32: Pediatric Principles

Phone calls to poison centers regarding childhood exposures to xenobiotics are more frequent than those regarding any other age group. Because of this and the frequent role of poisoning as a cause of pediatric injury, pediatricians have been active for many years in helping to establish and promote the study of medical toxicology, as well as in establishing and supporting the use of regional poison centers. Although the basic approaches to the medical management of toxicologic problems outlined in Chaps. 3 and 4 are generally applicable to both children and adults, issues such as child abuse by poisoning are of particular concern. This chapter provides a perspective on the application of generally accepted toxicologic principles for children.

To analyze the problem of pediatric poisoning, it is necessary to understand the magnitude of the problem. When assessing the impact of a particular type of injury such as poisoning, epidemiologists examine multiple parameters, such as exposure, morbidity, mortality, and cost, to measure the effect of the injury; however, these parameters are difficult to measure accurately. An important source for information on the extent and effects of poisoning exposures in the United States is the American Association of Poison Control Centers (AAPCC). Every year, the AAPCC compiles standardized data collected from poison centers throughout the United States; the 2012 annual review includes information submitted by 57 poison centers. In the following discussion, comments on AAPCC data refer to cumulative information from the previous five published reports covering the years 2007 to 2011 (Chap. 136).

Each year, the AAPCC reports approximately 1.2 million potentially toxic exposures in children and adolescents from birth to 19 years, which account for 66% of all reported exposures. In fact, children younger than age 6 years account for 53% of all reported exposures. Of the reported exposures in children and adolescents, children younger than age 6 years account for 79%, children between 6 and 12 years of age account for 10%, and adolescents between 13 and 19 years of age account for 11%. Girls represent 47% of the reported poisoning exposures in young children and 54% of the reported exposures among adolescents.

Among the AAPCC reported xenobiotic exposures in children younger than age 6 years, 99% are labeled unintentional. In contrast, only 44% of the reported adolescent exposures are unintentional; 50% of exposures in adolescents are labeled intentional, mostly resulting from substance use or suicide attempts. The high frequency of intentional poisoning in adolescents has been reported by others.^34,183,184 The remaining 6% of adolescent exposures include adverse drug events and other miscellaneous or unknown causes. Differences in the reasons for exposure between young children and adolescents account for differences in the outcomes of these exposures.

Approximately 125,000 xenobiotic exposures each year are classified by the AAPCC as therapeutic errors, accounting for approximately 6% of exposures in children younger than 6 years of age, 24% in children 6 to 12 years of age, and 11% in adolescents. An additional 4700 exposures each year are classified as adverse drug reactions, which account for approximately 0.4% of exposures in children younger than 6 years of age, 2% in children 6 to 12 years of age, and 3% in adolescents.

Table 32–1 shows the leading causes of reported exposures in children and adolescents. According to the AAPCC, approximately 54% of childhood exposures are to xenobiotics that are commonly found around the house, such as cleaning products, cosmetics, plants, hydrocarbons, and insecticides; approximately 46% are to pharmaceuticals. In older children and adolescents, approximately 49% of exposures are to nonpharmaceutical xenobiotics, and approximately 51% are to pharmaceuticals. Most hospitalizations and deaths in both groups are caused by pharmaceuticals.

Table 32–1 lists the most common reported exposures, but not all of these exposures lead to serious morbidity and mortality (Table 32–2).For example, children frequently ingest cosmetic products, so the number of reported exposures is large, but most cosmetics manufactured in the United States are nontoxic. Clinically significant poisoning is unusual in children younger than age 6 months but may result from the inadvertent administration of an incorrect drug or drug dose by a parent,^60,123 intentional administration of a drug by a parent or sibling,^43,74 or passive exposure (eg, to the smoke of “crack” cocaine or phencyclidine).^{16,73,124,158,192} Any poisoning in a child younger than one year of age should be carefully evaluated for possible child abuse or neglect (see later discussion).⁷⁴

Several typical characteristics associated with ingestions by toddlers differentiate them from ingestions by adolescents or adults: (1) they are without suicidal intent; (2) there is usually only one xenobiotic involved; (3) the xenobiotics are usually nontoxic; (4) the amount is usually small; and (5) toddlers usually present for evaluation relatively soon after the ingestion is discovered, generally within 1 to 2 hours. As many as 30% of children who experience one ingestion will experience a repeat ingestion; adolescents may be particularly prone to recidivism.^61,81 Children who ingest poisons may also be at a greater risk for other types of injuries.^14,51

The peak age for childhood poisoning is between 1 and 3 years.²⁹ Unintentional ingestion is unusual after age 5 years, although when it occurs, it can sometimes be the result of mistaken consumption of a xenobiotic from a mislabeled container.²⁶ Between the ages of 5 and 9 years, poisoning may result from intrafamilial stress or suicidal intent. After age 9 years and through adolescence, overdose or poisoning frequently results from either suicidal gestures and attempts or from the adverse effects of alcohol or substance use. Unintentional poisonings are largely preventable (Chap. 136).

Because many children are exposed to nontoxic xenobiotics or to only small amounts of potentially toxic xenobiotics, the proportion of children and adolescents who experience significant morbidity is small (Table 32–3). However, because there are millions of such exposures each year, the number of children and adolescents who experience at least moderate effects is large.

Another source of data related to poisoning morbidity is the National Injury Surveillance database maintained by the US Centers for Disease Control and Prevention (CDC), which provides information on emergency department (ED) visits and hospitalizations.³⁰ For the period 2001 to 2011, the CDC estimates approximately 59,000 ED visits (246 per 100,000) and 3900 hospitalizations (~7%) per year for children 0 to 5 years who are exposed to a xenobiotic. Children 6 to 12 years account for approximately 11,000 ED visits (40 per 100,000) and 1000 hospitalizations (9%) per year, and adolescents 13 to 19 years old account for approximately 100,000 ED visits (349 per 100,000) and 21,000 hospitalizations (21%) per year. Overall, approximately 80% of the patients hospitalized are adolescents, and approximately 75% of those cases are the result of intentional poisonings.

