Are One or Two Dangerous? Calcium Channel Blocker Exposure in Toddlers

The Journal of Emergency Medicine, Vol. 33, No. 2, pp. 145–154, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/07 $–see front matter

doi:10.1016/j.jemermed.2007.02.010

Selected Topics: Toxicology

ARE ONE OR TWO DANGEROUS? CALCIUM CHANNEL BLOCKER EXPOSURE IN TODDLERS Claudia Ranniger,

MD, PHD

and Colleen Roche,

MD

Department of Emergency Medicine, George Washington University, Washington, DC Reprint Address: Claudia Ranniger, MD, PHD, Department of Emergency Medicine, George Washington University, 2150 Pennsylvania Avenue NW, Suite 2B-417, Washington, DC 20037

e Keywords— calcium channel blockers; pediatric; accidental ingestion; toxicity; overdose

e Abstract—Unintentional pediatric ingestions of calcium channel blockers are increasing in frequency due to increased use of this antihypertensive class. Potential toxic effects include severe refractory hypotension and death; however, the true toxicity of unintentional pediatric ingestions of 1–2 pills is poorly defined. A literature review was conducted to more closely determine toxic and lethal dosages of calcium channel blockers in the pediatric population under 6 years of age. Results indicate that, although most accidental pediatric ingestions are asymptomatic, a small number do result in cardiovascular instability or even death. The dihydropyridines, particularly nifedipine, and the phenylalkylamine verapamil are most often implicated in symptomatic ingestions. There are no adequate data to identify which children are predisposed to illness, or to determine cutoffs for toxic dosages. However, ingestions of only one pill have been documented to cause severe symptoms, including death. Thus, emergency evaluation to assess potential toxicity is necessary, and gastrointestinal decontamination and in-hospital observation of at least 6 h after toxic ingestion for regular release medications, and 12–24 h after toxic ingestion for sustained release medications is recommended for all cases of unintentional calcium channel blocker ingestion in children younger than 6 years of age. © 2007 Elsevier Inc.

INTRODUCTION Calcium channel blockers (CCB) are commonly found in America’s medicine cabinets; they have increased in popularity since their introduction in the 1960s and are now the most frequently prescribed class of cardiac medications (1). As a result, these medications are more accessible to the curious toddler than ever before. The frequency of unintentional pediatric ingestions has increased steadily in the United States; calcium channel and beta blocker ingestions rank in the top 10 causes of toxin-related deaths in children under 6 years of age (2,3). Despite this increase, the toxic dose and management of pediatric CCB ingestions has not been well defined, and literature has been limited to several retrospective chart reviews and case reports with adverse outcomes (4 –9). The relative danger of these medications is controversial, and requirements for observation and appropriate therapy in symptomatic cases are generally guided by experience gleaned from adult cases (10). Case reports of toddler deaths after ingestion have reinforced concern regarding toxicity of these medications; however, no consensus regarding toxic dosages is available. Furthermore, few data regarding the incidence of toxic effects after ingestion are available. The purpose of

Series Editors: Jeffrey N. Love, MD, The Georgetown University Emergency Department, Washington, DC; Wendy Klein-Schwartz, PHARMD, MPH, the Maryland Poison Center, Baltimore, MD; Liesl A. Curtis, MD, The Georgetown University Emergency Department, Washington, DC.

RECEIVED: 30 March 2005; FINAL ACCEPTED: 16 November 2006

SUBMISSION RECEIVED:

23 August 2006; 145

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Table 1. Calcium Channel Blockers Available in the USA (15) Pill formulations Medication Benzothiazepine Diltiazem

Brand names

Immediate release (mg)

Sustained release (mg)

Cardizem Cartia Dilacor Tiazac

30, 60, 90, 120 tabs 5 mg/mL suspension

60, 90, 120, 180, 240, 300 tabs

Isoptia Calan Covera Verelan

40, 80, 120 tabs 2.5 mg/mL suspension

120, 180, 240 tabs

Dihydropyridines Nifedipine Amlodipine Felodipine Isradipine Nimodipine Nisoldipine Nicardipine

Adalat Procardia Norvasc Plendil Dynacirc Nimotop Sular Cardene

10, 20 caps 2.5, 5, 10 tabs

30, 60, 90 caps

Diarylaminopropylamine ether Bepridil

Vascor

Phenylalkylamine Verapamil

this article is to attempt to quantify the toxicity of CCB ingestions in pediatric patients 0 –5 years old, to better identify the frequency of toxic sequelae after ingestion, and to determine if as few as one or two pills can pose fatal danger.

