1
Toddler ToxicologyDrugs That Can Kill a Child
with One Pill or Swallow

• Joe Lex, MD, FAAEM
• Temple University School of Medicine
• Philadelphia, PA
• Joseph.Lex_at_TUHS.Temple.edu

2
Disclosure
Nothing to declare
3

Cape Cod June 28th July 1st, 2007
Giant Steps in Emergency Medicine The Sun, The
Seaand CME! Visit our website for
details www.GiantSteps-EM.com
Mattu
Lex
Sharieff
DeBlieux
4
How Far Weve Come

• 1950 gt400 pediatric overdose deaths
• 2003 34 fatalities from overdose in children lt6
  years
• Can we be smug??

Intro
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Intro
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Intro
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Intro
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Peak Incidence 1 to 3

• Attracted to toxic substances based on color or
  appearance of agent or container
• More willing to taste dangerous substances
• Hand-mouth behavior nearly 10 times / hour

Intro
10
Peak Incidence 1 to 3

• Physical environment change plays significant
  role
• Half of accidental poisonings due to product in
  use at time of ingestion or recently moved from
  usual storage site
• Top category cosmetics and personal care products

Intro
11
Peak Incidence 1 to 3

• Plants also popular
• Amounts ingested by toddlers small
• Ingestion of toxic substance usually results in
  nontoxic or minimally toxic outcomes

Intro
12
Poison Hunting on eBay

• 10 month hunt on eBay
• 121 products identified
• 24 supertoxic strychnine, arsenic trioxide,
  cyanide, etc.
• 63 extremely toxic
• 21 very toxic
• 13 moderately-slightly toxic

Intro
Cantrell FL. Clin Toxicol. 200543(5)375-9.
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Gideon Korens Article

• Koren G. Medications which can kill a toddler
  with one tablet or spoonful. Clin Toxicol
  19933140713
• Identified medicines lethal to 10-kg child in
  single pill or swallow

Koren
15
Interest Builds

• Liebelt EL,et al. Small doses, big problems a
  selected review of highly toxic common
  medications. Pediatr Emerg Care 199392927.

Koren
16
Interest Builds

• Michael JB, Sztajnkrycer MD. Deadly pediatric
  poisons nine common agents that kill at low
  doses. Emerg Med Clin North Am. 2004
  Nov22(4)1019-50.

Koren
17
Interest Builds

• Matteucci MJ. One pill can kill assessing the
  potential for fatal poisonings in children.
  Pediatr Ann. 2005 Dec 34(12)964-8.

Koren
18
Gideon Korens Return

• Bar-Oz B, Levichek Z, Koren G. Medications that
  can be fatal for a toddler with one tablet or
  teaspoonful a 2004 update. Paediatr Drugs.
  2004 6(2)123-6.

Koren
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Some Assumptions

• Assume healthy toddler with bodyweight 10 kg and
  normal drug metabolism
• Use lowest described fatal dose from literature
• Use maximal dose unit available

Assume
20
Major Miscreants

• TCAs
• Antimalarials
• Antipsychotics
• Anti-arrhythmics
• Methyl salicylate
• Oral hypoglycemics
• Calcium channel blockers

• Theophylline
• Narcotics
• Camphor

Villains
21
Liquids
22
Camphor
23
Camphor A Case Study

• Multiple pediatric deaths
• AAP editorial in 1978 Camphor Who Needs It?
• 20 camphorated oil removed from US pharmacies
• OTC camphor concentration limited to 11 in OTCs

Camphor
Camphor Who needs it? Pediatrics. 1978
Sep62(3)404-6.
24
Camphor

• Topical rubefacient induces local hyperemia,
  warmth
• Analgesic, antipruritic, and antitussive agent
• Variety of OTC liniments Vicks VapoRub,
  Ben-Gay, Absorbine, Tiger Balm

Camphor
25
Camphor

• Aromatic terpene ketone derived from plants
• Distinct odor, pungent taste
• Some cultures use in cooking
• As little as 700 to 1000 mg fatal

Camphor
AAP Policy Statement. Pediatrics 199494127.
26
Camphor

• 7805 cases of topical camphor ingestion in
  children younger than age 6 reported to poison
  control centers in US in 2001
• Deaths rare since loss of 20 oil

