Pediatric Single-Dose Fatal Ingestions

Infants, toddlers, and small children are naturally curious, but do not have an appreciation of risk, or understanding of warning labels.  This puts them at increased risk of harm and death from ingestions.  The use of child-safe containers for medications and household chemicals helps to decrease this risk.  However, many adults do not fully appreciate the potential toxicity of their medications and household chemicals, and may transfer these substances into less secure containers such as daily pill organizers or open cups for ease of use.  

Pathophysiology varies according to the ingested substance. Children are particularly susceptible to injury from ingestion of small doses for the following reasons:

• The low body mass and circulating blood volumes of children means that a single ingested dose of a substance may easily achieve concentrations in plasma or target tissues that far exceed concentrations in adults.

• While exploring their surroundings, younger children, especially toddlers, may ingest substances with objectionable tastes or odors that would be rejected by older children and adults.

• The metabolic pathways of young children, particularly infants, are less developed and use sulfonation rather than glucuronidation to process some toxins.

• Many of the hepatic enzyme systems in smaller children may not be efficient at clearing substances or their metabolites from the circulation, increasing their concentrations and half-lives.

The following medications are of most concern:

• Calcium channel blockers (especially verapamil, nifedipine, and diltiazem)
• Sulfonylureas
• Opioids
• Amphetamines
• Sodium channel blockers (chloroquine, tricyclic antidepressants [TCAs], propranolol, dextropropoxyphene)
• Theophylline

The drugs of abuse that are potentially fatal include all amphetamines (including methamphetamine and MDMA) and opiates.

Non-pharmaceuticals that pose a risk of significant toxicity include the following:

• Organophosphate and carbamate insecticides
• Paraquat
• Toxic alcohols (including glycols)
• Hydrocarbons (solvents, eucalyptus oil, kerosene, naphthalene)
• Camphor

The availability of non-pharmaceuticals in the community is extensive and any potential chemical ingestion requires a detailed review of the individual components. It is beyond the scope of this article to list every potential toxic ingestion. Included in the list below are case reports of fatalities associated with specific ingestions however expert assistance is required and the regional poison control center should be contacted for detailed risk assessment.

Pharmaceuticals

Tricyclic antidepressants: A dose of 10-20 mg/kg can be fatal. ^{[4, 5, 6, 7]}  Toxicity is characterized by coma, seizures, hypotension, and ventricular arrhythmias. Case reports include the following:

• Desipramine: Two 75-mg tablets may be fatal.

• A 3-year-old boy on long-term therapy using desipramine 100-mg tablets died within 47 hours postingestion after obtaining two or three extra tablets either from his own or a 6-year-old sibling's prescription. ^[8]

• A 2-year-old boy ingested one desipramine 50-mg tablet and died a few hours postingestion. ^[9]

• A 4-year-old boy died after ingesting 90 ml (450 mg) of imipramine syrup ^{[10, 11]}

• A 6-year-old girl on long-term imipramine therapy for attention deficit disorder was found dead in her home after her mother had given the child 15-20 mg to induce sleep. ^[12]

• A 9-month-old girl was given half of a 100-mg amitriptyline tablet to induce sleep. She arrived unresponsive at the emergency department (ED) 2-3 hours postingestion and died a few hours after admission. ^[13]

• Amoxapine (tetracyclic compound): The minimum fatal dose is 250 mg in children; seizures are a risk. ^{[14, 15]}

Monoamine oxidase inhibitors: Fatal ingestions have occurred with 4-mg/kg to 6-mg/kg doses. ^[16] . Ingestions of one or two tablets of irreversible non-selective MAOIs maybe associated with toxicity. ^[17]

The antimalarial drugs chloroquine and hydroxychloroquine: Toxicity is characterized by rapid onset of hypokalemia, coma, seizures, and cardiorespiratory arrest within 1-3 hours. ECG changes include prolonged PR, QRS, and QT intervals and ventricular dysrhythmias. ^[18]

