PEDIATRIC TOXICOLOGY

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PEDIATRIC TOXICOLOGY

• Nga B. Pham, M.D.

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Epidemiology

• 64 Poison Centers serving 295 million people
• 2.4 million exposures last year
• 39 are children younger than 3 years
• 52 in children younger than 6 years
• 106 deaths in age lt19 for 2003
• 2003 Annual report of the American Association
  of Poison Control Centers Toxic Exporure
  Surveillance System Watson et. al

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Epidemiology

• Most commonly fatal classes of poisoning
• Analgesics (375)
• 62 Tylenol only, 52 Tylenol 1 other, 100
  Tylenol combination products (Lortab, etc.)
• 23 ASA more than half did not have ASA levels
  gt100mg/dl early and more aggressive dialysis
  recommended
• Street drugs (124)
• Antidepressants (112)
• Amitriptyline

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Epidemiology

• Most common Pediatric Exposure
• Cosmetics and personal care products (13)
• Cleaning substances (10)
• Analgesics (7.8)
• Foreign Bodies (7.4)
• Topicals (7.4)
• Cold and Cough Preparations (5.5)
• Plants (4.6)
• Pesticides (4.1)

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Epidemiology

• Unintentional (1-2 years)
• Exploratory
• Boys gt girls
• Unable to discriminate safe from unsafe liquid
• Intentional (adolescent)
• Purposeful
• Girls gt boys

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Epidemiology

• Around meal time
• Grandparents home
• Kerosene or gasoline in a soda bottle
• Older sibling can pharmaceutically treat younger
  sibling

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Evaluation of Suspected Poisoning

• ABCs and routine ICU management
• Establishing the diagnosis
• Must consider poisoning, especially in at risk
  age groups
• Less than 6 year old with acute decompensation
  (AMS, arrhythmias, hypotension, metabolic
  acidosis, etc.)

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Evaluation

• History of poisoning
• Physical Examination
• Laboratory studies
• Gastrointestinal decontamination

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History

• What?
• When?
• How much?
• Reliability

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What?

• Medication
• Illicit drug
• Hazardous chemical

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What forms?

• Pill
• Solid
• Liquid
• Gaseous

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What route?

• Ingestion
• Inhalation
• Topical
• Intravenous

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When?

• Elapsed time

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How much?

• Estimate amount
• Concentration

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PICU Admission

• Tricyclic antidepressants (TCA)
• Anticonvulsants
• Digoxin
• Opiates
• Hydrocarbon-based household products

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Toxic Exposure - Death

• Analgesics
• Sedative-hypnotics
• Alcohols
• Gases fumes
• Cleaning substances

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Toxidromes

• Anticholinergics
• Atropine, scopolamine, TCAs, phenothiazines,
  antihistamines, mushrooms, jimson weed
• Hot as a hare, dry as a bone, red as a beet, mad
  as a hatter
• Neuro agitation, hallucinations, coma,
  extrapyramidal movements, mydriasis, hyperthermia
• CV tachycardia, hypotension, hypertension,
  arrhythmia
• GI/GU decreased bowel sounds, urinary retention

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Toxidromes

• Cholinergics
• Organophosphates and carbamates

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Muscarinic Effects of Organophosphate Poisoning

• S alivation D iaphoresis/diarrhea
• L acrimation U rination
• U rination M iosis
• D efecation B radycardia/bronchospasm
• G I secrestion/upset E mesis
• E mesis L acrimation excess
• S alivation excess

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Nicotinic Effects of Organophosphate Poisoning

• Muscle fasciculation
• Cramping
• Weakness (extreme is diaphragmatic failure)
• Autonomic nicotinic effects include hypertension,
  tachycardia, pupillary dilation, and pallor

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CNS Effects ofOrganophosphate Poisoning

• Anxiety
• Restlessness
• Confusion
• Ataxia
• Seizures
• Insomnia
• Dysarthria
• Tremors
• Coma

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Toxidromes

• Opiates
• Morphine, Methadone, Dextromethorphan

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Toxidromes

• Opiates
• Morphine, methadone, dextromethorphan
• Resp decreased respiratory rate, pulmonary edema
• CV hypotension, bradycardia
• Neuro miosis, AMS, coma, hypothermia, seizures

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Toxidromes

• Sedatives/hypnotics
• Benzodiazepines, barbiturates
• Resp slow respirations
• CV tachycardia, hypotension
• Neuro AMS, coma, seizures, hypothermia

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Toxidromes

• Tricyclic antidepressants
• Amitryptiline, nortryptiline, etc.
• See anticholinergic effects
• CV arrhythmias, hypotension
• Neuro coma, seizures