Camphor
27
Camphor

• Cause of death respiratory depression, status
  epilepticus
• 3-year-old ingested 15mL Vicks VapoRub ?
  seizures, coma, respiratory depression
• 700 mg of camphor

Camphor
Ruha AM, et al. Acad Emerg Med 200310691.
28
Camphor

• 2-year-old ingested 10mL Campho-Phenique
• Seizures in 10 minutes, then coma, respiratory
  depression lasting 24 hours

Camphor
Gibson DE, et al. Am J Emerg Med 19897413.
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Vicks VapoRub Cream
Camphor
31
Campho-Phenique Gel
Camphor
32
Campho-Phenique (10.8)
Camphor
33
Today

• 1996 9,387 camphor exposures reported to AAPCC
• 7404 in children under 6 years
• NO deaths reported
• Virtually eliminated as a source of lethality in
  this country

Camphor
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SUCCESS!!
Camphor
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Methyl Salicylate
36
Salicylates

• Present in numerous over-the-counter products
• Aspirin (acetylsalicylic acid)
• Oil of wintergreen (methyl salicylate)
• Pepto-Bismol (bismuth subsalicylate)

Salicylate
37
Methyl Salicylate

• Methyl ester of salicylic acid
• Oil of wintergreen
• Deceptively toxic
• Minimal toxic ingested dose in children 150 mg/kg

Salicylate
38
Methyl Salicylate

• Betula oil
• Panalgesic
• o-hydroxybenzoic acid methyl ester
• Gaultheria oil
• Methyl o-hydroxy -benzoate
• Sweet birch oil
• Teaberry oil
• Analgit

• Exagien
• Flucarmit
• 2-(methoxy carbonyl)-phenol
• Anthrapole ND
• 2-carbo-methoxyphenol
• Methyl hydroxybenzoate
• Linsal
• Metsal Liniment

Salicylate
39
Methyl Salicylate

• One teaspoon of 98 methyl salicylate contains
  7000 mg of salicylate
• Equivalent to 90 baby aspirin
• gt 4 times potentially toxic dose for 10-kg child

Salicylate
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Methyl Salicylate

• Therapeutic serum ASA for analgesia 15 to 30
  mg/dL
• Signs and symptoms of toxicity gt30 mg/dL
• Life-threatening levels gt100 mg/dL

Salicylate
41
Methyl Salicylate

• Vd doubles or triples in toxic states
• Therapeutic half-life 1 to 2 hours
• Toxic levels with acid urine half-life up to 30
  hours

Salicylate
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Methyl Salicylate

• Children with rheumatoid disease at steady state
  toxic through minor dietary changes
• Infants may show just dehydration, rapid
  breathing
• Older kids GI symptoms, CNS depression

Salicylate
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Methyl Salicylate

• Non-aspirin salicylates can be converted to
  aspirin equivalent doses with the help of
  tables found in any standard toxicology book

Salicylate
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Methyl Salicylate 15
Salicylate
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Methyl Salicylate 18.3
Salicylate
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Methyl Salicylate 30
Salicylate
47
Methyl Salicylate 30
Salicylate
48
Methyl Salicylate 40
Salicylate
49
Methyl Salicylate ??
50
Methyl Salicylate ??
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Methyl Salicylate 0.06
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Methyl Salicylate

• 21-month-old significant poisoning, peak serum
  concentration of 81 mg/dL, after ingesting 4 mL

Salicylate
Howrie DL, et al. Pediatrics 19857586971.

• Fatality with ingestion lt1 tsp

Stevenson CS. Am J Med Sci 193719377288.
53
Methyl Salicylate

• 1996 report to AAPCC
• 10,733 toxic exposures to methyl salicylate
• 7,712 were children
• Two deaths reported, both in adults

Salicylate
54
Podophyllin 25
55
Podophyllin 25

• Resinous powder from rhizome of American Mayapple
  
• Used to treat genital warts
• Occasional adulterant in herbal medicines
• 1989 Hong Kong outbreak

Podophyllin
Ng THK, et al. J Neurol Sci 1991101107-13.
56
Podophyllin 25

• Transient toxicity hallucinatory psychosis, bone
  marrow depression, hepatic dysfunction
• Persistent severe peripheral neuropathy

