Toxicology

Martha C. Kutko, M.D.

Assistant Professor of Pediatrics
Weill Medical College of Cornell
University
Epidemiology
 Ingestion of a potentially poisonous
substance by a young child is common.
 American Association of Poison Control
Centers reported 1.2 million ingestions in
children < 6 years of age in 2001.
 Death is uncommon in this age group.
 Decline in death rate from 500
mortalities per year in the 1940s to
25 mortalities in 1997
Epidemiology
Decline in mortality attributed to:
 child resistant containers
 safer medications
 anticipatory guidance
 public education
 legislation
 establishment of poison control centers
 sophisticated medical care
 antidotes
Approach to the Poisoned Patient
History

 Time of ingestion
 Medications in the household
 Amount ingested
 Onset of symptoms
 Intentionality
 Underlying medical conditions
Approach to the Poisoned Patient
Physical Examination

 Vital Signs
 Pupillary exam (miosis, mydriasis)
 Skin (dry, cyanotic)
 Lungs (crackles, wheezing)
 Cardiac (tachycardia, bradycardia)
 Abdomen (decreased bowel sounds,
tenderness)
 Neurologic (altered mental status, seizure)
Approach to the Poisoned Patient
Initial Management

 Airway
 Breathing
 Circulation
 Disability
 Exposure
Approach to the Poisoned Patient
Diagnostic Evaluation

 CBCD  AXR
 Electrolytes  Serum Tox
 ABG  Urine Tox
 LFTs  ASA level
 CXR  Tylenol level
 ECG  Serum OSM
Useful Toxin Levels
Set time point Serial levels
 Acetaminophen  Salicylates
 Carbon Monoxide  Carbamazepine
 Ethanol  Digoxin
 Ethylene glycol  Phenobarbital
 Heavy metals  Phenytoin
 Iron
 Theophylline
 Methanol
 Methemoglobin
 Valproate
Radiopaque drugs
 Bezoars/Bags
 Calcium carbonate
 Chloral hydrate
 Enteric-coated tablets
 Heavy metals
 Iodine
 Fe
 Phenothiazines
 Potassium compounds
 Anion Gap (AG)

Anion Gap = Na+ - [Cl- + HCO3 -]

Normal AG: 3-16

Toxins associated with increased AG
 Methanol  Hydrogen Sulfide
 Paraldehyde  ETOH (ketones)
 INH
 Metformin
 Fe
 Phenformin
 Ethylene glycol
 Sulfur
 Salicylates
 CO
 Theophylline

 Cyanide  Toluene
Toxins associated with decreased AG

 Lithium
 Bromide
 Osmolal Gap (OG)
Serum OSM: 2[Na] + [Glc]/18 + [BUN]/2.6

OG: Measured OSM-Calculated OSM

Normal OG: -3 to 10 mOSM/kg H2O

Toxins associated with increased OG

 Methanol
 Ethanol
 Ethylene glycol
 Acetone
 Isopropanol
Toxidromes
(Toxicologic Syndromes)
-a constellation of signs and
symptoms associated with a
specific group of toxins
Toxidromes
Opiates
 Miosis
 Respiratory depression
 Hypotension
 Sedation
 Decreased GI motility
 Urinary retention
Toxidromes
Opiates

 Seizures-Meperidine; occur secondary

to the metabolite normeperidine
 Dysrhythmias-Propoxyphene; occur
from the metabolite norpropoxyphene
 Rigid Chest-Fentanyl
Toxidromes
Cholinergics-Muscarinic Effects

 Salivation
 Lacrimation
 Urination
 Defecation
 Gastrointestinal Distress
 Emesis
Toxidromes
Cholinergics-Nicotinic Effects

 Muscle Fasciculations
 Weakness
 Paralysis
Toxidromes
Anticholinergics
 “Red as a beet”- Flushed skin
 “Hot as a hare”-Hyperthermia
 “Mad as a hatter”-Psychosis
 “Dry as a bone”-Dry skin, urinary
retention
 Tachycardia
 Mydriasis
Toxidromes
Sympathomimetics
 Hypertension
 Tachycardia
 Psychomotor Agitation
 Hyperthermia
 Diaphoresis
 Mydriasis
Gastric Decontamination

