Chairman’s Rounds Chairman’s Rounds October 16, 2009;October 16, 2009;

15 year old with an 15 year old with an unintentional overdoseunintentional overdose

David H. Rubin, MD, FAAPDavid H. Rubin, MD, FAAPChairman and Program Director Chairman and Program Director

Department of Pediatrics Department of Pediatrics St. Barnabas HospitalSt. Barnabas Hospital

Professor of Clinical PediatricsProfessor of Clinical PediatricsAlbert Einstein College of MedicineAlbert Einstein College of Medicine

OBJECTIVESOBJECTIVES

• Epidemiology Epidemiology • ResuscitationResuscitation• DetoxificationDetoxification• Antidotes/ToxidromesAntidotes/Toxidromes• Case report: 15 year old Case report: 15 year old

with an unintentional with an unintentional overdose overdose

EPIDEMIOLOGYEPIDEMIOLOGY(Lapus, 2007)(Lapus, 2007)

• 2004 data from American Association 2004 data from American Association of Poison Control Centersof Poison Control Centers• 2.4 million exposures2.4 million exposures

• 1.9 million secondary to ingestion1.9 million secondary to ingestion

• 93% occurred in the home93% occurred in the home• Majority of calls to poison control centers Majority of calls to poison control centers

involve children < 6 years of ageinvolve children < 6 years of age• 27 fatalities in children < 6 years of age27 fatalities in children < 6 years of age

• 20 unintentional20 unintentional• 7 intentional7 intentional• 2.3% of all fatalities (n=1,183)2.3% of all fatalities (n=1,183)

EPIDEMIOLOGYEPIDEMIOLOGY (Watson et al, 2005)(Watson et al, 2005)

Children < 6 years of age, 2004:Children < 6 years of age, 2004:• Cosmetics and personal care productsCosmetics and personal care products• Cleaning substancesCleaning substances• AnalgesicsAnalgesics• TopicalsTopicals• Foreign bodiesForeign bodies• Cough and cold preparationCough and cold preparation• PlantsPlants• PesticidesPesticides• VitaminsVitamins• AntihistaminesAntihistamines• AntimicrobialsAntimicrobials• Gastrointestinal preparationsGastrointestinal preparations• Arts/crafts/office suppliesArts/crafts/office supplies• Electrolytes/mineralElectrolytes/mineral• Hormone related preparationsHormone related preparations

AMERICAN SOCIETY OF AMERICAN SOCIETY OF POISON CONTROL CENTERS – POISON CONTROL CENTERS –

20042004(Watson et al, 2005)(Watson et al, 2005)

Age:Age: < 6 years< 6 years 13-19 years13-19 years

Number of Number of DeathsDeaths

27 27 (23% of (23% of all all

pediatric pediatric deaths)deaths)

90 90 (77% of (77% of all pediatric all pediatric

deaths)deaths)

IntentionalIntentional 7 (26%)7 (26%) 70 (78%)70 (78%)

UnintentionUnintentionalal

20 (74%) 20 (74%) 20 (22%)20 (22%)

TOP 10 CAUSES OF DEATH IN TOP 10 CAUSES OF DEATH IN CHILDREN < 6 YEARS 1995-CHILDREN < 6 YEARS 1995-

1999 1999 (Abbruzzi and Stork, 2002)(Abbruzzi and Stork, 2002)

• Carbon monoxide inhalationCarbon monoxide inhalation• Hydrocarbon aspirationHydrocarbon aspiration• Opioid ingestionOpioid ingestion• Caustic (with and without hydrofluoric acid Caustic (with and without hydrofluoric acid

ingestion)ingestion)• Iron ingestionIron ingestion• Toxic alcohol ingestionToxic alcohol ingestion• Tricyclic antidepressant ingestionTricyclic antidepressant ingestion• Calcium channel blocker or beta-agonist Calcium channel blocker or beta-agonist

sustained release ingestionsustained release ingestion• Adrenergic ingestionAdrenergic ingestion• Salicylate ingestionSalicylate ingestion

NINE COMMON AGENTS THAT NINE COMMON AGENTS THAT KILL AT LOW DOSESKILL AT LOW DOSES

(Michael, 2004)(Michael, 2004)

• Calcium channel blockersCalcium channel blockers: bradycardia : bradycardia and hypotension; 1 - 10 mg tablet of and hypotension; 1 - 10 mg tablet of nifedipinenifedipine

• CamphorCamphor: respiratory depression and : respiratory depression and seizures; 15 mL of Vicks vapo-rub (700 seizures; 15 mL of Vicks vapo-rub (700 mg of camphor)mg of camphor)