Physiology of Calcium Channels and Calcium Channel Blockers Myocardial and smooth muscle cells depend heavily on extracellular calcium for activation and muscle contraction. Abundant voltage-dependant L-type Ca channels exist on the surface membranes of these cells, and enable Ca influx down the large potential gradient across the cellular membrane in response to an action potential. The inflowing Ca binds to calcium channels on the sarcoplasmic reticulum, promoting more Ca release from intracellular stores, which in turn support myocyte contraction via troponin C and tropomyosin inhibition. In sinoatrial (SA) nodal cells, the slow L channel-mediated Ca influx contributes to Phase 4 of the action potential, promoting spontaneous depolarization in the pacemaker cells. In addition, these channels participate in atrioventricular (AV) nodal conduction. In vascular smooth muscle, extracellular calcium influx via L-type channels is directly responsible for contraction. Calcium from extracellular reserves binds with calmodulin, enabling myosin activation and actin-myosin binding. In addition, Ca channels are instrumental in the release of insulin from pancreatic

5, 10 table 2.5, 5 caps 30 caps 20, 30 caps 2.5 mg/mL suspension

10, 20, 30, 40 tabs 30, 45, 60 caps

200, 300, 400 tabs

islet cells. Blockade results in a relative hyperglycemia and decreased substrate delivery to cells. Subtypes of L channels are classified according to the alpha-1 subunit, which acts as the pore of the channel. Small variations in this subunit exist in cardiac myocyte, pacemaker, and smooth muscle cells. Classes of CCBs display varying affinities for these subunits, thus providing rationale for their differing effects on the cardiovascular system (1,11). Four classes of calcium channel blockers are currently available in the United States. The drug class, individual medications, brand names, and available formulations are shown in Table 1. Benzothiazepines (diltiazem) act to slow cardiac conduction, and exert milder effects on smooth muscle tone and cardiac contraction (12,13). Phenylalkylamines (verapamil) have moderate effects on both smooth muscle tone and cardiac conduction (14). These medications are used primarily for antidysrhythmic, rate controlling, anti-hypertensive, and anti-anginal purposes. Dihydropyridines, which include nifedipine, amlodipine, felodipine, isradipine, nimodipine, nisoldipine, and nicardipine, have the most significant effect on vascular smooth muscle tone, yet very little effect on cardiac conduction. In fact, baroreceptor-mediated reflex increases in heart rate due to relative hypotension may be seen at therapeutic doses. An exception in this class is isradipine, which slows SA nodal activity and suppresses the reflex chronotropic effect. Due to their potent vasodilatory effect, dihydropyridines are typically used for vasospastic and hypertensive therapy. Bepridil, the only diarylaminopropylamine ether, affects primarily myocar-

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dial contractility and cardiac conduction (15). It also antagonizes sodium and potassium channels, and, due to serious side effects, its use is rare.

Manifestations of Toxicity The morbidity and mortality of CCB toxicity are due to conduction system delays and blocks, loss of myocardial contractility, and loss of systemic vascular smooth muscle tone. Toxicity of CCBs typically manifests as an exaggeration of the therapeutic response (13,14,16). Verapamil and diltiazem generally exhibit the most cardiac (negative inotropic and chronotropic) effects, and overdoses present with bradycardia, heart block, AV conduction disturbances, and myocardial dysfunction. In contrast, dihydropyridine overdoses present initially with baroreceptor-mediated tachycardia in response to decreased systemic vascular resistance. However, as receptor selectivity is overwhelmed by the available CCB and all L-type channels are blocked, bradycardia and sustained hypotension may result (1,16). Systemic complaints and physical findings are related to these physiologic events. The most common physical finding after CCB overdose is hypotension (13,17). Systemic hypoperfusion results in a variety of symptoms ranging from mild orthostatic dizziness accompanied by nausea and vomiting, to more concerning manifestations including syncope, mental status changes, seizures, ce-