With chloroquine, a single 500-mg tablet can be fatal. Case reports include the following:

• A 24-month-old boy was found with a single tablet in his hand; his respiratory system became compromised, and he required cardiopulmonary resuscitation (CPR) shortly thereafter; lfe support was withdrawn 8 days postingestion. ^[19]

• A 12-month-old boy who ingested 1 g was unresponsive 30 minutes postingestion and died within 3 days. ^[20]

• Chloroquine phosphate and primaquine (Aralen): A 12-month-old child was pronounced brain dead approximately 24 hours after ingesting a single Aralen tablet and sucking the coating of 12 tablets. ^[21]

• Fatal chloroquine poisoning in children has been reported with doses of 1 g and 3.5 g ^[22]

• Literature review of 22 unintentional ingestions in children between 1961 and 1990 included 16 deaths (73%) and three patients left in persistent vegetative state; ^[23]  fatalities also associated with iatrogenic exposure

Cardiovascular drugs.

Calcium channel blocker toxicity includes severe cardiovascular collapse due to the combination of decreased mycardial contractility, decrease in heart rate due to decreased electrical conduction, and vasodilation by relaxation of arteriolar smooth muscle.  This results in decreased cardiac output (by decreasing stroke volume and rate) and hypotension from vasodilation..This toxicity may be delayed 4-16 hours after ingestion with extended-release preparations. Verapamil and nifedipine are more likely to be associated with symptomatic toxicity. Potential ingestion of an extended-release preparation mandates a prolonged observation period (minimum of 12 hours up to 24 hours). ^[24]

Verapamil case reports include the following:

• One or two 240 mg tablets can be fatal

• Literature review ^[24]  identified five case reports of fatal verapamil ingestion; toxic doses for the sustained release preparation ranged from 12-120mg/kg.

• A 4-year-old boy who ingested 6-10 sustained-release verapamil tablets and 2-4 cold capsules (acetaminophen, chlorpheniramine, pseudoephedrine, dextromethorphan) went into cardiac arrest approximately 5 hours postingestion and died within 24 hours of admission. ^{[25, 26]}

• A 7-day-old boy inadvertently ingested 25 mg verapamil and died 20 hours postingestion. ^[27]

Nifedipine case reports include the following:

• Literature review ^[24]  identified 18 case reports of toxic or fatal nifedipine ingestions in toddlers; of the nine toddlers who died, three ingested only 1-2 pills, four ingested an unknown number, and two ingested more than 10 tablets.

• A 14-month-old girl who ingested a single 10-mg nifedipine capsule died 3 hours postingestion. ^[28]

• An 11-month-old boy ingested four 10-mg nifedipine capsules and died 2 days postingestion. ^[29]

• A 14-month-old child ingested a single 10-mg nifedipine capsule and died 4 hours postingestion. ^[30]

Beta-blockers: Although beta-blockers (including propranolol, commonly used to treat infantile hemangiomas) ^[85] can be associated with systemic toxicity, a literature review found no documented case of death or serious toxicity related to beta-blocker ingestion in pediatric patients younger than 6 years old. ^[31]  Reported toxicity includes hypoglycemia, ^{[31, 32]}  second-degree heart block, ^[32] and QRS widening and ventricular arrhythmias from sodium channel blockade;  it also crosses the blood-brain barrier and may be associated with reduced Glasgow coma scale score and seizure activity. ^[33]

Clonidine:  An alpha-2 agonist, clonidine is often used for management of hypertension, but is also used to treat insomina. Ingestion of 0.1 mg/kg may cause bradycardia, hypotension, respiratory depression, and apnea. Because clonidine also has some alpha-1 activity, patients with clonidine overdose may initially have normal or even elevated blood pressure, obscuring the diagnosis of clonidine ingestion .  A retrospective review of the American Association of Poison Control Centers' National Poison Data System from January 2000 to December 2011 identified seven cardiac arrests and three deaths from clonidine. ^[34]   

Lorcainide: Approximately 50 mg/kg can be fatal. ^[35]

Quinidine: Two 300-mg tablets can be fatal.

