Toxicology Toxidromes

Specific symptom complexes used to categorize exposure

The Problem: Sympathomimetic/stimulant
~ 2,300,000 exposures/year Depressant
50% (>1,000,000) involving children Cholinergic
MC at home Anticholinergic
60% involved medicinal agents Miscellaneous
Under-reporting problems Delayed Toxicity
Extended release preparations
Top Acute Poisonings Antihypertensives, theophylline, hypoglycemic agents
10% Cosmetics and personal care Slow onset
10% Analgesics anticoagulants
8% Cleaning Substance Anticholinergic effect
5.2% Foreign Bodies/Toys decreased gut motility and delayed absorption
4.8% Topical Preparations Diphenhydramine, cyclic antidepressants
4.0% Pesticides Treatment
3.2% Antihistamines Remove from dangerous environment
3.1% Bites/Envenomation Skin decontamination if indicated
3% Sedative/Hypnotics Remove clothing (use caution)
2.6% Cough and cold preps Wash skin and irrigate eyes PRN
2.1% Plants Supportive care usually more important than most other therapy
Airway protection and ventilation
Clinical Evaluation Sedation for agitation
History Blood pressure/perfusion control
Why: accidental, intentional (about 10-15% of cases) Acid-base and electrolyte balance
Where: home, workplace, outdoors Temperature regulation
What: medications, plants, chemical at work
When: onset, how long since exposure
Sequence of events: seizures, lethargy, etc
Assessment
A - airway: patency, suctioning, odor Gases
B - breathing: cyanosis, oxygen, intubation Simple asphyxiants (e.g. nitrogen, CO2 )
C - circulation: capillary, pulse, pressure o No direct toxicity.
D - disability: LOC, movement, pupils o Injury is due to displacement of oxygen hypoxia
E - expose: undress, remove surface toxins Irritants many gases and agents
The Poison o Ex: bleach & ammonia noxious gas
Medical history o Generally non-toxic with notable exceptions
EMS or family/friends o Water soluble agents irritate mucous membranes
Containers and medication vials Chlorine
Employer/co-workers o Illness is self-limiting and recovery is usually rapid.
MSDS and the internet Cyanide (CN)
Poison Control Center 1-800-222-1222 o bitter almond odor on the patients breath
The Red Herrings o Cellular interference with oxygen utilization O2
Illness and poisoning mimic each other saturation in blood
Conditions may co-exist o cytochrome a-a3
Verify exposure/ingestion if possible o Poisonous & rapidly absorbed
Rule out metabolic and traumatic causes Carbon monoxide
Vital signs - vital for a reason o Odorless, colorless from carbon combustion
Metabolic Acidosis DDX Car exhaust, smoke inhalation,
Consider toxiciology if the pt isnt septic, hypotensive or o Binds to Hgb (displaces O2) O2 delivery
hypoperfusing o Suspect if HA & acute AMS
M - methanol Hydrogen sulfide (H2S)
U - uremia knock down gas in grain silos
D - DKA Inhibits cytochromes hypoxemic
P - paraldehyde Initial sulfur odor then fatigue of olfaction
I - iron, INH Deadly after prolonged exposure
L - lactic acidosis Not the same at grain-fillers disease
E - ethylene glycol, ethanol
S - salicylates
Complicating Conditions
Chronic disease (hepatic, renal)
Ibu & renal insufficiency
Pregnancy crosses placenta
Current medication:
P450 inhibition or induction
Watch for inhibitors like tagament
Drug-drug interactions
Drug dependency
Opioids & reversing withdraw
Gut decontamination
Emesis make them vomit
Spontaneous emesis may not be sufficient
Syrup of ipecac - traditional
extract from Cephaelis ipecacuanha shrub
Central and intestinal emetic receptors
Fairly rapid onset - 17 minutes
Not recommended routinely anymore
Contraindicated in
caustic and hydrocarbon exposure
LOC, seizure
delayed medical attention
Repeated or violent vomiting
Mallory-Weiss, Borhaave
Gastric lavage pumping out the stomach
o Large bore catheter to remove stomach contents
o Aliquots of water or saline used until clear