rebrovascular ischemic events, renal failure, intestinal ischemia, and liver infarction (13,18). Activation of insulin secretion by the pancreatic beta islet cell has been shown to produce hypoglycemia via inhibition of a slow Ca channel on the cell membrane (17). Acute pulmonary edema occurring via an unknown mechanism has also been reported with CCB overdose (1). Toxic Dosage Lethal and toxic doses of calcium channel blockers in humans are poorly described. Inferences on toxic doses are made from therapeutic ranges and case reports of toxic ingestions. Calcium channel blockers have not been approved for use in the pediatric population; nevertheless, nifedipine, diltiazem, amlodipine, and verapamil are frequently prescribed for hypertensive children (19 –29). Dosing is inconsistent and varies widely in both adults and children. Table 2 compares adult and pediatric doses of these medications, and shows known lethal doses in animal studies. Of note, many animal studies are conducted using i.v. medications and are not directly comparable to oral dosing, nor do they account for interspecies differences. Therapeutic Modalities Therapeutic options for CCB overdoses in toddlers are drawn from adult literature and pediatric case reports.

Table 2. Therapeutic doses of CCB* Suggested pediatric dose (mg/kg/day) Medication

Adult dose (mg) recommended

Recommended

Maximum

Diltiazem

30–60 QID

1.5–2 (7) 3–6 (21)

3.5

Verapamil

80–120 TID

3–4 (21)

8

Nifedipine

10–20 TID

1–2 (25,32) 0.25–0.5 SR (21)

1–2 3 SR

Amlodipine

5–10 QD

0.6

Felodipine Isradipine Nimodipine Nisoldipine Nicardipine

2.5–10 QD 2.5–5 BID 60 every 4 h 20–40 QD 20–40 QD

0.1–0.6 (19) 0.12–0.29 (28) 0.3 ⫾ 0.16 (34) 0.08–0.25 (24) 0.07–0.22 (26) 0.18–0.56 SR (21) 0.15–0.6 (21)

Bepridil

0.5–1.0 ␮g/kg/min IV (21,25) None

Animal LD50 (Oral formulations unless otherwise noted) Mouse 415–740 mg/kg Rat 560–810 mg/kg Dog ⬎ 50 mg/kg Monkey ⬎ 360 mg/kg (15) Rabbit 7.1 mg/kg IV (30) Rat 7.6 mg/kg IV (31) Mouse 920–1550 mg/kg Rat 4240–8250 mg/kg Rabbit 504 mg/kg (35)

0.6 SR 0.8 4–5 ␮g/kg/min

Mouse 480–570 mg/kg (oral) Rat 320–574 mg/kg (oral) (35)

* Adult dosages from Mosby’s Drug Consult (15). QD ⫽ daily; BID ⫽ twice daily; TID ⫽ three times daily; QID ⫽ four times daily; SR ⫽ sustained release.

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There is no evidence that gastric lavage improves outcomes, and in cases where heart block or bradycardia is already present, this procedure may increase vagal tone to the overall detriment of the patient. The American Academy of Clinical Toxicology states that charcoal administration may be considered in the case of potentially toxic ingestions up to 1 h after ingestion (36). Immediate treatment with charcoal in healthy adult volunteers given a therapeutic dose of either regular- or sustained-release CCB reduced absorption and peak plasma levels by 85–99% (37,38). Charcoal administration 2 h after ingestion of amlodipine reduced the total absorption by 49%, and the peak blood concentration by 43% (37). Charcoal administration 2 h after regularrelease verapamil ingestion, and 2 and 4 h after sustained release verapamil ingestion, reduced total absorption by one-third, with statistically insignificant trends toward reductions in peak plasma level (38). It is not known whether the lethality of CCB poisoning is related to total absorption or peak concentration; however, in the setting of a toxic dose CCB ingestion, the administration of charcoal within 2 h of ingestion is reasonable, particularly because no antidote is available. Recent case reports of charcoal-related complications mandate a careful history-taking to determine the likelihood of a toxic ingestion, and emphasize the need for airway monitoring and protection in these patients who are at risk for hypotension and altered sensorium. Interestingly, two case reports of pediatric CCB ingestions indicate that blood concentrations of drug increased even after a single dose of charcoal (9,39). It is postulated that this effect is due to slowed gastrointestinal motility, which prolongs transit time, and increased absorption from the gastrointestinal tract after resuscitative efforts have improved splanchnic blood flow. Further study on the use of multidose charcoal and whole bowel irrigation in the treatment of CCB overdose is needed. Intravenous fluids to counteract hypotension and intravenous calcium to compete at the channel receptors can be used to support the circulatory system (3,13,17,39 – 46). Use of atropine and transcutaneous pacing to support heart rate, epinephrine, and pressors to improve cardiac contractility and maintain vascular tone, heart-lung bypass, and extracorporeal membrane oxygenation to augment cardiac function, and glucagon to support cellular metabolism are indicated, although their therapeutic efficacy in the calcium channel blocker overdose patient is variable (3,17,39 – 41,46 – 49). High dose insulin drips, combined with supplemental glucose, improve intracellular metabolism and have been associated with improved outcomes in animal studies of parenteral and oral CCB overdose (50). Case reports in humans support

