Pediatric Annals

One Pill Can Kill: Assessing the Potential for Fatal Poisonings in Children

Michael J Matteucci, MD

Abstract

Asymptomatic children should be observed for a minimum of 6 hours. Those with symptoms need admission to an intensive care setting for aggressive monitoring and treatment.

SULFONYLUREAS

Oral hypoglycemic agents are among the most commonly prescribed medications. Sulfonylureas are indicated for the treatment of type II diabetes. AAPCC TESS data showed 1,443 exposures in children younger than 6 in 2003.1 Only one death has been reported, but the incidence of symptomatic hypoglycemia (30%) is relatively high, making this an ingestion of concern.22'23

Sulfonylureas are absorbed rapidly in the GI tract but may have a prolonged duration of action, especially extended-release preparations. They are metabolized in the liver to active metabolites that may be excreted renally. They induce hypoglycemia by stimulating insulin secretion from the pancreas in addition to inhibiting gluconeogenesis and reducing hepatic clearance of insulin.24 Hypoglycemia typically occurs within 8 hours of ingestion and has been noted with as little as one tablet in toddlers.23 There are several reports of delayed hypoglycemia, but these are associated with intravenous dextrose infusions that may delay the presentation of hypoglycemia.25'27

Monitoring recommendations include frequent (every 2 hours while awake or every hour while sleeping) finger stick blood glucose monitoring with free access to oral glucose sources. For patients with blood glucose levels of less than 60 mg/dL or symptoms of hypoglycemia, dextrose can be given as boluses (0.5 to 1 g/kg; 1 to 24 months: D25W 2 to 4 mL/kg; older than 2: D50W 1 to 2 mL/kg) or as an intravenous infusion to maintain the blood glucose above 60 mg/dL.28 Octreotide, a synthetic analogue of somatostatin that acts to inhibit secretion of insulin and other hormones may be useful in this setting as it will improve hypoglycemia without inducing the rebound hyperinsulinemia that can be seen with dextrose infusions. It is given as a subcutaneous injection of 4 to 5 mcg/kg/day divided every 6 hours.28

Asymptomatic children should be monitored for at least 8 hours for nonextended-release products or for 20 to 24 hours for extended-release products. Children who have received intravenous dextrose or subcutaneous octreotide should be monitored for at least 6 hours following the last dose for recurrent hypoglycemia.

SUMMARY

Antimalarials, camphor, clonidine, methyl salicylates, and sulfonylureas all may result in serious poisonings and are potentially fatal in small doses in toddlers. Early recognition and appropriate management, including antidotal and supportive care, may prevent poor outcomes in these patients.

1. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2004;22(5):335404.

2. Smith ER, Klein-Schwartz W. Are 1-2 dangerous? Chloroquineand hydroxychloroquineexposure in toddlers. J Emerg Med. 2005;28(4):437443.

3. Jordan P, Brookes JG, NikoHc G, Le Couleur DG. Hydroxychloroquine overdose: toxicokinetics and management. JToxicol Clin Toxicol. 1999;37(7):86 1-864.

4. Don Michael TA, Aiwazzadeh S. The effects of acute chloroquine poisoning with special reference to the heart. Am Heart J. 1970;79(6):831842.

5. Kelly JC, Wasserman GS, Bernard WD, Schultz C Knapp J. Chloroquine poisoning in a child. Am Emerg Med. 1990;19(1):47-50.

6. ClemesseyJL.FavierC.BorronSWetal.Hypokalemia related to acute chloroquine ingestion. lancet. 1995;346(8979): 877-880.

7. Tracy JW, Webster, Jr LT. Drugs used in the chemotherapy of protozoal infections: malaria. In: Hardman JG, Iimbird LE, Oilman AG, eds. Goodman and Gilmans's Pharmacological Basis ofTherapeutics. 10th ed. New York, NY: McGraw-Hill; 2001: 1069-1095.

8. Riou B, Barriot P, Rimailho A, Baud EJ. Treatment of severe chloroquine poisoning. N Engl J Med. 1988;318(l):l-6.

9. Love JN, Sammon M, Smereck J. Are one or two dangerous? Camphor exposure in toddlers. J Emerg Med. 2004;27(l):49-54.

10. Liebert EL, Shannon MW Small doses,…

Pediatrie poisonings are common, making up 66.1% of the 2,395,582 calls to the American Association of Poison Control Centers (AAPCC) in 2003.1 Data from the AAPCC Toxic Exposure Surveillance System (TESS) show that children and adolescents younger than 19 make up 9.8% of the 1,106 deaths that were reported in 2003 (Table 1, see page 966). The most commonly reported medication-related poisonings included analgesics (7.8%), topical medications (7.4%), and gastrointestinal preparations (2.4%), with analgesics associated with the most deaths attributed to medications. Unintentional poisonings are the rule with younger ages, while intentional poisonings are more common in adolescents.