Podophyllin
Filley CM, et al. Neurology. 1982 Mar
32(3)308-11.
57
Podophyllin 25

• Minimal potential fatal dose 15 20 mg/kg
• Maximal dose unit available 1.25 g/5mL
• Volume for potential lethality 1mL

Podophyllin
Filley CM, et al. Neurology. 1982 Mar
32(3)308-11.
58
Pastes, Ointments, Liniments
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Dibucaine
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Dibucaine

• Potent amide anesthetic
• Topical uses hemorrhoids, sunburn, episiotomy
  pain
• 10x as toxic as lidocaine
• 20x as toxic as procaine

Dibucaine
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Dibucaine

• CNS toxicity
• Seizure
• Coma

BAD STUFF
Dibucaine
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Dibucaine

• Cardiotoxicity
• Increased PR
• Widened QT
• Slowed conduction
• Slowed repolarization
• Reentrant dysrhythmias
• SVT
• PVC

Dibucaine
63
Dibucaine

• 1 of topical anesthetics sold in US
• lt5 nonfatal exposures to topical anesthetics
• Caused 3 of 4 deaths due to topical anesthetics
  over last 20 years

Dibucaine
Dayan PS, et al. Ann Emerg Med. 1996 Oct
28(4)442-5.
64
Dibucaine

• In 1995, US Consumer Product Safety Commission
  issued rule requiring childproof packing for
  containers with gt0.5 mg dibucaine or gt5 mg
  lidocaine
• Corticaine Dibucort
• Dibusone Nupercainal

Dibucaine
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Pills, Tablets Capsules
67
Anti-Arrhythmics
68
Quinidine

• D-isomer of quinine
• Derived from cinchona bark
• Side effects and toxicity similar to quinine
• Main concerns dysrhythmias, cardiogenic shock,
  coma, seizures, retinal damage

Quinidine
Dellocchio T, et al. Pediatrics. 1976 Aug
58(2)288-90
69
Interesting History

• Founder of homoeopathy, Dr. Samuel Hahnemann,
  took large daily dose of quinine bark
• After 2 weeks, he felt malaria-like symptoms
• Like cures like philosophy was start of
  homoeopathy

Quinidine
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Disopyramide

• Another Class 1A
• Falling out of favor
• More anticholinergic than others in class
• 1 pill potentially lethal

Disopyramide
Singer P, et al. J Anal Toxicol. 1995 Oct
19(6)529-30.
71
Encainide

• Encainide (Enkaid) removed from American market
  voluntarily, still available on compassionate
  basis
• Case report infant swallowed 1 tablet (25 mg)
  with rapid onset V-tach, but survival

Encainide
Mortensen ME, et al. Ann Emerg Med. 1992 Aug
21(8)998-1001.
72
Propafenone

• Propafenone (Rhythmol)
• 2 year-old ingested less than one tablet ? rapid
  cardiovascular collapse
• Eventual recovery

Propafenone
McHugh TP, et al. Ann Emerg Med. 1987 Apr
16(4)437-40.
73
Antiarrhythmics
74
Antimalarials
75
Quinine

• See quinidine

76
Chloroquine

• Primary treatment for malaria
• Anti-inflammatory
• Antihistamine
• Anti-prostaglandin
• Hydroxychloroquine chemically similar

Chloroquine
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Chloroquine

• Quinolone family
• Now used to treat rheumatoid arthritis, systemic
  / discoid lupus erythematosus, other connective
  tissue disorders

Chloroquine
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Chloroquine

• Initial symptom may be cardiac arrest
• Pediatric overdoses neuro symptoms in 30 min to
  1 hour
• Death seems related to cardiac conduction system
  depression and myocardium

Chloroquine
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Chloroquine

• Severity of hypokalemia closely correlates with
  level of chloroquine toxicity
• Potassium concentrations less than 1.9 mEq/L
  correlated with severe, life-threatening ingestion

Chloroquine
Angel G, et al. Lancet. 1995 Dec 16
346(8990)1625.
80
Chloroquine

• GI absorption rapid, almost complete
• Peak plasma concentration 1.5 to 3 hours
• Elimination half-life in children 75 to 136 hours

Chloroquine
Cann HM, et al. Pediatrics 19612795102.
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Chloroquine