These numbers are consistent with estimates of 100,000 to 170,000 ED visits for poisoning and overdose per year, or approximately 300 to 840 visits per 100,000 for children younger than 5 years of age and 290 to 360 per 100,000 visits for adolescents. Hospitalization rates are 10% to 20%.^{28,29,52,59,114,180}

As mentioned, adolescents are more frequently hospitalized than children after exposure to xenobiotics.⁶¹ This may be a result of the need for either medical management or psychiatric hospitalization. The peak age for hospitalizing young children exposed to xenobiotics is between 1 and 3 years, reflecting the peak age of exposure. Whereas among hospitalized children younger than age 2 years, exposure to nonpharmaceutical xenobiotics is more common, children older than age 2 years and adolescents are more commonly exposed to pharmaceuticals.^52,61,183

Although the AAPCC reports overall outcome related to age, it does not generally stratify outcome of exposure to individual xenobiotics by age. In a multiyear review published in 1992, the AAPCC reported the xenobiotics that caused the greatest number of major and fatal effects in children younger than 6 years old.¹⁰⁵Table 32–2 lists the xenobiotics causing significant morbidity and mortality. Other reports of hospitalized patients include a similar distribution of xenobiotics that cause significant morbidity.^8,31,45,197 However, in rural areas of many developing countries, kerosene and pesticides are the leading causes of xenobiotic-related hospitalizations, and the spectrum of pharmaceutical exposures is often different^{1,2,110,122,128} (Chap. 137).

Poisoning accounts for approximately 2% of childhood and 7% of adolescent injury-related deaths in the United States.³⁰ Based on information from death certificates filed in state vital statistics offices as well as demographic information provided by funeral directors, the CDC reports 1123 poisoning deaths in children younger than 6 years of age from 1999 to 2010 for an average of about 94 per year. These deaths represent approximately 10% of the reported poisoning fatalities for all children and adolescents for those years and a 79% decrease from the 456 deaths reported by the CDC in 1959.²⁹ There may be several factors responsible for this decrease. Some of the difference may be related to improved poisoning prevention strategies such as child-resistant closures or to improved medical care. In addition, some industrial or pharmaceutical products that were previously found around the home may have been replaced with less toxic products or been reformulated at safer concentrations. It is also possible that there may have been a decrease in reporting (Chap. 136).

Forty-seven percent of the AAPCC-reported childhood fatalities result from unintentional ingestions; 20% are from environmental exposures, mostly carbon monoxide poisoning; 12% are caused by therapeutic errors and adverse reactions; and 10% are malicious. The remaining 11% have miscellaneous causes or are unknown. In contrast, 50% of AAPCC-reported adolescent fatalities are the result of suicide, and 30% follow abuse or misuse of substances; only 2% are related to environmental exposures, and only 2% are caused by medication errors and adverse reactions; the remaining 16% have miscellaneous or unknown causes.

Although the AAPCC data provide a remarkable amount of epidemiologic information, there are questions about the accuracy of the data.^71,72,190 For example, as mentioned earlier, whereas the CDC reported 1123 poisoning-related deaths in children younger than 6 years of age from 1999 to 2010, the AAPCC reported 409 for those same years based on voluntary calls. Some of the differences may be related to methods of ascertainment. Nonetheless, there is recognition that many significant poisonings are not reported to poison centers. Physicians managing “common” toxicologic problems may not feel the need for the assistance of a local or regional poison center and may not feel compelled to participate in the reporting process. Therapeutic misadventures may also go unreported. In Rhode Island, only 45 of 369 poisoning deaths were reported to the regional poison center¹⁰³ (Chap. 136).

The most notable difference between the xenobiotics listed in Table 32–2 and studies from the 1960s and 1970s is that salicylates are no longer a leading cause of reported poisoning morbidity and mortality.^37,42 This change may be related to federal regulations requiring child-resistant closures as well as to the decreased use of aspirin for use in children after a now unproven association between Reye syndrome and aspirin was reported (Chap. 39).^{19,36,79,125,144}

There are some significant etiologic differences between children and adolescents (Table 32–1), particularly with regard to the lethality of xenobiotics. For 2007 to 2011, the xenobiotics causing the greatest number of childhood deaths were analgesics, carbon monoxide, cleaning agents and chemicals, and antihistamines and cough and cold preparations, which together account for 51% of all reported poisoning deaths. The xenobiotics causing the greatest number of adolescent deaths were analgesics, stimulants and street drugs, and antidepressants, which together account for 66% of reported poisoning deaths.

With respect to AAPCC-reported analgesic-related deaths, there are significant differences between children and adolescents for this population of exposed individuals. For children younger than 6 years, opioids accounted for 94% of the analgesic-related deaths (methadone, 52%; oxycodone or hydrocodone, 26%; fentanyl, 10%; and morphine, 10%). The high frequency of childhood exposures to these xenobiotics has been identified as a significant consequence of both the therapeutic and illicit use of prescription opioid analgesics.¹¹ These fatalities were related to unintentional exposures in 48% of the children, malicious exposures or intentional misuse in 23%, and therapeutic errors in 6%; the reasons in the rest of the cases were unknown.

In adolescents, opioids accounted for 55% of the analgesic-related deaths (methadone, 22%; oxycodone or hydrocodone, 16%), and aceta­minophen (APAP)-opioid combination products accounted for 13% of the deaths. Forty-one percent of the fatalities were the result of abuse or misuse, and 47% were suicides.

Hydrocarbon-related fatalities occur in both children and adolescents; whereas the hydrocarbon deaths of young children generally result from unintentional aspiration after ingestion, almost all of the hydrocarbon-related deaths in adolescents are related to inhalational abuse of hydrocarbons such as trichloroethanes or chlorofluorocarbons.

Poisoning also has an economic cost. Charges for hospitalized patients range from $2000 to $10,000, depending on the length of stay and outcome.^89,176,197 In a large-scale economic analysis of the cost of injury in the United States in 1985, the estimated average lifetime cost was $495 per child and $10,839 per adolescent or young adult injured or killed by poisoning for a total lifetime cost of approximately $140 million for children and $1.5 billion for adolescents and young adults.¹³⁷ According to the CDC, for 2005, the average combined medical and work loss cost for children and adolescents treated and released from the ED after an unintentional injury is approximately $714 and approximately $1390 after an intentional injury for a total cost of approximately $88 million. The average cost for a hospitalized patient is approximately $9000 for a total cost of approximately $358 million. For fatal injuries, the average medical cost is approximately $4800, but the average work loss cost is $1.5 million for a total cost of $1.5 billion.³⁰

An oversimplification of the etiology of childhood poisonings would be the formulation that unobserved toddlers exploring their environment inadvertently ingest xenobiotics. However, this approach ignores the complex interplay of factors that may contribute to some ingestions in children.