• ClonidineClonidine: severe bradycardia; 0.1 mg : severe bradycardia; 0.1 mg • Tricyclic antidepressantsTricyclic antidepressants: cardiovascular : cardiovascular

and CNS toxicity; 10-20mg/kgand CNS toxicity; 10-20mg/kg• OpioidsOpioids: CNS and respiratory : CNS and respiratory

depression; 2.5 mg of hydrocodonedepression; 2.5 mg of hydrocodone

NINE COMMON AGENTS THAT NINE COMMON AGENTS THAT KILL AT LOW DOSESKILL AT LOW DOSES

(Michael, 2004)(Michael, 2004)

• LomotilLomotil: anticholinergic overdose : anticholinergic overdose (tachycardia, seizures, coma); ½ tablet(tachycardia, seizures, coma); ½ tablet

• Salicylates:Salicylates: cerebral edema, coma; ½ cerebral edema, coma; ½ teaspoon of wintergreen fatalteaspoon of wintergreen fatal

• SulfonylureasSulfonylureas: severe hypoglycemia; 1 : severe hypoglycemia; 1 tablettablet

• Toxic alcoholsToxic alcohols: cardiac and CNS : cardiac and CNS depression; 2.9mL of 95% ethylene depression; 2.9mL of 95% ethylene glycol has been fatalglycol has been fatal

RESUSCITATION AND RESUSCITATION AND DETOXIFICATIONDETOXIFICATION

RESUSCITATION/RESUSCITATION/STABILIZATION STABILIZATION

(Osterhoudt, 2006)(Osterhoudt, 2006)• AAirwayirway

• NOT PATENT?NOT PATENT? jaw lift, jaw thrust, oropharyngeal jaw lift, jaw thrust, oropharyngeal

airway, nasaopharyngeal airway, airway, nasaopharyngeal airway, endotracheal tubeendotracheal tube

• BBreathingreathing• NONE DETECTABLE?NONE DETECTABLE?

mouth/resuscitator to mask or tracheal mouth/resuscitator to mask or tracheal tube, rescue breathingtube, rescue breathing

• CCirculationirculation• NONE DETECTABLE?NONE DETECTABLE? external compression/ventilation, volume external compression/ventilation, volume

therapy, blood studies, secure therapy, blood studies, secure intravenousintravenous line and assess perfusion line and assess perfusion

RESUSCITATION/RESUSCITATION/STABILIZATION STABILIZATION

(Osterhoudt, 2006)(Osterhoudt, 2006)

• DDisability: level of consciousness isability: level of consciousness (AVPU or GCS), pupillary size, (AVPU or GCS), pupillary size, reactivityreactivity

• DDrugsrugs• OxygenOxygen• Dextrose 0.25-1 g/kg (10 or 25% solution)Dextrose 0.25-1 g/kg (10 or 25% solution)• Naloxone (IV, IM, SC): birth-20 kg: 0.1 Naloxone (IV, IM, SC): birth-20 kg: 0.1

mg/kg/dose; > 20 kg: 2 mg/kg/dose; ETT mg/kg/dose; > 20 kg: 2 mg/kg/dose; ETT dose is 2-10 times IV dose diluted in 3-5 dose is 2-10 times IV dose diluted in 3-5 mL saline followed by positive pressuremL saline followed by positive pressure

DDECONTAMINATIONECONTAMINATION (Osterhoudt, 2006)(Osterhoudt, 2006)

• Ocular Ocular saline lavage saline lavage• Skin Skin water, then soap and water, then soap and

waterwater• GastrointestinalGastrointestinal

• NotNot recommendedrecommended::• IpecacIpecac – may delay administration of – may delay administration of

charcoal, complications (aspiration, charcoal, complications (aspiration, diaphragmatic rupture)diaphragmatic rupture)

• Gastric lavageGastric lavage – size of tube often – size of tube often smaller than pillssmaller than pills

• CatharticsCathartics – electrolyte problems, no – electrolyte problems, no benefit in RCTbenefit in RCT

ACTIVATED CHARCOALACTIVATED CHARCOAL(Lapus, 2007)(Lapus, 2007)

• 1500 BC: use of charcoal in 1500 BC: use of charcoal in medicine in Egypt; used to absorb medicine in Egypt; used to absorb odor from rotting woundsodor from rotting wounds

• 450 BC: charcoal filters used to 450 BC: charcoal filters used to purify drinking waterpurify drinking water

• 1773: absorptive powers of 1773: absorptive powers of charcoal demonstratedcharcoal demonstrated

• 1963: Holt published study 1963: Holt published study showing benefit in specific showing benefit in specific ingestionsingestions

ACTIVATED CHARCOALACTIVATED CHARCOAL

• Used in water filters, medicines that selectively remove toxins, and chemical purification processes

