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1300 SECTION 15: Toxicology  TREATMENT OF SYSTEMIC TOXICITY Morbidity or death from alkali injuries usually results from the com plications of direct tissue necrosis, but acid ingestions may result in additional systemic toxicity from absorption of the acid. 14 Acid-base disorders (increased anion gap or normal anion gap acidosis depending on acid ingested), hemolysis, coagulopathy, and renal failure may result. Acute lung injury (noncardiogenic pulmonary edema) may follow caustic ingestions as a complication of local or systemic effects.  NUTRITIONAL SUPPORT Nutritional support is often necessary following a severe caustic injury to the esophagus or stomach. Support can be achieved by percutaneous (usually jejunostomy) feeding, nasoenteral feeding, or total parenteral nutrition. 64,79  EXPERIMENTAL THERAPIES Animal experiments have found that drugs affecting collagen deposition, including interferon-α-2b, octreotide, β-aminopropionitrile, colchicine, N-acetylcysteine, d-penicillamine, and polaprezinc, can prevent or treat esophageal strictures after caustic ingestion. 77,80,81 Pentoxifylline, a local inflammatory and microcirculation mediator, has experimental benefit. Mitomycin C, a fibroblast proliferation inhibitor, has been used topically on strictures with some success. 82 Oral agents to coat and protect the GI tract from insult, including sucralfate, bismuth subsalicylate, and sodium polyacrylate, are beneficial in animal experiments. None of these agents have been evaluated in controlled human clinical trials, and no specific recommendation can be made regarding their use. H 2 blockers and proton pump inhibitors are often used in the treatment protocols, 64 but no evidence supports or refutes their use. COMPLICATIONS AND PROGNOSIS Short-term prognosis is worse with grade 3 GI injury, systemic com plications, and age >65 years. 47,83 Most long-term sequelae from caustic exposure are related to injuries to the GI tract. Acid ingestions may scar the pylorus and result in gastric outlet obstruction. Caustic alkali ingestions may cause esophageal strictures that may result in dysphagia, odynophagia, and malnutrition. Persistent drooling, reluctance to eat, severe oropharyngeal burns, and persistent fever correlate with the development of esophageal stricture after unintentional caustic ingestion in children. Patients with grade 3 caustic injuries to the esophagus have about a 1000-fold increased risk for squamous cell cancer of the esophagus, which can occur decades after the initial ingestion and resulting esophageal injury. 85 Because cancer can develop if a portion of the esophagus remains after reconstructive surgery for esophageal stricture, total removal of the esophagus is recommended. DISPOSITION AND FOLLOW-UP Asymptomatic patients with low-risk ingestions and no signs of drool ing, stridor, or vomiting and who tolerate food or drink may be dis charged from the ED after a period of observation. Admit all patients with symptomatic caustic ingestions. Patients with grade 1 injuries can be discharged from hospital after endoscopy, provided they can tolerate oral fluids and food. Grade 2A injuries warrant hospitalization to ensure that symptoms and injury do not progress. Grade 2B and 3 injuries are significant, require enteral or parenteral nutrition, and have an early risk for bleeding or perforation; admit these patients to an intensive care unit.

ided they can tolerate oral fluids and food. Grade 2A injuries warrant hospitalization to ensure that symptoms and injury do not progress. Grade 2B and 3 injuries are significant, require enteral or parenteral nutrition, and have an early risk for bleeding or perforation; admit these patients to an intensive care unit. 64 Contact the regional poison control center for data collection purposes and assistance with management. SPECIAL CONSIDERATIONS  LAUNDRY DETERGENT POD INGESTIONS Laundry detergent pods , also known as capsules, liquitabs, or sachets, have long been available in Europe and were introduced to the U.S. market in 2010. 87,88 Each pod contains concentrated detergent within a dissolvable plastic membrane. An individual pod may have internal chambers that contain a stain remover and brightener separate from the detergent. Exposure to the concentrated preparation in these pods is more likely to produce symptoms than exposure to traditional laundry detergent products. 89,90 Dermal or ocular exposure to the contents can produce irritation of the skin, conjunctiva, or cornea. Ingestion by young children can produce serious toxicity with profuse vomiting, respiratory distress, and neurologic depression. 91,92 The etiology of these systemic symptoms is unknown. Caustic injury to the pharynx and esophagus can produce difficulty swallowing with drooling and aspiration during recovery. Treatment is supportive with airway protection and mechanical ventilation. In severe cases, ventilation may be required for days. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Pesticides Shaun Greene Pesticides include insecticides, herbicides, and rodenticides. 1 Pesticide toxicity results from intentional, accidental, and occupational exposures. More than 150,000 pesticide poisoning deaths occur each year world wide, with insecticides accounting for the majority of the mortality. Pesticides are marketed as multiple formulations, often under shared brand names. Therefore, complex clinical syndromes can result from exposure to both active and other ingredients. Human toxicity can occur from many ingredients in proprietary formulations, including solvents and surfactants. Pesticides have class-specific toxicities, with many having both local and systemic effects. Management often includes consultation with a hazardous materials and toxins database or with a poison control center. Cornerstones of management are meticulous supportive care and early identification of exposures that may benefit from administration of an antidote. The World Health Organization classifies pesticides according to toxicity based on rodent median lethal oral and dermal exposures. However, human case-fatality rates display large variation for compounds within the same chemical and/or World Health Organization toxicity classification. 3 Toxicity classification should not be used to predict severity after human exposure. INSECTICIDES Chemical insecticides are toxic to the human nervous system, producing acute and chronic manifestations, as well as delayed sequelae after acute exposure. Six major classes of insecticides are in common use (Table 201-1 ). Other compounds used to control insects include repellents. CHAPTER TABLE 201-1 Insecticides and Repellents Insecticides Repellents Organophosphates Amitraz Carbamates N,N-diethyl-3-methylbenzamide (DEET) Organochlorines Pyrethrins/pyrethroids Neonicotinoids Nereistoxin analogs Tintinalli_Sec15_p1187-1332.indd 1300 8/2/19 8:40 PM

unds used to control insects include repellents. CHAPTER TABLE 201-1 Insecticides and Repellents Insecticides Repellents Organophosphates Amitraz Carbamates N,N-diethyl-3-methylbenzamide (DEET) Organochlorines Pyrethrins/pyrethroids Neonicotinoids Nereistoxin analogs Tintinalli_Sec15_p1187-1332.indd 1300 8/2/19 8:40 PM CHAPTER 201: Pesticides 1301 least rapid with transdermal absorption; however, dermatitis or skin excoriation may hasten this. Acetylcholine is the presynaptic neurotransmitter at nicotinic recep tors in the sympathetic ganglia and adrenal medulla. Inhibition of acetylcholinesterase at these locations results in sympathetic stimulation, producing pallor, mydriasis, tachycardia, and hypertension. In most patients, parasympathetic stimulation usually predominates, but mixed autonomic effects are common. Nicotinic stimulation at neuromuscular junctions results in muscle fasciculations, cramps, and muscle weakness. This syndrome may progress to paralysis and areflexia, making it difficult to detect seizure activity. Respiratory muscle paralysis can lead to ventilatory failure. Death is often due to respiratory failure caused by bronchorrhea and respiratory muscle weakness. Abdominal pain is common, with rare cases of pancreatitis and peritonitis. 11 The clinical course may be complicated by aspiration of gastric contents and hydrocarbon solvents within insecticide prepara tions; this causes lipoid pneumonia and contributes to respiratory failure. Myocardial ischemia can occur in the early stages of severe toxicity.12 More lipid-soluble organophosphates may not produce immediate symptoms of toxicity, but instead produce delayed sequelae. Lowgrade chronic organophosphate exposures occur among farmworkers, pesticide manufacturing plant workers, exterminators, and patients taking cholinergic ophthalmologic preparations. 13 Symptoms and signs are often less dramatic and nonspecific and occur without the cholinergic syndrome. An intermediate syndrome occurring 1 to 5 days after an organo phosphate exposure is reported in up to 40% of patients following ingestion.14 Clinical features include paralysis of neck flexor muscles, muscles innervated by the cranial nerves, proximal limb muscles, and respiratory muscles (respiratory support may be needed). Symptoms or signs of cholinergic excess are absent in this syndrome. Electromyog raphy may assist in making the diagnosis. 15 Aggressive, early antidote therapy and supportive measures may prevent or ameliorate the severity  ORGANOPHOSPHATES Commonly used organophosphates include diazinon, acephate, mala thion, parathion, and chlorpyrifos. Organophosphate and carbamate compounds are the insecticide exposures most commonly resulting in healthcare facility attendance in the United States. 4 Potency among organophosphates varies; highly potent compounds, such as parathion, are used primarily in agriculture, whereas those of intermediate potency, including coumaphos and trichlorfon, are used in animal care. Diazinon and chlorpyrifos were phased out from household use in the United States in 2000 due to neurotoxicity, particularly on the developing brains of children, but they continue to be used in many other parts of the world. The organophosphate structure can be modified into chemical agents of mass destruction (see Chapter 8, “Chemical Disasters”). Globally, organophosphate poisoning results most commonly from deliberate self-poisoning. 2,5 Accidental exposures occur in agricultural and industrial settings through use of pesticide spray applicators or spills during transport. 6 Inadvertent exposure can occur from flea-dip products in pet groomers and children and from contaminated food.

