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Aldicarb Poisoning

A Case Report With Prolonged Cholinesterase Inhibition and Improvement After Pralidoxime Therapy

Jefferey L.Burgess, MD; Jeffrey N.Bernstein, MD; Katherine Hurlbut, MD

Aldicarb is the most potent of the commercially available carbamate pesticides and is an unusual source of acute human poisonings. We present the case of a 43-year-old man exposed to aldicarb who developed severe cholinergic symptoms and progressive weakness requiring intubation for 5 days. Both his red blood cell cholinesterase and plasma pseudocholinesterase levels were depressed for a minimum of 44 hours. He demonstrated neuromuscular improvement concurrent with pralidoxime administration. The pertinent medical literature on aldicarb poisoning is reviewed. (Arch Intern Med. 1994;154:221–224)

Both carbamate and organophosphate pesticides cause a decrease in cholinesterase activity, which can be measured through red blood cell (RBC) cholinesterase and plasma pseudocholinesterase levels. Carbamate pesticide poisonings tend to be less severe because they bind reversibly to the active site on the cholinesterase enzyme, in contrast to the organophosphate pesticides that, over time, bind irreversibly. Carbamate poisoning causes the same excess in muscarinic stimulation and nicotinic stimulation followed by weakness seen in organophosphate poisonings, but for a relatively shorter duration. Pralidoxime is generally not used for treating carbamate poisonings, and in some animal studies has reportedly worsened the clinical course.1,2

Aldicarb (2-methyl-2-[methylthio] propionaldehyde-O-[methylcarbamoyl]-oxime) was first distributed in the United States in 1970 by the Union Carbide Corp (Danbury, Conn) under the trade name Temik. It is now produced by Rhône-Poulenc Ag Co (Research Triangle Park, NC) in both dust-free gypsum granules and low-dust corn cob grit formulations. Its primary use is as a treatment incorporated into

   

From the Section of Emergency Medicine, University of Arizona Health Sciences Center, Tucson. Dr Hurlbut is now with the Denver (Colo) General Hospital.

the soil against nematodes, mites, and insects. It is taken up systemically by plants. A 1988 estimate of the amount of aldicarb applied annually in the United States was 5.2 to 5.7 million pounds.3 It is registered for use on cotton, sugar beets, sugar cane, potatoes, sweet potatoes, peanuts, oranges, pecans, dry beans, soy beans, and ornamental plants.4

Aldicarb has an LD50 (median toxic dose) of 0.8 mg/kg in rats,5 which makes it the most toxic on a per weight basis of any of the commercially available carbamate pesticides. Severe clinical poisonings with aldicarb are uncommon and therefore clinical experience in treatment is limited. This case describes a severe aldicarb poisoning with prolonged RBC cholinesterase and plasma pseudocholinesterase inhibition, and improvement temporally associated with pralidoxime administration.

REPORT OF A CASE

A 43-year-old previously healthy man suddenly developed severe nausea, vomiting, and diarrhea 15 to 20 minutes after eating dinner. He was profoundly weak, had slurred speech, and complained of continually needing to clear his throat be-

Reprinted with permission from Archives of Internal Medicine 154:221–4, Copyright 1994, American Medical Association.



