Over-the-Counter Agents

Caustics

Many household products are caustic agents and can cause significant toxicity with small exposures. Caustic agents are classified as alkaline or acid corrosives, depending on their pH (Table 158.4). Passed in 1970, the Federal Hazardous Substances Act and the Poison Prevention Packaging Act stated that caustic agents with a concentration higher than 10% must be placed in child-resistant containers. By 1973, the household product concentration limit had been lowered to 2%.

Table 158.4 Household Caustic Agents

Alkaline corrosives cause liquefaction necrosis, which is characterized by protein dissolution, collagen destruction, fat saponification, cell membrane emulsification, and cell death. Damage continues after surface exposure because of the ability of alkaline corrosives to penetrate tissue. In contrast, acids cause coagulation necrosis, which leads to desiccation of epithelial cells and produces eschar, with resulting edema, erythema, mucosal sloughing, ulceration, and necrosis of the surface tissues.

The dose of a caustic agent causing significant toxicity varies by product and concentration. Information on specific agents can be obtained from product packaging and from a poison control center.

Hydrofluoric Acid

Hydrofluoric acid and related compounds, such as ammonium bifluoride, ammonium fluoride, potassium bifluoride, and sodium bifluoride, are found in rust removers, automobile wheel cleaners, toilet bowl cleaners, air conditioner coil cleaners, dentifrices, and insecticides. The bifluorides can form hydrofluoric acid in the presence of body water and can thus cause delayed presentation of symptoms.⁷ The fluoride ion is directly toxic to numerous cellular enzymes and also forms complexes with calcium and magnesium. These complexes precipitate in tissues and cause significant pain and tissue destruction. At high enough levels of fluoride, these complexes can lead to systemic depletion of calcium and magnesium that can precipitate life-threatening arrhythmias.

The toxic ingested dose of hydrofluoric acid is between 5 and 10 mg/kg, and death occurs after a dose of 15 to 30 mg/kg. This translates into a lethal dose of 50 mg for a 10-kg child, a quantity contained in 5 mL of 10% hydrofluoric acid.

Calcium Channel Blockers

Calcium channel blockers are widely prescribed for their chronotropic and antihypertensive effects. They exert their action through L-type voltage-gated channels present in cardiac myocytes, vascular smooth muscle, and the sinoatrial and atrioventricular nodes. The three main classes of calcium channel blockers are the phenylalkylamines, the benzothiaprines, and the dihydropyridines. The phenylalkylamines (verapamil) and the benzothiaprines (diltiazem) act predominantly on myocytes and cardiac tissue, and the dihydropyridines (nifedipine) work predominantly on vascular tissue. Bepridil, the sole agent representing a fourth class, is not in widespread use because of its poor side effect profile.

Calcium channel blocker overdose causes severe hypotension and bradycardia, although reflex tachycardia may also be seen in overdose of the vascular tone–predominant dihydropyridines. Calcium channel blockade is responsible for dysrhythmias ranging from heart block to idioventricular arrhythmias. Impaired insulin release and systemic insulin resistance lead to the classic finding of hyperglycemia. Pulmonary edema may occur; the mechanism is unknown, but the edema may be caused by selective precapillary vasodilation or aggressive fluid resuscitation.⁸

Data on the minimum dose required to produce significant toxicity in children are mixed, but published cases have reported that one to two pills caused significant morbidity or death in children less than 6 years of age.⁹

Calcium channel blocker overdose and beta-blocker overdose are commonly discussed together in the adult literature because of their similarity of presentation and the therapeutic coadministration of these medications. A review of the pediatric literature found no published cases of death in young children as a result of accidental ingestion of beta-blockers, so these agents do not appear on the “One Pill Can Kill” list.¹⁰

Clonidine and Topical Imidazolines

Clonidine is a centrally acting α-receptor agonist that inhibits sympathetic pathways. It was developed in the 1960s as a nasal decongestant, but it is most commonly used as an antihypertensive and in the treatment of narcotic and alcohol withdrawal, of perimenopausal hot flashes, and, more recently, in the treatment of pediatric attention-deficit hyperactivity disorder and Tourette disorder. Topical imidazolines are found in over-the counter decongestants for the nose and eyes, including oxymetazoline (Afrin), naphazoline (Naphcon), xylometazoline (Otrivin Pediatric Nasal) and tetrahydrozoline (Visine).

