Project: Ghana Emergency Medicine Collaborative
Document Title: Toddler Toxicology: Drugs That Can Kill a Child With One
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Toddler Toxicology:
Drugs That Can Kill a Child with
One Pill or Swallow
Joe Lex, MD, FAAEM
Temple University School of Me...
How Far We’ve Come
• 1950: >400 pediatric overdose
deaths
• 2003: 34 fatalities from
overdose in children <6 years
• Can w...
Peak Incidence: 1 to 3
• Attracted to toxic substances
based on color or appearance
of agent or container
• More willing t...
Peak Incidence: 1 to 3
• Physical environment change
plays significant role
• Half of accidental poisonings
due to product...
Peak Incidence: 1 to 3
• Plants also popular
• Amounts ingested by toddlers
small
• Ingestion of toxic substance
usually r...
Poison Hunting on eBay
10 month hunt on eBay
• 121 products identified
• 24 “supertoxic”: strychnine,
arsenic trioxide, cy...
Baby Proof Home
“I baby-proofed
my home, but the
kids still somehow
manage to get
inside.”
Gideon Koren’s Article
Koren G. Medications which can
kill a toddler with one tablet
or spoonful. Clin Toxicol
1993;31:407...
Interest Builds
Liebelt EL,et al. Small doses,
big problems: a selected
review of highly toxic common
medications. Pediatr...
Interest Builds
Michael JB, Sztajnkrycer MD.
Deadly pediatric poisons: nine
common agents that kill at low
doses. Emerg Me...
Interest Builds
Matteucci MJ. One pill can kill:
assessing the potential for
fatal poisonings in children.
Pediatr Ann. 20...
Gideon Koren’s Return
Bar-Oz B, Levichek Z, Koren G.
Medications that can be fatal
for a toddler with one tablet
or teaspo...
Some Assumptions
• Assume healthy toddler with
bodyweight 10 kg and normal
drug metabolism
• Use lowest described fatal
do...
Major Miscreants
• TCAs
• Antimalarials
• Antipsychotics
• Anti-arrhythmics
• Methyl salicylate
• Oral hypoglycemics
• Cal...
Liquids
Cydone, Wikimedia Commons
Camphor
Camphor – A Case Study
• Multiple pediatric deaths
• AAP editorial in 1978:
Camphor: Who Needs It?
• 20% camphorated oil r...
Camphor
• Topical rubefacient: induces
local hyperemia, warmth
• Analgesic, antipruritic, and
antitussive agent
• Variety ...
Camphor
• Aromatic terpene ketone
derived from plants
• Distinct odor, pungent taste
• Some cultures use in cooking
• As l...
Camphor
• 7805 cases of topical camphor
ingestion in children younger
than age 6 reported to poison
control centers in US ...
Camphor
• Cause of death: respiratory
depression, status epilepticus
• 3-year-old ingested 15mL
Vicks VapoRub®  seizures,...
Camphor
• 2-year-old ingested 10mL
Campho-Phenique
• Seizures in 10 minutes, then
coma, respiratory depression
lasting 24 ...
Vicks VapoRub® Cream
Tatsuo Yamashita, Flickr
Campho-Phenique® (10.8%)
• Pain relieving antiseptic liquid
• For insect bites, scrapes & minor burns
Today
• 1996: 9,387 camphor
exposures reported to AAPCC
• 7404 in children under 6 years
• NO deaths reported
• Virtually ...
Methyl
Salicylate
Salicylates
• Present in numerous over-the-
counter products
– Aspirin (acetylsalicylic acid)
– Oil of wintergreen (methyl...
Methyl Salicylate
• Methyl ester of salicylic acid
• Oil of wintergreen
• Deceptively toxic
• Minimal toxic ingested dose ...
Methyl Salicylate
• Betula oil
• Panalgesic
• o-hydroxybenzoic
acid methyl ester
• Gaultheria oil
• Methyl o-hydroxy -
ben...
Methyl Salicylate
• One teaspoon of 98% methyl
salicylate contains 7000 mg of
salicylate
• Equivalent to 90 baby aspirin
•...
Methyl Salicylate
• Therapeutic serum ASA for
analgesia: 15 to 30 mg/dL
• Signs and symptoms of
toxicity: >30 mg/dL
• Life...
Methyl Salicylate
• Vd doubles or triples in toxic
states
• Therapeutic half-life: 1 to 2
hours
• Toxic levels with acid u...
Methyl Salicylate
• Children with rheumatoid
disease at steady state: toxic
through minor dietary changes
• Infants: may s...