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Environmental Medicine: Integrating a Missing Element into Medical Education Aldicarb Poisoning A Case Report With Prolonged Cholinesterase Inhibition and Improvement After Pralidoxime Therapy Jefferey L.Burgess, MD; Jeffrey N.Bernstein, MD; Katherine Hurlbut, MD Aldicarb is the most potent of the commercially available carbamate pesticides and is an unusual source of acute human poisonings. We present the case of a 43-year-old man exposed to aldicarb who developed severe cholinergic symptoms and progressive weakness requiring intubation for 5 days. Both his red blood cell cholinesterase and plasma pseudocholinesterase levels were depressed for a minimum of 44 hours. He demonstrated neuromuscular improvement concurrent with pralidoxime administration. The pertinent medical literature on aldicarb poisoning is reviewed. (Arch Intern Med. 1994;154:221–224) Both carbamate and organophosphate pesticides cause a decrease in cholinesterase activity, which can be measured through red blood cell (RBC) cholinesterase and plasma pseudocholinesterase levels. Carbamate pesticide poisonings tend to be less severe because they bind reversibly to the active site on the cholinesterase enzyme, in contrast to the organophosphate pesticides that, over time, bind irreversibly. Carbamate poisoning causes the same excess in muscarinic stimulation and nicotinic stimulation followed by weakness seen in organophosphate poisonings, but for a relatively shorter duration. Pralidoxime is generally not used for treating carbamate poisonings, and in some animal studies has reportedly worsened the clinical course.1,2 Aldicarb (2-methyl-2-[methylthio] propionaldehyde-O-[methylcarbamoyl]-oxime) was first distributed in the United States in 1970 by the Union Carbide Corp (Danbury, Conn) under the trade name Temik. It is now produced by Rhône-Poulenc Ag Co (Research Triangle Park, NC) in both dust-free gypsum granules and low-dust corn cob grit formulations. Its primary use is as a treatment incorporated into     From the Section of Emergency Medicine, University of Arizona Health Sciences Center, Tucson. Dr Hurlbut is now with the Denver (Colo) General Hospital. the soil against nematodes, mites, and insects. It is taken up systemically by plants. A 1988 estimate of the amount of aldicarb applied annually in the United States was 5.2 to 5.7 million pounds.3 It is registered for use on cotton, sugar beets, sugar cane, potatoes, sweet potatoes, peanuts, oranges, pecans, dry beans, soy beans, and ornamental plants.4 Aldicarb has an LD50 (median toxic dose) of 0.8 mg/kg in rats,5 which makes it the most toxic on a per weight basis of any of the commercially available carbamate pesticides. Severe clinical poisonings with aldicarb are uncommon and therefore clinical experience in treatment is limited. This case describes a severe aldicarb poisoning with prolonged RBC cholinesterase and plasma pseudocholinesterase inhibition, and improvement temporally associated with pralidoxime administration. REPORT OF A CASE A 43-year-old previously healthy man suddenly developed severe nausea, vomiting, and diarrhea 15 to 20 minutes after eating dinner. He was profoundly weak, had slurred speech, and complained of continually needing to clear his throat be- Reprinted with permission from Archives of Internal Medicine 154:221–4, Copyright 1994, American Medical Association.