• How does it work? • Carbon treated with oxygen resulting in

porous charcoal• Surface area of 300-2000 m2/g allows

liquids or gases to pass through and bind with the carbon

• Interaction with carbon required for absorption

• Large organic molecules absorbed better than smaller

ACTIVATED CHARCOAL ACTIVATED CHARCOAL NOTNOT RECOMMENDED RECOMMENDED

(Lapus, 2007)(Lapus, 2007)

• PP – Pesticides, petroleum – Pesticides, petroleum distillates, distillates, unprotected airway unprotected airway

• HH – Hydrocarbons, heavy metals, – Hydrocarbons, heavy metals, > 1h delay in administration > 1h delay in administration

• AA – Acids, alkali, alcohol, altered – Acids, alkali, alcohol, altered level level of consciousness, of consciousness, aspiration riskaspiration risk

• II – Iron, ileus, intestinal obstruction – Iron, ileus, intestinal obstruction• LL – Lithium, lack of gag reflex – Lithium, lack of gag reflex• SS – Solvents, seizures – Solvents, seizures

BEZOAR CAUSING SMALL BOWEL OBSTRUCTION AFTER REPEATED

ACTIVATED CHARCOAL ADMINISTRATION

ACTIVATED CHARCOALACTIVATED CHARCOAL (Osterhoudt, 2006)(Osterhoudt, 2006)

• Single dose activated charcoalSingle dose activated charcoal• 0.5-1 gm/kg, adolescents 50-100 grams 0.5-1 gm/kg, adolescents 50-100 grams

PO; maximum dose 100 grams PO; maximum dose 100 grams • More benefit if administered within 1 More benefit if administered within 1

hour of ingestion, but still good for hour of ingestion, but still good for poison which slows gastric motility poison which slows gastric motility (anticholinergic, opiates, salicylates) (anticholinergic, opiates, salicylates)

• Strongly consider for acetaminophen Strongly consider for acetaminophen overdose > 4 hours overdose > 4 hours

• Not recommended forNot recommended for: lithium, iron, : lithium, iron, alcohols, cyanide, acid/alkali, alcohols, cyanide, acid/alkali, hydrocarbonshydrocarbons

ACTIVATED CHARCOALACTIVATED CHARCOAL (Osterhoudt, 2006)(Osterhoudt, 2006)

• Multidose activated charcoalMultidose activated charcoal• 1 gram/kg q4-6 hours1 gram/kg q4-6 hours• After absorption, drugs will re-enter After absorption, drugs will re-enter

the gut by passive diffusion if the the gut by passive diffusion if the concentration there is lower than concentration there is lower than bloodblood

• MDAC maintains a concentration MDAC maintains a concentration gradient drawing the drug into the gut gradient drawing the drug into the gut for absorptionfor absorption

• Recommended forRecommended for:: theophylline, theophylline, phenobarbital, digoxin, salicylate, phenobarbital, digoxin, salicylate, tricyclic antidepressants, tricyclic antidepressants, carbamazepine, phenytoincarbamazepine, phenytoin

ACTIVATED CHARCOALACTIVATED CHARCOAL(Lapus, 2007)(Lapus, 2007)

• If vomiting, carefully consider NG If vomiting, carefully consider NG tube tube

• ContraindicationsContraindications• Unprotected airway and Unprotected airway and level of level of

consciousness IF not intubatedconsciousness IF not intubated• Increased risk of aspiration – eg Increased risk of aspiration – eg

hydrocarbons (especially low viscosity hydrocarbons (especially low viscosity kerosene, lighter fluid, lamp oil)kerosene, lighter fluid, lamp oil)

• Potential risk of seizures: clonidine, TCA’sPotential risk of seizures: clonidine, TCA’s• Complications: Complications:

• Most common: emesisMost common: emesis• Most serious: aspirationMost serious: aspiration

WHOLE BOWEL IRRIGATIONWHOLE BOWEL IRRIGATION(Erickson, 2005)(Erickson, 2005)

• Nonabsorbable, isotonic Nonabsorbable, isotonic polyethylene glycolpolyethylene glycol

• Toxins “pushed” through GI Toxins “pushed” through GI tract; prevents absorptiontract; prevents absorption

• Concentration gradient created Concentration gradient created - allowing absorbed toxin to - allowing absorbed toxin to diffuse back into GI tractdiffuse back into GI tract

• Use where toxins Use where toxins NOTNOT absorbed absorbed by charcoal by charcoal

WHOLE BOWEL IRRIGATIONWHOLE BOWEL IRRIGATION(Erickson, 2005)(Erickson, 2005)

• Recommended forRecommended for::• Iron tabletsIron tablets• Lead paint chipsLead paint chips• TheophyllineTheophylline• Crack vials/packetsCrack vials/packets• Button batteriesButton batteries• Sustained release calcium Sustained release calcium

channel blockers channel blockers

WHOLE BOWEL IRRIGATIONWHOLE BOWEL IRRIGATION(Am Acad Clin Tox, 2004)(Am Acad Clin Tox, 2004)