Methyl Salicylate
Non-aspirin salicylates can be
converted to “aspirin
equivalent doses” with the
help of tables found in ...
Methyl Salicylate 15%
Jeroen Elfferich, Flickr
Methyl Salicylate 29%
Eli Sagor, Flickr
Methyl Salicylate 40%
Steffen Buus Kristensen, Wikimedia Commons
Methyl Salicylate 0.06%
Jagwire, Wikimedia Commons
Methyl Salicylate
• 21-month-old: significant
poisoning, peak serum
concentration of 81 mg/dL,
after ingesting 4 mL
Howrie...
Methyl Salicylate
• 1996 report to AAPCC
• 10,733 toxic exposures to
methyl salicylate
• 7,712 were children
• Two deaths ...
Podophyllin
25%
Podophyllin 25%
• Resinous powder from rhizome
of American Mayapple
• Used to treat genital warts
• Occasional adulterant ...
Podophyllin 25%
• Transient toxicity:
hallucinatory psychosis, bone
marrow depression, hepatic
dysfunction
• Persistent: s...
Podophyllin 25%
• Minimal potential fatal dose:
15 – 20 mg/kg
• Maximal dose unit available:
1.25 g/5mL
• Volume for poten...
Pastes, Ointments, Liniments
Scott Ehardt, Wikimedia Commons
Dibucaine
Dibucaine
• Potent amide anesthetic
• Topical uses: hemorrhoids,
sunburn, episiotomy pain
• 10x as toxic as lidocaine
• 20...
Dibucaine
CNS toxicity
• Seizure
• Coma
Dibucaine
Cardiotoxicity
• Increased PR
• Widened QT
• Slowed conduction
• Slowed repolarization
• Reentrant dysrhythmias
...
Dibucaine
• ~1% of topical anesthetics
sold in US
• <5% nonfatal exposures to
topical anesthetics
• Caused 3 of 4 deaths d...
Dibucaine
• In 1995, US Consumer Product
Safety Commission issued rule
requiring childproof packing
for containers with >0...
Dibucaine
• Ointment USP, 1%
• Topical Anesthetic
• For External Use Only; Do not use in the eyes
Pills, Tablets & Capsules
Chaos, Wikimedia Commons
Anti-
Arrhythmics
Quinidine
• D-isomer of quinine
• Derived from cinchona bark
• Side effects and toxicity
similar to quinine
• Main concern...
Interesting History
• Founder of homoeopathy, Dr.
Samuel Hahnemann, took large
daily dose of quinine bark
• After 2 weeks,...
Disopyramide
• Another Class 1A
• Falling out of favor
• More anticholinergic than
others in class
• 1 pill potentially le...
Encainide
Encainide (Enkaid®) removed
from American market
voluntarily, still available on
“compassionate” basis
• Case re...
Propafenone
Propafenone (Rhythmol®)
• 2 year-old ingested less than
one tablet  rapid
cardiovascular collapse
• Eventual ...
Antiarrhythmics
Drug
Minimal
potential
fatal dose
Maximal
dose
available
No. of
tabs that
can cause
fatality
Quinidine 15 ...
Antimalarials
Quinine
• See quinidine
CYL, Wikimedia Commons
Chloroquine
• Primary treatment for malaria
– Anti-inflammatory
– Antihistamine
– Anti-prostaglandin
• Hydroxychloroquine:...
Chloroquine
• Quinolone family
• Now used to treat rheumatoid
arthritis, systemic / discoid
lupus erythematosus, other
con...
Chloroquine
• Initial symptom may be
cardiac arrest
• Pediatric overdoses: neuro
symptoms in 30 min to 1 hour
• Death seem...
Chloroquine
• Severity of hypokalemia
closely correlates with level
of chloroquine toxicity
• Potassium concentrations les...
Chloroquine
• GI absorption: rapid, almost
complete
• Peak plasma concentration: 1.5
to 3 hours
• Elimination half-life in...
Chloroquine
• Therapeutic dose: 10 mg/kg
• Toxic effects: 20 mg/kg
• Lethal dose: 30 mg/kg
• Confirmed toddler death at
27...
Chloroquine
Antimalarials
Drug
Minimal
potential
fatal dose
Maximal
dose
available
No. of tabs
that can
cause fatality
Chloroquine 20 ...
Clonidine
Clonidine
• Initially nasal decongestants
• Later marketed as central
acting antihypertensive
• Alpha2-adrenergic agonist
...
Imidazolines
• Decongestant imidazolines:
naphazoline, oxymetazoline,
tetrahydrozoline,
xylometazoline
• Ophthalmologic br...