In children younger than 6, many medication-related poisonings are related to therapeutic error, including incorrect dosing (usually a 10-times error), inadvertent overdosing, administration of the wrong medication, use of another person's medication, or incorrect formulations.1 Children may be exposed to various types of medications including over-the-counter (OTC) preparations, herbal remedies, and medications prescribed for them or others. The great majority of these exposures are benign, and the child can be watched at home. However, a small but significant number of these exposures result in intoxication or poisonings and need to be evaluated and treated in the emergency department.

This article focuses on five medications or medication classes that potentially are lethal to children when ingested in small amounts. In a 10-kg child, each of these substances is potentially lethal with the ingestion of just one tablet, capsule, or teaspoonful (Table 2, see page 967). Rapid recognition of the seriousness of these exposures by the caretaker, poison control center (PCC), primary physician, and emergency physician may prevent poor outcomes.

ANTIMALARIAL MEDICATIONS

Chloroquine and hydroxychloroquine are antiparasitic agents indicated for prophylaxis and treatment of malaria. They are also increasingly being prescribed for their anti-inflammatory effects and as such are becoming more common in American households. A review ofAAPCC TESS data from 1986 through 2001 showed 1,177 antimalarial exposures and two deaths in children younger than 6.2 Chloroquine has a narrow index of safety with the therapeutic dose of 5 to 10 mg/kg and the potentially lethal dose of 30 to 50 mg/kg. There is a paucity of data for hydroxychloroquine, but animal studies suggest lower toxicity than Chloroquine.3

These antimalarial agents contain a quinidine ring and exhibit similar cardiotoxic effects by acting as Class Ia antiarrhythmics, blocking sodium and potassium channels and causing QRS and QT prolongation, negative inotropy, and Torsades de Pointes.4 Respiratory depression occurs by an unclear mechanism. Central nervous system (CNS) effects occur early, with drowsiness being most common but agitation and seizures also occurring. The mechanism of toxicity is thought to be due to direct effects, as well as hypoperfusion and hypoxia.5 Hypokalemia due to an intracellular potassium shift is common and correlates with the severity of poisoning.6

Chloroquine is very well absorbed in the gastrointestinal (GI) tract, with a maximal plasma concentration within 3 hours, followed by a slower redistribution throughout the body.7 It is metabolized in the liver and excreted renally.7 In injestions of concern, symptoms occur quickly, with sedation within 30 to 60 minutes and progress to apnea, seizures, and cardiopulmonary arrest within 3 hours.5

Decontamination using activated charcoal is useful if given early. Retrospective and prospective studies in adults have demonstrated the efficacy of a three-pronged treatment strategy.6'8 Although these therapies are not well studied in children, it seems reasonable to use them. Early intubation without use of barbiturates should be instituted, as thiopental has been shown to cause refractory hypotension.6 Benzodiazepines are indicated for seizures, dysrhythmias, or QRS widening, while epinephrine (0. 1 to 1.0 mcg/kg/min) is the recommended medication for hypotension unresponsive to fluids or benzodiazepines.8 Sodium bicarbonate (1 to 2 mEq/kg) may also be useful to counteract the Class Ia antiarrhythmic effects but may further worsen the hypokalemia.

Asymptomatic children should be observed with cardiopulmonary monitoring for 6 hours after a potential ingestion. Any symptomatic children should be treated as above and admitted to an intensive care unit (ICU) setting.

Table

TABLE 1.Toxic Exposure and Death Rates Reported to the AAPCC in 2003 1

TABLE 1.

Toxic Exposure and Death Rates Reported to the AAPCC in 2003 1

CAMPHOR

Historically, camphorated oil was most often responsible for camphor toxicity; however, the Food and Drug Administration (FDA) limited its concentration to 11% in 1983. Camphor was also the major component of mothballs, but it is no longer used. Today, camphor is still found in many over-the-counter preparations used for cold symptoms and analgesics in concentrations of 4.6 to 16.7%.9 AAPCC TESS data for 2003 showed 7,823 exposures in children younger than 6 in 2003.1

Camphor is rapidly absorbed through the skin, mucous membranes, and GI tract and is metabolized by the liver. Toxicity usually manifests within 5 to 90 minutes.10 Common early symptoms include burning of the mouth, throat, nausea, vomiting, and tachycardia.9 The mechanism of action is not known. The neurological effects are the most worrisome - they include irritability, myoclonic jerks, confusion, seizures, and apnea. Toxicity generally resolves within 24 hours.

