Lecture 24 Flashcards
What is ethylene glycol (EG)?
The chemical found in most automotive ________ _______ products
◦ Not all products have EG: some contain _________ glycol (also toxic)
◦ Antifreeze component in windshield washer fluid most often ________ (also toxic)
Usually comes as _____% EG in undiluted product.
Diluted 50/50 with water in radiator
The chemical found in most automotive radiator antifreeze products
◦ Not all products have EG: some contain propylene glycol (also toxic)
◦ Antifreeze component in windshield washer fluid most often methanol (also toxic)
Usually comes as 95% EG in undiluted product.
Diluted 50/50 with water in radiator
Minimum lethal dose
Dogs
◦ ____-____ ml/kg undiluted
◦ 10 kg dog: ~ 50 ml (~1/4 cup), ~ 25 licks
Cats
◦ _____-____ ml/kg undiluted
◦ 5 kg cat: ~7.5 ml (~ ½ tablespoon)
Dogs
◦ 4.4 - 6.6 ml/kg undiluted
◦ 10 kg dog: ~ 50 ml (~1/4 cup), ~ 25 licks
Cats
◦ 0.9 - 1.5 ml/kg undiluted
◦ 5 kg cat: ~7.5 ml (~ ½ tablespoon)
How does EG taste?
Misconception that EG tastes good? Dogs avoid
EG if other water sources are available
◦ Dec 2012: Antifreeze manufacturers in USA agreed
to add bittering agent
Why does EG poisoning commonly occur?
Most commonly see poisoning if: (i) no other
water source is readily available for thirsty animal,
(ii) puppy chews on product container, (iii) cat
walks through antifreeze spill and grooms self
EG is readily absorbed from the ____ _______
◦ Peak blood conc. ~ __-__ h post-ingestion
◦ ~50% is excreted _________ in urine
◦ ~50% metabolized in ______ to toxic metabolites – a bunch of nasty acid metabolites
Acid metabolites cause metabolic ______ – can be fatal. Also directly injure ____ cells – can be fatal
Calcium in blood & urine combines with ____ ___
◦ Form _______ that precipitate in kidney and elsewhere
◦ Contribute to renal ______
◦ Crystals can be seen ~___ h post-ingestion in dogs and ~___ h in cats
EG is readily absorbed from the GI tract
◦ Peak blood conc. ~ 1-4 h post-ingestion
◦ ~50% is excreted unchanged in urine
◦ ~50% metabolized in liver to toxic metabolites – a bunch of nasty acid metabolites
Acid metabolites cause metabolic acidosis – can be fatal. Also directly injure renal cells – can be fatal
Calcium in blood & urine combines with oxalic acid
◦ Form crystals that precipitate in kidney and elsewhere
◦ Contribute to renal failure
◦ Crystals can be seen ~6 h post-ingestion in dogs and ~3 h in cats
What are the stages of EG toxicosis?
Stage 1: CNS phase
Stage 2: Acidotic phase
Stage 3: Renal failure phase
When do the clinical signs of Stage 1 EG toxicity appear?
◦ ____ min to ____ h post-ingestion
◦ Signs are due to effects of __________ EG
Clinical signs
◦ 30 min to 12 h post-ingestion
◦ Signs are due to effects of unmetabolized EG
What are the CNS signs of Stage 1 EG toxicity?
CNS signs: ataxia/incoordination, inebriation.
Some vomit (due to gastric irritation)
PU/PD, dehydration
◦ Due to osmotic and central effects of EG
(stimulation of the thirst center)
Owners often do not know animal is ill
◦ Clinical signs may be mild in some animals. Some
curl up and sleep it off
How do you Dx Stage 1 EG toxicity?