C. Ranniger and C. Roche

these data (50,51). Unfortunately, no direct antidote exists.

METHODS A literature review was conducted to identify case reports of CCB overdose to more closely determine toxic and lethal dosage in the pediatric population. A Medline search incorporating the words “pediatric” and “overdose” or “toxicity” and “calcium channel blocker” or the generic medication name (nifedipine, verapamil, diltiazem, amlodipine, isradipine, nicardipine, felodipine) was used to identify articles describing CCB ingestions in children. A second search eliminating the term “pediatric” was conducted to identify case series in which children may have been included. References from the Poisindex management on CCB ingestions with specific mention of pediatric cases were also located (33). American Association of Poison Control Center (AAPCC) yearly reports from 1984 –2005 were reviewed and pediatric case fatalities identified. Articles, abstracts, and case reports were included if the cases involved CCB ingestion or suspected ingestion, and the patients were ⬍ 6 years old. The articles, case reports, and case series were reviewed for patient age, weight, medication and dosage ingested, clinical effects, time elapsed to presentation, time to onset of symptoms, duration of symptoms, blood concentrations of drug, therapeutic interventions, observation time, and outcomes. In addition, individual author’s definitions of toxicity were reviewed to determine whether a consensus definition of toxicity exposure exists.

RESULTS Five retrospective case reviews of CCB ingestions were identified. Results are summarized in Table 3. Two of these reviews included a combined total of 93 exposed children aged 0 –12 years (8,52). The authors categorize toxic symptoms according to the AAPCC Toxic Exposure Surveillance System (TESS) definitions as mild (not requiring treatment), moderate (requiring treatment but not life-threatening), or severe (life-threatening), and identify either mean or minimum toxic and maximum non-toxic pediatric doses for individual CCBs. Unfortunately, no range of doses, description of toxic effects, or number of symptomatic cases are documented for the pediatric subgroup alone. Two additional studies of fewer than 30 exposures each identify a total of 5 children with mild non-specific symptoms of fatigue, sleepiness, and increased appetite after nifedipine or verapamil ingestion (9,53). Evaluation and treatment of the exposed

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Table 3. Case Series of CCB Ingestion in Pediatric Patients in which Toxic or Non-toxic Dosages are Reported Reference Nifedipine Belson (4)

RSWB (40) RSM (8) Diltiazem Belson (4) RSWB (40) RSM (8) Verapamil RSWB (40) RSM (8) Amlodipine Belson (4) Felodipine Belson (4)

Cohort

Preparation

Dose

Descriptor

103 children 0–6 years 2 children 0–6 yearsⴱ

Reg and SR Regular

0–20 mg/kg 2.8 mg/kg

4 children 0–6 yearsⴱ Subset of 51 children 0–12 years who ingested any CCB

SR Reg and SR

2.7–40 mg/kg 2.0 mg/kg

Range of non-toxic ingestions Single documented dose in toxic ingestionⴱ Range of toxic ingestionsⴱ Mean non-toxic dose

Subset of 42 children 0–12 years who ingested any CCB

Reg and SR

8.0 mg/kg 0.9 mg in 18-month-old

Mean toxic dose Largest non-toxic dose

200 mg in 18-month-old

Smallest toxic dose*

8 children Subset of 51 children 0–12 years who ingested any CCB

Reg and SR Reg and SR

1.4–7.5 mg/kg 4.5 mg/kg

Range of non-toxic ingestions Mean non-toxic dose

Subset of 42 children 0–12 years who ingested any CCB

Reg and SR

5.7 mg/kg 120 mg in 18-month-old

Mean toxic dose Largest non-toxic dose

Subset of 51 children 0–12 years who ingested any CCB

Reg and SR

13.5 mg/kg

Subset of 42 children 0–12 years who ingested any CCB

Reg and SR

16.1 mg/kg 25 mg/kg

Mean non-toxic dose—after elimination of outlier Mean toxic dose Largest non-toxic dose