e poisoning results most commonly from deliberate self-poisoning. 2,5 Accidental exposures occur in agricultural and industrial settings through use of pesticide spray applicators or spills during transport. 6 Inadvertent exposure can occur from flea-dip products in pet groomers and children and from contaminated food. Systemic absorption of organophosphates occurs by inhalation and after mucous membrane, transdermal, transconjunctival, or GI exposure. Consultation with a poison control center or medical toxicologist can be useful to assist in patient management and to collect data for surveillance reports. When consulting, precise communication of the specific product name from the container label is essential to identify both active and inert ingredients. As noted, confusion can arise because similar brand names are used for more than one agent. Pathophysiology Organophosphate and carbamate compounds inhibit the enzyme cholinesterase. 3 Acetylcholinesterase (true or red blood cell acetylcholinesterase) is found primarily in erythrocyte membranes, nervous tissue, and skeletal muscle. Plasma cholinesterase (pseudocholinesterase or butyrylcholinesterase) is found in the serum, liver, pancreas, heart, and brain. Inhibition of cholinesterase leads to acetylcholine accumulation at nerve synapses and neuromuscular junctions, resulting in overstimulation of acetylcholine receptors. This initial overstimulation is followed by paralysis of cholinergic synaptic trans mission in the CNS, in autonomic ganglia, at parasympathetic and some sympathetic nerve endings (e.g., sweat glands), and in somatic nerves. Excess acetylcholine results in a cholinergic crisis that manifests as a central and peripheral clinical toxidrome. Organophosphate compounds bind irreversibly to acetylcholinester ase, thus inactivating the enzyme through the process of phosphoryla tion. The term aging describes the permanent, irreversible binding of the organophosphorus compound to the cholinesterase. The time to aging is highly variable among different agents and can range from minutes to a day or more. Once aging occurs, the enzymatic activity of cholinesterase is permanently destroyed, and new enzyme must be resynthesized over a period of weeks before clinical symptoms resolve and normal enzymatic function returns. Antidotes are more effective if given before aging occurs. Clinical Features Clinical presentations depend on the specific agent involved, the quantity absorbed, route of exposure, and the amount and character of additives (including solvents) in any preparation. 7,8 Organophosphate insecticide poisoning can have substantial variability in clinical course, response to treatment, and outcome. 8,9 Four clinical syndromes are described following organophosphate exposure: acute poisoning, intermediate syndrome, chronic toxicity, and organophosphateinduced delayed neuropathy.10 In acute organophosphate poisoning, most poisoned patients are symptomatic within the first 8 hours and nearly all within the first 24 hours. Organophosphate agents such as malathion are associ ated with local irritation of the skin (dermatitis) and respiratory tract (wheezing) without evidence of systemic absorption. Acute organophosphate poisoning results in CNS, muscarinic, nicotinic, and somatic motor manifestations ( Table 201-2). In mild to moderate poisoning, symptoms occur in various combinations. In severe exposures, nicotinic features may be observed first. Time to symptom onset varies according to exposure route, occurring within minutes of massive ingestion.

s in CNS, muscarinic, nicotinic, and somatic motor manifestations ( Table 201-2). In mild to moderate poisoning, symptoms occur in various combinations. In severe exposures, nicotinic features may be observed first. Time to symptom onset varies according to exposure route, occurring within minutes of massive ingestion. Symptom onset is most rapid with inhalation and TABLE 201-2 Clinical Effects of Cholinergic Excess Secondary to Organophosphorus Insecticide Poisoning Mnemonics for the Muscarinic Effects of Cholinesterase Inhibition S Salivation L Lacrimation U Urinary incontinence D Defecation G GI pain E Emesis D Defecation U Urination M Miosis B Bradycardia, bronchorrhea, bronchospasm E Emesis L Lacrimation S Salivation “Killer Bs” Bradycardia, bronchorrhea, bronchospasm Nicotinic Effects of Cholinesterase Inhibition •   Muscle fasciculations,  cramps, and weakness (including  diaphragm) •   Mydriasis, pallor •   Tachycardia, hypertension CNS Effects of Cholinesterase Inhibition •   Anxiety, restlessness, emotional lability •   Tremor, headache, dizziness •   Confusion, delirium, hallucinations •   Seizures, coma Tintinalli_Sec15_p1187-1332.indd 1301 8/2/19 8:40 PM

, and weakness (including  diaphragm) •   Mydriasis, pallor •   Tachycardia, hypertension CNS Effects of Cholinesterase Inhibition •   Anxiety, restlessness, emotional lability •   Tremor, headache, dizziness •   Confusion, delirium, hallucinations •   Seizures, coma Tintinalli_Sec15_p1187-1332.indd 1301 8/2/19 8:40 PM 1302 SECTION 15: Toxicology of this syndrome. Symptoms usually resolve within 7 days. Nerve gas poisoning has not been reported to cause the intermediate syndrome. Chronic toxicity, seen primarily in agricultural workers with daily exposure, manifests as symmetrical sensorimotor axonopathy. 16 This mixed sensorimotor syndrome may begin with leg cramps and progress to weakness and paralysis, mimicking features of the Guillain-Barré syndrome. Organophosphate-induced delayed neuropathy is characterized by cognitive dysfunction, impaired memory, mood changes, auto nomic dysfunction, peripheral neuropathy, and extrapyramidal signs. Chronic fatigue syndrome and multiple chemical sensitivity have been reported in some (predominantly female) patients after exposure to very low doses of organophosphate insecticides. 17 Children are at greater risk of toxicity when exposed, due to smaller body size and lower baseline levels of cholinesterase activity. Chemical warfare nerve agents, such as soman, sarin, tabun, and VX, are organophosphate compounds that inactivate acetylcholinesterases. They are rapid acting and extremely potent; death can occur within minutes of inhalation or dermal exposure, as was reported during the 2013 Syrian conflict. 18 Soman ages within minutes; thus, there is little time to administer antidotes. Diagnosis Diagnosis and treatment are based on history and the presence of a suggestive toxidrome; laboratory cholinesterase assays and reference laboratory testing for specific compounds take time and have limitations, and waiting for results delays administration of potentially lifesaving therapy. Diagnosis is often difficult due to a constellation of clinical findings that can be variable in both acute and chronic poisonings. Noting a characteristic hydrocarbon or garlic-like odor may assist in diagnosis. The cholinergic toxidrome may vary depending on the intoxication’s severity and the predominance of muscarinic, nicotinic, and CNS manifestations. The majority of patients severely poisoned with an organophosphorus insecticide will have altered mental status, pinpoint pupils, excessive sweating, and difficulty breathing. Plasma butyrylcholinesterase and red cell acetylcholinesterase enzyme activity are both quantifiable but serve only as markers of cholinesterase activity at the synaptic junction. Red cell acetylcholines terase is a more accurate indicator of synaptic cholinesterase inhibition, but plasma butyrylcholinesterase is easier to assay and more available. Baseline cholinesterase activity varies among individuals, and the degree of cholinesterase inhibition necessary to produce symptomatic illness is variable. In addition, there is poor standardization of normal ranges between laboratories. Plasma butyrylcholinesterase activity may be decreased by up to 50% following exposure in asymptomatic patients not requiring treat ment. Red cell acetylcholinesterase is typically reduced to 10% to 20% of normal activity in moderate poisoning and to <10% in severe cases. Plasma butyrylcholinesterase activity usually decreases first following a significant exposure and takes 28 to 42 days to normalize in cases where an oxime (e.g., pralidoxime) has not been administered. Red cell acetylcholinesterase requires regeneration of red blood cells to recover, and following a severe exposure, full activity may not be restored for up to 120 days.

