113: Insecticides: Organic Phosphorus Compounds and Carbamates

The first potent synthetic organic phosphorus anticholinesterase, tetraethylpyrophosphate (TEPP), was synthesized by Clermont in 1854. Clermont’s report described the taste of the compound, a remarkable achievement because a few drops should be rapidly fatal.¹¹¹ In 1932, Lange and Krueger wrote of choking and blurred vision following inhalation of dimethyl and diethyl phosphorofluoridates. This account inspired Schrader in Germany to begin investigating these agents, initially as pesticides, and later for use in warfare (Chap. 132). During this research, Schrader’s group synthesized hundreds of compounds, including the popular pesticide parathion and the chemical weapons sarin, soman, and tabun. Allied scientists were also motivated during the same period by the work and independently discovered other extremely toxic compounds such as diisopropylphosphofluoridate (DFP).²¹⁴ Since that time, it is estimated that more than 50,000 organic phosphorus compounds have been synthesized and screened for pesticidal activity, with dozens being produced commercially.⁴⁰

The history of carbamates was first recorded by Westerners in the 19th century when they observed that the Calabar bean (Physostigma venenosum Balfour) was used in tribal cultural practice in West Africa.¹¹² These beans were imported to Great Britain in 1840, and in 1864 Jobst and Hesse isolated an active alkaloid component they named “physostigmine.” Vée and Leven (1865) claimed to have obtained physostigmine in crystallized form and named it eserine, from ésére, the African term for the ordeal bean. ­Physostigmine was first used medicinally to treat glaucoma in 1877.¹¹² In the 1930s, the synthesis of aliphatic esters of carbamic acid led to the development and introduction of carbamate pesticides, marketed initially as ­fungicides. In 1953, the Union Carbide Corporation developed and marketed carbaryl, the insecticide being prepared at the plant in Bhopal, India, during the catastrophic release of methyl isocyanate in 1984 (Chap. 2).^8,193

Organic phosphorus compounds (OPs) and carbamates are the two groups of cholinesterase-inhibiting pesticides that commonly produce human toxicity. Although the term organophosphate is often used in both clinical practice and in the literature to refer to all phosphorus-containing pesticides that inhibit cholinesterase, phosphates are compounds in which the P atom is surrounded by four O atoms, and there are other derivatives of phosphoric and phosphonic acids such as phosphonates that can exhibit cholinesterase inhibition. Some chemicals, such as parathion, contain thioesters, whereas others are vinyl esters. Those cholinesterase-inhibiting (anticholinesterase) insecticides that contain phosphorus will be collectively termed organic phosphorus compounds in this chapter. Those that contain the OC=ON linkage will be termed carbamates.

Anticholinesterase pesticides are broadly grouped according to their toxicity by the World Health Organization’s Classification of Pesticides into five groups: Class Ia “Extremely hazardous,” Class Ib “Highly hazardous,” Class II “Moderately hazardous,” Class III “Slightly hazardous,” and “Active ingredients unlikely to present acute hazard in normal use” (Table 113–1). This classification is based upon comparative rat oral LD₅₀ data of the active ingredient. It seems useful to distinguish very toxic OPs (such as parathion, rat oral LD₅₀ 13 mg/kg) that have killed many thousands of people from relatively safe OPs (such as temephos, rat oral LD₅₀ 8600 mg/kg) that have not been reported to cause harm. However, the rat LD₅₀ seems to be less useful to distinguish between pesticides within the same class. Here, the differential toxicity may be due to differences in response to treatment, speed of onset, or coformulants.^51,69

Globally, anticholinesterase insecticides likely kill more people each year than acute poisoning by any other chemical. An estimated 200,000 die in rural Asia where intentional self-harm is common and extremely toxic organophosphorus insecticides are widely used in agriculture and therefore available in households at times of stress.^62,99 Around 3000 to 6000 ventilators are constantly required in Asia alone to provide mechanical ventilation to poisoned patients.⁹⁹ Banning of the most toxic organic phosphorus insecticides has resulted in a 50% fall in total suicides in Sri Lanka, showing that regulation can be effective.¹⁰⁰ Severe occupational or unintentional poisoning also happens where such insecticides are used,²²⁷ but deaths are generally less common.

Anticholinesterase poisoning is less important in industrialized countries where access to toxic pesticides is much more controlled. However, when anticholinesterase poisoning does occur, patients often require intensive care with long hospital stays.^79,180 A further threat is the terrorist use of organic phosphorus insecticides, such as parathion, to poison a water supply or flour used in bread baking. Such events occur regularly in rural India^57,164 and might result in many hundreds of casualties being treated by clinicians with little experience of this potentially lethal toxic syndrome.

The case fatality for OP and carbamate poisoning will vary according to which pesticides are used in local agriculture and the health facilities available. Where fast acting, highly toxic pesticides are used in agriculture and therefore for self-harm (as in much of the rural developing world), deaths will occur before patients present to hospital. Hospital based data therefore has a falsely low case fatality, although often still high at 10% to 30%.⁶²

Before the ban of parathion in Germany, the case fatality in Munich’s toxicology intensive care unit was approximately 40%.^79,240 This was likely because the excellent ambulance services in Germany were able to get to patients early, before death, but after they had become symptomatic with this fast acting OP. Some had already aspirated or suffered hypoxic brain injury prior to arrival of the ambulance. Despite resuscitation at the scene, many of these patients died subsequently from complications of the pre-hospital events rather than from direct cholinergic effects of the OP insecticide. Few of these patients would have survived to hospital admission in the developing world.

During the 5-year period of 2002 through 2006, the American Association of Poison Control Centers (AAPCC) recorded almost 30,000 exposures to OP compounds and more than 14,000 exposures to carbamates. Although these totals are large, the number of reported exposures to both insecticides has each dropped annually since 2002, likely due in part to a phase out of their residential use during this period.²⁰¹ However, the number of fatalities reported to the AAPCC remained constant, during this time averaging about five per year. These insecticides still rank as the most lethal insecticides in use in the United States and are among the most lethal poisonings (Chap. 136).

Since the overall case fatality for OP and carbamate pesticide poisoning is on the order of 10% to 20%, the 200,000 deaths a year in rural Asia must represent 1 to 2 million poisonings. Respiratory failure is a major problem with OP and carbamate poisoning. Modeling suggests that the 20% to 30% of patients who develop respiratory failure will receive 1,147,000 to 2,294,000 days of ventilation every year.⁹⁹ This will require constant use of 3140 to 6280 ventilators worldwide solely for managing self-poisoning with pesticides.⁹⁹ These figures for acute poisoning undoubtedly omit numerous unreported and possibly unrecognized illnesses resulting from lower level environmental exposure to these chemicals.

Typically, patients present following unintentional or suicidal ingestion of anticholinesterase insecticides or after working in areas recently treated with these compounds. Children and adults can develop toxicity while playing in or inhabiting a residence recently sprayed or fogged with OP insecticides by a pesticide applicator.²⁴¹ Direct dermal contact with certain types of these insecticides may be rapidly poisonous.¹⁴⁵ Outbreaks of mass poisoning regularly occur in the developing world, and less commonly in the United States, from contamination of crops or food.^{30,41,56,57,78,181,217} Epidemics of toxicity are also reported among groups illegally importing and using the potent carbamate aldicarb.^159,175 Unfortunately, OPs and carbamates have also been used for homicide.^{26,54,184,205,220}

Organic Phosphorus Compounds

OP poisoning results in a rise in the concentration of acetylcholine (ACh) at muscarinic and nicotinic cholinergic synapses, which, in turn, leads to the syndrome of cholinergic excess. Figure 113–1 shows the basic formula for cholinesterase inhibiting OP compounds.^88,207 The “X” or “leaving group” determines many of the characteristics of the compound and provides a means of classifying OP insecticides into four main groups (Table 113–2). Group 1 compounds contain a quaternary nitrogen at the X position and are collectively termed phosphorylcholines. These chemicals were originally developed as weapons of war, are powerful cholinesterase inhibitors, and can directly stimulate cholinergic receptors, presumably because of their structural resemblance to ACh. Group 2 compounds are called fluorophosphates because they possess a fluorine molecule as the leaving group. Like group 1 compounds, these compounds are volatile and highly toxic, making them well-suited for chemical warfare. The leaving group of group 3 compounds is a cyanide molecule or a halogen other than fluorine. The most well-known agents in this group are cyanophosphates, such as the chemical weapon tabun.

The fourth group is the broadest and comprises various subgroups based on the configuration of the R₁ and R₂ groups, with the majority falling into the category of either a dimethoxy or diethoxy compound. Most of the insecticides in use today fall into this last class.⁸⁸

“Direct”-acting OP insecticides (“oxons”) inhibit acetylcholinesterase (AChE) without being metabolized in the body. However, many pesticides, such as parathion and malathion, are “indirect” inhibitors (prodrugs or “thions”) requiring partial metabolism (to paraoxon and malaoxon, respectively) within the body to become active. Desulfuration to the oxon occurs in the intestinal mucosa and liver following absorption.^131,202

The OPs bind to a hydroxyl group at the active site of the AChE enzyme. As the leaving group of the OP insecticide is split off by AChE, a stable but reversible bond results between the remaining substituted phosphate of the OP and AChE, effectively inactivating the enzyme (Figs. 113–2 and 113–3).

