project: ghana emergency medicine collaborative document title: toddler toxicology: drugs that can...

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

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Toddler Toxicology:Toddler Toxicology:Drugs That Can Kill a Child with Drugs That Can Kill a Child with

One Pill or SwallowOne Pill or Swallow

Joe Lex, MD, FAAEMJoe Lex, MD, FAAEMTemple University School of MedicineTemple University School of Medicine

Philadelphia, PAPhiladelphia, PA

How Far WeHow Far We’’ve Comeve Come

• 1950: >400 pediatric 1950: >400 pediatric overdose deathsoverdose deaths

• 2003: 34 fatalities from 2003: 34 fatalities from overdose in children <6 overdose in children <6 yearsyears

• Can we be smug??Can we be smug??

Peak Incidence: 1 to 3Peak Incidence: 1 to 3

• Attracted to toxic Attracted to toxic substances based on color substances based on color or appearance of agent or or appearance of agent or containercontainer

• More willing to taste More willing to taste dangerous substances dangerous substances

• Hand-mouth behavior Hand-mouth behavior nearly 10 times / hour nearly 10 times / hour


• Physical environment Physical environment change plays significant rolechange plays significant role

• Half of accidental poisonings Half of accidental poisonings due to product in use at time due to product in use at time of ingestion or recently of ingestion or recently moved from usual storage moved from usual storage sitesite

• Top category: cosmetics and Top category: cosmetics and personal care productspersonal care products


• Plants also popularPlants also popular• Amounts ingested by Amounts ingested by

toddlers smalltoddlers small• Ingestion of toxic substance Ingestion of toxic substance

usually results in nontoxic usually results in nontoxic or minimally toxic outcomesor minimally toxic outcomes

Poison Hunting on eBayPoison Hunting on eBay

10 month hunt on eBay10 month hunt on eBay• 121 products identified121 products identified• 24 24 ““supertoxicsupertoxic””: strychnine, : strychnine,

arsenic trioxide, cyanide, etc. arsenic trioxide, cyanide, etc. • 63 63 ““extremely toxicextremely toxic””• 21 21 ““very toxicvery toxic””• 13 13 ““moderately-slightly toxicmoderately-slightly toxic””

Cantrell FL. Clin Toxicol. 2005;43(5):375-9.Cantrell FL. Clin Toxicol. 2005;43(5):375-9.

Baby Proof HomeBaby Proof Home

““I baby-proofed my I baby-proofed my home, but the home, but the

kids still somehow kids still somehow manage to get manage to get

inside.inside.””

Gideon KorenGideon Koren’’s Articles Article

Koren G. Koren G. Medications which Medications which can kill a toddler with one can kill a toddler with one tablet or spoonfultablet or spoonful. Clin . Clin Toxicol 1993;31:407–13Toxicol 1993;31:407–13

• Identified medicines lethal Identified medicines lethal to 10-kg child in single pill to 10-kg child in single pill or swallowor swallow

Interest BuildsInterest Builds

Liebelt EL,et al. Liebelt EL,et al. Small doses, Small doses, big problems: a selected big problems: a selected review of highly toxic review of highly toxic common medicationscommon medications. . Pediatr Emerg Care Pediatr Emerg Care 1993;9:292–7.1993;9:292–7.


Michael JB, Sztajnkrycer MD. Michael JB, Sztajnkrycer MD. Deadly pediatric poisons: Deadly pediatric poisons: nine common agents that nine common agents that kill at low doseskill at low doses. Emerg . Emerg Med Clin North Am. 2004 Med Clin North Am. 2004 Nov;22(4):1019-50.Nov;22(4):1019-50.


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

Gideon KorenGideon Koren’’s Returns Return

Bar-Oz B, Levichek Z, Bar-Oz B, Levichek Z, Koren Koren GG. . Medications that can be Medications that can be fatal for a toddler with one fatal for a toddler with one tablet or teaspoonful: a tablet or teaspoonful: a 2004 update2004 update. Paediatr . Paediatr Drugs. 2004; 6(2):123-6. Drugs. 2004; 6(2):123-6.

Some AssumptionsSome Assumptions

• Assume healthy toddler Assume healthy toddler with bodyweight 10 kg and with bodyweight 10 kg and normal drug metabolismnormal drug metabolism

• Use lowest described fatal Use lowest described fatal dose from literaturedose from literature

• Use maximal dose unit Use maximal dose unit availableavailable

Major MiscreantsMajor Miscreants

• TCAsTCAs• AntimalarialsAntimalarials• AntipsychoticsAntipsychotics• Anti-arrhythmicsAnti-arrhythmics• Methyl salicylateMethyl salicylate• Oral hypoglycemicsOral hypoglycemics• Calcium channel blockersCalcium channel blockers

• TheophyllinTheophyllinee

• NarcoticsNarcotics• CamphorCamphor

LiquidsLiquids

Cydone, Wikimedia Commons

http://en.wikipedia.org/wiki/File:Laudanum_poison_100ml_flasche.jpg

CamphorCamphor

Camphor – A Case StudyCamphor – A Case Study

• Multiple pediatric deathsMultiple pediatric deaths• AAP editorial in 1978: AAP editorial in 1978:

Camphor: Who Needs It?Camphor: Who Needs It?• 20% camphorated oil 20% camphorated oil

removed from US removed from US pharmaciespharmacies

• OTC camphor concentration OTC camphor concentration limited to 11% in OTCslimited to 11% in OTCsCamphor: Who needs it? Pediatrics. 1978 Camphor: Who needs it? Pediatrics. 1978 Sep;62(3):404-6.Sep;62(3):404-6.