ses first following a significant exposure and takes 28 to 42 days to normalize in cases where an oxime (e.g., pralidoxime) has not been administered. Red cell acetylcholinesterase requires regeneration of red blood cells to recover, and following a severe exposure, full activity may not be restored for up to 120 days. Plasma butyrylcholinesterase levels may be depressed in patients with genetic variants, chronic disease states, liver dysfunction, hypersensitivity reactions, infection, pregnancy, and low serum albumin states and by drugs ( succinylcholine, codeine, morphine), neoplasms, and malnutri tion. Red blood cell acetylcholinesterase measurements are factitiously lowered by hemoglobinopathies, pernicious anemia, oxalate-containing blood containers, and concurrent antimalarial treatment. Routine laboratory test abnormalities are nondiagnostic but may include evidence of pancreatitis, hypo- or hyperglycemia, leukocytosis, and abnormal liver function. 10 In severe cases, a chest radiograph may show pulmonary edema. Common abnormalities include torsades de pointes, ventricular tachycardia, and ventricular fibrillation. ECG changes include ST-segment changes, peaked T waves, atrioventricular block, and prolongation of the QT interval. 10 Electromyography may identify and quantify acetylcholinesterase inhibition at neuromuscular junctions. Treatment Treatment consists of airway control, intensive respiratory support, general supportive measures, decontamination, prevention of absorption, and the administration of antidotes (Table 201-3). 8,19 Death occurs in untreated patients through a combination of bronchorrhea, respiratory muscle paralysis, and CNS depression. Therefore, imme diate priorities following decontamination are airway protection, provision of ventilation, reduction of bronchorrhea via adequate atropinization, and reversal of respiratory muscle paralysis through administration of an oxime. Therapy should not be withheld pending determination of cholinesterase levels. In cases of acute cutaneous exposure, protective clothing must be worn to prevent secondary poisoning of healthcare workers. Neoprene or nitrile gloves should be used instead of latex. Patients with suspected exposure must be removed from the contaminated environment and transported to the ED, in a manner that is safe for patients and healthcare workers (e.g., no transport by helicopter). All clothes and accessories must be removed completely, placed in plastic bags, and disposed of as hazardous materials. 21 The patient should be immediately decontaminated externally with copious amounts of a mild detergent such as dishwashing liquid and water. Decontamination includes the scalp, hair, fingernails, skin, conjunctivae, and skin folds. Body fluids should be treated as contaminated. Abrasion or irritation of the skin should be avoided. Contaminated runoff water should be contained and disposed of as hazardous material. Instruments used can be decontaminated using chlorine bleach. Patients with acute exposures should be placed on oxygen, a cardiac monitor, and pulse oximeter. A 100% nonrebreather mask will opti mize oxygenation in the patient with excessive airway secretions and bronchospasm; however, atropine administration should not be delayed or withheld if oxygen is not immediately available. 22 Gentle suction will assist in clearing airway secretions resulting from hypersalivation, bronchorrhea, or emesis. Coma, seizures, respiratory failure, excessive respiratory secretions, or severe bronchospasm necessitates endotra cheal intubation. Establish an IV line with baseline blood sampling that can include determination of cholinesterase levels.

aring airway secretions resulting from hypersalivation, bronchorrhea, or emesis. Coma, seizures, respiratory failure, excessive respiratory secretions, or severe bronchospasm necessitates endotra cheal intubation. Establish an IV line with baseline blood sampling that can include determination of cholinesterase levels. A nondepolarizing TABLE 201-3 Treatment for Organophosphate Poisoning Decontamination Protective clothing must be worn to prevent secondary poisoning of healthcare workers. Handle and dispose of all clothes as hazardous waste. Wash patient with soap and water. Handle and dispose of water runoff as hazardous waste. Monitoring Cardiac monitor, pulse oximeter, 100% oxygen Gastric lavage No proven benefit Activated charcoal No proven benefit Atropine Initial bolus of 1.2–3.0 milligrams IV in an adult depending on severity of symptoms (doses in children should start at 0.05 milligram/kg IV). Double the dose of IV atropine every 5 min to achieve adequate atropinization: •  Clear  chest on auscultation •  Heart  rate >80 beats/min •  Systolic  blood pressure >80 mm Hg Follow with continuous infusion of 10%–20% per hour of the initial dose of atropine that was required to achieve adequate atropinization (typical infusion rates vary from 0.4 to 4 milligrams/h IV in adults). Adjust infusion rate to maintain adequate atropinization and avoid atropine toxicity (absent bowel sounds, hyperthermia, delirium). Pralidoxime Give as soon as possible, may even be given 24–48 h after exposure 30 milligrams/kg IV in adults (30 milligrams/kg up to 1 gram in children), mixed with normal saline and infused over 5–10 min Followed by continuous infusion: 8 milligrams/kg per hour for 24–48 h Seizures Benzodiazepines IV Tintinalli_Sec15_p1187-1332.indd 1302 8/2/19 8:40 PM

e, may even be given 24–48 h after exposure 30 milligrams/kg IV in adults (30 milligrams/kg up to 1 gram in children), mixed with normal saline and infused over 5–10 min Followed by continuous infusion: 8 milligrams/kg per hour for 24–48 h Seizures Benzodiazepines IV Tintinalli_Sec15_p1187-1332.indd 1302 8/2/19 8:40 PM CHAPTER 201: Pesticides 1303 agent should be used when neuromuscular blockade is needed. Succinylcholine is metabolized by plasma butyrylcholinesterase; therefore, prolonged paralysis may result. Hypotension is initially treated with fluid boluses of isotonic crystalloid. There is no published evidence demonstrating that gastric lavage improves outcome following organophosphate ingestion.23 Gastric lavage undertaken within 1 hour of a very large ingestion (following airway protection via endotracheal intubation) may be beneficial, but its performance should not delay timely administration of antidotal therapy. Activated charcoal is sometimes recommended because organophosphates do bind in vitro, although there is no evidence that single or multiple doses of activated charcoal improve patient outcome. 24 H emodialysis, hemofiltration, and hemoperfusion are of no proven value. Atropine is the antidote for significant organophosphate poisonings (Table 201-3). 8,25-27 As a competitive antagonist of acetylcholine at central and peripheral muscarinic receptors, atropine will reverse the effects secondary to excessive cholinergic stimulation. Pinpoint pupils, excessive sweating and secretions, and respiratory distress are triggers for treatment with atropine. In adults, an initial dose of 1.2 to 3.0 milligrams is given depending on severity of symptoms. The dose is doubled every 5 minutes until the following are achieved: chest clear on auscultation, heart rate >80 beats/min, and systolic blood pressure >80 mm Hg. Large amounts of atropine, on the order of hundreds of milligrams, may be necessary in massive ingestions. Proactive contact with the hospital pharmacy (or even other centers) may be necessary to ensure access to adequate amounts of atropine. Pupillary dilatation is not a therapeutic end point. Tachycardia is not a contraindication to the use of atropine in organophosphorus poisoning because tachycardia can occur secondary to bronchospasm or bronchorrhea with hypoxia, which can be reversed with atropine. The initial atropine should be IV when possible, but 2 to 6 milligrams IM should be considered when IV access is not possible. Normally, this initial dose of atropine should produce clinically obvious antimuscarinic symptoms; absence of anticholinergic symptoms after an initial dose is thus consistent with organophosphate poisoning. Once an effective amount of atropine has been given, an infusion of 10% to 20% per hour of the initial dose of atropine that was required to achieve adequate atropinization should be started in order to maintain an anticholiner gic state. Importantly, atropine reduces respiratory tract secretions but does not reverse muscle weakness. Respiratory support through endotracheal intubation and artificial ventilation is required in severe poisoning. Glycopyrrolate, an alternate anticholinergic agent that does not produce CNS toxicity, may be used. However, its dosing is not well defined, and there is no proven benefit compared to atropine. The need for glycopyrrolate is unclear because adequate atropinization (using atropine) without significant CNS toxicity can be achieved via monitoring for anticholinergic effects (e.g., absent bowel sounds, hyperthermia, delirium) and adjusting the atropine infusion rate as needed. Compounds called oximes are used to displace organophosphates from the active site of acetylcholinesterase, thus reactivating the enzyme.

