Pediatric Toxicology: Part 3

     As discussed in Parts 1 and 2 in the April and May issues, most toxic exposures in children under 6 years old are secondary to exploration rather than intentional attempts to harm and therefore do not involve enough substance to cause significant toxicity. It is not until the teen years that toxic exposures with intent to cause personal harm begin to occur. There are several substances, however, that can result in significant toxicity, even when taken at low doses. These are referred to as "one-pill" or "one-dose" killers. Although it may take more than one pill or dose for death to occur, this is a good tenet to remember, as low doses of these substances can indeed cause significant toxicity or death. Therefore, it is imperative that prehospital providers be familiar with both the generic and trade names of these medications so exposure can be recognized and appropriate treatment initiated.

OPIATES AND OPIOIDS
     Opiates and opioids (narcotics) have agonistic actions on the opiate receptors, thereby altering the perception of pain. They have been used for centuries for pain control. There are natural, synthetic and semi-synthetic forms available, as well as combinations of narcotics and other medications. Infants and children are more susceptible to toxic effects than adults, and, as a result, even small amounts can cause significant toxic exposure or death. Narcotics can be administered orally, transdermally or by injection. As with other exposures in children, the most common route of exposure is oral, including chewing on transdermal narcotic patches. In 2006, there were 21,868 exposures where opiates and opioids were the lone agent, resulting in 2,178 moderate outcomes, 731 major outcomes and 91 deaths. Of the total exposures, 2,911 occurred in children younger than 6 years, and 2,096 exposures occurred in children ages 6–19. Interestingly, 21 children under age 6 were exposed to heroin as the lone agent. The largest proportion of opiate exposure occurred when combined with acetaminophen. Of the total exposure to narcotics and narcotic-containing medications, there were 3,467 moderate outcomes, 945 major outcomes and 125 deaths. Children younger than age 6 accounted for 9,356 of these exposures, and children 6–19 years old accounted for 5,909 exposures.

CLINICAL EFFECTS
     The effects of opiates and opioids generally peak within one hour of ingestion, and the duration of action varies based on the substance ingested. Narcotics may cause minimal vasodilatation, but the majority of their toxic effects are exhibited through CNS depression. Most deaths in narcotic exposures are secondary to hypoxia resulting from respiratory depression. Seizures may occur at high doses, and they are more common in exposures to propoxyphene (Darvon) and meperidine (Demerol). These agents have minimal cardiovascular effects; however, propoxyphene can block sodium channels and widen the QRS complex or cause AV blockade. These conditions can be treated with sodium bicarbonate, lidocaine or atropine, as applicable. Additional signs and symptoms of narcotic exposure are shown in Table I.

MANAGEMENT
     Immediately initiate general supportive care, with particular attention to airway management and support of respirations as necessary. Activated charcoal can be administered if the airway reflexes are intact or the airway is protected.

     Specific treatments include administration of naloxone (Narcan), a competitive antagonist for opioid receptor sites, to reverse the effects of opioid agonists. Naloxone has a rapid onset but a short half-life compared to most narcotics. The patient must be continually monitored for the return of signs and symptoms of the narcotic exposure. It may take higher doses of naloxone for narcotic/naloxone combinations such as buprenorphine combined with naloxone (Suboxone). Subutex (buprenorphine alone) and Suboxone are being used more frequently for the outpatient treatment of narcotic addiction. Unlike treatment with methadone, direct observation is not required. These medications undergo rapid sublingual absorption and are administered in this manner.

     There are multiple case reports of significant toxicity after a child has simply placed a Subutex or Suboxone tablet in the mouth. In many of these cases, higher than normal doses of naloxone were needed to reverse the effects of the narcotic, and reversal was delayed as compared to other narcotics. Although it may seem that the presence of naloxone in Suboxone would provide some protection in the case of overdose, this is not the case. Naloxone is absorbed very poorly by the sublingual route and provides no antagonistic effect. The presence of naloxone is to deter Suboxone abuse by injecting the medication. Interestingly, both Subutex and Suboxone are poorly absorbed from the GI tract. As a result, the child who swallows a tablet of these medications will likely experience little, if any, toxic effects, as compared to the child who places a tablet in the mouth without swallowing it.

