Metabolic acidosis, methanol poisoning

Management of methanol and ethylene glycol poisoning is similar. Symptomatic support of respiration and circulation is augmented by correction of metabolic acidosis with intravenous bicarbonate infusion, and control of seizures with diazepam. Ethanol inhibits the metabolism of methanol and ethylene glycol to the toxic metabolites, and can give time for further treatment. The goal is to maintain blood ethanol concentrations between 100 and 150 mg per decilitre, sufficient to saturate alcohol... 

It is critical that the blood methanol level be determined as soon as possible if the diagnosis is suspected. Methanol concentrations higher than 50 mg/dL are thought to be an absolute indication for hemodialysis and treatment with fomepizole or ethanol, although formate blood levels are a better indication of clinical pathology. Additional laboratory evidence includes metabolic acidosis with an elevated anion gap and osmolar gap (see Chapter 59). A decrease in serum bicarbonate is a uniform feature of severe methanol poisoning. 

The first treatment for methanol poisoning, as in all critical poisoning situations, is support of respiration. There are three specific modalities of treatment for severe methanol poisoning suppression of metabolism by alcohol dehydrogenase to toxic products, hemodialysis to enhance removal of methanol and its toxic products, and alkalinization to counteract metabolic acidosis. 

The result of formate accumulation is metabolic acidosis. However, at later stages, the acidosis may also involve the accumulation of other anions such as lactate. This may be a result of inhibition of cytochrome oxidase and hence of mitochondrial respiration, tissue hypoxia due to reduced circulation of blood, or an increase in the NADH/NAD ratio. The acidosis that results from methanol poisoning will result in more formic acid being in the nonionized state and hence more readily able to enter the CNS. This will cause central depression and hypotension and increased lactate production. This situation is known as the "circulus hypoxicus."... 

On the other hand, drugs may inhibit the metabolism of other drugs. For example, allopurinol (a xanthine oxidase inhibitor that inhibits the synthesis of uric acid) increases the effectiveness of anticoagulants by inhibiting their metabolism. Chloramphenicol (a potent inhibitor of microsomal protein synthesis) and cimetidine (an H2-receptor blocker used in acid-pepsin disease) have similar properties. In addition, drugs may compete with each other in metabolic reactions. In methyl alcohol (methanol) poisoning, ethyl alcohol may be given intravenously to avert methanol-induced blindness and minimize the severe acidosis. Ethyl alcohol competes with methyl alcohol for... 

Two other measures are commonly taken. Because of profound metabolic acidosis in methanol poisoning, treatment with bicarbonate often is necessary. Since folate-dependent systems are... 

Methanol is available in a variety of commercial products (antifreeze prepM-ations, windso een-washer additives, duplicating fluids). Poisoning is often associated witii a delayed onset of coma, marked metabolic acidosis, electrolyte imbalance, and hyperglycaemia, with a raised serum amylase. Therapy with ethanol infrisions must be instituted without delay. 

Intoxication may present as inebriation and drowsiness similar to ethanol use. Other symptoms are vomiting, diarrhea, delirium and agitation, back and abdominal pain, and clammy skin. Toxic effects usually follow a latent period of several hours. Formate inhibits mitochondrial cytochromes resulting in neurotoxicity. Ocular signs include blurred vision, dilated pupils, and direct retinal toxicity with optic disc hyperemia and ultimately permanent blindness [91]. Cerebral hemorrhagic necrosis has been reported [92]. Severe poisoning may result in Kussmaul respiration, inspiratory apnea, coma, and death. Urine samples may have the characteristic smell of formaldehyde. An elevated serum osmolal gap from methanol will be evident early in presentation but may disappear after approximately 12 hours. At this time, an elevated anion gap metabolic acidosis from retained formate may be evident. 

The toxic properties of methanol are the result of accumulation of the formate intermediate in the blood and tissues of exposed individuals. Formate accumulation produces metabolic acidosis leading to the characteristic ocular toxicity (blindness) observed in human methanol poisonings. 

Typically, the effects noted in methanol poisoning can be divided into three stages (1) narcosis or CNS depression similar to that observed in ethanol intoxication (2) a latent period, generally 10-15 h but can be prolonged if ethanol is coingested and (3) visual disturbances, metabolic acidosis and possibly multiorgan failure leading to death. 

Martin KE, Ambre JJ, Tephly TR. Methanol poisoning in human subjects. Role for formic acid accumulation in the metabolic acidosis. Am J Med 1980 68 414-8. 

In all poisoning situations, it is important to establish adequate respiration. Bicarbonate may be needed to counteract metabolic acidosis. In patients with suspected methanol intoxication, ethanol (10% solution) is often given intravenously before laboratory diagnosis is confirmed to block the formation of toxic products of ADH-catalyzed metabolism of methanol. Blood levels of methanol in excess of 50 mg/dL are an absolute indication for hemodialysis. Activated charcoal does not bind alcohols. The answer is (B). 

Treatment depends on the cause. If ethylene glycol (see p 194) or methanol (p 260) poisoning is suspected, based upon an elevated osmolar gap not accounted for by ethanol or other alcohols and on the presence of metabolic acidosis, then antidotal therapy (eg, ethanol [see p 444] or fomepizole [p 443]) and hemodialysis may be indicated. 

Alcoholic ketoacidosis is characterized by anion gap metabolic acidosis and elevated levels of beta-hydroxybutyrate and, to a lesser extent, ace-toacetate. The osmolar gap may also be elevated, causing this condition to be mistaken for methanol or ethylene glycol poisoning. 

D. Enhanced elimination. Hemodialysis rapidly removes both methanol (half-life reduced to 3-6 hours) and formate. The indications for dialysis are suspected methanol poisoning with significant metabolic acidosis, visual abnormalities, an osmolar gap greater than 10 mOsm/L, or a measured serum methanol concentration greater than 50 mg/dL. Dialysis should be continued until the methanol concentration is less than 20 mg/dL. 

Formic acid is the species responsible for the toxic effects of methanol poisoning— including metabolic acidosis, in which the blood becomes dangerously acidic. 

Systemically administered ethanol is confined to the treatment of poisoning by methyl alcohol and ethylene glycol. Treatment consists of sodium bicarbonate to combat acidosis, hemodialysis, and the administration of ethanol, which slows the formation of methanol s metabolites, formaldehyde and formic acid, by competing with methanol for metabolism by ADH (Figure 22-1). Formic acid causes nerve damage its effects on the retina and optic nerve can cause blindness. 

The human toxicology of methanol has been studied [6,71,72]. The skin absorption rate has been reported to be 0.19 m cm2/min [73]. Methanol vapor uptake by the lungs is effective, usually 7080% (74). In the liver, methanol goes through oxidation metabolism catalyzed by alcohol dehydrogenase (an enzyme), producing toxic formaldehyde and formic acid. The accumulation of formic acid leads to acidosis, dama g the nervous system, particularly the optic nerves, and the retina. In the copresence of ethanol, ethanol is selectively metabolized by alcohol dehydrogenase over methanol this delays methanol intoxication and allows detoxication by the natural elimination of methanol via respiration and urination. The methanol elimination half-life is about 23 h [6]. Because of the slow elimination, methanol can be re rded as a cumulative poison [68]. Chronic oq)osure may result in sufficient methanol accumulation in the body, and illness. 

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