• Use nasogastric tube Use nasogastric tube • No dose-response studies upon which No dose-response studies upon which

to base dosing. However, to base dosing. However, recommended dosing schedule is: recommended dosing schedule is: • Children 9 months to 6 years: 500 mL/h Children 9 months to 6 years: 500 mL/h • Children 6-12 years: 1000 mL/h Children 6-12 years: 1000 mL/h • Adolescents and adults: 1500-2000 mL/h Adolescents and adults: 1500-2000 mL/h

• Continue until rectal effluent clearContinue until rectal effluent clear• Treatment extended based on Treatment extended based on

corroborative evidence of continued corroborative evidence of continued presence of toxins in gastrointestinal presence of toxins in gastrointestinal tract (e.g., radiographs or ongoing tract (e.g., radiographs or ongoing elimination of toxins) elimination of toxins)

WHOLE BOWEL IRRIGATION - WHOLE BOWEL IRRIGATION - CONTRAINDICATIONSCONTRAINDICATIONS

(Am Acad Clin Tox, 2004)(Am Acad Clin Tox, 2004)

• Bowel Bowel perforationperforation • Bowel Bowel obstruction obstruction • Clinically significant Clinically significant

gastrointestinal hemorrhage gastrointestinal hemorrhage • Ileus Ileus • Unprotected or compromised Unprotected or compromised

airway airway • Hemodynamic instability Hemodynamic instability • Uncontrollable intractable vomiting Uncontrollable intractable vomiting

WHOLE BOWEL IRRIGATION - WHOLE BOWEL IRRIGATION - COMPLICATIONSCOMPLICATIONS(Am Acad Clin Tox, 2004)(Am Acad Clin Tox, 2004)

• Nausea, vomiting, abdominal cramps, Nausea, vomiting, abdominal cramps, and bloating when WBI used to prepare and bloating when WBI used to prepare for colonoscopy and barium enema for colonoscopy and barium enema

• Insufficient clinical data for incidence of Insufficient clinical data for incidence of complications associated with use of complications associated with use of WBI WBI

• Nausea and vomiting may complicate Nausea and vomiting may complicate use of WBI use of WBI vomiting if patient treated with ipecac or vomiting if patient treated with ipecac or

ingested agent that produces vomiting ingested agent that produces vomiting • If compromised and unprotected airway, If compromised and unprotected airway,

high risk for pulmonary aspiration high risk for pulmonary aspiration

ENHANCED EXCRETIONENHANCED EXCRETION

• Urinary alkalinization Urinary alkalinization • Salicylate, phenobarbitalSalicylate, phenobarbital

• HemodialysisHemodialysis• Lithium, ethylene glycol, Lithium, ethylene glycol,

methanol, salicylatemethanol, salicylate• Charcoal hemoperfusion Charcoal hemoperfusion

• Theophylline, phenobarbital, Theophylline, phenobarbital, carbamazepine, procainamidecarbamazepine, procainamide

• PlasmapheresisPlasmapheresis• PhenytoinPhenytoin

ANTIDOTESANTIDOTESTOXIDROMESTOXIDROMESLABORATORYLABORATORY

ANTIDOTES IANTIDOTES I• AcetaminophenAcetaminophen nn-Acetylcysteine (NAC)-Acetylcysteine (NAC)• AnticholinergicAnticholinergic PhysostigminePhysostigmine• AnticholinesteraseAnticholinesterase AtropineAtropine• OrganophosphatesOrganophosphatesAtropine/pralidoximeAtropine/pralidoxime• CarbamateCarbamate Atropine/pralidoximeAtropine/pralidoxime• BenzodiazepineBenzodiazepine FlumazenilFlumazenil• Beta adrenergic blockerBeta adrenergic blocker GlucagonGlucagon• Calcium channel blockerCalcium channel blocker Calcium chloride/calcium Calcium chloride/calcium

gluconategluconate• BotulismBotulism Botulin antitoxin trivalent Botulin antitoxin trivalent

(A,B,E)(A,B,E)• Carbon monoxideCarbon monoxide OxygenOxygen• CyanideCyanide Amyl nitrateAmyl nitrate• DigitalisDigitalis Fab. antibodiesFab. antibodies• Ethylene glycolEthylene glycol Fomepizole (4-Methylpyrazole)Fomepizole (4-Methylpyrazole)• FluorideFluoride Calcium gluconateCalcium gluconate• Heavy MetalsHeavy Metals BALBAL• ArsenicArsenic BALBAL• MercuryMercury BAL, DMSABAL, DMSA