Ethylene glycol test kits (PRN Pharmacal, Pensacola, FL)
◦ A colorimetric assay to indicate the presence of EG
◦ Can be done on whole blood or serum
Biochemical profile
◦ Increased osmolarity
◦ Phosphorus may be elevated –> Due to ↓GFR and phosphate rust inhibitors added to antifreeze solutions
Urinalysis
◦ Negative at this point
Wood’s lamp
◦ Sodium fluorescein sometimes in antifreeze
◦ Examine urine, vomit, face or paws
EG test kit
EG conc. must be > ____ mg/dL to get positive
◦ Note: ____ can ingest lethal dose and never get a positive
False negative if:
◦ Test too early – not enough ______
◦ Test too late – all EG ________
Best test window: ___-___ h post-exposure
False positive with compounds of _________
structure e.g:?
EG conc. must be > 50 mg/dL to get positive
◦ Note: Cats can ingest lethal dose and never get a positive
False negative if:
◦ Test too early – not enough absorbed
◦ Test too late – all EG metabolized
Best test window: 1-24 h post-exposure
False positive with compounds of comparable
structure e.g:
◦ Propylene glycol
◦ Metaldehyde
◦ Sorbitol
◦ Glycerol
◦ Others
Wood’s lamp
Fluorescein is added to EG to detect leaks
Gives green fluorescence in UV light
What are the principles of treatment of EG toxicity?
Want to ______ EG from going down its metabolic pathway
◦ ___________ production of toxic acid metabolites
Force EG to be excreted ________ in urine
◦ EG is _____ toxic than its metabolites
◦ EG has CNS toxicity similar to ______ but is not
________ and does not cause _________
Want to stop EG from going down its metabolic pathway
◦ Prevent production of toxic acid metabolites
Force EG to be excreted unchanged in urine
◦ EG is less toxic than its metabolites
◦ EG has CNS toxicity similar to alcohol but is not
nephrotoxic and does not cause acidosis
How do you treat EG toxicity?
_________ and __________ may be indicated depending on the stage of the toxicosis. Will discuss the antidotes
Two antidotes are available?
Decontamination and antidote may be indicated depending on the stage of the toxicosis. Will discuss the antidotes
Two antidotes are available:
◦ 4-methylpyrazole (fomepizole; 4-MP)
◦ Ethanol
◦ Use one or the other – NOT both together
4-methylpyrazole (fomepizole, 4-MP)
Fomepizole inhibits ______ so that EG cannot bind with it
◦ A very effective _________ inhibitor of ADH.
ADH has ____-_____x higher affinity for 4-MP than
ethanol
It is the drug of choice in ____, and has been shown to be effective in ____
◦ Dose needed in cats is MUCH _______ than in dogs (e.g., loading dose: 125 vs. 20 mg/kg)
Need to treat _____ after EG ingestion
◦ Best if tx within first __ h in dogs, first ___ h in cats
4-methylpyrazole (fomepizole, 4-MP)
Fomepizole inhibits alcohol dehydrogenase (ADH) so that EG cannot bind with it
◦ A very effective competitive inhibitor of ADH.
ADH has 500-1000x higher affinity for 4-MP than
ethanol
It is the drug of choice in dogs, and has been shown to be effective in cats
◦ Dose needed in cats is MUCH HIGHER than in dogs (e.g., loading dose: 125 vs. 20 mg/kg)
Need to treat SOON after EG ingestion
◦ Best if tx within first 5 h in dogs, first 3 h in cats
Vet product: Antizol-Vet® (Paladin)
◦ FDA approval withdrawn in April 2015 at the
request of manufacturer (Paladin)
No new lot of the drug since October 2014
The last lot of Antizol-Vet sold had an expiry date of
August 2017
◦ Comes as 1.5 g kit for injection. One kit will
treat a 58-lb dog
Human product: Antizol® (Paladin)
◦ Comes as 1 g/mL in 1.5 mL vials
What to do without Antizol-Vet® ?