One approach to understanding injury causation that can be applied to poisoning uses an infectious diseaselike model.⁷⁰ According to this model, there are three interacting factors: host, agent, and environment. These factors interact during three phases: preinjury, injury, and postinjury. The factors themselves contribute to the likelihood, nature, magnitude of, and host response to an injury.

During the preinjury phase, there is an interaction of the host, agent, and environment. Under the proper circumstances, an injury may occur. Modification of these factors may help to prevent an injury. For example, if a 2 year-old child finds two pills on a bedside table, there is a fair chance the child will ingest the tablets. However, storing the pills out of reach of the child can prevent the ingestion.

The injury phase covers both the ingestion and the initial pathophysiologic host response. Again, particular factors determine the nature and extent of injury. Continuing the example, if the two pills are 325-mg APAP tablets, the ingestion will not lead to injury. However, if the pills are 0.2-mg clonidine tablets, there is a high likelihood of toxicity.

The postinjury phase is concerned both with the ongoing host response and the medical management of the patient who has been poisoned. In this phase, it would be determined whether the 2 year-old child with a clonidine ingestion manifests signs of toxicity, such as coma or hypotension; whether the child requires treatment with activated charcoal (AC), intravenous (IV) fluid, or naloxone; and whether the child requires hospital admission.

This paradigm is only a model; in reality, it is often difficult to examine any individual factor independently, and the relative contributions of these factors are not well defined. Nonetheless, consideration of the individual factors of host, agent, and environment allows us to focus on several relevant aspects of poisoning in children.

Childhood and adolescence are times of tremendous growth and development.²⁰³ Some of these physical and social changes place children and teenagers at increased risk for poisonings. By 7 months of age, an infant sitting up can pivot to grab an object; by 9 to 10 months of age, most infants can creep and crawl; by 15 months of age, most toddlers are walking quite competently and eagerly exploring. Between 9 and 12 months of age, a skillful pincer grasp with the thumb and forefinger develops that allows the child to pick up small objects. Throughout this period, one of the child’s primary sensory experiences is sucking on or gumming objects that are placed in the mouth. Thus, the combination of three developmental skills—the ability to move around the home and go beyond the immediate view of a guardian, the ability to pick up and manipulate small objects, and the tendency of children to put things in their mouths—places them at risk for poisoning.

As children develop socially, they desire to become more similar to their parents, and they tend to imitate behaviors, such as taking medicine or using mouthwash. Children are taught that medicine is good for them when they are sick. Many children’s medicines are sweetened and flavored to make them more palatable, and many parents inappropriately encourage their children to take medicines by telling them “it tastes like candy.” Children have been observed “making tea” from plants or “making pizza” with mushrooms from the yard.²⁶

As children become more mobile, agile, and curious, xenobiotics that were previously outside their reach become accessible even when stored in some difficult-to-reach places. Some evidence suggests that parents underestimate the developmental skills of their children.⁵¹ The meaning of the term unintentional with respect to childhood poisoning should also be reconsidered—a toddler quite purposefully intends to get to a pill and eat it, but the child does not intend to injure him- or herself.

Some of the reasons why a child wants to ingest a pill are because it is there, it looks and maybe tastes like candy or food, or the child is mimicking the behavior of a parent who ingests medicines or vitamins to cure illness and improve health. However, these reasons may not be sufficient to explain why xenobiotic exposures occur. Another aspect of poisoning that must be considered is the interaction between the child’s temperament and the social environment.

Many authors have tried to identify psychosocial predictors for childhood poisoning in general and for repeat poisoning in particular.^{22,53,83,169,185} As many as 30% of children repeatedly ingest xenobiotics, frequently the same xenobiotic. Certain risk factors have been identified for single and repeat episodes of childhood poisoning, such as hyperactivity, impulsive risk-taking behavior, rebelliousness, and negativistic attitude. Other factors seem to be associated more with the quality of supervision by parents or guardians, who themselves are experiencing medical illnesses, depression, or social isolation.¹⁸⁵ Finally, a stressful environment or a major social problem may also contribute.^166,170 It is not difficult to imagine a situation of a parent who is depressed, uses antidepressant medication that is kept at the bedside, and cannot give adequate attention to a demanding child. In a bid for attention or as an expression of anger or frustration, the child ingests some of the parent’s medication.

With regard to the agent, a number of issues affect the preinjury and injury phases, and modification of any one of the interacting factors of host, agent, or environment may potentially prevent or reduce the severity of injury. When household products of lower toxicity are available around the house, the likelihood of injury is reduced if one of these products is ingested. For example, less toxic rodenticides such as warfarin have replaced more toxic ones such as thallium or sodium monofluoroacetate, and relatively nontoxic paradichlorobenzene mothballs have largely replaced the relatively more toxic camphor-containing mothballs.

It may also be possible to reduce the likelihood of ingestion by making a xenobiotic unpalatable. Denatonium benzoate is an aversive, bitter xenobiotic that is added to some liquids such as windshield washer fluid and antifreeze to prevent unintentional poisoning.⁸⁰ However, some trials show that whereas older children may respond negatively to these xenobiotics with the first taste, younger children may ingest 1 to 2 teaspoonfuls before being deterred by the bitter flavor.^20,165 This is an important consideration because even a small amount of a xenobiotic such as methanol can be toxic (see later discussion). The actual usefulness of denatonium benzoate in poison prevention is largely unstudied.¹⁴⁵

The problem of unintentional ingestions is compounded by poison “look-alikes,” that is, xenobiotics that resemble candy or food products.⁵⁴ Some common examples are ferrous sulfate tablets and vitamins that look like common candies and fuel oils that come in cans resembling soft drink containers. Many shampoos and dishwashing detergents are given lemon or strawberry scents and have pictures of fruits on the labels. Children are not always able to distinguish poison “look-alikes” from real candies, fruits, and sodas, and they may be attracted to bright colors, pleasant smells, and appealing packages. Eliminating these “look-alikes” might prevent some unintentional ingestions.