ANTIDOTES IIANTIDOTES II• IronIron DeferoxamineDeferoxamine• IsoniazidIsoniazid PyridoxinePyridoxine• LeadLead BAL, EDTA, penicillamine. DMSABAL, EDTA, penicillamine. DMSA• MethanolMethanol Fomepizole (4-Fomepizole (4-

Methylpyrazole)Methylpyrazole)• MethemoglobinMethemoglobin Methylene blueMethylene blue• Neuroleptic syndromeNeuroleptic syndrome DantroleneDantrolene• OpioidsOpioids NaloxoneNaloxone• Phenothiazine (dystonic)Phenothiazine (dystonic) DiphenhydramineDiphenhydramine• SulfonylureaSulfonylurea OctreotideOctreotide• Tricyclic antidepressantsTricyclic antidepressants Sodium bicarbonateSodium bicarbonate• Warfarin Warfarin Vitamin KVitamin K• Snakes, spidersSnakes, spiders::• Black widowBlack widow Antivenin, Black widow spiderAntivenin, Black widow spider• CoralCoral Antivenin, coralAntivenin, coral• CrotalineCrotaline Antivenin, crotalineAntivenin, crotaline• ElapidElapid Antivenin, elapidAntivenin, elapid

DIAGNOSISDIAGNOSIS

• HistoryHistory• Substance, how much, where, whenSubstance, how much, where, when• Regular/sustained releaseRegular/sustained release• Past illnesses/hospitalizationsPast illnesses/hospitalizations• AllergiesAllergies

• Physical examinationPhysical examination• Vital signsVital signs• Neurologic examNeurologic exam

SEDATIVE/ HYPNOTIC

ExamplesExamples Benzodiazepines, Benzodiazepines, barbiturates barbiturates

Mental Mental StatusStatus

Sedations, delirium, ataxiaSedations, delirium, ataxia

PupilsPupils Blurred vision (miosis or Blurred vision (miosis or mydriasis)mydriasis)

Vital SignsVital Signs Bradycardia, hypotension, Bradycardia, hypotension, hypothermiahypothermia

Physical Physical ExamExam

Decreased bowel sounds, Decreased bowel sounds, nystagmusnystagmus

TreatmentTreatment Decontamination, Decontamination, Supportive, Flumazenil Supportive, Flumazenil

(rarely)(rarely)

SYMPATHOMIMETIC

ExamplesExamples Cocaine, amphetaminesCocaine, amphetamines

Mental Mental StatusStatus

Restless, insomnia, Restless, insomnia, hallucinationshallucinations

PupilsPupils MydriasisMydriasis

Vital SignsVital Signs Tachycardia, hypertension, Tachycardia, hypertension, hyperthermiahyperthermia

Physical Physical ExamExam

Tremor, warm skin, Tremor, warm skin, diaphoresisdiaphoresis

TreatmentTreatment Benzodiazepines, Mixed Benzodiazepines, Mixed alpha/beta blockade, Treat alpha/beta blockade, Treat

MI, CVAMI, CVA

OPIATES

ExamplesExamples Heroin, morphine, Heroin, morphine, clonidineclonidine

Mental statusMental status Sedation, confusion, Sedation, confusion, euphoria, comaeuphoria, coma

PupilsPupils MiosisMiosis

Vital signsVital signs Shallow respirations, Shallow respirations, hypotension, hypotension,

bradycardia, hypothermiabradycardia, hypothermia

Phys examPhys exam Decreased bowel sounds, Decreased bowel sounds, hyporeflexiahyporeflexia

TreatmentTreatment Decontaminate, narcanDecontaminate, narcan

CHOLINERGIC

ExamplesExamples Organophosphates, Organophosphates, muscarinic mushrooms, muscarinic mushrooms,

nerve gasesnerve gases

Mental Mental StatusStatus

Altered mental status, Altered mental status, confusion, weakness, confusion, weakness,

drowsiness, comadrowsiness, coma

PupilsPupils MiosisMiosis

Vital SignsVital Signs Bradycardia, hypothermia, Bradycardia, hypothermia, tachypneatachypnea

Physical Physical ExamExam

Salivation, lacrimation, Salivation, lacrimation, urination, defecation urination, defecation

(SLUDGE)(SLUDGE)

TreatmentTreatment Decontaminate, atropine, Decontaminate, atropine, pralidoximepralidoxime

ANTICHOLINERGIC

ExamplesExamples Atropine, TCA, antihistamineAtropine, TCA, antihistamine

Mental Mental StatusStatus

Psychosis, delirium, Psychosis, delirium, seizures, comaseizures, coma

PupilsPupils MydriasisMydriasis

Vital SignsVital Signs Tachycardia, fever, Tachycardia, fever, hypertensionhypertension