Use:
◦ Compounded versions
◦ Human-use fomepizole
◦ Ethanol
Note: the manufacturer requested Antizol-
Vet® withdrawal because of low demand
◦ Drug too expensive and not enough profits
Fomepizole
Dogs
◦ Load with 20 mg/kg IV then give 15 mg/kg IV 12 and
24 h post initial dose. At 36 h post initial dose give 5
mg/kg IV. May give additional 5 mg/kg doses if
necessary (until EG test become negative)
Cats
◦ Much higher dose required to inhibit ADH in cats
than dogs.
Load with 125 mg/kg slow IV injection then give q12h
at 31.25 mg/kg IV for 3 treatments
Adverse effects? Almost none
◦ Rare cases of short-duration salivation and tremors
◦ Mild sedation in cats
Ethanol
___________ inhibitor of ADH
◦ Has _____x higher affinity for ADH than EG
Not as effective as _________
MUCH MORE TOXIC than ________
◦ Very ___________ margin of safety
◦ Amount needed to outcompete EG is very close to the ________ dose in dogs and cats
◦ Puts animal into a drunken stupor for __-___ days
◦ Use only if ________ is not available
Competitive inhibitor of ADH
◦ Has 100x higher affinity for ADH than EG
Not as effective as fomepizole
MUCH MORE TOXIC than fomepizole
◦ Very narrow margin of safety
◦ Amount needed to outcompete EG is very close to the lethal dose in dogs and cats
◦ Puts animal into a drunken stupor for 2-3 days
◦ Use only if fomepizole is not available
Ethanol
Note: proof is considered ___X the % of ethanol, e.g., 40% ethanol = ___ proof
2, 80
Ethanol
Availability
◦ ________ grade ethanol from vet supplier. ______ in US, more _________ in Canada
◦ _____% ethanol available in liquor stores in US
◦ In Canada liquor stores mostly stock ____% ethanol
Dilute down to much ______ concentration
(___%) before administering
Cost
◦ Ethanol is cheap, but intensive nursing care and
hospitalization increase cost
◦ Cost of overall Tx is probably higher than if
fomepizole is used
Availability
◦ Medical grade ethanol from vet supplier. Cheap in US, more expensive in Canada
◦ 95% ethanol available in liquor stores in US
◦ In Canada liquor stores mostly stock 40% ethanol
Dilute down to much lower concentration
(20%) before administering
Cost
◦ Ethanol is cheap, but intensive nursing care and
hospitalization increase cost
◦ Cost of overall Tx is probably higher than if
fomepizole is used
Ethanol
Can give either as _______ or as ______ boluses
◦ CRI has no _____ & ________ hence more effective
◦ Bolus injections have peaks & troughs –> less
consistent inhibition of ADH
Can give either as constant rate infusion
(CRI) or as repeated boluses
◦ CRI has no peaks & troughs hence more effective
◦ Bolus injections have peaks & troughs less
consistent inhibition of ADH
Ethanol dosing
Dogs
◦ 20% solution: give 5.5 mL/kg IV q4h for 5
treatments then q6h for 4 additional treatments.
Administer each dose as CRI over 1h
Cats
◦ 20% solution: give 5 mL/kg IV q6h for 5
treatments then q8h for 4 additional treatments.
Administer each dose as CRI over 1h
Ethanol adverse effects
MANY. Animal in ______-______ drunken state for the duration of Tx
◦ CNS _________
◦ Respiratory _________
◦ Osmotic ______ and _________
Can easily progress to ______
Animal needs intensive care when treated with ethanol
MANY. Animal in semi-comatose drunken state for the duration of Tx
◦ CNS depression
◦ Respiratory depression
◦ Osmotic diuresis and dehydration
Can easily progress to death
Animal needs intensive care when treated with ethanol
Disadvantages of ethanol
Enhances many of the ____________ effects of EG
Ethanol is CNS ___________. This is the most important factor limiting the use of ethanol as an
antidote
Ethanol is metabolized to ___________ which impairs ________ metabolism and is a cerebral
_________
Ethanol contributes to metabolic acidosis by enhancing formation of _____ acid from ________
Ethanol may potentiate __________
Ethanol compounds the effects of EG-induced
osmotic diuresis and serum hyperosmolality
Enhances many of the metabolic effects of EG
Ethanol is CNS depressant. This is the most important factor limiting the use of ethanol as an
antidote
Ethanol is metabolized to acetaldehyde which impairs glucose metabolism and is a cerebral
irritant
Ethanol contributes to metabolic acidosis by enhancing formation of lactic acid from pyruvate
Ethanol may potentiate hypocalcemia
Ethanol compounds the effects of EG-induced
osmotic diuresis and serum hyperosmolality
What are the clinical signs of Stage 2 Ethylene Glycol Toxicity?