The exact mechanism of clonidine toxicity is not fully understood. Because of functional overlap between α₂ and µ receptors, symptoms of clonidine toxicity can mimic those of opioid toxicity. Peripheral α₁-receptor stimulation may cause a transient period of hypertension before centrally mediated bradycardia and hypotension predominate. In contrast to clonidine, the topical imidazolines are specifically designed to induce local α₂-mediated peripheral vasoconstriction for their desired clinical effect. Toxicity from these agents may manifest as agitation, tachycardia, and hypertension, although CNS and respiratory depression similar to that seen with clonidine toxicity have also been reported with these agents.^11,12

A minimum toxic dose of imidazoline has not been established. A clonidine level as low as 0.01 mg/kg has been shown in case reports to cause altered mental status in children, which correlates with ingestion of a single 0.1-mg tablet by a 10-kg child. Larger doses have been associated with more severe symptoms.¹²

Diphenoxylate-Atropine (Lomotil)

Diphenoxylate-atropine, most commonly known as Lomotil, is an antidiarrheal agent consisting of a combination of opioid and anticholinergic medications. Diphenoxylate, a meperidine derivative, decreases smooth muscle action of the gut. Atropine is added to decrease the drug’s abuse potential. Lomotil toxicity can be both prolonged and delayed, secondary to its combined opioid and anticholinergic effect on gut motility. Diphenoxylate’s primary metabolite, difenoxine, is more active and has a longer half-life than diphenoxylate and thus exacerbates the phenomenon of delayed presentation.

Lomotil has classically been included on most “One Pill Can Kill” lists, but one review of the literature revealed a paucity of data demonstrating that significant morbidity is caused by small doses.¹³ Most deaths are attributed to ingestion of multiple pills or repetitive, incorrect dosing over time. No established minimum toxic dose exists, but the review found no reports of significant toxicity with ingestions of fewer than six to eight tablets in small children.

Sulfonylureas

Sulfonylureas are used for the treatment of non–insulin-dependent diabetes mellitus and can cause significant hypoglycemia after the ingestion of one or two pills by young children. Examples are chlorpropamide, glyburide, glimepiride, glipizide, tolazamide, and tolbutamide. Sulfonylureas lower blood glucose primarily by stimulating endogenous insulin secretion and secondarily by enhancing peripheral insulin receptor sensitivity and reducing glycogenolysis.

Death is rare with sulfonylurea exposure. Only one case was found in a literature review.¹⁴ However, many children less than 6 years old become symptomatic from sulfonylurea ingestion, and numerous case reports have noted symptoms in children who ingested of one to two pills.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) represent a diverse group of medications that have been historically responsible for many poisoning deaths. In addition to their use in the treatment of depression, TCAs have been used to treat migraines, chronic pain, and enuresis, and they have been administered as second-line therapy for several pediatric psychiatric disorders.

TCA toxicity manifests primarily with cardiovascular and CNS effects. Inhibition of the fast sodium channel causes cardiac conduction disturbances, resulting in a widened QRS complex. Blockade of catecholamine reuptake can cause tachycardia and mild hypertension, although these effects are usually offset by peripheral α-adrenergic blockade causing vasodilation and hypotension. CNS effects of delirium, seizure, and coma are likely caused by anticholinergic effects, as well as by central blockade of neurotransmitter uptake. Anticholinergic effects can also slow gastric emptying and produce delayed or unpredictable absorption.