Although splitting of the choline-enzyme bond in normal ACh metabolism is completed within microseconds, the severing of the OP compound–enzyme bond is prolonged. The half-life of this reaction depends on the chemistry of the substituted phosphate. The in vitro half-life for spontaneous reactivation of human AChE inhibited by dimethoxy OPs is 0.7 to 0.86 hours, while that of diethoxy inhibition is 31 to 57 hours.⁸¹ Spontaneous reactivation is therefore far quicker with dimethoxy OPs.

Oximes, such as pralidoxime or obidoxime, markedly speed up the rate of reactivation.⁸¹ However, if the phosphate is allowed to remain bound to the AChE, because of late or inadequate administration of oximes, an alkyl group is non-enzymatically lost (Fig. 113–3)—a process called “aging.” Once aging has occurred, the AChE can no longer be reactivated by oximes. Again, the half-life of this reaction is determined by the substituted phosphate. The in vitro half-life of human AChE after poisoning with dimethoxy OPs is 3.7 hours, compared to 31 hours after diethoxy poisoning.⁸¹ Clinically, this means that patients who present to a hospital 4 hours after poisoning with a dimethoxy OP will already have 50% of their AChE irreversibly inhibited; after 14 hours, the patients will be completely refractive to oxime therapy. In contrast, patients poisoned by diethoxy OPs presenting within 14 hours will have very little aged AChE and should be responsive to oximes. De novo synthesis of AChE is required to replenish its supply once aging has occurred (see Diagnostic Testing section below).²⁰⁷

OPs also vary by lipid solubility,²¹ rate of activation (conversion from thion to oxon), rate of AChE inhibition,⁸¹ and relative inhibition of the plasma enzyme butyrylcholinesterase. Some OPs do not fulfill the usual dimethoxy or diethoxy classification and have one of the alkyl groups linked to the phosphate by a sulfur molecule, rather than oxygen (eg, profenofos, methamidophos). Aging seems to be particularly rapid for these OPs.^65,76

Carbamates.

Carbamate insecticides are N-methyl carbamates derived from carbamic acid (Fig. 113–4).¹⁸ Medicinal carbamate compounds include physostigmine, pyridostigmine, and neostigmine.²⁰⁷ Xenobiotics such as meprobamate and various urethanes are carbamate derivatives, but do not inhibit cholinesterase. Thiocarbamate fungicides and herbicides (eg, maneb, zineb, nabam, and mancozeb) also do not inhibit AChE and do not produce the cholinergic toxic syndrome (Chap. 112).

When exposed to carbamates, AChE undergoes carbamylation in a manner similar to phosphorylation by OPs,²³¹ allowing ACh to accumulate in synapses. Aging cannot occur, and the carbamate-AChE bond hydrolyzes spontaneously, reactivating the enzyme. As such, the duration of cholinergic symptoms in carbamate poisoning is generally less than 24 hours. However, complications that result from the cholinergic syndrome, in particular aspiration, can last much longer.

Organic Phosphorus Compounds

OP insecticides are well absorbed from the lungs, gastrointestinal tract, mucous membranes, and conjunctiva following inhalation, ingestion, or topical contact.⁸⁸ Although absorption through intact skin appears to be relatively low,⁹⁴ percutaneous exposure to highly toxic compounds can cause severe toxicity.^{43,45,145,226} The presence of broken skin and dermatitis and higher environmental temperatures further enhances cutaneous absorption.⁸⁸

Poisonings can be chronic or acute, although the differentiation has little clinical relevance. The difficulty in removing these compounds from the skin and clothing may explain some chronic poisonings; inadequate skin and respiratory protection during pesticide application is responsible for many cases of occupational exposures.

The time to peak plasma concentration after self-poisoning is unknown. Human volunteer studies, using very low doses of chlorpyrifos, found Cmax to be around 6 hours after oral ingestion.¹⁶⁰ However, patients ingesting large amounts of oxon or fast acting thion OPs can become symptomatic within minutes,^79,138 suggesting that the onset of absorption is rapid.

Most OPs are lipophilic²¹ and are therefore predicted to have a large volume of distribution and to rapidly distribute into tissue and fat where they are protected from metabolism. Radiolabeled parathion injected into mice distributes most rapidly into the cervical brown fat and salivary glands, with high concentrations also measured in the liver, kidneys, and ordinary adipose tissue.⁸⁶ Adipose tissue gradually accumulates the highest concentrations. Redistribution from these stores may allow for measurement of circulating insecticide concentrations for up to 48 days post-ingestion.^49,90,187

Cholinergic crisis may recur in patients when unmetabolized OPs are mobilized from fat stores.⁸⁸ The more lipophilic compounds such as fenthion and dichlofenthion (both with a log P {octanol/water coefficient} >4.0) are particularly likely to cause this phenomenon.^49,69,148 Dimethoate, methamidophos, and oxydemeton methyl are three common OPs that are not lipophilic (log P <1.0), with predicted small volumes of distribution and high plasma OP concentrations.⁵⁰

The distribution of OPs into fat will likely include both activated and unactivated compound. When released from the fat hours to days later, the unactivated thion will require activation to cause clinical features.

Thion OPs are activated by cytochrome P450 enzymes in the liver and intestinal mucosa. The precise CYP450s responsible appears to vary according to the concentration of OP. For example, chlorpyrifos, diazinon, parathion, and malathion are all activated by CYP1A2 and 2B6 at low concentrations.^33,34 However, at the higher concentrations more likely to occur after self-poisoning, CYP3A4 becomes dominant. The particular enzymes involved in metabolism of the active oxon to inactive metabolites are less clear.

Studies have investigated possible relationships between human plasma paraoxonase (PON) activity and susceptibility to acute and chronic effects of OP poisoning.^44,194,196 Paraoxonase is an A-esterase that can hydrolyze the active (oxon) metabolites of some OP insecticides. Activity differs significantly among animal species. Some animal models of OP poisoning demonstrate protection from toxicity when exogenous PON is administered, and greater susceptibility to poisoning when enzyme-deficient animals (such as genetically engineered knockout mice) are exposed.¹⁹⁴ Some authors have postulated that genetic polymorphisms in human PON activity may lead to variations in interindividual susceptibility to some OP insecticides.⁴⁴

Carbamates.

Carbamate insecticides are absorbed across skin and mucous membranes, and by inhalation and ingestion. Peak cholinesterase inhibition occurs within 30 minutes of oral administration in rats.¹⁶² Most carbamates undergo hydrolysis, hydroxylation, and conjugation in the liver and intestinal wall, with 90% excreted in the urine within 3 to 4 days.¹⁸

There is a view that carbamates, unlike OPs, do not easily enter the brain. However, carbamates cause CNS depression in humans,¹⁷⁵ have lipophilic log P values,²¹ and rat studies show inhibition of brain cholinesterases with multiple carbamates.¹⁶² Furthermore, post mortem studies have shown high concentrations of carbamates in CSF and brain.^109,150,151 The evidence at present therefore suggests that in this aspect they do not differ markedly from OPs. One important distinction between carbamates and OPs is that the carbamate-cholinesterase bond does not “age.” Thus AChE inhibition is reversible, with spontaneous hydrolysis occurring usually within several hours.

Acetylcholine is a neurotransmitter found at both parasympathetic and sympathetic ganglia, skeletal neuromuscular junctions, terminal junctions of all postganglionic parasympathetic nerves, post-ganglionic sympathetic fibers to most sweat glands, and at some nerve endings within the central nervous system (Fig. 113–5).²²⁸ As the axon terminal is depolarized, vesicles containing ACh fuse with the nerve terminal, releasing ACh into the synapse or neuromuscular junction (NMJ). Acetylcholine then binds postsynaptic receptors leading to activation (G proteins for muscarinic receptors and ligand-linked ion channels for the nicotinic receptors). Activation alters the flow of K⁺, Na⁺, and Ca²⁺ ionic currents on nerve cells, and alters membrane potential of the postsynaptic membrane, resulting in propagation of the action potential.

OPs and carbamates are inhibitors of carboxylic ester hydrolases within the body, including variably acetylcholinesterase (AChE, EC 3.1.1.7), butyrylcholinesterase (plasma or pseudocholinesterase, BuChE, EC 3.1.1.8), plasma and hepatic carboxylesterases (aliesterases), paraoxonases (A-esterases), chymotrypsin, and other nonspecific proteases.³⁷

AChE hydrolyzes ACh into two inert fragments: acetic acid and choline. Under normal circumstances, virtually all ACh released by the axon is hydrolyzed almost immediately, with choline undergoing reuptake into the presynaptic terminal where it is reused to synthesize ACh.²²⁸ AChE is found in human nervous tissue and skeletal muscle, and on erythrocyte (RBC) cell membranes.¹⁴³ Acutely, RBC AChE activity correlates well with the function of nervous system AChE for some OPs.^210,212 However, recent findings from profenofos poisoned humans⁷⁶ and dimethoate poisoned pigs⁷⁴ have raised questions about the validity of using AChE activity on RBCs as a marker of poisoning severity.⁸²

Butyrylcholinesterase is a hepatic derived protein that is found in human plasma, liver, heart, pancreas, and brain. Although the function of this enzyme is not well understood, its activity can be easily measured and has important clinical implications in anesthesia (Chap. 69).