CamphorCamphor

• Topical rubefacient: induces Topical rubefacient: induces local hyperemia, warmthlocal hyperemia, warmth

• Analgesic, antipruritic, and Analgesic, antipruritic, and antitussive agentantitussive agent

• Variety of OTC liniments: Variety of OTC liniments: VickVick’’s VapoRub, Ben-Gay, s VapoRub, Ben-Gay, Absorbine, Tiger BalmAbsorbine, Tiger Balm

CamphorCamphor

• Aromatic terpene ketone Aromatic terpene ketone derived from plantsderived from plants

• Distinct odor, pungent tasteDistinct odor, pungent taste• Some cultures use in Some cultures use in

cookingcooking• As little as 700 to 1000 mg As little as 700 to 1000 mg

fatalfatalAAP Policy Statement. Pediatrics AAP Policy Statement. Pediatrics 1994;94:127.1994;94:127.

CamphorCamphor

• 7805 cases of topical 7805 cases of topical camphor ingestion in camphor ingestion in children younger than age 6 children younger than age 6 reported to poison control reported to poison control centers in US in 2001centers in US in 2001

• Deaths rare since loss of Deaths rare since loss of 20% oil20% oil

CamphorCamphor

• Cause of death: respiratory Cause of death: respiratory depression, status depression, status epilepticusepilepticus

• 3-year-old ingested 15mL 3-year-old ingested 15mL Vicks VapoRub® Vicks VapoRub® seizures, seizures, coma, respiratory coma, respiratory depressiondepression– 700 mg of camphor700 mg of camphorRuha AM, et al. Acad Emerg Med Ruha AM, et al. Acad Emerg Med 2003;10:691.2003;10:691.

CamphorCamphor

• 2-year-old ingested 10mL 2-year-old ingested 10mL Campho-PheniqueCampho-Phenique

• Seizures in 10 minutes, then Seizures in 10 minutes, then coma, respiratory coma, respiratory depression lasting 24 hoursdepression lasting 24 hours

Gibson DE, et al. Am J Emerg Med Gibson DE, et al. Am J Emerg Med 1989;7:41–3.1989;7:41–3.

Vicks VapoRub® CreamVicks VapoRub® Cream

Tatsuo Yamashita, Flickr

http://www.flickr.com/photos/yto/4297543240/

Campho-Phenique® Campho-Phenique® (10.8%)(10.8%)

• Pain relieving antiseptic liquid• For insect bites, scrapes & minor burns

TodayToday

• 1996: 9,387 camphor 1996: 9,387 camphor exposures reported to AAPCCexposures reported to AAPCC

• 7404 in children under 6 7404 in children under 6 yearsyears

• NO deaths reportedNO deaths reported• Virtually eliminated as a Virtually eliminated as a

source of lethality in this source of lethality in this countrycountry

Methyl Methyl SalicylateSalicylate

SalicylatesSalicylates

• Present in numerous over-Present in numerous over-the-counter productsthe-counter products– Aspirin (acetylsalicylic Aspirin (acetylsalicylic

acid)acid)– Oil of wintergreen (methyl Oil of wintergreen (methyl

salicylate)salicylate)– Pepto-Bismol (bismuth Pepto-Bismol (bismuth

subsalicylate)subsalicylate)

Methyl SalicylateMethyl Salicylate

• Methyl ester of salicylic acidMethyl ester of salicylic acid• Oil of wintergreenOil of wintergreen• Deceptively toxicDeceptively toxic• Minimal toxic ingested dose Minimal toxic ingested dose

in children: 150 mg/kgin children: 150 mg/kg

Methyl SalicylateMethyl Salicylate• Betula oil Betula oil • Panalgesic Panalgesic • o-hydroxybenzoic o-hydroxybenzoic

acid methyl ester acid methyl ester • Gaultheria oil Gaultheria oil • Methyl o-hydroxy -Methyl o-hydroxy -

benzoate benzoate • Sweet birch oil Sweet birch oil • Teaberry oil Teaberry oil • AnalgitAnalgit

• Exagien Exagien • Flucarmit Flucarmit • 2-(methoxy 2-(methoxy

carbonyl)-phenol carbonyl)-phenol • Anthrapole ND Anthrapole ND • 2-carbo-2-carbo-

methoxyphenol methoxyphenol • Methyl Methyl

hydroxybenzoate hydroxybenzoate • Linsal Linsal • Metsal Liniment Metsal Liniment


• One teaspoon of 98% One teaspoon of 98% methyl salicylate contains methyl salicylate contains 7000 mg of salicylate7000 mg of salicylate

• Equivalent to 90 baby Equivalent to 90 baby aspirinaspirin

• > 4 times potentially toxic > 4 times potentially toxic dose for 10-kg childdose for 10-kg child


• Therapeutic serum ASA for Therapeutic serum ASA for analgesia: 15 to 30 mg/dLanalgesia: 15 to 30 mg/dL

• Signs and symptoms of Signs and symptoms of toxicity: >30 mg/dLtoxicity: >30 mg/dL

• Life-threatening levels: Life-threatening levels: >100 mg/dL>100 mg/dL


• Vd doubles or triples in toxic Vd doubles or triples in toxic statesstates

• Therapeutic half-life: 1 to 2 Therapeutic half-life: 1 to 2 hourshours

• Toxic levels with acid urine: Toxic levels with acid urine: half-life up to 30 hourshalf-life up to 30 hours


• Children with rheumatoid Children with rheumatoid disease at steady state: toxic disease at steady state: toxic through minor dietary through minor dietary changeschanges

