Toxicology - sums.ac.ir
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Transcript Toxicology - sums.ac.ir
IN THE NAME OF GOD
AN APPROACH TO A
POISONED PATIENT
DR. FAZEL GOUDARZI;TRAUMATO
PATHOLOGIST AND CLINICAL
TOXICOLOGIST
SHIRAZ UNIVERCITY OF MEDICAL
SCIENCES
Introduction
What is a poison?
In common usage - poisons are
chemicals or chemical products that
are distinctly harmful to human
More precisely - a poison is a
foreign chemical (xenobiotic) that is
capable of producing a harmful
effect on a biologic system
Other terminology
What is a toxin?
It originally referred to a
poison of animal or plant
origin
Toxicant is the currently
preferred scientific term for
all poisons.
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
Clinical assessment
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
Clinical assessment
Airway - ensure clear airway, clear secretions,
check for cough/gag
Breathing - check oxygenation, supplemental
O2, breathing pattern & adequacy
Circulation - heart rate, rhythm, blood pressure
Clinical assessment
Neurologic - GCS, seizures, agitation, spasms,
pupils, autonomic dysfunction
Miscellaneous - odour, temperature, pallor,
cyanosis, jaundice
Abdomen - rigidity, bleeding, urine output
Laboratory and
imaging(paraclinical) assessment
Approach to the Poisoned Patient
Diagnostic Evaluation
CBCD
Electrolytes
ABG
LFTs
CXR
ECG
AXR
Serum
Tox
Urine Tox
ASA level
Tylenol level
Serum OSM
Cholinstrase
Laboratory assessment
Electrolytes
Hypokalemia
– Oduvanthalai poisoning (Clistanthis collinis)
– Diuretics, Methyl xanthine, Toluene
Hyperkalemia
– Digoxin
– Beta-blocker
Liver function tests
– Acetaminophen, Ethanol, Carbon tetrachloride
Renal function tests
– Ethylene glycol, NSAIDS
Anion Gap (AG)
Anion Gap = Na+ - [Cl- + HCO3 -]
Normal AG: 8-16
Toxins associated with increased AG
Methanol
Paraldehyde
INH
Fe
Ethylene glycol
Salicylates
CO
Cyanide
Hydrogen Sulfide
ETOH (ketones)
Metformin
Phenformin
Sulfur
Theophylline
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
Useful Toxin Levels
Set time point
Acetaminophen
Carbon Monoxide
Ethanol
Ethylene glycol
Heavy metals
Iron
Methanol
Methemoglobin
Serial levels
Salicylates
Carbamazepine
Digoxin
lithium
Phenobarbital
Phenytoin
Theophylline
Valproate
ECG and Imaging Assessment
ECG
Digoxin toxicity
TCA overdose - sinus tachycardia, QT prolongation,
increased QRS
Beta-blockers - conduction abnormalities
Imaging
Chest x-ray
Abdominal x-ray
Cervical x-ray (lateral)
C.T scan or MRI in decrease L.O.C.
Radiopaque drugs
Bezoars/Bags
Calcium carbonate
Chloral hydrate
Enteric-coated tablets
Heavy metals
Iodine
Fe
Phenothiazines
Potassium compounds
Other terminology
What is a toxidrome?(TOXICOLOGIC
SYNDROME)?
It is the association of several clinically
recognizable features, signs, symptoms,
phenomena or characteristics which often occur
together, so that the presence of one feature
alerts the physician to the presence of the
others.
Common toxidromes
Opiate toxidrome
Opiate toxidrome
Opiate toxidrome
Toxidromes
Opiates
Miosis
Respiratory depression
Cns 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
Common toxidromes
The cholinergic toxidrome
The cholinergic toxidrome
The cholinergic toxidrome
Toxidromes
Cholinergics-Muscarinic Effects
Salivation
Lacrimation
Urination
Defecation
Gastrointestinal
Emesis
Distress
TOXIDROME
CHOLINERGIC CNS EFFECT
RESTLESSNESS
AGITATION
CONFUSION
CONVULSION
COMA
DEATH
Toxidromes
Cholinergics-Nicotinic Effects
Muscle
Fasciculations
Weakness
Paralysis
Sympathomimetic effect
What toxidrome?
The anticholinergic toxidrome
Hot as a hare
Dry as a bone
Red as a beet
Mad as a hatter
Blind as a bat
The anticholinergic toxidrome
Hot as a hare
Dry as a bone
Red as a beet
Mad as a hatter
Blind as a bat
The anticholinergic toxidrome
Hot as a hare
Dry as a bone
Red as a beet
Mad as a hatter
Blind as a bat
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
What toxidrome?