Probably the most significant changes have occurred in the physical characteristics with regard to packaging and dispensing of pharmaceuticals and some other xenobiotics with child-resistant closures mandated by the Poison Prevention Packaging Act of 1972 (Chap. 1). This legislation is credited with causing a significant reduction in morbidity and mortality caused by poisoning from aspirin and other regulated products, although this analysis has been challenged.^36,143,187 Child-resistant closures have also been credited with reducing the number of toxic exposures to kerosene.⁹⁷

Nonetheless, problems with child-resistant closures include the dispensing of pharmaceuticals in nonresistant containers, not properly closing child-resistant containers, and leaving pharmaceuticals out of the child-resistant container.^28,168 Seventy percent of potentially toxic pharmaceuticals may be in non–child-resistant or in improperly functioning child-resistant containers. Several studies have identified poor functioning of the closures when there is sticky liquid or pill residue around the top or in the screw threads of the child-resistant container.^81,89,196

Although child-resistant containers are a significant deterrent to unintentional ingestions in toddlers, they are not completely effective, and even without the problems noted, some children can open them. A false sense of security associated with these closures may lead some parents to be less compulsive regarding safe storage of the containers. A double barrier, such as a unit-dose dispenser within a child-resistant container or a blister pack, has been recommended for a few pharmaceuticals associated with a large number of significant poisonings such as iron and antidepressants.⁸⁹

In fact, in 1997, the Food and Drug Administration (FDA) issued a regulation to package products with 30 mg or more of elemental iron per tablet in unit-dose packages such as blister packs.³⁰ The intent of this regulation was to reduce the likelihood of iron poisoning in children. Even before this regulation was instituted, the number of fatal childhood iron ingestions had declined significantly; therefore, it is not known how much if any of the decrease is related to the mandated packaging changes. In any case, the rule was overturned in 2003, when it was determined that the FDA did not have the statutory authority to regulate a drug for the purpose of poison prevention.¹¹ As yet there is no evidence of a resurgence of iron-related fatalities.

A discussion of containers and storage naturally leads to a consideration of the third factor in the injury-causation model discussed earlier, the environment, which is particularly important in the preinjury and the injury phases. Approximately 80% of childhood pharmaceutical ingestions occur at home; the remainder occurs at the homes of grandparents, other relatives, and friends. At home, the medicine usually belongs either to the child or to a parent, although a significant number of medications, both at home and away from home, belong to a grandparent.^81,104 Grandparents, other relatives, and family friends without children at home may not obtain or retain medications in child-resistant containers and may not be as attentive to safe storage practices. Poison prevention education directed to these groups may be particularly helpful.¹¹⁷

Medications are frequently kept in the kitchen or bedroom while they are being used.^81,196 In the kitchen, medications are stored in the refrigerator, on the table, or on the counter; in the bedroom, medications are left on a dresser or bedside table. A mother’s or grandmother’s purse is another location where medications are commonly found. Interestingly, there are no significant differences in the storage practices in the homes of children who ingest and those who do not ingest medicines, so storage practices alone cannot predict the likelihood of childhood poisoning.^169,196

One important caveat relates to the storage of nonpharmaceutical xenobiotics, particularly those in liquid form. These types of xenobiotics should never be transferred for storage to familiar household containers, such as food jars or wine or soda bottles; stored in areas low to the ground such as beneath sinks; or kept in cabinets that do not have child-resistant locks. Both children and adults have been unintentionally exposed to xenobiotics, such as sodium hydroxide, pesticides, hydrocarbons, and potassium cyanide, that was stored in bottles in the refrigerator.¹⁸¹ Many of the kerosene exposures reported from developing countries occur because the kerosene is stored in water bottles, jugs, or other containers in easily accessible locations. When the weather is hot, children may mistake the clear liquid kerosene for water.^1,40,101

The appropriate management of any poisoned patient is influenced by the history of the exposure. Except in rare cases of child abuse–related poisoning, parents or guardians generally provide information to the fullest extent possible. As a rule, in the case of children, the xenobiotic and time of ingestion are known. However, the reported number of pills or volume of liquid ingested may not be as accurate. Clues to the amount ingested are the number of pills or volume of liquid in a bottle before and after an ingestion, the number of pills set out on the night table, or the area of a spot of liquid after a spill. When symptoms are suggestive of poisoning but the history is inadequate, information about possible exposure outside of the home, such as with a babysitter, grandparent, friend, or other relative, should be obtained because approximately 15% of childhood poisonings occur outside the home.^81,132

In contrast, adolescents may not be forthcoming when relating the history of an intentional ingestion, especially when they are depressed, suicidal, or concerned about the response of their guardian or parent. When caring for these patients, the clinician must use the history provided but should remain skeptical about the reported type and number of xenobiotics ingested, as well as the time of ingestion.

When a child may be the victim of abuse or intentionally poisoned by a parent or guardian, the health care provider must ensure that (1) the history of the poisoning remains consistent over time and among people providing the details of the event, (2) the child’s clinical presentation is consistent with the history of the poisoning, and (3) the reported actions are consistent with the child’s developmental level.

Chapter 8 is devoted to a complete discussion of gastrointestinal (GI) decontamination. This section reiterates and emphasizes only a few important points.

As described earlier, children generally ingest small quantities of a single xenobiotic. For most of these ingestions, gastric emptying is unnecessary. Some examples of nontoxic ingestions are eating a crayon or the leaf of a jade plant, licking the cap of a household bleach container, or swallowing two adult-strength APAP tablets.

Orogastric lavage is the preferred method of gastric emptying when indicated for most serious ingestions. Small children can generally tolerate orogastric lavage with a large-bore 28- or 34-French tube; however, the smaller “large-bore” tubes may not be effective for removing large pills or fragments from the stomach of a small child. Placement of an orogastric tube is an unpleasant and frightening procedure for an infant or small child to undergo. Some local trauma may result from tube placement, and rarely, there may be more serious injury, such as esophageal perforation. Also, many children vomit during placement of an orogastric tube. Therefore, the use of orogastric lavage should be limited to cases in which the risk of significant morbidity or mortality is high, the likelihood of benefit is at least moderate, and the likely risk of injury to the child from the procedure is small. Orogastric lavage should never be used as a form of punishment. The patient should be intubated to protect the airway before orogastric lavage is used in a child with a diminished gag reflex or a depressed level of consciousness.

