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Authors: Daryl Emery, MD, Clinical Instructor, Wright State University School of Medicine; Jonathan I. Singer, MD, FACEP, FAAP, Professor of Emergency Medicine and Pediatrics, Wright State University School of Medicine, Department of Emergency Medicine, Dayton, OH.
Peer Reviewer: Leslie Wolf, MD, Associate Professor/Toxicology Coordinator, Department of Emergency Medicine, Wright State University School of Medicine, Dayton, OH.
Certain medications and substances may place a child at risk for a fatality—even when ingested in very small quantities. Substances such as prenatal iron supplements, antidepressants, hydrocarbons, and gun blueing agents have all been reported to cause severe toxicity in toddlers. Of particular importance to the emergency department physician are substances that may be fatal in doses as low as 1-2 tablets or 1-2 tsp. These ingestions must be identified quickly and appropriate therapy promptly administered.
Acute ingestions of medications and household products are frequent, particularly in children younger than 3 years of age. Of the more than 4 million ingestions reported in 1996 and 1997 by the American Association of Poison Control Centers, 39% were in this age group.1,2 Unintentional encounters with pharmaceuticals and non-pharmaceutical agents usually result in mild or no symptoms, and significant morbidity is uncommon. Fatalities in this age group are rare and have been declining.1,2
Less collective data exist for children younger than 2 years of age, herein referred to as toddlers. Oral exposure in this group may either be the result of child abuse or from unintentional behavior.3,4 Improper storage of substances, temporary distraction of care givers, exploratory mobility, and misinterpretation of substances may singularly or combine to result in ingestions among the very young.5
Toddlers are equally capable of ingesting liquids or pills. Children younger than 2 years of age, as a whole, are unable to discriminate safe from unsafe liquids, particularly if the agent is stored in a recognized container (i.e., kerosene or gasoline in a soda bottle). Toddlers fail to recognize the suitability of the drink, and a toxic volume may be consumed before taste aversion leads to discontinuing the drink. A 2-year-old child can equally mistake a medication for an edible ingredient.6 Toddlers may observe the ritual of self medication in another family member and imitate that behavior. Alternately, younger children may be given pharmaceuticals by older siblings.
Whatever physical factors or behavioral events contribute to an ingestion, there are a plethora of edible items in a typical household.4
Fortunately, the natural curiosity and oral gratification of a toddler rarely results in serious intoxication. A majority of household products, plants, and medications are nontoxic or have limited toxicity.7 If ingested by toddlers, they present no problem or create transient symptoms that spontaneously resolve. A finite number of household products, plants, and medications are potentially toxic. As early as 1991, the peer literature categorized a number of household products, plants, and medications that, if ingested, could create life-threatening effects.8 With newer pharmaceuticals and expanded non-pharmaceuticals, more products now have the capacity to cause toxicity. Tables 1 and 2 list the materials that have been reported to create pronounced or prolonged signs and symptoms in a child following ingestion.
The rating of a product as "toxic" is a relative term.9 The products typically considered to be of moderate or severe toxicity significantly alter a single organ system or effect multiple organ systems. An overwhelming majority of toxic ingredients are dangerous only if a large volume of liquid or a great number of pills is consumed in a toddler’s misadventure.
|Table 1. Pharmaceuticals Toxic for Children|
|Table 2. Household Products and Plants Toxic for Children|
|Acid/Alkali||Antiseptics||Burtyrolactone (solvent for acrylate polymers)||Nitromethane (artificial nail remover)||Na Hwang||Weed/bug killers|
|Boric acid||Camphor||Methylene chloride (paint thinner)||Organophosphates||Mushrooms, specific||Lindane|
|Bowl cleansers||Hydrogen peroxide||Selenious acid (gun blueing)||Carbamate||Nutmeg||Nicotine|
|Clinitest tablet||Phenol||Zinc chloride (soldering flux)||Plants||Oleander||Paraquat|
|Disc battery||Pine oil||Mothballs||Aconite||Pennyroyal oil|
|Ethanol||Hydrocarbons||Nail products||Castor bean||Arsenic|
|Ethylene glycol||Aliphatics||Acetone (polish remover)||Clove oil||Hydroxycoumarin|
|Isopropyl alcohol||Aromatics||Acetonitrile (sculptured nail remover)||Comfrey||Indanediones|
|Methanol||Industrial Chemicals||Methacrylic acid (artificial nail primer)||Fox glove||Strychnine|
Extent of Exposure
The potential toxicity of a product is typically judged on the basis of mg/kg dosage or cc/kg volume of ingestion. The need for an accurate assessment of quantity consumed is obviously desirable.10 If the event was unwitnessed, accuracy is compromised. If the event was witnessed, the caretaker may provide insight. Unfortunately, the accuracy of even observant parents may be suspect.11 If directly witnessed, the volume consumed can be theoretically calculated. The volume of a swallow by individuals of all ages is a function of body mass. The volume of a swallow is 0.21 ml/kg, or roughly 1 tsp for a 2 year old.12
There are particular medications and substances that place children at risk for fatality. These substances are lethal because of the pharmacoactivity that can be pronounced in individuals with small body mass. Inherently, these highly-toxic substances create acute, disabling sequelae that tend to be pronounced in toddlers. Even if signs and symptoms are promptly addressed, fatalities may still occur.