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Toxidromes

• Salicylates
• ASA, oil of wintergreen
• Resp tachypnea

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Laboratory Tests Suggestive ofPoisoning

• Elevated osmolar gap (gt10)
• Serum osm (Na x 2) BUN/2.8 glucose/18
• Volatile alcohols, mannitol
• Elevated anion gap (gt12)
• MUDPILES
• Low anion gap
• Lithium, iodine, bromine, fluoride
• Hyperkalemia
• Postassium, lithium, digoxin, fluoride
• Hypokalemia
• Theophylline, toluene

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Laboratory Tests Suggestive ofPoisoning

• Hyperglycemia
• ASA, theophylline, caffeine, iron
• Hypocalcemia
• Ethylene glycol, ASA
• UA
• Glowing urine ethylene glycol
• Calcium oxalate crystals ethylene glycol

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Laboratory Testing

• What is in a urine drug screen?
• Amphetamines, Barbiturates, Cocaine,
  Benzodiazepine, Opiates, THC, PCP
• What is in a serum drug screen?
• Acetaminophen, ETOH, Salicylate, TCA
• What is in a comprehensive drug screen?
• Barbiturates, Salicylates, Cannabinoids, PCP,
  TCA, Sedatives, Benzodiazepines, Stimulants,
  Opium alkaloid, Synthetic Narcotics,
  Tranquilizers, Cocaine

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Laboratory Testing

• Grady unfortunately doesnt do HPLC anymore
• Options for more comprehensive screen
• Quest lab if needed in 24 hours or less
• ARUP 2-4 days turn around
• SERUM Acetaminophen, alcohols, barbiturates,
  benzodiazepines, carbamazepine, carisoprodol,
  disopyramide, meprobamate, phenytoin, primidone,
  salicylate, theophylline, tricyclic and other
  antidepressants
• URINE acetaminophen, alcohols, barbiturates,
  benzodiazepines, carbamazepines, carisoprodol,
  chlorpheniramine, cocaine metabolites,
  diphenhydramine,ethchlorvynol, ibuprefen,
  lidocaine, meprobamate, narcotics synthetics,
  phencyclidine, phenothiazines, phenytoin,
  primidone metabolites, pyrilamine, salicylate,
  sympathomimetic amines, theophylline, tricyclic
  and other antidepressants, trimethoprim

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Laboratory Testing

• Additional testing is helpful if you have a
  specific substance that you suspect
• Usually less helpful as a fishing expedition
  and wont affect management
• Am J Emerg Med. 1999 May17(3)221-4. Belson MG,
  Simon HK
• Evaluate the clinical utility and
  cost-effectiveness of the limited component vs
  the HPLC component of comprehensive toxicologic
  screens in children
• Retrospective from HSCH ED Jan 1994-July 1995
• The comprehensive test included a broad-spectrum
  HPLC component as well as a limited component
  that examined serum for ethanol, aspirin, and
  acetaminophen and urine for benzodiazepines,
  barbiturates, amphetamines, cocaine,
  phencyclidien, and opiates
• Comprehensive toxicology screens were performed
  in 463 cases during the study period 234 (510
  were positive for exogenous toxin

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Laboratory Testing

• In 227 of 234 positive screens (97), toxins were
  either suspected by history and/or physical, were
  present on the limited portion of the toxicology
  screens, or were clinically insignificant
• The remaining 7 of the 234 positive screens (3)
  were clinically significant and detected solely
  by the broad-spectrum HPLC portion of the
  comprehensive screen
• However, in none of these 7 cases was patient
  management clinically altered as a result of the
  positive screen
• The total additional cost of the HPLC component
  was 16,205 (35x464), an average distributive
  charge of 2,315 per patient in whom the HPLC
  portion provided additional clinical information
  (16,205/7)
• Although adding significant charges to the
  evaluation of suspected toxic exposures in
  children, the HPLC component of the comprehensive
  drug screen was of no additional clinical benefit
  compared with its limited component alone

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Urine Drug Screens

• THC 1-3 weeks
• Cocaine 2-4 days
• Amphetamine 2 days
• Barbiturates 1-2 days
• Opiates 1-2 days
• PCP 5-7 days
• LSD 1-2 days
• Steroids 3 days or longer
• Longer if prolonged exposure

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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Antidotes
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Elimination of Poisons

• Surface decontamination
• Reduce any additional absorption
• Ipecac
• Not routinely recommended anymore
• Possible useful in an observed, in hospital
  poisoning
• Gastric Lavage
• Most effective 1-2 hours after ingestion
• Can be effective later in drugs that delay
  gastric emptying