ficant CNS toxicity can be achieved via monitoring for anticholinergic effects (e.g., absent bowel sounds, hyperthermia, delirium) and adjusting the atropine infusion rate as needed. Compounds called oximes are used to displace organophosphates from the active site of acetylcholinesterase, thus reactivating the enzyme. 8,25,28 Pralidoxime is the oxime in common use and amelio rates muscarinic, nicotinic, and CNS symptoms. Importantly, prali doxime reverses muscle paralysis if given early, before aging occurs. If possible, blood samples for acetylcholinesterase levels are obtained before administration of pralidoxime, but it is important that pralidoxime be administered as soon as possible before permanent and irreversible aging occurs. Although pralidoxime is more effective in acute than in chronic intoxications, it is recommended for use even later than 24 to 48 hours after exposure. The pralidoxime dose recommended by the World Health Organization is a 30-milligram/kg IV bolus followed by an IV infusion of 8 milligrams/kg per hour. Pralidoxime should be continued for 24 to 48 hours while monitoring acetylcholinesterase levels. Despite theoretical and experimental benefit and worldwide clinical use, current evidence is inadequate to show that oximes reduce mortality or the complication rate in acute organophos phate poisoning. 28-30 Pralidoxime is not recommended for asymp tomatic patients or for patients with known carbamate exp osures presenting with minimal symptoms. Seizures are treated with airway protection, oxygen, atropine, and benzodiazepines.8 Atropine may prevent or abort seizures (due to cholinergic overstimulation) that occur within the first few minutes of exposure. Pulmonary edema and bronchospasm are treated with oxygen, intubation, positive-pressure ventilation, atropine, and prali doxime. Succinylcholine, ester anesthetics, and β-adrenergic blockers may potentiate poisoning and should be avoided. Although there is some evidence for the benefit of magnesium sulfate and calcium channel blockers in the treatment of organophosphate poisoning, they are not yet recommended for routine clinical use.31 Disposition and Follow-Up Minimal exposures may require only decontamination and 6 to 8 hours of observation in the ED to detect delayed effects. Reexposure should be avoided because sequential exposures can result in cumulative toxicity. Patients returning to work should be limited from further exposure. Admission to the intensive care unit is necessary for significant poi sonings. Most patients respond to pralidoxime therapy with an increase in acetylcholinesterase levels within 48 hours. If there is no post-hypoxic brain damage and if the patient is treated early, symptomatic recovery occurs in 10 days. If toxins are fat soluble, the patient may be symptomatic for prolonged periods of time and may be dependent on continuous pralidoxime infusion. During this period, which may last weeks while awaiting resynthesis of new enzyme, supportive care and respiratory support may be needed. The end point of therapy is determined by the absence of signs and symptoms on withholding of pralidoxime.  CARBAMATES The carbamate insecticides—aldicarb, carbofuran, carbaryl, ethi enocarb, fenobucarb, oxamyl, methomyl, pirimicarb, propoxur, and trimethacarb—are cholinesterase inhibitors that are structurally related to the organophosphate compounds.10 These agents are primarily used as insecticides, but illegally imported rodenticides may contain aldicarb.32 Pathophysiology Carbamates can be toxic after dermal, inhalation, and GI exposure. Carbamates transiently and reversibly bind to and inhibit the cholinesterase enzyme.

related to the organophosphate compounds.10 These agents are primarily used as insecticides, but illegally imported rodenticides may contain aldicarb.32 Pathophysiology Carbamates can be toxic after dermal, inhalation, and GI exposure. Carbamates transiently and reversibly bind to and inhibit the cholinesterase enzyme. Regeneration of enzyme activity by dissociation of the carbamate–cholinesterase bond occurs within minutes to a few hours and involves rapid, spontaneous hydrolysis of the carbamate–cholinesterase bond. Therefore, aging does not occur, and as a major difference from organophosphate poisoning, in carbamate poisoning, restoration of normal function does not require generation of new enzyme. Clinical Features In adults, symptoms of acute carbamate poison ing are similar to the cholinergic syndrome observed with organo phosphate agents but are of shorter duration. Because carbamates do not effectively penetrate the CNS in adults, less central toxicity is seen, and seizures do not occur. However, in children, presentation of acute carbamate poisoning differs, with a predominance of CNS depression and nicotinic effects. Carbamates can also produce the intermediate syndrome. Diagnosis Diagnosis is based on clinical history and findings. Mea surement of acetylcholinesterase activity is generally not helpful because enzymatic activity may spontaneously return to normal 4 to 8 hours after a carbamate exposure. Treatment Initial treatment of carbamate poisoning is the same as for organophosphorus compounds. Atropine is the antidote of choice and is administered for muscarinic symptoms. Atropine is usually all that is necessary while waiting for the carbamylated acetylcholinesterase com plex to dissociate spontaneously and recover function (usually within 24 hours). Therapy is usually not needed for more than 6 to 12 hours. The use of pralidoxime in carbamate poisoning is controversial. The carbamate-binding half-life to cholinesterase is approximately 30 minutes, and irreversible binding does not occur; therefore, there is little need for pralidoxime. Human case reports and some (but not all) animal studies suggest that pralidoxime may potentiate the toxicity of carbamates such as carbaryl. 33 Pralidoxime should be avoided in known single-agent carbaryl poisonings. However, pralidoxime should be considered in mixed poisonings with an organophosphorus compound and a carbamate or if the type of insecticide is unknown. Tintinalli_Sec15_p1187-1332.indd 1303 8/2/19 8:40 PM

icity of carbamates such as carbaryl. 33 Pralidoxime should be avoided in known single-agent carbaryl poisonings. However, pralidoxime should be considered in mixed poisonings with an organophosphorus compound and a carbamate or if the type of insecticide is unknown. Tintinalli_Sec15_p1187-1332.indd 1303 8/2/19 8:40 PM 1304 SECTION 15: Toxicology Disposition and Follow-Up Because carbamate poisonings have transient cholinesterase inhibition and rapid enzyme reactivation, the clinical course tends to be more benign than seen with organophos phates. Most patients recover completely within 24 hours. However, patients with depressed levels of consciousness have a significant mortality,34 and methomyl poisoning is associated with a high risk of cardiac arrest at presentation as well as subsequent death after resuscitation. In mild poisonings, observation suffices, and the patient may be discharged with follow-up. Moderate poisonings necessitate 24 hours of observation that includes evaluation for possible concomitant exposure to (and toxicity from) inactive ingredients or vehicles such as hydrocarbons.  ORGANOCHLORINES Dichlorodiphenyltrichloroethane (DDT) is the prototype insecticide of these chlorinated hydrocarbons. Chlordane, heptachlor, dieldrin, and aldrin are compounds used for termite and roach control. Most have been restricted or banned in the United States, Europe, and many other countries because of their toxicity as well as their persistence in the environment and long half-life in the human body. Worldwide, these insecticides continue to be used. Hexachlorocyclohexane (lindane) is a general garden organochlorine insecticide that is also used in some countries to treat scabies and head lice infestations. This compound is well absorbed by ingestion and inhalation. Dermal absorption occurs, particularly if the skin is abraded or repeated applications are used. Children and the elderly can develop neurotoxicity and seizures with therapeutic use of lindane. Pathophysiology Organochlorines are central neurologic stimulants that can be toxic after dermal, inhalation, and GI exposures. Transder mal absorption is affected by the type of vehicle and the agent’s (liquid or solid) physical state. Organochlorines antagonize γ-aminobutyric acid–mediated inhibition of the central neurons, leading to hyperexcit ability with repetitive neuronal discharges following the action potential. Organochlorines are highly lipid soluble and accumulate in human tissues. Most are capable of inducing the hepatic microsomal enzyme system. Presence of organochlorines therefore reduces therapeutic efficacy of drugs that are inactivated by this system. Clinical Features Neurologic symptoms predominate in acute organochlorine intoxication. 37,38 Mild poisoning presents with diz ziness; ataxia; fatigue; malaise; headache; neurologic stimulation with hyperexcitability, irritability, and delirium; apprehension; tremulous ness; myoclonus; and facial paresthesias. More severe exposures may result in seizures, hyperthermia, coma, renal injury, and death. 37-39 Seizures may occur early, without prodromal syndromes, and are usually short lived (although status epilepticus may occur). Organochlorines are marketed dissolved in hydrocarbon solvents that, by themselves, can cause sedation, coma, and aspiration pneumonitis. Either the organo chlorines or the solvents can sensitize the myocardium to endogenous catecholamines, posing risk for cardiac dysrhythmia. Chlorfenapyr is a prodrug insecticide that is converted into the active form after absorption by the insect. Chlorfenapyr manifests biphasic neurotoxicity. 40 Initial symptoms are nonspecific and include headaches, body aches, drowsiness, and weakness.