• Therapeutic dose 10 mg/kg
• Toxic effects 20 mg/kg
• Lethal dose 30 mg/kg
• Confirmed toddler death at 27 mg/kg
• Equivalent to 300mg tablet in 8 kg 12-month-old

Chloroquine
Cann HM, et al. Pediatrics 19612795102.
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Chloroquine
Chloroquine
83
Antimalarials
84
Clonidine
85
Clonidine

• Initially nasal decongestants
• Later marketed as central acting antihypertensive
• Alpha2-adrenergic agonist
• ? central adrenergic tone
• Also bind to imidazoline receptors in medulla

Clonidine
86
Imidazolines

• Decongestant imidazolines naphazoline,
  oxymetazoline, tetrahydrozoline, xylometazoline
• Ophthalmologic brimonidine and apraclonidine used
  to treat glaucoma

Clonidine
87
Imidazolines

• 2001 1438 clonidine exposures in children
  younger than 6 years old
• 922 tetrahydrozoline exposures in preschool
  children

Clonidine
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Toxicity

• Oral, transdermal delivery
• Patches contain 2.5 mg, 5 mg, and 7.5 mg of
  clonidine,
• OD resembles opioid ?LOC, bradycardia,
  hypotension, respiratory depression, miosis,
  hypotonia

Clonidine
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Toxicity

• Toxicity in 30 to 90 minutes
• May persist for 1 to 3 days
• Children most at risk for bradycardia,
  respiratory depression, intermittent apnea

Clonidine
90
Cases

• Case series 80 children admit for clonidine
  ingestion
• Average time to onset of symptoms 35 minutes
• Most common presenting sign or symptom reduced
  level of consciousness (96)

Clonidine
Nichols MH, et al. Ann Emerg Med 199729511
91
Cases

• Six required intubation
• No deaths reported
• 54 of the clonidine belonged to patients
  grandmothers

Clonidine
Nichols MH, et al. Ann Emerg Med 199729511
92
Cases

• 21-month-old girl coma, bradycardia, hypotension
  after ingesting 0.3-mg tablet

Neuvonen PJ, et al. Clin Toxicol 19791436974.
Clonidine

• 6-year-old girl obtundation, bradycardia after
  applying patch she mistook for bandage

Killian CA, et al. Pediatr Emerg Care 1997
133401.
93
Cases

• 9-month-old boy lethargic 90 minutes after
  sucking on a discarded clonidine patch

Caravati EM, et al. Ann Emerg Med 198817175
Clonidine

• 2-year-old child bradycardic, recurrent apnea
  after ingesting 5 mL apraclonidine

Everson G, et al. J Toxicol Clin Toxicol 1999
37629.
94
Management

• Imidazoline supportive
• Symptomatic patients respond variably to naloxone
  up to a total of 10 mg
• Retrospective review 39 / 80 patients (49) got
  naloxone
• Positive response in 4 patients

Clonidine
Nichols MH, et al. Ann Emerg Med 199729511
95
Management

• Symptomatic bradycardia start with atropine
• Hypotension unresponsive to fluid resuscitation
  or complicated by persistent bradycardia dopamine

Clonidine
Maggi JC, et al. Clin Paediatr 1986254535.
96
Tricyclic Anti-depressants
97
Cyclic Antidepressants

• Leading cause of poisoning fatality in the United
  States until 1993
• Presently 2nd most common class of agents
  ingested in fatalities reported to AAPCC

T C A
Litovitz TL, et al. Am J Emerg Med 2002
20391452.
98
Cyclic Antidepressants

• All TCAs dangerous in excess
• Desipramine seems especially dangerous in
  children
• Anticholinergic toxidrome (remember
  the mnemonic??)

T C A
99
Toxidrome Mnemonic

• blind as a bat dilated pupils
• dry as a bone dehydrated
• mad as a hen hallucinations
• red as a beet skin flushing
• urinary retention
• tachycardia

T C A
100
Pathophysiology

• Mortality 2o to cardiotoxicity, CNS toxicity
• ?BP may be 2o arrhythmia-induced cardiogenic
  shock, ?PVR 2o to alpha-adrenergic blockade,
  sympathomimetic amine depletion

T C A
101
Pathophysiology

• Seizures associated with cyclic antidepressant
  toxicity typically generalized tonic-clonic,
  self-limited
• Status epilepticus has been reported