Inhibition of AChE is generally thought to account for all, or the majority, of clinical features of both OP and carbamate poisoning. However, these compounds also inhibit many other enzymes.³⁷ The clinical effects of these interactions are not yet understood.

Patients also ingest formulated pesticides rather than the pure anticholinesterase compound or “active ingredient” (AI). OPs sold for agricultural use are typically emulsifiable concentrates (EC) in which the AI (eg, dimethoate) is mixed with an organic solvent such as xylene or cyclohexanone and a surfactant/emulsifier. Unfortunately, the compounds used for co-formulation are highly variable, being optimized by each pesticide manufacturer for each OP. As a result, co-formulants often differ between the same OP produced by two companies, and for two OPs produced by one company.

The clinical effect of poisoning with these co-formulants, in addition to the carbamate or OP, has not been completely evaluated and remains unclear. Complications of surfactant poisoning have been well described in glyphosate poisoning²⁸ (Chap. 112) but not with insecticides. The acute toxicity of the solvents appears to be low—for example, the rat oral LD₅₀s for xylene and cyclohexanone are 4000 to 5000 and 1620 mg/kg, respectively. However, in a minipig model of acute oral dimethoate EC40 poisoning, early respiratory arrest occurred at a point when red cell AChE was less than 30% inhibited, suggesting a non-AChE mechanism.⁷⁴ Early work showed that dimethoate toxicity could be increased markedly by changing the ­solvent^38; more recent work with chlorpyrifos has shown a modest change in toxicity after changing the solvent.²¹⁶ The minipig model has shown that the toxicity of dimethoate EC40 requires both the dimethoate AI and the cyclohexanone solvent. Changes in the solvent reduced toxicity.⁷⁴ While potentially important, the major differences in clinical syndrome noted in patients between dimethoate EC40, chlorpyrifos EC40, and fenthion EC50 cannot be attributed to the solvent since most pesticides are generic, using 40% xylene as the solvent.⁶⁹

A further effect of the solvents and surfactants occurs after aspiration. Ingestion of both OPs and carbamates can cause rapid loss of consciousness and respiratory arrest, increasing the risk of aspiration with pesticide AI, solvent, surfactant, and gastric contents. The relative role of gastric contents and pesticide is not yet clear. Aspiration pneumonitis is a major clinical problem in OP poisoning and the treatment of the pneumonitis will not be achieved by the oximes and atropine.⁶³

Pesticides are frequently co-ingested with alcohol, particularly by men,^130,219 raising questions about the effect of this alcohol on outcome after OP poisoning.⁶⁶ Analysis of a cohort of patients self-poisoned with dimethoate EC40 showed that the alcohol did not directly affect the clinical outcome of poisoning⁷¹; however, higher blood concentrations of alcohol were associated with higher blood concentrations of dimethoate, suggesting that inebriation caused people to drink larger amounts of pesticide, resulting in a worse outcome.

Acute Toxicity–Organic Phosphorus Compounds

Clinical findings of acute toxicity from OPs derive from excessive stimulation of muscarinic and nicotinic cholinergic receptors by ACh in the central and autonomic nervous systems, and at skeletal neuromuscular junctions (Fig. 113–5). The classically described patient with severe OP poisoning is one who is unresponsive, with pinpoint pupils, muscle fasciculations, diaphoresis, emesis, diarrhea, salivation, lacrimation, urinary incontinence, and an odor of garlic or solvents. Less severe poisoning is often not so typical.

The timing of onset of symptoms varies according to the route, the degree of exposure, and particularly the OP. This is important since more rapid onset of poisoning will reduce the likelihood of the patient reaching health care safely, before need for intubation and ventilation, or onset of complications such as aspiration. Onset of respiratory failure outside of a hospital in most parts of the world will result in the patient’s death.

Patients suffering massive ingestions can become symptomatic as quickly as 5 minutes following ingestion. Most patients with acute poisoning become symptomatic within a few hours of exposure, and practically all who will become ill show some features within 24 hours.

Oxon OPs (such as mevinphos and monocrotophos) are already active on exposure, and patients become symptomatic very soon after ingestion. One man was reported to have died within 15 minutes of mevinphos ingestion.¹³⁸ Some thion OPs are very rapidly converted to oxons and can similarly produce symptoms rapidly—patients ingesting parathion can be unconscious within minutes.⁷⁹ In contrast, patients ingesting thions that are slowly converted to active oxons (such as fenthion) may not show symptoms for hours.

The speed of onset will also be affected by the quantity ingested and the toxicity⁸¹ of the OP. Patients ingesting very large doses or less toxic pesticides or small doses of highly toxic pesticides will rapidly inhibit a clinically significant proportion of their AChE and exhibit features earlier.

Lipid solubility also likely affects time to onset. Fat soluble OPs (with log P of >3–4) will rapidly distribute to fat stores, in the process reducing their concentration in extracellular fluid where they impart their clinical effect (eg, fenthion⁶⁹). Significant poisoning with such OPs is commonly delayed as respiratory failure with fenthion, for example, typically occurs after 24 hours, in contrast to less fat soluble OPs.⁷³

Symptoms following OP exposure may last for variable lengths of time, again based on the compound and the circumstances of the poisoning. For example, the more lipophilic compounds, such as dichlofenthion or fenthion, can cause recurrent cholinergic effects for many days following oral ingestion as they are released from fat stores.^49,148,172

A variety of CNS findings are reported after exposure. Many patients present awake and alert, complaining of anxiety, restlessness, insomnia, headache, dizziness, blurred vision, depression, tremors, or other nonspecific symptoms.^17,158 The level of consciousness may deteriorate rapidly to confusion, lethargy, and coma, and patients may display inappropriate behavior. Where careful observational studies have been done, convulsions appear to be uncommon in OP pesticide poisoning compared to OP nerve agent poisoning.^69,122 The few convulsions that do occur may be due to hypoxia as a complication of acute cholinergic poisoning.

The effects of excessive ACh on the autonomic nervous system may be variable because cholinergic receptors are found in both the sympathetic and parasympathetic nervous systems (Fig. 113–5). Excessive muscarinic activity can be characterized by several mnemonics, including “SLUD” (salivation, lacrimation, urination, defecation) and “DUMBBELS” (defecation, urination, miosis, bronchospasm or bronchorrhea, emesis, lacrimation, salivation). Of these, miosis may be the most consistently encountered sign. Bronchorrhea can be so profuse that it mimics pulmonary edema.¹⁵⁸

Although muscarinic findings are emphasized in these mnemonics, muscarinic signs may not always be clinically dramatic or initially predominant. Parasympathetic effects can be offset by excessive autonomic activity from stimulation of nicotinic adrenal receptors (resulting in catecholamine release) and postganglionic sympathetic fibers.²⁰⁷ Mydriasis, bronchodilation, and urinary retention can occur as a result of sympathetic activity. Increased sympathetic activity usually precipitates white blood cell demargination, resulting in leukocytosis.^156,158

Excessive adrenergic influences on metabolism cause glycogenolysis²⁰⁸ with hyperglycemia and ketosis that have been mistaken for diabetic ketoacidosis.^146,238 Hypoglycemia can also occur, although the mechanism is unclear.¹¹⁴ Disturbances of glucose metabolism do not seem to be common. Two studies of patients with OP or carbamate poisoning showed hyperglycemia in 6% to 8%.^105,195 It is possible that effects on glucose metabolism may be associated with specific OPs, such as the malathion¹¹⁴ and diazinon,¹⁸⁸ rather than all OPs. Larger cohorts of patients exposed to single OPs are required to determine whether such associations exist.

Hyperamylasemia appears to be relatively common in OP poisoning, occurring in 4/47 (9%) adults in one series¹⁸⁶ and 5/17 (29%) children in a second.²²⁵ However, both included various anticholinesterase pesticides; a series of only malathion poisoned patients reported hyperamylasemia in 47/75 (63%).⁴⁶ The amylase likely comes from the pancreas since animal studies show OP-induced damage¹¹⁵ and human poisoning cases show associated pancreatic edema and, rarely, necrotizing pancreatitis.^29,103,165 The incidence of subclinical and clinical pancreatitis probably varies according to the OP ingested and perhaps the co-formulants. Elevations of hepatic enzymes can also occur following OP pesticide exposures.^161,174,239

Cardiovascular manifestations reflect mixed effects on the autonomic nervous system (including increased sympathetic tone), together with the consequences of OP-induced hypoxia and hypovolemia. Admission heart rate is usually normal, with relatively few patients expressing a tachycardia or bradycardia. Patients who have received atropine before admission may be tachycardic. The literature is filled with reports of QT prolongation and ventricular dysrhythmias.^{15,95,128,183,185} However, these reports are complicated by the fact that most patients had an ECG done before they received any atropine to counter the cholinergic syndrome or were so ill that atropine was ineffective. The first is illustrated by a description of 46 patients with OP or carbamate poisoning in which “ECG recordings [were] taken on arrival … before the start of atropine treatment.”¹⁸⁵ The reported cardiac rhythms may be confounded by the hypoxia and hypovolemia that characterize the cholinergic syndrome. In another study, 29 of the 35 patients with such dysrhythmias died.¹⁴⁰ In contrast, when more than 1000 patients poisoned with WHO Class II OPs were evaluated, serious dysrhythmias were very rare in patients adequately resuscitated with oxygen, atropine, and fluids (Eddleston, unpublished data).

