EM Toxicology 18: Methanol & Ethylene Glycol Flashcards
Most contemporary methanol exposures in the US occur from?
unintentional ingestion of windshield washer fluid and other automotive cleaning products
sources of ethylene glycol
M/C: automotive coolant (antifreeze)
preservative
component of hydraulic brake fluid
Remarks on ethylene glycol
Virtually all ethylene glycol toxicity results from ingestion, because it has a low vapor pressure and does not penetrate skin well.
minimum lethal dose without treatment for methanol and ethylene glycol
1 g/kg or about 100 mL in an adult
metabolism of methanol
methanol –> formaldehyde –> formic acid
At higher methanol concentrations, metabolism switchees to zero-order kinetics, and blood methanol decreases at a fixed rate, roughly 8.5 mg/dL/hour
metabolism of ethylene glycol
ethylene glycol –> glycoaldehyde –> glycolic acid –> glycoxylic acid –> oxalic acid
MOA of methanol toxicity
Formic acid is the metabolite responsible for the toxicity and metabolic acidosis that occur with methanol poisoning
Formic acid’s MOA:
- binds to cytochrome oxidase and blocks oxidative phosphorylation, leading to anaerobic metabolism and lactic acidosis
- metabolism of methanol increases the NADH/NAD+ ratio, favoring pyruvate -> lactate
remarks on methanol and metabolic acidosis
1.) Formic acid’s inhibition of cytochrome oxidase increases with decreasing pH, so acidemia worsens the blockade of aerobic metabolism
2.) At lower pH, more formic acid can enter the brain and ocular tissues, worsening CNS depression and retinal and optic nerve injury
3.) Lower pH may also prolong formic acid elimination by increasing tubular reabsorption
MOA of ethylene glycol toxicity
Glycolic acid is the toxic metabolite, and its buildup is responsible for most of the metabolic acidosis.
Glycolic acid can be metabolized to oxalic acid.
- oxalic acid can complex with calcium, which leads to hypocalcemia and precipitation of calcium oxalate crystals in tissues and urine.
End-organ damage is though to be due to
a.) direct cytotoxicity of glycolic acid (mechanism is unclear)
b.) tissue damage from precipitation of calcium oxalate crystals
Methanol poisoning is characterized by
CNS depresssion, metabolic acidosis, and visual changes
Severity of poisoning correlates more with the level of acidosis than with the methanol level
Clinical signs and symptoms may be signifianctly delayed after exposure, often by 12-24 hours, because metabolism to formic acid is required for tissue damage
Because ethanol competes for alcohol dehydrogenase, formation of the toxic metabolites from methanol will be delayed if ethanol has also been ingested
methanol is only a mild inebriant
Ocular toxicity in methanol poisoning
Retinal and optic nerve tissue seems to be especially sensitive to the toxic effects of formic acid.
photophobia or blurred or “snow field” vision
with papilledema, nystagus (rare), and nonreactive mydriasis once permanent damage has occurred
Ethylene glycol poisoning is characterized by
CNS depression, metabolic acidosis, and renal failure
First stage of ethylene glycol poisoning
“neurologic stage”
30 mins to 12 hours after ingestion
due to intoxicating effects of the ethylene glycol parent compound
may range from mild depression to seizure and coma
the generation of toxic metabolites takes 4-12 hours, or more if ethanol was co-ingested
* hypocalcemia may contribute to seizures
* metabolic acidosis appears as toxic metabolites are generated
CNS tissue effects in ethylene glycol poisoning
CNS tissue effects are from glycolic acid and calcium oxalate crystals
include cerebral edema, basal ganglia hemorrhagic infarction, and meningoencephalitis
second stage of ethylene glycol poisoning
“cardiopulmonary stage”
begins 12-24 hours after ingestion
ch’zd by tachycardia and possibly hypertension
glycolate and oxalate cyrstal deposition in tissues leads to multiorgan system failure, including heart failure, acute lung injury, and myositis
‼️ Most deaths occur during this stage ‼️
third stage of ethylene glycol poisoning
“renal stage”
often delayed 24-72 hours after ingestion
renal failure due to calcium oxalate crystal deposition in the proximal tubules (m/c major complication of serious ethylene glycol poisoning)
time it takes for the formation of toxic metabolites
methanol: 12-24 hours
ethylene glycol: 4-12 hours
hence acidosis will not be present immediately after exposure
remarks on blood levels of methanol
<20 mg/dL: asymptomatic
>20 mg/dL: CNS symptoms
>50 mg/dL: ocular problems
>150 mg/dL: fatality rises
remarks on osmolar gap
In general, an osmolar gap of more than 10-15 mOsm/kg H2O raises concern
> 50 mOsm/kg H2O is highly suggestive of either methanol or ethylene glycol poisoning and is associated with increased mortality
“osmolar gap has many shortcomings and cannot be relied on to definitively diagnose or exclude a toxic alcohol poisoning”
remarks on calcium oxalate crystals
If present, they start to appear 4-6 hours after ingestion and may persist for days, especially in patients with renal failure
the monohydrate form is more common, and the dihydrate form is more specific for ethylene glycol poisoning
basic principles of treatment for both metanol and ethylene glycol poisoning
1.) initial resuscitation
2.) cardiopulmonary support
3.) preventing formation of toxic metabolites
4.) enhancing clearance of the parent compound and toxic metabolites
Correcting acidosis and toxic alcohols
Improves outcome in methanol poisoning because acidsois worsens toicity of formate
rapid improvement in visual and other systemic symptoms reported with correction of acidosis
also, alkalinization may help increase formic acid clearance by decreasing reabsorption in the proximal renall tubules
When used in methanol poisoning, give IV sodium bicarbonate infusions to maintain a serum pH of >7.30
There is no evidence that alkalinization is specifically beneficial in ethylene glycol poisoning, but it seems reasonable to use sodium bicarbonate IV if pH <7.20
remarks on metabolic blockade
Start treatment while sorting out the clinical picture to protect to protect the patient from serious toxicity, such as blindness or renal failure
Treatment with either ethanol or fomepizole greatly slows the elimiantion of methanol and ethyelene glycol.
