Pediatric Toxicology: Part 2

What EMS providers need to know about “one-pill killers”

As discussed in part 1 in the April issue, 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.

CALCIUM CHANNEL BLOCKERS

Use of calcium channel blockers has continued to increase since their introduction in the 1960s; they are now the most frequently prescribed class of cardiac medications. As their use has increased, so has the frequency of accidental ingestions in pediatric patients. As a result, they are among the top 10 causes of poison-related deaths in children younger than age 6.

In 2006, there were 4,806 exposures to calcium channel blockers when they were ingested as a single agent. This resulted in 316 moderate outcomes, 69 major outcomes and 13 deaths (see Table 1). There were 1,363 exposures in children younger than 6 years and 234 exposures in children 6–19 years. Even low doses of calcium channel blockers can cause significant morbidity and mortality in pediatric patients. In two separate cases, a 14-month-old experienced a fatal outcome after ingesting one 10 mg nifedipine (Procardia, Adalat) tablet, and an 11-month-old experienced significant toxic exposure after ingesting five 80 mg verapamil (Calan, Isoptin) tablets.

All calcium channel blockers act on L-type calcium channels, resulting in the blockade of calcium influx into the cells. This results in a decrease in the force of muscular contraction in the heart and peripheral vasculature, as well as a decrease in the automaticity (rate) and speed of electrical conduction in the heart. These medications are divided into four categories based on their chemical composition. Although they all have similar actions, their effects on the body have slight differences. Many of these medications are available in both regular and extended-release tablets, and the toxic effects secondary to ingestion of extended-release tablets may be delayed and/or prolonged.

• Phenylalkylamines, such as verapamil, act on cardiac tissue by slowing the heart rate (negative chronotropy), slowing the speed of conduction (negative dromotropy) and decreasing the force of contraction (negative inotropy). Verapamil also causes peripheral vascular dilation. This class has the most severe potential due to the combination of cardiac and peripheral effects.
• Benzothiaprines, such as diltiazem (Cardizem), primarily slow the rate and speed of cardiac conduction. This class causes minimal decreases in the force of contractility and minimal peripheral vasodilation.
• Dihydropyridines, such as nifedipine, act primarily on vascular smooth muscle, causing peripheral vasodilation. They do have a slight negative inotropic effect; however, this is offset by the cardiac response to vasodilation.
• Diarylaminopropylamine ether, of which bepridil (Vascor) is the only medication, is chemically unrelated to the other calcium channel blockers. In addition to blocking calcium channels, sodium channels are also inhibited. The effects of this medication are a decrease in cardiac conduction and contractility. Since it has significant side effects, it is rarely used.

CLINICAL EFFECTS

The clinical effects of calcium channel blockers are directly related to reduced cardiac conduction, blocks in cardiac conduction, reduced force of cardiac contractility and vasodilation. Signs and symptoms often appear within 1–5 hours of ingestion of regular tablets. Cardiac effects include bradycardia (a reflex tachycardia may be seen with dihydropyridine ingestion), and second- and third-degree heart blocks. Cardiogenic shock secondary to negative inotropy may occur. Hypotension, which may persist more than 24 hours, even with treatment, can be present. Hyperglycemia is possible secondary to impaired insulin release and increased insulin resistance. Hyperglycemia associated with bradycardia and hypotension strongly suggests calcium channel blocker overdose.

Other signs and symptoms, such as dizziness, syncope and mental status changes, are secondary to systemic hypotension. Seizures are not common in calcium channel blocker exposures. If they are present, exposure to multiple agents should be considered. Seizures are more common in pediatric ingestions of calcium channel blockers than in adult overdoses. If seizures occur, they may respond to calcium administration. If not, they are treated with diazepam (Valium) or another benzodiazepine.

MANAGEMENT

After the addressing of any immediate life threats, the patient should receive early and continued monitoring of the cardiac rhythm and hemodynamic status. Calcium channel blockers are well absorbed by activated charcoal, which should be given within one hour of ingestion for regular tablets, and may be considered after one hour if sustained-release tablets were ingested. If the patient is asymptomatic, supportive care, charcoal, observation and transport are all that is required. There is no evidence that gastric lavage is beneficial in the setting of calcium channel blocker ingestion. If the patient is bradycardic, atropine is the first-line medication; however, it is often not effective until calcium has been administered. Pacing may also be considered to increase the heart rate in the event atropine is unsuccessful. If the patient is hypotensive, an initial fluid bolus of 20 ml/kg should be administered and repeated as necessary to a total of 60 ml/kg. Persistent hypotension may require the administration of vasopressors.

Specific antidotes include administration of calcium, either as 10% calcium chloride or 10% calcium gluconate (see Table 2). Conflicting data regarding the effectiveness of calcium administration exists, showing more benefit in mild ingestions as opposed to severe ones. Current recommendations support its administration in confirmed exposure to calcium channel blockers if significant signs and symptoms exist. Glucagon may be administered, as it binds with receptor sites on cardiac cells, causing calcium channels to open, as well as stimulating the release of intracellular calcium stores. Subsequent doses can be doubled or tripled if the initial dose is ineffective. Glucagon generally exerts its effects within five minutes of administration and has duration of 15 minutes.