Hallucinogenic
Toxidrome
disorientation
Amphetamine
hallucinations
Cocaine
hyperactive bowel
Pseudoephedrine
panic
Phencyclidine
seizure
Ephedrine
Hypertension
Tachycardia
Tachypnea
Benzodiazepenes
Hallucinogenic
Sympathomimetic toxidrome
disorientation
Amphetamine
hallucinations
Cocaine
hyperactive bowel
Pseudoephedrine
panic
Phencyclidine
seizure
Ephedrine
Hallucinogenic and
stimulants
Toxidrome
Hypertension
Tachycardia
Tachypnea
Benzodiazepenes
Hallucinogenic
Sympathomimetic toxidrome
Hallucinogenic
Toxidrome
disorientation
Amphetamine
hallucinations
Cocaine
hyperactive bowel
Pseudoephedrine
panic
Phencyclidine
seizure
Ephedrine
Hypertension
Tachycardia
Tachypnea
Benzodiazepenes
Hallucinogenic
Sympathomimetic toxidrome
Hallucinogenic
Toxidrome
disorientation
Amphetamine
hallucinations
Cocaine
hyperactive bowel
Pseudoephedrine
panic
Phencyclidine
seizure
Ephedrine
Hypertension
Tachycardia
Tachypnea
Benzodiazepenes
Hallucinogenic
Sympathomimetic toxidrome
Hallucinogenic
Toxidrome
disorientation
Amphetamine
hallucinations
Cocaine
hyperactive bowel
Pseudoephedrine
panic
Phencyclidine
seizure
Ephedrine
Hypertension
Tachycardia
Tachypnea
Benzodiazepenes
Common toxidromes
Sedative/hypnotic toxidrome
Sedative/hypnotic toxidrome
Sedative/hypnotic toxidrome
Common toxidromes
Serotonergic syndrome
Serotonergic syndrome
Serotonergic syndrome
Toxidromes
Sympathomimetics
Hypertension
Tachycardia
Psychomotor
Hyperthermia
Diaphoresis
Mydriasis
Agitation
Recognition of poisoning
May be difficult because of non-specific symptoms
High index of suspicion - especially occult
poisoning
history may be unreliable
look for corroborative history - missing pills, empty
container
Course that a poison runs (toxidromes) ! - may
help
Toxicology screening - helpful only in a few
Clinical manifestations
Very diverse and varied - depends on the
poison
Clinical examination should be focused on
the possible manifestations of common
poisons in the geographical area
Clinical manifestations
Skin and mucosal damage
Neurotoxic manifestations
Cardiovascular manifestations
Metabolic consequences
Eye manifestations
Hepatic dysfunction
When do you consider ICU?
Respiratory
Airway protection
Respiratory failure
Cardiovascular
Hypotension despite fluid challenge
Heart block, arrhythmias, QTc prolongation as in TCA
When do you consider ICU?
Neurologic
GCS < 8 (grade 3 and4)
Seizures
Metabolic
Hypoglycaemia
Significant electrolyte abnormalities
metabolic acidosis
Hepatic failure
Coagulopathy with bleeding
Goals of treatment
Goals of treatment
Reduce absorption of the toxin (xenobiotic)
Enhance elimination
Neutralise toxin
Reduce absorption of the toxin
Reduce absorption
Removal from surface skin & eye
Emesis induction
Gastric lavage
Activated charcoal administration & cathartics
Dilution - milk/other drinks for corrosives
Whole bowel irrigation
Endoscopic or surgical removal of ingested chemical
Reduce absorption
Skin decontamination
– Important aspect – not to be neglected
– Remove contaminated clothing
– Wash with soap and water (soaps
containing 30% ethanol advocated)
– However, no evidence for benefit even in
OP poisoning
Decontamination
Gastric decontamination
– Forced emesis if patient is awake by gag
stimulation or by ipecac(?)
