Answers

Short answers

1 This patient most likely has methanol poisoning.

2 Acid-base status and serum methanol concentration should be measured to confirm diagnosis. If the latter is not possible, calculation of the osmolal gap and the anion gap might be helpful.

3 The osmolal gap is the difference between the measured serum osmolarity and the calculated osmolarity. The anion gap is the difference between the measured serum cation concentration and the measured serum anion concentration. Measurement of the acid-base status in an individual with severe methanol poisoning is useful to determine metabolic acidosis, which was present in this patient.

4 Urgent treatment should include haemodynamic support with fluid and vasopressors; correction of metabolic acidosis; haemodialysis or haemodiafiltration (to enhance elimination of methanol and formate and to correct acidosis); and treatment of seizures.

5 Fomepizole is the treatment of choice to reduce further conversion of methanol to its harmful metabolites. Ethanol may be used if fomepizole is not immediately available.

6 Patients with methanol poisoning should also be given folinic acid (calcium folinate) or folic acid to enhance formate metabolism.

Long answers
1 Diagnosis
This patient’s history of drinking illicit alcohol and the onset of visual impairment, confusion, seizures, and circulatory shock suggest strongly a diagnosis of severe methanol poisoning. After the ingestion of a substantial amount of methanol, patients develop progressive blindness, metabolic acidosis, coma, seizures (which are rare), and circulatory collapse.¹ The onset of these symptoms can be delayed for 12-24 hours, particularly if the patient has also ingested ethanol.

Methanol is oxidised by the hepatic enzyme alcohol dehydrogenase into formaldehyde, which is subsequently oxidised by formaldehyde dehydrogenase to formate. The next stage is conversion of formate to 10-formyl tetrahydrofolate by the ATP dependent activity of 10-formyl tetrahydrofolate synthetase. This step is followed by the oxidation of 10-formyl tetrahydrofolate to carbon dioxide and water, which is catalysed by 10-formyl tetrahydrofolate dehydrogenase (fig). As the oxidation of formaldehyde occurs rapidly, the substance does not accumulate in the serum; instead, the adverse effects of methanol metabolism are largely caused by the accumulation of formate.²

View larger version (44K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Biochemical pathway for the metabolism of methanol. Methanol is metabolised by alcohol dehydrogenase and formaldehyde dehydrogenase to form formate. Both oxidative steps depend on the reduction of the cofactor NAD+ (oxidised nicotinamide adenine dinucleotide) to NADH (the reduced form of nicotinamide adenine dinucleotide). This cofactor is oxidised by the reduction of pyruvate to lactate. Formate is combined with tetrahyrofolate by ATP-dependent reaction catalysed tetrahyrofolate synthetase to form 10-formyl tetrahyrofolate, which is ultimately converted to carbon dioxide and water by 10-formyl tetrahydrofolate dehydrogenase

 
2 Investigations
Measurement of the acid-base status in an individual with severe methanol poisoning is likely to show a severe metabolic acidosis, which was present in this patient (arterial pH 6.6, pCO₂ 2.0 kPa (15 mm Hg), pO₂ 10.6 kPa (80 mm Hg), HCO₃ 4.0 mmol/l, and base deficit 20.0 mmol/l). The serum methanol concentration will usually provide a definitive diagnosis; however, correlation between serum methanol concentration and the severity of poisoning is often poor, as this relation depends on the time at which the sample was taken. The severity and outcome of poisoning correlate more closely with the degree of metabolic acidosis than with the serum methanol concentration.³ Nevertheless, a serum methanol concentration of more than 500 mg/l within a few hours of ingestion of methanol indicates severe poisoning.⁴ The serum methanol concentration in this patient was 2100 mg/l. Serum methanol concentrations can be determined using gas chromatography-mass spectrometry or, alternatively, methods such as qualitative colorimetric methanol assay.

3 The osmolal gap and the anion gap
If measurement of the serum methanol concentration is not possible (this test is not readily available in many hospitals), calculation of the osmolal gap and the anion gap may be helpful. A large osmolal gap (>20 mOsm/l) early in the clinical course supports the diagnosis of methanol poisoning.⁴ As methanol is metabolised, a big osmolal gap will return to normal and an anion gap—indicating metabolic acidosis—will develop.^{5 6} Hence, a high anion gap suggests late presentation and that a substantial amount of methanol has been metabolised. Samples taken within 1-2 hours of methanol ingestion may not fully reflect osmolal change, and maximum change in acid-base status may take up to 12 hours to develop.