Hypotension may occur because of stimulation of vascular receptors by excessive circulating Ach, severe volume loss, or myocardial dysfunction.^11,124 Severe hypotension is a particularly significant problem in poisoning with the unusually fat-insoluble OP dimethoate.^50,69 Fatal poisoning is characterized by early respiratory failure followed by hypotension that can be treated only transiently with vasopressors. Such a syndrome was not found in poisoning with fat-soluble OPs such as chlorpyrifos and fenthion.⁶⁹ The exact role of direct cardiotoxicity and peripheral vasodilation is not yet clear, or whether this syndrome occurs with other fat-insoluble OPs, such as methamidophos and oxydemeton methyl.⁵⁰ Recent studies indicate that the solvent in branded dimethoate EC40, cyclohexanone, is partially responsible for this severe hypotension.⁷⁴

Respiratory complications of OP poisoning include the direct pulmonary effects of bronchorrhea and bronchoconstriction, neuromuscular junction failure in the diaphragm and intercostal muscles, and loss of central respiratory drive.⁵³ If severe and occurring before patients reach medical care, these effects will lead to hypoxemia and respiratory arrest, the most common cause of death after OP poisoning.⁸⁸ Both bronchorrhea and bronchoconstriction respond to adequate atropine therapy. Unfortunately, neither neuromuscular junction failure nor loss of central respiratory drive respond to atropine, and patients must be intubated and ventilated until respiratory function returns.

An additional early respiratory complication is hydrocarbon aspiration that may occur after ingestion of commercially formulated pesticides. The incidence of aspiration and the consequences of aspiration—whether chemical pneumonitis, pneumonia, or acute respiratory distress syndrome—are not yet known and likely differ according to the OP and formulation ingested.

Acetylcholine stimulation of nicotinic receptors also governs skeletal muscle activity. The effects of excessive cholinergic stimulation at these sites are similar to that of a depolarizing neuromuscular blocker (succinylcholine) and initially result in fasciculations or weakness. Although this effect is often considered to be the most reliable sign of parathion toxicity,¹⁵⁸ it is the author’s clinical experience that many patients severely poisoned with other OP insecticides do not display this sign. Acute cranial nerve abnormalities are uncommon.

Severe poisoning results in paralysis.²²³ Rarely, patients may present with paralysis from nicotinic effects without any other initial signs and symptoms suggestive of OP toxicity.^84,92 Extrapyramidal effects such as rigidity and choreoathetosis occur uncommonly after severe anticholinesterase poisoning but can persist for several days after cholinergic features have resolved.^9,25,134,153

Acute Toxicity–Carbamates.

The acute effects of poisoning from carbamate insecticides appear identical to those of OP insecticides except for the relative short duration of cholinergic features due to rapid hydroxylation of the carbamate-AChE bond. Persistent cholinergic features are not reported for carbamate poisoning.

Chronic Toxicity

Illness may result from chronic exposure to excessive amounts of OP insecticides. Chronic exposure most commonly occurs in workers who have regular contact with OPs, but may also occur in individuals who have repeated contact with excessive amounts of insecticides in their living environments. Cholinergic ophthalmic preparations can lead to toxicity in this manner.¹⁴¹ Although tolerance to acute cholinergic systemic effects of OP insecticides (including death in rats) may be observed with long-term exposures,⁸⁸ persons who have such repeated contact may begin to describe symptoms after substantial lengths of time. These effects can range from vague neurological complaints, such as weakness and blurred vision, to miosis, nausea, vomiting, diarrhea, diaphoresis, and other cholinergic effects.^6,7,141,198 Butyrylcholinesterase activity is usually the most sensitive measure of exposure, and workers in contact with these chemicals should have baseline butyrylcholinesterase testing for comparison and monitoring.^88,110

Recent literature has linked Parkinson disease with chronic exposure to pesticides including OP insecticides.^58,199 Some individuals may have a possible genetic susceptibility.²⁵ Additionally, significant acute exposures to OP insecticides can lead to self-limited movement disorders resembling Parkinson disease that resolve over weeks to months (see above). Although statistics derived from some epidemiologic studies suggest the connection,^77,108 other studies have failed to find an association between OP compounds and Parkinson disease.²⁰⁶ All studies thus far have been retrospective in nature and therefore likely confounded by recall bias.

Delayed Syndromes

Neuromuscular Junction Dysfunction.

A syndrome of delayed muscle weakness without cholinergic features or fasciculations resulting in respiratory failure was first reported by Wadia in 1974 as type II paralysis²²³ and further refined by Senanayake and Karalliedde in 1987 as the intermediate syndrome.¹⁹⁰ The syndrome is defined as occurring 24 to 96 hours after acute OP poisoning, and after resolution of the cholinergic crisis.^125,190,223 Patients develop proximal muscle weakness, especially of the neck flexors, and cranial nerve palsies and progress to respiratory failure that may last for several weeks.¹²⁵ Consciousness is preserved unless complicated by hypoxia or pneumonia. The syndrome is important since apparently stable patients can suddenly develop a respiratory arrest; all patients must be evaluated for muscle weakness if deaths are to be prevented.^20,166 The first sign is often weakness of neck flexion such that patients cannot lift their head off the bed.

Although the exact pathophysiology of the syndrome is unknown, it is clearly due to dysfunction of the neuromuscular junction, with respiratory failure resulting from weakness affecting the diaphragm and intercostal muscles. Preservation of consciousness suggests that the central respiratory drive is not involved. Clinicians have proposed that overwhelming NMJ stimulation causes downregulation of the NMJ synaptic machinery.^52,190 This would require time to be repaired, even after the pesticide has been removed from the body, explaining the long duration of ventilation needed by many patients.⁷³

Cases and small case series are reported from around the world, with resulting comments that the intermediate syndrome is more common with certain OPs, such as parathion, methyl parathion, malathion, and fenthion. Unfortunately, large cohorts of poisoning with specific OPs receiving standardized treatments are rarely reported, making comparisons of incidence between OPs difficult. However, two cohorts have shown that the intermediate syndrome causing respiratory failure is more common in fenthion poisoning than chlorpyrifos, malathion, or fenitrothion poisoning.^73,222

Clinical examination remains the most reliable means of identifying the occurrence of intermediate syndrome.¹²⁵ Electromyograms will often show tetanic fade in these patients, and suggest both pre- and postsynaptic involvement.¹²⁵ Recent work has noted characteristic electrophysiological features that can be identified before onset of neurological features and respiratory paralysis.¹¹⁷ The majority of patients developing weakness in this series did not progress to respiratory failure, indicating that intermediate syndrome is a spectrum disorder.

Another study of severely poisoned patients suggested that the occurrence of intermediate syndrome strongly correlated with the initial degree of cholinergic crisis and seemed to be a continuum with the neuromuscular paralysis resulting from the early stages of poisoning.¹¹⁸ This view is supported by early work⁵² and a more recent study of dimethoate poisoning which showed that peripheral NMJ dysfunction can occur simultaneously with the cholinergic syndrome.⁷³ Patients with moderate to severe dimethoate poisoning typically require intubation for respiratory failure soon after ingestion, during the acute cholinergic syndrome. However, this is relatively short-lived, and patients recover consciousness after a few days. As the cholinergic syndrome settles and the patients regain consciousness, with recovery of the central respiratory drive, they are still unable to ventilate. Similar to patients with classical intermediate syndrome, they require ventilatory support for several weeks until their NMJ recovers function. In addition, this case series showed that the classic intermediate syndrome—respiratory failure after resolution of the cholinergic syndrome—can occur before 24 hours and after 96 hours.⁷³

These studies suggest that the original intermediate syndrome is just one important aspect of OP-induced peripheral NMJ dysfunction. It seems likely that the relative incidence and timing of the intermediate syndrome or delayed NMJ dysfunction for different OPs is determined by the rapidity and quantity of AChE inhibition. Where inhibition is intense, with fat-insoluble OPs like dimethoate that have very high plasma concentrations, NMJ dysfunction comes on early, before recovery from the cholinergic crisis. Fat-soluble OPs, such as fenthion, cause a more protracted AChE inhibition, likely explaining why fenthion-induced NMJ dysfunction and respiratory failure occur later.⁷³

Some authors have suggested that insufficient oxime therapy explains the intermediate syndrome.²² Of note, AChE inhibited by dimethoate or fenthion responds poorly to oximes, in contrast to chlorpyrifos, which responds well to oximes and has a lower incidence of intermediate syndrome.^69,73 The occurrence of NMJ dysfunction in chlorpyrifos poisoning may well be due to inadequate oxime therapy. However, adequate oxime therapy after, for example, malathion poisoning,²⁰⁰ may be irrelevant since this dimethyl OP responds poorly to oximes. Regardless, delayed NMJ dysfunction may be due to ineffective AChE reactivation, whether due to inadequate doses or to poisoning with OPs that do not respond to oxime therapy.