The most frequent pediatric fatal pharmaceutical ingestions have been prenatal iron supplements, antidepressants, cardiotonic agents, and salicylates. Hydrocarbons, alcohols, cleaning substances, pesticides, and gun blueing agents have been the most commonly reported pediatric fatal non-pharmaceutical ingestions.1,2,7
Fatal Sip or Malignant Swallow
A diverse group of medications have been identified as particularly toxic to children younger than 2 years of age and weighing less than 10 kg. From 1983 through 1989, Koren identified eight specific medicinal preparations and two general categories of medications that were fatal upon ingestion of 1-2 tablets or 1-2 tsp. (See Table 3.)13 Drs. Liebelt and Shannon expanded the selected list by emphasizing three additional preparations in their 1993 publication (imidazoline compounds, benzocaine, diphenoxylate).14 It is our intent to revisit and update the pharmaceutical and non-pharmaceutical agents that have previously been emphasized to be highly toxic in small doses. The discussion will focus on pharmacology, available sources for exposure, projected toxicity, and specific treatments. By our review, there are roughly two dozen agents that have the potential to be fatal to a toddler upon 1-2 swallows or 1-2 tablets of a marketed dose unit. (See Table 4.)
|Table 3. Medicinal Preparations Fatal to a 10 kg Toddler*|
|* upon ingestion of 1-2 tablets, capsules, or teaspoonfuls|
|Adapted from Koren G. Medications which can kill a toddler with a tablet or teaspoon. Clin Toxicol 1993;31:407-413.|
|Table 4. Pharmaceutical and Household Products Highly Toxic to Toddlers|
|Acetonitrile||Chloroquine||Hyoscyamine sulfate||Pennyroyal oil|
|Ammonium fluoride||Chlorpromazine (others)||Imidazoline products||Quinine|
|Brodifacoum (others)||Desipramine (others)||Methadone||Selenious acid|
Acetonitrile. Acetonitrile is a 2-carbon aliphatic nitrile. It is also known as methyl cyanide, ethanitrile, and ethyl nitrite. The parent molecule has no intrinsic toxicity but is metabolized in the liver via cytochrome p450 enzyme yielding hydrogen cyanide.15
The major use for acetonitrile is in the artificial nail cosmetic industry. To be receptive, nails must be cleaned, degreased, and etched prior to adherence. This "nail priming" is best accomplished with a product containing methacrylic acid, which is a corrosive hazard for toddlers.16 After etching, an acrylic compound creates the plastic surface of an artificial nail. In order to remove the artificial nail, one of several chemical compounds need be applied. One artificial nail removing compound is nitromethane. Following ingestion, this has been reported to cause severe methemoglobinemia in a toddler.17 The other toxic compound used as an artificial nail remover is acetonitrile.
Almost pure concentrations of acetonitrile are distributed by the cosmetic industry in 1-2 ounce bottles. Brand names available in the United States typically suggest the function of the product, for example, Artificial Nail Tip Remover®. The commercially available acetonitrile products should not be confused with fingernail polish removers. The principle component of the latter is acetone, a product that must be consumed in large volume to create serious pediatric poisoning.18
Acetonitrile is highly toxic. The original case report of pediatric fatality from oral acetonitrile ingestion was reported in 1988.19 Other fatal intoxications as a result of hydrogen cyanide overdose have been subsequently reported.20 The median oral lethal dose for children is not known. However, as little as 5 mL, or one swallow, in a 10 kg toddler has been reported to result in fatality.21
The signs and symptoms from acetonitrile ingestion are typically delayed at least four hours. Cyanide is eliminated by the rhodanese-mediated oxidation of endogenous thiosulfate to non-toxic thiocyanate. This pathway must be overwhelmed to cause symptoms. As the pathway is overcome, nausea and vomiting herald toxicity. This is followed by central nervous system aberrations and cardiac manifestations as cyanide renders cells unable to use oxygen.
All children suspected of an ingestion of acetonitrile should be admitted because manifestations have been reported beyond 12 hours.20 Activated charcoal may be of benefit, although specific data are not available.19
Symptomatic patients should be admitted to an intensive care facility and treated with intravenous sodium thiosulfate. A continuous infusion of 1.65 mL/kg of the 25% solution is suggested.
Ammonium Fluoride. Sodium fluoride is placed in municipal water systems and in some bottled water to prevent dental carries. It is also found in toothpaste or as the main ingredient in anti-cavity rinses. Glass etching, de-rusting, and wheel cleaning commercial products may contain fluoride. Armoral Quick Silver Wheel Cleaner® is a 17% solution of ammonium fluoride and ammonium bifluoride.22 Rust Bust’R® contains up to 30% ammonium bifluoride, and glass etching cream contains 20% ammonium bifluoride and 13% sodium bifluoride.24
Adverse effects from elemental fluoride can occur after acute ingestion of 3-5mg/kg. A toddler may experience nausea, vomiting, diarrhea, or abdominal pain after ingesting a whole tube of a fluoride containing toothpaste or a whole bottle of anti-cavity rinse. A toddler who consumes a generous portion of a higher concentrated sodium fluoride-containing roach poison would be at risk for both gastrointestinal and systemic effects. However, as little as 2 mL can be fatal for a 10 kg child if the formulation contains 17% ammonium fluoride or ammonium bifluoride.22-24
Fluoride salts inactivate proteolytic and glycolytic enzymes. Additionally, fluoride binds with circulating calcium and magnesium. Manifestations of toxicity generally develop within an hour of ingestion. Most symptoms are mild and self-limited if less than 8 mg/kg of elemental fluoride is ingested. The GI manifestations, when severe, can include hematemesis. In large doses, fluoride may act directly on the central nervous system, producing abnormalities such as visual disturbance, paresthesia, headache, optic neuritis, and seizures. Seizures, acidosis, dysrhythmia, and coagulopathy can occur as a complication of hypocalcemia and hypomagnesemia.
Individuals who ingest less than 8 mg/kg of elemental fluoride may be monitored in the emergency department. Those with any symptoms other than gastrointestinal complaints should be admitted with evaluation of serum electrolytes, calcium, magnesium, and cardiac monitoring.
Benzocaine. Benzocaine is a local anesthetic that blocks sodium channels in axons, interfering with the generation of impulses through sensory fibers.26 Over-the-counter products such as teething gels, intra-oral rinses, pharyngeal anesthetics, hemorrhoidal preparations, vaginal creams, and first aid creams contain 3-20% benzocaine.