o Not effective if delayed (1 hour), limited in # can be
removed
o Need for patent airway - risk of aspiration
Adsorption stick something to the substance
Adhere toxin to non-absorbable substance
Resins, clays, charcoal
Activated charcoal
MC used recommend for home
Controlled wood burning and CO2
Pores in each particle so huge SA
Usual dose 0.5 - 1 gm/kg
Low efficacy for certain agents, e.g.
electrolytes - K+, Li+
alcohols (20:1)
hydrocarbons
Contraindicated in
caustics or perforation
MDAC- multi dose activated charcoal
Giving repeated doses , Q4 - 6 hours
Best for entero-hepatic circ
drug eliminated through bile and reabsorbed
Works even if drug is not taken PO
Prevents the reabsorption half-life, elim rate
e.g. theophylline, phenobarbital, phenytoin
Polystyrene (Kayexalate), Fullers earth, Bentonite (kitty litter)
Cathartics make the guts move along
Usually given in conjunction with charcoal
GI motility in eliminating charcoal-toxin complex
Traditional use, not proven of benefit
Usually recommended for first charcoal dose only
sorbitol, magnesium citrate or sulfate
Whole bowel irrigation
PO admin of polyethylene glycol to eliminate gut contents
Golytely, Colyte
Given 0.5 to 2 L/hr until clear effluence
Non-absorbable, osmotically balanced
Used for packets (drug mules), extended release products and
foreign bodies
Elimination
Renal Elimination use kidney flow & pH to elim
Small molecules filter through glomerulus and get reabsorbed in
tubules (variable)
Ion trapping
Ionized molecules not reabsorbed well from the renal
tubules
Ex: if kidney is positively charged & convert ASA to
positive charge, it will bounce off it & less likely to be
reabsorbed
Varying urinary pH changes ionization and enhances total body
clearance & prevent reabsorption
Most efficient if Vd is small
For weak acid, goal is urine pH 7.5 - 8.5 so it is ionized more
Sodium bicarbonate
elim of Aspirin
Hyperventilation
If pt is intubated, will make them alkalotic
For weak base, goal is urine pH 5.5 - 6.5
ammonium chloride
ascorbic acid
Not recommended anymore bc risk systemic
acidosis (HR , hypotensive)
Supportive care is preferred
Forced diuresis
aggressive IV fluid + loopdiuretic
fluid and electrolyte disturbances
Hemodialysis
Passing blood adjacent to a membrane allowing diffusion across
into dialysate fluid
Requires dialysis (venous) catheter
Very effective for small toxins with VD
alcohols
electrolytes
Not effective for large Vd
Good if poor kidney function or need to elimination
Peritoneal Dialysis
Infusion and removal of fluid into the peritoneal cavity for renal
failure
Requires peritoneal catheter
Not useful in toxicology: clearance ~ 1/10 of hemodialysis
Hemoperfusion (dialysis + charcoal cartridge)
Passing blood through a column of adsorbant particles (charcoal,
resin)
Removal of larger molecules (113 - 40,000 Daltons)
Clearance better than HD if adsorbable
barbiturates, theophylline, methaqualone,
meprobamate
glutethimide, paraquat, trichloroethanol, ethchlorvinyl
Transient glucose, Ca+, platelets and leukocytes
Rarely used
Hyperbaric Oxygen
Chamber of pressurized air/oxygen
Allows serum to carry oxygen when rbcs cannot (carbon
monoxide) - 6x the O2
Forces gradient when enzymes poisoned (H2S, cyanide, CO)
Small risk of seizure, pneumothorax, air embolus
Intravenous Lipid Emulsion
Use of IL20 and similar compounds
Alters bodys volume of distribution (fat/sponge)
Successful use in local anesthetic overdose (bupivicaine)
Theoretical benefit in other lipophilic drugs
*Off-label and experimental* - case reports and animal models
Antidotes
Range from true reversal of toxicity to enhancement of elimination
Varying cost - charcoal to immune (Fab) globulins ($10 - $10,000)
Some can be more dangerous than the toxin
(horse serum, physostigmine)
Acetaminophen, APAP, Paracetamol NAC Therapy

