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 the 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 methanol ingestion have few symptoms due to the methanol (other than mild CNS depression), but may have symptoms due to other drugs or toxins (e.g. ethanol). Additionally co-ingestion of ethanol also contributes to the latent period by delaying metabolism of methanol.
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 (e.g. 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 at short notice in laboratories because of infrequent need and because the test is labour intensive. Specimens often are transferred to a larger hospital where batch testing may only be done every week or two. Treatment should NOT be delayed because of delays in obtaining a blood methanol level. Methanol levels >20mg/dl are associated with severe toxicity.
The most serious toxic manifestations are:
- metabolic acidosis
- visual impairment which can be permanent blindness
- CNS depression ('intoxication') up to coma
- death
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), then rapidly to formic acid (by formaldehyde dehydrogenase) in the liver. Formic acid is then slowly metabolised (by 10-formyl tetrahydrofolate dehydrogenase). This particular combination of slow, fast, then slow reactions accounts for the delay in onset of toxic effects (latency), and the prolonged effect (accumulation of formic acid).
As little as 10 mls of pure methanol can cause permanent visual disturbance, 30mls can be fatal, but 100mls is the median lethal dose in an adult. (See ref)
Methanol is not directly toxic, but formic acid is both directly toxic (e.g. direct optic nerve toxicity) and inhibits mitochondrial cytochrome oxidase (causing a form of histotoxic hypoxia). The acidosis is due to both formic acid, and acidic metabolites (such as lactate) from the mitochondrial dysfunction. The worsening of the acidosis due to these other acids results in lower dissociation of formic acid and more diffusion of this undissociated formic acid across cell membranes to produce more intracellular effects. As methanol is converted to its metabolites, the osmolar gap falls (due less low MW uncharged methanol) and the anion gap rises (due increased charged formate anion).
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. In addition to its high ethanol content (say 95%) this product contains other chemicals to discourage human ingestion. These additives may be toxic (e.g. methanol) or have a very disagreeable taste (e.g. pyridine). Methylated spirits in Australia and New Zealand no longer contains methanol, but the situation may be different in other countries.
Treatment
This is a general guide only presented in the context of understanding acid-base disorders, and is not meant to be a practical guide to the treatment of any individual patient.
Treatment must be individualised to individual patient circumstances. The best outcome is obtained with patients who present early, particularly during the latent period, and when clinical suspicion leads to prompt appropriate management by experienced clinicians. For details see the AACT Practice Guidelines for the Treatment of Methanol Toxicity.
|
|
Fomepizole Use
Fomepizole is preferred to ethanol if it is available. The drug is an orphan drug in some countries. It is not currently (2014) available in Australia. In 2012 an application was made to include fomepizole in the WHO list of essential drugs. IV ethanol can be used instead but may even that may not be readily available in sufficient amounts in Australian hospitals.
A typical course of fomepizole would be:
- Initial 15mg/kg IV bolus (over 30 minutes)
- 10mg/kg IV bolus at 12 hourly intervals for 4 doses
- Increase to 15mg/kg IV after 48 hours
- Continue until methanol levels are low (eg <20mg/dl)
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 and methanol is slowly excreted in urine. Haemodialysis can remove methanol from the body more rapidly. 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.
Australian perspective: Methanol poisoning is now rare within Australia. Methanol produced in Australia is present in some model and racing car fuels, and may be present in toxic amounts in home-distilled alcohol beverages, but the current risk is ingestion of adulterated alcoholic drinks by locals on holiday in Bali.
[Example Acid-base Case: Child with ingestion of Windscreen washer fluid]