• Infants: may show just Infants: may show just dehydration, rapid breathingdehydration, rapid breathing

• Older kids: GI symptoms, Older kids: GI symptoms, CNS depressionCNS depression


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

Methyl Salicylate 15%Methyl Salicylate 15%

Jeroen Elfferich, Flickr

http://www.flickr.com/photos/jeroen020/278090825/

Methyl Salicylate 29% Methyl Salicylate 29%

Eli Sagor, Flickr

http://www.flickr.com/photos/esagor/6841491660/

Methyl Salicylate 40%Methyl Salicylate 40%

Steffen Buus Kristensen, Wikimedia Commons

http://en.wikipedia.org/wiki/File:Tigerbalm.jpg

Methyl Salicylate 0.06% Methyl Salicylate 0.06%

Jagwire, Wikimedia Commons

http://en.wikipedia.org/wiki/File:Listerine_products.jpg


• 21-month-old: significant 21-month-old: significant poisoning, peak serum poisoning, peak serum concentration of 81 mg/dL, concentration of 81 mg/dL, after ingesting 4 mLafter ingesting 4 mLHowrie DL, et al. Pediatrics 1985;75:869–71.Howrie DL, et al. Pediatrics 1985;75:869–71.

• Fatality with ingestion <1 tspFatality with ingestion <1 tsp

Stevenson CS. Am J Med Sci 1937;193:772–Stevenson CS. Am J Med Sci 1937;193:772–88.88.


• 1996 report to AAPCC1996 report to AAPCC• 10,733 toxic exposures to 10,733 toxic exposures to

methyl salicylatemethyl salicylate• 7,712 were children7,712 were children• Two deaths reported, both Two deaths reported, both

in adultsin adults

Podophyllin Podophyllin 25%25%

Podophyllin 25%Podophyllin 25%

• Resinous powder from Resinous powder from rhizome of American rhizome of American Mayapple Mayapple

• Used to treat genital wartsUsed to treat genital warts• Occasional adulterant in Occasional adulterant in

herbal medicinesherbal medicines• 1989: Hong Kong outbreak1989: Hong Kong outbreak

Ng THK, et al. J Neurol Sci 1991;101:107-13. Ng THK, et al. J Neurol Sci 1991;101:107-13.


• Transient toxicity: Transient toxicity: hallucinatory psychosis, hallucinatory psychosis, bone marrow depression, bone marrow depression, hepatic dysfunctionhepatic dysfunction

• Persistent: severe Persistent: severe peripheral neuropathyperipheral neuropathy

Filley CM, et al. Neurology. 1982 Mar; Filley CM, et al. Neurology. 1982 Mar; 32(3):308-11.32(3):308-11.


• Minimal potential fatal dose: Minimal potential fatal dose: 15 – 20 mg/kg15 – 20 mg/kg

• Maximal dose unit available: Maximal dose unit available: 1.25 g/5mL1.25 g/5mL

• Volume for potential Volume for potential

lethality: lethality: 1mL1mLFilley CM, et al. Neurology. 1982 Mar; Filley CM, et al. Neurology. 1982 Mar; 32(3):308-11.32(3):308-11.

Pastes, Ointments, Pastes, Ointments, LinimentsLiniments

Scott Ehardt, Wikimedia Commons

http://en.wikipedia.org/wiki/File:Toothpaste.jpg

DibucaineDibucaine

DibucaineDibucaine

• Potent amide anestheticPotent amide anesthetic• Topical uses: hemorrhoids, Topical uses: hemorrhoids,

sunburn, episiotomy painsunburn, episiotomy pain• 10x as toxic as lidocaine10x as toxic as lidocaine• 20x as toxic as procaine20x as toxic as procaine• Mixed with secobarbitone, Mixed with secobarbitone,

used IV to euthanize large used IV to euthanize large animals (Somulose®)animals (Somulose®)

DibucaineDibucaine

CNS toxicityCNS toxicity• SeizureSeizure• ComaComa

DibucaineDibucaine

CardiotoxicityCardiotoxicity• Increased PRIncreased PR• Widened QTWidened QT• Slowed conductionSlowed conduction• Slowed repolarizationSlowed repolarization• Reentrant dysrhythmiasReentrant dysrhythmias

– SVTSVT– PVCPVC

DibucaineDibucaine

• ~1% of topical anesthetics ~1% of topical anesthetics sold in USsold in US

• <5% <5% nonfatalnonfatal exposures to exposures to topical anestheticstopical anesthetics

• Caused 3 of 4 deaths due to Caused 3 of 4 deaths due to topical anesthetics over last topical anesthetics over last 20 years20 yearsDayan PS, et al. Ann Emerg Med. 1996 Oct; Dayan PS, et al. Ann Emerg Med. 1996 Oct; 28(4):442-5.28(4):442-5.

