Transcript David H. Rubin, MD St. Barnabas Hospital and Weill Medical

Chairman’s Rounds
October 16, 2009;
15 year old with an
unintentional overdose
David H. Rubin, MD, FAAP
Chairman and Program Director
Department of Pediatrics
St. Barnabas Hospital
Professor of Clinical Pediatrics
Albert Einstein College of Medicine
OBJECTIVES
• Epidemiology
• Resuscitation
• Detoxification
• Antidotes/Toxidromes
• Case report: 15 year old
with an unintentional
overdose
EPIDEMIOLOGY
(Lapus, 2007)
• 2004 data from American Association of
Poison Control Centers
• 2.4 million exposures
• 1.9 million secondary to ingestion
• 93% occurred in the home
• Majority of calls to poison control centers
involve children < 6 years of age
• 27 fatalities in children < 6 years of age
• 20 unintentional
7 intentional
• 2.3% of all fatalities (n=1,183)
•
EPIDEMIOLOGY
(Watson et al, 2005)
Children < 6 years of age, 2004:
• Cosmetics and personal care products
• Cleaning substances
• Analgesics
• Topicals
• Foreign bodies
• Cough and cold preparation
• Plants
• Pesticides
• Vitamins
• Antihistamines
• Antimicrobials
• Gastrointestinal preparations
• Arts/crafts/office supplies
• Electrolytes/mineral
• Hormone related preparations
AMERICAN SOCIETY OF POISON
CONTROL CENTERS – 2004
(Watson et al, 2005)
Age:
Number of
Deaths
Intentional
Unintentional
< 6 years
13-19 years
27 (23% of
90 (77% of
all pediatric
deaths)
all pediatric
deaths)
7 (26%)
70 (78%)
20 (74%)
20 (22%)
TOP 10 CAUSES OF DEATH IN
CHILDREN < 6 YEARS 1995-1999
(Abbruzzi and Stork, 2002)
•
•
•
•
•
•
•
•
•
•
Carbon monoxide inhalation
Hydrocarbon aspiration
Opioid ingestion
Caustic (with and without hydrofluoric acid
ingestion)
Iron ingestion
Toxic alcohol ingestion
Tricyclic antidepressant ingestion
Calcium channel blocker or beta-agonist sustained
release ingestion
Adrenergic ingestion
Salicylate ingestion
NINE COMMON AGENTS THAT
KILL AT LOW DOSES
(Michael, 2004)
• Calcium channel blockers: bradycardia and
hypotension; 1 - 10 mg tablet of nifedipine
• Camphor: respiratory depression and
seizures; 15 mL of Vicks vapo-rub (700 mg
of camphor)
• Clonidine: severe bradycardia; 0.1 mg
• Tricyclic antidepressants: cardiovascular
and CNS toxicity; 10-20mg/kg
• Opioids: CNS and respiratory depression;
2.5 mg of hydrocodone
NINE COMMON AGENTS THAT
KILL AT LOW DOSES
(Michael, 2004)
• Lomotil: anticholinergic overdose
(tachycardia, seizures, coma); ½ tablet
• Salicylates: cerebral edema, coma; ½
teaspoon of wintergreen fatal
• Sulfonylureas: severe hypoglycemia; 1
tablet
• Toxic alcohols: cardiac and CNS
depression; 2.9mL of 95% ethylene glycol
has been fatal
RESUSCITATION AND
DETOXIFICATION
RESUSCITATION/STABILIZATION
(Osterhoudt, 2006)
• Airway
• NOT PATENT?
 jaw lift, jaw thrust, oropharyngeal airway,
nasaopharyngeal airway, endotracheal tube
• Breathing
• NONE DETECTABLE?
 mouth/resuscitator to mask or tracheal
tube, rescue breathing
• Circulation
• NONE DETECTABLE?