Imidazolines
• 2001: 1438 clonidine
exposures in children younger
than 6 years old
• 922 tetrahydrozoline
exposures in pre...
Toxicity
• Oral, transdermal delivery
• Patches contain 2.5 mg, 5 mg,
and 7.5 mg of clonidine,
• OD resembles opioid: LOC...
Toxicity
• Toxicity in 30 to 90 minutes
• May persist for 1 to 3 days
• Children most at risk for
bradycardia, respiratory...
Cases
• Case series: 80 children admit
for clonidine ingestion
• Average time to onset of
symptoms: 35 minutes
• Most comm...
Cases
• Six required intubation
• No deaths reported
• 54% of the clonidine belonged
to patients’ grandmothers
Nichols MH,...
Cases
• 21-month-old girl: coma,
bradycardia, hypotension
after ingesting 0.3-mg tablet
• 6-year-old girl: obtundation,
br...
Cases
• 9-month-old boy lethargic 90
minutes after sucking on a
discarded clonidine patch
• 2-year-old child bradycardic,
...
Management
• Imidazoline: supportive
• Symptomatic patients respond
variably to naloxone up to a
total of 10 mg
• Retrospe...
Management
• Symptomatic bradycardia:
start with atropine
• Hypotension unresponsive to
fluid resuscitation or
complicated...
Tricyclic Anti-
depressants
Cyclic Antidepressants
• Leading cause of poisoning
fatality in the United States
until 1993
• Presently 2nd most common
c...
Cyclic Antidepressants
• All TCAs dangerous in excess
• Desipramine seems especially
dangerous in children
• Anticholinerg...
Toxidrome Mnemonic
“blind as a bat” – dilated pupils
“dry as a bone” – dehydrated
“mad as a hen” – hallucinations
“red as ...
Pathophysiology
• Mortality 2o to cardiotoxicity,
CNS toxicity
• BP may be 2o arrhythmia-
induced cardiogenic shock,
PVR...
Pathophysiology
• Seizures associated with
cyclic antidepressant toxicity
typically generalized tonic-
clonic, self-limite...
Pathophysiology
• Seizure activity greatest in
antidepressants showing
dopamine and norepinephrine
reuptake inhibition: bu...
Morbidity / Mortality
• 10 to 20 mg/kg ingestion of
most TCAs likely to result in
significant CNS, CV symptoms
• 15 to 20 ...
TCA Case Reports
• 3-year-old girl: seizures,
cardiac dysrhythmias after
ingestion 100 mg desipramine
• 250 mg imipramine,...
Management
• Lecture in itself
• Sodium bicarbonate remains
mainstay of treatment to
reverse cardiotoxic effects
• Benefic...
Tricyclic Antidepressants
Drug
Minimal
potential
fatal dose
Maximal
dose
available
No. of tabs
that can
cause fatality
Ami...
Calcium
Channel
Antagonists
Epidemiology
• 9264 CCA exposures in 2001
• 100% increase from 1990
• 2249 in children under 6 years
• 88 moderate to majo...
Categories
• Phenylalkylamines: verapamil
• Benzothiaprines: diltiazem
– Act predominantly on cardiac
tissue
• Dihydropyri...
Presentation
• Hallmark: disturbance of
cardiovascular system
• Classic manifestations:
hypotension, bradycardia,
• Reflex...
Presentation
• Conduction: 2nd and 3rd degree
heart block
• Negative inotropy: cardiogenic
shock or cardiac arrest
• Can b...
Presentation
• Hypotension can last >24
hours despite therapy,
• Hyperglycemia: multifactorial
– Hyperglycemia in setting ...
Case #1
• 11-month-old girl developed
seizures 45 minutes after
ingesting 400 mg verapamil
Passal DB, Crespin FH. Pediatri...
Case #2
• 14-month-old girl pale,
hypotensive, tachycardic
after ingesting single 10 mg
nifedipine tablet
– Aggressive int...
Case Series
• Pediatric case series: 16
symptomatic patients among
283 recorded exposures
• Five occurred after ingestion
...
Therapy
• Atropine: 1st-line agent in
bradycardia, only moderately
successful
• Optimal pharmacotherapy
poorly defined
• C...
Therapy
• TOC refractory CCA toxicity:
high-dose glucose-insulin
– Insulin: positive inotrope
• Case series: 5 patients wi...
Calcium Channel Blockers
Drug
Minimal
potential
fatal dose
Maximal
dose
available
No. of tabs
that can
cause fatality
Nife...
Sulfonylureas
Sulfonylureas
• Children 12 years and under
• Hypoglycemia in 56/185 (30%)
• 54/56 (96%) developed
hypoglycemia within 8 h...