36 children 0–6 years 3 children 0–6 years

1.3 mg/kg 0.4 mg/kg

Highest non-toxic dose Only recorded toxic doseⴱ

11 children 0–6 years

0.1–2.0 mg/kg

Non-toxic ingestions

SR ⫽ sustained release.

children varies widely in these studies; some patients receive gastrointestinal decontamination whereas others are evaluated solely via telephone call to the local poison control center. Belson et al. provide the only large case series of pediatric CCB ingestions (4). Data from a single regional poison control center reveal 16 cases of toxicity in 283 pediatric ingestions over a 6-year period. Recorded toxic sequelae include cardiovascular, central nervous system, and gastrointestinal effects, and cases are categorized as mild, moderate, and severe according to the AAPCC TESS definitions. The authors categorize 11 (4%) cases as mild and 5 (2%) as moderate toxicity. Only 5 of the 16 patients ingested 1 or 2 pills, whereas 6 ingested an unknown quantity. Unfortunately, differentiation of mild vs. moderate toxicity based on number of pills ingested cannot be determined from the available data. Toxicity was noted only in nifedipine, amlodipine, and verapamil overdoses. More specific data regarding individual CCB overdose cases are presented below.

Dihydropyridines Nifedipine. Review of the literature reveals 18 case reports of toxic or fatal nifedipine ingestions in tod-

dlers. Pertinent features of these cases are identified in Table 4. Fatalities occurred after 6 regular- and 3 sustained-release nifedipine ingestions. Of these 9 deaths, 3 toddlers ingested 1 or 2 pills, 4 an unknown number, and 2 ingested 10 or more pills. Time to onset of symptoms parallels expected absorption; regular formulation medication caused toxicity within 1–2 h, and all but two fatalities occurred within 4 h of ingestion. Sustained-release formulations had a more variable onset of effects. The most common adverse effect noted after both regular- and sustained-release preparations was hypotension. No prodromal symptoms predicted which patients were more likely to sustain adverse outcomes. In cases where patient weight was available, dose in mg/kg was calculated. No uniformly fatal dose can be identified. Of note, in three case fatalities where blood levels of CCB were measured, all had levels ⬎ 500 ␮g/mL. Review of case series reveals a similar variation in toxic and nontoxic dose ranges. These case studies are tabulated in Table 3, and results are variably described by individual authors as mean, minimum, or range of toxic dosages. Significant overlap between toxic and nontoxic ranges occurs. Other Dihydropyridines. Few data are available regarding pediatric overdoses of other dihydropyridines. Only

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Table 4. Toxic Dihydropyridine Ingestions

Age Nifedipine regular release formulation 5 months (69) 14 months (52,54,55) 16 months (57) 18 months (4) 11 months (56) 2 years (52,58) 1 year (8) 14 months (41) 14 months (59) 3 years (4) 1 year (60) Nifedipine sustained release formulation 16 months (4) 20 months (4) 2 years (4) 2 years (4) 2 years (61) 19 months (63) 3 years (62) Amlodipine 2 years (4) 2 years (4) 3 years (4) Other dihydropyridines 2 years (64) 2 years (4)

Dose

20 mg 10 mg Unknown 30 mg 40 mg 200 mg (20 tab) 200 mg 800 mg (20 tab) 20 tabs Unknown Unknown

Adjusted dose (mg/kg)

Serum level (␮g/L)

3.6 0.8

590

HT

BC

TC

D

V

X X X

X X

X

X X

X X

X X

X X

X X X

X X

X X

X X

2.8

X 540

70

X

30 mg 60 mg 120 mg 480 mg 1200 mg Unknown Unknown

2.7 5.7 10 40

5 mg Unknown Unknown

0.4

2.5 mg isradipine 15 mg nicardipine

MS

X X X

X X

X X X X 560

X X X

X X

X X X

20 min Expired 3 h Expired 17 h 1h 1h Expired 5 h 0.5 h Expired 12 h 1h Expired in ED 2h 4h 10 h 14 h 3h Expired in ED