The ED course of treatment may include high-dose insulin and glucose therapy. Insulin has positive inotropic effects and can reverse myocardial depression. Co-administration of glucose prevents hypoglycemia.

CYCLIC ANTIDEPRESSANTS

First introduced in the 1950s, cyclic antidepressants (Table 3) were the leading cause of death secondary to toxic ingestion until 1993. Although their use as a first-line treatment for depression has diminished with the introduction of new antidepressant medications, they are still used for a variety of other conditions. As a result, they continue to be responsible for a large number of fatalities and were the second most common cause of death secondary to a toxic ingestion in 2001. Cyclic antidepressant fatalities are secondary to their effects on the cardiovascular system and the central nervous system (CNS).

When an ingestion involved a cyclic antidepressant alone, there were 4,766 total exposures resulting in 964 moderate outcomes, 365 major outcomes and 13 deaths in 2006, with the majority being attributed to amitriptyline. Of the ingestions, 852 occurred in children younger than 6 years and 684 in children 6–19. Although only 13 deaths were attributed to the ingestion of cyclic antidepressants as the lone agent, they were implicated in numerous overdoses involving multiple substances and continue to be a leading cause of death due to ingestions.

Cyclic antidepressants exert their effects on the central nervous system, autonomic nervous system and cardiovascular system by a variety of mechanisms. All cyclic antidepressants inhibit the reuptake of norepinephrine in the presynaptic neurons of the CNS, and some also inhibit reuptake of serotonin and dopamine. The characteristic EKG findings of cyclic antidepressant toxicity are the result of the blockade of fast sodium channels in the cardiac conduction system. Adrenergic blockade leads to hypotension. These medications also cause anticholinergic effects.

Mortality is secondary to cardiovascular effects and hypotension, rather than effects on the CNS. Doses of 10–20 mg/kg result in significant toxic effects, and doses of 15–20 mg/kg can be fatal. The presenting signs and symptoms cannot be correlated to serum levels of medication. Therefore, aggressively treating any presenting signs or symptoms is paramount in these patients.

CLINICAL EFFECTS

Cyclic antidepressants are rapidly absorbed and generally have an onset of 2–8 hours after ingestion. Patients may appear stable at initial contact, then experience rapid deterioration. Effects on the CNS include respiratory depression, convulsions, seizures and coma. Seizures are generally tonicclonic and self-limited, but status epilepticus has been reported.

Several changes in the electrical and mechanical function of the heart occur in the setting of cyclic antidepressant toxicity. An R wave of greater than 3 mm in aVR indicates a significant chance of seizures or arrhythmias. A QRS complex of greater than 0.10 seconds is a significant indicator of cardiac toxicity, as well as coma, hypotension and the need for airway management. There is a 34% chance of seizures and a 14% chance of arrhythmias when the QRS is greater than 0.10 seconds. If the QRS complex is greater than 0.16 seconds, there is a 50% chance of ventricular arrhythmias occurring. An important concept in evaluating a possible cyclic antidepressant overdose is that a narrow QRS on an EKG can be used to rule out an overdose, but a wide QRS cannot be used by itself to confirm an overdose, as there are multiple causes of a wide QRS complex. Inhibited release of intracellular calcium results in negative inotropic effects on the heart. The development of hypotension is secondary to alpha-adrenergic inhibition and cardiac rhythm disturbances. Signs and symptoms associated with the anticholinergic toxidrome are also possible (see Table 4).

MANAGEMENT

Airway management and support of respirations are typically needed in a significant exposure to cyclic antidepressants. Respiratory acidosis must be avoided, as this will further inhibit fast sodium channels. Induced respiratory alkalosis has been suggested in the past, although this procedure has not shown any benefit to patient outcome and is absolutely contraindicated if sodium bicarbonate is administered. Several studies have shown that gastric lavage has no effect on outcome with minimal recovery of the ingested dose. Other studies demonstrate no clinical benefit to combining gastric lavage and administration of activated charcoal, as compared with administration of charcoal alone. Current recommendations are that lavage should be reserved for ingestion of life-threatening doses and, if possible, be performed within one hour of the ingestion. Activated charcoal can be administered, but caution is warranted due to the potential for airway compromise and aspiration.