Mucosal application of benzocaine leads to rapidly measurable serum levels. Benzocaine is metabolized by serum pseudocholinesterase to several metabolites that are methemoglobin-forming compounds. Increased methemoglobin concentrations occur with higher benzocaine levels or reduced concentrations of methemoglobin reductase. Infants younger than 6 months are relatively deficient in methemoglobin reductase and are most susceptible to methemoglobinemia.27
Methemoglobinemia has been reported in toddlers from both transdermal and transmucosal exposure. Ointment applied to diaper denudations and hemorrhoidal cream application have produced toxicity in infants.28 However, the most frequent and potentially toxic exposures result from a single overzealous application or too-frequent applications of preparations intended for oral mucosal anesthesia.30 As little as 1.3 mL of 7.5% benzocaine (Baby Orajel®) has produced toxicity in infants.14 An oral ingestion of 0.5 tsp of the same product in a toddler has reportedly produced methemoglobin levels of 33%.31
Topical benzocaine can produce toxicity within an hour of exposure. Vomiting typically precedes central nervous system manifestations. In a verbal child, headache, tingling of the lips, dizziness, dysarthria, ataxia, and confusion may precede the "chocolate cyanosis." Toddlers may only exhibit irritability or somnolence concurrently with cyanosis with significant methemoglobinemia.34 Hypotonia, tachypnea, and tachycardia progress to seizure and severe metabolic acidosis. Vascular collapse in untreated cases is a result of decreased contractility and ventricular ectopy.26
Gastric lavage and charcoal adminstration should be based on individual patients. The mainstay of therapy is to address methemoglobinemia. This is accomplished with methylene blue, which works by activating the enzyme NADPH-dependent methemoglobin reductase. The enzyme transfers electrons to methylene blue, which uses these electrons to reduce methemoglobin.32 Methylene blue is indicated for methemoglobin levels greater than 30% or the presence of symptoms. It should be given at a dose of 1-2 mg/kg intravenously over a period of five minutes (0.1 mL/kg of 1% solution). An improvement should occur within 30 minutes. Depending upon the response and the measured methemoglobin level, repeat doses may be adminstered at 20-30 minute intervals to a maximum of 4 mg/kg in infants. Methylene blue should not be given to patients with G6PD deficiency, as they may experience severe red cell hemolysis. Exchange transfusion can also be considered to treat methemoglobinemia.33
Brodifacoum. Brodifacoum is one of several 4-hydroxy derivatives of coumarin. Along with diphenacoum, chlorphacione, and bromadiolone, and some other "superwarfarins," brodifacoum possesses at least 100 times the activity and markedly longer duration of action than coumarin.34 The superwarfarins produce anticoagulant effects by compromising vitamin K metabolism. Vitamin K is a co-factor in the synthesis of clotting factors II, VII, IX, and X. Vitamin K facilitates the carboxylation of glutamyl residues on clotting factor precursors. During the carboxylation reaction, vitamin K1 is converted to an inactive form. A reductase enzyme reduces the inactive form back to the active vitamin K1. This step is inhibited by brodifacoum and the other 4-hydroxy-coumarin anticoagulants.35
The superwarfarin compounds were developed in the 1980s to kill warfarin-resistant rats. The products have been successful rodenticides. Single ingestions uniformly produce fatal coagulation abnormalities in animals. Reported human exposures to brodifacoum have largely been deliberate ingestions in adults. Acute adult ingestion has rarely resulted in fatal coagulopathy.35 More often, acute or chronic intentional ingestion leads to prolonged anticoagulant effects for up to nine months.36 A toddler who ingests a few mouthfuls of brodifacoum-containing rat bait is theoretically at risk for prolonged, symptomatic coagulopathy. Unintentional and potentially abusive exposures in children, where volumes consumed are uncertain, have led to prolonged coagulopathy.37,38 Fatalities have not been reported in children. However, a toddler who ingests a few mouthfuls of brodifacoum-containing rat bait is at risk for prolonged, symptomatic coagulopathy.
Following acute ingestion, children are typically asymptomatic or experience only transient abdominal pain. In an unwitnessed event, particularly if the volume is low, most toxicologists suggest followup and de-emphasize any treatment.39
For those toddlers with a witnessed ingestion of more than a few mouthfuls, or those who become symptomatic (heme-positive stools or spontaneous mucous membrane bleeding) treatment with vitamin K1 should be initiated. Vitamin K1 may be given by oral, intramuscular, intravenous, or subcutaneous routes. The route and frequency must be determined by the clinical urgency and the results of the coagulation profile.
Butyrolactone. Butyrolactone is an intermediate compound used in the synthesis of methionine, piperidine, and phenylbuteric acid. Butyrolactone is a constitute of some paint removers and is used as a solvent for acrylate polymers such as Super Glue®. A pure butyrolactone product called Bullet® is commercially available in two-ounce bottles without a child-resistant cap. Ingestion of a few swallows of this product in a previously healthy toddler has been reported to cause severe toxicity.40 The mechanism postulated is in vivo conversion to gamma hydroxy butyrate.
Knowledge of clinical manifestations following ingestion are limited by the number of reported exposures. However, respiratory depression with apnea, altered mental status, decreased peripheral perfusion, loss of gag reflex, and bradycardia may occur shortly after exposure.40 The treatment is symptomatic and supportive
Camphor. Camphor is a cyclic ketone of the hydroaromatic terpene group that was obtained from the bark of the camphor tree. It is now produced synthetically from terpentine oil. Camphor has been used with variable success for centuries for a wide variety of supposedly therapeutic effects.14 It is currently used by the public as a rubefacient, a chest cold inhalant, and a topical anesthetic.
Camphor is available in multiple products, many that are not child proofed. Most over-the-counter sources include liniments (for example Ben-Gay Children’s Vaporizing Rub®, Vicks VapoRub®, Deep Down Rub®, and Mentholatum Ointment®) that range from 0.5% to 9.0% camphor. Campho-phenique®, containing 10.8% camphor, is the most widely available liquid preparation of camphor. The 20%-containing camphorated oil has not been distributed in the United States since 1983.