Sulfonylureas
• Clear symptoms hypoglycemia
or glucose levels < 60 mg/dL:
admit for supplemental
glucose (oral or IV), mon...
Sulfonylureas
• 2-year-old boy observed to
ingest 5 mg glipizide
• Activated charcoal given
within 35 minutes
• Hypoglycem...
Oral Hypoglycemics
Drug
Minimal
potential
fatal dose
Maximal
dose
available
No. of tabs
that can cause
fatality
Chlorpropa...
Opioids &
Opiates
Epidemiology
• 5914 reported ingestions by
children younger than 6 years
old in 2001
• Most common: hydrocodone
with aceta...
Pathophysiology
• Infants and children more
susceptible to toxic effects
• Half of children exposed to
more than 1 mg/kg o...
Treatment
• Supportive
• Naloxone as needed
– Onset of action: < 2 minutes
– Duration of action: 20 – 90
minutes
– Elimina...
Opioids / Narcotics
Drug
Minimal
potential
fatal dose
Maximal
dose
available
No. of tabs
that can
cause fatality
Codeine
7...
Special Case: Lomotil®
• Antidiarrheal agent
– 2.5 mg opioid diphenoxylate
– 0.025 mg antimuscarinic
atropine
• Both absor...
Special Case: Lomotil®
• Diphenoxylate metabolized to
difenoxin, 5x more active than
parent compound
• Elimination half-li...
Special Case: Lomotil®
Classically described as
“biphasic reaction”
• Initial antimuscarinic
symptoms in 2 – 3 hours
• Del...
Special Case: Lomotil®
Case series
• 4/36 developed early
anticholinergic symptoms
• 15/36 developed opioid
toxicity only
...
Special Case: Lomotil®
• Catastrophic outcomes
reported after ingestion by
children
Wasserman GS, et al. Am Fam Physician ...
Management
• Similar to other opioids
• Initial symptoms, including
coma, may be delayed
• Symptoms have recurred 24
hours...
Household Products
• Methanol in deicing solutions,
windshield washer fluid,
carburetor cleaners
• Concentration may be 95...
Household Products
• Ethylene glycol in antifreeze,
some fire extinguishers, inks,
and adhesives
• Concentration may be 95...
…and Don’t Forget
• Theophylline still in use
• Extended release preparation
available
• Minimal fatal dose: 8.4 mg/kg
• M...
Primum non Nocere
• No literature suggests better
outcomes with charcoal
• Deaths reported from
activated charcoal aspirat...
Drugs Causing Toddler
Deaths: 1990-2000
Number of
Fatalities
Iron supplements 32
Antidepressants 13
Methadone 6
Nifedipine...
Summary
• Vast majority of toddler
ingestions are benign
• Dozen or so medicines can kill
10-kg toddler with one pill or
s...
GEMC- Toddler Toxicology- Resident Training
GEMC- Toddler Toxicology- Resident Training
GEMC- Toddler Toxicology- Resident Training
GEMC- Toddler Toxicology- Resident Training
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GEMC- Toddler Toxicology- Resident Training

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This is a lecture by Joe Lex, MD from the Ghana Emergency Medicine Collaborative. To download the editable version (in PPT), to access additional learning modules, or to learn more about the project, see http://openmi.ch/em-gemc. Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Share Alike-3.0 License: http://creativecommons.org/licenses/by-sa/3.0/.

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GEMC- Toddler Toxicology- Resident Training

  1. 1. Project: Ghana Emergency Medicine Collaborative Document Title: Toddler Toxicology: Drugs That Can Kill a Child With One Pill or Swallow Author(s): Joe Lex, MD, FACEP, FAAEM, (Temple University) 2013 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Share Alike-3.0 License: http://creativecommons.org/licenses/by-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. These lectures have been modified in the process of making a publicly shareable version. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/privacy-and-terms-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers. 1
  2. 2. Attribution Key for more information see: http://open.umich.edu/wiki/AttributionPolicy Use + Share + Adapt Make Your Own Assessment Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation License Creative Commons – Zero Waiver Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair. { Content the copyright holder, author, or law permits you to use, share and adapt. } { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } { Content Open.Michigan has used under a Fair Use determination. } 2
  3. 3. Toddler Toxicology: Drugs That Can Kill a Child with One Pill or Swallow Joe Lex, MD, FAAEM Temple University School of Medicine Philadelphia, PA
  4. 4. How Far We’ve Come • 1950: >400 pediatric overdose deaths • 2003: 34 fatalities from overdose in children <6 years • Can we be smug??