Treatment should include activated charcoal, if it can be given, within 1 hour of ingestion. Supportive care is the mainstay of therapy. Benzodiazepines should be used in cases with irritability or seizures. Barbiturates may be used, but there are conflicting data on whether they are more beneficial than benzodiazepines.9 Airway support may be needed, especially if large doses of benzodiazepines or barbiturates are required. Lipid hemodialysis or hemoperfusion only remove a very small amount of camphor but may be useful in severely ill patients.11

Asymptomatic children should be monitored for at least 3 hours for development of symptoms. Symptomatic children should be aggressively supported in an intensive care setting.

CLONIDINE

Clonidine was originally developed as a nasal decongestant. It is approved in the US by the Food and Drug Administration for the treatment of hypertension, but its many off-label uses include treatment of attention-deficit/hyperactivity disorder, Tourette syndrome, and ethanol or opioid withdrawal. With the broadened uses, the number of exposures increased 2.5-fold between 1993 and 1999. 12 In 2003, 1,736 exposures in children younger than 6 were reported to the AAPCC.1

Toxicity can occur with just one or two tablets of clonidine, or 2.5 to 5 ml of over-the-counter imidazolines.12'13 Of particular concern are clonidine transdermal patches, which may contain up to 7.5 mg when new; up to 75% of that amount may remain after a week's use.14

Clonidine and several over-the-counter agents, such as tetrahydrozoline, naphazoline, and oxymetazoline, are agonists at imidazoline and «2 receptors. The imidazoline receptors are not well studied, but ot2 agonism by these agents results in transient hypertension due to the stimulation of receptors in peripheral vascular smooth muscle. This is followed by hypotension, bradycardia, mental status depression and respiratory depression that is due to decreased sympathetic nervous system output caused by stimulation of central a2 receptors.15 Absorption of these agents is rapid; symptoms usually are seen within 1 to 3 hours but may persist for 24 hours.

Treatment includes activated charcoal if it can be given early. Hypertension should be treated with caution, as it is usually transient Hypotension usually responds to fluids but may require direct acting vasopressors such as norepinephrine. Bradycardia usually responds to atropine. Reports are varied as to the efficacy of naloxone in this setting, and it is not generally recommended except for severe respiratory depressioa 16 In fact, the respiratory effort may be supported by frequent tactile stimulation of the patient13

All exposures of at least 0.002 to 0.005 mg/kg, or of unknown amounts, need to be evaluated by a physician.16'17 Asymptomatic children should be monitored for at least 6 hours, and symptomatic children should be admitted to an intensive care setting

METHYL SALICYLATES

Although the incidence of childhood salicylate poisoning decreased markedly in the late 20th century due to its association with Reye's syndrome and the resulting decrease in its use in children, exposures still are relatively common. In 2003, more than 12,000 exposures and one pediatrie death were reported to the AAPCC.1 More than 7,500 of these exposures were due to substances containing methyl salicylate, such as balms, salves, or oil of wintergreen.1

Most salicylate preparations are rapidly absorbed, with oil of wintergreen being the quickest and topical preparations slower. Each milliliter of oil of wintergreen contains approximately 1.5 grams of salicylates, reaching the potentially lethal level in a 10-kg child, while 1 teaspoon of a common menthol muscle rub contains 1.77 grams of salicylates.18'19 Large ingestions of regular or enteric-coated tablets can lead to the formation of concretions within the GI tract, leading to delayed and persistent absorption.

Salicylate poisoning causes direct stimulation of the medullary respiratory center, leading to a respiratory alkalosis that seems less common in young infants.18 It also leads to a metabolic acidosis by interfering with the Krebs cycle and uncoupling oxidative phosphorylation.18 Other significant findings include noncardiogenic pulmonary edema due to capillary leak and cerebral hypoglycemia even in the presence of peripheral euglycemia.20

Salicylate, a weak acid, is mostly ionized at physiologic pH. As patients become more acidotic, it becomes nonionized and is free to enter tissues such as the brain, increasing toxicity. Early symptoms include tachypnea, nausea and vomiting, irritability, and tinnitus and are associated with serum salicylate levels of greater than 20 to 30 mg/dL.20 As levels increase, mental status depression worsens to coma. Serum salicylate levels and chemistry panels should be obtained every 1 to 2 hours until the patient improves.21

Activated charcoal binds salicylates well and should be considered in salicylate poisonings. Whole bowel irrigation may reduce absorption and is recommended in a patient with increasing or persistently elevated levels. Fluid losses should be replaced, but care should be taken not to overhydrate.