Both ethanol and fomepizole have a much higher affinitiy for alcohol dehydrogenase than does methanol or ethylene glycol
Indications for metabolic blockade with fomepizole or ethanol
Elevated plasma levels >20 mg/dL
if methanol or ethylene glycol level not available:
- documented or suspected significant methanol or EG ingestion with ethanol level lower than approx 100 mg/dL
- unclear history, but patient is in coma or with AMS, AND
» unexplaned serum osmolar gap of >10 mOsm/L, OR
» unexplained metabolic acidosis and ethanol level of <100 mg/dL
remarks on metabolic blockade and history of co-ingestion of alcohol
If serum ethanol level is >100 mg/dL, the patient will be protected from the formation of toxic metabolites by co-ingestion of ethanol, and specific metabolic blockade treatment can be delayed until toxic alcohol level is available.
If the ethanol elvel is likely to fall to <100 mg/dL before the toxic alcohol results are back, then initiate metabolic blockade
remarks on fomepizole
ADV:
- lack of s/e such as CNS depression, GI irritation, and hypoglycemia caused by ethanol therapy
- less susceptible to dosing errors than ethanol
DIS:
- increased cost
how to give fomepizole
Fomepizole 15 mg/kg IV over 30 minutes and then 10 mg/kg IV over 30 minutes every 12 hours
Fomepizole is continuted until the toxic alcohol level is <20 mg/dL and the metabolic acidosis has resolved.
increase to 15 mg/kg every 12 hours if treatment lasts >48 hours (fomepizole is believed to induced its own metabolism)
how to give ethanol for metabolic blockade
Ethanol 10 mL/kg of 10% IV ethanol at 100 mg/kg/hour to keep ethanol level 100-150 mg/dL until the toxic alcohol level is <20 mg/dL and the metabolic acidosis has resolved
If oral:
80-proof liquor
LD 1.5 to 2 mL/kg followed
MD 0.2 to 0.5 mL/kg/hour
Remarks on ethanol as metabolic blockade
Do not use oral ethanol preparations via the IV
For both IV and PO routes, serum ethanol concentrations should be monitored every 1 to 2 hours
All maintenance doses need to be doubled for patients undergoing hemodialysis
With severe adult poisoning and when fomepizole therapy may be delayed or transport time to the hospital may be long, what can we do?
adminsiter three or four 1-oz (30-mL) “shots” of 80-proof liquor. this should raise blood ethanol concentrations sufficiently to block toxic alcohol metabolism in a 70-kg adult
Maintenance dosages are approximately one to two shots per hour
disadvantages of using ethanol is metabolic blockade
1.) induction of state of inebriation, so monitor for neurologic and respiratory depression
2.) children and malnourished individuals are particularly at risk for hypoglycemia
3.) 10% ethanol IV requires central venous access because it is hyperosmolar and irritating to peripheral veins
Use of less concentrated solutions (5%) may require administration of large fluid volumes
Indications for hemodialysis in toxic alcohol poisoning
1.) refractory metabolic acidosis: pH <7.25 with AG >30 mEq/L and/or base deficit <-15
2.) visual abnormalities (methanol)
3.) renal insufficiency
4.) deteriorating vital signs despite aggressve supportive care
5.) electrolyte abnormalities refractory to conventional therapy
6.) serum methanol/EG >50 mg/dL
Vitamin therapy in methanol poisoning
Folinic or folic acid 1 mg/kg IV every 4-6 h
(up to 50 mg per dose)
continue until toxicity resolved
High doses of folate or folinic acid may facilitate breakdown of formic acid into carbon dioxide and water
Folinic acid, the activated form of folic acid, is preferred, but folic acid may be used if the former is not available
Vitamin therapy in EG poisoning
Pyridoxine 50-100 mg IV every 6 hours for 2 days
Thiamine 100 mg IV every 6 hours for 2 days
Magnesium sulfate 2 g IV (once)
These may be used to facilitate metabolism of glyoxylate to nontoxic glycine and a-hydroxy-B-ketoadipoic acid
remarks regarding visual impairment in methanol poisoning
Visual impairment can be a permanent complication of methanol poisoning.
Although treatment with fomepizole or ethanol and bicarbonate can prevent ocular toxicity, there is no other proven therapy to restore established visual damage