Replaced aspirin as the MC used antipyretic prior to the release of NAPQI

NSAIDS.
NAC Glutathione
MC medicinal exposure reported to poison control centers N-acetylcysteine

Generally, very safe with a large therapeutic window

Normal doses are non-toxic (~10-15 mg/kg) Non-toxic metabolites
(Mercaptate,cysteine conjugates)
Large overdoses saturate normal pathways and push metabolism to a PO form
toxic one (chart) traditional US treatment, Q4hrs
Need a dose above 200 mg/kg to be toxic Required 72 hrs of poorly accepted tx foul taste
Hepatic glutathione prevents toxicity until less than 30% left (8 hours) IV form
100% recovery rate if treated in the 1st 8hrs shorter, 20-hr course,
Diminished recovery if treated w/in 15hrs recent FDA approval, used off-label prior.
APAP Metabolism
Rate-related anaphylactoid response
Releases histamine
APAP
Flushing, hypotension
Reduce the rate
Glucoronide Sulfonation P450

Aspirin/Salicylate
40-67% 20-46% 5-15% Potent anti-inflammatory, antipyretic, analgesic
Found in several products
Non-toxic Non-toxic NAPQI-toxic OTC headache powders, oil of wintergreen, topical liniments
Once the Glucoronide & Sulfonation systems are saturated (bengay), bismuth preparations (pepto)
in OD, the P450 system is used In standard doses (~15 mg/kg) inhibits inflammatory cascade
P450 system is what forms NAPQI Stimulates respiratory centers
Peds use sulfonation more so they tend to be more resilient In overdose, uncouples oxidative-phosphorylation
to APAP overdose than adults Creates acidosis and extreme heat production
Alcoholics & patients taking INH have P450 activity & Clinical Presentation
risk for hepatotoxicity Ototoxic causes tinnitus
Very toxic in overdose Mixed respiratory alkalosis with metabolic acidosis may be difficult to
Hepatotoxic metabolite - NAPQI diagnose
Toxicity = AST or ALT > 1,000 Hyperthermia can be severe (~108F)
Untreated can lead to hepatic failure and death without liver transplant Penetrates CNS and causes confusion, stupor, and coma in large
Management ingestions
APAP level should be drawn 4 hours after ingestion (absorption & Inhibits platelet function potential hemorrhage
distribution) Levels not reliable acidosis causes decreased serum presence and
Baseline LFTs, repeat daily if toxic increased tissue penetration
Coagulation panel if LFTs elevated Chronic intoxication subtle CNS, NCPE (noncardio pulm edema)
Renal function and bicarbonate Chronic intoxication does not require as high of doses as
Once toxicity established, repeat APAP levels of no use (i.e. toxic acute to be toxic
is toxic) Treatment
Aimed at reducing further absorption and eliminating what is present
Rumack Matthew Nomogram Activated charcoal effective adsorption
Prognosticates need for tx with NAC NaHCO3 very effective therapy
Starts with 4hrs post ingestion o tissue binding less CNS toxicity
Single ingestion if the time is knownnot for chronic OD o renal elimination ion trapping
Doesnt factor in chronic liver disease o Treats metabolic acidosis
Infers the amount of NAPQI based on the APAP levels, time Alkalinize serum and urine (pH 8 ), watch potassium
since ingestion Hemodialysis and hemoperfusion warranted in severe cases coma,
unstable vitals, persistent toxicity
Peritoneal dialysis not effective
Multidose charcoal and whole bowel irrigation controversial in
ingestion

Reyes Syndrome
Hepatic disease associated with aspirin use in children treated for viral
illnesses flu, varicella, measles
Nausea, vomiting, elevated LFTs, fatty liver, coma
Mechanism unknown, but decreased incidence with reduction of aspirin
use

