At a Glance
Methanol intoxication is not common but is frequently severe or fatal. Rapid recognition and prompt treatment, especially of the acidosis, are crucial to outcome if permanent visual impairment and brain damage are to be prevented. In the absence of an exposure history, methanol intoxication is difficult to diagnose. Clinical manifestations are usually delayed 12-24 hours while toxic metabolites accumulate, and the patient may, therefore, already have severe metabolic compromise on presentation. It is important to know whether ethanol has also been ingested, as the latency period is markedly increased. Every effort should be made to identify the source of the exposure. The lethal dose is in the region of 1g/kg.
In its early stages, mild inebriation belies the severity of the situation, which evolves as methanol is converted into toxic metabolites. Methanol ingestion should be considered in any patient who presents with altered mental status, unexplained anion gap metabolic acidosis, osmolal gap, visual disturbance, gastrointestinal symptoms, dyspnea, headache, and less frequently chest pain. The patient may progress to coma, followed by circulatory and respiratory arrest.
Loss of visual acuity and normocalcemia distinguish methanol intoxication from ethylene glycol poisoning.
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What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
In contrast to ethanol measurements, there are no widely available or easily performed tests for methanol. Ideally, the diagnosis should be made by determination of methanol in the serum or urine by gas chromatography. This test distinguishes between methanol and other small alcohols and can often provide a quantitative result. If the methanol determination is negative, ethylene glycol intoxication should be considered because of its similarity in the initial phases. The limited availability and delay in reporting of these tests means diagnosis and decision to give antidote will invariably be based on clinical history and other tests.
It is important to determine whether ethanol is present by a qualitative test, and, if positive, a quantitative serum or breath ethanol should be obtained. The presence of methanol in the serum elevates the osmolal gap, but this declines as the methanol is metabolized and is replaced by an anion gap metabolic acidosis (routine chemistries required). Osmolality should be determined by freezing point depression and the osmolal gap calculated.
It is important to determine the osmolality prior to administration of ethanol antidote, as this will contribute to the elevated osmolal gap; 4-methlpyrazole antidote does not. The patient’s progress should be monitored regularly by acid-base status and osmolality. These readily available tests are rapid and inexpensive. They are not, however, sufficiently sensitive to detect a small ingestion, since the population variability means the gap can still lie within the normal range (up to about 26 mg/dL methanol). Regular monitoring of serum ethanol antidote is required; 4-methylpyrazole monitoring is not indicated.
Few conditions besides methanol, ethylene glycol, or propylene glycol intoxication produce such a profound metabolic acidosis (bicarbonate <8 mmol/L), and most of these present in a characteristic fashion with a high serum lactate (status epilepticus, shock, ischemic bowel, or diabetic ketoacidosis). In contrast, the majority of organic acid in methanol intoxication is formate, and the relative lack of lactate may provide a clue to diagnosis. Formate assays, although relatively simple to perform, are not widely available because of low demand.(Table 1)
Table 1
| Methanol | Electrolytes and Blood Gas | Osmolality | Acids |
|---|---|---|---|
| Serum > 10 mg/dL | (Metabolic acidosis, compensating respiratory alkalosis) pH < 7.35 Bicarbonate < 8 mmol/L | Elevated > 300 mOsm/kg | Lactate usually < 3 mmol/L |
| Urine > 20 mg/dL | pCO2 decreased Elevated anion gap > 20 mmol/L, especially later | Osmolal Gap > 20 mOsm/kg, especially early | Formate > 5 mmol/L |
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
Methanol is widely available and has many legitimate uses as a solvent, cleaner, and antifreeze, and there can be confusion regarding whether methanol, ethylene glycol, or another glycol is present in the product. Since the purchase of methanol is tax-free, it is used by alcoholics as an ethanol substitute and may be present in high concentrations in illegally distilled spirits. Methanol is added to nonbeverage ethanol to render it unfit to drink. When the history is of social ethanol use, multiple victims might be anticipated.