Disopyramide: A 2-year-old child ingested 600 mg and died 12 hours postingestion. ^[36]

Lidocaine: Ingestion of 1 oz of 2% viscous lidocaine solution was almost fatal in a 20-month-old girl. ^[37]

Opioids

Opioid analgesic agents may lead to significant CNS and respiratory depression. ^[38]  Methadone is the most toxic opioid; a single dose can lead to fatalities in children. A literature review identified 21 fatalities associated with methadone ingestion (up to 2002) and 64 cases of significant CNS/respiratory depression. ^[38]  Case reports include the following:

• A 2-year-old boy who ingested approximately 12 mL (10 mg/mL) of his mother's methadone died within 3 days of presentation. ^[12]

• A 5-year-old girl given a single 10-mg tablet to stop coughing died 6.5 hours postingestion. ^[25]

• A 12-month-old boy who drank 1.5 oz of a bottle containing 35 mg of methadone in 8 oz of formula died approximately 24 hours postingestion. ^[39]

Codeine may be fatal to a toddler who ingests three 60-mg tablets. ^[40]  Limited data suggest that children who ingested > 5 mg/kg of codeine require up to 6 hours of observation in the ED. ^[38]   Because the action of codeine depends on conversion to morphine via the cytochrome P450 enzyme CDP2D6, individuals with increased enzyme activity are especially prone to codeine toxicity through rapid conversion of codeine to morphine, even at clonidine doses which would otherwise not produce toxicity in individuals with normal enzyme activity.  The FDA updated warnings regarding the use of codeine in 2018, issuing a statement the codeine was contraindicated for the treatment of pain or cough in children under the age of 18 years. ^[84]

Fentanyl patches have caused death in opioid-naive patients who have chewed or sucked on the patches. This has led the FDA to release a statement on the risks to children and advice for safe disposal of patches. The release comments on 12 deaths associated with inadvertent fentanyl patch exposure. ^[41] Case reports include the following:

• In a retrospective review of data over 5 years at the Texas Poison Center Network, one death was recorded following the improper administration of a fentanyl patch by a care giver. ^[42]

• A 1-year-old child died after ingestion of a transdermal fentayl patch. ^[43]

Toxicity from other opioids includes the following:

• Five or six tablets of diphenoxylate at 2.5 mg and atropine at 0.025 mg (Lomotil) may cause coma or respiratory depression. ^[44]

• Propxyphene may induce sodium channel blockade with subsequent widening of the QRS, AV blockade, and dysrhythmias. ^[38]

• A 13-month-old child died after being found with a sublingual buprenorphine/naloxone (8 mg/2 mg) tablet in his mouth. ^[45]

Sulfonylureas

Ingestion of 1 or 2 tablets can lead to profound hypoglycemia and fatalities if not adequately treated. ^[46]  All children with potential sulfonylurea ingestion should be observed in hospital with blood sugar levels taken for a minimum of 8 hours and potentially longer. ^[47]  Symptomatic hypoglycemia may occur late.

Theophylline

Symptoms of theophylline toxicity include vomiting, tremors, agitation and seizures. Metabolic changes include hyperglycemia, hypokalemia, hypophosphatemia, metabolic acidosis, and respiratory alkalosis. In addition, theophylline can cause significant arrhythmias. ^[48]

Ingestion of one 200-mg modified-release tablet will lead to toxicity in a 10-kg child. Ingestion of more than one tablet may be life threatening. ^[49]  In one case report, an 8-kg child who ingested three tablets (445 mg) of theophylline presented with delayed seizures and tachycardia of 250 beats/min. ^[50]

Antipsychotic drugs

Life-threatening toxicity may include the following:

• Thioridazine: One 200-mg tablet can be fatal.