 external compression/ventilation, volume
therapy, blood studies, secure
intravenous
line and assess perfusion
RESUSCITATION/STABILIZATION
(Osterhoudt, 2006)
• Disability: level of consciousness
(AVPU or GCS), pupillary size,
reactivity
• Drugs
• Oxygen
• Dextrose 0.25-1 g/kg (10 or 25% solution)
• Naloxone (IV, IM, SC): birth-20 kg: 0.1
mg/kg/dose; > 20 kg: 2 mg/kg/dose; ETT
dose is 2-10 times IV dose diluted in 3-5 mL
saline followed by positive pressure
DECONTAMINATION
(Osterhoudt, 2006)
• Ocular  saline lavage
• Skin  water, then soap and water
• Gastrointestinal
• Not recommended:
• Ipecac – may delay administration of
charcoal, complications (aspiration,
diaphragmatic rupture)
• Gastric lavage – size of tube often smaller
than pills
• Cathartics – electrolyte problems, no benefit
in RCT
ACTIVATED CHARCOAL
(Lapus, 2007)
• 1500 BC: use of charcoal in
medicine in Egypt; used to absorb
odor from rotting wounds
• 450 BC: charcoal filters used to
purify drinking water
• 1773: absorptive powers of charcoal
demonstrated
• 1963: Holt published study showing
benefit in specific ingestions
ACTIVATED 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 NOT
RECOMMENDED
(Lapus, 2007)
• P – Pesticides, petroleum distillates,
•
•
•
•
•
unprotected airway
H – Hydrocarbons, heavy metals,
> 1h delay in administration
A – Acids, alkali, alcohol, altered level
of consciousness, aspiration risk
I – Iron, ileus, intestinal obstruction
L – Lithium, lack of gag reflex
S – Solvents, seizures
BEZOAR CAUSING SMALL BOWEL
OBSTRUCTION AFTER REPEATED
ACTIVATED CHARCOAL ADMINISTRATION
ACTIVATED CHARCOAL
(Osterhoudt, 2006)
• Single dose activated charcoal
• 0.5-1 gm/kg, adolescents 50-100 grams PO;
maximum dose 100 grams
• More benefit if administered within 1 hour of
ingestion, but still good for poison which slows
gastric motility (anticholinergic, opiates,
salicylates)
• Strongly consider for acetaminophen overdose
> 4 hours
• Not recommended for: lithium, iron, alcohols,
cyanide, acid/alkali, hydrocarbons
ACTIVATED CHARCOAL
(Osterhoudt, 2006)
• Multidose activated charcoal
• 1 gram/kg q4-6 hours
• After absorption, drugs will re-enter the
gut by passive diffusion if the
concentration there is lower than blood
• MDAC maintains a concentration gradient
drawing the drug into the gut for
absorption
• Recommended for: theophylline,
phenobarbital, digoxin, salicylate,
tricyclic antidepressants, carbamazepine,
phenytoin
ACTIVATED CHARCOAL
(Lapus, 2007)
• If vomiting, carefully consider NG tube
• Contraindications
• Unprotected airway and  level of
consciousness IF not intubated
• Increased risk of aspiration – eg
hydrocarbons (especially low viscosity
kerosene, lighter fluid, lamp oil)
• Potential risk of seizures: clonidine, TCA’s
• Complications:
• Most common: emesis
• Most serious: aspiration
WHOLE BOWEL IRRIGATION
(Erickson, 2005)
• Nonabsorbable, isotonic
polyethylene glycol
• Toxins “pushed” through GI tract;
prevents absorption
• Concentration gradient created allowing absorbed toxin to diffuse
back into GI tract
• Use where toxins NOT absorbed by
charcoal
WHOLE BOWEL IRRIGATION
(Erickson, 2005)
• Recommended for:
• Iron tablets
• Lead paint chips
• Theophylline
• Crack vials/packets
• Button batteries
• Sustained release calcium channel
blockers
WHOLE BOWEL IRRIGATION
(Am Acad Clin Tox, 2004)
• Use nasogastric tube
• No dose-response studies upon which to
base dosing. However, recommended
dosing schedule is:
• Children 9 months to 6 years: 500 mL/h
• Children 6-12 years: 1000 mL/h
• Adolescents and adults: 1500-2000 mL/h
• Continue until rectal effluent clear
• Treatment extended based on corroborative
evidence of continued presence of toxins in
gastrointestinal tract (e.g., radiographs or
ongoing elimination of toxins)
WHOLE BOWEL IRRIGATION CONTRAINDICATIONS
(Am Acad Clin Tox, 2004)
• Bowel perforation
• Bowel obstruction
• Clinically significant gastrointestinal
•
•
•
•
hemorrhage
Ileus
Unprotected or compromised airway
Hemodynamic instability
Uncontrollable intractable vomiting
WHOLE BOWEL IRRIGATION COMPLICATIONS
(Am Acad Clin Tox, 2004)
• Nausea, vomiting, abdominal cramps, and
bloating when WBI used to prepare for
colonoscopy and barium enema
• Insufficient clinical data for incidence of
complications associated with use of WBI
• Nausea and vomiting may complicate use
of WBI
•  vomiting if patient treated with ipecac or
ingested agent that produces vomiting
• If compromised and unprotected airway,
high risk for pulmonary aspiration
ENHANCED EXCRETION
• Urinary alkalinization
• Salicylate, phenobarbital
• Hemodialysis
• Lithium, ethylene glycol, methanol,
salicylate
• Charcoal hemoperfusion
• Theophylline, phenobarbital,
carbamazepine, procainamide
• Plasmapheresis
• Phenytoin
ANTIDOTES
TOXIDROMES
LABORATORY
ANTIDOTES I
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Acetaminophen
Anticholinergic
Anticholinesterase
Organophosphates
Carbamate
Benzodiazepine
Beta adrenergic blocker
Calcium channel blocker
Botulism
Carbon monoxide
Cyanide
Digitalis
Ethylene glycol
Fluoride
Heavy Metals
Arsenic
Mercury
n-Acetylcysteine (NAC)
Physostigmine
Atropine
Atropine/pralidoxime
Atropine/pralidoxime
Flumazenil
Glucagon
Calcium chloride/calcium gluconate
Botulin antitoxin trivalent (A,B,E)
Oxygen
Amyl nitrate
Fab. antibodies
Fomepizole (4-Methylpyrazole)
Calcium gluconate
BAL
BAL
BAL, DMSA
ANTIDOTES II
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Iron
Isoniazid
Lead
Methanol
Methemoglobin
Neuroleptic syndrome
Opioids
Phenothiazine (dystonic)
Sulfonylurea
Tricyclic antidepressants
Warfarin
Snakes, spiders:
Black widow
Coral
Crotaline
Elapid
Deferoxamine
Pyridoxine
BAL, EDTA, penicillamine. DMSA
Fomepizole (4-Methylpyrazole)
Methylene blue
Dantrolene
Naloxone
Diphenhydramine
Octreotide
Sodium bicarbonate
Vitamin K
Antivenin, Black widow spider
Antivenin, coral
Antivenin, crotaline
Antivenin, elapid
DIAGNOSIS
• History
• Substance, how much, where, when
• Regular/sustained release
• Past illnesses/hospitalizations
• Allergies
• Physical examination
• Vital signs
• Neurologic exam
SEDATIVE/ HYPNOTIC
Examples
Mental Status
Pupils
Benzodiazepines, barbiturates
Sedations, delirium, ataxia
Blurred vision (miosis or
mydriasis)
Vital Signs
Bradycardia, hypotension,
hypothermia
Physical Exam
Decreased bowel sounds,
nystagmus
Treatment
Decontamination, Supportive,
Flumazenil (rarely)
SYMPATHOMIMETIC
Examples
Mental Status
Pupils
Vital Signs
Physical Exam
Treatment
Cocaine, amphetamines
Restless, insomnia,
hallucinations
Mydriasis
Tachycardia, hypertension,
hyperthermia
Tremor, warm skin,
diaphoresis
Benzodiazepines, Mixed
alpha/beta blockade, Treat MI,
CVA
OPIATES
Examples
Mental status
Pupils
Vital signs
Phys exam
Treatment
Heroin, morphine, clonidine
Sedation, confusion,
euphoria, coma
Miosis
Shallow respirations,
hypotension, bradycardia,
hypothermia
Decreased bowel sounds,
hyporeflexia