to endogenous catecholamines, posing risk for cardiac dysrhythmia. Chlorfenapyr is a prodrug insecticide that is converted into the active form after absorption by the insect. Chlorfenapyr manifests biphasic neurotoxicity. 40 Initial symptoms are nonspecific and include headaches, body aches, drowsiness, and weakness. A latent period of apparent recovery is followed, on the seventh day after ingestion, by rapidly pro gressive paralysis leading to coma with a fatal outcome. No treatment is effective once the delayed symptoms start. Diagnosis History is important, and valuable information can be obtained from the package label regarding the product and vehicle involved. Laboratory evaluation generally is not helpful, but organochlorines can be detected in the serum and urine by specialty laboratories. Treatment Decontamination with removal of clothes and wash ing of the skin with mild detergent and water should occur following dermal exposure. Treatment includes administration of oxygen, with intubation indicated to treat hypoxia secondary to seizures, aspi ration, and res piratory failure. Benzodiazepines are indicated for seizure control. Dysrhythmia control may be indicated, but epinephrine should be avoided because both organochlorines and the associated co-ingested organic solvents can sensitize the myocardium to endog enous catecholamines. Hyperthermia is managed by external cooling. Activated charcoal and possibly gastric lavage (in large, recent ingestions) may be useful. The exchange resin cholestyramine is potentially useful for symptomatic patients exposed to chlordecone. Disposition and Follow-Up Exposed patients should be observed for 6 hours and admitted to the hospital if signs of toxicity develop or if ingestion involved a hydrocarbon.  PYRETHRINS AND PYRETHROIDS Pyrethroid use and poisonings have increased since the phaseout of organophosphate insecticides for use in human dwellings. Pyrethrins are naturally occurring active extracts derived from the chrysanthemum plant. Pyrethroids are synthetic analogs of the pyrethrins with greater potency and environmental persistence, but they are considered safer than organochlorine and organophosphate insecticides. 41 Pyrethroids are used commonly as aerosols in automated insect sprays in public areas; therefore, inhalation is the most common source of exposure. These agents are available as dusts and liquids in a hydrocarbon base. Pyrethrins are common ingredients in over-the-counter household insecticides, pediculicides, and scabicides. They are rapidly hydrolyzed by mammals and therefore pose low risk of human toxicity. Pathophysiology Toxicity results from dermal absorption, inhalation, or ingestion. Pyrethroids block the sodium channel at the neuronal cell membrane, causing repetitive neuronal discharge. 42 Additional effects include inhibition on γ-aminobutyric acid receptors, increased nicotinic cholinergic transmission, norepinephrine release, and interference with sodium–calcium exchange across cell membranes. Pyrethrin antigens are cross-antigenic with ragweed pollen, so allergic reactions are com mon after exposure. Clinical Features These compounds can cause dermal, pulmonary, GI, and neurologic illness. Allergic hypersensitivity reactions are the most common effects of pyrethrins and manifest as dermatitis, bronchospasm, rhinitis, hypersensitivity pneumonitis, or anaphylaxis .41,43 Skin contact may lead to paresthesias and burning within 30 minutes of exposure that usually dissipates within 24 hours. Systemic toxicity can occur from occupational poisonings and following large intentional ingestions.

anifest as dermatitis, bronchospasm, rhinitis, hypersensitivity pneumonitis, or anaphylaxis .41,43 Skin contact may lead to paresthesias and burning within 30 minutes of exposure that usually dissipates within 24 hours. Systemic toxicity can occur from occupational poisonings and following large intentional ingestions. Features of systemic toxicity include fatigue and lethargy, nausea and vomiting, paresthesias, hyperexcitability, tremors, muscle fasciculations, pulmonary edema, respiratory failure, and seizures. Diagnosis Diagnosis is dependent on a history of exposure. Differen tial diagnosis includes allergic reactions and ingestions with neurologic stimulants. Laboratory tests have no diagnostic value. Treatment Treatment includes removal from exposure; dermal, ocu lar, and GI decontamination; treatment of allergic manifestations; and supportive care. Disposition and Follow-Up Disposition is usually related to the severity of asthmatic and allergic manifestations. The clinical course is usually benign, and hospitalization is not necessary for most accidental exposures.  NEONICOTINOIDS Neonicotinoids are structurally similar to nicotine, acting as agonists at the postsynaptic acetylcholine receptor. Neonicotinoids have high affinity for insect CNS nicotinic acetylcholine receptors, producing paralysis and death. Commercially available agents from this family include imidacloprid, thiamethoxam, clothianidin, acetamiprid, thiacloprid, dinotefuran, and nitenpyram. Data regarding human toxicity are limited to case reports. Toxicity from imidacloprid poisoning is relatively mild to moderate in most cases, with symptoms of nausea, emesis, diarrhea, and headache. However, uncommon cases of respiratory failure, encephalopathy, hypoten sion, rhabdomyolysis, and renal failure have occurred. 45,46 Toxicity from acetamiprid poisoning has been associated with severe nausea and vomiting, muscle weakness, hypothermia, convulsions, and hyp othermia.47 Treatment is supportive. Tintinalli_Sec15_p1187-1332.indd 1304 8/2/19 8:40 PM

lure, encephalopathy, hypoten sion, rhabdomyolysis, and renal failure have occurred. 45,46 Toxicity from acetamiprid poisoning has been associated with severe nausea and vomiting, muscle weakness, hypothermia, convulsions, and hyp othermia.47 Treatment is supportive. Tintinalli_Sec15_p1187-1332.indd 1304 8/2/19 8:40 PM CHAPTER 201: Pesticides 1305  NEREISTOXIN ANALOGS Analogs of nereistoxin are considered low-toxicity insecticides and include bensultap, cartap, thiocyclam, and thiosultap. These insecticides induce neurotoxicity by promoting extracellular calcium influx and stimulating the release of intracellular calcium from the sarcoplasmic reticulum. Occupational skin exposure can produce nausea, vomiting, muscle tremors, dyspnea, and mydriasis. Intentional ingestions are associated with depressed level of consciousness, muscle fasciculations and spasms, seizures, hypotension, hypoxia, and death. 48-50 Animal studies suggest that sulfhydryl-containing compounds including l-cysteine, acetylcysteine, d-penicillamine, and dimercaprol, may be effective antidotes, but human data are lacking. Treatment is supportive.  AMITRAZ Amitraz is an insect repellent, topical insecticide, and acaricide used as a spray on agricultural crops and as a wash solution to treat ectoparasites found on domesticated animals. Amitraz possesses agonist activity at the postsynaptic α 2-adrenergic receptor, interacts with the neuromodulator octopamine, inhibits monoamine oxidase, and impairs prostaglandin synthesis. The clinical manifestations following human overdose include mental status depression, bradycardia, respiratory depression, miosis, hypotension, and hypothermia. 51,52 Mechanical ventilation may be required, but with supportive therapy, recovery is expected.  N,N-DIETHYL-3-METHYLBENZAMIDE (DEET) DEET is used extensively as an over-the-counter insect repellent, formulated within products at concentrations from 5% to 100%. When used as directed, these products are generally safe. Toxicity can occur with ingestion or prolonged exposure on covered or damaged skin. DEET is a neurotoxin that causes seizures after large ingestions or extensive dermal exposures of high-concentration products. Small children are most susceptible to systemic toxicity from skin absorption. Dermal absorption occurs within 2 hours of topical application, but peak concentrations may be delayed several hours. Systemic toxicity is rare but manifests as restlessness, insomnia, altered behavior, confusion, neurologic depression, slurred speech, ataxia, tremors, muscle cramps, hypertonia, and seizures occurring with or without prodrome. Hypotension and bradycardia have been reported with large dermal or oral exposures. Treatment includes benzodiaz epines for seizures, skin decontamination with mild detergent and water, and activated charcoal for recent ingestions. Most patients recover with supportive care. HERBICIDES Herbicides are used to kill weeds. Mechanisms of toxicity to plants include inhibition of photosynthesis, respiration, protein synthesis, or growth stimulation (by mimicking plant hormones called auxins). Some classes pose a health hazard to humans ( Table 201-4). Herbicidal formulations contain multiple ingredients such as organic solvents, surfactants, and preservatives that may have their own toxic effects; these may not always be disclosed on the product label.  CHLOROPHENOXY HERBICIDES Chlorophenoxy herbicides are synthetic plant hormones that disrupt transport of nutrients and growth, leading to plant death. 53 The most commonly used compounds are 2,4-dichlorophenoxyacetic acid and 4-chloro-2-methylphenoxy-acetic acid. 2,4,5-Trichlorophenoxy acetic acid has been banned throughout much of the world because of its contamination with 2,3,7,8,-tetrachlorodibenzo-p-dioxin.

