Acid-Base Physiology

8.6 Metabolic Acidosis due to Drugs and Toxins


Several drugs and toxins have been implicated as direct or indirect causes of a high-anion gap metabolic acidosis (HAGMA). A consideration of these drugs needs to be included in an differential diagnosis of a HAGMA. The three most common ones to consider are methanol, ethylene glycol and salicylates. Other toxins which can cause acidosis are isopropyl alcohol and butoxyethanol. Toluene also causes an acidosis and the anion gap may be normal or elevated.

The acidosis caused by these toxins may sometimes present as a normal anion-gap hyperchloraemic acidosis so don't exclude the diagnosis in such a circumstance.

Co-ingestion of ethanol delays the metabolism of the more toxic methanol and ethylene glycol but can also delays the diagnosis. In this situation the osmolar gap will be even more elevated than can be explained by the measured ethanol level alone.

[See also Section 11.3: Acid-Base Disorders due to Drugs & Toxins.]

8.6.1 Methanol Poisoning

Presentation & Diagnosis

Ingestion of methanol can occur accidentally, or deliberately if used as an ethanol substitute.

Methanol itself is non-toxic. Onset of symptoms is delayed until the toxic metabolites are produced by liver. Because the hepatic metabolism is slow, there is usually a considerable latent period (12-48 hours) before any toxic effects develop. Patients presenting early with a history of ingestion will be asymptomatic.

Patients presenting late are often deeply comatose and bradycardic with depressed respirations. Survivors have a high incidence of irreversible blindness. Abdominal pain is a common symptom and may be due to acute pancreatitis.

Diagnosis may be delayed if the history is not available (eg obtunded patient) or because of the significant delay between ingestion and symptoms. Early diagnosis is important because prompt and effective treatment can decrease mortality and decrease the incidence of blindness. A useful screening test is determination of the osmolar gap. If the osmolar gap is greater than 10, it indicates the presence of appreciable quantities of low molecular weight substances such as methanol. This can alert you to the diagnosis before the acidosis (due to metabolites) develops. As the methanol is metabolised, the osmolar gap returns toward normal and the anion gap increases. A patient presenting late after a significant ingestion may have a normal osmolar gap and a high anion gap acidosis. The osmolar gap is more likely to be elevated in methanol ingestion than with ethylene glycol ingestions because of the lower molecular weight of methanol. Osmolar gaps of >100 have been reported.

The ideal way to assess and monitor response to treatment is to measure methanol blood levels. This test is NOT readily available in laboratories because of infrequent need and because the test is labour intensive. Treatment should NOT be delayed by delays in obtaining a blood methanol level. Methanol levels >20mg/dl are associated with severe toxicity.

The most serious toxic manifestations are:

In patients with severe acidosis (indicating high formic acid levels), the mortality rate may be 50% or more.

Pathophysiology

Methanol is slowly converted to formaldehyde (by alcohol dehydrogenase) and then to formic acid in the liver. Methanol is not toxic but both the major metabolites interfere with oxidative phosphorylation and it is these metabolites that cause the toxic effects. The acidosis is due to formic acid. As methanol is converted to its metabolites the osmolar gap falls and the anion gap rises.

Fig. Metabolism of Methanol

Some patients ingest ethanol as well as methanol and this (fortuitously) is protective as it further delays the metabolism and limits the peak levels of the toxic metabolites. Such co-ingestion of ethanol can cause diagnostic problems. Clinicians are typically alerted to the possibility of ingestion of methanol (or ethylene glycol) by the combination of an acidosis and CNS symptoms (eg intoxication). Ethanol can mislead the clinician because its further delays the onset of the acidosis, 'explains' the presence of intoxication and also explains the presence of an osmolar gap. (See here for more details).

'Methylated spirits' is freely available in Australia from hardware stores. It is used by some down-and-out alcoholics. This product contains 95% ethanol and up to 5% methanol; pyridine is added to give a bitter taste to discourage drinking. Ingestion of this product may cause methanol toxicity but the ethanol content is protective.


Acid-Base Disorders in Methanol Toxicity
  • Initially no acid-base disorder due to long latent period while methanol is metabolised
  • Later, typically develop a high anion gap metabolic acidosis -due to formic acid
  • May also develop a respiratory acidosis secondary to CNS depression (with depression of respiratory centre and/or airway obstruction)
  • May occasionally present with normal anion gap acidosis if smaller ingestion
  • If patient is an alcoholic, there may other types of acidosis present as well (eg alcoholic ketoacidosis, starvation ketoacidosis, lactic acidosis, respiratory acidosis due aspiration, respiratory alkalosis due chronic liver disease.)
Treatment

General principles of treatment are outlined below. Treatment must be individualised to individual patient circumstances. The best outcome is obtained with patients who present early, particularly during the latent period.


Principles of Treatment of Methanol Poisoning
1. Emergency Management

Resuscitation: Airway, Breathing, Circulation. Obtunded patients require intubation for airway protection and ventilation.

2 . Methanol Removal from body

Haemodialysis is the most effective technique; it also removes ethanol so ethanol infusion rate must be increased during periods of dialysis

3 . Blocking of Metabolism

This involves competitive inhibition of alcohol dehydrogenase (ADH). The aim is to delay the production of the toxic metabolites and limit the peak concentrations achieved. Two agents are currently in use:

  • Ethanol: "Ethanol blocking" treatment is the traditional treatment but has the disadvantage of causing intoxication (CNS depression). It is also irritant and should be given via a central line.
  • Fomepizole (aka 4-methylpyrazole): This is currently approved for this use in some countries ( eg USA and Canada as 'Antizol'). Its advantages are effectiveness, ease of administration and absence of intoxication. Its use may obviate the need for haemodialysis in patients without visual impairment or severe acidosis.
4. Intensive supportive care & monitoring

Management in an Intensive Care Unit is recommended; Intubation & mechanical ventilation may be indicated if there is inadequate airway protection (eg CNS depression) or inadequate ventilation; Monitor response to treatment with methanol levels (if available).

If intubated, hyperventilation must be maintained to mimic the body's compensatory response


Fomepizole Use

Fomepizole is preferred to ethanol if it is available. The drug is considered an 'orphan drug' and can be specially obtained in Australia from Orphan Australia Pty Ltd.  The cost of a pack of four 1.5g ampoules is $AUD6,000 (in 2005). The company does not keep any stock within Australia so you have to order well ahead.

A typical course of fomepizole would be:

Fomepizole has an affinity for alcohol dehydrogenase which is 8,000 times higher than that of methanol. Its use can result in methanol levels remaining almost constant. This effectively blocks production of the toxic metabolites but the methanol remains in the body. Because of this, haemodialysis is now required to remove the drug from the body. Fomepizole is an extremely effective antidote to methanol poisoning if started soon after the ingestion. Fomepizole induces its own metabolism so its dose needs to be increased after 48 hrs.

Ethanol therapy requires a blood level of 100-150 mg/dl to be effective and to maintain this level regular monitoring of blood ethanol level and adjustment of infusion rate is required. The patient is significantly intoxicated by this therapeutic  ethanol level. Fomepizole does not cause any intoxication.

[Example Case - Child with ingestion of Windscreen washer fluid]