Previously, administration of syrup of ipecac to poisoned patients was considered a primary emergency intervention, and the availability of syrup of ipecac in the home was a primary tenet of pediatric anticipatory guidance. The AAPCC reports that the use of syrup of ipecac for case management declined from 13% in 1983 to 0.1% by 2005. This is not surprising because syrup of ipecac is contraindicated in cases associated with hemodynamic instability, seizures, or a depressed level of consciousness. Although syrup of ipecac is highly effective at making children vomit, the efficacy of preventing morbidity after an ingestion is questionable.

Even before the use of syrup of ipecac was abandoned, it had been used only infrequently in the ED management of poisonings, with lavage favored when evacuation of the stomach was considered important. However, it was only 10 years ago that it was still advocated for use at home at the direction of a poison center to avoid an unnecessary evaluation in an ED. However, in 2003, the American Academy of Pediatrics (AAP) recommended against the use of syrup of ipecac at home, and in 2004, the American Academy of Clinical Toxicology and the European Association of Poison Control Centres and Clinical Toxicologists recommended against the general use of syrup of ipecac for the management of poisoning.^4,6 The reasons for the new recommendations include its unproven benefit, its adverse effects, its interference with and complication of subsequent ED evaluation, its abuse potential, and its administration in cases in which there is no indication or there is a contraindication because of lack of consultation with a poison center.

Activated charcoal (AC) is a current mainstay of poison treatment in EDs.^3,35 Children generally will not drink AC willingly, although some children can be coaxed to do so if the AC is disguised in a baby bottle or soft drink container or sweetened with juice or sorbitol.¹⁹³ A nasogastric or orogastric tube may have to be inserted to administer AC. This can be a small-bore tube because it is not intended for lavage, although the smaller the bore, the more difficult it is to administer the thick slurry of AC. Placement of the tube, the presence of AC in the stomach, the effects of the xenobiotic, or the previous use of an emetic all may make the child vomit, making aspiration of AC or stomach contents a risk. For AC to be used safely in a patient who is comatose and who does not have a gag reflex, the patient should be intubated and the airway protected. Because of this risk, AC alone is unnecessary for a nontoxic or minimally toxic ingestion.

AC is available for home use.^98,174 Administration of AC at home or by prehospital personnel allows for administration significantly earlier than can be achieved after arrival and evaluation in the ED.^38,174 Although it would seem to have potential benefit as home therapy, AC is unpalatable, quite messy, and not always available; as a result, it has not achieved widespread use in the home.^127,142 It is also unclear how well parents can administer AC at home.^154,155,175 Whether the earlier administration of AC would affect outcome is unknown. If AC is to become a standard to replace syrup of ipecac for home therapy, it will require a substantial reeducation effort on the part of pediatricians, toxicologists, and pharmacists.

For consequential poisoning with xenobiotics such as methanol, ethylene glycol, salicylates, lithium, and theophylline, either hemodialysis or charcoal hemoperfusion is the optimal technique to enhance elimination, depending on the particular xenobiotic. These extracorporeal techniques can be performed on newborns or small infants in specially equipped centers with dedicated personnel. The primary limiting factor is the ability to obtain vascular access.^18,48,50,182 However, even large centers that routinely do hemodialysis in children may not be able to manage very small infants. There has been a report of the use of peritoneal dialysis for the treatment of alcohol intoxication in a child,⁶⁹ but this technique is not generally recommended.

Exchange transfusion is occasionally used to enhance xenobiotic elimination. This technique might be useful when multiple-dose AC cannot be administered, the xenobiotic is poorly adsorbed to AC, or access to specialized hemodialysis or hemoperfusion is not readily available. Exchange transfusion has been used successfully for poisoning by salicylates^49,113 and theophylline.^15,129,161 Another xenobiotic for which exchange transfusion may be a therapeutic alternative is chloral hydrate.⁹

When children ingest even small quantities of toxic xenobiotics, they are potentially ingesting large relative doses because of their small size. There are a number of xenobiotics that may cause significant toxicity or even death with as little as one pill or one teaspoonful.^13,102Table 32–4 lists these xenobiotics.

Several xenobiotics warrant particular concern because their effects may be significantly delayed. Classic examples are atropine–diphenoxylate (Lomotil)^23,39,115 and sulfonylureas such as glipizide.^67,134,178 Both of these xenobiotics may cause serious morbidity with initial symptoms or recurrence of symptoms delayed by as much as 24 hours after ingestion.

Children with real or possible ingestions of Lomotil or a sulfonylurea should be admitted for observation and monitoring even if they are asymptomatic because effects may not become apparent for 24 hours (Chaps. 38 and 53).

With the advent of new modified-release formulations of calcium channel blockers and β-adrenergic antagonists, concern for delayed toxicity and possibly death has become even greater.¹²³

Benzyl Alcohol: Gasping Syndrome

Benzyl alcohol is a preservative added to liquid pharmaceutical preparations; for small-volume medications administered to adults, the benzyl ­alcohol additive is quite safe (Chap. 55). However, at toxic doses, benzyl ­alcohol may cause respiratory failure, vasodilation, hypotension, convulsions, and paralysis. IV flush solutions containing benzyl alcohol were implicated as the cause of the “gasping syndrome” in sick newborns; the syndrome includes severe metabolic acidosis, encephalopathy, respiratory depression, and gasping.⁵ The association was made when infants with this syndrome were found to have elevated concentrations of benzoic acid and hippuric acid, metabolites of benzyl alcohol.^27,63 Benzyl alcohol is metabolized by the conjugation of benzoic acid with glycine to form hippuric acid; this pathway may not be functional in premature infants. Benzyl alcohol administration has also been associated with kernicterus and intraventricular hemorrhage in premature infants.^76,82 Although benzyl alcohol has been removed from many of the medications used for neonates, some preparations may still contain this agent.¹⁹¹

Imidazolines and Clonidine: Central Nervous System Effects

Imidazolines such as tetrahydrozoline, oxymetazoline, xylometazoline, and naphazoline are nonprescription sympathomimetics used as nasal decongestants and conjunctival vasoconstrictors (Chap. 49). Clonidine is an imidazoline derivative used as an antihypertensive (Chap. 63). In small children, these xenobiotics can cause central nervous system (CNS) depression, respiratory depression, bradycardia, miosis, and hypotension.^12,112,194 The presumed mechanism of action is by stimulation of central α₂-adrenergic and imidazole receptors. Although naloxone has been reported to reverse some of the CNS effects of clonidine, there are no reports of its successful use with the other imidazolines (Chap. 63).