Physical Physical ExamExam

Dry as a bone, blind as a Dry as a bone, blind as a bat, etc. depressed, bat, etc. depressed,

confusedconfused

TreatmentTreatment Decontaminate, treat Decontaminate, treat seizures, fever, seizures, fever, hypertension, hypertension,

benzodiazepinesbenzodiazepines

LABORATORYLABORATORY• Electrolytes, BUN, creatinineElectrolytes, BUN, creatinine

• Anion Gap = (Na+K)-(CL+HCOAnion Gap = (Na+K)-(CL+HCO33))• 8-14 is normal8-14 is normal• Elevated seen in “MUDPILES” Elevated seen in “MUDPILES”

• MMethanol, ethanol, uuremia, remia, DDKA, KA, pparaldehyde,araldehyde, iiron/ron/iisoniazid, soniazid, llactic acidosis (cyanide), actic acidosis (cyanide), eethanol/thanol/eethylene glycol, thylene glycol, ssalicylatealicylate

• [[(Calculated osmolality) – (Serum (Calculated osmolality) – (Serum osmolality)osmolality)]] = -9 to +5 (normal range) = -9 to +5 (normal range)

• Calculated osmolality=2Na + glucose/18 + Calculated osmolality=2Na + glucose/18 + BUN/2.8+ ethanol/4.6BUN/2.8+ ethanol/4.6

• Elevated with ethanol, isopropanol, methanol, Elevated with ethanol, isopropanol, methanol, ethylene glycol intoxicationethylene glycol intoxication

LABORATORYLABORATORY• ECGECG• Arterial blood gasArterial blood gas• Pregnancy testPregnancy test• ToxicologyToxicology

• QuantitativeQuantitative: acetaminophen, : acetaminophen, carbamazepine, carboxyhemoglobin, carbamazepine, carboxyhemoglobin, digoxin, ethanol, ethylene glycol, iron, digoxin, ethanol, ethylene glycol, iron, lead, lithium, methanol, lead, lithium, methanol, methemoglobin, phenobarbital, methemoglobin, phenobarbital, phenytoin, salicylate, theophylline, phenytoin, salicylate, theophylline, valproic acidvalproic acid

LABORATORYLABORATORY

• Common urine substance Common urine substance abuse screensabuse screens

• AmphetamineAmphetamine• BarbituratesBarbiturates• BenzodiazepineBenzodiazepine• CannabinoidsCannabinoids• CocaineCocaine• OpioidsOpioids• PhencyclidinePhencyclidine

ACETAMINOPHEN (APAP) ACETAMINOPHEN (APAP) TOXICITYTOXICITY

(Amer Assoc Poison Cntl Center, 2001)(Amer Assoc Poison Cntl Center, 2001)

• Total reported exposures: 57,516 Total reported exposures: 57,516 • Reported exposures, < 19 years: 40,774 Reported exposures, < 19 years: 40,774 • Unintentional overdoses: 35,705 Unintentional overdoses: 35,705 • Intentional overdoses: 20,002 Intentional overdoses: 20,002 • Total treated for the exposure: 24,934 Total treated for the exposure: 24,934 • Impact on health from the incident: Impact on health from the incident:

none, 15,029; minor, 6,223; moderate, none, 15,029; minor, 6,223; moderate, 3,138; major, 829; fatal: 1203,138; major, 829; fatal: 120

ACETAMINOPHEN OVERDOSE IN THE ACETAMINOPHEN OVERDOSE IN THE CALGARY HEALTH REGION BY AGE AND CALGARY HEALTH REGION BY AGE AND

SUICIDAL INTENT (1997–2002)SUICIDAL INTENT (1997–2002)

ACETAMINOPHEN (APAP) ACETAMINOPHEN (APAP) TOXICITYTOXICITY

Most common drug overdose at any ageMost common drug overdose at any age Target organ: liverTarget organ: liver Principle metabolism (>90%) by sulfation Principle metabolism (>90%) by sulfation

and glucoronidation - with renal excretionand glucoronidation - with renal excretion 5% metabolized by cytochrome P-450 to 5% metabolized by cytochrome P-450 to

toxic n-acteyl-p-benzoquinoneimine toxic n-acteyl-p-benzoquinoneimine (NAPQI) (NAPQI)

Toxicity produced by saturation of Toxicity produced by saturation of metabolic pathway with excess toxic metabolic pathway with excess toxic metabolite (NAPQI)metabolite (NAPQI)

Normally glutathione detoxifies the Normally glutathione detoxifies the metabolite; with overdose, glutathione is metabolite; with overdose, glutathione is depleted causing severe hepatic injury depleted causing severe hepatic injury (centrilobular necrosis)(centrilobular necrosis)