• Chlorpromazine: A 1-year-old child went into coma and respiratory arrest after ingesting 200 mg. ^[51]

• Clozapine: A 2-year-old girl who weighed 10.5 kg was found chewing a single 100-mg clozapine tablet; she was brought to the ED an hour later after becoming ataxic, and died 16 days later from cardiac arrest secondary to respiratory failure. ^[52]

Miscellaneous drugs

Colchicine ingestion is potentially life-threatening. Effects are dose dependent, with doses of 0.5–0.8 mg/kg causing systemic toxicity. Doses >0.8 mg/kg lead to multi-organ failure and mortality approaches 100%. In a series of 23 cases of colchicine ingestion treated at a single pediatric intensive care unit (from November 1985 to March 2011), four patients had taken more than 0.8 mg/kg and three of them died. ^[53]

Iron ingestion can be life-threatening; 10 adult tablets may be fatal in a child. Children are more likely to consume more than one or two tablets of iron as the tablets are brightly colored, often sugar coated, and often considered harmless by care givers. Public education and changes in packaging has led to the reduction of significant toxicity from iron ingestion. Iron supplements were thought to be the primary cause of death in 16 pediatric patients over an 8-year period. ^[54]

Pseudoephedrine: A 2-year-old child was found dead after ingesting approximately seven 60-mg tablets. ^[36]

Topical preparations

Oil of wintergreen (methyl salicylate): less than 5 mL (ie, 1 tsp) of oil of wintergreen is a potentially fatal dose, as it contains 7 g of salicylate. Case reports of fatal ingestions of oil of wintergreen include a 2-year-old boy who ingested 7.5 mL, ^[55]  a 2-year-old girl who ingested 15 mL, ^[9]  and another 2-year-old girl who ingested 10 mL. ^[25]   Other methyl salicylate formulations have been associated with toxicity from topical application, either through enhanced absorption, chronic use, or both.   ^[88]

Benzocaine topical gels and liquids are contraindicated in children younger than 2 years due to a risk of methemoglobinemia ^[86] . Small doses may lead to significant toxicity.

Camphor: Five milliliters (ie, 1 tsp) of 20% camphor oil or more than 50 mg/kg is a potentially lethal dose. ^[15]  A 19-month-old child who ingested 5 mL of camphorated oil died 5 days postingestion. ^[56]  Concentrations of 0.1 to 11% when used on unbroken skin is likely to be safe. Toxicity may be more likely to occur if the oil is used on broken skin or higher concentrations are used.

Dibucaine (Proctosedyl): A 8-month-old girl who ingested approximately half of a 30-g tube (ie, 150 mg, or 15 mg/kg) died 7 hours postingestion. ^[52]  A 17-month-old girl ingested approximately 22.5 g of ointment, developed cardiorespiratory arrest, and died approximately 4 hours postingestion. ^[27]

Drugs of Abuse

Symptoms of nicotine toxicity include vomiting, tachycardia, agitation and seizures. Toxicity can progress to lethal dysrhythmias and paralysis. ^[57]

A lethal dose of nicotine is estimated to be 1 mg/kg. Electronic cigarette (e-cigarette) solutions come in 5-20 ml vials with concentrations that vary from 8.5-22.2 mg/ml. ^[58]  Epidemiological studies note an increase in exposures of children to e-cigarettes with 717 exposures in children < 5 years between June 2010 and September 2013. ^[59]  Most patients experienced only minor effects. However, there is a real risk of significant toxic ingestion of nicotine in pediatric patients.