DIPHENOXYLATE/ATROPINE
     Diphenoxylate/atropine (Lomotil, Diphenatol, Enoxa, Lofene, Lonox, Lotrol, Lo-Quel) is an anti-diarrheal agent that contains 2.5 mg of the opioid diphenoxylate and 0.025 mg of atropine per dose. It was first introduced in 1960 and historically is believed to be potentially fatal with one or two pills. Although it is a very toxic medication, significant effects generally occur only after many or repetitive doses. While there is no known minimal toxic dose, amounts as small as one-half tablet have been reported to cause signs and symptoms of mild toxicity. Toxic exposures present as a long-acting opioid overdose associated with anticholinergic effects due to the opioid-anticholinergic combination.

     The medication is not recommended for children under age 4 and is rarely prescribed to children in general. Although there are reports of parents who are unaware of the toxic potential when treating children with this medication, most exposures are due to accidental ingestion.

     Diphenoxylate decreases GI motility by inhibiting smooth muscle contraction. An overdose can lead to delayed absorption, causing signs and symptoms to persist for up to 24 hours as the medication remains in the system. The atropine component is not part of the anti-diarrheal function, but rather to reduce the risk of abuse of diphenoxylate, which is classified as a schedule II medication.

     Toxic exposures have declined over the last decade due to decreased use of this medication. In 2006, there were 469 total exposures to diphenoxylate as a single agent, with 23 moderate outcomes, 1 major outcome and no deaths. Of the total exposures, 155 occurred in children less than 6 years old, and 24 occurred in children 6–19 years old.

CLINICAL EFFECTS
     Because the effects of diphenoxylate/atropine are a combination of opioid and anticholinergic components, there is a biphasic presentation of signs and symptoms. The first phase is secondary to anticholinergic response and may last two to three hours, followed by a much longer phase in which the opioid signs and symptoms prevail. Table I lists the signs and symptoms associated with each of these toxidromes. It must be recognized, though, that many patients do not have the classic biphasic response. It has been shown that all patients experience opioid effects during toxic exposure, but in almost half of the exposed patients, those are the only effects.

     Signs and symptoms can reappear after initial treatment and improvement. There are two theories regarding this phenomenon. One is that the improvement in gastric motility causes reabsorption of the remaining medication. The second is that the metabolite of diphenoxylate (difenoxin), which is more active and longer-lasting than diphenoxylate, causes the return of signs and symptoms.

MANAGEMENT
     As with any overdose, supportive care, including monitoring of mental status and vital signs, is paramount. Because of the opioid component of the exposure, pay close attention to the status of the airway and respiratory effort, providing support as needed. Naloxone may be considered in the presence of the opioid toxidrome. Due to the anticholinergic effects, cardiac activity should be monitored. Activated charcoal can be administered several hours after ingestion because of the slowed GI motility.

CAMPHOR
     Camphor is a colorless, or white crystalline, solid that has a distinct taste and a pleasant odor. It is contained in several over-the-counter preparations and is a common ingredient in several topical ointments, as it produces a cooling sensation and analgesia when applied to skin (see Table II). At one time, camphor was an ingredient in mothballs. Although this is no longer the case, these products may still exist in some homes. Oral ingestion of low doses of camphor can cause significant toxicity. There are also case reports of significant toxicity in children from ingesting over-the-counter transdermal cold remedy patches containing camphor. Dosages as small as 15 ml of Vicks VapoRub and 10 ml of Campho-Phenique have caused significant toxic effects; ingestion of 700 mg–1 g of camphor can cause death.

     Because of its toxic effects, the AAP stated in 1978 that there is no need or indication for camphor-containing products. In 1983, an FDA regulation stated that OTC products cannot contain more than 11% camphor. This policy was revisited in 1994, and the conclusion was the same as in 1978. Toxicity of camphor-containing products remains a problem, and parents should be made aware of the potential dangers. It further recommended that alternative therapies be considered before using camphor-containing products. This policy was reaffirmed by the AAP in May 2005.

     Despite these positions and regulations, camphor ingestion continues to be a cause of toxic exposure, accounting for 10,000 annual ingestions between 1990 and 2003. In 2006, there were 9,295 total exposures to camphor as a single substance, resulting in 74 moderate outcomes, seven major outcomes and one death. Children younger than 6 years accounted for 7,398 exposures; children 6–19 years of age accounted for 528 exposures. Additionally, there were 2,047 total exposures to camphor/methylsalicylate combined preparations, which included 1,792 exposures in children younger than age 6 and 79 exposures in ages 6–19. There were no deaths or major outcomes and 10 moderate outcomes as a result of exposure to these combined preparations.