X

3h 1h 1.5 h

X

30 min 1h

X X 1.25

X X

Time to onset of symptoms

X

MS ⫽ change in mental status, seizure or CVA; V ⫽ vomiting; HT ⫽ hypotension; BC ⫽ bradycardia; TC ⫽ tachycardia; D ⫽ death.

one case of nicardipine ingestion with toxic sequelae has been documented (4). In this case, an ingested dose of 1.25 mg/kg caused vomiting in a 2-year-old child. Belsen et al. report 39 ingestions of amlodipine; of these, three resulted in toxicity (4). The most common reported effects are lethargy and hypotension. The only recorded toxic dose of amlodipine was 0.4 mg/kg; however, 26 asymptomatic patients ingested doses ranging from 0.4 to 1.3 mg/kg. Eleven patients ingesting 0.1–2.0 mg/kg of felodipine experienced no symptoms (4).

Phenylalkylamines (Verapamil) Twelve cases of verapamil intoxication, with 5 case fatalities, were identified in the pediatric population (4,17,39,42,43,65,67,68) (Table 5). The most common clinical effect is altered mental status. At least one child ingesting only 1 tablet experienced mild clinical toxicity, primarily lethargy. Of the four fatalities, two ingested an unknown amount of the regular release formulation, whereas the other two patients ingested at least six sustained-release tablets each. Two of the four fatalities exhibited bradycardia at some time during their clinical

evaluation; otherwise, no prodromal events can be identified as indicators of severe intoxication. Onset of effects is poorly documented for immediate release formulations, due in part to delayed recognition of symptomatology in at least one patient. As with nifedipine, time to symptom onset varies widely for the sustained-release (SR) preparations. Toxic doses for the SR preparation ranged from 12–120 mg/kg; interestingly, the maximum recorded dose was not fatal. As shown in Table 3, at least one case series reports a mean toxic dose of 16 mg/kg and a mean non-toxic dose at 13 mg/kg. Unfortunately, no range or standard deviations are noted, and overlap between toxic and nontoxic doses cannot be excluded.

Benzothiazepines (Diltiazem) One fatal case of diltiazem toxicity was identified in a 10-month-old child who ingested an unknown quantity of extended release diltiazem (66) (Table 5). The patient presented with altered mental status and bradycardia, and expired 7 h after presentation. In a study of 34 combined adult and pediatric ingestions, the mean pediatric toxic

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Table 5. Toxic Verapamil and Benzothiazepine Ingestions

Age

Dose (ng)

Verapamil regular release formulation 7 days (43) 11 months (42) 1 year (67) 4 years (65,68) Verapamil sustained release formulation 4 years (4) 4 years (4) 25 months (17,39) 3 years (4) 4 years (68) 3 years (4) 4 years (4) 5 years (4) Diltiazem sustained release formulation 10 months (66)

Adjusted dose (mg/kg)

25 (medical error) 400 (5 tablets) Unknown Unknown 180 240 1440 (6 tablets) 2160 1440–2400 Unknown Unknown Unknown

Serum level (mg/L)

MS

V

HT

BC

X

X

TC

D

X X 2.02 12 15 106 120

Unknown

2–4 0.07

X X X X X X X

X

X X

X X X

X

X

X X

X

X

X

X X

X X

X

X

Time to onset of symptoms

Death in 20 h 30–45 min Overnight 2h 1h 3h 5.5 h 4–5 h 4h 3h 1h Expired 7 h

MS ⫽ change in mental status, seizure or cerebrovascular accident; V ⫽ vomiting; HT ⫽ hypotension; BC ⫽ bradycardia; TC ⫽ tachycardia; D ⫽ death.