In the setting of significant cardiovascular changes, the initial treatment is administration of sodium bicarbonate to reverse cardiac effects and to decrease incidence of ventricular arrhythmias. Historically, the administration of sodium bicarbonate has been reserved for cases where the QRS is greater than 0.10 seconds. There are reports in the literature of sodium bicarbonate administration in the setting of cyclic antidepressant overdose associated with heart block, hypotension or ventricular irritability, even in the absence of a widened QRS complex. Hypotension is initially treated with 20 ml/kg of an isotonic fluid and repeated as necessary to a maximum dose of 60 ml/kg. Vasopressors can be considered in hypotension refractory to sodium bicarbonate and fluid administration. Norepinephrine is the vasopressor of choice; however, this is often not available in the prehospital setting. Dopamine is the second choice and is acceptable if it is the only option. High doses (20–30 mcg/kg/min) of dopamine may be required in the setting of cyclic antidepressant toxicity.

Wide-complex tachycardias may be the result of ventricular irritability or aberrant supraventricular rhythms. In either case, they are typically suppressed with administration of sodium bicarbonate and correction of hypoxia and hypovolemia. In the setting of ventricular irritability that is refractory to sodium bicarbonate, lidocaine can be considered, but its effectiveness has been inconsistent, and it should be a last resort.

Procainamide and other class IA medications are contraindicated because of their inhibitory effects on sodium channels. Class IC antiarrhythmics are also contraindicated, but these are generally not available in the prehospital setting. Amiodarone and other class III antiarrhythmics are contraindicated, as they can prolong the QT interval, which may result in arrhythmias. Because of the interaction of cyclic antidepressants and antiarrhythmics, combined overdoses can be very deadly.

Most seizures are self-limited and do not require treatment. Refractory seizures are treated with diazepam or other benzodiazepines.

CLONIDINE (CATAPRES)

Clonidine is a centrally acting antihypertensive that is also used in the management of attention deficit hyperactivity disorder, migraine headaches, and narcotic and nicotine withdrawal. The medication can be administered orally or transdermally, and acts as a central alpha-antagonist, resulting in decreased sympathetic stimulus to the heart, periphery and kidneys. It is also believed to have inhibitory effects on the respiratory center in the medulla.

When ingested as a single substance, clonidine was involved in 3,250 total exposures in 2006. There were no deaths secondary to clonidine in 2006, which is consistent with prior years, but there were 728 moderate and 94 major outcomes. Children younger than 6 years accounted for 1,365 exposures; children 6–19 years accounted for 1,068 exposures.

Exposures have been reported secondary to children sucking on transdermal patches, application of transdermal patches, and by orally ingesting tablets. The medication can be toxic in children at doses of 0.1 mg.

CLINICAL EFFECTS

Clonidine acts rapidly and can decrease blood pressure 30–60 minutes after oral ingestion. Toxic effects can occur in 30–90 minutes, with an average onset of 35 minutes, and may last 1–3 days. It is important to note that the severity of the patient’s presentation does not always correlate to the amount of medication ingested. Onset of symptoms after four hours postingestion is rare; however, in some cases, symptoms within the first four hours were minimal, and significant symptoms occurred after that point. In many cases, hypotension develops after hospital admission.

Toxic exposure may mimic exposure to narcotics by causing an altered level of consciousness, miosis (constricted pupils), bradycardia, hypotension, respiratory depression and decreased muscle tone. CNS depression can range from drowsiness to coma. Transient hypertension is possible due to inhibition of norepinephrine reuptake in the periphery before the central effects cause hypotension and bradycardia. Children are especially susceptible to respiratory depression and apnea, and may become hypothermic.

MANAGEMENT

Management is largely supportive and is geared toward treating the patient’s presentation. Assessment and management of the airway, oxygenation and respiratory effort is paramount in these patients. There is a risk of bradycardia and AV block; therefore, continuous cardiac monitoring is indicated. Activated charcoal is successful in binding with clonidine.

The use of naloxone (Narcan) has been advocated in the setting of clonidine toxicity; however, its use is controversial due to its variable response. Narcan’s effect is thought to be due to the relationship between the receptors for clonidine and the receptors for narcotics. In one retrospective study, only 4% of patients who were given naloxone showed any clinical signs of improvement, while others have found that 50% of patients respond. In another study, patients who received naloxone were more likely to require intubation than those who did not receive the medication. Additionally, hypertension has been associated with naloxone administration in the setting of clonidine toxicity. Because of the questionable efficacy and associated side effects of naloxone, its use in clonidine overdose is unclear. Routine administration is not indicated, and it should only be considered in those patients whose mental status and inability to control the airway would necessitate intubation.

In the setting of symptomatic bradycardia, atropine is generally effective, but repeat doses may be required due to the long half-life of clonidine. Increased heart rates have minimal effects on hypotension, but fl uid administration usually corrects this finding. In the event fluid is ineffective, or bradycardia persists, dopamine can be considered.

The conclusion to this series will appear in the June issue. To access the bibliography, see Part 1 in the April issue, or visit emsresponder.com.

Robert Vroman, BS, NREMT-P, has been involved in all levels of EMS for 17 years, working with both rural and urban services as a provider and educator. He is currently a member of the Paramedic Education Program faculty at HealthONE EMS in Englewood, CO.