 Ipecac
 Gastric Lavage
 Activated Charcoal
 Whole Bowel Irrigation
Ipecac
 NO!!!!
 Had been previously been recommended
for administration at home immediately
following ingestion
 No longer recommended in the AAP policy
statement - Poison Treatment in the Home
(Pediatrics Vol. 112 No. 5, November 2003)
Why Not Ipecac?
 Variable percentage of removal of toxic medication
In adult volunteers:
51-83% removal (5 minutes after ingestion)
2-59% removal (30 minutes after ingestion)
 May cause persistent vomiting, lethargy, and
diarrhea
 Vomiting may preclude later administration of oral
antidotes
Why Not Ipecac?

 Lethargy and vomiting together

increase risk of aspiration
 Inappropriate use-following
ingestion of acid or lye
 Misuse-children with eating
disorders
 Misuse-Munchausen by proxy
Gastric Lavage
 Earlyfollowing ingestion
 Airway must be protected
 Use the largest available tube
(40 French)
 Contraindicated in caustic ingestions,
hydrocarbons, previous vomiting
Activated Charcoal
Single Dose
 Toxic ingestions that adhere to charcoal
 Dose is 1 g/kg PO or NGT
 Administered with Sorbitol
 Airway must be protected
 Contraindicated in caustics,
hydrocarbon, foreign body, ileus or
gastric perforation
Activated Charcoal
Multiple Doses
 Large ingestions
 Drugs that undergo enterohepatic
circulation
 Drugs with low Vd
 Drugs with low protein binding
 Drugs with long t1/2
Activated Charcoal
Multiple Doses

 Only the FIRST dose should be

administered with Sorbitol
 Dose 1 g/kg PO or NGT Q6 x 24
hours or until charcoal is passed in
the stool
Which drugs do not adsorb to charcoal?
 Lithium
 Iron
 Alcohols
 Acids
 Alkalis
 Cyanide
 Hydrocarbons
Whole Bowel Irrigation

 Life threatening ingestion

 Sustained-release toxin
 Prolonged absorption time of the toxin
 Must protect the airway
 Contraindicated in caustic, hydrocarbon,
foreign body, ileus, gastric perforation
Whole Bowel Irrigation
Polyethylene Glycol
 Dose: up to 500 ml/h
 Continue until stool is clear
 Patient may get bloated and vomit
 Antiemetics (metoclopramide or
ondansetron) may be helpful
 Monitor electrolytes closely
Toxins and their Antidotes
Acetaminophen N-acetylcysteine

Anticholinergics Physostigmine
Atropine
(muscarinic effects)
Anticholinesterases/
Cholinergics Pralidoxime
(nicotinic effects)
-controversial in
carbamate
ingestions
Toxins and their Antidotes
Benzodiazepines Flumazenil
Botulism Botulinum antitoxin
Beta-blockers Glucagon
Calcium channel blockers Calcium
Carbon monoxide Hyperbaric O2, O2
Cyanide, Nitrites Sodium thiosulfate
 Toxins and their Antidotes
Digoxin Digibind aka Digoxin Fab antibodies
Ethylene Glycol Ethanol

Heparin Protamine
Iron Deferoxamine

Isoniazid Pyridoxine
Toxins and their Antidotes
Lead EDTA, BAL, DMSA

Methanol Ethanol

Methemoglobin Methylene blue

Opioids Naloxone

Tricyclic antidepressants NaHCO3

Warfarin (Superwarfarins) Vitamin K

Enhance Elimination
Methods

 Alkalinization and Urinary ion trapping

 Hemodialysis

 Charcoal hemoperfusion
Alkalinization/Urinary Ion Trapping
 Effective for drugs that are excreted
renally
 The drugs must be either weak acids or
weak bases e.g. ASA and Phenobarbital
HA  H+ +A-
pKa
At a Urine pH < pKa At a Urine pH > pKa
Non-ionized form Ionized form
*Not excreted in urine *Excreted in urine
Hemodialysis

 Low volume of distribution

 Low protein binding
 Low molecular weight
 Also helpful in managing acidosis,
electrolyte abnormalities
Which drugs are dialyzable?
 Salicylates
 Methanol
 Lithium
 Ethyleneglycol
 Amphetamines
 Theophylline
Hemoperfusion
 Blood is passed through a cartridge
containing charcoal or carbon
 Drugs with low Vd
 Toxins can be larger than those
removed by hemodialysis
 Can be more protein bound than
those cleared by hemodialysis
 Toxin must bind well to charcoal
Which drugs can be removed by
hemoperfusion?