Several case reports published since the 1970s demonstrated that one or two pills can kill a small child. Significant morbidity or mortality tends to occur at doses greater than 15 to 30 mg/kg; ingestion of one or two 150-mg pills by a 10-kg toddler can easily reach this level.¹⁵

Camphor

Camphor toxicity most often develops 5 to 90 minutes from the time of ingestion, but some case reports have noted presentations as late as 9 hours after ingestion.¹⁶ Clinical toxicity may first manifest with gastrointestinal complaints, from oral burning to nausea and vomiting. Initial CNS effects of hyperactivity such as irritability, hyperreflexia, and myoclonic jerking may progress to seizure, delirium, and coma. Seizures are common and may persist for up to 24 hours, although this does not seem to have prognostic implications.² When death occurs, it is usually the result of status epilepticus or respiratory failure.

Salicylates

Patients may present with vomiting, hyperpnea, tinnitus, and a mixed metabolic picture of respiratory alkalosis and metabolic acidosis. In contrast to adults, children less than 2 years old tend to present with metabolic acidosis only, rather than the classic mixed picture, because respiratory alkalosis appears to be transient. Salicylate-induced hypoglycemia may also be more pronounced in children than in adults. More serious intoxications may progress to CNS symptoms, including lethargy, agitation, delirium, or seizures. Respiratory acidosis suggests pulmonary edema and fatigue. Hyperthermia reflects oxidative uncoupling and is often a preterminal finding.

Symptoms of oil of wintergreen ingestion may progress much faster than symptoms caused by other agents because of the high concentrations of salicylate. One review found that patients who progressed to life-threatening toxicity from oil of wintergreen ingestion almost uniformly experienced emesis within minutes to a few hours of ingestion, followed by signs of CNS toxicity.⁴

Topical Anesthetics

Lidocaine or dibucaine overdose manifests with signs and symptoms of CNS toxicity that progress from agitation, confusion, or ataxia to generalized seizures and coma. Cardiac toxicity, such as heart block or arrhythmia, is infrequently seen with ingestion other than dibucaine and usually occurs only after CNS toxicity has manifested. The onset of symptoms has been reported to occur any time from minutes to hours following exposure, with significantly faster onset if the exposure involves aspiration or the respiratory tract.⁵

Benzocaine exposures manifest with signs and symptoms that correlate with the percentage of methemoglobin present in the blood. At approximately 15%, patients may exhibit cyanosis unresponsive to supplemental oxygen; weakness, tachycardia, and nausea may occur at approximately 30%. Lethargy and stupor, seizure, coma, and dysrhythmia may occur when methemoglobin levels reach more than 55%; death related to methemoglobinemia, although never reported as a result of benzocaine ingestion, may occur at levels higher than 70%. The onset of symptoms following benzocaine ingestion is usually rapid, occurring within 30 to 60 minutes.

Pulse oximetry and arterial oxygen measurements are not accurate and may be falsely reassuring in these patients. If methemoglobinemia is suspected, methemoglobin must be measured on a cooximeter.

Caustics

Contact of caustic substances with mucosa generally causes severe pain, which often limits the quantity of substance ingested. However, even one mouthful of a sufficiently concentrated caustic substance may cause severe injury. Common signs include lip or tongue swelling and erythema or intraoral ulceration. The most common presenting features of a clinically significant exposure include drooling, vomiting, and refusal of oral intake. Substernal chest pain or abdominal pain should raise concern for esophageal or stomach perforation. In severe cases, progressive oropharyngeal edema may lead to drooling and rapid airway compromise.