N-acetylcysteine NAC
Regenerates hepatic glutathione and detoxifies NAPQI
Admin w/in 8 hours of a toxic ingestion for maximal benefit
Toxic Alcohols Ethanol Tx Dosing
Goal - maintain 100 mg/dl
Ethylene Glycol Theoretical load of 0.6 g/kg but 0.8 g/kg
Sweet, viscous fluid used for metabolism during load
Used extensively in industry Infuse as E10 or E20 in 20 - 60 min
antifreeze air-conditioning, inks, pesticides Maintain infusion to elimination rate
Accelerant in fermentation (ethical?) 4 Methylpyrazole (Antizol)
Fluorescein (Woods lamp) gives it the green color, allows us to track Competitive inhibition of ADH
it Allows alternate elimination of alcohol
Dynamics: without toxic metabolite formation
Fairly rapid absorption and distribution Easy IV dosing:
Peak levels in first few hours Load 15 mg/kg
Metabolized endogenously (ADH first) Then 10 mg/kg q12o for 4 doses
Some renal excretion: < 20% parent Pros:
Negligible pulmonary elimination wont breathe it out Eliminates need for HD or ICU
T1/2 = 3 - 4 hours (parent) Intravenous form
Metabolites toxic ~ 6 - 12 hours later Easy dosing schedule (q 12o)
Complex pathway to glycolic and oxalic acid products Cons:
Oxalic acid is worst Expensive: $ 4,000
Clinical Presentation Might not eliminate need for
Initial CNS effects similar to ethanol: dialysis
Nausea / vomiting Availability (or lack thereof)
Inebriation Hemodialysis - removal of toxin
CNS depression and lethargy Direct elimination of the alcohol & its toxic metabolites
Seizures Low Vd (~0.8) makes HD highly effective
Effects seen early (unmetabolized EG) before it gets metabolized Readily available at most hospitals
Can lead to severe acidosis Indications:
anion and osmolal gap Metabolic acidosis
Low EG levels seen early and late Renal insufficiency / failure
Leukocytosis Serum ethylene glycol > 25 mg/dl
Oxalic acid calcium oxalate Peritoneal dialysis has no role
Development of profound hypocalcemia Risks/Problems:
QT segment prolongation Vascular access and its complications
dysrhythmias Expense
Muscle tetany Hypotension
EG Organ Toxicity Adjustment of ethanol infusion
Urinalysis: More than one session may be needed
Calcium oxalate and hippurate crystals Methanol a.k.a. Methyl alcohol, wood alcohol
deposit in renal tubules - Clear, colorless, flammable liquid, volatile
Acute tubular necrosis with hematuria and Found in windshield fluid, canned fuels sterno, paint thinners,
renal insufficiency or failure embalming fluid, home brews
Late findings > 24h: can be produced from fermentation of pectin
Cardiac failure Dynamics:
pulmonary edema Very rapid absorption: peaks ~ 1 hour
Death Pulmonary and dermal absorption
Treatment ADH metabolism primary
Removal from stomach (not efficient) Metabolized to formaldehyde and then formic acid
Activated charcoal - theoretical benefit Some pulmonary (15%) and renal (3%) excretion
Supportive care, fluids, electrolytes ca+ T1/2 = 3 hours, ~ 40 hours with ethanol
Alkalinize urine - glycolates excreted easier in ionized form Clinical Presentation
Theoretical: Initial CNS effect of alcohols
Thiamine: glyoxilic acid to a-oh-b ketoadipic acid Development of severe acidosis
Pyridoxine: glyoxilic acid to glycine Retinal toxicity - hyperemia of optic disc, retinal edema, loss of light
Blockade of metabolism reflex
Ethanol Symptoms: snowstorm, blizzard, blindness
Ethanol is preferentially metabolized over Toxicity can develop early or late (up to 72 hours later)
other alcohols by ADH. anion and osmolal gap
EG t1/2 increases to 17 hours Levels may be low despite toxicity (metabolites)
Parent alcohol eliminated unchanged Treatment
IV and PO forms Supportive care, acid-base, electrolytes
Cheap and readily available (PO) Removal from GI tract
Cons of Ethanol tx: Activated charcoal - 20:1 ratio
Inebriation of patient Sodium bicarbonate - May require large amounts
Need to maintain level for Metabolic inhibition: Ethanol and 4-MP therapy
blockade Folate may help enhance elimination
Highly variable metabolism Hemodialysis
Maintenance - need to check Level > 25 mg/dl
levels Acidosis
Hypoglycemia Visual complaints
Isopropanol Antidotes
Isopropyl alcohol or rubbing alcohol Immune Globulin Fab
Clear, colorless, flammable liquid VERY specific, effective, expensive
Volatile Currently used for:
Used in toiletries, window cleaners, solvents, antifreeze Digoxin (Digibind TM)
Dynamics: reverses effects, even beneficial ones
Rapid absorption and distribution Snake envenomation (CroFab TM)
ADH primary metabolism to acetone
Small renal and pulmonary (larger for acetone) elimination Naloxone
Variable elimination half life (1st order) Competitive antagonist of opiate receptors
Dermal and pulmonary absorption Complete reversal of opiate toxicity with appropriate doses
Clinical Presentation Parenteral administration
Initial CNS toxicity Short effective life vs. relatively long toxin
High ketone levels (acetone) Can induce withdrawal in dependent state
Abdominal pain, gastritis
No acidosis despite osmolal gap Flumazenil
Can progress to hypotension and coma with large exposures Receptor antagonist of benzodiazepines
Treatment Good for acute toxicity
Removal and adsorption i.e. oversedation or single dose ingestion
Supportive care main therapy Avoid in
hemodialysis for severe cases only mixed ingestions
seizure disorder
Alcohols Summary chronic use or dependence
Easily dialyzed
Small size/weight, low Vd Chelators
All create osmolal gap Multiple agents in this category
Not all create an acidosis Bind to heavy metals for removal in urine
Isopropanol doesnt May acutely raise levels and worsen CNS, liver, or renal toxicity
Level of parent alcohol not reliable Treatment usually over weeks
Small amounts are very toxic Pb, Hg, Fe, As, et al
1 cc/kg ! Fringe theory treatment

Anticholinergic Testing
Mad as a hatter (confusion) Urine
Blind as a bat (midriasis) Urine generally better than serum
Hot as a hare (hyperthermia) cheaper, larger screening panel
Red as a beet (cutaneous vasodilatation) blood good for serum levels of specific drugs
Dry as a bone (anhydrosis) Blood/serum
Clinical Presentation Hair
Similar to sympathomimetic Nails
tachycardia, hypertension, agitation Breath
dry vs. wet skin not always reliable Vitreous fluid / spinal fluid
Slowed GI motility EMIT
Urinary retention TLC
Pupils usually significantly dilated HPLC
E.g. diphenhydramine, TCAs GC/MS
Treatment
Treatment is usually supportive Legal Considerations
Physostigmine a carbamate that can induce cholinergic effects Privacy
to counter poison Employment
Adult dosage usually 500mg-2gm Chain of evidence
Required testing