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.

 

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.)

 

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

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Ethylene Glycol Poisoning
Ethylene glycol is a colorless sweet tasting solvent which is used in antifreeze solutions. It is nontoxic itself but is converted to toxic metabolites in the liver:
    * Glycolic acid  (->glycolate anion) is the major contributor to the often severe high anion gap acidosis that develops
    * Oxalic acid (->oxalate anion)  is one of the final metabolic products which is excreted in the urine. Precipitation of calcium oxalate crystals in the kidney causes renal failure if a sufficient dose has been ingested

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Stages of Ethylene Glycol Toxicity
Stage 1: Intoxication
Up to 12 hours post-ingestion
    * An ethanol-like intoxicated state (without an appropriate odour on the breath) progressing to CNS depression
    * Fits and coma may occur
    * A high anion gap metabolic acidosis develops
    * Nausea, vomiting, arrhythmias and tetany (due to hypocalcaemia) may occur
Stage 2: Cardiorespiratory Changes
From 12 to 24 hours post-ingestion.
    * Tachycardia, tachypnoea. Shock may occur in major ingestions
Stage 3: Renal Toxicity
At 24-72 hrs post-ingestion
Acute anuric renal failure may occur due to precipitation of calcium oxalate crystals in the renal tubules.

 

 

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Salicylate Toxicity
Salicylate overdose causes a high anion gap metabolic acidosis in both children and adults. Adults commonly develop a mixed acid-base disorder as a respiratory alkalosis due to direct respiratory centre stimulation occurs as well. This second disorder is uncommon in children.
  Acid-Base Disorders in Salicylate Toxicity
Adults: Metabolic acidosis AND Respiratory alkalosis
Children: Metabolic acidosis
If fasting=>starvation ketosis may develop

 

# Absorption: Salicylates are readily absorbed in the unionised form from the small intestine
# Metabolism: The major route of biotransformation is conjugation with glycine in the liver
# Excretion: The amount of drug excreted unchanged in the urine is small but can be markedly increased if urine is alkaline

 

Large overdoses of aspirin can cause a large tablet mass or bezoar in the stomach. This delays absorption and plasma salicylate levels continue to rise over 20 hours or more. For this reason, serial salicylate levels should be measured until the peak has been reached. Repeated oral doses of activated charcoal are indicated in this situation.
High levels of salicylate are toxic because the drug uncouples oxidative phosphorylation as well as inhibiting some enzymes in the cell.
Salicylates directly stimulate the respiratory center to cause hyperventilation (respiratory alkalosis) which is dose-dependent. This stimulation is much more pronounced in adults than in children.

 

Metabolic acidosis is the most serious acid-base disorder and is due to increased production of endogenous acids rather than the salicylate itself. Plasma salicylate levels rarely exceed a maximum of about 5 mmol/l and the decrement in the [HCO3] is significantly higher than this in these severe cases.
Acidosis is much more pronounced in infants as compared to adults, which is the reverse of the situation with the hyperventilation. In adults, respiratory alkalosis usually predominates. The particular organic acid anions involved in the acidosis of salicylate intoxication have not been identified.
Ketoacidosis may also occur in children who are ill and fasted (ie starvation ketosis).
The combination of metabolic acidosis and respiratory alkalosis can be a difficult situation to diagnose from the blood gases. The problem relates to whether the hyperventilation is primary (ie respiratory alkalosis) or is compensatory for the metabolic acidosis.

 

Simple urinary alkalinisation with administration of sodium bicarbonate is used to increase urine pH to between 7.5 and 8.5. Hypokalaemia is a risk and potassium should be given at the same time. Hypokalaemia also interferes with the kidney's ability to alkalinise the urine. One recommended regime for an adult is to administer one litre of 1.26% sodium bicarbonate solution (containing 20-40mmols of K+) IV over a 3 hour period

 

Principles of Treatment of Salicylate Toxicity
1. Emergency Management
Resuscitation: Airway, Breathing, Circulation. Obtunded patients require intubation for airway protection and ventilation.
2. Salicylate Removal from body
    * Alkaline diuresis: Urinary excretion is very significantly increased by alkalisation of the urine. This may be easily achieved by giving IV sodium bicarbonate to raise urine pH to between 7.5 and 8.5; It is advisable to give K+ to avoid hypokalaemia. Plasma [K+] should be regularly monitored. ('Forced alkaline diuresis' should be avoided as it confers no advantage and can cause fluid overload.) However, IV fluid loading is generally important to assist in maintaining an adequate urine output.
    * Haemodialysis is more effective and is the treatment of choice in severe poisonings. Criteria for dialysis are severe clinical features, resistant metabolic acidosis, renal failure or salicylate level >700mg/l.
    * Gastic lavage is not useful unless time from ingestion is short.
    * Activated charcoal - repeated doses can delay absorption; particularly indicated if tablet concretion has formed in the stomach
3. Intensive supportive care & monitoring
Management in Intensive Care Unit is recommended; Intubation & mechanical ventilation is indicated in comatose or significantly obtunded patients.
If intubated, hyperventilation must be maintained to mimic the body's compensatory response

 

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Important Points in Diagnosing High Anion Gap Acidosis

Ketoacidosis
Can be excluded if normoglycaemia & urine negative for ketones

Lactic acidosis
Excluded if lactate level is normal. Suggested if shock or peripheral hypoperfusion.

Renal failure
Excluded as cause of acidosis if urea and creatinine normal or only slightly elevated. (In chronic renal failure acidosis is uncommon if creatinine is < 0.30 mmol/l )

Methanol
Suggested if visual impairment and CNS depression or intoxication. Abdominal pain is common. Check the osmolar gap. Do NOT delay therapy until blood level obtained.

Ethylene glycol
Suggested if appear intoxicated and no visual disturbance. Check the osmolar gap but it is often normal.

Salicylate 
Suggested if marked hyperventilation (esp in adults) and mental obtundation.