The severity and rapidity of symptom development are related to the type of agent, concentration, volume, viscosity, duration of contact, and pH. The emergency physician must keep in mind that an absence of oropharyngeal burns does not exclude esophageal injury.¹⁷

Hydrofluoric Acid

Local apparent injury may be minimal because of a paucity of free hydrogen ions, which are responsible for the caustic tissue injuries caused by other acids. A hallmark sign of dermal exposure to hydrofluoric acid is pain out of proportion to physical findings. Evidence of ingestion commonly manifests with gastrointestinal symptoms of nausea, vomiting, and abdominal pain. Respiratory symptoms ranging from dyspnea to acute respiratory distress syndrome can indicate direct inhalational injury, increased secretions caused by fluoride’s effect on acetylcholinesterase, or muscle fatigue.⁷

CNS manifestations include lethargy, obtundation, weakness, and loss of deep tendon reflexes. Cardiac toxicity, in particular ventricular fibrillation and torsades de pointes, results from hypocalcemia and can develop precipitously. The QTc interval is often prolonged in these patients. The onset of severe systemic symptoms can be delayed, but cardiac toxicity generally occurs within 6 hours.

Calcium Channel Blockers

Bradycardia and hypotension are the hallmarks of calcium channel blocker overdose. Patients may exhibit sequelae of hypoperfusion and shock, including mental status changes, lactic acidosis, renal or hepatic failure, and intestinal ischemia. Patients may have cardiac arrhythmias including second- and third-degree heart block. Seizures rarely occur in the absence of cardiovascular collapse because these agents, with the exception of nimodipine, do not cross the blood-brain barrier. CNS manifestations out of proportion to the cardiovascular effects should raise the suspicion of coingestions.¹¹ Hyperglycemia is a hallmark of calcium channel blocker toxicity.

Symptom onset usually occurs in 1 to 2 hours, but it may be delayed for up to 24 hours if an extended-release formulation is ingested.

Clonidine and Topical Imidazolines

Clonidine toxicity often resembles opioid intoxication, with symptoms consisting of miosis, bradycardia, hypotension, and, in severe cases, respiratory depression and hypothermia. CNS depression is a common symptom. Unlike with opioid intoxication, patients are often rousable by stimulation, but they may quickly return to a depressed mental state.^12,18 Toxicity from topical imidazolines also manifests most commonly with altered mental status and respiratory depression.¹² Both topical imidazolines and clonidine may cause tachycardia or bradycardia and hypertension or hypotension.

Both clonidine and the topical imidazolines are rapidly absorbed. Symptoms usually appear in 30 to 90 minutes and may last for 1 to 3 days, depending on the dose ingested.

Diphenoxylate-Atropine (Lomotil)

The classic teaching regarding Lomotil toxicity is that it exhibits a biphasic course: an early, anticholinergic-predominant phase lasting 2 to 3 hours followed by a prolonged, opioid-predominant phase. This notion was challenged by a review in 1991 that suggested that most patients exhibited a prolonged opioid toxidrome, and only 11% presented with a biphasic course.¹⁹ In serious intoxications, patients may exhibit CNS excitation, coma, or profound respiratory depression.

The onset of symptoms may occur as early as 2 hours or as late as 24 to 30 hours after ingestion. Respiratory or CNS depression may recur after 12 to 24 hours. The cause is thought to be an accumulation of the long-acting opioid metabolite of diphenoxylate.

Sulfonylureas

The clinical presentation of sulfonylurea toxicity is that of hypoglycemia: lethargy, confusion, headache, seizures, tachycardia, and diaphoresis. If untreated, hypoglycemia can result in permanent neurologic sequelae or death. The onset of symptoms is usually seen within 8 hours of ingestion, but it can be delayed with ingestion of extended-release formulations. Chlorpropamide, glyburide, and the long-acting form of glipizide tend to have a longer clinical effect. Delayed presentation also seems to correlate with patients in whom a prophylactic dextrose drip is started; this practice may mask emerging hypoglycemia and create a false sense of security.¹⁴

Tricyclic Antidepressants

The TCA-poisoned pediatric patient presents similarly to the adult patient, with an anticholinergic syndrome of delirium, mydriasis, flushing, tachycardia, dry mucous membranes, or hyperthermia. Hypotension and a widened QRS complex are concerning findings. Pediatric patients exhibit electrocardiographic (ECG) changes similar to those seen adult patients, but no correlation between ECG findings and prognosis has been established.^15,18 As with adults, seizure is an ominous sign of potential impending circulatory collapse. When death occurs, it is usually the result of cardiac arrest.