Decontaminate, narcan
CHOLINERGIC
Examples
Mental Status
Pupils
Vital Signs
Physical Exam
Treatment
Organophosphates, muscarinic
mushrooms, nerve gases
Altered mental status, confusion,
weakness, drowsiness, coma
Miosis
Bradycardia, hypothermia,
tachypnea
Salivation, lacrimation, urination,
defecation (SLUDGE)
Decontaminate, atropine,
pralidoxime
ANTICHOLINERGIC
Examples
Mental Status
Pupils
Vital Signs
Physical Exam
Treatment
Atropine, TCA, antihistamine
Psychosis, delirium, seizures,
coma
Mydriasis
Tachycardia, fever,
hypertension
Dry as a bone, blind as a bat,
etc. depressed, confused
Decontaminate, treat seizures,
fever, hypertension,
benzodiazepines
LABORATORY
• Electrolytes, BUN, creatinine
• Anion Gap = (Na+K)-(CL+HCO3)
• 8-14 is normal
• Elevated seen in “MUDPILES”
•
Methanol, uremia, DKA, paraldehyde, iron/isoniazid,
lactic acidosis (cyanide), ethanol/ethylene glycol,
salicylate
• [(Calculated osmolality) – (Serum osmolality)]
= -9 to +5 (normal range)
• Calculated osmolality=2Na + glucose/18 + BUN/2.8+
ethanol/4.6
• Elevated with ethanol, isopropanol, methanol,
ethylene glycol intoxication
LABORATORY
•
•
•
•
ECG
Arterial blood gas
Pregnancy test
Toxicology
• Quantitative: acetaminophen,
carbamazepine, carboxyhemoglobin,
digoxin, ethanol, ethylene glycol, iron,
lead, lithium, methanol, methemoglobin,
phenobarbital, phenytoin, salicylate,
theophylline, valproic acid
LABORATORY
• Common urine substance abuse
screens
• Amphetamine
• Barbiturates
• Benzodiazepine
• Cannabinoids
• Cocaine
• Opioids
• Phencyclidine
ACETAMINOPHEN (APAP)
TOXICITY
(Amer Assoc Poison Cntl Center, 2001)
•
•
•
•
•
•
Total reported exposures: 57,516
Reported exposures, < 19 years: 40,774
Unintentional overdoses: 35,705
Intentional overdoses: 20,002
Total treated for the exposure: 24,934
Impact on health from the incident: none,
15,029; minor, 6,223; moderate, 3,138;
major, 829; fatal: 120
ACETAMINOPHEN OVERDOSE IN THE
CALGARY HEALTH REGION BY AGE AND
SUICIDAL INTENT (1997–2002)
ACETAMINOPHEN (APAP)
TOXICITY
 Most common drug overdose at any age
 Target organ: liver
 Principle metabolism (>90%) by sulfation and
glucoronidation - with renal excretion
 5% metabolized by cytochrome P-450 to toxic
n-acteyl-p-benzoquinoneimine (NAPQI)
 Toxicity produced by saturation of metabolic
pathway with excess toxic metabolite (NAPQI)
 Normally glutathione detoxifies the metabolite;
with overdose, glutathione is depleted causing
severe hepatic injury (centrilobular necrosis)
APAP TOXICITY - CLINICAL
FINDINGS




Stage I “Gastrointestinal” (24 hours):
anorexia, nausea, vomiting, lethargy,
diaphoresis, anion gap metabolic acidosis
Stage II “Latent” (24-48 hours): patient
may feel better, subclinical increase in
hepatic enzymes
Stage III (>48 hours): progressive hepatic
encephalopathy, clinical hepatitis, overt
coma
Stage IV (4-14 days): recovery
ACETAMINOPHEN (APAP)
TOXICITY/LABORATORY EVALUATION




Toxic dose: usually > 150 mg/kg or >
7.5 grams
Try to obtain at 4 hours post ingestion
Plot on nomogram – predictor of liver
toxicity
Nomogram



Not accurate for chronic ingestion
Not accurate for multiple doses/overdoses
If level is > potential toxic line, additional
workup needed
DIFFERENTIAL DIAGNOSIS
•
•
•
•
•
•
•
•
Amanita mushrooms
Hydrocarbon
Heavy metals
Isoniazid
Non steroidal anti-inflammatory
Erythromycin estolate
Vitamin A
Steroids
APAP TOXICITY MANAGEMENT

Decontamination
• Activated charcoal: may give up to 4 hours post