dose is identified as 5.7 mg/kg, and the mean pediatric nontoxic dose is 4.5 mg/kg (40). In comparison, Belson et al. identify eight ingestions ranging from 1.4 –7.5 mg/kg, with no child exhibiting symptoms (4). DISCUSSION Are calcium channel blockers toxic to toddlers when only 1–2 tablets are ingested? The answer is yes in some children, although it is unclear who is at risk. Based on the available data, most ingestions of small numbers of tablets pose little or no risk to the toddler. However, in those cases where effects are noted, rapid fatality may ensue. Dihydropyridines, particularly nifedipine, and the phenylalkylamine verapamil are most closely associated with severe toxicity. Both fatalities and cardiovascular instability have been documented with ingestion of only 1 pill of nifedepine. Cardiovascular instability has also been noted with other dihydropyridine ingestions. Verapamil-related fatalities typically occur with higher dosage ingestions; in the cases presented here, there are frequently no prodromal events to suggest severe toxicity. The relative difference in toxicity of the various calcium channel blockers may be related to the toxic threshold. The LD50 of diltiazem in animals is 10 –100 times the therapeutic dose; thus, the potential for toxic sequelae after ingestion of only 1–2 pills may be much lower than for a medication with a smaller toxic-to-therapeutic ratio. This is corroborated by the finding that in adults, mor-

tality has been associated with blood concentrations in excess of 1500 ␮g/mL, many times the therapeutic blood concentrations of 100 –200 ␮g/mL (71). However, LD50 varies significantly between species (Table 2) and extrapolation of animal data to humans is difficult. Differences in drug efficacy and metabolism may also contribute to variations in CCB toxicity. Interestingly, hypertensive children ⬍ 6 years of age require higher amlodipine doses and more frequent dosing intervals than their older counterparts to control blood pressure; their higher tolerance may explain the low incidence of toxic sequelae after unintentional amlodipine ingestion in this young age group (21,28,34). It is difficult to draw conclusions regarding the toxic dose of these medications, in part because the nature of the exposure is so difficult to determine. Multiple medication and host variables can affect the toxicity of an ingestion. The amount of drug ingested, time interval to discovery, the rate of absorption and fed state of the child, presence of co-ingestants, patient comorbidities, and rapidity of gut decontamination all contribute to exposure severity. As is evidenced by the isolated fatality from extended-release diltiazem, sustained-release formulations may pose an increased risk for children because the potential dose from a single pill is much higher, and may be released immediately if the child sucks or bites the pill. Finally, the ranges of toxic and nontoxic doses often overlap, making identification of clear toxic cutoffs difficult. Based on a case series of 18 patients with accidental CCB ingestion of only 1 pill in which no significant

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adverse effects were noted, Riggs suggests that single pill ingestions may be observed at home (9). In contrast, Belson et al., in their retrospective study of 283 accidental ingestions, suggest that the lowest known toxic dose can be used as a threshold for patient observation and treatment (4). However, data from that study indicate that the lowest toxic dose of sustained-release nifedipine and verapamil, causing mild–moderate toxicity, corresponds to a single pill. Similarly, one death can be attributed to a single pill of regular nifedipine (52). Although the data presented here support Belson et al.’s conclusion regarding lowest toxic dose, it suggests that even one pill, particularly of nifedipine and verapamil, can cause clinically significant symptoms and death. A consensus article delineating guidelines for Poison Control Center referrals recommends that ingestions greater than either the maximum single therapeutic dose or the lowest reported toxic dose should be referred to a healthcare facility (72). The difficulty in identifying toxic doses is similar to results found previously in adults (13,73,74). Hofer et al. reviewed 30 cases of adult verapamil ingestions, and found widely varying toxic doses and blood levels (75). Mean blood concentration in non-fatal ingestions is 1.6 ␮g/mL, with maximum survived blood concentration of 4.0 ␮g/mL. In the 16 fatal adult ingestions reported, mean blood concentration was 4.9 ␮g/mL, with minimum blood concentration in a fatality at 0.7 ␮g/mL. Unfortunately, no differentiation between regular- and sustained-release preparations was made. Furthermore, no information regarding when blood concentrations were obtained is available. Nevertheless, it is clear that the fatal dose varies widely, and no fixed toxic cutoff will be appropriate for the general population. It should be noted that categorization of toxicity is somewhat nebulous despite authors’ adherence to AAPCC TESS guidelines. These guidelines provide only general guidance regarding toxicity and it is left to the authors’ discretion to categorize cases appropriately. This can lead to wide variations in symptom severity within a category. For instance, one study categorizes a 3-year-old patient with a heart rate of 30 beats/min, blood pressure of 54/30 mm Hg, and lethargy who received intravenous calcium, atropine, dopamine, fluids, charcoal, and whole bowel irrigation as a case of “moderate” toxicity, in the same category as a patient with low blood pressure requiring only intravenous fluids (4). A more rigorous definition of each category, including objective findings such as duration of symptoms, number of organ systems involved, and treatment modalities may improve stratification. Authorities’ opinions regarding minimum safe observation time after pediatric CCB ingestion vary. Consensus guidelines for hospital referrals of potentially toxic