Camphor, in its liquid form, has a potential morbidity with an ingestion of as little as 50 mg/kg, and as little as 5 mL of a camphorated oil resulted in death in a toddler.41 Significant toxicity is likely with four mouthfuls of Vicks VapoRub® or two swallows of Campho-phenique®.42
Clinical manifestations that follow oral overdose are heralded by gastrointestinal complaints and dominated by central nervous systems changes.There are feelings of warmth, nausea, vomiting, and epigastric burning at the onset. Patients may experience a headache, confusion, restlessness, muscular excitability, and twitching, particularly of the face. Generalized seizure activity occurs in 4-42% of cases.14 Occasionally, patients may precipitously seize without antecedent signs or symptoms.42 Seizures are invariably prolonged, and status epilepticus with respiratory depression has led to most fatalities.43
Most often, clinical toxicity is quite rapidly evident. Seizures have been described within five minutes of ingestion.42 However, onset may be delayed for two hours post-ingestion.44 Therefore, an asymptomatic toddler, who may have ingested a small volume of camphor-containing product, should be observed in the emergency department for 3-4 hours. Activated charcoal has been reported to be ineffective,14 yet is still recommended.42 The patient should be maintained NPO and have seizure precautions taken.
Those who display early symptoms characteristic of camphor intoxication should be admitted for monitoring and supportive care. Benzodiazepine administration is the suggested first-line treatment of seizures. Barbiturates have been shown to prevent neuronal damage in an animal model and are known to enhance hepatic enzymes that metabolize camphor. Hence, phenobarbital is recommended for recurrent or prolonged generalized seizures.42
Chloroquine. Chloroquine is a synthetic 4-aminoquinoline anti-malarial agent. It also has been employed with success in the treatment of rheumatoid arthritis and discoid lupus. Chloroquine is available in tablet form as chloroquine phosphate tablets containing either 250 or 500 mg.
The therapeutic dose for pediatric patients suffering from malaria is roughly 5 mg/kg/24 hours. Manifestations of toxicity can be seen at doses that exceed 10 mg/kg/day. Following acute ingestion, a minimum fatal dose for children is estimated to be 20 mg/kg.13,45 A 10 kg toddler who consumes a single tablet is at theoretical risk for a morbid outcome.
Manifestations of acute chloroquine toxicity primarily relate to the gastrointestinal and cardiovascular systems. Gastrointestinal complaints, such as epigastric discomfort, nausea, vomiting, and diarrhea, are seen within 30 minutes of ingestion.46 Central nervous system stimulation, with or without seizures, is followed by a rapid clinical decline due to cardiovascular effects. Hypotension, vasodilatation, depressed myocardial function, QRS prolongation, and hypokalemia may precede cardiac standstill.13,47
Gastric lavage may be useful if employed within one hour of ingestion. Activated charcoal is known to be efficacious.48 Treatment for symptomatic patients is largely supportive. Benzodiazepines have shown neuronal protective effects in animal models and are suggested for treatment of seizures. Hypotension unresponsive to fluids should be treated with either dopamine, norepinephrine, or epinephrine infusion.49
Chlorpromazine/Thioridazine. Chlorpromazine (Thorazine®) is a member of the aliphatic class of phenothiazines. It has been used since the 1950s to therapeutically modify behavior. In addition to antipsychotic effects, it exhibits anticholinergic properties and a quinidine-like action.50
Side effects seen in acute overdose of phenothiazines are the summed result of the many pharmacologic actions. Other phenothiazines share much of the pharmacologic properties of chlorpromazine. One such agent, thioridazine (Mellaril), like chlorpromazine, has been found to be highly toxic for pediatric patients. Thioridazine also has a quinidine-like action that can cause myocardial depression and dysrhythmia.
Chlorpromazine is available in multiple dosage forms, including tablets and syrup. The tablets range from 10 mg to 300 mg. The syrups contain either 30 mg/mL or 100 mg/mL. The maximal unit dose available for thioridazine is 200 mg. The minimal potential lethal doses for thioridazine and chlorpromazine are 15 mg/kg and 25 mg/kg, respectively. One to two tablets of either medication, or several mLs of chlorpromazine syrup, can produce a morbid pediatric outcome.13,51
An acute overdose of a phenothiazine results in classic anticholinergic effects (flushed skin, dry mucous membranes, decreased bowel sounds, urinary retention, changes in affect), plus alterations in temperature regulation, a variety of neurologic syndromes, and cardiovascular depression. The onset of symptoms can occur within one hour of ingestion. The most consistent sign of toxicity is a depressed level of consciousness that results from disturbances of the reticular activating system. Patients may rapidly progress to profound coma, which typically is associated with miosis.52 Seizures may occur from a lowered seizure threshold. Patients may also exhibit a wide variety of dystonic effects.53 Central control of temperature regulation is disturbed and hypothermia can occur. Alternately, hyperthermia or neuroleptic malignant syndrome can occur. The cardiovascular effects can be clinically significant, and include hypotension and electrophysiologic changes. There may be ST segment depression and T wave changes. Prolongation of the PR, QRS, and QT intervals may also occur. Presenting rhythms include sinus tachycardia, ventricular tachycardia, and ventricular fibrillation.
Asymptomatic toddlers, following low-dose ingestion, should be monitored for six hours in the emergency department, since pharmacologic effects may not peak for 2-4 hours.54 Gastric lavage should be employed, if the ingestion occurred within one hour. Charcoal is also recommended.