DibucaineDibucaine

• In 1995, US Consumer Product In 1995, US Consumer Product Safety Commission issued rule Safety Commission issued rule requiring childproof packing for requiring childproof packing for containers with >0.5 mg containers with >0.5 mg dibucaine or >5 mg lidocainedibucaine or >5 mg lidocaine

Corticaine® Dibucort®Corticaine® Dibucort®

Dibusone® Nupercainal® Dibusone® Nupercainal®

DibucaineDibucaine

• Ointment USP, 1%• Topical Anesthetic• For External Use Only; Do not use in the eyes

Pills, Tablets & CapsulesPills, Tablets & Capsules

Chaos, Wikimedia Commons

https://commons.wikimedia.org/wiki/File:VariousPills.jpg

Anti-Anti-ArrhythmicsArrhythmics

QuinidineQuinidine

• D-isomer of quinineD-isomer of quinine• Derived from cinchona barkDerived from cinchona bark• Side effects and toxicity Side effects and toxicity

similar to quininesimilar to quinine• Main concerns: Main concerns:

dysrhythmias, cardiogenic dysrhythmias, cardiogenic shock, coma, seizures, shock, coma, seizures, retinal damageretinal damageDellocchio T, et al. Pediatrics. 1976 Aug; Dellocchio T, et al. Pediatrics. 1976 Aug; 58(2):288-9058(2):288-90

Interesting HistoryInteresting History

• Founder of homoeopathy, Founder of homoeopathy, Dr. Samuel Hahnemann, Dr. Samuel Hahnemann, took large daily dose of took large daily dose of quinine barkquinine bark

• After 2 weeks, he felt After 2 weeks, he felt malaria-like symptomsmalaria-like symptoms

• ““Like cures likeLike cures like”” philosophy philosophy was start of homoeopathywas start of homoeopathy

DisopyramideDisopyramide

• Another Class 1AAnother Class 1A• Falling out of favorFalling out of favor• More anticholinergic than More anticholinergic than

others in classothers in class• 1 pill potentially lethal1 pill potentially lethal

Singer P, et al. J Anal Toxicol. 1995 Oct; Singer P, et al. J Anal Toxicol. 1995 Oct; 19(6):529-30. 19(6):529-30.

EncainideEncainide

Encainide (Enkaid®) removed Encainide (Enkaid®) removed from American market from American market voluntarily, still available on voluntarily, still available on ““compassionatecompassionate”” basis basis

• Case report: infant Case report: infant swallowed 1 tablet (25 mg) swallowed 1 tablet (25 mg) with rapid onset V-tach, but with rapid onset V-tach, but survivalsurvivalMortensen ME, et al. Ann Emerg Med. 1992 Mortensen ME, et al. Ann Emerg Med. 1992 Aug; 21(8):998-1001. Aug; 21(8):998-1001.

PropafenonePropafenone

Propafenone (Rhythmol®)Propafenone (Rhythmol®)• 2 year-old ingested less 2 year-old ingested less

than one tablet than one tablet rapid rapid cardiovascular collapsecardiovascular collapse

• Eventual recoveryEventual recovery

McHugh TP, et al. Ann Emerg Med. 1987 McHugh TP, et al. Ann Emerg Med. 1987 Apr; 16(4):437-40. Apr; 16(4):437-40.

AntiarrhythmicsAntiarrhythmics

DrugDrugMinimal Minimal potential potential fatal dosefatal dose

Maximal Maximal dose dose

availableavailable

No. of No. of tabs that tabs that

can can cause cause

fatalityfatality

QuinidineQuinidine 15 mg/kg15 mg/kg 324 mg324 mg 11DisopyramiDisopyramidede 15 mg/kg15 mg/kg 150 mg150 mg 11

ProcainamiProcainamidede 70 mg/kg70 mg/kg 1000 1000

mgmg 11

FlecainideFlecainide 25 mg/kg25 mg/kg 150 mg150 mg 1 – 21 – 2

AntimalarialsAntimalarials

QuinineQuinine

• See quinidineSee quinidine

CYL, Wikimedia Commons

https://commons.wikimedia.org/wiki/File:Quinine.svg

ChloroquineChloroquine

• Primary treatment for Primary treatment for malariamalaria– Anti-inflammatoryAnti-inflammatory– AntihistamineAntihistamine– Anti-prostaglandinAnti-prostaglandin

• Hydroxychloroquine: Hydroxychloroquine: chemically similarchemically similar


• Quinolone familyQuinolone family• Now used to treat Now used to treat

rheumatoid arthritis, rheumatoid arthritis, systemic / discoid lupus systemic / discoid lupus erythematosus, other erythematosus, other connective tissue disordersconnective tissue disorders


• Initial symptom may be Initial symptom may be cardiac arrestcardiac arrest

• Pediatric overdoses: neuro Pediatric overdoses: neuro symptoms in 30 min to 1 symptoms in 30 min to 1 hourhour

• Death seems related to Death seems related to cardiac conduction system cardiac conduction system depression and myocardiumdepression and myocardium


• Severity of hypokalemia Severity of hypokalemia closely correlates with level closely correlates with level of chloroquine toxicityof chloroquine toxicity

• Potassium concentrations Potassium concentrations less than 1.9 mEq/L less than 1.9 mEq/L correlated with severe, life-correlated with severe, life-threatening ingestionthreatening ingestion

Angel G, et al. Lancet. 1995 Dec 16; Angel G, et al. Lancet. 1995 Dec 16; 346(8990):1625.346(8990):1625.


• GI absorption: rapid, almost GI absorption: rapid, almost completecomplete

• Peak plasma concentration: Peak plasma concentration: 1.5 to 3 hours1.5 to 3 hours

• Elimination half-life in Elimination half-life in children: children: 75 to 136 hours75 to 136 hours

Cann HM, et al. Pediatrics 1961;27:95–102.Cann HM, et al. Pediatrics 1961;27:95–102.


• Therapeutic dose: Therapeutic dose: 10 mg/kg10 mg/kg• Toxic effects: Toxic effects: 20 mg/kg20 mg/kg• Lethal dose: Lethal dose: 30 mg/kg30 mg/kg• Confirmed toddler death at 27 Confirmed toddler death at 27

mg/kgmg/kg• Equivalent to 300mg tablet in Equivalent to 300mg tablet in

8 kg 12-month-old8 kg 12-month-old

Cann HM, et al. Pediatrics 1961;27:95–102.Cann HM, et al. Pediatrics 1961;27:95–102.