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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” Cantrell FL. Clin Toxicol. 2005;43(5):375-9.
  9. 9. Baby Proof Home “I baby-proofed my home, but the kids still somehow manage to get inside.”
  10. 10. Gideon Koren’s Article Koren G. Medications which can kill a toddler with one tablet or spoonful. Clin Toxicol 1993;31:407–13 • Identified medicines lethal to 10-kg child in single pill or swallow
  11. 11. Interest Builds Liebelt EL,et al. Small doses, big problems: a selected review of highly toxic common medications. Pediatr Emerg Care 1993;9:292–7.
  12. 12. Interest Builds Michael JB, Sztajnkrycer MD. Deadly pediatric poisons: nine common agents that kill at low doses. Emerg Med Clin North Am. 2004 Nov;22(4):1019-50.
  13. 13. Interest Builds Matteucci MJ. One pill can kill: assessing the potential for fatal poisonings in children. Pediatr Ann. 2005 Dec; 34(12):964-8.
  14. 14. Gideon Koren’s 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.
  15. 15. 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
  16. 16. Major Miscreants • TCAs • Antimalarials • Antipsychotics • Anti-arrhythmics • Methyl salicylate • Oral hypoglycemics • Calcium channel blockers • Theophylline • Narcotics • Camphor
  17. 17. Liquids Cydone, Wikimedia Commons
  18. 18. Camphor
  19. 19. 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: Who needs it? Pediatrics. 1978 Sep;62(3):404-6.
  20. 20. Camphor • Topical rubefacient: induces local hyperemia, warmth • Analgesic, antipruritic, and antitussive agent • Variety of OTC liniments: Vick’s VapoRub, Ben-Gay, Absorbine, Tiger Balm
  21. 21. Camphor • Aromatic terpene ketone derived from plants • Distinct odor, pungent taste • Some cultures use in cooking • As little as 700 to 1000 mg fatal AAP Policy Statement. Pediatrics 1994;94:127.
  22. 22. 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
  23. 23. Camphor • Cause of death: respiratory depression, status epilepticus • 3-year-old ingested 15mL Vicks VapoRub®  seizures, coma, respiratory depression – 700 mg of camphor Ruha AM, et al. Acad Emerg Med 2003;10:691.
  24. 24. Camphor • 2-year-old ingested 10mL Campho-Phenique • Seizures in 10 minutes, then coma, respiratory depression lasting 24 hours Gibson DE, et al. Am J Emerg Med 1989;7:41–3.
  25. 25. Vicks VapoRub® Cream Tatsuo Yamashita, Flickr
  26. 26. Campho-Phenique® (10.8%) • Pain relieving antiseptic liquid • For insect bites, scrapes & minor burns
  27. 27. 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
  28. 28. Methyl Salicylate
  29. 29. Salicylates • Present in numerous over-the- counter products – Aspirin (acetylsalicylic acid) – Oil of wintergreen (methyl salicylate) – Pepto-Bismol (bismuth subsalicylate)
  30. 30. Methyl Salicylate • Methyl ester of salicylic acid • Oil of wintergreen • Deceptively toxic • Minimal toxic ingested dose in children: 150 mg/kg
  31. 31. 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
  32. 32. Methyl Salicylate • One teaspoon of 98% methyl salicylate contains 7000 mg of salicylate • Equivalent to 90 baby aspirin • > 4 times potentially toxic dose for 10-kg child
  33. 33. Methyl Salicylate • Therapeutic serum ASA for analgesia: 15 to 30 mg/dL • Signs and symptoms of toxicity: >30 mg/dL • Life-threatening levels: >100 mg/dL
  34. 34. 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
  35. 35. 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
  36. 36. Methyl Salicylate Non-aspirin salicylates can be converted to “aspirin equivalent doses” with the help of tables found in any standard toxicology book
  37. 37. Methyl Salicylate 15% Jeroen Elfferich, Flickr
  38. 38. Methyl Salicylate 29% Eli Sagor, Flickr
  39. 39. Methyl Salicylate 40% Steffen Buus Kristensen, Wikimedia Commons
  40. 40. Methyl Salicylate 0.06% Jagwire, Wikimedia Commons
  41. 41. Methyl Salicylate • 21-month-old: significant poisoning, peak serum concentration of 81 mg/dL, after ingesting 4 mL Howrie DL, et al. Pediatrics 1985;75:869–71. • Fatality with ingestion <1 tsp Stevenson CS. Am J Med Sci 1937;193:772–88.