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Elimination of Poisons

• Activated charcoal
• Adsorbs many drugs, thus decreasing systemic
  absorption
• Doesnt work well for lithium, iron,
  hydorcarbons, alcohols, solvents, acid/alkali
  ingestions
• Role of charcoal in gastrointestinaldialysis
• Cathartics
• Not generally used
• Some charcoal has sorbitol in it
• Whole bowel irrigation
• Golytely infusions
• Initially done with success in iron ingestions
• Used mostly for drugs that charcoal doesnt work
  well with

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Elimination of Poisons

• Diuresis /- alteration of urine pH
• Obviously, only useful for renally excreted drugs
• Altering pH example
• ASA pkA3
• At a pH of 3, there is a 11 ratio of
  ionized/unionized
• At a pH of 7.4, the ratio is 25,0001
• Ionized form cant cross cell membranes so when
  you dump ASA into the tubule, if the pH is 4.5
  you would have about 5,001 ratio, if you
  increase urine pH to 8.0, then essentially all of
  it is in the ionized form, and cant get
  reabsorbed

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Elimination of Poisons

• Altering pH
• Alkalinize the urine ASA, isoniazid, phenobarb
• Use bicarb in the fluids
• Dont use acetazolamide (Diamox) in ASA poisoning
• Metabolic acidosis increases unionized form which
  can cross into CNS, worsening poisoning
• Acidify the urine (usually not needed)
  quinidine, PCP, fenfluramine, amphetamine

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Elimination of Poisons

• Dialysis
• What makes things dialyzable
• Low molecular weight
• Low volume of distribution
• Low protein binding
• Charge
• Methods
• Intermittent Hemodialysis
• CVVH/CVVHD/CVVHDF
• Albumin dialysis

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Elimination of Poisons

• Charcoal hemoperfusion
• Clear chemicals by direct adsorbtion with
  charcoal in an extracorporeal circuit
• Doesnt depend of molecular size, protein binding
• Can be used for a variety of otherwise difficult
  to manage poisonings
• Digoxin, ASA, barbiturates, TCAs, theophylline
• Not used that much anymore

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Elimination of Poisons

• Plasmapheresis
• Works very well with highly protein (albumin)
  bound drugs
• Not a routine methodology, but has been used to
  remove theophylline and digoxin/digibind
  complexes
• Exchange transfusion
• Use in smaller infants where vascular access for
  extracorporeal techniques cant be done

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Tylenol Ingestion

• Clinical manifestations
• Stage 1
• First 12-24 hours
• Nausea, vomiting, anorexia
• No CNS involvement of you see it, think of
  polysubstance ingestion
• Stage 2
• Resolution of GI symptoms
• 36 hours after ingestion see biochemical evidence
  of liver dysfunction AST/ALT, bilirubin, PT

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Tylenol Ingestion

• Clinical manifestation
• Stage 3
• Liver dysfunction reaches a peak on day 3-4
• Start GI symptoms again
• High transaminases (gt10,000) do not necessarily
  predict liver failure
• Fulminant liver failure can occur
• Stage 4
• Recovery stage lasts 7-8 days
• Chronic hepatitis does not occur LFTs/biopsy
  return to normal

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Tylenol Ingestion

• Prediction of toxicity
• Rumack nomogram for single ingestion
• Rough guide for potential toxicity
• Children 150 mg/kg
• Adults 7.5 gm
• Uncommon 150mg/kg
• 50 with 250 mg/kg
• 100 with 350mg/kg

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Tylenol Ingestion

• Therapy
• N-acetylcysteine (Mucomyst)
• Oral 140 mg/kg load, followed by 70mg/kg q4
  hours for 17 doses
• Repeat dose if vomits within 1 hour
• Can mix with carbonated drinks or grapefruit
  juice
• Intravenous 150 mg/kg load over 15 minutes,
  then 50mg/kg over 4 hours, then 100mg/kg over 16
  hours

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Volatile Alcohols

• Diagnosis
• High index of suspision
• Elevated osmolar gap
• Volatile alcohol screen separate test for
  ethylen glycol
• Methanol and ethylene glycol no ketones
• Isopropyl alcohol marked acetone
• Ethanol acetoacetate and B-hydroxybutyrate

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Volatile Alcohols

• Isopropyl Alcohol
• Toxic dose is 1 ml/kg of 70 solution
• More than one swallow in children should be
  presumed toxic
• About 20 is broken down by liver ADH to acetone
• Symptoms are like ethanol ingestion
• Nystagmus is common
• More CNS depressant than ETOH, because acetone is
  a CNS depressant as well
• Management
• Supportive (without hypotension essentially 0
  mortality)
• Levels dont mean much prognostically
• Dialysis will remove it
• Coma hypotension 30 mortality
• Level over 400 (implied severe ingestion)