Recent animal studies of dimethoate poisoning may shed further light on this condition. These studies produced NMJ dysfunction and showed that it did not occur after poisoning with dimethoate active ingredient alone. However, it did occur after poisoning with the agricultural EC40 formulation that included both the dimethoate active ingredient and its solvent, cyclohexanone.⁷⁴ This raises the possibility that NMJ dysfunction is due to an interaction of solvent and active ingredient. All reported cases have occurred after poisoning with agricultural formulations of OP insecticides; further studies are required to clarify the role of solvents and the possible mechanisms of their effects.

The treatment of intermediate syndrome is supportive with airway protection and mechanical ventilation. There are no substantial data demonstrating that pralidoxime or atropine is effective in the treatment of this disorder, although patients may require these medications to control concurrent cholinergic symptoms. The weakness and paralysis commonly resolve in 5 to 18 days.^{73,106,117,118}

Organic Phosphorous Compound-Induced Delayed Neuropathy (OPIDN).

Peripheral neuropathies can occur with chronic OP pesticide exposures days to weeks following acute exposures. OPIDN results from inhibition by phosphorylation of the enzyme neuropathy target esterase (NTE, now identified as a lysophospholipase) within nervous tissue.^{36,91,119,120} This enzyme catalyzes breakdown of endoplasmic reticulum-membrane phosphatidylcholine, the major phospholipid of eukaryotic cell membranes. Neuropathic OPs cause a transient loss of NTE activity, putatively disrupting membrane phospholipid homeostasis, axonal transport, and glial-­axonal interactions.⁹¹

Such neuropathies may result from exposure to OPs that do not inhibit red blood cell cholinesterase or produce clinical cholinergic toxicity.³⁹ The more commonly implicated chemicals include triaryl phosphates, such as triorthocresyl phosphate (TOCP), and dialkyl phosphates, such as mephosfolan, mipafox, and chlorpyrifos.¹²⁰ Pathologic findings demonstrate effects primarily on large distal neurons, with axonal degeneration preceding demyelination.

Contaminated foods and beverages were responsible for epidemics of OP compound–induced delayed polyneuropathies and encephalopathy. In the 1930s, thousands of individuals in the United States became weak or paralyzed after drinking a supplement containing TOCP—an outbreak nicknamed “ginger Jake paralysis”^10,149 (Chap. 2). Contaminated cooking and mineral oils were responsible for outbreaks of delayed polyneuropathies in Vietnam and Sri Lanka.^56,189 Vague distal muscle weakness and pain are often the presenting symptoms and may progress to paralysis.⁹⁷ The administration of atropine or pralidoxime does not alter the onset and clinical course of these symptoms.²²¹ Pyramidal tract signs can appear weeks to months after acute exposures. Electromyograms and nerve conduction studies may be helpful in diagnosing this disorder by identifying the type of neuropathy (such as axonopathy, myelinopathy, or transmission neuropathy) and differentiating it from similar presentations such as Guillain-Barré syndrome.² Recovery of these patients is variable and occurs over months to years, with residual deficits common.^149,189

Delayed neuropathies are not usually associated with carbamate insecticides. One reason for this difference is presumed to be that aging of the neuropathy target esterase pesticide complex is a requirement for neuronal degeneration. Paradoxically, one study suggested that subgroups of carbamates may actually bind neuropathy target esterase and exert a protective effect against more toxic OP compounds.⁵ However, several cases of possible delayed neuropathy associated with carbamates have been reported.^59,218,237 These cases involved ingestions of carbaryl, m-tolyl methyl carbamate, and carbofuran, included both sensory and motor tracts, and tended to resolve over 3 to 9 months. EMG findings were variable.

Behavioral Toxicity

Behavioral changes may also occur after acute or chronic exposure to OP compounds.⁸⁰ Signs and symptoms include confusion, psychosis, anxiety, drowsiness, depression, fatigue, and irritability. Electroencephalographic changes may be noted and can last for weeks.⁹⁶ Single photon emission computed tomography (SPECT) scanning revealed morphologic changes in the basal ganglia of one child following poisoning.²⁷ Recent studies have shown a deficit in cognitive processing after acute OP self-poisoning that lasts for at least 6 months and is not found in matched patients who had poisoned themselves with paracetamol.^47,48 Thus far there appears to be no clear evidence for neuropsychiatric deficits resulting from subclinical exposure to OPs, although multiple small studies have suggested some effects.^80,182

Organic Phosphorus Compounds

When confronted with a patient in cholinergic crisis who presents with a history of acute exposure to an OP cholinesterase inhibitor insecticide, the diagnosis is straightforward. Although textbooks list a variety of clinical signs for the cholinergic crisis (DUMBELS, SLUD—see above), most patients with significant poisoning can be simply identified by the presence of pinpoint pupils, excessive sweat, and breathing difficulty.⁶⁷ However, when the history is unreliable or does not suggest poisoning, the physician must turn to other means to confirm the diagnosis of OP or carbamate poisoning. Treatment of an ill patient with a cholinergic syndrome should not await confirmation of diagnosis.

The most appropriate laboratory tests for confirming cholinesterase inhibition by insecticides are tests that measure (1) specific insecticides and active metabolites in biologic tissues and (2) cholinesterase activity in plasma or blood. Unfortunately, although urine and serum assays for OP compounds and their metabolites are available,³ such testing is rarely obtainable within hours. Moreover “normal” ranges and toxic concentrations are not established for most compounds. Therefore, verifying cholinesterase inhibitor poisoning currently relies on measurement of cholinesterase activity.^65,88

Cholinesterase Activity.

The two cholinesterases commonly measured are butyrylcholinesterase (BuChE, plasma cholinesterase, EC 3.1.1.8) and red cell acetylcholinesterase (AChE, EC 3.1.1.7). The former is produced by the liver and then secreted into the blood, where it metabolizes xenobiotics, including succinylcholine, pyrethroid insecticides, and cocaine. Red cell AChE is expressed from the same gene as the enzyme found in neuronal synapses. The main difference is in their mechanism of membrane attachment which is due to post-translational modification (red cell AChE is GPI-linked to the red cell while neuronal AChE forms dimers and tetramers that are attached to the postsynaptic membrane by other proteins).¹⁴³ Inhibition of either red cell AChE or BuChE only serves as markers for cholinesterase inhibitor poisoning, as inhibition of these enzymes does not contribute to signs and symptoms of poisoning. However, in some cases, red cell AChE activity seems to reflect AChE activity in the NMJ soon after poisoning.²¹²

There is tremendous interindividual and interchemical variability in the degree and duration with which the OP insecticides affect particular cholinesterases. After a significant exposure, butyrylcholinesterase activity usually falls first, followed by a decrease in red blood cell AChE activity. The sequence may be highly variable, but by the time patients present with acute symptoms, activities of both cholinesterase have usually fallen well below baseline values.¹⁵⁸ Of note, the presence of BuChE, AChE, and other esterases varies markedly between species,¹³⁵ complicating the interpretation of animal studies. Furthermore, AChE occurs at very low concentrations in human plasma; therefore, papers citing human serum acetylcholinesterase activity^13,215 are likely measuring serum BuChE.

Butyrylcholinesterase.

BuChE activity usually recovers before red blood cell AChE activity, returning to normal within a few days after a mild exposure in the absence of a repeat exposure to the inciting agent.⁴⁵ However, BuChE activity is less specific for exposure than is red cell AChE activity.⁸⁸ Low BuChE activity can be found in patients with a number of disorders, including hereditary deficiency of the enzyme, malnutrition, hepatic parenchymal disease, chronic debilitating illnesses, and iron deficiency anemia.¹²⁶

The wide normal range of BuChE activity allows for patients with high normal values to suffer significant falls in activity, yet still register near normal BuChE activity on laboratory assay.⁴⁵ Additionally, day-to-day variation in the activity of this enzyme in healthy individuals may be as high as 20%.⁸⁸

Furthermore, since BuChE inhibition varies between OPs and does not cause clinical effects, an admission value by itself is of little value in predicting outcome. An admission value can only be used to predict outcome if the ingested OP is known and its clinical usefulness has been studied specifically for this OP.⁷⁰ For example, most patients who die with chlorpyrifos poisoning have a BuChE activity of around zero on admission; however, since chlorpyrifos is a very potent BuChE inhibitor, many other chlorpyrifos poisoned patients who do not die also present with very low BuChE activities. In contrast, since dimethoate is a poor inhibitor of BuChE, the majority of patients who die from dimethoate poisoning have a BuChE activity higher than many chlorpyrifos poisoned patients who remain clinically well.⁷⁰

Red Blood Cell Acetylcholinesterase.

Red blood cell (RBC) AChE activity is thought to more accurately reflect nervous tissue AChE activity because the AChE in red blood cells is true AChE. Some authors suggest that clinical OP pesticide poisoning occurs when RBC AChE activity falls to below 50% of baseline values.¹⁵⁸ Neuromuscular dysfunction is typically associated with a value of 30% of normal or less.²¹² A major advantage of RBC AChE is that its activity can be related to blood hemoglobin (Hb) concentration, reducing variation due to varying hematocrits.²³⁴ Most people have a normal value of 600 to 700 mUnit/μmol Hb; a small study of Caucasians reported a mean of 651 with an SD of +/–18 mUnit/μmol Hb.²³⁴

After poisoning, and in the absence of oximes, RBC AChE may take many weeks to recover since erythrocytes in circulation at the time of OP exposure must be replaced. An average of 66 days may be necessary for RBC AChE activity to recover following severe inhibition (assuming no treatment with oxime), and activity may take up to 120 days to return to normal. Rat studies suggest that neuronal AChE activity may return to normal more rapidly than RBC AChE.⁹⁸ Patients have been reported with normal NMJ activity and no cholinergic features, yet still have low RBC AChE laboratory values. For this reason, in subacute poisoning with OP agents, it is difficult to accurately predict the actual time of onset or duration of exposure when only the RBC AChE activity is known.