Stage 2 – Acidotic phase
Clinical signs
◦ From ~8h post-ingestion
◦ Metabolic acidosis
◦ All systems are affected
◦ Vomiting, depression, anorexia, weakness,
tachypnea, cardiac arrhythmias, coma, death
◦ Many animals die during this stage
How do you Tx Stage 2 Ethylene Glycol toxicity?
Ethylene glycol test will be ________ for most cases
Wood’s lamp (urine) __________
Fluorescein ___________ in urine
Ethylene glycol test will be positive for most cases
Wood’s lamp (urine) positive
Fluorescein fluorescence in urine
What would you see on UA in Stage 2 Ethylene Glycol toxicity?
Calcium oxalate crystalluria
◦ Picket fence posts, dumbbell, and cross forms
Ca oxalate monohydrate and dihydrate
Stage 2 DX: Urinalysis
Dihydrate (square envelopes)
Monohydrate (picket fence, rods, dumbbells)
How do you Dx Stage 2 Ethylene Glycol Toxicity with Ultrasound?
Precipitation of ____ _______ crystals in renal
_______ and ________ with _____ line between (______ effect) in dogs
Renal cortical _________ is increased
Precipitation of Ca oxalate crystals in renal
medulla and cortex with clear line between (halo effect) in dogs
Renal cortical echogenicity is increased
Stage 2 Anion Gap
Elevated by ____ h post-ingestion
Remains _________ for duration of toxicosis
Anion gap = ([Na+] + [K+]) – ([Cl-] + [HCO3-])
◦ Note: TCO2 ~ HCO3-
Normal AG = ~___-____ mEq/L
Elevated AG is due to ____ metabolites (acids)
and _________ serum HCO3- because HCO3- is
used to buffer ____
Elevated by 3 h post-ingestion
Remains elevated for duration of toxicosis
Anion gap = ([Na+] + [K+]) – ([Cl-] + [HCO3-])
◦ Note: TCO2 ~ HCO3-
Normal AG = ~8-20 mEq/L
Elevated AG is due to EG metabolites (acids)
and reduced serum HCO3- because HCO3- is
used to buffer H+
Stage 2 Serum osmolarity/osmolality
Increased by ___ h
◦ Can remain high for more than _____ h
◦ Due to _____
Measured with an _____________
Normal osmolarity = ____ to ____ mOsm/L
Increased by 1 h
◦ Can remain high for more than 18 h
◦ Due to EG
Measured with an osmometer
Normal osmolarity = 280 to 310 mOsm/L
Osmometer: It measures ______ osmotically active particles in _______. This includes ___ and its _________.
Osmometer: It measures ALL osmotically active particles in serum. This includes EG and its metabolites.
Osmolar Gap
Difference between _________ (with osmometer) osmolarity and _________ osmolarity
Normal osmolar gap is ___ mOsm/L
EG intoxication increases osmolar gap to >/= ____ mOsm/L
◦ Reason: EG and its metabolites are measured
by an osmometer but are not considered in the __________ used to calculate osmolarity.