– Gastric lavage
– Activated charcoal 1g/kg and MDAC in
some cases
– Sorbitol as cathartic
– 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
Early
following ingestion
Airway must be protected
Use the largest available tube
(40 French)
Contraindicated in caustic ingestions,
hydrocarbons, previous vomiting
Reduce absorption
Gastric lavage
Gastric lavage decreases absorption by 42% if done
20 min and by 16% if performed at 60 min
Performed by first aspirating the stomach and then
repetitively instilling & aspirating fluid
Left lateral position better - delays spont. absorption
No evidence that larger tube better
Simplest, quickest & least expensive way - funnel
Choice of fluid is tap water - 5-10 ml/kg
Choice of fluid is NL SALIN for children
Reduce absorption
Gastric lavage
Preferrably done on awake patients
Presence of an ET tube does not preclude
aspiration, though preferred if GCS is low
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
Anticholinesterases/
Cholinergics
(muscarinic effects)
Pralidoxime
(nicotinic effects)
-controversial in
carbamate
ingestions
Toxins and their Antidotes
Benzodiazepines
Botulism
Flumazenil
Botulinum antitoxin
Beta-blockers
Calcium channel blockers
Glucagon
Calcium
Carbon monoxide
Hyperbaric O2, O2
Cyanide, Nitrites
Amil nitrit;Na nitrit(3
thiosulfate(12.5g/50m
Toxins and their Antidotes
Digoxin
Digibind aka Digoxin Fab antibodies
Ethylene Glycol
Heparin
Iron
Isoniazid
Ethanol
Protamine
Deferoxamine
Pyridoxine
Toxins and their Antidotes
Lead
EDTA, BAL, DMSA
Methanol
Ethanol
Methemoglobin
Opioids
Methylene blue
Naloxone
Tricyclic antidepressants
Warfarin (Superwarfarins)
NaHCO3
Vitamin K
Enhance elimination
Enhance elimination
Increased elimination is possible only if
the drug is distributed predominantly in the ECF
has a low protein binding
the induced rate of elimination is faster than the
normal rate
hazards of having a longer time of exposure to the
drug are potentially fatal
Enhance elimination
Methods
Keep a good urine output 150-200 ml/hr
Alkalinisation of urine - clinical efficacy accepted
for salicylate & phenobarbital poisoning
Extracorporeal removal
– Hemodialysis - Barbiturates, Salicylates,
Acetaminophen, Valproate, Alcohols, Glycols
– Hemoperfusion - theophylline, digitalis, lipid
soluble drugs
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+ +ApKa
At a Urine pH < pKa
Non-ionized form
*Not excreted in urine
At a Urine pH > pKa
Ionized form
*Excreted in urine
Hemodialysis
Low
volume of distribution less than 1L/Kg
Low protein binding
Low molecular weight less than 500 DAL.
Also helpful in managing acidosis,
electrolyte abnormalities
Low fat solubility
High Water Solubility
Which drugs are high dialyzable?
Salicylates
Methanol
and ethanol
Lithium
Ethylene
glycol
Amphetamines
Theophylline
Vancomycin
(p. brophy)
CVVHD following HD for Lithium
6
L poisoning
Pt #1
HD started
Li Therapeutic range
i
0.5-1.5 mEq/L
5
CVVHD started
m 4
E
q 3
/
2
L
CT-190 (HD)
Multiflo-60
both patients
BFR-pt #1 200 ml/min
HD & CVVHD
-pt # 2 325 ml/min
HD & 200 ml/min
CVVHD
PO4 Based dialysate at
2L/1.73m2/hr
1
0
Pt #2
Hours
24
12
6
5
0
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
Paraquate
Complications of Hemoperfusion
Thrombocytopenia
Hypocalcemia
Leukopenia
Rigors
(p. brophy)
HEMOFILTRATION
optimal drug characteristics for removal:
relative molecular mass less than the cut-off of
the filter fibres (usually < 40,000)
small Vd (< 1 L/Kg)
single compartment kinetics
low endogenous clearance (< 4ml/Kg/min)
(Pond, SM - Med J Australia 1991; 154: 617-622)
(p. brophy)
Continuous Detoxification methods
CAVHF, CAVHD, CAVHP, CVVHF,
CVVHD, CVVHP
Indicated in cases where removal of
plasma toxin is then replaced by
redistributed toxin from tissue
Can be combined with acute high flux
HD
(p. brophy)
Intoxicants amenable to Hemofiltration
vancomycin
methanol
procainamide
hirudin
thallium
lithium
methotrexate
(p. brophy)
Plasmapheresis / Exchange Blood
Transfusions
Plasmapheresis
(Seyffart G. Trans Am Soc Artif Intern
Organs 1982; 28:673)
role in intoxication not clearly established
most useful for highly protein bound agents
Exchange Blood Transfusions
Pediatric experience > than adult
Methemoglobinemia
overall very limited role in poisoning
Summary
Poisoning a common problem in our country
A high index of suspicion required to diagnose
Know common toxidrome
Don’t panic and follow a plan of action
Decreasing absorption
Enhancing elimination
Neutralising toxins
Avoid potentially harmful Rxs - risk vs benefit
Thank you
Case Presentation 1
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-pbenzoquinoneimine (NAPQI)
NAPQI
Electrophile
Covalently binds to hepatocytes
Results in cell death
Half life is about
POTENTIAL TOXICITY
Acute: 7g (10g)
Chronic: 4g per day (7g)
Susceptible patients (alcoholics,
ACs, INH)
Similar risk for acute ingestion
Potential higher risk in chronic
ingestions (4g)
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
N-ACETYLCYSTEINE
Very effective – 100% within 8 hours
Oral in U.S. – IV in Europe
Dose: 140mg/kg load, 70mg/kg Q 4hrs
Traditional – 72 hours
Short course – reassess at 20 hours
INTRAVENOUS NAC
Oral preparation vs Acetadote®
Concern is anaphylactoid reactions
Indications:
Can’t tolerate oral NAC
Contraindication to oral therapy
Ongoing GI decon (coingestant)
Fulminant hepatic failure?
Pregnant patient?
N-acetylcysteine (NAC)
mechanism
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
Use hydrocortisoe and antihistamin in
sensitvity cases
Review of case
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.