APAP TOXICITY - CLINICAL APAP TOXICITY - CLINICAL FINDINGSFINDINGS

Stage IStage I “Gastrointestinal” (24 “Gastrointestinal” (24 hours): anorexia, nausea, vomiting, hours): anorexia, nausea, vomiting, lethargy, diaphoresis, anion gap lethargy, diaphoresis, anion gap metabolic acidosismetabolic acidosis

Stage IIStage II “Latent” (24-48 hours): “Latent” (24-48 hours): patient may feel better, subclinical patient may feel better, subclinical increase in hepatic enzymesincrease in hepatic enzymes

Stage IIIStage III (>48 hours): progressive (>48 hours): progressive hepatic encephalopathy, clinical hepatic encephalopathy, clinical hepatitis, overt comahepatitis, overt coma

Stage IVStage IV (4-14 days): recovery(4-14 days): recovery

ACETAMINOPHEN (APAP) ACETAMINOPHEN (APAP) TOXICITY/LABORATORY TOXICITY/LABORATORY

EVALUATIONEVALUATION Toxic dose: usually > 150 mg/kg or > Toxic dose: usually > 150 mg/kg or >

7.5 grams7.5 grams Try to obtain at 4 hours post ingestionTry to obtain at 4 hours post ingestion Plot on nomogram – predictor of liver Plot on nomogram – predictor of liver

toxicitytoxicity NomogramNomogram

Not accurate for chronic ingestionNot accurate for chronic ingestion Not accurate for multiple doses/overdosesNot accurate for multiple doses/overdoses If level is > potential toxic line, additional If level is > potential toxic line, additional

workup neededworkup needed

DIFFERENTIAL DIFFERENTIAL DIAGNOSISDIAGNOSIS

• Amanita mushroomsAmanita mushrooms• HydrocarbonHydrocarbon• Heavy metalsHeavy metals• IsoniazidIsoniazid• Non steroidal anti-inflammatoryNon steroidal anti-inflammatory• Erythromycin estolateErythromycin estolate• Vitamin AVitamin A• SteroidsSteroids

APAP TOXICITY APAP TOXICITY MANAGEMENTMANAGEMENT

DecontaminationDecontamination• Activated charcoal: may give up to 4 hours Activated charcoal: may give up to 4 hours

post ingestion; however need 2 hour post ingestion; however need 2 hour separation between charcoal and antidoteseparation between charcoal and antidote

Antidote: NAC (Antidote: NAC (n-acetylcysteinen-acetylcysteine))• Sulfhydryl donor to increase glutathione Sulfhydryl donor to increase glutathione

synthesis or bind with NAPQIsynthesis or bind with NAPQI• Indications: Indications: any level above nomogram any level above nomogram

lineline• Optimal use: within 8 hours of ingestion - Optimal use: within 8 hours of ingestion -

but still may be useful > 24 hrs but still may be useful > 24 hrs • Oral dose: 140 mg/kg, then 70 mg/kg q4h x Oral dose: 140 mg/kg, then 70 mg/kg q4h x

17 doses (17 doses (may dilute with cola or juice)may dilute with cola or juice)

CONSIDERATIONS FOR IV CONSIDERATIONS FOR IV NAC NAC

(Marzulo, 2005)(Marzulo, 2005)• 20 hours of 300 mg/kg (cumulative) for 10 20 hours of 300 mg/kg (cumulative) for 10

hourshours• Antihistamine therapy helpful in patients who Antihistamine therapy helpful in patients who

experience “anaphylactoid reactions” (rash, experience “anaphylactoid reactions” (rash, urticaria, pruritis) to IV NACurticaria, pruritis) to IV NAC

• Recent reports of deaths secondary to IV NAC; Recent reports of deaths secondary to IV NAC; no overwhelming support to automatically no overwhelming support to automatically choose IV over PO NAC – decide on case by choose IV over PO NAC – decide on case by case basiscase basis

• Standard IV dosing caused hyponatremia and Standard IV dosing caused hyponatremia and secondary seizures because of excess free secondary seizures because of excess free water; adjustment for pediatric patients has water; adjustment for pediatric patients has been madebeen made• Dilute 20% NAC to final concentration of 40 mg/ml Dilute 20% NAC to final concentration of 40 mg/ml

(see chart)(see chart)

UDATE ON APAP UDATE ON APAP POISONING POISONING (White, PedEmergCare, 2006)(White, PedEmergCare, 2006)

• Recent FDA revisions (2006) extended the Recent FDA revisions (2006) extended the loading dose infusion time from 15 to 60 loading dose infusion time from 15 to 60 minutes – making it a 21 hour infusionminutes – making it a 21 hour infusion

• PediatricPediatric: see revised dosing; : see revised dosing; anaphylactoid reactions usually occur anaphylactoid reactions usually occur during loading doseduring loading dose

