and (3) nicotine alkaloids. Included among cholinesterase inhibitors are insecticidal cholinesterase inhibitors such as carbamates and organophosphates and noninsecticidal cholinesterase inhibitors such as pyridostigmine physostigmine, neostigmine, and echothiophate. Of the noninsecticidal cholinesterase inhibitors, the most common etiology of toxicity is the ingestion of additional doses of pyridostigmine for the treatment of myasthenia gravis. Toxicity from cholinesterase inhibitors for the treatment of Alzheimer dementia (i.e., donepezil) is rare.

Cholinomimetic compounds either stimulate nicotinic or muscarinic receptors directly, without inhibition of AChE. Laboratory tests of BuChE and RBC AChE activity in these cases will be normal. Exposures can occur from cholinomimetic medications such as carbachol, methacholine, and pilocarpine or nonpharmacologic agents such as muscarine-containing mushrooms. Nicotinic alkaloids such as nicotine and coniine cause similar symptoms to carbamate toxicity with CNS excitation, autonomic activation, and skeletal muscle stimulation via ganglionic autonomic stimulation of the parasympathetic and sympathetic nervous systems as well as the nicotinic receptors on skeletal muscle.

Prognosis

Studies are limited for initially assessing patient morbidity and mortality. Data is often reported with combined statistics for carbamate and organophosphate exposures. Given the shorter duration of carbamate toxicity, data assessing mortality, ventilator days, and healthcare cost are likely representative of OP poisonings. One prospective trial of acutely poisoned patients with either OPs or carbamates found that a Glasgow coma score of less than 13 on presentation was indicative of a poor prognosis. Methomyl poisoning specifically is associated with a high risk of cardiac arrest at presentation.