To estimate serum EG conc. (mg/dL) multiply osmolar gap by 6.2 (Mw of EG (62)/10)
Difference between measured (with osmometer) osmolarity and calculated osmolarity
Normal osmolar gap is 10 mOsm/L
EG intoxication increases osmolar gap to
>/= 60 mOsm/L
◦ Reason: EG and its metabolites are measured
by an osmometer but are not considered in the formula used to calculate osmolarity.
To estimate serum EG conc. (mg/dL) multiply osmolar gap by 6.2 (Mw of EG (62)/10)
How to calculate plasma osmolality
Osmolarity vs Osmolality
Measures of osmotic concentration
Osmolarity = millimoles of solute per _____ of solution
Osmolality = millimoles of solute per _______ of solution
Measures of osmotic concentration
Osmolarity = millimoles of solute per liter of solution
Osmolality = millimoles of solute per kilogram of solution
Stage 2 Treatment
Briefly:
◦ Too late to decontaminate
◦ Need to correct acidosis and dehydration
Give fluids with bicarb. Dose of bicarb is
calculated as:
Bicarbonate replacement (in mEq) = HCO3- deficit
x 0.3 x body weight (kg)
where 0.3 indicates that the treatable volume
(ECF) is 30% of body weight and,
HCO3- deficit (mEq/L) = desired HCO3- - measured HCO3-
Antidote (Fomepizole) needed for as long
as unmetabolized EG is in the body
Symptomatic/supportive care
Stage 3 – renal failure phase
Clinical signs
◦ 24-96 h post-ingestion of EG. Earlier in cats: azotemia
at 12 h, renal failure at 24 h
◦ Renal failure: vomiting, anorexia, depression,
dehydration, abdominal pain, etc.
◦ Coma, death
These are the animals that survived stages 1&2
Apparent “recovery” period between acidosis
stage and renal failure stage
◦ Owner thinks animal is getting better and waits to
bring in
Stage 3 Dx
Biochemical profile
◦ Severe __________ (elevated _____ & _________)
Urinalysis
◦ Can see ______-; sometimes almost ________-
Ultrasound
◦ Increased renal ________- with _______- effect
________ palpation
◦ Can be VERY _______!!
◦ _________, _________- capsule
Stage 3 Dx
Biochemical profile
◦ Severe azotemia (elevated BUN & creatinine)
Urinalysis
◦ Can see crystals; sometimes almost sludge
Ultrasound
◦ Increased renal echogenicity with halo effect
Kidney palpation
◦ Can be VERY PAINFUL!!
◦ Swollen, stretched capsule
Stage 3 Treatment
Mainly __________ care
Maintain or re-establish _____ output
◦ ________, ________, _________ drip
For renal failure:
◦ __________ dialysis
◦ _________ (not widespread in veterinary
species)
Too late for ________ to be of much use
◦ But, for as long as there is _________ EG,
antidote is indicated
Stage 3 Treatment
Mainly supportive care
Maintain or re-establish urine output
◦ Fluids, diuretics, dopamine drip
For renal failure:
◦ Peritoneal dialysis
◦ Hemodialysis (not widespread in veterinary
species)
Too late for antidote to be of much use
◦ But, for as long as there is unmetabolized EG,
antidote is indicated
Prognosis
Depends on:
◦ Dose ingested
◦ Rate of absorption: slow when food is present
GI tract
◦ Time interval between exposure and treatment
The sooner Tx is initiated, the better
◦ Dogs: if treated within 5 h of exposure,
prognosis is good
◦ Cats: if treated in <3 h, prognosis is good
If already azotemic before treatment starts,
prognosis is poor
Other species
__________
◦ Not many cases reported
Cattle
◦ Calves: signs similar to those in ___________
◦ Adults: high dose needed for __________, and
other signs (_________, _________) are seen
Humans
Horses
◦ Not many cases reported
Cattle
◦ Calves: signs similar to those in monogastrics
◦ Adults: high dose needed for toxicosis, and
other signs (hemolysis, epistaxis) are seen
Humans