Symptomatic patients require admission for at least 24 hours. Seizure precautions are mandated. Benzodiazepines and barbiturates are mandatory to treat brief seizures. Hypotension unresponsive to a fluid resuscitation should be treated with bicarbonate. If bicarbonate administration fails, norepinephrine is the pressor of choice. Epinephrine may be detrimental, with resulting hypotension from peripheral beta adrenergic stimulation. Dopamine may be ineffective due to depleted norepinephrine stores. Dantrolene is the drug of choice for neuroleptic malignant syndrome. Diphenhydramine or benzatropine mesylate can be used to treat dystonia.53
Clozapine. Clozapine is a member of the dibenzodiazepine class of antipsychotic drugs. It has been available since 1990 for the treatment of adult schizophrenia that is resistant to other neuroleptics. Clozapine is a dopamine receptor antagonist. It also possesses antiserotonergic, anticholinergic, and antihistaminic activity.55
In adults, some of the undesirable side effects seen at therapeutic doses are magnified with an acute overdose. Symptoms of acute overdose in adults include altered mental status (agitation, confusion, drowsiness, and coma), anticholinergic effects, cardiovascular instability (hypotension, hypertension, brady and tachydysrhythmias), and neuroleptic malignant syndrome.56 Mortality, which has occurred with as little as a 200 mg ingestion in adults, results from sudden cardiac death.57
Experience with accidental acute ingestion in the pediatric population is limited. Several case reports suggest prominent neurologic events such as ataxia, confusion, and unresponsiveness.58 Significant altered mental status with extrapyramidal effects was reported after a toddler ingested a single 100 mg tablet.55
Asymptomatic toddler ingestors of a single 100 mg tablet of clozapine should receive ED monitoring for a 4-6 hour period. Gastric decontamination, activated charcoal, and cathartics are all suggested, although no studies are available to substantiate efficacy.59
A symptomatic toddler should be admitted for extended observation and supportive care. Hypotension unresponsiveness to intravenous fluids should be treated with dopamine or norepinephrine. Epinephrine may be detrimental.60 Lidocaine and bicarbonate are recommended for ventricular dysrhythmias. Benzodiazepines and barbiturates are recommended for seizure activity.
Desipramine/Tricyclics. Desipramine is a congener and major metabolite of imipramine. Imipramine is a dibenzazepine compound structurally similar to phenothiazines that has been used since the late 1950s for treatment of depression. Desipramine and imipramine are classic three-ringed, older "tricyclic" agents. Newer agents (1, 3, and 4-ringed structures) possess similar therapeutic and toxic effects.61
Tricyclics are among the most commonly encountered causes of intentional overdose in the adult population.1,2 Adult and adolescent self-poisoning with these agents is particularly lethal. In the pediatric population, exposure to tricyclics is largely unintentional.62 Acute ingestion in young children carries life-threatening potential. Tricyclic fatalities during a select period have accounted for up to 10% of total toddler deaths from acute ingestion.13
The maximal unit dose available for desipramine and imipramine is 150 mg. The minimal lethal dose for these compounds is 15 mg/kg.13 Thus, an ingestion of 1-2 tablets could prove fatal to a toddler.
Clinical consequences of overdose in the adult and pediatric population are similar.63 Anticholinergic effects are typically seen but overshadowed by the central nervous system (excitement, restlessness, ataxia, hallucinations, lethargy, coma, seizures), cardiovascular effects (hypotension, re-entrant dysrhythmia), and metabolic derangements (hypoxia and metabolic acidosis).64
Most often, clinical toxicity from older and newer antidepressant overdose in children is evident quite rapidly.65 However, it is possible for pediatric patients, like adults, to remain asymptomatic for prolonged periods.66 Since benign appearance at emergency department presentation may not predict a toddler’s clinical course, conservative management (gastric decontamination and activated charcoal) and monitoring is appropriate. If the patient doesn’t have any central nervous system derangements, no changes in vital signs, and no changes in QRS axis or QRS interval changes, six hours of observation may be sufficient, particularly in an unwitnessed ingestion.67,68
Toddlers symptomatic with seizures, acidosis, or electrocardiographic abnormalities are at increased risk for significant morbidity and mortality.67 Like adults, they should be treated with fluids, sodium bicarbonate, and ionotropes.
Diphenoxylate. Diphenoxylate is a meperidine congener. It is a synthetic phenylperidine that, at high doses, has typical opioid activity. Diphenoxylate is combined with atropine in order to reduce the abuse potential in a number of marketed products, all prescribed for diarrheal illness. Diphenoxylate may ameliorate symptoms of adult enteritis by slowing gastrointestinal motility.
Lomotil® may be used as an antidiarrheal product. It contains 0.025 mg of atropine and 2.5 mg of diphenoxylate in each 5 mL of syrup or a single tablet. Adverse symptoms from Lomotil® in toddlers has been reported from both therapeutic antidiarrheal trials and from accidental ingestion.69 Toxicity in the very young has been seen with ingestion of as little as two tablets.70 The senior author failed to report his personal experience of a toddler death following an accidental ingestion of two Lomotil® tablets. In the literature, the minimal lethal dose is projected to be 1.25 mg/kg of diphenoxylate.71 This translates to roughly four tablets for a toddler.
As reported by Curtis, there may be poor correlation between the dose ingested and the severity of symptoms manifested by a pediatric patient in the emergency department.72 There may also be a variation in the time course and presenting features. The elapsed time of initial toxicity with Lomotil® may range from 1 to 12 hours post-ingestion. Most children present with effects by 2-4 hours post-ingestion.73 Atropinism can be the presenting constellation (dry mouth, difficulty swallowing, blurred vision, tachycardia, flushed skin, urgency, abdominal distention). Atropinism can occur concomitantly with central nervous system effects, or patients may have isolated opioid effects (respiratory depression, bradycardia, miosis, hypotension, altered mental status).