Ethanol: Hypoglycemia

Ethanol is the primary component of alcoholic beverages, as well as a major constituent of many liquid preparations, such as mouthwash, vanilla flavoring, and perfume. Besides its well-known sedative–hypnotic effects, ethanol poisoning in children is associated with hypoglycemia because of reduced hepatic glycogen stores in children. Ethanol-induced hypoglycemia may cause seizures and may exacerbate the other CNS effects induced by ethanol poisoning. Hypoglycemia results from the inhibition of gluconeogenesis in the setting of alcohol poisoning. There does not seem to be a blood ­alcohol concentration threshold for the development of hypoglycemia, which has been reported with blood alcohol concentrations as low as 20 mg/dL⁴² (Chap. 80).

Chloramphenicol: Gray Baby Syndrome

Chloramphenicol is a broad-spectrum antibiotic that has been used in children because of its activity against Haemophilus influenzae. It has largely been replaced by other antibiotics in the United States because of its association with aplastic anemia. When administered at high doses, chloramphenicol can produce the “gray baby syndrome,” which includes abdominal distension, vomiting, metabolic acidosis, progressive pallid cyanosis, irregular respirations, hypothermia, hypotension, and vasomotor collapse. Although these effects occur primarily in premature newborn infants, they may also occur in older children and adults (Chap. 57).

Gray baby syndrome is associated with serum concentrations greater than 100 mg/L. Increased chloramphenicol concentrations may result from (1) inadequate conjugation of chloramphenicol with glucuronic acid because of inadequate activity of glucuronyl transferase in the newborn liver and (2) decreased renal elimination of unconjugated chloramphenicol. The exact mechanism of toxicity is unknown; there is speculation that free radicals produced during the metabolism of chloramphenicol may interfere with mitochondrial function.⁷⁸

Ever since the publication of the Institute of Medicine’s report titled To Err is Human in 1999, increasing attention has been paid to the issue of medical errors in medicine.⁹⁰ Although most of the research regarding medication errors has focused on adults (Chap. 140), this problem also affects children. Remarks in this section are generally limited to the pediatric literature.

Approximately 125,000 exposures each year are classified by the AAPCC as therapeutic errors, accounting for approximately 6% of exposures in children younger than 6 years of age, 24% in children 6 to 12 years of age, and 11% in adolescents. For 2007 to 2011, there were a total of 26 deaths attributed to therapeutic errors, representing 3% of all reported deaths in children and adolescents. Eight percent of the AAPCC-reported fatalities in young children were related to therapeutic errors, but only 1% of the adolescent fatalities were related to therapeutic errors. Of children younger than the age of 6 years, approximately 40% of the errors resulting in severe injury or death occur in children younger than the age of 1 year.¹⁸⁴

Medication errors may occur at any phase of a process that includes ordering, order transcription, pharmacy dispensing, preparation and administration of the medication, and monitoring of medication effects. In fact, the same types of errors can occur at different points in the process. Table 32–5 lists the types of errors that can occur, and Table 32–6 provides some examples of errors.

Most of the analyses of medication errors have occurred in inpatient settings. The reported frequencies of medication errors vary widely—from 0.47% to 5.7% of written orders and from 0.51 to 157 per 1000 patient-days.^{55,62,77,84,87,151} The variance largely depends on whether the definition of “error” does or does not include prescribing errors, regardless of whether or not they are corrected, and whether potential, or only actual, adverse drug events are included. The reported frequencies also vary depending on whether there is active case finding or whether there is only voluntary reporting.

In a 2001 study of pediatric inpatients in which orders were actively monitored for a 6-week period, 5.7% of 10,778 prescriptions had errors in the order for the medication, transcription of the order, dispensing or administration of the medication, or monitoring of medication effects (56 per 100 admissions, 157 per 1000 patient-days);⁸⁷1.1% could have potentially caused an adverse effect (10 per 100 admissions, 29 per 1000 patient-days). Eighty-four percent of the errors occurred during the ordering or transcription phase, so most of the errors were intercepted and corrected before drug administration. There were 26 true adverse drug events, but only five were considered preventable errors (0.05%, 0.52 per 100 admissions, 1.8 per 1000 patient-days). Although the overall error rate was similar to that reported by the same group in a study of adults, the rate of errors that could potentially have caused harm was three times greater; 41% of the potentially harmful errors were not intercepted. However, one review suggests that the prescription error rate is higher in adults than in children.¹⁰¹

Generally, error rates are higher in intensive care units, where the sickest patients are cared for; such patients often receive multiple medications with complex administration regimens.^{55,77,87,135,151,186,195} Results similar to those from inpatient settings have been reported in pediatric EDs.^{62,95,153,159,164}

The studies cited suggest that the frequency of significant errors leading to significant adverse drug events is low; however, even a low frequency applied to a large population of patients could result in a large number of patients being harmed. The most important outcome of the analysis would be to try to reduce the overall number of errors to reduce the number of potential and actual adverse drug events.

The causes of medication errors are numerous, varied, and complex; they are organizational, environmental, and personal, which includes factors such as the level of training, knowledge and competence, the time of day, workload, staff interactions, communications, number of distractions or interruptions, ambient noise, and drug formulation and drug packaging^{41,57,65,90,189} (Chap. 140).