Ingestion of a single whole cigarette can be fatal. An 11-month-old girl was found dead at home. Autopsy revealed five undigested cigarettes and one tablet of diazepam. ^[12]

Amphetamines produce central and peripheral sympathomimetic effects. A single methamphetamine tablet may produce life-threatening toxicity. As methamphetamine abuse grows in the community, higher numbers of methamphetamine toxicity in pediatric patients occur. ^[60]  In one review, the most common presenting complaint was agitation; two patients developed seizures. ^[60]

The substance 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can be life-threatening. Status epilepticus from MDMA was reported in a 13-month-old boy. ^[61]  Two other case reports of seizures and significant sympathomimetic effects have been reported. ^{[62, 63]} Para-methoxyamphetamine, which may be sold as MDMA, can significantly increase blood pressure, body temperature, and pulse rate. ^[64]  Ingestion of a single tablet is potentially fatal.

Hallucinogen toxicity includes the following:

• Lysergic acid diethylamide (LSD): A dose of 0.2 mg/kg is potentially fatal. ^[15]

• Ibogaine: Approximately 29 mg/kg can be fatal.

Non-pharmaceuticals

Alcohols have been involved in fatal poisonings, at the following doses:

• Methanol - 15 mL of 40% solution ^[15]

• Ethylene glycol - 1-1.5 mL/kg ^[15]

• Isopropyl alcohol - 2-4 mL/kg of 70% solution ^[15]

• Ethanol -1-2 oz of cologne. Ethanol hand sanitizer. ^[15]

Chemical agents

Pesticide and herbicide fatalities have included the following:

• Diquat: Ingestion of 20 mL of a 20% solution was fatal in a 2-year-old child. ^[65]

• Paraquat: A dose of 25-50 mg/kg is deadly (7.5-10ml of 20%). ^[15]  The delayed pulmonary effects of paraquat is the most significant cause of its toxicity, with initial pulmonary edema and acute lung injury followed by pulmonary fibrosis. Multi-organ failure and severe gastrointestinal corrosive injury are also associated with toxic ingestion. Most cases involving paraquat ingestion occur when drink containers are filled with left-over solutions. ^{[66, 67]}

• Methylene iodide: A 20-month-old girl who ingested 10-15 mL developed acute hepatic failure within 2 days and died 9 days postingestion. ^[27]

• Lindane (chlorinated hydrocarbon), used as a second-line pharmaceutical treatment for lice and scabies: Two teaspoons (ie, 10 mL) or 6 mg/kg can be fatal, primariliy from central nervous system toxicity. ^{[68, 69]}

Rodenticides that can cause fatal toxicity include the following:

• Sodium monofluoroacetate (Compound 1080) and sodium fluoroacetamide (1081) were previously used as a rodenticide and are currently used in herbivore collars to kill coyotes and as poison to kill introduced mammals in Australia and New Zealand; 3-7 mg/kg is a potentially fatal dose, while 13-14 mg/kg of Compound 1080 is a potentially fatal dose. ^[15]

• Strychnine: A dose of 5-8 mg/kg is deadly; an accidental taste could potentially be lethal in a toddler. ^{[70, 15]}

• Zinc phosphide: A dose of 10 mg/kg is deadly. ^[15]

Other chemicals include the following:

• Aniline is used in dyes and pigments, as herbicides and rubber processing. A 4.5-year-old child developed a potentially life-threatening blood methemoglobin (metHb) level of 77% at 13 hours after ingesting 5 mL of aniline. ^[71]

• Hydrogen cyanide: 50 milligrams may be deadly. ^[70]

• Acetonitrile is used as a solvent and has been used as false fingernail glue remover (although it has been banned in Europe since 2000). Acetonitrile is metabolized to hydrogen cyanide. Several case reports describe fatalities associated with ingestion of nail glue remover (acetonitrile). Physicians need to carefully distinguish between nail polish remover (acetone) and acetonitrile-containing solutions for removal of false nails.