The mainstay of treatment is alkalinization. This results in more ionized salicylate in both the plasma and in the renal tubules, which prevents migration into tissues and enhances excretion. Blood pH should be maintained between 7.40 and 7.55 by boluses of sodium bicarbonate or infusions (three ampules of sodium bicarbonate in D5W infused at two times maintenance).20 If intubation is required, care should be taken to at least match the patient's minute ventilation, as an acute respiratory acidosis may cause a rapid shift of salicylate into the brain.20 Dialysis is indicated for renal insufficiency or failure, respiratory acidosis, hypotension, pulmonary edema, altered mental status, seizures, or salicylate levels of 90 mg/dL or greater.21

Table

TABLE 2.Toxicity Levels of Selected Medications and Medication Classes

TABLE 2.

Toxicity Levels of Selected Medications and Medication Classes

Asymptomatic children should be observed for a minimum of 6 hours. Those with symptoms need admission to an intensive care setting for aggressive monitoring and treatment.

SULFONYLUREAS

Oral hypoglycemic agents are among the most commonly prescribed medications. Sulfonylureas are indicated for the treatment of type II diabetes. AAPCC TESS data showed 1,443 exposures in children younger than 6 in 2003.1 Only one death has been reported, but the incidence of symptomatic hypoglycemia (30%) is relatively high, making this an ingestion of concern.22'23

Sulfonylureas are absorbed rapidly in the GI tract but may have a prolonged duration of action, especially extended-release preparations. They are metabolized in the liver to active metabolites that may be excreted renally. They induce hypoglycemia by stimulating insulin secretion from the pancreas in addition to inhibiting gluconeogenesis and reducing hepatic clearance of insulin.24 Hypoglycemia typically occurs within 8 hours of ingestion and has been noted with as little as one tablet in toddlers.23 There are several reports of delayed hypoglycemia, but these are associated with intravenous dextrose infusions that may delay the presentation of hypoglycemia.25'27

Monitoring recommendations include frequent (every 2 hours while awake or every hour while sleeping) finger stick blood glucose monitoring with free access to oral glucose sources. For patients with blood glucose levels of less than 60 mg/dL or symptoms of hypoglycemia, dextrose can be given as boluses (0.5 to 1 g/kg; 1 to 24 months: D25W 2 to 4 mL/kg; older than 2: D50W 1 to 2 mL/kg) or as an intravenous infusion to maintain the blood glucose above 60 mg/dL.28 Octreotide, a synthetic analogue of somatostatin that acts to inhibit secretion of insulin and other hormones may be useful in this setting as it will improve hypoglycemia without inducing the rebound hyperinsulinemia that can be seen with dextrose infusions. It is given as a subcutaneous injection of 4 to 5 mcg/kg/day divided every 6 hours.28

Asymptomatic children should be monitored for at least 8 hours for nonextended-release products or for 20 to 24 hours for extended-release products. Children who have received intravenous dextrose or subcutaneous octreotide should be monitored for at least 6 hours following the last dose for recurrent hypoglycemia.

SUMMARY

Antimalarials, camphor, clonidine, methyl salicylates, and sulfonylureas all may result in serious poisonings and are potentially fatal in small doses in toddlers. Early recognition and appropriate management, including antidotal and supportive care, may prevent poor outcomes in these patients.

REFERENCES

1. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2004;22(5):335404.

2. Smith ER, Klein-Schwartz W. Are 1-2 dangerous? Chloroquineand hydroxychloroquineexposure in toddlers. J Emerg Med. 2005;28(4):437443.

3. Jordan P, Brookes JG, NikoHc G, Le Couleur DG. Hydroxychloroquine overdose: toxicokinetics and management. JToxicol Clin Toxicol. 1999;37(7):86 1-864.

4. Don Michael TA, Aiwazzadeh S. The effects of acute chloroquine poisoning with special reference to the heart. Am Heart J. 1970;79(6):831842.