AntimalarialsAntimalarials


MaximaMaximal dose l dose

availablavailablee

No. of tabs No. of tabs that can that can

cause cause fatalityfatality

ChloroquiChloroquinene

20 20 mg/kgmg/kg

500 500 mgmg 11

Hydroxy-Hydroxy-chloroquichloroquinene

20 20 mg/kgmg/kg

200 200 mgmg 11

Quinine Quinine 80 80 mg/kgmg/kg

650 650 mgmg 11

ClonidineClonidine

ClonidineClonidine

• Initially nasal decongestantsInitially nasal decongestants• Later marketed as central Later marketed as central

acting antihypertensiveacting antihypertensive

• AlphaAlpha22-adrenergic agonist-adrenergic agonist central adrenergic tonecentral adrenergic tone

• Also bind to imidazoline Also bind to imidazoline receptors in medullareceptors in medulla

ImidazolinesImidazolines

• Decongestant imidazolines: Decongestant imidazolines: naphazoline, oxymetazoline, naphazoline, oxymetazoline, tetrahydrozoline, tetrahydrozoline, xylometazolinexylometazoline

• Ophthalmologic brimonidine Ophthalmologic brimonidine and apraclonidine used to and apraclonidine used to treat glaucomatreat glaucoma

ImidazolinesImidazolines

• 2001: 1438 clonidine 2001: 1438 clonidine exposures in children exposures in children younger than 6 years oldyounger than 6 years old

• 922 tetrahydrozoline 922 tetrahydrozoline exposures in preschool exposures in preschool childrenchildren

ToxicityToxicity

• Oral, transdermal deliveryOral, transdermal delivery• Patches contain 2.5 mg, 5 Patches contain 2.5 mg, 5

mg, and 7.5 mg of mg, and 7.5 mg of clonidine,clonidine,

• OD resembles opioid: OD resembles opioid: LOC, LOC, bradycardia, hypotension, bradycardia, hypotension, respiratory depression, respiratory depression, miosis, hypotoniamiosis, hypotonia

ToxicityToxicity

• Toxicity in 30 to 90 minutesToxicity in 30 to 90 minutes• May persist for 1 to 3 daysMay persist for 1 to 3 days• Children most at risk for Children most at risk for

bradycardia, respiratory bradycardia, respiratory depression, intermittent depression, intermittent apneaapnea

CasesCases

• Case series: 80 children Case series: 80 children admit for clonidine ingestionadmit for clonidine ingestion

• Average time to onset of Average time to onset of symptoms: 35 minutessymptoms: 35 minutes

• Most common presenting Most common presenting sign or symptom: reduced sign or symptom: reduced level of consciousness level of consciousness (96%)(96%)Nichols MH, et al. Ann Emerg Med Nichols MH, et al. Ann Emerg Med 1997;29:5111997;29:511

CasesCases

• Six required intubationSix required intubation• No deaths reportedNo deaths reported• 54% of the clonidine 54% of the clonidine

belonged to patientsbelonged to patients’’ grandmothersgrandmothers

Nichols MH, et al. Ann Emerg Med Nichols MH, et al. Ann Emerg Med 1997;29:5111997;29:511

CasesCases

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

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

Killian CA, et al. Pediatr Emerg Care 1997; Killian CA, et al. Pediatr Emerg Care 1997; 13:340–1.13:340–1.

Neuvonen PJ, et al. Clin Toxicol 1979;14:369–Neuvonen PJ, et al. Clin Toxicol 1979;14:369–74.74.

CasesCases

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

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

Everson G, et al. J Toxicol Clin Toxicol 1999; Everson G, et al. J Toxicol Clin Toxicol 1999; 37:629.37:629.

Caravati EM, et al. Ann Emerg Med Caravati EM, et al. Ann Emerg Med 1988;17:1751988;17:175

ManagementManagement

• Imidazoline: supportiveImidazoline: supportive• Symptomatic patients respond Symptomatic patients respond

variably to naloxone up to a variably to naloxone up to a total of 10 mg total of 10 mg

• Retrospective review: 39 / 80 Retrospective review: 39 / 80 patients (49%) got naloxonepatients (49%) got naloxone– Positive response in 4 patientsPositive response in 4 patients

Nichols MH, et al. Ann Emerg Med Nichols MH, et al. Ann Emerg Med 1997;29:5111997;29:511


• Symptomatic bradycardia: Symptomatic bradycardia: start with atropinestart with atropine

• Hypotension unresponsive Hypotension unresponsive to fluid resuscitation or to fluid resuscitation or complicated by persistent complicated by persistent bradycardia: dopaminebradycardia: dopamine

Maggi JC, et al. Clin Paediatr 1986;25:453–5.Maggi JC, et al. Clin Paediatr 1986;25:453–5.

Tricyclic Anti-Tricyclic Anti-depressantsdepressants

Cyclic AntidepressantsCyclic Antidepressants

• Leading cause of poisoning Leading cause of poisoning fatality in the United States fatality in the United States until 1993until 1993

• Presently 2Presently 2ndnd most common most common class of agents ingested in class of agents ingested in fatalities reported to AAPCCfatalities reported to AAPCC

Litovitz TL, et al. Am J Emerg Med 2002; Litovitz TL, et al. Am J Emerg Med 2002; 20:391–452.20:391–452.

Cyclic AntidepressantsCyclic Antidepressants

• All TCAs dangerous in All TCAs dangerous in excessexcess

• Desipramine seems Desipramine seems especially dangerous in especially dangerous in childrenchildren

• AnticholinergicAnticholinergic toxidrome toxidrome (remember the(remember themnemonic??)mnemonic??)