Depressed RBC AChE activity may be the result of exposures or conditions other than OP or carbamate poisoning, for example, in pernicious anemia and during therapy with antimalarial or antidepressant medicines (Table 113–3).^127,152

Recently, patients with acute profenofos poisoning have been noted to have complete inhibition of their RBC AChE activity without any cholinergic or neuromuscular signs.⁷⁶ Similarly, in an animal model, RBC AChE activity does not always reflect clinical severity, perhaps here due to the role of co-formulated solvents.⁷⁴ It is therefore unclear at present how useful RBC AChE activity is in grading poisoning severity.⁸²

Blood samples for cholinesterase activity must be obtained in the appropriate blood tubes. Tubes containing fluoride will permanently inactivate the enzymes, yielding falsely low activities, and should never be used. Specimens for RBC AChE are usually drawn into tubes containing a chelating anticoagulant such as EDTA to prevent clot formation. BuChE does not require an anticoagulant and can be drawn into a tube without chelators or anticoagulants.

Of note, OPs and oximes in collected blood samples will continue to interact with red cell AChE; small differences in time between sampling and assay can result in marked artificial variation in results. The most accurate way to take blood for AChE activity measurement is to immediately dilute it 1:20 or 1:100 into 0.9% sodium chloride solution or water cooled to 39°F (4°C) at the bedside, before rapidly freezing the sample. This process slows down both inhibitory and reactivating reactions in the tube, allowing more uniform results.^65,234 Such rapid reactions do not occur with BuChE, and bedside dilution and cooling are therefore not required.

Protein Adducts.

Current research is attempting to find ways of detecting OP exposure many weeks after the event. New techniques using mass spectrometry aim to identify phosphorylated proteins, such as albumin or BuChE, in blood samples.^168,203

Carbamates

Carbamates inhibit neuronal AChE, RBC AChE, and BuChE. The relative ease with which spontaneous decarbamylation of AChE takes place may result in the measurement of relatively normal RBC AChE activity despite severe cholinergic symptoms if the assay is not performed within several hours of sampling.¹⁵⁹ This emphasizes the importance of cooling and freezing the blood sample within minutes of collection (see above). As with OP pesticide poisoning, the wide “normal” range of BuChE activity makes interpretation of BuChE activity difficult at times when the patient’s baseline values are unknown. Unlike OP insecticides, carbamates generally do not produce persistently depressed RBC AChE and BuChE activities.

Atropine Challenge

An atropine challenge may be helpful in diagnosing cholinergic poisoning in a patient who presents with findings suggestive of this disorder, but in whom no history is available to suggest exposure to an OP or carbamate insecticide. In such individuals, a test dose of 1 mg of atropine in adolescents or adults, or 0.05 mg/kg in children up to an adult dose, should produce classic antimuscarinic findings, in particular tachycardia, mydriasis, and dry mucous membranes. Conversely, the persistence of cholinergic signs and symptoms after an atropine challenge strongly suggests the presence of anticholinesterase poisoning.¹⁵⁸ However, some patients suffering from mild anticholinesterase poisoning may respond to this dose of atropine. Therefore, the reversal of cholinergic findings does not completely exclude poisoning by one of these compounds.

Electromyogram (EMG) Studies

Although measuring cholinesterase activity is the test most often used to estimate tissue and neuronal AChE activity, studies support the use of repetitive nerve stimulation testing as an accurate method of quantifying AChE inhibition at the neuromuscular junction.^12,23,117 Spontaneous repetitive potentials or fasciculations following single-nerve stimulation resulting from persistent ACh at nerve terminals can be a sensitive indicator of AChE inhibition at the motor endplate, and may be useful in the early diagnosis of anticholinesterase poisoning.²³ This type of evaluation may also be of benefit in early detection of rebound cholinergic crisis caused by continued insecticide absorption or redistribution from adipose, or onset of an intermediate syndrome.^12,23,117

Differential Diagnosis

The differential diagnosis for cholinergic poisoning includes three main categories (Table 113–4). The first comprises insecticides and other non-insecticidal cholinesterase inhibitors including the medicinal anticholinesterases neostigmine, pyridostigmine, physostigmine, and echothiophate iodide. The most common patients to suffer cholinergic poisoning syndrome from medicinal cholinesterase inhibitors are patients with myasthenia gravis who are given excessive doses of pyridostigmine. This entire group of xenobiotics should produce low butyrylcholinesterase and low RBC AChE activity. Newer agents used to treat Alzheimer disease, such as donepezil, may inhibit AChE, but symptomatic overdose of these agents appears rare.

The second category of compounds that produce a syndrome of cholinergic poisoning includes agents with cholinomimetic activity. These compounds directly stimulate muscarinic or nicotinic cholinergic receptors, but do not inhibit AChE. In exposed individuals, BuChE and RBC AChE activity should be normal. Cholinomimetic medications include preparations of carbachol, methacholine, pilocarpine, and bethanechol. Nonpharmaceutical agents such as muscarine-containing mushrooms can be cholinomimetic (Chap. 120). Finally, a third group of xenobiotics, the nicotine alkaloids (eg, nicotine, lobeline, and coniine) cause CNS, autonomic, and skeletal muscle symptoms similar to those occurring in OP and carbamate toxicity (Chap. 85).

Organic Phosphorus Insecticides

The primary cause of death after anticholinesterase poisoning is respiratory failure and hypoxemia. This results from muscarinic effects on the cardiovascular and pulmonary systems (bronchospasm, bronchorrhea, aspiration, bradydysrhythmias, or hypotension), nicotinic effects on skeletal muscles (weakness and paralysis), loss of central respiratory drive, and, rarely, seizures. Therefore, initial treatment for a patient exposed to OP compounds is directed at ensuring an adequate airway and ventilation, and at stabilizing cardiorespiratory function by reversing excessive muscarinic effects.^65,67 Seizures not secondary to hypoxemia are treated with standard anticonvulsants such as benzodiazepines.

Maintenance of the patient’s airway is best assured by early endotracheal intubation, and by positive pressure ventilation in patients who are comatose, have significant weakness, or who are unable to handle copious secretions that may accompany the poisoning. Only a neuromuscular blocker that is not primarily metabolized by cholinesterases should be used to induce pharmacologic paralysis if needed. The duration of action of the depolarizing agent succinylcholine and the nondepolarizing agent mivacurium, for example, will be extended in the presence of low BuChE activity, resulting in paralysis that can be prolonged for several hours.^170,191,192

Antimuscarinic Therapy.

Simultaneously, excessive muscarinic activity should be controlled since this will aid respiration and oxygenation. Atropine competitively antagonizes ACh at muscarinic receptors to reverse excessive secretions, miosis, bronchospasm, vomiting, diarrhea, diaphoresis, and urinary incontinence.^87,107,158

For adolescents and adults, intravenous doses should begin with boluses of 1 to 3 mg depending on the severity of symptoms; doses for children should start at 0.05 mg/kg up to adult doses. Although many authors state that repeat doses of 1 to 5 mg should be given every 2 to 20 minutes until “atropinization” occurs,⁶⁴ the most rapid method of obtaining control is to give doubling doses every 5 minutes if the response to the previous dose has been inadequate.^{64,65,66, and 67}

This approach, of doubling or incremental doses, was tested against a standard bolus dose approach in a randomized controlled trial.¹ Patients were randomized to receive either 2 to 5 mg of atropine (depending on severity), repeated every 10 to 15 minutes as required, or 1.8 to 3 mg of atropine (depending on severity) followed by doubling doses every 5 minutes as required. Atropine doses were continued until all clinical signs of “atropinization” (see below) were clearly evident; atropine was given as further bolus doses at increasing intervals or as a constant infusion, respectively. All patients received pralidoxime (1–2 g q8–12h). The incremental approach was associated with reaching atropinization at 24 minutes versus 152 minutes with standard bolus dosing, despite administration of similar total doses of atropine (136 mg versus 109 mg, respectively). This faster administration of atropine was likely associated with more rapid resuscitation and stabilization as shown by the improved outcome: mortality with bolus atropine was 22.5% (18/80) and with incremental atropine was 8% (6/75) (P < 0.05). Incremental dosing was also associated with less atropine toxicity, less neuromuscular failure, and less requirement for ventilation.¹

“Atropinization” is classically said to occur when patients exhibit dry skin and mucous membranes, decreased or absent bowel sounds, tachycardia, reduced secretions, no bronchospasm (in absence of other causes such as aspiration), and usually, mydriasis.⁶⁴ However, patients die from cardiorespiratory compromise, not wet skin or miosis. Therefore, cardiorespiratory parameters, not pupil size or the presence of sweating, should guide administration of atropine. Atropine dosing should aim to reverse bronchorrhoea and bronchospasm and to provide adequate blood pressure and heart rate for tissue oxygenation (for example, systolic BP >90 mmHg and heart rate >80 bpm). All can be easily and rapidly assessed.