Gastric lavage is only effective if performed within one hour of ingestion. Charcoal and cathartics have been shown to be benecial for related opiates, but not specifically for diphenoxylate. All patients should be admitted because opioid symptoms may be delayed.14
Those symptomatic with opioid toxicity can be managed with intermittent naloxone injections or continuous naloxone infusion.74
Hydrocarbons. Hydrocarbons are a broad group of organic compounds that contain carbon and hydrogen. The hydrocarbons are arranged in straight-chain molecules (aliphatic) and benzene-based forms (aromatic). The products can further be divided by physical properties (such as viscosity, surface tension, volatility) and chemical makeup (such as halogenated and admixed with heavy metal pesticides). These characteristics influence the toxicity pattern following ingestion.75
Hydrocarbon products are ubiquitous. They are among the most common substances involved in pediatric toxic exposure.1,2 Most hydrocarbons ingested by small children are household cleaning products, solvents, and fluids such as gasoline, kerosene, and naphtha. At one point, 16% of pediatric poisoning deaths were the result of oral exposure to hydrocarbons.76 Of late, deaths from hydrocarbons are less common.1,2
The minimal amount of ingestion of a hydrocarbon product required to produce adverse clinical effects may be as little as a swallow. Most reports suggest that pediatric patients inadvertently drink less than 30 cc.77 Although some toddlers have not succumbed with ingestions estimated above 60-90 cc, as little as 15 cc has been reported to be fatal for a 2 year old.76
Adverse effects following ingestion are prompt in onset and include gag, choke, cough, transient drowsiness, and, if the quantity ingested is sufficient, spontaneous vomiting.77 Further symptoms may be more insidious. These symptoms include paroxysmal cough, tachypnea, bronchospasm, retractions, grunting, fatigue, decreased motor tone, cyanosis, and seizures.77,78 Death may result from pulmonary insufficiency, myocardial infarction, or dysrhythmia.79
Asymptomatic children may be observed in the emergency department for four hours. No effort should be made to perform gut decontamination as this may increase the likelihood of vomiting. An child who remains asymptomatic (i.e., no cough, no increase in work of breathing, and no evidence of hypoxia) requires no further diagnostic evaluation. Asymptomatic patients who are discharged are unlikely to develop later signs or symptoms.81
Symptomatic patients require cardiovascular and pulmonary support that may include extracorporeal membrane oxygenation.75
Hyoscyamine. Hyoscyamine, a naturally occurring tertiary amine, is one of the anticholinergic alkaloid components of the Solanaceae family of plants. Atropine is racemized during the extraction from belladonna plants and consists of a mixture of equal parts of d-and-l hyoscyamine. Like other anticholinergics, hyoscyamine inhibits gastrointestinal motility and decreases gastric acid secretion. In adults, hyoscyamine has been used in the treatment of peptic ulcer disease and hypermotility syndromes. For children, there is anecdotal support for treatment of excessive infantile crying (colic).82
The maximal unit dose available for hyoscyamine as a tablet is 0.375 mg. The elixirs contain 0.125 mg/tsp. Drops commonly prescribed for infants (such as Levsin®) contain 0.125 mg/mL (20 drops) hyoscyamine sulfate.
The projected pediatric therapeutic dose of Levsin as drops for a 10 kg child is 8 drops. A single exposure of as little as 2 mL can cause adverse symptoms.82 Death has not been reported with hyoscyamine sulfate. Life-threatening symptomatology and death are in fact rare with all anticholinergic medication poisoning.83 There have, however, been a few deaths reported from atropine administration in children.84 A fatal dose of atropine was reported with1.6 mg.85
Adverse effects from hyoscyamine sulfate overdose may be seen promptly after ingestion. Toddlers experience the classic toxidrome of anticholinergic crisis. They will be febrile and tachycardiac, with flushed skin, dilated pupils, absent bowel sounds, and alteration of mental status.
Supportive care remains the mainstay of treatment. Benzodiazepines are recommended for seizures. Physostigmine is rarely required but may be of utility in the management of anticholinergic toxicity.86
Imidazoline Products. Sympathetic amines that are imidazoline derivatives are the active ingredients in over-the-counter and prescription nasal and ocular decongestants.Oxymetazoline, naphazoline, tetrahydrozoline, and xylometazoline are in ocular drops and nasal sprays at a wide variety of concentrations. The 15-30 mL packages contain from 1.8-20 mg of imidazoline.
Adverse effects from inadvertent ingestion of imidazoline intended for topical application have been seen in infants with ingestions of less than 1 mL.14 As little as 2.5 mL of 0.5% tetrahydrozoline (1.25 mg) has resulted in respiratory depression.87 An oral exposure of 3 mg tetrahydrozoline in a toddler resulted in profound alteration in sensorium.88 Similar systemic effects have been witnessed with a small-volume ingestion of naphazoline and oxymetazoline.89
Central nervous system and cardiovascular changes predominate following oral ingestion.90 The central nervous signs and symptoms can fluctuate, with alternating excitation (agitation, tremor, nervousness, seizures) and depression (from lethargy to coma).88,90 The cardiovascular changes may also be in opposition. Either hypertension and tachycardia or hypotension and bradycardia may occur.89
Clinical toxicity is prompt due to rapid absorption from the gastrointestinal tract. Gastric emptying is of no value. The role for activated charcoal has not been established.88 Naloxone has been suggested as a potential treatment of altered sensorium, but clinical effectiveness has been debated. Dopamine is suggested for hypotension refractory to fluids. Atropine or isoproterenol is suggested for bradycardia.89
Lindane. Lindane is an organochlorine insecticide. It is available in a 1% concentration as a lotion, cream, and shampoo. A popular product, Kwell®, can cause toxicity with topical application.91 Oral exposure is uncommon.1,2 Typically, large doses are required to cause fatality.92
Inadvertent oral exposure to lindane in young children has lead to toxicity. Aks et al reported vomiting, lethargy, respiratory depression, and seizures in three toddlers who ingested from 1 to 3 tsp of lotion.93
Seizures from lindane exposure via any route can be treated with benzodiazepines or barbiturates.
Methadone. Methadone is an opioid analgesic that has pharmacologic properties qualitatively similar to morphine. Since the inception of methadone as an alternate opiate for the treatment of heroin addiction, there have been reports of pediatric intoxications. Deaths in toddlers throughout the late 60s and 70s were frequently reported tragedies.94 The incidence of pediatric methadone toxicity has decreased markedly since 1980, yet inadvertent pediatric exposures and deaths continue.2
The initial maximal dose recommended for adults of methadone is 15 mg. Doses in excess of 30 mg can cause respiratory depression. Toddler deaths have been reported with ingestions of 50 mg.94 Methadone is dispensed in 10 mg/mL suspension, and 1 tsp in a toddler can be fatal.