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Volatile Alcohols

• Methanol
• No safe dose. 5ml is lethal in toddler age and
  can cause blindness in adults. 1ml/kg is lethal
  in adults
• Metabolism
• 30 excreted by lungs
• 5 kidneys
• Rest to liver to make toxic metabolites

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Volatile Alcohols

• Methanol
• Clinical symptoms Biphasic
• Initial CNS depression secondary to direct
  action of methanol on CNS
• Delayed
• Visual disturbances
• Photophobia, snowflakes, blurred vision
• CAN HAVE FIXED DILATED PUPILS
• Metabolic acidosis
• Laboratory
• Elevated anion gap is due to formic acid and
  lactate
• Retinal damage is due to locally produced formic
  acid

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Volatile Alcohols

• Methanol
• Treatment
• Supportive
• Ethanol/dialysis
• Fomepizole /- dialysis now

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Volatile Alcohols

• Ethylene Glycol
• Minimum lethal dose is 1.4-1.6 ml/kg
• Clinical symptoms
• Severe neurotoxicity, metabolic acidosis, renal
  failure, cardiovascular collapse
• 1st phase 30 min 12 hours CNS symptoms, N/V
• If LP pleocytosis and elevated protein
• 2nd phase cardiorespiratory failure with
  pulmonary edema
• 3rd phase renal failure
• Metabolism
• 25 excreted unchanged by kidneys
• Remainder rapidly metabolized by liver and
  kidneys to toxic metabolites

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Volatile Alcohols

• Ethylene Glycol
• Lactic acidosis develops secondary to altered
  NADH/NAD ratio
• Oxalic acid chelates calcium
• Tetany and myocardial dysfunction
• Renal failure is likely due to glycoaldehyde,
  glycolic acid, glyoxylic acid
• Most recover can be prolonged up to 2 months
• Can see calcium oxalate crystals in urine

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Volatile Alcohols

• Ethylene Glycol
• Treatment
• Fomepixole /- dialysis

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Cyanide Poisoning

• Exposures
• Mostly from fires in children
• Acetonitrile in some cosmetics reported lethal
• Vitamin B17 cyanogenic glycosides sold in
  health food stores from pits of apricots and
  bitter almonds
• Laetrile only when given orally or rectally
• Nipride use sodium thiosulfate to reduce
  incidence 1 gram per 100mg of Nipride

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Cyanide Poisoning

• Pathophysiology
• Reversible binding to a-a3 cytochrome
• Halts aerobic metabolism and ATP formation
• Pushes to anaerobic metabolism and resultant
  lactic acidosis
• Inability to use oxygen at the cellular level
• Normal oxygen content and oxygen delivery

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Cyanide Poisoning

• Treatment
• 100 oxygen always
• Eli Lilly Cyanide Antidote Kit No M-76
• Amyl nitrate pearls inhale for 15-30 secs
• Produces about 5 methemoglobinemia
• IV sodium nitrite
• IV sodium thiosulfate
• Aiming for methemoglobin of 30

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Hydrocarbon Ingestion

• Unintentional vs intentional
• Clinical presentation
• Respiratory distress
• Hydrocarbons dissolve the lipid layer in the lung
• Surfactant inactivation, distal airway closure,
  hypoxemia, V/Q mismatch
• Can progress to ARDS
• CNS abnormalities
• Mostly due to hypoxia
• GI abnormalities

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Hydrocarbons Ingestion

• Clinical presentation
• Fever and leukocytosis common in first 24-48
  hours
• Treatment
• Supportive
• Treat the hypoxia
• No induction of vomiting

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Iron Intoxication

• Relatively common ingestion
• About 5-10 require hospitalization
• Can be lethal
• lt20 mg/kg elemental Fe insignificant
• 20-60 mg/kg mild toxicity
• gt60 mg/kg moderate to severe toxicity
• gt200 mg/kg rapidly lethal if not treated

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Iron Intoxication

• Pathophysiology
• Huge uptake of iron from small bowel
• Overwhelm transferrins ability to bind and thus
  get free iron circulating in blood
• Disruption of CMS, GI, CV systems
• Major oxidant stress possibly shunts electrons
  away from cytochromes in the mitochondria
• Interferes with activation of thrombin and clot
  formation, leading to coagulopathy
• Direct gut toxicity with hemorrhagic gastritis
  and bowel perforation