nsport of nutrients and growth, leading to plant death. 53 The most commonly used compounds are 2,4-dichlorophenoxyacetic acid and 4-chloro-2-methylphenoxy-acetic acid. 2,4,5-Trichlorophenoxy acetic acid has been banned throughout much of the world because of its contamination with 2,3,7,8,-tetrachlorodibenzo-p-dioxin. These compounds are effective against broadleaf plants and are used as weed killers on lawns and grain crops. Pathophysiology Mechanisms leading to human toxicity following chlorophenoxy herbicide exposure include cell membrane damage, disruption of neuronal transport mechanisms, formation of false neu rotransmitters acting at muscarinic and nicotinic receptors, and uncoupling of mitochondrial oxidative phosphorylation. 53 Oral absorption of chlorophenoxy herbicides is rapid. Dermal and inhalational absorption is poor and rarely results in systemic toxicity. Clinical Features Local exposure leads to eye and mucous membrane irritation that may last for days. After ingestion, nausea, vomiting, and diarrhea occur. Pulmonary complications may include dyspnea, hemoptysis, and pulmonary edema. Cardiovascular findings include hypotension, tachycardia, and dysrhythmias. Mental status changes and seizures may occur. Muscle toxicity manifests as muscle tenderness, fasciculations, myotonia, and rhabdomyolysis. Metabolic acidosis and hyperthermia may occur secondary to uncoupling of oxidative phosphorylation; hypercapnia and ventilatory failure can follow. Peripheral neuropathy and myopathy have been described in the recovery phase after acute and chronic exposure. Diagnosis Diagnosis is based on a history of exposure. Ancillary tests generally are nonspecific but may demonstrate a metabolic acidosis, rhabdomyolysis, or evidence of hepatorenal dysfunction. Toxin levels are not immediately available. Treatment Treatment is supportive and includes decontamination measures, respiratory support for myopathic-related respiratory failure, and maintenance of adequate urine output for rhabdomyolysis. 53,54 Although urinary alkalinization will increase the elimination of these compounds and is recommended for severely poisoned patients, it should be used with caution in cases of hyperthermia since bicarbonate administration will increase carbon dioxide production. 54,55 Hemodialysis can also be used to enhance chlorophenoxy herbicide clearance. Disposition and Follow-Up Severe toxicity and serious complica tions are not common following exposure to chlorophenoxy herbicides. Because toxic effects usually appear within 4 to 6 hours, patients with mild symptoms can be observed and discharged after that time.  BIPYRIDYL HERBICIDES The bipyridyl compounds, paraquat and diquat , are nonselective contact herbicides. Both are used widely and are responsible for significant morbidity if ingested. 57 Paraquat is a fast-acting, nonselective herbicide. It is used for killing grass and weeds and is manufactured as a liquid, granules, or as an aerosol. Paraquat is commonly combined with diquat and other herbicides. Most products contain a blue dye, a stenchant, and an emetic. Ingestion is responsible for the majority of paraquat deaths, although deaths have been reported after transdermal exposure. Inhalation of and exposures to sprays can be very irritating to conjunctivae and the airway but are unlikely to cause systemic toxicity. Diquat poisoning is less commonly reported than paraquat poisoning, but clinical features of toxicity are similar. Management of diquat toxicity is considered the same as for paraquat. Pathophysiology Paraquat is a severe local irritant and devastating systemic toxin.57 There is minimal transdermal absorption of paraquat in the absence of preexisting skin lesions. Ingested paraquat is absorbed rapidly, particularly if the stomach is empty.

nt of diquat toxicity is considered the same as for paraquat. Pathophysiology Paraquat is a severe local irritant and devastating systemic toxin.57 There is minimal transdermal absorption of paraquat in the absence of preexisting skin lesions. Ingested paraquat is absorbed rapidly, particularly if the stomach is empty. Plasma concentration peaks within minutes to 2 hours after ingestion. Paraquat is then distributed to most organs, with the highest concentrations found in the kidneys and lungs. A lethal oral dose of the 20% concentrate solution is about 10 to 20 mL in an adult and 4 to 5 mL in a child. Paraquat actively accumulates in the alveolar cells of the lungs, where it is transformed into a reactive oxygen species, the superoxide radical. This anion is responsible for lipid peroxidation that leads to degradation TABLE 201-4 Selected Herbicide Classes That Pose Potential Harm to Humans •  Chlorophenoxy  compounds •  Bipyridyls:  paraquat and diquat •  Urea  substituted herbicides •  Organophosphates •  Glyphosate Tintinalli_Sec15_p1187-1332.indd 1305 8/2/19 8:40 PM

is responsible for lipid peroxidation that leads to degradation TABLE 201-4 Selected Herbicide Classes That Pose Potential Harm to Humans •  Chlorophenoxy  compounds •  Bipyridyls:  paraquat and diquat •  Urea  substituted herbicides •  Organophosphates •  Glyphosate Tintinalli_Sec15_p1187-1332.indd 1305 8/2/19 8:40 PM 1306 SECTION 15: Toxicology of cell membranes, cell dysfunction, and necrosis. Lung injury has two phases. An initial destructive phase is characterized by loss of type I and type II alveolar cells, infiltration by inflammatory cells, and hemorrhage. These changes may be reversible. The later, proliferative phase is char acterized by fibrosis in the interstitium and alveolar spaces. Paraquat and oxygen enhance each other’s toxicity by sustaining the redox cycle. Myocardial injury and necrosis of the adrenal glands may occur. Diquat’s structure and action mechanism are similar to those of paraquat. Formulations containing diquat do not contain the dye, stenching agent, or emetic usually added to paraquat. The lethal dose for diquat is similar to that of paraquat, but there is less occurrence of pulmonary injury and fibrosis because of diquat’s lower affinity for pulmonary tissue. Diquat is caustic to the skin and GI tract, and exposure can result in renal and liver necrosis. Clinical Features Clinical features depend on both the amount and route of exposure. Paraquat’s severe caustic effects produce local skin irritation and ulceration of epithelial surfaces. Severe corrosive corneal injury may result from eye exposure. Upper respiratory tract exposure may result in mucosal injury and epistaxis. Inhalation may lead to cough, dyspnea, chest pain, pulmonary edema, epistaxis, and hemoptysis. Respiratory symptoms may persist for several weeks after inhalation exposure. Ingestion causes GI irritation and mucosal damage with ulcerations (Table 201-5). A burning sensation of the lips or mouth may occur within a few minutes to hours, followed by ulceration 1 to 2 days later. Nausea, vomiting, diarrhea, buccopharyngeal pain, esophageal pain, and abdominal pain may develop. Hypovolemia occurs from GI fluid losses and decreased oral intake. Multisystem effects include GI tract corrosion, acute renal failure, cardiac failure, hepatic failure, and extensive pulmonary injury. The effects can be evident within a few hours following large ingestions, but more typically, manifestations of renal failure and hepatocellular necrosis develop between the second and fifth days; progressive pulmonary fibrosis leading to refractory hypoxemia occurs 5 days to several weeks after exposure. Metabolic (lactic) acidosis is common as a result of pul monary effects (e.g., hypoxemia) combined with multisystem failure. Diagnosis Early diagnosis, prognostication, and subsequent therapy are important. Obtain details of the exposure, including its timing, route, accidental or intentional nature, and amount and concentration of the product. The quantity of paraquat ingested is directly related to outcome. Age over 50 years and a history of renal disease are associated with worse prognosis. 58,59 A sensation of generalized skin burning is associated with increased risk of death.60 Laboratory abnormalities generally reflect the consequences of vomiting, diarrhea, and multiorgan failure. Acute kidney injury is common and is associated with increased mortality. Creatinine increase is driven by paraquat-induced oxidative stress as well as acute kidney injury; thus, it is not an accurate marker of glomerular filtration rate in the setting of paraquat toxicity. An increase in creatinine of <0.034 milligram/dL (3 micromole/L) per hour over 5 hours is associated with recovery.

ty. Creatinine increase is driven by paraquat-induced oxidative stress as well as acute kidney injury; thus, it is not an accurate marker of glomerular filtration rate in the setting of paraquat toxicity. An increase in creatinine of <0.034 milligram/dL (3 micromole/L) per hour over 5 hours is associated with recovery. An increase in creatinine of >0.049 milligram/dL (4.3 micromole/L) per hour over 6 hours or an increase in serum cystatin C concentration of >0.009 milligram/L over 6 hours is associated with death. Serum lactate may aid with prognosis. 62 Two retrospective studies assessed lactate levels associated with death. One identified a lactate of >3.35 mmol/L (30 mg/dL) as having 74% sensitivity for mortality, whereas the other found an 82% sensitivity for death associated with a lactate level exceeding 4.4 mmol/L (40 mg/dL). 63,64 Radiographic abnormalities of diffuse pulmonary infiltrates may indicate aspiration or direct paraquat-induced parenchymal injury. Radiographic extent of pulmonary involvement is related to outcome. Chest radiographs may also show pneumomediastinum or pneumothorax due to corrosive rupture of the esophagus; these findings are associated with increased mortality risk. A urinary dithionite test can be performed to detect paraquat within a few hours after ingestion and has some prognostic value; a clear test color between 6 and 24 hours after paraquat exposure favors survival. The test is semiquantitative; patients with a darker blue color change have a worse prognosis. 66,67 A commercially available semiqualitative colorimetric test (Paraquat Test Kit® ; Syngenta CTL, Surrey, United Kingdom) is available for detecting paraquat in urine or plasma. Quantitative analyses for paraquat in blood can assist in the diagnosis.57 Nomograms are used for predicting survival based on plasma paraquat concentration and time of ingestion, but require availability of specific analytical methods that may not always be available. 65 A predictive nomogram based on plasma concentration has not been developed for diquat poisoning. Consult with gastroenterology about the need for endoscopy to identify the extent and severity of mucosal lesions. Treatment The goal of early and vigorous decontamination is to prevent absorption and thus reduce pulmonary toxicity. Any exposure to paraquat is a medical emergency, with hospitalization indicated even if the patient is asymptomatic. Commencement of treatment should never be delayed to wait for the results of diagnostic testing. The outcome for patients with evidence of severe poisoning is extremely poor, despite best available treatments instituted in advanced critical care settings. In some cases, the most humane approach will be to pro vide analgesia and supportive care, rather than invasive interventions. Early treatment is mainly supportive but is an important determinant of survival. Do not administer supplemental oxygen unless the patient is severely hypoxic because added oxygen stimulates superoxide radical formation and promotes oxidative stress. Remove clothing and decontaminate skin with mild detergent and water. Take care to avoid skin abrasions that may increase absorption. If there is conjunctival irritation, irrigate with copious amounts of water or saline. Replace fluid and electrolytic losses and maintain intravas cular volume and urine output. Treat pain with opioids. Gastric lavage is contraindicated due to the high likelihood of paraquat-induced cor rosive injury. Consult with GI for consideration of potential esophageal corrosive injury and need for endoscopy.57 In patients presenting within 2 hours of ingestion, GI decontamina tion with absorbents that bind paraquat should be undertaken as a matter of urgency, either via oral ingestion or via a nasogastric tube.