Toxidrome MnemonicToxidrome Mnemonic

““blind as a batblind as a bat”” – dilated – dilated pupilspupils

““dry as a bonedry as a bone”” – dehydrated – dehydrated

““mad as a henmad as a hen”” – – hallucinationshallucinations

““red as a beetred as a beet”” – skin flushing – skin flushing

urinary retentionurinary retention

tachycardiatachycardia

PathophysiologyPathophysiology

• Mortality 2Mortality 2oo to to cardiotoxicity, CNS toxicitycardiotoxicity, CNS toxicity

BP may be 2BP may be 2oo arrhythmia- arrhythmia-induced cardiogenic shock, induced cardiogenic shock, PVR 2PVR 2oo to alpha-adrenergic to alpha-adrenergic blockade, sympathomimetic blockade, sympathomimetic amine depletionamine depletion


• Seizures associated with Seizures associated with cyclic antidepressant cyclic antidepressant toxicity typically generalized toxicity typically generalized tonic-clonic, self-limited tonic-clonic, self-limited

• Status epilepticus has been Status epilepticus has been reportedreported

Lipper B, et al. Am J Emerg Med Lipper B, et al. Am J Emerg Med 1994;12:451–7.1994;12:451–7.


• Seizure activity greatest in Seizure activity greatest in antidepressants showing antidepressants showing dopamine and dopamine and norepinephrine reuptake norepinephrine reuptake inhibition: bupropion, inhibition: bupropion, amoxapine, venlafaxineamoxapine, venlafaxine

• Significant toxicity presents Significant toxicity presents within 6 hours of ingestionwithin 6 hours of ingestionLipper B, et al. Am J Emerg Med Lipper B, et al. Am J Emerg Med 1994;12:451–7.1994;12:451–7.

Morbidity / MortalityMorbidity / Mortality

• 10 to 20 mg/kg ingestion of 10 to 20 mg/kg ingestion of most TCAs likely to result in most TCAs likely to result in significant CNS, CV significant CNS, CV symptomssymptoms

• 15 to 20 mg/kg ingestion 15 to 20 mg/kg ingestion believed to represent lethal believed to represent lethal exposureexposure

Frommer DA, et al. JAMA 1987;257:521–6.Frommer DA, et al. JAMA 1987;257:521–6.

TCA Case ReportsTCA Case Reports

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

• 250 mg imipramine, 250 mg imipramine, amoxapine have resulted in amoxapine have resulted in child fatalitychild fatality

Jue SG. Drug Intell Clin Pharm 1976;10:52–3.Jue SG. Drug Intell Clin Pharm 1976;10:52–3.

Linakis JG. Clin Toxicol Rev 1988;10.Linakis JG. Clin Toxicol Rev 1988;10.

Manoguerra AS. Crit Care Q 1982;43–51.Manoguerra AS. Crit Care Q 1982;43–51.


• Lecture in itselfLecture in itself• Sodium bicarbonate remains Sodium bicarbonate remains

mainstay of treatment to mainstay of treatment to reverse cardiotoxic effects reverse cardiotoxic effects

• Beneficial with even normal Beneficial with even normal arterial pHarterial pH

• Optimal dosing strategy Optimal dosing strategy remains to be determinedremains to be determined

Tricyclic AntidepressantsTricyclic Antidepressants



availablavailablee



AmitriptyliAmitriptylinene

15 15 mg/kgmg/kg

100 100 mgmg 1 – 21 – 2

ImipraminImipraminee

15 15 mg/kgmg/kg

150 150 mgmg 11

DesipramiDesipramine ne

15 15 mg/kgmg/kg 75 mg75 mg 1 – 21 – 2

Calcium Calcium Channel Channel

AntagonistsAntagonists

EpidemiologyEpidemiology

• 9264 CCA exposures in 20019264 CCA exposures in 2001• 100% increase from 1990100% increase from 1990• 2249 in children under 6 years 2249 in children under 6 years • 88 moderate to major 88 moderate to major

outcomesoutcomes• No pediatric deaths reported No pediatric deaths reported • 10 CCAs available in US10 CCAs available in US

CategoriesCategories

• Phenylalkylamines: Phenylalkylamines: verapamilverapamil

• Benzothiaprines: diltiazem Benzothiaprines: diltiazem – Act predominantly on cardiac Act predominantly on cardiac

tissuetissue

• Dihydropyridines: nifedipineDihydropyridines: nifedipine– Acts predominately on Acts predominately on

vascular smooth musclevascular smooth muscle

PresentationPresentation

• Hallmark: disturbance of Hallmark: disturbance of cardiovascular systemcardiovascular system

• Classic manifestations: Classic manifestations: hypotension, bradycardia, hypotension, bradycardia,

• Reflex tachycardia can be Reflex tachycardia can be seen with dihydropyridines seen with dihydropyridines


• Conduction: 2Conduction: 2ndnd and 3 and 3rdrd degree heart blockdegree heart block

• Negative inotropy: Negative inotropy: cardiogenic shock or cardiac cardiogenic shock or cardiac arrestarrest

• Can be delayed in Can be delayed in sustained-release sustained-release preparation ingestionpreparation ingestion


• Hypotension can last >24 Hypotension can last >24 hours despite therapy, hours despite therapy,

• Hyperglycemia: Hyperglycemia: multifactorialmultifactorial– Hyperglycemia in setting of Hyperglycemia in setting of

bradycardia and hypotension bradycardia and hypotension suggests CCA ingestionsuggests CCA ingestion

Case #1Case #1

• 11-month-old girl developed 11-month-old girl developed seizures 45 minutes after seizures 45 minutes after ingesting 400 mg verapamilingesting 400 mg verapamilPassal DB, Crespin FH. Pediatrics 1984;73:543–5.