 Theophylline
 Phenobarbital
 Carbamazepine
 Phenytoin
 Salicylates
Complications of Hemoperfusion

 Thrombocytopenia
 Hypocalcemia
 Leukopenia
 Rigors
A 15 year old girl presents to the ED four hours
after taking 20 extra-strength (500 mg/tablet)
Tylenol tablets. The ingestion was prompted by a
fight with her boyfriend earlier that day. She has
a history of an attempted suicide in the past.
She is awake and alert with stable vital signs.
She complains of nausea and has had one
episode of vomiting. Physical exam is normal.
Baseline labs show normal electrolytes, with
normal LFTs, normal coags and a Tylenol level of
120 microgram/ml.
 What would you do?
 A. Call psychiatry to evaluate the patient. No
medical intervention is required.
 B. Administer 1g/kg of activated charcoal
with sorbitol every 6 hours and 17 doses of
oral N-acetylcysteine.
 C. Administer one dose of activated charcoal
with sorbitol followed by intravenous
N-acetylcysteine for 21 hours.
 D. Gastric lavage in an attempt to recover pill
fragments.
Acetaminophen Poisoning

 Toxic dose: 150 mg/kg or a

total dose of
7.5 g
 Toxic level: 150 microgram/ml at 4
hours
 Antidote: N-acetylcysteine
Acetaminophen Metabolism
 90% undergoes glucuronidation and
sulfate conjugation in the liver to harmless
metabolites excreted in the kidney
 < 5%, together with some insignificant
metabolites are excreted in the kidney
unchanged
 Remainder undergoes oxidation by the
cyt-p450 system to N-acetyl-p-
benzoquinoneimine (NAPQI)
NAPQI

 Electrophile

 Covalently binds to hepatocytes

 Results in cell death

N-acetylcysteine (NAC)

 Prevents binding of NAPQI to

hepatocytes
 Reduces NAPQI
 Conjugates NAPQI
 Increases sulfation metabolism***
 NAC
 Must be administered within 8 hours
 IV dose: 150 mg/kg infused over 60 minutes;
followed by a 4-hour infusion of 50 mg/kg;
followed by a 16-hour infusion of 100 mg/kg;
equivalent to a total dose of 300 mg/kg infused
over 21 hours
 Oral dose: 140 mg/kg x 1 followed by
70
mg/kg x 17 doses
NAC

 Smells like rotten eggs

 Oral formulation may need to be given
via NGT
 Dilute with juice
 Use metoclopramide or ondansetron if
not tolerated due to vomiting
Phases of Toxicity
 I: (½-24 h):nausea, vomiting, diaphoresis
May be normal
 II: (24-72 h): less nausea, vomiting; RUQ pain;
LFTs and coags begin to rise
 III: (72-96 h): Coagulation abnormalities, renal
failure, encephalopathy, death related to
hepatic failure
 IV: (4 d-2 wk):If stage III damage is
reversible, resolution of hepatic dysfunction
A 15 year old girl presents to the ED four hours
after taking 20 extra-strength (500 mg/tablet)
Tylenol tablets. The ingestion was prompted by a
fight with her boyfriend earlier that day. She has
a history of an attempted suicide in the past.
She is awake and alert with stable vital signs.
She complains of nausea and has had one
episode of vomiting. Physical exam is normal.
Baseline labs show normal electrolytes, with
normal LFTs, normal coags and a Tylenol level of
120 microgram/ml.
What would you do for our patient?
 A. Call psychiatry to evaluate the patient. No
medical intervention is required.
 B. Administer 1g/kg of activated charcoal with
sorbitol every 6 hours and 17 doses of oral N-
acetylcysteine.
 C. Administer one dose of activated charcoal with
sorbitol followed by intravenous N-
acetylcysteine for 21 hours.
 D. Gastric lavage in an attempt to recover pill
fragments.
The correct answer is:

C. Administer one dose of activated

charcoal with sorbitol followed
by intravenous N-acetylcysteine
for 21 hours.
 Key Points
 Despite the fact that our patient’s Tylenol level
was only 120 microgram/ml at four hours and
falls below the toxic level on the nomogram,
she must be treated with NAC. She ingested
a total of 10 g (20 tablets x 500 mg) which is
> 7.5 g and toxic.
 NAC may be given orally or IV.
 IV NAC has only recently been approved for
use in the US.
 Key Points
 The administration of activated charcoal in
Tylenol ingestion has been controversial as it
may interfere with oral NAC.
 Some studies have shown decreased
absorption of Tylenol when activated charcoal
is given in a timely fashion.
 Activated charcoal will not interfere with
administration of IV NAC and therefore may be
given.
Key Points
 If activated charcoal is administered, only
one dose should be given.
 For ingestions requiring administration of
multiple doses of charcoal, only the first
should be given with sorbitol.
 Gastric lavage is not likely to be efficacious
four hours following ingestion.
A one month old full term male infant presents to
the ED with a several day history of watery
diarrhea, decreased PO intake and occasional
vomiting. He has been afebrile. VS are
significant for a HR of 180 bpm, RR of 70/min,
oxygen saturation is 85% on room air. Physical
exam is significant for retractions, a clear lung
exam, no heart murmur, a soft non-distended
abdomen with hyperactive bowel sounds, and
poor peripheral perfusion.
Diagnostic evaluation reveals a negative
CXR with clear lungs fields and a normal
heart size. WBC count is 12,000, Hgb
10.0 gm/dl, Plt 200,000, Na 136, K 4.5, Cl
100, HCO3 5, BUN 3, Creatinine 0.3, Glc
is 90

ABG: 7.10/22/100/97%
What’s the Diagnosis?

 A. Metabolic disorder
 B. Congenital heart disease
 C. Sepsis
 D. Congenital adrenal hyperplasia
 E. Met hemoglobinemia
Met Hgb
 Hgb in which the Fe ++ has been oxidized
to the Fe +++
 Cannot carry oxygen
 Impairs oxygen release to tissues
 May lead to inadequate oxygen delivery to
meet the metabolic needs of the tissues
-------> SHOCK
Met Hgb

 Formed when RBCs are exposed to

oxidative stress
 Occurs normally
 Enzyme NADH methemoglobin
reductase reduces Hgb to its ferric (2+)
form
Met Hgb
Causes
 Local anesthetics
 Dapsone
 Pyridium
 Nitrites
 Aniline
 Diarrhea (nitrite producing bacteria)
 UTI (nitrite producing bacteria)
 **Neonates have ~50% of the adult
levels of NADH methemoglobin reductase
Met Hgb
Diagnosis

 Clinicalsuspicion-exposure to
offending agent
 Chocolate brown colored blood
 Cyanosis
 Presence of a saturation gap
Saturation Gap
 Difference between pulse oximeter
saturation, saturation on the ABG, and
saturation obtained by co-oximetry
 ABG: PaO2 is measured; saturation is
calculated
 Pulse oximetry measures absorbance at
two wavelengths-assumes oxyhgb or
deoxyhgb
Co-oximetry

 Measures absorbance at 4 different

wavelengths
 Uses equations to calculate % oxyhgb,
deoxyhgb, methgb, and carboxyhgb
Treatment
Methylene Blue
 Is reduced to leukomethylene blue by
NADPH met hgb reductase (Requires
G6PD)
 In turn, reduces metHgb to Hgb as it
gets oxidized back to methylene blue.
 Indications: tissue hypoxia, dyspnea,
metabolic acidosis, dysrhythmias,
altered mental status, methgb> 20%
Methylene Blue
 Contraindicated in G6PD deficiency
 Dose: 1-2 mg/kg IV slowly
 Will change the urine color to blue-green
 May cause dysuria
 Pulse oximeter will drop very low following
administration due to the blue color in the
blood.
The End