T C A
Lipper B, et al. Am J Emerg Med 1994124517.
102
Pathophysiology

• Seizure activity greatest in antidepressants
  showing dopamine and norepinephrine reuptake
  inhibition bupropion, amoxapine, venlafaxine
• Significant toxicity presents within 6 hours of
  ingestion

T C A
Lipper B, et al. Am J Emerg Med 1994124517.
103
Morbidity / Mortality

• 10 to 20 mg/kg ingestion of most TCAs likely to
  result in significant CNS, CV symptoms
• 15 to 20 mg/kg ingestion believed to represent
  lethal exposure

T C A
Frommer DA, et al. JAMA 19872575216.
104
TCA Case Reports

• 3-year-old girl seizures, cardiac dysrhythmias
  after ingestion 100 mg desipramine

Jue SG. Drug Intell Clin Pharm 197610523.
T C A

• 250 mg imipramine, amoxapine have resulted in
  child fatality

Linakis JG. Clin Toxicol Rev 198810.
Manoguerra AS. Crit Care Q 19824351.
105
Management

• Lecture in itself
• Sodium bicarbonate remains mainstay of treatment
  to reverse cardiotoxic effects
• Beneficial with even normal arterial pH
• Optimal dosing strategy remains to be determined

T C A
106
Tricyclic Antidepressants
107
Calcium Channel Antagonists
108
Epidemiology

• 9264 CCA exposures in 2001
• 100 increase from 1990
• 2249 in children under 6 years
• 88 moderate to major outcomes
• No pediatric deaths reported
• 10 CCAs available in US

CCAs
109
Categories

• Phenylalkylamines verapamil
• Benzothiaprines diltiazem
• Act predominantly on cardiac tissue
• Dihydropyridines nifedipine
• Acts predominately on vascular smooth muscle

CCAs
110
Presentation

• Hallmark disturbance of cardiovascular system
• Classic manifestations hypotension, bradycardia,
  
• Reflex tachycardia can be seen with
  dihydropyridines

CCAs
111
Presentation

• Conduction 2nd and 3rd degree heart block
• Negative inotropy cardiogenic shock or cardiac
  arrest
• Can be delayed in sustained-release preparation
  ingestion

CCAs
112
Presentation

• Hypotension can last gt24 hours despite therapy,
• Hyperglycemia multifactorial
• Hyperglycemia in setting of bradycardia and
  hypotension suggests CCA ingestion

CCAs
113
Case 1

• 11-month-old girl developed seizures 45 minutes
  after ingesting 400 mg verapamil

Passal DB, Crespin FH. Pediatrics 1984735435.
CCAs
114
Case 2

• 14-month-old girl pale, hypotensive, tachycardic
  after ingesting single 10 mg nifedipine tablet
• Aggressive interventions
• Bradycardia ? pulseless
• Died 3 hours after presentation

CCAs
Lee DC, et al. J Emerg Med 20001935961.
115
Case Series

• Pediatric case series 16 symptomatic patients
  among 283 recorded exposures
• Five occurred after ingestion single tablet
• Maximal time to symptom onset from 3 to 14 hours

CCAs
Belson MG, et al. Am J Emerg Med 200018581.
116
Therapy

• Atropine 1st-line agent in bradycardia, only
  moderately successful
• Optimal pharmacotherapy poorly defined
• Calcium conflicting data
• Most beneficial in mild toxicity

CCAs
117
Therapy

• TOC refractory CCA toxicity high-dose
  glucose-insulin
• Insulin positive inotrope
• Case series 5 patients with refractory shock
  after CCA overdose improved after glucose-insulin
  infusions

CCAs
Yuan TH, et al. J Toxicol Clin Toxicol
19993746374.
118
Calcium Channel Blockers
119
Sulfonylureas
120
Sulfonylureas

• Children 12 years and under
• Hypoglycemia in 56/185 (30)
• 54/56 (96) developed hypoglycemia within 8 hours
  of ingestion
• Clinical observation with oral feeding alone
  appears safe

Sulfonylurea
Spiller HA, et al. J Pediatr. 1997 Jul131(1 Pt
1)141-6.
121
Sulfonylureas

• Clear symptoms hypoglycemia or glucose levels lt
  60 mg/dL admit for supplemental glucose (oral
  or IV), monitor
• Refractory to IV glucose octreotide, diazoxide
  may help

