EM Toxicology 18: Methanol & Ethylene Glycol

Question 1

Most contemporary methanol exposures in the US occur from?

Answer 1

unintentional ingestion of windshield washer fluid and other automotive cleaning products

Question 2

sources of ethylene glycol

Answer 2

M/C: automotive coolant (antifreeze)
preservative
component of hydraulic brake fluid

Question 3

Remarks on ethylene glycol

Answer 3

Virtually all ethylene glycol toxicity results from ingestion, because it has a low vapor pressure and does not penetrate skin well.

Question 4

minimum lethal dose without treatment for methanol and ethylene glycol

Answer 4

1 g/kg or about 100 mL in an adult

Question 5

metabolism of methanol

Answer 5

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

Question 6

metabolism of ethylene glycol

Answer 6

ethylene glycol –> glycoaldehyde –> glycolic acid –> glycoxylic acid –> oxalic acid

Question 7

MOA of methanol toxicity

Answer 7

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

Question 8

remarks on methanol and metabolic acidosis

Answer 8

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

Question 9

MOA of ethylene glycol toxicity

Answer 9

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

Question 10

Methanol poisoning is characterized by

Answer 10

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

Question 11

Ocular toxicity in methanol poisoning

Answer 11

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

Question 12

Ethylene glycol poisoning is characterized by

Answer 12

CNS depression, metabolic acidosis, and renal failure

Question 13

First stage of ethylene glycol poisoning

Answer 13

“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

Question 14

CNS tissue effects in ethylene glycol poisoning

Answer 14

CNS tissue effects are from glycolic acid and calcium oxalate crystals

include cerebral edema, basal ganglia hemorrhagic infarction, and meningoencephalitis

Question 15

second stage of ethylene glycol poisoning

Answer 15

“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 ‼️

Question 16

third stage of ethylene glycol poisoning

Answer 16

“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)

Question 17

time it takes for the formation of toxic metabolites

Answer 17

methanol: 12-24 hours
ethylene glycol: 4-12 hours

hence acidosis will not be present immediately after exposure

Question 18

remarks on blood levels of methanol

Answer 18

<20 mg/dL: asymptomatic
>20 mg/dL: CNS symptoms
>50 mg/dL: ocular problems
>150 mg/dL: fatality rises

Question 19

remarks on osmolar gap

Answer 19

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”

Question 20

remarks on calcium oxalate crystals

Answer 20

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

Question 21

basic principles of treatment for both metanol and ethylene glycol poisoning

Answer 21

1.) initial resuscitation
2.) cardiopulmonary support

3.) preventing formation of toxic metabolites
4.) enhancing clearance of the parent compound and toxic metabolites

Question 22

Correcting acidosis and toxic alcohols

Answer 22

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

Question 23

remarks on metabolic blockade

Answer 23

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

Question 24

Indications for metabolic blockade with fomepizole or ethanol

Answer 24

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

Question 25

remarks on metabolic blockade and history of co-ingestion of alcohol

Answer 25

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

Question 26

remarks on fomepizole

Answer 26

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

Question 27

how to give fomepizole

Answer 27

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)

Question 28

how to give ethanol for metabolic blockade

Answer 28

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

Question 29

Remarks on ethanol as metabolic blockade

Answer 29

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

Question 30

With severe adult poisoning and when fomepizole therapy may be delayed or transport time to the hospital may be long, what can we do?

Answer 30

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

Question 31

disadvantages of using ethanol is metabolic blockade

Answer 31

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

Question 32

Indications for hemodialysis in toxic alcohol poisoning

Answer 32

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

Question 33

Vitamin therapy in methanol poisoning

Answer 33

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

Question 34

Vitamin therapy in EG poisoning

Answer 34

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

Question 35

remarks regarding visual impairment in methanol poisoning

Answer 35

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