Children may be placed at increased risk of a medication error for several reasons: (1) someone other than the child administers the medication, so there is little opportunity to prevent or limit drug administration; (2) a young child cannot warn practitioners about possible problems such as allergies; (3) a young child cannot inform practitioners when he or she is experiencing an adverse event; (4) medication ordering and administration in children frequently requires dose calculations; (5) inexperienced practitioners may be uncomfortable with pediatric dosing or related calculations; and (6) incorrect measurement or dilution of concentrated stock solutions may yield a small volume, which is not perceived as containing a relatively large dose of medication.^32,44,65

One of the most common errors is prescription, preparation, or administration of an incorrect dose, particularly in children, for whom almost every prescription requires knowledge of the patient’s weight and a calculation of a weight-based dose.^87,96,100 In addition, even the milligram per kilogram dose may vary depending on the age of the patient or the diagnosis. Although pediatric doses are generally determined on a milligram per kilogram basis, if the weight is recorded in pounds and this weight is used in the calculation, there will be a built-in twofold error. Calculation errors also occur when drug preparation requires dilution of a concentrated stock solution or special compounding.¹⁸⁴ Further confusion can arise when mg is written as or misinterpreted as mL or μg in a calculation or vice versa.⁴⁰

When an extra zero is added or a required zero is omitted from calculations, written or verbal prescriptions, or in dispensed and administered medications, a 10-fold error occurs. These large errors are common and result in significant under- or overdosing; 10-fold errors have been reported in testing scenarios, case series, and case reports.^{47,92,93,96,139,147,151,184} These errors are of particular concern because the risk of toxicity generally increases with significant overdose.

Because the causes of medication error are numerous and complex, the solutions must be multifaceted and interdisciplinary. The approach to the problem is contained within the field of human factors research and potentially requires changes in individual factors such as knowledge; environmental factors such as interruptions; and system problems such as how medications are ordered, stocked, and dispensed^90,177,189 (Chap. 140).

The most commonly recommended solutions to reduce the frequency of medication errors are computerized physician order entry (CPOE) with clinical decision support systems^85,185; ward-based clinical pharmacists; and improved communication among and between all levels of medical, nursing, and pharmacy staff.^{86,99,141,177} In one of the studies cited earlier, it was estimated that these three solutions together could have prevented more than 90% of the potential errors,⁵⁶ although the effect of interventions other than CPOE has generally not been studied.

In its simplest form, CPOE eliminates errors related to legibility. Decision support adds the ability to check a prescription against age, weight, dose, allergies, and drug–drug interactions, but it may not prevent ordering the wrong drug or dose, so there is still a need for education and human oversight in additional to other safeguards. The implementation of CPOE is generally associated with at least some reduction in errors related to medication ordering, although an effect on morbidity or mortality has not yet been demonstrated.^1,185 Sometimes there are unanticipated consequences associated with computerized systems.^91,116,188

In the future, all inpatient medication orders and outpatient prescriptions may be transmitted electronically, but until that time, it will be necessary to ensure that prescriptions are written legibly and correctly. The Joint Commission and many other groups have issued recommendations to reduce errors in medication ordering (Chap. 140).

Standardized tests of the math skills necessary to calculate doses and administer medications have demonstrated deficiencies in both nursing and physician groups.^{17,21,126,130,133,146,152} Tests of this nature may be a means of identifying practitioners at risk for making calculation errors, highlighting areas in need of remediation, and serving as ongoing educational tools.

As described earlier, there may be an increased risk of medication errors in critical care areas because of severity of illness and intensity of medication therapy. In many cases, such as during resuscitations, critically ill patients require immediate therapy, verbal orders are common, and there is often insufficient time to carefully review all of the particulars related to medication ordering and administration.^{45,62,96,108,131}

Critical care areas, including the ED, benefit from having precalculated dosing charts available for resuscitation medications and for other commonly prescribed medications; this is a recommendation of the American Heart Association.⁷ Many clinical units have developed their own dosing schemes. Commercial products, such as the Broselow-Luten system, are also available and have been shown to reduce the number of medication errors in simulated^{2,107,109,160} and actual resuscitations.¹⁵⁰ There has been some controversy related to the ability of these length-based commercial products to accurately predict the weights of children from diverse domestic and international populations for the purpose of medication dose calculation.^110,122

The previous discussion has been almost exclusively related to hospital-based medication use, but significant errors also may occur in outpatient settings.

Antipyretics are among the most frequently recommended medications for children. Although significant toxicity after unintentional ingestions in toddlers is now rare, administration of multiple supratherapeutic doses of APAP is common and can cause significant hepatotoxicity.⁹⁴

In fact, many parents have difficulty calculating the appropriate dose of APAP and measuring out the appropriate amount after it is calculated despite having received instructions and graduated cups or oral-dosing syringes.^{68,111,119,167,171} Relevant factors related to these errors include the characteristics of the instructions regarding medication measurement and administration, the health literacy of caregivers, and the accuracy of different measuring devices.

Two of the most commonly used measuring devices are also the most inaccurate—the teaspoon and the graduated cup.^153,199 The household teaspoon is not standardized for volume and can easily be confused with a household tablespoon.¹¹¹ APAP and ibuprofen elixirs are typically packaged with a graduated cup for administration even though graduated syringes are considered the most accurate of the measuring instruments available and are recommended by the AAP for young children. In addition, the instructions and measuring devices distributed with these products, as well as other nonprescription medications, are highly variable and inconsistent.²⁰⁰

Health literacy and health numeracy are becoming increasingly understood factors with regard to the safe and effective delivery of health care in general and the reduction of the rate of medical errors in particular. Health literacy plays a key role in a caregiver’s ability to read and understand instructions about and labels on prescriptions and nonprescription medications.¹⁶⁴ The labels on medication containers are not standardized with respect to the layout and placement of information or the use of abbreviations or units of measure, may be printed in small fonts that are physically difficult to read, and may be difficult to understand by people with lower health literacy or limited English proficiency.^106,200,202 Instructions for medication administration have the same problems. Visual cues using pictograms in the instructions or color-coded or premarked syringes are practical ways to improve the accuracy of parental medication dosing.^58,198,201

Intentional poisoning of children is an unusual, but significant, form of child abuse. Most cases are related to pathologic characteristics of the parent or guardian and have been categorized as (1) undifferentiated child abuse, neglect, or impulsive acts under stress; (2) factitious illness (Munchausen syndrome by proxy {MSBP}); (3) overt parental psychosis; and (4) the Medea complex, or the vengeful killing of a child out of spite for one’s spouse.^74,149,179 Rare cases of intentional poisoning may be related to bizarre childrearing practices.