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Environmental Medicine: Integrating a Missing Element into Medical Education cause of abundant secretions. His wife and child were not affected. He denied previous medical problems or taking medications. However, over the previous 6 months he had had several similar episodes, one of which required emergency treatment and resolved spontaneously over several hours. The paramedics responded and found the patient combative, cyanotic, incontinent of stool and urine, vomiting, salivating, and lacrimating excessively. He was bradycardic with a pulse rate of 50 beats per minute and a stable blood pressure. He was washed down, given 5 mg of atropine intravenously, and transported to a local hospital. On arrival his blood pressure was 155/ 122 mm Hg, with a pulse rate of 127 beats per minute, a respiratory rate of 20, and a temperature reading of 36.9°C. He was alert but mildly confused. The patient’s clothes were removed and he was showered to remove any possible skin contamination. Gastric lavage was performed and 1 g/kg of body weight of activated charcoal with sorbitol was administered. Results of his initial laboratory studies were remarkable for a serum potassium concentration of 2.6 mmol/L, a serum carbon dioxide concentration of 19 mmol/L, and an anion gap of 19. Over a 2-hour period he received potassium supplements, 4 mg of atropine, and 1 g of pralidoxime intravenously prior to being transported to a tertiary facility. ON ARRIVAL at the tertiary hospital his vital signs had normalized with a blood pressure of 130/100 mm Hg, a pulse rate of 90 beats per minute, a respiratory rate of 20, and a temperature of 34.8°C. He was alert but disoriented to time. His skin was diaphoretic and pale. He had pinpoint pupils, twitching of the eyelids, fasciculations of the facial muscles and tongue, bibasilar rales, and hypoactive bowel sounds. His neurologic examination revealed profound weakness and clonus that was greatest on the right side. He was able to lift his left arm against gravity but was limited to moving his fingers on the right side. Sensation and deep tendon reflexes were intact. Thiocyanate, tylenol, aspirin, iron, and lactate levels were within normal limits. Results of non-contrasted computed tomographic scan of the head and lumbar puncture were unremarkable. After admission he became progressively weaker and had difficulty clearing his secretions. Arterial blood gases drawn 7 hours after admission demonstrated a pH of 7.32, a PCO2 of 32.9 mm Hg, and a PO2 of 72.1 mm Hg on 4 L/min of oxygen administered by nasal cannula. Owing to progressive worsening of the patient’s clinical status, he received a second treatment of 1 g of pralidoxime intravenously. Twenty minutes after the bolus of pralidoxime, and 10 hours after onset of his symptoms, he had a 3-minute tonic-clonic seizure that resolved spontaneously and was treated with 5 mg of diazepam intravenously. His condition continued to worsen, and 30 minutes later he was intubated after pretreatment with 80 mg of succinylcholine intravenously and thiopental intravenously for failure to maintain his airway. He was given two additional treatments of 1 g of pralidoxime intravenously over a 30- to 60-minute period within a 6-hour period followed by an infusion of 0.5 g per hour over a 40-hour time frame. His strength began to improve after the drip was initiated, more than 16 hours after the onset of his symptoms. He progressed from only moving his fingertips to moving his entire right arm and writing notes within 60 minutes of starting the infusion. The initial pralidoxime infusions were temporally associated with hypertensive episodes to as high as 195/100 mm Hg. The continu Cholinesterase Concentrations* Time (Hours†) Plasma Red Blood Cell 02:00 (6) 469 … 16:30 (44) 3107 6.4 06:00 (58) 7287 … 04:00 (80) 7144 … 06:00 (130) … 13.7 20:00 (168) 8719 11.5 22 days 8320 11.8 *Normal range, plasma (4499 to 13320 U/L), red blood cell (9.9 to 18.0 IU/mL). †Hours after the onset of symptoms. ous infusion did not elevate his blood pressure. Concurrent with the pralidoxime administration, the patient was given an additional 2 mg of atropine intravenously, followed by an atropine drip of 0.5 mg/h for 22 hours. During this time he became severely agitated and required sedation. The atropine was stopped. Fifteen hours later he was given 0.25 mg of glycopyrrolate mg per hour for 9 hours to control continued excess secretions while limiting central nervous system effects. He developed a temperature of 39°C, presumably from aspiration pneumonia, and was given 2 million units of penicillin per hour intravenously, 1 g of cefotaxime every 8 hours, and 1 g of vancomycin every 12 hours. The RBC and plasma cholinesterase levels are presented in the Table. His initial plasma cholinesterase level 6 hours after onset of symptoms was 469 U/L (6% of normal) and did not increase to the normal range for another 52 hours. The initial RBC cholinesterase level 44 hours after admission was 6.4 U/mL (54% of normal). A repeated level 4 days later was 13.7 U/mL, and follow-up tests remained normal. His condition gradually improved and he was extubated on the fifth day of hospitalization. After extubation, discussions with the patient and his family raised the possibility of poisoning with aldicarb (Temik). The earliest available blood