Osmolality should be measured by freezing point depression (vapor dew point pressure methods are not reliable with volatile osmolytes). Any small osmolyte, such as ethanol, isopropanol, acetone, ethylene or propylene glycol, will contribute an elevated osmolal gap. Of these, however, only methanol and ethylene glycol produce an elevated anion gap. For calculation of the osmolal gap, a simultaneous measurement of serum sodium, glucose, and blood urea nitrogen (BUN) are required.
There are two reasons why coingestion of ethanol is important for the diagnosis and evolution of methanol intoxication. First, since it prevents the formation of toxic metabolites by inhibition of alcohol dehydrogenase, the onset of symptoms (and the possibility of detecting the anion gap or formate) is diminished. Second, ethanol’s contribution to the osmolal gap confounds the diagnosis and possibly delays treatment. When the patient has a significant ethanol load together with a marked metabolic acidosis, the likelihood of methanol intoxication should be seriously reconsidered; consider propylene glycol, since its metabolism to lactate progresses in the presence of ethanol.
Because of the nature of the toxicity, serum methanol does not relate to the severity of the condition. It is not toxic at almost any level so long as its metabolism is blocked.
Methanol does not appreciably affect rapid point of care or enzymatic assays for ethanol or breathe ethanol tests.
What Lab Results Are Absolutely Confirmatory?
Methanol is relatively stable in blood, but fluoride oxalate preservative should be used if ethanol determination is also required.
Methanol analysis by gas chromatography is the gold standard for establishing diagnosis of methanol intoxication. In addition, this test can usually detect and quantitate ethanol, acetone, and isopropanol. A variety of home-brew solvent screens may be offered, and it is important to ascertain exactly what compounds are included, otherwise a diagnosis may be missed.
The blood methanol concentration does not correlate with the severity of the intoxication, even if the time of ingestion is known, since the degree of acidosis is the major determinant of outcome. Once the diagnosis is established and treatment instigated, repeat serum methanol determinations are not helpful unless the intoxication does not resolve in the expected time. If the patient presents late, it may not be possible to demonstrate the presence of methanol. In this situation or if methanol testing is unavailable, demonstration of formate in the serum is considered diagnostic. Enzymatic tests are available using formate dehydrogenase, but these are not often available (concentrations vary from 5 to 35 mmol/L).
In the absence of methanol or formate assays, diagnosis and treatment is based predominantly on history, acid-base status, and exclusion of other metabolic causes.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Urine pregnancy test should be performed in age-appropriate females.
A urine drug screen should be requested if there is suspicion that other agents are involved. This can be a set of simple immunoassays for recreational drugs, which can be performed as a Point of Care or a laboratory-based test. Laboratory tests frequently include acetaminophen and salicylate. This determines whether the clinical picture is due to methanol alone or is confounded by coingestion of sedative hypnotic agents, such as benzodiazepines, barbiturates, or opioids, and can provide an indication of other toxins that might contribute to the metabolic acidosis.
Urinalysis
Although absence of calcium oxalate crystals favors the diagnosis of intoxication with methanol rather than ethylene glycol, it should not be used as confirmation. Sometimes, a fluorescent marker is added to a product by the manufacturer, and this may be detected in the urine with the use of a ultraviolet (UV) lamp. This test is subject to false positives, and the absence of fluorescence does not exclude a significant ingestion.
Calcium and Creatinine
Although these may be ordered for routine care, absence of hypocalcemia and absence of renal failure direct diagnosis toward methanol and away from ethylene glycol intoxication.