Intentional poisoning is rarely suspected unless the patient dies and an autopsy is performed, a wide-ranging drug screen is ordered, or the history is bizarre enough to raise suspicions. In many cases in which children are later found to be poisoned, the initial diagnoses were sepsis, meningitis, seizures, intracranial hemorrhage, gastroenteritis, apnea, apparent life-threatening events, or metabolic derangements.⁷⁴ In addition to many pharmaceuticals, salt, pepper, water, caffeine, ethylene glycol, herbs, plants, and traditional remedies have been used to poison children.^46,74 Although the death rate from unintentional poisoning in children is much less than 1%, the death rate from “malicious” intentional poisoning may be as high as 20% to 30%.^46,74,179

Intentional poisoning may be associated with other forms of abuse; approximately 20% of poisoned children may have evidence of physical abuse.^46,74 Of children presenting to EDs after presumed unintentional poisoning, 36% had previous ED visits for trauma, 7% for poisoning, 6% for both trauma and poisoning, and 1.4% for failure to thrive. At the time of the visit, only 7% were evaluated for possible abuse, and 2.7% were considered neglected.⁷⁴ These data do not prove an association between poisoning and physical trauma; however, in some children, repeat episodes of trauma or poisoning may be a manifestation of significant intrafamilial stress. Health care providers must remain vigilant to the possibility that a presumed unintentional poisoning may have been “malicious” intentional, especially in the setting of a repeat ingestion or when there have been previous evaluations for trauma.

Substance abuse by a parent or guardian may play a role in unintentional or intentional poisoning of children. Children have been poisoned with cocaine or phencyclidine by passive inhalation of side smoke,^{16,73,124,157,192} unintentional ingestion,^88,140 and rectal administration,¹³⁶ as well as through breast milk.³³ Children have been given doses of alcohol, methadone, and other xenobiotics to quiet them or to prevent withdrawal.^42,75,138 There are reports of babysitters blowing marijuana smoke into babies’ faces to “get them high” or to quiet them.¹⁵⁸

In 1977, the term Munchausen syndrome by proxy was first used to describe a condition in which a parent or guardian, typically the mother, fabricates a history of nonexistent disease(s) in a child or creates the signs and symptoms of disease in a child (factitious illness).^120,121,149 This is usually a manifestation of the parent’s complex psychiatric illness, which may include Munchausen syndrome itself.^24,66,156 There may be only a fine line separating MSBP from an intentional poisoning with intent to harm or kill a child. However, regardless of the specific intent, this condition is considered a form of child abuse.

Over the years, child protection experts have tried to develop more specific terminology than MSBP. In light of the fact that this entity involves two individuals—the child victim and the adult perpetrator—the American Professional Society on the Abuse of Children recommends that the child victim be diagnosed with “pediatric condition falsification” and that the psychiatric diagnosis of “factitious disorder by proxy” be applied to the adult perpetrator. The diagnosis of MSBP requires that both criteria be met.^10,156

A child’s fabricated illness may lead to multiple medical evaluations by several different physicians, frequent hospitalizations, unnecessary surgeries and diagnostic testing, unneeded prescribing and administration of medication, and at times even the death of the child. Administration of medications to the child by the adult perpetrator is frequently how a particular set of signs and symptoms is created. Xenobiotics used to create factitious illness have included analgesics, antidepressants, insulin, syrup of ipecac, Lomotil, phenothiazines, sedative–hypnotics, warfarin, phenolphthalein, and hydrocarbons.¹⁴⁸ Several warning signals may suggest a diagnosis of MSBP (Table 32–7).

In one illustrative case of MSBP, a 29 month-old boy who had undergone a previous appendectomy was hospitalized multiple times for vomiting, diarrhea, and dehydration.⁶⁴ Evaluation included multiple blood and stool analyses, a gastric pH probe, endoscopy, upper GI series, computed tomography, and magnetic resonance imaging. On the fourth admission, a small bowel obstruction was identified, and the child had lysis of adhesions. Nonetheless, symptoms recurred every 2 to 4 months, necessitating hospitalization. The child failed to thrive and required a nasoduodenal tube for feeding, which frequently became dislodged. The child went on to have a jejunostomy tube and a permanent central venous catheter placed. Eighteen months after his initial presentation, the child presented in congestive heart failure with evidence of cardiomyopathy. A urine screen identified emetine and cephaline, components of syrup of ipecac. The child was removed from his home to protective custody after which he recovered and remained asymptomatic on a regular diet.

Siblings of children evaluated and treated for poisoning may also have suffered from factitious illness. In addition, significant psychiatric problems may be manifested by the victim, parents, and siblings.^{25,118,156,162}

Child abuse or neglect must be part of the differential diagnosis of any case of childhood poisoning. Intentional poisoning should be considered for;^74,75

• An “ingestion” in a child younger than one year of age

• A case with a confusing history or presentation

• A child with a previous poisoning or a child whose siblings have previously been evaluated for poisoning

• A child with a previous presentation for a rare or unexplained medical condition

• A child with apnea, unexplained seizures, or an apparent life-threatening event

• A massive ingestion by a small child

• An ingestion of multiple xenobiotics by a small child

• An exposure to substances of abuse

• An intoxication with a xenobiotic to which a child could or would not typically have access

• “Accidental ingestions” in a school-age child

• A history of previous trauma, child abuse, or neglect

• Sudden infant death syndrome or an unexplained death

These considerations of child abuse notwithstanding, rare diseases do occur. One child’s rare, inherited metabolic disorder, methyl malonic acidemia, was misdiagnosed as ethylene glycol poisoning because of the chromatographic appearance of the metabolite propionic acid, which was similar to that of ethylene glycol.¹⁶³

• Children are frequently exposed to potentially toxic xenobiotics; fortunately, most childhood exposures are ingestions of nonpoisonous xenobiotics or small nontoxic quantities of potentially toxic xenobiotics.

• When a child sustains a significant toxic exposure, management follows general toxicologic principles.

• Although most childhood exposures are unintentional, the clinician should be alert to the possibility of intentional poisoning of a child with pharmaceutical or household products.

• The normal development of children places them at risk for unintentional ingestions. A chaotic home environment or a disorganized social structure may compound these risks.

• Small size puts children at increased risks for medication dosing and dispensing errors, and their immature metabolic processes may lead to unexpected toxicity from pharmaceuticals.

• Toxicologists should encourage parents to provide as safe a home environment as possible to prevent unintentional ingestions and must encourage practitioners to exercise special vigilance when administering medications to children.

References