• Paraldehyde: A single fatality has been reported with a 25-mL dose. ^[15]

• Selenious acid (a component of gun bluing with copper sulfate and nitric acid): A single swallow may be fatal. A 22-month-old boy who ingested 15 mL of gun-bluing solution was unresponsive upon arrival at an ED 3 hours after ingestion and died after lengthy unsuccessful CPR. ^[72]  A 30-month-old boy who ingested less than 1 oz of gun-bluing solution was unconscious when the ambulance arrived 10 minutes postingestion, and died less than 90 minutes after arrival at an ED. ^[25]

Hydrocarbons - pulmonary aspiration of hydrocarbons causes denaturing of surfactant, leading to atelectasis.  Due to the low viscosity of many hydrocarbons, even a small amount can affect a large surface area in the lungs.  Bone marrow suppression can occur as a later effect of systemic absorption.

• Aliphatic hydrocarbon: An 18-month-old boy who ingested/aspirated a mouthful of saddle dressing died 20 days postingestion. ^[27]

• Eucalyptus oil: Ingestion of 10mls may lead to CNS depression and seizures. ^[73]

• Lighter fluid: A 14-month-old boy ingested/aspirated a mouthful of lamp oil and died. ^[74]

• Motor oil: A 15-month-old boy who ingested/aspirated one swallow of motor oil died 51 days postingestion. ^[74]

• Mineral oil and mineral spirits: A 2-year-old girl ingested/aspirated 15-30 mL of hair weaving remover (ie, 20% mineral oil, 30% mineral spirits) and died 2 days postingestion. ^[29]  A 3-year-old boy who ingested/aspirated "a couple of swallows" of fabric protector containing mineral spirits died 19 days postingestion. ^[9]

• Xylene: A dose of 15 mL can be deadly. ^[36]

Plants and natural toxins

• Aconite found in Chinese herbal medicines. ^[75]

• Amatoxin (ie, mushroom): A dose of 0.1 mg/kg is potentially fatal. ^[15]

• Amygdalin is a cyanogenic glycoside (toxicity or death occurs secondary to cyanide ingestion): In separate case reports, 2 of 9 ^[76]  and 1 of 8 ^[77]  intoxicated children died after eating apricot seeds. Cassava and Tapioca also contain cyanogenic compounds and ingestion has been associated with fatal toxicity. ^[78]

• Anticholinergic poisoning - Datura, Atropa belladonna, Henbane.

• Cardiac Glycosides - Lily of the Valley, Foxglove, Oleander

• Castor beans (ie, ricin): One milligram per kilogram or approximately 8 seeds can be fatal. ^[15]

• Nicotinic poisoning - Poison hemlock, Wild Tobacco, Golden Chain.

• Pennyroyal: A 12-week-old boy with a history of rhinorrhea and mild cough was administered 4 oz of tea made from 3-4 pennyroyal leaves. The child developed fulminant hepatotoxicity and died within 2.5 days postingestion. ^[8]

Most ingestions by children involve nontoxic substances. More than 1 million ingestions are believed to occur annually, most involving children younger than 6 years.

Race and frequency of toxic ingestions appear to have no correlation. Toxic ingestions from a single dose occur most often as unintentional ingestions by young children aged 1-6 years.

Mortality and morbidity depend on the substance or drug ingested and the quantity relative to body weight (ie, mg/kg/dose).  Most ingestions do not have specific antidotes, so prognosis depends on the ability to counteract the effect of the ingested substance if an antidote is not available.  Timely access to intensive care units that can provide supportive care for young children may not be available in remote areas or areas with limited resources.

Public education about the potentially fatal hazards posed by chemicals, medications, and common cleaning compounds is the key to prevention. Basic steps include the following:

• Keep hazardous and toxic substances in their original containers. Containers should be appropriately marked.
• Never store food near toxic substances.
• Keep hazardous and toxic compounds in a secure place out of the reach of children.

Parents and the public should know how to contact the regional poison control center for suspected toxic ingestions.

For patient education information, see First Aid for Poisoning in Children and Child Safety Proofing.