• AdultAdult: : • 150mg/kg in 200 mL of 5% dextrose for 150mg/kg in 200 mL of 5% dextrose for

60 minutes, followed by 60 minutes, followed by • 50 mg/kg in 500 mL of 5% dextrose for 4 50 mg/kg in 500 mL of 5% dextrose for 4

hours and hours and • 100 mg/kg in 1000 mL 5% dextrose for 100 mg/kg in 1000 mL 5% dextrose for

16 hours16 hours

RECENT LITERATURERECENT LITERATURE

• James et al. Predictors of outcome after James et al. Predictors of outcome after acetaminophen poisoning in children acetaminophen poisoning in children and adolescents (2002)and adolescents (2002)• Retrospective analysis of 10 years of Retrospective analysis of 10 years of

admissions for acute acetaminophen admissions for acute acetaminophen toxicitytoxicity

• Best predictor of low risk of hepatotoxicity Best predictor of low risk of hepatotoxicity was normal values for PT, AST or ALT within was normal values for PT, AST or ALT within 48 hours of ingestion48 hours of ingestion

• Authors concluded inpatient stay of 48 Authors concluded inpatient stay of 48 hours justified post ingestion of hours justified post ingestion of acetaminophenacetaminophen

RECENT LITERATURERECENT LITERATURE• Kanter MK. Comparison of oral and IV Kanter MK. Comparison of oral and IV

acetylcysteine in the treatment of acetylcysteine in the treatment of acetaminophen poisoning (2006)acetaminophen poisoning (2006)• Consider efficacy, safety, cost; both equally Consider efficacy, safety, cost; both equally

effectiveeffective• IV prep problems: anaphylactoid reactions in IV prep problems: anaphylactoid reactions in

3-6% of patients, dosing errors, hypoNa, very 3-6% of patients, dosing errors, hypoNa, very expensiveexpensive

• Oral prep: strongly consider in those with Oral prep: strongly consider in those with history of asthma or atopyhistory of asthma or atopy

• Most important: severity of toxicity, time Most important: severity of toxicity, time interval between ingestion and treatmentinterval between ingestion and treatment

• If ingestion > 10 hours or underlying If ingestion > 10 hours or underlying reasons preventing oral use, use IV prepreasons preventing oral use, use IV prep

RECENT LITERATURERECENT LITERATURE

• Yarema et al. Comparison of the 20 hr IV Yarema et al. Comparison of the 20 hr IV and 72 hr PO protocols for treatment of and 72 hr PO protocols for treatment of acute acetaminophen toxicityacute acetaminophen toxicity• Of 4 ,048 patients analyzed, 2,086 in the 20 Of 4 ,048 patients analyzed, 2,086 in the 20

hour and 1,962 in the 72 hour groupshour and 1,962 in the 72 hour groups• No risk difference when between groups No risk difference when between groups

when treatment was started 12-18 hours when treatment was started 12-18 hours after ingestionafter ingestion

• Anaphylactoid reactions: IV 148/2,086 (7.1%); Anaphylactoid reactions: IV 148/2,086 (7.1%); • Risk of hepatotoxicity favored 20 hr protocol Risk of hepatotoxicity favored 20 hr protocol

for those presenting early and the 72 hour for those presenting early and the 72 hour protocol for those presenting lateprotocol for those presenting late

COMPETENCY ISSUESCOMPETENCY ISSUES• Medical Knowledge: treatment of poisoningMedical Knowledge: treatment of poisoning• Patient Care: careful history taking is criticalPatient Care: careful history taking is critical• System Based Practice: rapid lab turnaround System Based Practice: rapid lab turnaround

and recognition of potential for liver and recognition of potential for liver transplanttransplant

• Practice Based Learning and Improvement: Practice Based Learning and Improvement: use literature to guide treatment optionsuse literature to guide treatment options

• Interpersonal and Communication skills: Interpersonal and Communication skills: explain illness and risk to familyexplain illness and risk to family

• Professionalism: caution regarding sensitivity Professionalism: caution regarding sensitivity toward patient and family with any ingestiontoward patient and family with any ingestion

SUMMARYSUMMARY• ABC’s for unstable patient with unknown ABC’s for unstable patient with unknown

ingestioningestion• DecontaminationDecontamination• Activated charcoal, WBI when indicatedActivated charcoal, WBI when indicated

• Focused history, physical exam, can Focused history, physical exam, can someone bring in a sample?someone bring in a sample?

• ToxidromesToxidromes• AntidotesAntidotes• Follow acetaminophen levels as guideline Follow acetaminophen levels as guideline

for toxicityfor toxicity• Strongly consider PO NAC for children – Strongly consider PO NAC for children –

especially is history of asthma/atopy; if especially is history of asthma/atopy; if vomiting need to consider IV prepvomiting need to consider IV prep

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