  42. 42. Methyl Salicylate • 1996 report to AAPCC • 10,733 toxic exposures to methyl salicylate • 7,712 were children • Two deaths reported, both in adults
  43. 43. Podophyllin 25%
  44. 44. Podophyllin 25% • Resinous powder from rhizome of American Mayapple • Used to treat genital warts • Occasional adulterant in herbal medicines • 1989: Hong Kong outbreak Ng THK, et al. J Neurol Sci 1991;101:107-13.
  45. 45. Podophyllin 25% • Transient toxicity: hallucinatory psychosis, bone marrow depression, hepatic dysfunction • Persistent: severe peripheral neuropathy Filley CM, et al. Neurology. 1982 Mar; 32(3):308-11.
  46. 46. Podophyllin 25% • Minimal potential fatal dose: 15 – 20 mg/kg • Maximal dose unit available: 1.25 g/5mL • Volume for potential lethality: 1mL Filley CM, et al. Neurology. 1982 Mar; 32(3):308-11.
  47. 47. Pastes, Ointments, Liniments Scott Ehardt, Wikimedia Commons
  48. 48. Dibucaine
  49. 49. Dibucaine • Potent amide anesthetic • Topical uses: hemorrhoids, sunburn, episiotomy pain • 10x as toxic as lidocaine • 20x as toxic as procaine • Mixed with secobarbitone, used IV to euthanize large animals (Somulose®)
  50. 50. Dibucaine CNS toxicity • Seizure • Coma
  51. 51. Dibucaine Cardiotoxicity • Increased PR • Widened QT • Slowed conduction • Slowed repolarization • Reentrant dysrhythmias – SVT – PVC
  52. 52. Dibucaine • ~1% of topical anesthetics sold in US • <5% nonfatal exposures to topical anesthetics • Caused 3 of 4 deaths due to topical anesthetics over last 20 years Dayan PS, et al. Ann Emerg Med. 1996 Oct; 28(4):442-5.
  53. 53. Dibucaine • In 1995, US Consumer Product Safety Commission issued rule requiring childproof packing for containers with >0.5 mg dibucaine or >5 mg lidocaine Corticaine® Dibucort® Dibusone® Nupercainal®
  54. 54. Dibucaine • Ointment USP, 1% • Topical Anesthetic • For External Use Only; Do not use in the eyes
  55. 55. Pills, Tablets & Capsules Chaos, Wikimedia Commons
  56. 56. Anti- Arrhythmics
  57. 57. 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 Dellocchio T, et al. Pediatrics. 1976 Aug; 58(2):288-90
  58. 58. 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
  59. 59. Disopyramide • Another Class 1A • Falling out of favor • More anticholinergic than others in class • 1 pill potentially lethal Singer P, et al. J Anal Toxicol. 1995 Oct; 19(6):529-30.
  60. 60. 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 Mortensen ME, et al. Ann Emerg Med. 1992 Aug; 21(8):998-1001.
  61. 61. Propafenone Propafenone (Rhythmol®) • 2 year-old ingested less than one tablet  rapid cardiovascular collapse • Eventual recovery McHugh TP, et al. Ann Emerg Med. 1987 Apr; 16(4):437-40.
  62. 62. Antiarrhythmics Drug Minimal potential fatal dose Maximal dose available No. of tabs that can cause fatality Quinidine 15 mg/kg 324 mg 1 Disopyramide 15 mg/kg 150 mg 1 Procainamide 70 mg/kg 1000 mg 1 Flecainide 25 mg/kg 150 mg 1 – 2
  63. 63. Antimalarials
  64. 64. Quinine • See quinidine CYL, Wikimedia Commons
  65. 65. Chloroquine • Primary treatment for malaria – Anti-inflammatory – Antihistamine – Anti-prostaglandin • Hydroxychloroquine: chemically similar
  66. 66. Chloroquine • Quinolone family • Now used to treat rheumatoid arthritis, systemic / discoid lupus erythematosus, other connective tissue disorders
  67. 67. 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
  68. 68. 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 Angel G, et al. Lancet. 1995 Dec 16; 346(8990):1625.
  69. 69. Chloroquine • GI absorption: rapid, almost complete • Peak plasma concentration: 1.5 to 3 hours • Elimination half-life in children: 75 to 136 hours Cann HM, et al. Pediatrics 1961;27:95–102.
  70. 70. 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 Cann HM, et al. Pediatrics 1961;27:95–102.