rosive injury. Consult with GI for consideration of potential esophageal corrosive injury and need for endoscopy.57 In patients presenting within 2 hours of ingestion, GI decontamina tion with absorbents that bind paraquat should be undertaken as a matter of urgency, either via oral ingestion or via a nasogastric tube. A single dose of activated charcoal (1 to 2 grams/kg), diatomaceous fuller’s earth (1 to 2 grams/kg in 15% aqueous suspension), or bentonite (1 to 2 grams/kg in a 7% aqueous slurry) should be used. TABLE 201-5 Paraquat Toxicity From Ingestion Category Clinical Features Approximate Amount Ingested Mild Asymptomatic or nausea, vomiting, and diarrhea. Renal and hepatic injury minimal or absent. Decreased pulmonary diffusion capacity may be present. Complete recovery expected. <20 milligrams/kg or <7.5 mL of 20% concentrated solution in average adult Severe Initially nausea, vomiting, diarrhea, abdominal pain, and mouth and throat ulceration. Positive colorimetric test for paraquat in the urine. 1–4 d: renal failure, hepatic impairment, hypotension. 1–2 wk: cough, hemoptysis, pleural effusion, pulmonary fibrosis. Survival possible, but majority of cases die within 2–3 wk from pulmonary failure. Between 20 and 40 milligrams/kg or between 7.5 and 15 mL of 20% concentrated solution in average adult Fulminant Initially nausea, vomiting, diarrhea, and abdominal pain. Rapid development of renal and hepatic failure, GI ulceration, pancreatitis, toxic myocarditis, refractory hypotension, coma, convulsions. Death from cardiogenic shock and multiorgan failure within 1–4 d. >40–50 milligrams/kg or >15–20 mL of 20% concentrated solution in average adult Tintinalli_Sec15_p1187-1332.indd 1306 8/2/19 8:40 PM

of renal and hepatic failure, GI ulceration, pancreatitis, toxic myocarditis, refractory hypotension, coma, convulsions. Death from cardiogenic shock and multiorgan failure within 1–4 d. >40–50 milligrams/kg or >15–20 mL of 20% concentrated solution in average adult Tintinalli_Sec15_p1187-1332.indd 1306 8/2/19 8:40 PM CHAPTER 201: Pesticides 1307 Hemoperfusion can remove paraquat and has been recommended to be started as soon as possible. Limited evidence suggests a possible survival benefit when hemoperfusion is commenced within 4 hours of paraquat exposure. 68,69 If hemoperfusion is not available, then other extracorporeal elimination therapies including intermittent hemodi alysis may be beneficial. 70-72 Although continuous venovenous hemo dialysis removes paraquat, it is unlikely to provide rapid reductions in paraquat concentrations and therefore should not be used if other therapies are available. Continuous venovenous hemodialysis may be used as a therapy in the event of acute kidney injury. Small methodologically limited studies suggested a benefit from repeated pulse doses of glucocorticoids and cyclophosphamide, but a large randomized controlled trial demonstrated no benefit. 73,74 Dexamethasone may be beneficial and should be administered at a dose of 8 milligrams IV every 8 hours for the first 72 hours. 75 Dexamethasone has relatively low toxicity and, in severe poisoning, may provide benefit if continued for weeks following exposure when there is the possibility of progression of pulmonary injury. Acetylcysteine may provide benefit and is of low toxicity. It should be administered continuously while there is evidence of acute toxicity in the inpatient setting. Serial pulmonary function tests, chest radiographs, renal function tests, and blood gas determinations may be used to monitor progression of toxicity.62 Treatment for diquat poisoning is similar to that for paraquat. Despite the lower toxicity for diquat, mortality approaches 50% after intentional diquat ingestion. Disposition and Follow-Up All patients should be observed for at least 12 hours following exposure. Clinically well patients with a negative urine dithionite test at this time are unlikely to develop toxicity. Patients with evidence of severe toxicity and prognostic markers indicating a fatal outcome should receive appropriate supportive and palliative care. Patients with clinical toxicity and an unclear prognosis are admit ted to a critical care environment.  UREA-SUBSTITUTED HERBICIDES Urea-substituted herbicides such as chlorimuron, diuron, fluome turon, and isoproturon are inhibitors of photosynthesis and have low systemic toxicity. In humans, methemoglobinuria may occur with ingestion. 77 Treatment includes decontamination, supportive care, and as-needed treatment for methemoglobinemia (with methylene blue) (see Chapter 207, “Dyshemoglobinemias”).  ORGANOPHOSPHATE HERBICIDES In addition to their use as insecticides, some organophosphate com pounds are effective herbicides. Butiphos is used commonly as a cotton defoliant applied prior to mechanical harvesting. Treatment is identical to that for organophosphate insecticides.  GLYPHOSATE Glyphosate is the active ingredient in many widely used preparations available for consumer use on lawns and gardens. Some lawn and garden products sold using a common or group brand name may contain different active ingredients; a common brand name may contain either glyphosate or the more toxic herbicide diquat. Glyphosate can produce severe toxicity with massive ingestions of the diluted product or smaller-volume ingestions of solutions that are con centrated (>10%).78 Ingestion of >150 mL of a 36% glyphosate solution is associated with severe multiorgan toxicity.

contain either glyphosate or the more toxic herbicide diquat. Glyphosate can produce severe toxicity with massive ingestions of the diluted product or smaller-volume ingestions of solutions that are con centrated (>10%).78 Ingestion of >150 mL of a 36% glyphosate solution is associated with severe multiorgan toxicity. Preparations may contain the toxic surfactant polyoxyethyleneamine, which is a corrosive, and the combination is more toxic than glyphosate alone. Inhalational exposures cause respiratory irritation. Dermal absorption is poor, so symptomatic poisonings are generally from ingestion. Clinical effects include mucous membrane irritation and erosions with nausea, vomiting, abdominal pain, and diarrhea. 79 Severe toxicity is characterized by airway burns, GI corrosive injury, metabolic acidosis, acute kidney injury, hyperkalemia, coma, refractory cardiovascular col lapse, and potentially death. Early airway evaluation is important in order to detect burns and edema. Airway protection may be required via endotracheal intubation. Treatment is primarily supportive. Along with oxygenation and ventilation, priorities include supporting circulation, treating hyperkalemia, and ameliorating complications due to corrosive GI effects. Hemodialysis may be supportive when severe acidosis and acute kidney injury are present. Patients with small, asymptomatic ingestions can be discharged after 6 hours of observation. Significant GI symptoms, altered level of consciousness, hypoxemia, metabolic acidosis, and cardiovascular abnormalities indicate admission to an intensive care unit. RODENTICIDES A number of agents with distinct toxicities are used as rodenticides. Rodenticides are commonly classified based on whether they are anticoagulants or nonanticoagulants. Although intentional ingestions are often associated with significant morbidity and mortality, most unintentional exposures occur in young children and result in minimal or no toxicity.  NONANTICOAGULANTS A number of nonanticoagulant rodenticides have been used throughout history. Many have been discontinued, although poisonings still occur from old products stored in garages, barns, and homes (Table 201-6).  ANTICOAGULANTS Warfarin-type anticoagulants were the first generation of anticoagulant rodenticides and distributed commonly disguised as yellow corn meal or rolled oats. 87 Most one-time warfarin rodenticide ingestions are insignificant accidental poisonings and do not cause any bleeding problems. Significant coagulopathy requires large amounts in a single exposure or a repetitive exposure over several days. Following a single large ingestion, onset of the anticoagulant effect takes place within 12 to 48 hours. Warfarin’s biologic half-life is approximately 42 hours. Therapy is not necessary for ingestion of a single mouthful of a warfarin rodenticide. For potentially toxic recent ingestion, consider activated charcoal. Obtain a baseline prothrombin time and INR determination and repeat it in 12 to 24 hours. Vitamin K 1 (phytonadione) administration is indicated if the INR is >2.0. The suggested total PO daily dose is 1 to 5 milligrams in children and 20 milligrams in adults, adminis tered in two to four divided doses. Second-generation superwarfarins and the indandione derivatives were introduced when rodent resistance to warfarin began to appear. They are currently responsible for approximately 80% of human rodenticide exposures reported in the United States. Their mechanisms are the same as that of warfarin, but they are more potent, have more prolonged anticoagulant activity, and therefore have the potential to be highly toxic.