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Environmental Medicine: Integrating a Missing Element into Medical Education sample, collected 15 hours after onset of symptoms, had an aldicarb concentration of 0.1 µg/mL, an aldicarb sulfoxide concentration of 1.7 µg/mL, and an aldicarb sulfone concentration of 3.4 µg/mL. A urine screen for 22 common organophosphate pesticides (National Medical Services Inc, Willow Grove, Pa) collected on the day of admission failed to demonstrate any concurrent exposure. The patient had an uneventful recovery, and on follow-up visits has remained asymptomatic. COMMENT Aldicarb is the most potent of the commercially available carbamate pesticides. It is absorbed through the skin, lungs, and gastrointestinal tract. In human trials, doses of 0.1 mg/kg produced symptoms,6 and doses of 0.025 mg/kg demonstrated the lowest observed effect level for cholinesterase inhibition.7 In the California watermelon-borne aldicarb poisonings, symptoms were reported at doses as low as 0.021 mg of aldicarb per kilogram of body weight.8 Aldicarb is rapidly absorbed via the gastrointestinal tract. After large doses the onset of symptoms may occur as quickly as 5 minutes.9 It is rapidly metabolized to aldicarb sulfoxide and then more slowly to aldicarb sulfone, as well as a number of additional metabolites. Both aldicarb sulfoxide and aldicarb sulfone are pharmacologically active, with the potency of aldicarb sulfoxide roughly equivalent to its parent compound. The potency of aldicarb sulfone is much less that of aldicarb.10 As with most carbamates, aldicarb has a short half life, and in 24 hours 80% to 90% of an ingested dose in the rat is excreted in the urine.11 Because of its method of application as a treatment injected into the soil, aldicarb is unlikely to cause inadvertent acute toxic effects to bystanders. It is systemically absorbed by plants, and therefore consumption of certain improperly treated crops may result in exposure. Soil application has also resulted in a number of reports of ground water contamination.12–14 Individuals working directly with the production and application of aldicarb may become inadvertently poisoned. The source of the aldicarb poisoning in our patient is not entirely clear. His history was not suggestive of any occupational source of exposure. Because of the sudden onset and severity of his gastrointestinal symptoms, and his lack of any known source of significant respiratory or dermal exposure, it is most reasonable to assume that he ingested the poison. The onset of his symptoms 15 to 20 minutes after eating suggests that his dinner was contaminated. The patient and the police were informed of our concerns. Only a small number of life-threatening human aldicarb poisonings have been reported. In the first reported case of accidental poisoning, the wife of a corporate scientist Aldicarb is the most potent of the commercially available carbamate pesticides developed cholinergic symptoms, muscle fasciculations, and difficulty breathing after ingesting a mint sprig growing near an aldicarb-treated rose bush.15 A 36-year-old woman who ingested one teaspoon of aldicarb in a suicide attempt developed marked cholinergic signs and symptoms with neuromuscular weakness. However, details of her treatment and hospital course were not given.16 A 7-month-old infant developed convulsions and cyanosis after exposure to aldicarb powder. She was intubated overnight and required treatment with more than 100 mg of atropine.17 Reported deaths from aldicarb poisoning are extremely rare. A farm-worker in California was crushed by a tractor while lying in a field after working with aldicarb without proper protection. Postmortem blood samples contained 0.108 parts per million of aldicarb sulfoxide and 0.374 parts per million of aldicarb sulfone, with a total concentration roughly one tenth of that in our patient. The total body burden was calculated to be 0.275 mg/kg.6 The cause of death was listed as trauma but the aldicarb exposure may have incapacitated him. At least three other deaths have been documented.18 Other aldicarb exposures have been associated with the ingestion of contaminated commercial food products. Aldicarb-contaminated watermelon produced clinical illness in California, Oregon, and Washington.19 In California there were 690 probable poisonings and 370 possible poisonings. Clinical findings included seizures, loss of consciousness, dysrhythmias, hypotension, dehydration, and anaphylaxis.20 Cases of illness from the consumption of aldicarb-contaminated cucumbers have also been reported,10,21 and contaminated potatoes have been reported.22 In a bizarre occurrence, 23 cows were killed by consuming feed that had been intentionally poisoned with aldicarb.23 Carbamates exert their toxic effect by inhibiting cholinesterase enzymes, with the resultant cholinergic excess and muscular weakness due to the effects of increased acetylcholine on nerve conduction. Unlike organophosphate chemicals, which may bind irreversibly, the carbamate chemicals bind reversibly, and therefore tend to have a shorter duration of action. Aldicarb exposure in humans inhibits both RBC cholinesterase and plasma pseudocholinesterase. Ingestion of 0.1 mg/kg resulted in a reduction of whole-blood cholinesterase activ-