Once atropinization occurs, it can be maintained by a constant infusion of atropine, typically initially giving 10% to 20% of the total loading dose per hour (usually maximum 2 mg/h). Regular checks for signs of under- or over-atropinization should guide the use of further boluses followed by changes in the infusion rate, or discontinuation of the infusion.⁶⁷ Continuous infusions have been used for as long as 32 days in patients severely poisoned by very fat soluble OPs that continue to redistribute from the fat and freshly inhibit AChE.⁹⁰

Many texts have previously recommended not giving atropine until oxygen has been administered due to the risk of inducing ventricular tachydysrhythmias.^4,176 If true, this would have serious implications for patients in developing nations or remote regions where oxygen is frequently unavailable and where the advice would delay administration of potentially life-saving atropine. However, the data that drove this advice is weak, being based upon just two human case reports^83,104 and one dog study.²²⁹ Overall, there is currently little evidence to support withholding atropine until after oxygen administration and clear possibilities for harm.

The presence of marked tachycardia (>120–140 beats/min in a well-hydrated patient not withdrawing from alcohol), mydriasis, absent bowel sounds, and urinary retention may indicate over-atropinization or atropine toxicity. This is unnecessary and possibly dangerous due to associated hyperthermia, confusion, and agitation.⁶⁷ Tachycardia is not, however, an absolute contraindication to atropine therapy since it can result from hypovolemia, aspiration pneumonitis, or agitation. Isolated pulmonary manifestations may respond to administration of nebulized atropine or ipratropium, and this treatment can accompany parenteral administration of these medications. However, the risk/benefit of this organ specific treatment has not yet been assessed.

Large doses of atropine may be needed to reverse the bronchospasm, bronchorrhea, and bradycardia associated with severe OP pesticide toxicity.¹⁵⁸ Some patients with mild symptoms need only 1 or 2 mg of atropine to reverse cholinergic toxicity, but the moderately poisoned adolescent or adult commonly requires total doses as large as 40 mg.^61,65 Some adults have received over 1000 mg of atropine in 24 hours (with adequate pralidoxime dosing) without demonstrating antimuscarinic effects,^61,224 and total doses as high as 11,000 mg during the course of treatment are reported.¹¹³ However, the additional benefit of such extreme doses over more modest doses is unclear. One study reported that much smaller doses of around 1 mg/h were associated with adequate control of muscarinic features after initial atropinization.²¹³

Atropine does not reverse nicotinic effects. Therefore, patients who improve after receiving atropine should ideally be closely monitored in a high dependency setting for impending respiratory failure from delayed NMJ dysfunction. Patients should be clinically examined regularly for proximal muscle weakness (in particular neck flexor weakness); once noted, tidal volume or negative inspiratory force measurements should be made at least every 6 hours to detect impending respiratory failure and allow early instigation of ventilatory support.

When antimuscarinic CNS toxicity becomes evident, yet peripheral cholinergic findings necessitate the administration of more atropine (eg, bradycardia, bronchorrhea, vomiting), glycopyrrolate can be substituted for atropine because its quaternary ammonium structure limits CNS penetration.¹⁷⁷ One randomized clinical trial compared atropine with glycopyrrolate in ICU management of OP poisoning but was too small to detect any difference between regimens.¹⁶ The initial intravenous dose of glycopyrrolate for adults and adolescents is 1 to 2 mg, repeated as needed or in children 0.025 mg/kg up to adult doses. As with atropine, much higher doses of glycopyrrolate may be required to stabilize patients with severe poisonings. Although scopolamine (hyoscine) has been used in place of atropine,^134,177 it may cause more pronounced CNS effects. If atropine supplies are exhausted during therapy, other antimuscarinic agents like diphenhydramine may be considered.

However, it is not clear that such an approach is required. In a large case series of patients treated by necessity outside of an ICU, atropinization without CNS toxicity could be safely accomplished by slowing atropine infusions whenever absent bowel sounds, confusion, or hyperthermia were detected.⁶⁷ It is therefore unclear whether glycopyrrolate or scopolamine is required for OP poisoning as long as the atropine regimen is adjusted for each patient.

Oximes

Phosphorylated AChE undergoes hydrolytic regeneration at a very slow rate. However, this process can be markedly enhanced by using an oxime such as pralidoxime chloride (2-PAM) or obidoxime (Fig. 113–3).⁸¹ Regeneration of AChE lowers ACh concentrations, improving both muscarinic and nicotinic effects. An immediate rise in RBC AChE activity, presumably paralleling a rise in neuronal AChE activity, can be seen after effective administration of oximes.^69,211

As discussed above, phosphorylated AChE becomes aged, and therefore unresponsive to oximes, at different rates according to the chemistry of the OP.⁸¹ Oximes therefore should be given early, within 3 to 4 hours of exposure, after dimethoxy OP poisoning. In contrast, they can still be highly efficacious 48 hours after diethoxy poisoning, with some effects even when given up to several days after exposure. Oximes can also be efficacious weeks after poisoning with a fat soluble OP. Therefore, some AChE may still be undergoing new inhibition for days or weeks after exposure in symptomatic patients, and such inhibition may be reversible by oximes.²³⁰ Case reports support this reasoning by noting dramatic effects in reversing paralysis, weakness, and cholinergic symptoms even after late administration of pralidoxime.^{148,149,150,151,152,153,154,155,156, and 157}

However, the clinical effectiveness of oximes in significant OP insecticide poisoning is still unclear. The first clinical experience with pralidoxime was reported in the late fifties by Namba who treated five patients with occupational parathion poisoning.¹⁵⁷ All patients responded well to around 1 g of pralidoxime IV. As expected from occupational inhalational exposure, none of the patients were very ill. Namba subsequently reported the use of much higher doses of pralidoxime, of 1 to 2 g bolus loading doses followed by 0.5 g/h, in patients with severe parathion poisoning.¹⁵⁵ He also noted that some OPs, including malathion, did not respond well to pralidoxime.¹⁵⁶ These caveats seem to have been lost subsequently, with most textbooks recommending the use of pralidoxime 1 g, followed by a second 1 g bolus after a few hours as necessary for all cases.

Extensive clinical experience of bolus pralidoxime regimens in Asia has led to widespread doubt about the efficacy of oximes.⁷⁵ Asian clinicians have traditionally used 1 g of pralidoxime every 4 to 6 hours for 1 to 3 days, producing high peaks and deep troughs in blood pralidoxime concentration. In a 1992 natural experiment, Sri Lankan doctors reported finding no difference in OP case fatality during a 6-month period when pralidoxime was not available in their hospital, compared to periods when it was available.⁵⁵ They argued that pralidoxime was of little clinical benefit, and since it was expensive, should not be routinely used for treating OP-poisoned patients. European clinician researchers responded that the doses being used in Asia were too low and that higher doses, more akin to Namba’s second regimen, were required.¹²² Two further trials from south India reported no effect¹²³ or even harm⁴² from pralidoxime therapy.

All these clinical trials aimed for a plasma oxime concentration of around 4 μg/mL; unfortunately, this target was based on a single study with a single nerve agent in cats²⁰⁴ and should not have been extrapolated to human OP pesticide poisoning in general.⁸¹ In vitro studies with human RBCs suggest that a higher concentration of around 100 μmol (∼20 μg/mL) is required for sustained reactivation,^81,211 resulting in the recommendation from a WHO group that all patients receive a loading dose of at least 30 mg/kg pralidoxime chloride, followed by at least 8 mg/kg/h.¹²¹ A subsequent randomized clinical trial from India showed that very high doses of pralidoxime iodide, a 2 g loading dose followed by 1 g/h, reduced death and length of ventilation in moderately poisoned patients who presented early and were treated in an ICU.¹⁶⁷ However, similar doses of pralidoxime chloride did not reactivate AChE in severe poisoning with dimethoate and other dimethoxy pesticides.⁶⁹

Additionally, another randomized controlled trial from Sri Lanka was unable to demonstrate a benefit from similar high doses of pralidoxime.⁶⁸ This trial compared no pralidoxime chloride with a 2 g bolus over 20 minutes followed by 0.5 g/h for up to 7 days or when atropine was no longer required, in addition to standard therapy. Although the study was stopped earlier than planned, pralidoxime was associated with an adjusted hazard ratio (HR) of 1.69 (95% confidence interval 0.88 to 3.26, p = 0.12) for death.

A subsequent Cochrane review concluded that current evidence was insufficient to indicate whether oximes are harmful or beneficial.³¹ It is possible that some of the difference between the outcomes in the two major ­trials is due to the very high level of supportive care available in India. Despite being less severely poisoned, 66% of Indian patients were intubated at baseline compared to 17% of Sri Lankan patients. This high level of supportive care is not available in rural district hospitals that see the majority of OP-poisoned patients globally.