  71. 71. Chloroquine
  72. 72. Antimalarials Drug Minimal potential fatal dose Maximal dose available No. of tabs that can cause fatality Chloroquine 20 mg/kg 500 mg 1 Hydroxy- chloroquine 20 mg/kg 200 mg 1 Quinine 80 mg/kg 650 mg 1
  73. 73. Clonidine
  74. 74. Clonidine • Initially nasal decongestants • Later marketed as central acting antihypertensive • Alpha2-adrenergic agonist –  central adrenergic tone • Also bind to imidazoline receptors in medulla
  75. 75. Imidazolines • Decongestant imidazolines: naphazoline, oxymetazoline, tetrahydrozoline, xylometazoline • Ophthalmologic brimonidine and apraclonidine used to treat glaucoma
  76. 76. Imidazolines • 2001: 1438 clonidine exposures in children younger than 6 years old • 922 tetrahydrozoline exposures in preschool children
  77. 77. 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
  78. 78. Toxicity • Toxicity in 30 to 90 minutes • May persist for 1 to 3 days • Children most at risk for bradycardia, respiratory depression, intermittent apnea
  79. 79. 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%) Nichols MH, et al. Ann Emerg Med 1997;29:511
  80. 80. Cases • Six required intubation • No deaths reported • 54% of the clonidine belonged to patients’ grandmothers Nichols MH, et al. Ann Emerg Med 1997;29:511
  81. 81. Cases • 21-month-old girl: coma, bradycardia, hypotension after ingesting 0.3-mg tablet • 6-year-old girl: obtundation, bradycardia after applying patch she mistook for bandage Killian CA, et al. Pediatr Emerg Care 1997; 13:340–1. Neuvonen PJ, et al. Clin Toxicol 1979;14:369–74.
  82. 82. Cases • 9-month-old boy lethargic 90 minutes after sucking on a discarded clonidine patch • 2-year-old child bradycardic, recurrent apnea after ingesting 5 mL apraclonidine Everson G, et al. J Toxicol Clin Toxicol 1999; 37:629. Caravati EM, et al. Ann Emerg Med 1988;17:175
  83. 83. 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 Nichols MH, et al. Ann Emerg Med 1997;29:511
  84. 84. Management • Symptomatic bradycardia: start with atropine • Hypotension unresponsive to fluid resuscitation or complicated by persistent bradycardia: dopamine Maggi JC, et al. Clin Paediatr 1986;25:453–5.
  85. 85. Tricyclic Anti- depressants
  86. 86. 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 Litovitz TL, et al. Am J Emerg Med 2002; 20:391–452.
  87. 87. Cyclic Antidepressants • All TCAs dangerous in excess • Desipramine seems especially dangerous in children • Anticholinergic toxidrome (remember the mnemonic??)
  88. 88. 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
  89. 89. Pathophysiology • Mortality 2o to cardiotoxicity, CNS toxicity • BP may be 2o arrhythmia- induced cardiogenic shock, PVR 2o to alpha-adrenergic blockade, sympathomimetic amine depletion
  90. 90. Pathophysiology • Seizures associated with cyclic antidepressant toxicity typically generalized tonic- clonic, self-limited • Status epilepticus has been reported Lipper B, et al. Am J Emerg Med 1994;12:451–7.
  91. 91. Pathophysiology • Seizure activity greatest in antidepressants showing dopamine and norepinephrine reuptake inhibition: bupropion, amoxapine, venlafaxine • Significant toxicity presents within 6 hours of ingestion Lipper B, et al. Am J Emerg Med 1994;12:451–7.
  92. 92. 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 Frommer DA, et al. JAMA 1987;257:521–6.
  93. 93. TCA Case Reports • 3-year-old girl: seizures, cardiac dysrhythmias after ingestion 100 mg desipramine • 250 mg imipramine, amoxapine have resulted in child fatality Jue SG. Drug Intell Clin Pharm 1976;10:52–3. Linakis JG. Clin Toxicol Rev 1988;10. Manoguerra AS. Crit Care Q 1982;43–51.
  94. 94. 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
  95. 95. Tricyclic Antidepressants Drug Minimal potential fatal dose Maximal dose available No. of tabs that can cause fatality Amitriptyline 15 mg/kg 100 mg 1 – 2 Imipramine 15 mg/kg 150 mg 1 Desipramine 15 mg/kg 75 mg 1 – 2
  96. 96. Calcium Channel Antagonists
  97. 97. 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
  98. 98. Categories • Phenylalkylamines: verapamil • Benzothiaprines: diltiazem – Act predominantly on cardiac tissue • Dihydropyridines: nifedipine – Acts predominately on vascular smooth muscle
  99. 99. Presentation • Hallmark: disturbance of cardiovascular system • Classic manifestations: hypotension, bradycardia, • Reflex tachycardia can be seen with dihydropyridines
  100. 100. Presentation • Conduction: 2nd and 3rd degree heart block • Negative inotropy: cardiogenic shock or cardiac arrest • Can be delayed in sustained- release preparation ingestion
  101. 101. Presentation • Hypotension can last >24 hours despite therapy, • Hyperglycemia: multifactorial – Hyperglycemia in setting of bradycardia and hypotension suggests CCA ingestion
  102. 102. Case #1 • 11-month-old girl developed seizures 45 minutes after ingesting 400 mg verapamil Passal DB, Crespin FH. Pediatrics 1984;73:543–5.