Osmolal Gap
For calculation of the osmolal gap, a simultaneous measurement of serum sodium, glucose, and blood urea nitrogen (BUN) are required. Once the presence of ethanol has been excluded, this information can be used to cautiously calculate the approximate amount of methanol present by the observed gap as follows:
Calculated osmolality mOsm/kg = 2[Na mmol/L] = [glucose mg/dL / 18] + [BUN mg/dL / 2.8]
Osmolal gap = Measured osmolality – Calculated osmolality which is normally <10 mosm/kg
Serum methanol (mg/dL) = (10 – osmolal gap ) x 3.2
Remember to measure and factor in for any ethanol administered. Once ethanol concentration is known, the portion of the osmolal gap attributed to the methanol can be used to calculate the methanol concentration:
Serum methanol mg/dL = 3.2 [(10 – Osmolal gap mOsm/kg) – (Serum ethanol mg/dL / 4.6)]
Stored specimens may lose methanol through evaporation, and methanol may be introduced into specimens during storage in refrigerators containing methanolic standard solutions. Specimens for solvent screens are often requested in specific containers with special handling conditions but should always be drawn with minimal airspace to avoid loss during transport.
Metabolism
Methanol itself is relatively benign. Less than 10% of the dose is excreted unchanged. Hepatic metabolism greatly increases its toxicity, but this can be effectively blocked either with ethanol (around 100 mg/dL in the serum) or preferably with 4-methylpyrazole (Fomepizole), as this does not compromise the patient’s mental status. The first metabolic step is the enzymatic conversion by alcohol dehydrogenase (ADH) to formaldehyde with subsequent conversion to formate by aldehyde dehydrogenase (ALDH). Both of these reactions generate acid (H+), deplete nicotinamide adenine dinucleotide (NAD), and shift the cell toward anerobic respiration, favoring hypoglycemia and a lactic acidosis.
Formic acid inhibits mitochondrial cytochrome a3 and compromises oxidative phosphorylation and mitochondrial viability. Since there is no effective mechanism for transport of formate out of the eye, visual impairment ensues. With increasing acidosis, formate is also retained in the brain with similar metabolic consequences. Similarly, renal excretion of folate is decreased in acidosis due to tubular transport competition. Full restoration of pH balance with bicarbonate infusion is the mainstay of metabolic recovery. Detoxification of formate to CO2 and water depend on the body’s folate pool, which is rate limiting. Formate also depletes glutathione, resulting in further oxidative damage. Folinic acid (leucovorin) or folic acid is administered to catalyze this final step.
Expected Kinetics
Peak methanol concentrations in the blood occur some 30-90 minutes after ingestion. Elimination is zero order at about one-half the capacity of ethanol (~8 mg/dL/hr). Formaldehyde half-life is rapid (1-2 min), but that of formate much longer. After 4-methylpyrazole, methanol metabolism approaches first order with half-life of 20-80 hours.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
If diagnosis is based on the osmolal gap, the presence of other osmolytes may confound the diagnosis. A number of intravenous medicines are solubilized in propylene glycol, which may accumulate in the plasma over time. The contribution to the osmolal gap is predictable from the molecular weight of propylene glycol (mOsm/kg = Propylene glycol mg/dL/7.6). Hemodialysis is sometimes used in severe methanol poisoning not only to remove methanol, but also to accumulate metabolic acids and to replace renal function. If the patient is on an ethanol infusion, this is also removed during dialysis, and either the dose should be doubled or ethanol added to the dialysis fluid to prevent methanol metabolism. Careful ethanol monitoring is required.
Critically ill patients may have elevated osmolal gaps. Categorical ruling out of methanol intoxication on the basis of an osmolal gap less than 10 mOsm’kg is unjustified, as is assuming a small elevation in the osmolal gap in a patient with a low pretest probability is due to methanol. Osmolal gaps greater than 25 mOsm/kg are caused by few other substances, and a large, unexplained gap is presumptive evidence of recent toxic alcohol ingestion in the appropriate clinical setting. Subsequent tests are needed to make the specific identification or narrow down the options.
Lactate tests are not affected by the presence of formate.
Large amounts of hippuric acid in the urine can produce crystals that may be mistaken for calcium oxalate and, hence, mislead the diagnosis away from methanol intoxication and toward ethylene glycol.
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