The osmolal gap, an artificially derived value, is calculated by working out the difference between measured serum osmolarity and calculated osmolarity. Osmolarity can be calculated using the following equation:

[2 x sodium (mmol/l)] + glucose (mmol/l) + blood urea nitrogen (mmol/l) + ethanol (mmol/l)⁷

Concentrations used in this equation must be in the SI units of mmol/l. The osmolal gap is normally less than 10 mOsm/l.

The anion gap is the difference in concentration between measured serum cations (sodium) and measured serum anions (chloride plus bicarbonate). Addition of potassium to the calculation is not required. A normal anon gap is typically 7 (4) mmol/l. The anion gap will increase during methanol metabolism owing to the accumulation of organic acid anions.⁸

4 Urgent treatment
If death is to be prevented, haemodynamic support with fluid resuscitation and vasopressors,⁹ correction of metabolic acidosis with intravenous bicarbonate (large amounts of bicarbonate were required in this patient), the treatment of seizures, and urgent haemodialysis or haemodiafiltration are necessary to enhance the elimination of methanol and formate and to correct severe acidosis.⁴ Continuous arteriovenous haemodiafiltration was used in this patient.

5 Antidote
Given that the serum methanol concentration in this patient was so high on presentation, an antidote should still be given to prevent the production of even more formate. Fomepizole and ethanol act by competitive inhibition of alcohol dehydrogenase to reduce the conversion of methanol to its toxic metabolites and thus minimise features of poisoning.⁹ Fomepizole is now the treatment of choice for poisoning with methanol,¹⁰ ethylene glycol,¹¹ and diethylene glycol,¹² because it has minimal adverse effects and the standard treatment regimen maintains a constant serum concentration of fomepizole, removing the need for monitoring.⁹

Ethanol is still widely used as a treatment for methanol poisoning despite its adverse effects,¹³ which include changes in mental status, the risk of hypoglycaemia in paediatric patients, and possible pancreatitis.^{9 14} In addition, frequent monitoring of blood ethanol is necessary to maintain therapeutic concentrations because of this agent’s unpredictable kinetics. If ethanol is employed, the patient is administered a 5% or 10% (weight/volume) ethanol solution in dextrose (50 g or 100 g pharmaceutical grade ethanol in 1 litre of 5% dextrose); 10% solutions should be given preferably by a central vein. After a bolus dose of 50 g ethanol over one hour for a typical adult, patients should be given 5.6-13 g of ethanol an hour to saturate alcohol dehydrogenase and inhibit methanol metabolism. This dose depends on whether the patient drinks alcohol regularly or not: alcoholics will have a greater rate of elimination and, therefore, may require higher dosing. The blood ethanol concentration should be maintained between 1000-1500 mg/l (22-33 mmol/l).⁴

Antidotes are most successful if given early in the course of poisoning, before clinically significant amounts of formate are produced.⁹ Patients with a serum methanol concentration of greater than 200 mg/l should receive an antidote. In the absence of a measured serum methanol concentration, an antidote should be commenced if more than 10 g of methanol has been ingested by an adult within the last 12 hours (or more than 0.1 g/kg in a child). Alternatively, if the patient has a history of methanol ingestion and an osmolal gap of >10 mOsm/l, an antidote should be commenced while waiting for the serum methanol concentration to be measured.⁴

6 Other treatments
Folic acid enhances formate metabolism and is thereby postulated to reduce toxicity. Folinic acid (calcium folinate) is the reduced form of folic acid. In vivo, folinic acid is converted rapidly to tetrahydrofolic acid derivatives, which are the primary bioactive and storage forms of folic acid in the body. Folinic acid should be given 1 mg/kg intravenously (up to a maximum of 50 mg) every six hours for 48 hours. If folinic acid is unavailable, folic acid is an acceptable alternative.⁴

Administration of an antidote, haemodialysis or haemodiafiltration, and other supportive care should be continued until serum methanol concentrations are below 200 mg/l, metabolic acidosis has been corrected, and the patient becomes asymptomatic.⁴

Patient outcome
The patient described in this case died from methanol poisoning because of his late presentation. If he had presented earlier and received fomepizole or ethanol promptly, he might have survived.

Cite this as: BMJ 2009;339:b3929