Nausea, vomiting, miosis, depressed sensorium, and respiratory drive can be seen within 30 minutes after ingestion. Coma, pulmonary edema, and apnea can have a latency up to four hours post-ingestion.95
Treatment includes gastric emptying (within 1 hour of ingestion), charcoal, high-dose naloxone, and respiratory support.96,97
Methanol. Methanol intoxication is possible through dermal absorption, inhalation, or ingestion.98 Inadvertent oral pediatric encounters are facilitated by unsafe household storage and lack of childproof containers. Multiple sources exist in the typical home—glass cleaners, paint stripper, windshield deicer, and windshield solution containing from 2-100% methanol.
Reports of fatalities from oral exposure to methanol are yearly occurrences.1,2 As little as 15 cc of a 40% methanol solution has been reported to be fatal to an adult. Most authors suggest the untreated lethal dose for an adult approximates 0.5-1.0 cc/kg.99 The minimal fatal dose for a toddler who ingests a concentrated methanol solution may be as little as a teaspoon.100
Clinical symptoms may appear within an hour of ingestion. However, a latency of 12-24 hours is typically needed to accumulate the toxic product, formic acid. Prominent manifestations include nausea, vomiting, abdominal pain, headache, and visual disturbance. The latter, a hallmark of methanol intoxication, will not be elicited in a toddler. The other neurologic symptoms that may occur include lethargy that may progress to coma, focal neurologic deficit, and seizure.101 Gastric emptying, activated charcoal, or cathartic adminstration are ineffective techniques, even if carried out promptly in an asymptomatic child shortly after methanol ingestion. Admission for 24 hours of observation in a suspected ingestion may be appropriate.
Symptomatic ingestors are managed with intravenous ethanol and hemodialysis.102 The new antidote, 4-Methylpyrazole, was effective in one case report of pediatric methanol toxicity.
Methyl Salicylate. Methyl salicylate is found in over-the-counter liniments, lotions, and food-flavoring additives. Popular topical products typically contain 15-30% methyl salicylate. Oil-of-wintergreen liniment contains 98% methyl salicylate, as does oil-of-wintergreen candy flavoring.103
An untreated acute ingestion of 150 mg/kg of salicylate can prove to be toxic. An untreated ingestion 300 mg/kg or higher can be fatal.104 One teaspoon of oil-of-wintergreen is equivalent to 7 gm of salicylate. A 10 kg child who ingests 0.5 tsp of oil-of-wintergreen or a few mouthfuls of a 20-30% methyl salicylate liniment could experience serious toxicity. As little as 4 mL ingestion of oil-of-wintergreen has caused a pediatric death.105
The earliest signs and symptoms of acute methyl salicylate poisoning in children are seen within several hours.106 Hyperpnea and vomiting are typical. Nausea and tinnitus or diminished hearing, usual findings in a verbal population, will not be expressed by toddlers. Hyperthermia, excitation, and delirium may progress to seizures or coma. Hypoglycemia may contribute to the blunted mental status. Rarely, hyperglycemia may contribute to an exaggerated fluid loss.107 Ultimately, the poor perfusion state is magnified by myocardial dysfunction, bradydysrhythmia, pulmonary edema, and rhabdomyolysis with renal failure.108-110
Treatment for asymptomatic children who present within one hour of ingestion include gastric lavage and activated charcoal. Repeat doses of charcoal at 3-4 hour intervals may be of benefit.111
The cornerstone of treatment for symptomatic patients includes ventilatory support, hydration, establishment of a normoglycemic state, correction of acid-base imbalance, and hyperthermia while enhancing the urinary excretion of salicylates by alkalinization of the urine. Hemodialysis may be crucial to successful management in circumstances of renal failure, pulmonary edema, severe acid-base abnormalities, or severe neurologic symptoms.14,108,109
Pennyroyal Oil. Available to consumers through health food stores are an array of natural remedies that are toxic. Among the most toxic to a toddler are a number of herbal preparations.90 Among the most potentially toxic to toddlers is pennyroyal oil. This is a volatile oil produced from the leaves and flowering tips of the pennyroyal plant. Pennyroyal oil is sold to remedy respiratory complaints, to serve as a digestive aid, and to induce menses.112
The main constituent of pennyroyal oil is pulegone. In man, pulegone is converted in the liver to methofuran by the cytochrome P450 enzyme system. Pulegone depletes glutathione, methofuran accumulates, and causes direct tissue injury to the liver, and to a lesser extent, the lung. This mechanism of cellular injury is similar to that seen with acetaminophen.113
The data on the volume of pennyroyal oil needed to produce harmful serum levels of pulegone and methofuran are limited. However, in adults, it has been reported that less than a teaspoon of pennyroyal oil can cause hepatotoxicity, and a tablespoon has proved fatal.114 There have been only a few cases of toxicity in the pediatric population, and these children’s symptoms followed exposure to several ounces of brewed tea.113
Charcoal and cathartics plus a four-hour period of observation are suggested for asymptomatic children.
Despite animal studies that refute its utility, authors recommend the early use of N-acetylcysteine as a glutathione substitute in symptomatic children.115
Quinine. Quinine can be synthesized or acquired from the bark of the cinchona tree. The alkaloid primarily acts as a blood schizonticide. It is principally used by physicians to treat chloroquine-resistant strains of Plasmodium falciparum. Quinine may also be used to treat adult recumbency cramps. The public has long used quinine as an abortifacient.116
The fatal adult dose of quinine approximates 50-80 mg/kg. The minimal potential fatal dose for children is 80 mg/kg.13 The most commonly used quinine is the sulfate that is available in 650 mg tablets. Hence, 1-2 tablets may prove fatal for toddlers.