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Environmental Medicine: Integrating a Missing Element into Medical Education ity to 28% of baseline within 2 hours of ingestion, with resolution of symptoms by 4 hours.6 In vitro the half life of cholinesterase inhibition activity is 30 to 40 minutes.24 In rats, drinking water concentrations of 19.2 parts per million of a 1:1 mixture of aldicarb sulfoxide and aldicarb sulfone resulted in a decrease in plasma pseudocholinesterase levels to 23% to 32% of normal with a decrease in RBC cholinesterase to 37% to 43% of normal.25 The treatment of carbamate poisonings is supportive in the majority of cases. Patients with dermal exposures should have their contaminated clothing removed and the involved skin cleansed with alkaline soap and water, with appropriate care to prevent exposure of the medical staff. For ingestions, gastric lavage and the administration of activated charcoal are recommended. In severe poisonings atropine may be useful in controlling secretions, and large quantities may be required. Since carbamates do not readily cross the blood-brain barrier, glycopyrrolate may be substituted for atropine to avoid significant central neurologic effects. Administration of cholinergic drugs, such as the succinylcholine given in our patient, should be avoided in carbamate poisonings. The use of pralidoxime for carbamate pesticide poisoning is controversial. Most carbamate poisonings resolve within several hours without treatment other than atropine. Since the binding to cholinesterase enzymes is reversible, there is usually no need for oxime therapy. Clinical worsening after administration of pralidoxime, toxogonin, and obidoxime to animals has been described in animal experiments with the carbamate pesticide carbaryl.1,2 Obidoxime also interfered with the protective effect of atropine in carbaryl poisonings.2 However, for aldicarb poisoning, pralidoxime and obidoxime have been shown to improve mortality in rats,2 and toxogonin reduced toxicity in rats.1 In our patient we noted hypertension with the bolus administration of pralidoxime, but not with continuous intravenous infusion. While it is impossible to determine if the patient’s seizure was related to the second dose of pralidoxime, his clinical status was clearly deteriorating prior to the pralidoxime with documented acidemia and progressive difficulty maintaining his airway. Subsequent doses of pralidoxime appeared to improve our patient’s weakness without significant adverse effects. In summary, we presented an unusual case of severe poisoning with aldicarb, a carbamate pesticide. To our knowledge, this is the first article on prolonged cholinesterase inhibition with aldicarb poisoning, and documents the highest combined blood concentration of aldicarb and its metabolites of any human poisoning in the medical literature. The patient appeared to benefit from oxime therapy, demonstrating neuromuscular improvement temporally associated with pralidoxime administration. Severe aldicarb poisonings may be life threatening and can be successfully managed in the same manner as organophosphate poisonings. Accepted for publication June 8, 1993. Presented at the American Academy of Clinical Toxicology in Tampa, Fla, September 19–22, 1992. Reprints not available. REFERENCES 1. Sterri S, Rognerud B, Fiskum S, Lyngaas S. Effect of toxogonin and P2S on the toxicity of carbamates and organophosphorus compounds. Acta Pharmacol Toxicol. 