Case #2Case #2

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

presentationpresentationLee DC, et al. J Emerg Med 2000;19:359–61.

Case SeriesCase Series

• Pediatric case series: 16 Pediatric case series: 16 symptomatic patients symptomatic patients among 283 recorded among 283 recorded exposuresexposures

• Five occurred after ingestion Five occurred after ingestion single tabletsingle tablet

• Maximal time to symptom Maximal time to symptom onset from 3 to 14 hoursonset from 3 to 14 hoursBelson MG, et al. Am J Emerg Med 2000;18:581.

TherapyTherapy

• Atropine: 1Atropine: 1stst-line agent in -line agent in bradycardia, only bradycardia, only moderately successfulmoderately successful

• Optimal pharmacotherapy Optimal pharmacotherapy poorly definedpoorly defined

• Calcium: conflicting dataCalcium: conflicting data– Most beneficial in mild Most beneficial in mild

toxicitytoxicity

TherapyTherapy

• TOC refractory CCA toxicity: TOC refractory CCA toxicity: high-dose glucose-insulinhigh-dose glucose-insulin– Insulin: positive inotropeInsulin: positive inotrope

• Case series: 5 patients with Case series: 5 patients with refractory shock after CCA refractory shock after CCA overdose improved after overdose improved after glucose-insulin infusionsglucose-insulin infusions

Yuan TH, et al. J Toxicol Clin Toxicol 1999;37:463–74.

Calcium Channel Calcium Channel BlockersBlockers



availablavailablee



NifedipineNifedipine 15 15 mg/kgmg/kg 90 mg90 mg 1 – 21 – 2

VerapamilVerapamil 15 15 mg/kgmg/kg

360 360 mgmg 11

Diltiazem Diltiazem 15 15 mg/kgmg/kg

360 360 mgmg 11

SulfonylureasSulfonylureas


• Children 12 years and under Children 12 years and under • Hypoglycemia in 56/185 (30%)Hypoglycemia in 56/185 (30%)• 54/56 (96%) developed 54/56 (96%) developed

hypoglycemia within 8 hours hypoglycemia within 8 hours of ingestionof ingestion

• Clinical observation with oral Clinical observation with oral feeding alone appears safe feeding alone appears safe

Spiller HA, et al. J Pediatr. 1997 Jul;131(1 Pt 1):141-6.


• Clear symptoms Clear symptoms hypoglycemia or glucose hypoglycemia or glucose levels < 60 mg/dL: admit levels < 60 mg/dL: admit for supplemental glucose for supplemental glucose (oral or IV), monitor(oral or IV), monitor

• Refractory to IV glucose: Refractory to IV glucose: octreotide, diazoxide may octreotide, diazoxide may helphelpLittle GL, et al. J Emerg Med. 2005 Apr; 28(3):305-10.


• 2-year-old boy observed to 2-year-old boy observed to ingest 5 mg glipizideingest 5 mg glipizide

• Activated charcoal given Activated charcoal given within 35 minutes within 35 minutes

• Hypoglycemia with serum Hypoglycemia with serum glucose 49 mg/dL 11 hrs glucose 49 mg/dL 11 hrs laterlaterSzlatenyi CS, et al. Ann Emerg Med. 1998 Jun; 31(6):773-6.

Oral HypoglycemicsOral Hypoglycemics


Maximal Maximal dose dose

availablavailablee



ChlorpropamChlorpropamideide 5 mg/kg5 mg/kg 25 mg25 mg 11

GlibenclamidGlibenclamidee

0.1 0.1 mg/kgmg/kg 2.5 mg2.5 mg 11

Glipizide Glipizide 0.1 0.1 mg/kgmg/kg 5 mg5 mg 11

Opioids & Opioids & OpiatesOpiates

EpidemiologyEpidemiology

• 5914 reported ingestions by 5914 reported ingestions by children younger than 6 years children younger than 6 years old in 2001old in 2001

• Most common: hydrocodone Most common: hydrocodone with acetaminophen with acetaminophen (Vicodin®)(Vicodin®)

• Time to peak toxicity: 1 hourTime to peak toxicity: 1 hour• Most deaths 2Most deaths 2oo to respiratory to respiratory

depression, hypoxiadepression, hypoxia


• Infants and children more Infants and children more susceptible to toxic effects susceptible to toxic effects

• Half of children exposed to Half of children exposed to more than 1 mg/kg of more than 1 mg/kg of codeine develop toxicitycodeine develop toxicity

• 2.5 mg of hydrocodone has 2.5 mg of hydrocodone has been lethal in infantbeen lethal in infant

OMA Committee on Pharmacy. Codeine: Ont OMA Committee on Pharmacy. Codeine: Ont Med Rev 1977;44:447–8.Med Rev 1977;44:447–8.