  103. 103. 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 Lee DC, et al. J Emerg Med 2000;19:359–61.
  104. 104. 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 Belson MG, et al. Am J Emerg Med 2000;18:581.
  105. 105. Therapy • Atropine: 1st-line agent in bradycardia, only moderately successful • Optimal pharmacotherapy poorly defined • Calcium: conflicting data – Most beneficial in mild toxicity
  106. 106. 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 Yuan TH, et al. J Toxicol Clin Toxicol 1999;37:463–74.
  107. 107. Calcium Channel Blockers Drug Minimal potential fatal dose Maximal dose available No. of tabs that can cause fatality Nifedipine 15 mg/kg 90 mg 1 – 2 Verapamil 15 mg/kg 360 mg 1 Diltiazem 15 mg/kg 360 mg 1
  108. 108. Sulfonylureas
  109. 109. 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 Spiller HA, et al. J Pediatr. 1997 Jul;131(1 Pt 1):141-6.
  110. 110. Sulfonylureas • Clear symptoms hypoglycemia or glucose levels < 60 mg/dL: admit for supplemental glucose (oral or IV), monitor • Refractory to IV glucose: octreotide, diazoxide may help Little GL, et al. J Emerg Med. 2005 Apr; 28(3):305-10.
  111. 111. 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 Szlatenyi CS, et al. Ann Emerg Med. 1998 Jun; 31(6):773-6.
  112. 112. Oral Hypoglycemics Drug Minimal potential fatal dose Maximal dose available No. of tabs that can cause fatality Chlorpropamide 5 mg/kg 25 mg 1 Glibenclamide 0.1 mg/kg 2.5 mg 1 Glipizide 0.1 mg/kg 5 mg 1
  113. 113. Opioids & Opiates
  114. 114. 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
  115. 115. 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 OMA Committee on Pharmacy. Codeine: Ont Med Rev 1977;44:447–8.
  116. 116. Treatment • Supportive • Naloxone as needed – Onset of action: < 2 minutes – Duration of action: 20 – 90 minutes – Elimination half-life: 60 – 90 minutes
  117. 117. Opioids / Narcotics Drug Minimal potential fatal dose Maximal dose available No. of tabs that can cause fatality Codeine 7-14 mg/kg 60 mg 1 – 2 Hydrocodone elixir 1.5 mg/kg 60 mg / 5mL <1 tsp Methadone 1-2 mg/kg 40 mg 1
  118. 118. Special Case: Lomotil® • Antidiarrheal agent – 2.5 mg opioid diphenoxylate – 0.025 mg antimuscarinic atropine • Both absorbed rapidly – May be delayed in overdose
  119. 119. 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
  120. 120. 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 McCarron MG, et al. Pediatrics 1991;87:694–700.
  121. 121. Special Case: Lomotil® Case series • 4/36 developed early anticholinergic symptoms • 15/36 developed opioid toxicity only McCarron MG, et al. Pediatrics 1991;87:694–700.
  122. 122. Special Case: Lomotil® • Catastrophic outcomes reported after ingestion by children Wasserman GS, et al. Am Fam Physician 1975; 11:93–7. • Toxicity reported after ingestion of one-half tablet Ginsberg CM, et al. Clin Toxicol 1969;2:377–82.
  123. 123. 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 Manoguerra AS, et al. Poisindex, Vol. 117; 9/2003.
  124. 124. 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
  125. 125. 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
  126. 126. …and Don’t 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
  127. 127. Primum non Nocere • No literature suggests better outcomes with charcoal • Deaths reported from activated charcoal aspiration – Some in children when they consumed nontoxic products Menzies DG, et al. BMJ 1988;297:459–460. Harsch HH. N Engl J Med 1986;314:318. Elliott CG, et al. Chest 1989;96:672–674.
  128. 128. Drugs Causing Toddler Deaths: 1990-2000 Number of Fatalities Iron supplements 32 Antidepressants 13 Methadone 6 Nifedipine 5 Methyl salicylate 3 Diphenoxylate 1 Clonidine 1 Flecainide 1 Glipizide 1
  129. 129. 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
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