Prehospital

Whenever possible, product or prescription containers should be transported to the hospital with the patient. Given the rapid onset of symptoms seen with many of the agents discussed in this chapter, patients should be transported by ambulance to a hospital facility.

The administration of syrup of ipecac at home is not recommended. A 2004 position paper from the American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) stated that data were insufficient to support or refute the use of syrup of ipecac in the prehospital setting.²⁰ In highly toxic ingestions by patients in remote locations (i.e., when hospital evaluation will be delayed by hours), ipecac may have a limited role in the prehospital setting if it is administered very early.²¹

Administration of a neutralizing agent, such as vinegar in the case of alkali ingestion, is not recommended because of concerns of inducing emesis or exacerbating injury by causing an exothermic reaction.

Hospital

Supportive care is the mainstay of treatment for toxic exposures. The ABCs (airway, breathing, and circulation) are of the utmost importance, and the airway is secured early in patients with compromised respiratory status, mental status depression, or risk of aspiration. Fluid resuscitation should be initiated early and aggressively in patients with hypotension. Seizures, regardless of causative agent, should generally be treated with benzodiazepines as first-line agents and with phenobarbital in refractory cases.

Gastric decontamination in toxic ingestions has historically been a controversial topic and poses unique problems in the pediatric patient. The AACT and EAPCCT’s joint position on the routine use of gastric lavage states that the weight of evidence does not demonstrate a beneficial clinical effect and that the risk of adverse outcomes such as aspiration, laryngospasm, or perforation outweighs the questionable benefits.²² An additional issue concerning lavage in the pediatric patient is that smaller children may not easily accommodate the 36 to 40 French catheter often needed to remove particulate material effectively.

Single-dose activated charcoal is similarly not recommended for routine use by the AACT and EAPCCT but may be considered in specific cases.²³ Risks associated with charcoal administration include vomiting and aspiration, decreased effectiveness of oral antidotes, and an obscured view of the oropharynx should intubation or endoscopy become necessary.²¹ Data from volunteers implied that the reduction of toxin absorption may not be clinically significant if activated charcoal is administered more than 1 hour following ingestion, but a potential benefit after 1 hour cannot be excluded.²³ Charcoal use is contraindicated in a patient without an intact or protected airway. Convincing a toddler to drink a gritty slurry may prove extremely difficult, and the distress caused by forcibly administering this therapy must be weighed against the benefits on a case-by-case basis.

Whole-bowel irrigation is not routinely recommended but should be considered in a patients who has ingested sustained-release or enteric-coated tablets, particularly if the patient presents more than 2 hours following ingestion.²⁴ This procedure is contraindicated in cases of ileus, bowel obstruction or perforation, hemodynamic instability, or compromised airway.

Agents with specific treatment antidotes or guidelines are discussed next (Table 158.5).

Observation and Admission Versus Discharge

Regardless of suspected agents, most pediatric patients with toxic exposures or suspected ingestions can be observed for 4 to 6 hours. Patients who remain asymptomatic may be safely discharged home. Exceptions and additional management information relevant to specific substances follow.

Children with suspected salicylate exposure who are found to have a positive blood level require hospital admission with levels rechecked every 2 hours until they are clinically improving, have a decreasing and nontoxic salicylate level, and have an alkalemic blood pH.¹¹

With respect to calcium channel blocker ingestion, although a 6-hour period of observation is sufficient for ingestions of immediate-release formulations, a 12- to 24-hour observation period is recommended if concern exists about exposure to extended-release formulations.

The observation period for suspected Lomotil ingestion is not well described, especially if significant exposure is a concern. Because symptoms have been shown to be delayed by up to 24 hours, patients with concerning ingestions should be observed for at least this long.

Patients who have ingested sulfonylureas should be monitored for 8 hours because of the possibility of delayed presentation. Patients should be monitored for longer if the ingested medication is a sustained-release formulation.