5. Kelly JC, Wasserman GS, Bernard WD, Schultz C Knapp J. Chloroquine poisoning in a child. Am Emerg Med. 1990;19(1):47-50.

6. ClemesseyJL.FavierC.BorronSWetal.Hypokalemia related to acute chloroquine ingestion. lancet. 1995;346(8979): 877-880.

7. Tracy JW, Webster, Jr LT. Drugs used in the chemotherapy of protozoal infections: malaria. In: Hardman JG, Iimbird LE, Oilman AG, eds. Goodman and Gilmans's Pharmacological Basis ofTherapeutics. 10th ed. New York, NY: McGraw-Hill; 2001: 1069-1095.

8. Riou B, Barriot P, Rimailho A, Baud EJ. Treatment of severe chloroquine poisoning. N Engl J Med. 1988;318(l):l-6.

9. Love JN, Sammon M, Smereck J. Are one or two dangerous? Camphor exposure in toddlers. J Emerg Med. 2004;27(l):49-54.

10. Liebert EL, Shannon MW Small doses, big problems: a selected review of highly toxic common medications. Pediatr Emerg Care. 1993;9(5): 292-297.

11. Kopelman R, Miller S, KeUy R, Sunshine I. Camphor intoxication treated with Urad hemodialysis. JAMA. 1979;241(7):727-728.

12. Klein-Schwatz W Trends and toxic effects from pediatrie clonidine exposures. Arch Pediatr Molesc Med. 2002; 156(4):392-396.

13. Daggy A, Kaplan R, Roberge R, Akhtar J. Pediatrie Visine (tetrahydrozoline) ingestion: case report and review of imidazoline toxicity. Vet Human Toxicol. 2003;45(4):210-212.

14. Caravati EM, Bennett DL. Clonidine transdsrmal patch poisoning. Ann Emerg Med. 1988;17(2):175-176.

15. Huffman BB. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. M: Hardman JG, Iimbird LE, Gilman AG, eds. Goodman and Gilmans's Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:233-234.

16. Eddy O, Howell JM Are one or two dangerous? Clonidine and topical imidazoline exposure in toddlers. J Emerg Med. 2003;25(3):297-302.

17. Spiller HA, Klein-Schwartz W, Colvin JM, et al. Toxic clonidine ingestion in children. J Pediatr. 2005; 146(2): 263-266.

18. Flomenbaum NE. Salicylates. M: Goldfrank LR, Flomenbaum NE, Lewin NA, et al., eds. Goldfrank's Toxicologie Emergencies. 7th ed. New York, NY: McGraw-Hill; 2002:507-518.

19. Wolowich WR, Hadley CM, Kelley MT. Plasma salicylate from methyl salicylate cream compared to oil of wintergreen. J Toxicol Clin Toxicol. 2003;41(4):355-358.

20. Yip L, Dart RC, Gabow PA. Concepts and controversies in salicylate toxiciiy. Emerg Med Clin. 1994; 12(2):35 1-364.

21. Yip L. Salicylates. In: Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:739-749.

22. Litovitz TL, Klein-Schwartz W, Dyer KS, et al. 1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 1998;16(5):443497.

23. Spiller HA, Villalobos D, Krenzelok EP, et al. Prospective multicenter study of sulfonylurea ingestion in children. J Pediatr. 1997;131(1 Pt 1):141-146.

24. Davis SN, Granner DK. Insulin, oral hypoglycemie agents, and the pharmacology of the endocrine pancreas. In: Hardman JG, LLmbird LE, Gilman AG, eds. Goodman and Gilmans 's Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001: 1679-1714.

25. Quadrarli DA, Spiller HA, Widder P. Fiveyear retrospective evaluation of sulfonylurea ingestion in children. J Toxicol Clin Toxicol. 1996;34(3):267-270.

26. Burkhart KK. When does hypoglycemia develop after sulfonylurea ingestion? Ann Emerg Med. 1998;31(6):771-772.

27. Szlatenyi CS, Capes KF, Wang RY. Delayed hypoglycemia in a child after ingestion of a single glipizide tablet. Ann Emerg Med. 1998; 31(6):773-776.

28. Little GL, Boniface KS. Are one or two dangerous? Sulfonylurea exposure in toddlers. J Emerg Med. 2005;28(3): 305-310.

TABLE 1.

Toxic Exposure and Death Rates Reported to the AAPCC in 2003 1

TABLE 2.

Toxicity Levels of Selected Medications and Medication Classes

10.3928/0090-4481-20051201-12

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