ce to warfarin began to appear. They are currently responsible for approximately 80% of human rodenticide exposures reported in the United States. Their mechanisms are the same as that of warfarin, but they are more potent, have more prolonged anticoagulant activity, and therefore have the potential to be highly toxic. Poisonings involving the indandione derivatives pin done, diphacinone, chlorophacinone, and valone have toxic and clinical characteristics similar to those of the superwarfarins. The superwarfarins include the 4-hydroxy-coumarins brodifacoum, difenacoum, coumafuryl, and bromadiolone. These are readily available over the counter as grain-based bait. After intentional ingestions, adults often develop a coagulopathy within 24 to 48 hours. Because the biologic half-life of brodifacoum is approximately 120 days, a single ingestion may result in marked anticoagulation effects for weeks to months. 88 Intentional repeated ingestions can cause severe bleeding. The diagnosis may not be readily apparent. Some patients may not report an intentional ingestion. Small children and depressed patients with an unexplained coagulopathy or bleeding should raise suspicion of superwarfarin poisoning. Although the prothrombin time and INR are usually monitored, large doses of warfarin can also cause prolongation of the activated partial thromboplastin time. Superwarfarins are not detected by warfarin assays, but specific serum assays are available in reference laboratories. Unintentional superwarfarin ingestions in the pediatric patient are unlikely to result in significant toxicity. 89 Obtain a baseline INR and repeat 24 and 48 hours after ingestion. For acute intentional ingestions, gastric lavage is indicated for early presentations, and activated charcoal should be administered. Obtain a baseline INR and repeat in 12 and 24 hours. If the INR is elevated but there is no active hemorrhage, oral Tintinalli_Sec15_p1187-1332.indd 1307 8/2/19 8:40 PM

after ingestion. For acute intentional ingestions, gastric lavage is indicated for early presentations, and activated charcoal should be administered. Obtain a baseline INR and repeat in 12 and 24 hours. If the INR is elevated but there is no active hemorrhage, oral Tintinalli_Sec15_p1187-1332.indd 1307 8/2/19 8:40 PM 1308 SECTION 15: Toxicology vitamin K1 is recommended. Forms of vitamin K other than vitamin K 1 are ineffective because the conversion of these other forms to the active form is blocked by superwarfarins. Because of the extended half-life of the anticoagulant, prolonged therapy with high doses of vitamin K may be required to maintain hemostasis. 90,91 Initial daily doses of 1 to 5 milligrams in children and 20 milligrams in adults are recommended with titration to maintain a normal INR. Doses up to 100 milligrams per day for 10 months have been reported. Upon discontinuation of vitamin K1 therapy, serial INR determinations are required to ensure that further therapy is not needed. Patients with acute hemorrhage may require repletion of volume losses with normal saline or blood transfusions. Vitamin K 1, 10 milligrams, should be administered by slow IV infusion to minimize the risk of a hypotensive reaction. Replacement of coagulation factors should be TABLE 201-6 Selected Non-anticoagulant Rodenticides Rodenticide Toxicity Mechanism Clinical Effects Treatment Arsenic Severe Binds sulfhydryl groups on proteins Dysphagia, muscle cramps, nausea and vomiting, bloody diarrhea, dysrhythmias (QT prolongation), cardiovascular collapse, altered mental status, seizures, and late peripheral neuropathies. Activated charcoal in conjunction with airway protection, supportive care, chelation therapy using succimer, and dimercaprol. Barium carbonate and other soluble forms such as barium chlorides, hydroxides, and sulfides Severe Inhibits potassium channels, leading to hypokalemia. Acts as depolarizing neuromuscular blocker. Onset occurs within 1–8 h with nausea, vomiting, diarrhea, abdominal pain, dysrhythmias, respiratory failure, muscular weakness, paresthesias, and paralysis. Gastric lavage with sodium or magnesium sulfate added to lavage solution to convert carbonate to less toxic sulfate; potassium replacement. Elemental or yellow phosphorus Severe, early cardiac and neurologic toxicity is a poor prognostic sign. Caustic. Possible mitochondrial toxin. Skin irritation, cutaneous burns, oral burns, abdominal pain, hematemesis, possible “ smoking” luminescent vomitus and stool, garlicky odor, direct toxic effects on the myocardium, kidney, and peripheral vessels, cardiovascular collapse; late neurologic depression with multisystem toxicity and hepatorenal syndrome. Supportive care, cardiac monitoring, correction of electrolyte abnormalities. Maintenance of serum glucose concentration may reduce cellular injury. Sodium fluoroacetate (SFA)81 Severe Blocks Krebs cycle Nausea, vomiting, apprehension, lactic acidosis, seizures, coma, respiratory depression, cardiac dysrhythmias, and pulmonary edema; ECG abnormalities include ST-segment and T-wave changes, tachycardia, premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation; hyperkalemia and hypocalcemia are common. Activated charcoal, seizure and dysrhythmia control, and supportive care; experimental regimens include glycerol monoacetate, calcium gluconate, sodium succinate, and ethanol loading; consultation with a toxicologist is recommended. Strychnine Severe Competitive antagonism of the inhibitory neurotransmitter glycine at the postsynaptic brainstem and spinal cord motor neuron Restlessness, muscle twitching, painful extensor spasms, opisthotonos, trismus, inability to swallow, and facial grimacing; medullary paralysis and death can follow.

ecommended. Strychnine Severe Competitive antagonism of the inhibitory neurotransmitter glycine at the postsynaptic brainstem and spinal cord motor neuron Restlessness, muscle twitching, painful extensor spasms, opisthotonos, trismus, inability to swallow, and facial grimacing; medullary paralysis and death can follow. Airway control, quiet environment (minimize sensory stimulation), and activated charcoal; avoid lavage (may precipitate seizures); benzodiazepines, barbiturates, analgesia; neuromuscular blockage if necessary. Tetramine 82 Severe Blocks γ-aminobutyric acid receptors in the CNS Rapidly acting; initial features include headache, nausea, dizziness, fatigue, anorexia, numbness, and listlessness; severe symptoms include loss of consciousness, seizures, and coma; death is usually caused by respiratory failure. The median lethal dose for tetramine is ∼0.1 milligram/kg; 6–12 milligrams sufficient to kill an adult; no antidote; supportive care; benzodiazepines or barbiturates for seizures. Thallium sulfate 83 Severe Combines with mitochondrial sulfhydryl groups, interfering with oxidative phosphorylation Early GI symptoms: nausea, vomiting, and abdominal pain; after 2–5 d, painful paresthesias, myalgias, muscle weakness, headache, lethargy, tremors, ataxia, delirium, seizures, and coma; death from respiratory failure and dysrhythmias; alopecia after approximately 2 wk; chronic neurologic sequelae. Supportive care; multiple doses of activated charcoal or Prussian blue (potassium ferric hexaniacinate) to interrupt enterohepatic circulation and increase elimination in stool; hemodialysis. Zinc or aluminium phosphide 84,85 Severe Combines with water and stomach acid to produce phosphine gas; cellular toxicity and necrosis to the GI tract, kidney, and liver if ingested and to the lungs if inhaled Immediate nausea, vomiting, epigastric pain, phosphorous or fishy breath, black vomitus, and GI irritation or ulceration; myocardial toxicity, shock, and acute lung injury; agitation, coma, seizures, hepatorenal injury, metabolic acidosis, hypocalcemia, tetany. Treat acidosis and hypocalcemia; consider acetylcysteine86; supportive care. Cholecalciferol (vitamin D3) Moderate Mobilization of calcium from bones Hypercalcemia, osteomalacia, and systemic metastatic calcifications. Treat hypercalcemia with IV normal saline, furosemide, steroids, calcitonin, and biphosphates as needed. Red squill Low (limited toxicity in humans due to early onset of emesis with gastric emptying) Blocks sodium-potassium adenosine triphosphatase (similar to digoxin poisoning) Nausea, protracted vomiting, diarrhea, abdominal pain; massive ingestion causes hyperkalemia, atrioventricular block, ventricular irritability with dysrhythmias, and death. Treat as digoxin toxicity (atropine, external pacing, digoxin-specific antibody fragments, activated charcoal). Tintinalli_Sec15_p1187-1332.indd 1308 8/2/19 8:40 PM