CLINICAL EFFECTS
     Camphor rapidly crosses the cell membranes, and signs and symptoms may occur within 5–20 minutes of ingestion. General complaints include oral and epigastric burning sensation, GI distress, nausea and vomiting, a sensation of generalized warmth and headache. Initially, camphor causes hyperactivity of the central nervous system (CNS), which can result in anxiety, confusion, irritability, seizures, excitement, delirium, tremors or convulsions. As the toxic effects progress, the CNS becomes depressed, potentially causing coma, respiratory depression or apnea. Asystole is possible, as is renal damage. Death is generally secondary to respiratory depression or status epilepticus.

MANAGEMENT
     In addition to clues from the scene and physical assessment, camphor toxicity can usually be recognized by its odor. Unfortunately, there is no specific antidote for camphor ingestion and care is essentially supportive. Maintain an open airway, provide oxygenation and support ventilation as needed. Suction should be nearby to avoid emesis aspiration. There is not sufficient evidence to support administration of activated charcoal, although it has been successful in some cases. Seizures are controlled with standard seizure therapy, including administration of benzodiazepines.

     Published guidelines for out-of- hospital management of camphor ingestions recommend transport for any patient who is exhibiting signs and symptoms of toxicity, or who intentionally ingested the substance, regardless of the dose ingested. Transport is also recommended if the ingestion was greater than 30 mg/kg, regardless of the presentation of signs and symptoms. If exposure occurred more than four hours prior to EMS' arrival and the patient is asymptomatic, recommendations say the patient can be safely observed at home.

SULFONYLUREAS
     Sulfonylureas have been available in the United States since 1954 and are the most common agents used in the treatment of type II diabetes mellitus. Medications in this class include glipizide, glyburide, chlorpropamide and glimepiride, among others. Oral hypoglycemics are the main treatment of this disorder. With the increased prevalence of type II diabetes, there has been an increase in pediatric toxic exposures to these agents.

     In 2006, there were 1,951 total exposures where a sulfonylurea was the sole agent ingested. Of those, there were 472 moderate outcomes, 52 major outcomes and one death. Of the total exposures, 974 occurred in children younger than 6 years and 99 in children ages 6–19. There are numerous case reports of significant toxic effects in pediatric patients after ingesting just one tablet in this medication class. Fortunately, death is unlikely with appropriate treatment. Between 1990 and 2004, only one death was reported in young children.

     Sulfonylureas inhibit a specific type of potassium channel in the beta cells of the islets of Langerhans. This results in an increase in intracellular potassium, causing the release of insulin that does not depend on blood glucose levels. They also enhance the effect of insulin on the body's cells. Insulin promotes the movement of glucose into cells, stimulates formation of glycogen and fat, and inhibits glucogenolysis. These actions effectively lower blood glucose levels and do not allow compensatory mechanisms for hypoglycemia to occur.

CLINICAL EFFECTS
     Due to their long half-life, sulfonylureas have a long duration of action. Their effects can be delayed, especially with exposure to extended-release tablets. While most patients exhibit effects within 8 hours, there are case reports of signs and symptoms being delayed or continuing for 24–36 hours after ingestion. If ingestion of any of these medications is suspected, the patient must be transported for monitoring.

     The primary effect of toxic exposure is hypoglycemia, which manifests through the sympathetic nervous system and disruption of the CNS. A patient may exhibit headache, altered mental status, confusion, irritability, combativeness, tremors, seizures, diaphoresis, tachycardia, tachypnea, nausea and vomiting.

MANAGEMENT
     Because of the potential for obstruction, the airway must be maintained if the patient is unresponsive. General treatment must be performed, and, if indicated and appropriate for the patient's condition, activated charcoal can be considered. The main focus of treatment is general supportive care, evaluating blood glucose and correcting hypoglycemia as it develops with dextrose administration. In the absence of intravenous access, it may be necessary to administer glucagon as a short-term measure until IV access is obtained. This is controversial, however, as it does not inhibit insulin release stimulated by sulfonylureas, and it may increase the release of insulin in response to rising glucose levels.

SALICYLATE
     Salicylates include several substances, such as acetylsalicylic acid (aspirin), methyl salicylate, (oil of wintergreen) and bismuth salicylate (Pepto-Bismol). Because parents may not be aware that a product contains salicylate, toxicity recognition may be delayed. The minimal toxic dose by ingestion is 150 mg/kg. To provide reference, one teaspoon of 98% methyl salicylate contains 7,000 mg of salicylate. This is the equivalent of 86 low-dose (81 mg) aspirin tablets.