Sulfonylurea
Little GL, et al. J Emerg Med. 2005 Apr
28(3)305-10.
122
Sulfonylureas

• 2-year-old boy observed to ingest 5 mg glipizide
• Activated charcoal given within 35 minutes
• Hypoglycemia with serum glucose 49 mg/dL 11 hrs
  later

Sulfonylurea
Szlatenyi CS, et al. Ann Emerg Med. 1998 Jun
31(6)773-6.
123
Oral Hypoglycemics
124
Opioids Opiates
125
Epidemiology

• 5914 reported ingestions by children younger than
  6 years old in 2001
• Most common hydrocodone with acetaminophen
  (Vicodin)
• Time to peak toxicity 1 hour
• Most deaths 2o to respiratory depression, hypoxia

Opioids
126
Pathophysiology

• Infants and children more susceptible to toxic
  effects
• Half of children exposed to more than 1 mg/kg of
  codeine develop toxicity
• 2.5 mg of hydrocodone has been lethal in infant

Opioids
OMA Committee on Pharmacy. Codeine Ont Med Rev
1977444478.
127
Treatment

• Supportive
• Naloxone as needed
• Onset of action lt 2 minutes
• Duration of action 20 90 minutes
• Elimination half-life 60 90 minutes

Opioids
128
Opioids / Narcotics
129
Special Case Lomotil

• Antidiarrheal agent
• 2.5 mg opioid diphenoxylate
• 0.025 mg antimuscarinic atropine
• Both absorbed rapidly
• May be delayed in overdose

Lomotil
130
Special Case Lomotil

• Diphenoxylate metabolized to difenoxin, 5x more
  active than parent compound
• Elimination half-life 12 14 hours
• Little correlation between ingested dose and
  outcome

Lomotil
131
Special Case Lomotil

• Classically described as biphasic reaction
• Initial antimuscarinic symptoms in 2 3 hours
• Delayed opioid symptoms
• Recent studies show this occurs in only few cases

Lomotil
McCarron MG, et al. Pediatrics 199187694700.
132
Special Case Lomotil

• Case series
• 4/36 developed early anticholinergic symptoms
• 15/36 developed opioid toxicity only

Lomotil
McCarron MG, et al. Pediatrics 199187694700.
133
Special Case Lomotil

• Catastrophic outcomes reported after ingestion by
  children

Wasserman GS, et al. Am Fam Physician 1975
11937.
Lomotil

• Toxicity reported after ingestion of one-half
  tablet

Ginsberg CM, et al. Clin Toxicol 1969237782.
134
Management

• Similar to other opioids
• Initial symptoms, including coma, may be delayed
• Symptoms have recurred 24 hours after initial
  resolution
• Recommend admit, monitor for no less than 24
  hours

Lomotil
Manoguerra AS, et al. Poisindex, Vol. 117
9/2003.
135
Household Products

• Methanol in deicing solutions, windshield washer
  fluid, carburetor cleaners
• Concentration may be 95
• Ingestion of 4 mL by 10-kg toddler ? serum
  methanol concentration of 50 mg/dL

Methanol
136
Household Products

• Ethylene glycol in antifreeze, some fire
  extinguishers, inks, and adhesives
• Concentration may be 95
• Ingestion of 2.9 mL by 10-kg toddler ? serum
  ethylene glycol concentration of 50 mg/dL

Ethylene Glycol
137
and Dont Forget

• Theophylline still in use
• Extended release preparation available
• Minimal fatal dose 8.4 mg/kg
• Maximal available unit dose 500 mg
• One tablet can definitely kill

Theo
138
Primum non Nocere

• No literature suggests better outcomes with
  charcoal
• Deaths reported from activated charcoal
  aspiration
• Some in children when they consumed nontoxic
  products

A C
Menzies DG, et al. BMJ 1988297459460.
Harsch HH. N Engl J Med 1986314318.
Elliott CG, et al. Chest 198996672674.
139
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140
Summary

• Vast majority of toddler ingestions are benign
• Dozen or so medicines can kill 10-kg toddler with
  one pill or swallow
• Treatment usually supportive
• Activated charcoal can kill

141
Joseph.Lex_at_ TUHS.Temple.edu