ingestion; however need 2 hour separation
between charcoal and antidote

Antidote: NAC (n-acetylcysteine)
• Sulfhydryl donor to increase glutathione
synthesis or bind with NAPQI
• Indications: any level above nomogram line
• Optimal use: within 8 hours of ingestion - but
still may be useful > 24 hrs
• Oral dose: 140 mg/kg, then 70 mg/kg q4h x 17
doses (may dilute with cola or juice)
CONSIDERATIONS FOR IV NAC
(Marzulo, 2005)
• 20 hours of 300 mg/kg (cumulative) for 10 hours
• Antihistamine therapy helpful in patients who
experience “anaphylactoid reactions” (rash,
urticaria, pruritis) to IV NAC
• Recent reports of deaths secondary to IV NAC;
no overwhelming support to automatically
choose IV over PO NAC – decide on case by case
basis
• Standard IV dosing caused hyponatremia and
secondary seizures because of excess free water;
adjustment for pediatric patients has been made
• Dilute 20% NAC to final concentration of 40 mg/ml
(see chart)
UDATE ON APAP POISONING
(White, PedEmergCare, 2006)
• Recent FDA revisions (2006) extended the
loading dose infusion time from 15 to 60
minutes – making it a 21 hour infusion
• Pediatric: see revised dosing; anaphylactoid
reactions usually occur during loading dose
• Adult:
• 150mg/kg in 200 mL of 5% dextrose for 60
minutes, followed by
• 50 mg/kg in 500 mL of 5% dextrose for 4
hours and
• 100 mg/kg in 1000 mL 5% dextrose for 16
hours
RECENT LITERATURE
• James et al. Predictors of outcome after
acetaminophen poisoning in children and
adolescents (2002)
• Retrospective analysis of 10 years of
admissions for acute acetaminophen toxicity
• Best predictor of low risk of hepatotoxicity was
normal values for PT, AST or ALT within 48
hours of ingestion
• Authors concluded inpatient stay of 48 hours
justified post ingestion of acetaminophen
RECENT LITERATURE
• Kanter MK. Comparison of oral and IV
acetylcysteine in the treatment of acetaminophen
poisoning (2006)
• Consider efficacy, safety, cost; both equally
effective
• IV prep problems: anaphylactoid reactions in 3-6%
of patients, dosing errors, hypoNa, very expensive
• Oral prep: strongly consider in those with history of
asthma or atopy
• Most important: severity of toxicity, time interval
between ingestion and treatment
• If ingestion > 10 hours or underlying reasons
preventing oral use, use IV prep
RECENT LITERATURE
• Yarema et al. Comparison of the 20 hr IV and 72
hr PO protocols for treatment of acute
acetaminophen toxicity
• Of 4 ,048 patients analyzed, 2,086 in the 20 hour
and 1,962 in the 72 hour groups
• No risk difference when between groups when
treatment was started 12-18 hours after ingestion
• Anaphylactoid reactions: IV 148/2,086 (7.1%);
• Risk of hepatotoxicity favored 20 hr protocol for
those presenting early and the 72 hour protocol for
those presenting late
COMPETENCY ISSUES
• Medical Knowledge: treatment of poisoning
• Patient Care: careful history taking is critical
• System Based Practice: rapid lab turnaround
and recognition of potential for liver
transplant
• Practice Based Learning and Improvement:
use literature to guide treatment options
• Interpersonal and Communication skills:
explain illness and risk to family
• Professionalism: caution regarding sensitivity
toward patient and family with any ingestion
SUMMARY
• ABC’s for unstable patient with unknown
ingestion
• Decontamination
• Activated charcoal, WBI when indicated
• Focused history, physical exam, can someone
•
•
•
•
bring in a sample?