     Salicylates are found in a variety of medications. In addition to aspirin (ASA), many cough and cold medications contain ASA and non-ASA salicylates, and some antacids contain salicylates.

     In additon to oil of wintergreen, methyl salicylate is contained in some rubbing alcohols and many topical creams, with concentrations ranging from 5%–30%. Many Asian liquid herbal remedies contain methyl salicylate that ranges in concentration from 15%–67%. Non-medical uses include essential oils and flavoring agents that have a pleasing odor and taste. Ingestion of any of these agents in a liquid form can lead to serious toxicity.

     Fortunately, there have been no cases reported in the literature of significant toxicity secondary to ingestion of topical agents. This is likely due to their lower concentration of methyl salicylate and the fact that their physical properties make it difficult for a child to ingest a large dose. There have been several reports of toxic effects of salicylate secondary to transmucosal absorption after intraoral exposure to salicylate-containing agents and percutaneous absorption after topical exposure to salicylate-containing agents.

     In 2006, there were 49,055 total exposures to products that contained salicylate. Of these exposures, there were 2,605 moderate outcomes, 253 major outcomes and 17 deaths. There were 30,115 exposures in patients younger than 6 years of age and 8,588 exposures in patients 6–19 years of age. It is important to note, however, that salicylate is found in combination with many other medications. It is difficult to ascertain if the reported outcome was due to salicylate or the medication it was combined with.

     In 2006, there were 3,603 exposures in patients younger than age 6 and 2,742 in patients 6–19 years where ASA was the lone toxic ingestion.

     Agents with methyl salicylate as the lone toxin accounted for 7,130 exposures in patients younger than age 6 and 583 exposures in ages 6–19.

CLINICAL EFFECTS
     Clinical effects, referred to as salicylism, are directly related to stimulation of the CNS and the respiratory center. If enteric-coated products were ingested, peak effects may not be present for 12 hours after exposure. Clinical pediatric toxicologys of the salicylate toxidrome can be found in Table 1. Early findings include nausea, vomiting, diaphoresis and tinnitus. Severe intoxications can cause noncardiogenic pulmonary edema, cerebral edema, seizures, coma, apnea and hyperthermia, which is often pre-terminal. There have been reports of acute laryngeal edema, angioedema and urticaria after exposure of non-ASA salicylates in patients with a history of ASA sensitivity.

     Stimulation of the respiratory center of the brain promotes hyperventilation and respiratory alkalosis. Because pediatric patients have minimal respiratory reserves, they can fatigue easily, leading to respiratory failure and respiratory acidosis. Respiratory acidosis is a grave finding that suggests pulmonary edema, respiratory fatigue or mixed ingestion.

     Electrolyte disturbances are uncommon in salicylate exposure; however, hypokalemia has been reported. In compensation for respiratory alkalosis, potassium ions are moved from the extracellular to the intracellular space in exchange for hydrogen ions, but this movement is not significant enough to cause hypokalemia by itself. The major cause of hypokalemia is renal loss of potassium to compensate for respiratory alkalosis and loss of potassium through vomiting. If this condition exists, signs and symptoms of hypokalemia such as cardiac arrhythmias, large P waves and flattened T waves may be present in addition to the signs and symptoms attributed to salicylates.

MANAGEMENT
     Control the airway and assist respirations as necessary. Evaluate the blood sugar and correct hypoglycemia. Support circulation and perfusion with isotonic IV fluids, as patients may need aggressive fluid resuscitation to maintain tissue perfusion and urinary output. When administering fluids, be cognizant of the possibility of pulmonary edema and evaluate lung sounds frequently.

     Activated charcoal may be considered if the airway is protected and it can be administered within one hour of ingestion. The use of multiple doses of activated charcoal has been advocated in the past, but clinical trials have not supported this treatment. Administration of sodium bicarbonate will enhance renal elimination by alkalinizing the urine. This will also assist in correcting existing metabolic acidosis.

SUMMARY
     Despite the decline in pediatric toxic exposures since the 1960s, they remain a common cause of pediatric emergencies. Airway maintenance, respiratory support, circulatory support, correction of hypoglycemia and hypothermia and continued monitoring of patients are vital to positive outcome. In a select few cases, more aggressive procedures such as gastric emptying and binding of toxins may be necessary. Although the majority of cases can be handled in this manner, there are several substances that can cause significant toxicity in children even at low doses. It is imperative that prehospital providers be familiar with these substances in order to avoid catastrophic outcomes.

     To access the bibliography for this series, see Part 1 in the April issue, or visit emsresponder.com.