TreatmentTreatment

• SupportiveSupportive• Naloxone as neededNaloxone as needed

– Onset of action: < 2 minutesOnset of action: < 2 minutes– Duration of action: 20 – 90 Duration of action: 20 – 90

minutesminutes– Elimination half-life: 60 – 90 Elimination half-life: 60 – 90

minutesminutes

Opioids / NarcoticsOpioids / Narcotics



availablavailablee



CodeineCodeine 7-14 7-14 mg/kgmg/kg 60 mg60 mg 1 – 21 – 2

HydrocodoHydrocodone elixirne elixir

1.5 1.5 mg/kgmg/kg

60 mg 60 mg / 5mL/ 5mL <1 tsp<1 tsp

MethadonMethadone e

1-2 1-2 mg/kgmg/kg 40 mg40 mg 11

Special Case: Lomotil®Special Case: Lomotil®

• Antidiarrheal agentAntidiarrheal agent– 2.5 mg opioid diphenoxylate2.5 mg opioid diphenoxylate– 0.025 mg antimuscarinic 0.025 mg antimuscarinic

atropineatropine

• Both absorbed rapidly Both absorbed rapidly – May be delayed in overdoseMay be delayed in overdose


• Diphenoxylate metabolized Diphenoxylate metabolized to difenoxin, 5x more active to difenoxin, 5x more active than parent compound than parent compound

• Elimination half-life 12 – 14 Elimination half-life 12 – 14 hourshours

• Little correlation between Little correlation between ingested dose and outcomeingested dose and outcome


Classically described as Classically described as ““biphasic reactionbiphasic reaction””

• Initial antimuscarinic Initial antimuscarinic symptoms in 2 – 3 hours symptoms in 2 – 3 hours

• Delayed opioid symptomsDelayed opioid symptoms• Recent studies show this Recent studies show this

occurs in only few casesoccurs in only few cases

McCarron MG, et al. Pediatrics 1991;87:694–McCarron MG, et al. Pediatrics 1991;87:694–700.700.


Case seriesCase series• 4/36 developed early 4/36 developed early

anticholinergic symptomsanticholinergic symptoms• 15/36 developed opioid 15/36 developed opioid

toxicity onlytoxicity only

McCarron MG, et al. Pediatrics 1991;87:694–McCarron MG, et al. Pediatrics 1991;87:694–700.700.


• Catastrophic outcomes Catastrophic outcomes reported after ingestion by reported after ingestion by childrenchildrenWasserman GS, et al. Am Fam Physician Wasserman GS, et al. Am Fam Physician 1975; 11:93–7.1975; 11:93–7.

• Toxicity reported after Toxicity reported after ingestion of one-half tabletingestion of one-half tabletGinsberg CM, et al. Clin Toxicol 1969;2:377–Ginsberg CM, et al. Clin Toxicol 1969;2:377–82.82.


• Similar to other opioidsSimilar to other opioids• Initial symptoms, including Initial symptoms, including

coma, may be delayedcoma, may be delayed• Symptoms have recurred 24 Symptoms have recurred 24

hours after initial resolutionhours after initial resolution• Recommend: admit, Recommend: admit,

monitor for no less than 24 monitor for no less than 24 hourshoursManoguerra AS, et al. Poisindex, Vol. 117; Manoguerra AS, et al. Poisindex, Vol. 117; 9/2003.9/2003.

Household ProductsHousehold Products

• Methanol in deicing Methanol in deicing solutions, windshield solutions, windshield washer fluid, carburetor washer fluid, carburetor cleanerscleaners

• Concentration may be 95%Concentration may be 95%• Ingestion of 4 mL by 10-kg Ingestion of 4 mL by 10-kg

toddler toddler serum methanol serum methanol concentration of 50 mg/dLconcentration of 50 mg/dL

Household ProductsHousehold Products

• Ethylene glycol in antifreeze, Ethylene glycol in antifreeze, some fire extinguishers, inks, some fire extinguishers, inks, and adhesivesand adhesives

• Concentration may be 95%Concentration may be 95%• Ingestion of 2.9 mL by 10-kg Ingestion of 2.9 mL by 10-kg

toddler toddler serum ethylene serum ethylene glycol concentration of 50 glycol concentration of 50 mg/dLmg/dL

……and Donand Don’’t Forgett Forget

• Theophylline still in useTheophylline still in use• Extended release Extended release

preparation availablepreparation available• Minimal fatal dose: 8.4 Minimal fatal dose: 8.4

mg/kgmg/kg• Maximal available unit dose: Maximal available unit dose:

500 mg500 mg• One tablet can definitely killOne tablet can definitely kill

Primum non NocerePrimum non Nocere

• No literature suggests better No literature suggests better outcomes with charcoaloutcomes with charcoal

• Deaths reported from Deaths reported from activated charcoal aspirationactivated charcoal aspiration– Some in children when they Some in children when they

consumed nontoxic productsconsumed nontoxic products

Menzies DG, et al. BMJ 1988;297:459–460.Menzies DG, et al. BMJ 1988;297:459–460.

Harsch HH. N Engl J Med 1986;314:318.Harsch HH. N Engl J Med 1986;314:318.

Elliott CG, et al. Chest 1989;96:672–674.Elliott CG, et al. Chest 1989;96:672–674.

Drugs Causing Drugs Causing Toddler Deaths: Toddler Deaths:

1990-20001990-2000

Number of Number of FatalitiesFatalities

Iron supplementsIron supplements 3232AntidepressantsAntidepressants 1313MethadoneMethadone 66NifedipineNifedipine 55Methyl salicylateMethyl salicylate 33DiphenoxylateDiphenoxylate 11ClonidineClonidine 11FlecainideFlecainide 11GlipizideGlipizide 11

SummarySummary

• Vast majority of toddler Vast majority of toddler ingestions are benigningestions are benign

• Dozen or so medicines can Dozen or so medicines can kill 10-kg toddler with one kill 10-kg toddler with one pill or swallowpill or swallow

• Treatment: usually Treatment: usually supportivesupportive

• Activated charcoal can killActivated charcoal can kill

project: ghana emergency medicine collaborative document title: toddler toxicology: drugs that can...

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