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CCB ingestions recommend post-ingestion observation times of 6 h for regular release and 18 –24 h for sustained release products (72). Brayer and Wax (53) investigated poison control center (PCC) recommendations by presenting a standardized pediatric case, in which an asymptomatic 2-year-old ingested a single 30-mg sustainedrelease nifedipine tablet, to poison specialists at 33 PCCs throughout the United States (53). Median suggested observation time was 14.5 h with a range of 2–24 h. The authors further evaluated data collected from one PCC over a 4-year period and found that of 29 children ⬍ 4 years old with CCB ingestion, only 26 were observed in a health care facility for periods of time ranging from 1–24 h. Patients with sustained-release preparations were observed for longer than those ingesting regular-release preparations. All patients had good outcomes. Based on these data, the authors recommend very limited observation time for these patients. However, the authors provide little information regarding the likelihood of true CCB ingestion or ingested dose in these patients, and the sample size is small. Time to presentation and observation times in a health care facility varied widely among pediatric patients. Data regarding time are difficult to tabulate in these cases; error resulting from delay in discovery at the incident scene may affect the time from ingestion to symptom onset or presentation to the Emergency Department. Furthermore, variations in ingestion and absorption may also contribute to variability of symptom onset. Nevertheless, some correlation with medication onset and half-life can be made. Overwhelmingly, toxic ingestions of regularrelease formulations of calcium channel blockers presented within 6 h, and death occurred within 12 h of ingestion. This correlates well with the known therapeutic onset and half-life of regular-release calcium channel blockers, and is similar to the recommendations of Belson et al. in their retrospective 283-patient series (4). Of notable exception is amlodipine, which has a half-life of over 24 h. However, in the cases presented herein, pediatric patients who became symptomatic after amlodipine ingestion did so within 3 h. Ingestion of sustainedrelease preparations had a more variable time to presentation and symptomatology, ranging from 2–14 h. This likely reflects variation in absorption of swallowed or chewed pills, as chewing the pills enables immediate availability of the total dose of medication for absorption. The true number of accidental pediatric ingestions of CCBs remains uncertain. Reporting bias may significantly alter the number of documented pediatric medication ingestions (5,70). In particular, ingestions may be falsely inflated by worried parents who cannot conclusively rule out potential ingestion although the likelihood of actual ingestion is quite low—“I put my pill on the

Calcium Channel Blocker Exposure in Toddlers

table and can’t remember whether I took it”—and falsely decreased by the underreporting of asymptomatic patients to Poison Control Centers by Emergency Departments. Thus, it is difficult to assess the true prevalence of accidental CCB ingestion in the pediatric population, and therefore calculation of morbidity and mortality percentages is meaningless. Thus, we recommend emergent evaluation for all suspected CCB overdoses, including a careful history to assess likelihood of ingestion, time since ingestion, and specific identification and dosage of the ingested medication. In cases where there is a reasonable suspicion of a toxic CCB ingestion, supportive care and observation are appropriate. Charcoal gastrointestinal decontamination within 2 h of ingestion should be considered, and patients should be observed for at least 6 h for regular release medications, and 12–24 h for sustained release medication.

CONCLUSION Calcium channel blocking medications are readily available, and unintentional pediatric ingestions are becoming more frequent. Data regarding the toxicity of these medications are incomplete, but pediatric morbidity and mortality have been reported, even after ingestion of only one or two pills. Toxic and nontoxic ranges overlap, and individual patient variables likely contribute significantly to the presence or absence of toxic effects. Prevalence of toxic sequelae cannot be well defined. Nifedipine and verapamil are most commonly implicated in morbidity and mortality. Symptoms appear rapidly with regularrelease medications, yet onset of symptoms in sustainedrelease ingestions is more variable. No definitive therapy or antidote for an overdose is available. Based on these data, emergency evaluation is mandated, charcoal gastrointestinal decontamination within 2 h should be considered, and observation of at-risk toddlers for 6 h (regular-release formulation) and 12–24 h (sustainedrelease formulation) after ingestion is recommended. Any signs of cardiovascular or central nervous system instability during this observation period warrant rapid and aggressive therapy.

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