Toxidromes
Antidotes
Follow acetaminophen levels as guideline for
toxicity
Strongly consider PO NAC for children – especially
is history of asthma/atopy; if vomiting need to
consider IV prep
REFERENCES
• Watson WA, Litovitz TL, Rodgers GC et al. 2004
Annual Report of the American Association of
Poison Control Centers Toxic Exposure
Surveillance System. Amer J Emer Med 2005
Sept;23(5):589-666.
• Abbruzzi G, Stork CM. Pediatric toxicologic
concerns. Emerg Med Clin North Amer 2002
Feb;(20)1:223-247.
• Osterhouldt KC, Ewald MD, Shannon M, Henretig
F. Toxicologic emergencies. In Textbook of
Pediatric Emergency Medicine 5th edition, Fleisher
G, Ludwig S, Henretig F (eds), Philadelphia,
Lippincott Williams and Wilkins, 2006, pp 9511007.
REFERENCES
• Ingels M. Hypoglycemic agents and insulin. In
Pediatric Toxicology 1st edition, Erickson TB,
Ahrens WR, Aks SE, Baum C, Ling LJ (eds),New
York, McGraw Hill, 2005, pp 277-282.
• Gussow L. Lethal toxins in small doses. In
Pediatric Toxicology 1st edition, Erickson TB,
Ahrens WR, Aks SE, Baum C, Ling LJ (eds),New
York, McGraw Hill, 2005, pp 197-203.
• Matteuci MJ. One pill can kill; assessing the
potential for fatal poisonings in children. Pediatr
Annals December 2005;34:12:964-968.
• Michael JB, Sztajnkrycer MD. Deadly pediatric
poisons: nine common agents that kill at low
doses. Emerg Med Clin North Amer 2004;22:10191050.
REFERENCES
• Henry K, Harris CR. Deadly ingestions. Ped
Clin North Amer 2006;53:293-315.
• Zell-Kanter M. Aspirin. In Pediatric
Toxicology 1st edition, Erickson TB, Ahrens
WR, Aks SE, Baum C, Ling LJ (eds),New
York, McGraw Hill, 2005, pp 224-227.
• Yip L, Dart RC, Gabow PA. Concepts and
controversies in salicylate toxicity. Emerg
Med Clin North America. 1994;12:351-363.
• James et al. Predictors of outcome after
acetaminophen poisoning in children and
adolescents. J. Pediatr 2002;140:522-6
REFERENCES
• Lapus RM. Activated charcoal for pediatric
poisonings: the universal antidote? Curr
•
•
•
•
Opin Peds 2007;19:216-222.
Caravati, EM. Acute hydrofluoric acid
exposure. Am J Emerg Med
1988;6(2):143-150.
http://www.emedicine.com/emerg/topic8
04.htm
http://www.mnpoison.org/index.asp?pag
eID=page_151.htm
Position paper: whole bowel irrigation
#." Journal of Toxicology: Clinical
Toxicology 42.6 (Oct 2004): 843
REFERENCES
• Kanter MK. Comparison of oral and IV
acetylcysteine in the treatment of
acetaminophen poisoning. Am J HealthSys Pharm 2006;63:1821-7.
• Yarema et al. Comparison of the 20 hr IV
and 72 hr PO protocols for treatment of
acute acetaminophen toxicity. Ann Emerg
Med 2009;54:606-614.