1979;45:9–15. 2. Natoff IL, Reiff B. Effect of oximes on the acute toxicity of anticholinesterase carbamates. Toxicol Appl Pharmacol. 1973;25:569–575. 3. US Environmental Protection Agency. Aldicarb Special Review Technical Support Document. Washington, DC: Office of Pesticides and Toxic Substances; June 1988. 4. Risher JF, Mink FL, Stara JF. The toxicologic effects of the carbamate insecticide aldicarb in mammals: a review. Environ Health Perspect. 1987;72:267–281. 5. Gaines TB. Acute toxicity of pesticides. Toxicol Appl Pharmacol. 1969;14:515–534. 6. Lee MH, Ransdell JF. A farmworker death due to pesticide toxicity: a case report. J Toxicol Environ Health. 1984;14:239–246. 7. Goldman LR, Beller M, Jackson RJ. Aldicarb food poisonings in California, 1985–1988: toxicity estimates for humans . Arch Environ Health. 1990; 45:141–147. 8. Witt JM. Aldicarb poisoning. JAMA. 1986;256: 3218. 9. Cambon C, Declume C, Derache R. Effect of the insecticidal carbamate derivatives (carbofuran, pirimicarb, aldicarb) on the activity of acetylcholinesterase in tissues from pregnant rats and fetuses. Toxicol Appl Pharmacol. 1979;49:203– 208. 10. Hirsch GR, Mori BT, Morgan GB, Bennett PR, Williams BC. Report of illnesses caused by aldicarb-contaminated cucumbers. Food Addit Contam. 1987;5:155–160. 11. Andrawes NR, Dorough HW, Lindquist DA. Degredation and elimination of Temik in rats. J Econ Entomol. 1967;60:979–987. 12. Zaki MH, Moran D, Harris D. Pesticides in groundwater: the aldicarb story in Suffolk County, NY. Am J Public Health. 1982;72:1391–1395. 13. Sun M. EPA proposes state action on aldicarb. Science. 1988;241:22. 14. Fiore MC, Anderson HA, Hong R, et al. Chronic exposure to aldicarb-contaminated groundwater and human immune function. Environ Res. 1986; 41:633–645. 15. Hayes WJ. Pesticides Studied in Man. Baltimore, Md: Williams & Wilkins; 1982:447–462. 16. Parks P, Lipman J, Eidelman J. Carbamate toxicity: a case report. S Afr Med J. 1987;72:222. 17. Ramasamy P. Carbamate insecticide poisoning. Med J Malaysia. 1976;31:150–152. 18. Baron RL. Carbamate insecticides. In: Hayes WJ, Laws ER eds. Handbook of Pesticide Toxicity, III: Classes of Pesticides. Orlando, Fla: Academic Press Inc; 1991;1125–1189. 19. Green MA, Heumann MA, Wehr HM, et al. An outbreak of watermelon-borne pesticide toxicity. Am J Public Health. 1987;77:1431–1434. 20. Aldicarb food poisoning from contaminated melons—California. MMWR Morb Mortal Wkly Rep. 1986;35:254–258. 21. Goes EA, Savage EP, Gibbons G, Aaronson M, Ford SA, Wheeler HW. Suspected foodborne carbamate pesticide intoxications associated with ingestion of hydroponic cucumbers. Am J Epidemiol. 1980;111:254–260. 22. Cairns T, Siegmund EG, Savage TS. Persistence and metabolism of aldicarb in fresh potatoes. Bull Environ Contam Toxicol. 1984;32: 274–281. 23. Kerr LA, Pringle JK, Rohrbach BW, Edwards WC, Offutt JE. Aldicarb toxicosis in a dairy herd. J Am Vet Med Assoc. 1991;198:1636–1639. 24. World Health Organization. Aldicarb Health and Safety Guide. Geneva, Switzerland: World Health Organization for the International Programme on Chemical Safety: 1991. 25. DePass LR, Weaver EV, Mirro EJ. Aldicarb sulfoxide/aldicarb sulfone mixture in drinking water of rats: effects on growth and acetylcholinesterase activity. J Toxicol Environ Health. 1985; 16:163–172.