Within 1-2 hours of toxic ingestion of quinine, headache, nausea, vomiting, abdominal pain, and diarrhea are seen. The central nervous system is stimulated, causing excitation, confusion, and seizures, as well as changes in vision and hearing. Central nervous system depression with coma can be compounded by drug-induced hypoglycemia. Hypotension is common. Cardiac effects may occur with widening of the QRS and the Q-Tc interval. High-grade SA block, ventricular tachycardia, or asystole may be fatal.117-118
Gastric lavage is largely ineffective in the symptomatic patient, but may be performed if the patient presents within one hour of ingestion. Activated charcoal may be of use. Hypotension unresponsive to fluids should be treated with bicarbonate, then norepinephrine. Benzodiazepines are recommended for seizures.118
Salt. A single overzealous or inadvertent ingestion of table salt can cause severe hypernatremia. Patients who are hypernatremic on the basis of pure sodium addition to their extracellular fluid become hypervolemic.
A teaspoon of table salt weighs approximately 7 g. In adults, a lethal dose of table salt ingestion has been reported with as little as 0.75 g/kg.The pediatric lethal dose is estimated to be 3 g/kg.119 A 10 kg child who ingests 2 tsp of table salt may elevate their serum sodium by 20-30 mEq/L.
Hypernatremia with serum sodium concentrations above 150 mEq/L that results from pure sodium excess causes restlessness, irritability, and muscular twitching. High-pitched cry, seizures, coma, and permanent neurologic sequelae occur with serum sodium concentrations reaching 160 mEq/L.120
Treatment for hypernatremic, hypervolemic patients includes augmentation of sodium excretion with diuretics as well as concomitant water administration. Cardiovascular compromise with pulmonary edema may require sodium and fluid removal through dialysis or hemofiltration.121
Selenious Acid. Selenium is a trace element; selenious acid is an inorganic selenium compound. Whereas elemental selenium is nontoxic, selenious acid is highly toxic. It may cause symptomatology when penetrated from the skin, inhaled, or taken orally.
Selenious acid is used by craftspeople to create a pewter resemblance of tin and by gun enthusiasts to restore a blue patina to metal. The gun blueing compounds contain 1-4% selenious acid plus other potential toxins including copper nitrate, copper sulfate, nitric acid, and occasionally methanol.
A 30-60 mL ingestion of gun blueing compound has caused fatality in an adult, and 15 mL has resulted in pediatric death.122
Symptoms are prompt following oral exposure to selenious acid. The corrosive nature can cause local toxicity to the oropharynx, the esophagus, or the stomach, producing dysphagia, dysphonia, or drooling. Absorption of selenious acid is rapid from the gut. A volatile metabolite, dimethylselenide creates a garlic-breath odor. Pulmonary edema may complicate respiratory depression. Initial hypertension is promptly followed by hypotension and shock. Decreased myocardial contractility and dysrhythmia may contribute to death.123
Management of oral selenious acid poisoning is supportive. Gastric lavage carries risk of perforation. Activated charcoal is unlikely to be of use. All patients with suspected ingestion of selenious acid should be admitted for observation.
Theophylline. Theophylline is a demethylated xanthine that has the ability to inhibit cyclic nucleotide phosphodiesterases and to antagonize receptor-mediated actions of adenosine. A large number of immediate-acting and sustained-released preparations have been marketed. Currently, theophylline’s widest use is for chronic obstructive pulmonary disease, and, to a lesser extent, for asthma unresponsive to beta-agonists.
The risk for serious toxicity after acute oral exposure to theophylline is effected by the patient’s age. Infants and toddlers are at greater risk of life-threatening events than older children.124 The relationship of clinical manifestations with the parameter of volume ingested is not well known.125 By and large, authors have reported clinical toxicity with measured serum theophylline levels rather than focusing on the adversity seen with a given volume of ingestion.126 Koren reported a minimum fatal dose in toddlers at 8.4 mg/kg.13 On the assumption that the threshold for toxicity approaches this value, a single 500 mg theophylline tablet may adversely effect a toddler. If completely absorbed, such a 50 mg/kg dose could result in a peak serum concentration of 100 mcg/mL.127 Serum concentrations of 100-120 mcg/mL in toddlers will uniformly produce toxic manifestations.126 Two tablets could produce a fatality.
In an acute overdose of an immediate-acting preparation, children become symptomatic within 1-2 hours. Symptoms from sustained-released preparations may be delayed for 6-8 hours. Gastrointestinal manifestations of nausea, vomiting, and abdominal pain predominate but are not as dramatic as generalized motor seizure nor as life threatening as various tachydysrhythmias, hypotension and asystole.126,127 Metabolic derangements such as hypokalemia, hyperglycemia, and acidosis may influence the presenting features and need to be addressed in management of the overdose patient.
Gut decontamination should be contemplated for an asymptomatic patient who presents promptly after suspected ingestion, especially of a sustained-release preparation. Whole bowel irrigation may be efficacious.128 Whole bowel irrigation can be combined with activated charcoal. Alternately, multiple doses of activated charcoal may be utilized.129 Hypotension and tachycardia unresponsive to fluid challenge may be treated with beta-adrenergic blockers. Diltiazem, lidocaine, and propranolol have been recommended for ventricular dysrhythmia. Benzodiazepines are recommended as the first line agents for seizure. Charcoal hemoperfusion may be technically challenging for toddlers. Exchange transfusion has been shown to increase theophylline clearance in small infants and has been recommended as a "last resort."130
Clearly, small quantities of some medications, household products, and plants can have significant devastating consequences in a child younger than 2 years of age. We have addressed the therapeutic interventions for asymptomatic and symptomatic patients who are at risk for a morbid outcome.
Fortunately, the emergency physician is unlikely to encounter many toddlers who need aggressive therapeutics following exposure to toxins. In addition to careful evaluation, appropriate monitoring, and aggressive intervention when indicated, the emergency physician should provide educational information for all children who are evaluated for an ingestion. Instruction on our part may contribute more to the future health of the child than any other strategy.131 We should not ever underestimate the influence of our secondary preventative efforts.132
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