All the clinical trials included in the Cochrane review assessed pralidoxime salts. Obidoxime⁸¹ has been used in some countries, including Germany^79,211 and Iran,¹⁴ with apparently beneficial effects. Although use of high dose obidoxime has been associated with liver injury,¹⁴ this does not seem to be the case with doses of 250 mg as a loading dose followed by 750 mg/24 h.⁸¹ The use of newer oximes such as HI-6 and HLo-7 has not yet been reported in pesticide poisoned patients. However, in vitro studies suggest that they will not be highly effective for human AChE inhibited by a range of OP pesticides.²³⁵

Currently, the exact role of oximes is unclear. However, they should be given as soon as possible after exposure to increase the chance of benefit. The difference between Indian and Sri Lankan studies indicates that high quality intensive care is probably required to reduce the risk of serious adverse effects. The duration of use is unclear; ideally, electrophysiological or clinical changes should be monitored to indicate whether oximes offer benefit to the patient.

Some effects of oximes are not well understood. Their quaternary ammonium compound structures are thought to reduce their passage across the blood–brain barrier and prevent CNS effects.²⁰⁷ However, obidoxime has been detected in CSF,⁸¹ and at least one case report describes pralidoxime-induced improvements in mental status and electroencephalograms not attributable to improved ventilation or perfusion.¹³⁹

Benzodiazepines

Animal studies demonstrate that administering benzodiazepines along with oximes in the treatment of poisoning with OP nerve agents or the insecticide dichlorvos can increase survival and decrease the incidence of seizures and neuropathy.^60,154 Diazepam can also decrease cerebral morphologic damage resulting from OP compound–related seizures.^24,144 One study suggests that diazepam may help attenuate OP-induced respiratory depression,⁶⁰ postulating that the benzodiazepines attenuate the overstimulation of central respiratory centers caused by OP insecticides. However, seizures have been uncommon in large case series of patients poisoned by OP insecticides,^69,222 and no clinical studies have yet been performed to determine whether benzodiazepines offer benefit to humans.¹⁴² In the absence of this evidence, benzodiazepines should be used to treat OP-related seizures and agitation and to aid intubation but should not be given routinely to all cases.¹⁴²

Other Treatments

These therapies affect only limited mechanisms involved in OP poisoning. Multiple additional therapies have been tested in animals, but none have been shown to be beneficial in large clinical trials, and none are used widely in clinical practice.^32,171 Future clinical trials may identify patients for whom they would be beneficial. Treatments that have been proposed include magnesium^19,163 or clonidine¹⁶⁹ to reduce presynaptic acetylcholine release, fresh frozen plasma as a source of BuChE for scavenging OP pesticides,^101,173 and sodium bicarbonate.¹⁷⁸

Decontamination

Cutaneous absorption of OP pesticides and carbamates necessitates removal of all clothing as soon as possible after resuscitation and administration of atropine and oxygen. Medical personnel should avoid self-contamination by wearing neoprene or nitrile gloves. Double-gloving with standard vinyl gloves may be protective. Skin should be triple-washed with water, soap, and water, and rinsed again with water. Although alcohol-based soaps are sometimes recommended to dissolve hydrocarbons,⁸⁵ these products can be difficult to find, and expeditious skin cleansing should be the primary goal. Cutaneous absorption can also result from contact with OP and carbamate compounds in vomitus and diarrhea if the initial exposure was by ingestion. Oily insecticides may be difficult to remove from thick or long hair, even with repeated shampooing, and shaving scalp hair may be necessary. Exposed leather clothing or products should be discarded because decontamination is very difficult once impregnation has occurred.

Military institutions are now experimenting with cholinesterase sponges for cutaneous OP decontamination.⁹³ The sponge consists of a cholinesterase enzyme covalently linked and immobilized in a polyurethane matrix. Reportedly, the sponge is effective in removing OP compounds from skin and surfaces.⁹³

In substantial, potentially life-threatening acute ingestions, if emesis has not occurred and the patient presents within one hour, evacuation of stomach contents by lavage using a nasogastric tube can be done. Because the onset of coma, seizures, and paralysis can be rapid, airway protection is necessary to perform the procedure safely. Although there are data suggesting that activated charcoal (AC) may adsorb some OP insecticides, a study of 1310 Sri Lankan patients with OP or carbamate poisoning found no benefit from the use of multiple dose AC.⁷² Thus, the present recommendation is that patients with anticholinesterase poisoning receive a single dose of 1 g/kg AC.

Health care providers must always maintain caution when coming into contact with stomach contents or other body fluids when managing these cases.¹³⁷ Bystanders have been poisoned by providing mouth-to-mouth resuscitation to a victim of an intentional ingestion of diazinon.¹²⁹ There have also been reports of nosocomial poisoning in ED staff.^35,89,197 However, in only one paper were BuChE activities tested³⁵ to support the hypothesis of nosocomial poisoning, and none showed any evidence of inhibition. Clinical experience from South Asia suggests that nosocomial poisoning with OP pesticides is unlikely as long as standard universal precautions are followed.¹⁷⁹ It is more likely that the nonspecific illnesses and anxiety reported are due to the solvents co-formulated with the pesticides.¹³⁷ An Australian consensus statement on nosocomial poisoning found little evidence that health care workers were at risk of such poisoning and noted that decontamination should not take place to the detriment of timely resuscitation and medical assessment.¹³⁷

Disposition

After atropinization, patients with cholinesterase inhibitor poisoning should be frequently observed for evidence of (1) deteriorating neurologic function and potential paralysis and (2) need for increases or reductions in atropine dosing.

RBC AChE and BuChE activities can be measured intermittently after the institution of pralidoxime therapy.^{79,81,209,230} Effective oxime therapy will normalize RBC AChE activity but usually does not affect BuChE activity. In the absence of effective oxime therapy, RBC AChE activity may be markedly depressed long after neuronal AChE activity has returned to normal. Therefore, an individual who remains asymptomatic may be discharged home with subnormal cholinesterase activity. BuChE begins to rise when no more OP is left in the body.⁶⁵ A sudden fall in BuChE activity suggests that OP is being redistributed from fat stores. The relevance of a fall in BuChE activity that is not clinically apparent is uncertain. Overall, there is little evidence at present that repeated testing of AChE or BuChE activity improves management and outcome over clinical monitoring alone. Such testing is, however, important for research assessing new interventions.

When available, electromyographic studies to detect signs of motor endplate dysfunction and early AChE inhibition may be a more sensitive method for identifying recurrent cholinergic toxicity.²³ Again, the clinical usefulness of this approach has not yet been studied.

A patient who becomes asymptomatic, not requiring pralidoxime or atropine for 1 to 2 days, may be discharged. Although recurrent cholinergic crises and/or respiratory failure can occur after several days, usually such patients have previously shown clinical signs of some form. Patients should not be allowed to go home wearing clothing that was worn when the poisoning occurred.

Carbamates

The treatment of patients with carbamate poisoning is identical to that of OP compound poisoning, with two exceptions. First, the use of oxime in monomethyl carbamate exposure is controversial, and many providers will not administer it because animal data imply that pralidoxime may increase AChE inactivation in carbaryl poisoning.^133,136 More recent reports suggest aldicarb poisoning may benefit from oxime therapy¹⁷⁵ and that the dose of pralidoxime may be important in carbaryl poisoning.¹⁴⁷ Comparative human data investigating the use of oximes in carbamate poisonings are currently lacking. Fortunately, because of the rapid hydrolysis of the carbamate-AChE complex, symptoms, including weakness and paralysis, usually resolve within 24 to 48 hours without pralidoxime therapy. However, administering pralidoxime to a poisoned patient in a cholinergic crisis is appropriate when it is not known whether the patient is suffering from OP or carbamate pesticide poisoning. If the poisoning is from a carbamate pesticide, pralidoxime therapy may not be necessary, but if used will likely not prove detrimental.

Second, significant inhibition of RBC AChE and BuChE by carbamates generally does not last for more than 1 to 2 days, assuming absorption is complete. Patients exposed to carbamates usually have normal cholinesterase activities by the time of discharge. There are no reported cases of recurrent or delayed poisonings following carbamate insecticide poisoning. Therefore, repeating cholinesterase tests after patients are asymptomatic is usually unnecessary. However, of note, complications of poisoning with carbamates—such as aspiration and hypoxic brain injury—can last many days.

• OP and carbamate insecticides kill hundreds of thousands of people each year.

• Poisoning with these pesticides is not uniform—they differ markedly in their human toxicity, pharmacokinetics, clinical syndrome, and response to therapy.

• Symptoms result from inhibition of AChE and overstimulation of muscarinic and nicotinic receptors in synapses of the autonomic and central nervous systems and at the neuromuscular junction.

• Patients with substantial poisoning present with the cholinergic crisis and show pinpoint pupils, excessive sweating and salivation, and respiratory failure due to bronchospasm, bronchorrhea, loss of central respiratory drive, and dysfunction of neuromuscular junction.

• For severe poisoning, atropine should be administered in doubling doses to attain atropinization before being continued as an infusion at a dose individualized for the patient.

• Patients may develop neuromuscular junction dysfunction that progresses to respiratory failure; such patients often require ventilatory support for weeks.

• Cholinergic features can recur many days after ingestion of very fat-soluble compounds such as fenthion due to redistribution from fat stores.

Acknowledgment

Richard F. Clark, MD, contributed to this chapter in previous editions.

References