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Iron Intoxication

• Clinical manifestation
• 1st phase GI symptoms (N/V/D, hemorrhagic
  gastritis, GI bleed) direct effect
• 2nd phase temporary recovery 6-12 hours from
  ingestion can last several days
• 3rd phase return of GIU symptoms and MSOF
• Metabolic acidosis, shock, CNS depression, liver
  dysfunction, renal failure, coagulopathy, etc.
• Die or get better
• 4th phase 4-6 weeks out pyloric, gastric, or
  intestinal obstruction due to healing of
  initial damage

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Iron Intoxication

• Prognosis
• Ingestion size
• Serum iron levels
• Peak 2-6 hours after ingestion
• lt100 unlikely toxicity
• 100-300 minimal
• 300-500 moderate
• 500-1,000 severe
• gt1,000 potentially lethal
• After 6 hours even in large ingestion, level may
  be normal

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Iron Intoxication

• Therapy
• Role of gastric lavage
• Desferoxamine iron chelator
• Binds iron to form ferrioxamine which can be
  safely excreted renally
• Red (vin rose) color to urine
• Also has a protective effect of increasing
  intracellular binding of iron, reducing toxicity
• Not dialysable

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Beta Blockers

• Widely prescribed and available
• Phamacology
• Lipophilicity
• Membrane stabilizing effect
• Selective vs non-selective agents
• Propranolol is most common and most dangerous

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Beta Blockers

• Toxic dose
• 2-3 times therapeutic dose
• Signs and symptoms
• Bradyarrhythmia
• Hypotension
• Decrease LOC
• Respiratory depression
• Seizure
• Ventricular arrhythmia

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Beta Blockers

• Prehospital management
• Aggressive airway management
• PALS protocol
• Atropine 1mg prn (max 3 mg)
• Peds 0.02 mg/kg
• Transcutaneous pacemaker
• Do not delay in symptomatic bradycardia

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Beta Blockers

• Prehospital management
• Glucagon 5mg IV bolus
• Peds 0.2 mg/kg IV bolus
• Fluid resuscitation peds 20 ml/kg
• Pressors
• Dopamine 5-10 mcg/kg/min
• Epinephrine drips
• Titrate to response. May need bigger than normal
  dose

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Beta Blockers

• Other management issues
• Treat dysrhytmia
• Pediatric patient
• Hypoglycemia more common
• Seizures more likely than adult
• Consider heroic measures - ECMO

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Calcium Channel Blocker

• Pharmacology
• Negative inotrope
• Blocks flow of calcium ions through slow channels
• Decreased amount of calcium from sarcoplasmic
  reticulum
• Negative chronotrope
• Decrease automaticity in SA node and AV junction
• Reduction in PVR

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Calcium Channel Blocker

• Agents
• Verapamil
• Significant cardiac depressant
• Vasodilation
• AV slowing
• Diltiazem
• Nifedipine
• Felodipine
• Amlodipine

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Calcium Channel Blocker

• Toxicity
• Hypotension
• Bradycardia
• Arrhythmias
• Respiratory depression
• Neurologic disorders
• Seizures etc.

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Calcium Channel Blocker

• Prehospital management
• Aggressive airway management
• PALS protocol
• Atropine 1 mg prn (max 3mg)
• Peds 0.02 mg/kg
• Atropine most often not effective
• Transcutaneous pacemaker
• Do not delay in symptomatic bradycardia

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Calcium Channel Blocker

• Prehospital management
• Calcium chloride 250-500 mg IV
• Peds 20mg/kg
• Glucagon 5mg IV bolus
• Peds 0.1 mg/kg IV bolus
• Fluid resuscitation peds 20 ml/kg

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Calcium Channel Blocker

• Other management issues
• Pressors prn
• Dopamine 5 mcg/kg/min
• Epinephrine drip 2 mcg/kg/min
• Titrate to response, may need bigger dose than
  normal
• Treat dysrhythmias
• Pediatric patient
• Small dose can be lethal
• Seizures are more likely than adult
• Consider heroic measures - ECMO

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Digoxin

• Toxicity
• Dysrhythmias
• PVCs
• Slow A-fib
• Bradycardia, V-fib. V-tach
• Hypotension
• Hyperkalemia ( Renal insufficiency is a risk
  factor)
• CNS
• Delirium, hallucinations, lethargy, agitation
• Ocular disturbances

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Digoxin

• Treatment
• Basic management (ABCs etc.)
• Electrolyte disturbances
• Hyperkalemia
• Atropine/Pacemaker
• Manage dysrhythmias
• Digoxin specific antibody

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Digoxin

• Treatment Digibind
• Indication
• Life threatening CV toxicity
• K gt 6.5 mEq/L (except in chronic renal failure)
• Steady state level gt10 ng/ml
• Ingested dose gt10mg (adult)