A gap metabolic acidosis is secondary to the addition of acid, either exogenous or endogenous. The major causes are lactic acidosis, ketoacidosis, kidney disease, and ingestions (Table 23-12). A useful mnemonic for the differential diagnosis of increased anion gap metabolic acidosis is GOLDMARK (glycols [ethylene glycol and propylene glycol], oxoproline, L-lactate, D-lactate, methanol, aspirin, renal failure, and ketoacidosis) (Table 23-13. Common Causes and Therapy for Increased Anion Gap Metabolic Acidosis).
Table 23-13. Common causes and therapy for increased anion gap metabolic acidosis.Cause | Treatment |
|---|---|
Lactic acidosis | Therapy aimed at correcting the underlying cause. Treatment of type A requires improving perfusion and matching oxygen consumption with fluids, packed red cells, vasopressors, and inotropes as needed. Treatment of type B generally requires removal of the offending agent or supplementing key cofactors of anaerobic metabolism. |
D-Lactic acidosis | Sodium bicarbonate may be administered in the setting of severe acidemia. Specific antimicrobial agents (metronidazole, neomycin) can be utilized in patients with short gut syndrome. A low-carbohydrate diet can be effective by decreasing substrate delivery to the distal colon. Fecal transplant has been utilized successfully in patients unresponsive to conventional therapies. |
Ketoacidosis Diabetes mellitus Alcoholic | Therapy involves correction of the state of insulin deficiency and glucagon excess. In diabetic ketoacidosis, this requires administration of exogenous insulin, generally with a continuous infusion. In starvation and alcoholic ketoacidosis, dextrose-containing fluids will stimulate endogenous insulin release. In all groups, correction of volume depletion with isotonic fluids as well as judicious repletion of electrolytes (particularly potassium and phosphorous) are imperative. |
Kidney failure | Supplemental alkali therapy (sodium bicarbonate or sodium citrate). Hemodialysis when necessary. |
Ingestions | |
Ethylene glycol Methanol | See Part 40. |
Salicylic acid | See Part 40. |
Pyroglutamic acid (5-Oxoproline) | Therapy is directed at the underlying cause. Generally requires withdrawal of the offending agent (acetaminophen) and sodium bicarbonate therapy for severe acidemia. N-Acetylcysteine may be effective in restoring glutathione stores. |
A. Lactic Acidosis
Lactic acidosis is a common cause of metabolic acidosis, producing an elevated anion gap and decreased serum pH when present without other acid-base disturbances. Lactate is formed from pyruvate in anaerobic glycolysis. Normally, lactate levels remain low (1 mEq/L) because of the metabolism of lactate principally by the liver through gluconeogenesis or oxidation via the Krebs cycle. In lactic acidosis, lactate levels are at least 4-5 mEq/L but commonly significantly higher. There are three types of lactic acidosis summarized below:
B. Ketoacidosis
All forms of ketoacidosis share the physiologic state of insulin deficiency and glucagon excess, which shifts the body's primary fuel source from glucose to fatty acid metabolism. The hypoglycemia from starvation suppresses insulin release. In diabetes mellitus, there is insufficient insulin production (particularly type 1). In the state of alcohol ketosis, lipolysis is stimulated, despite the presence of insulin. There are three types of ketones: acetone, acetoacetate, and beta-hydroxybutyrate.
1. Diabetic Ketoacidosis (Dka)
DKA is characterized by hyperglycemia and metabolic acidosis with an increased anion gap from absolute or relative insulin deficiency
H+ + B- + NaHCO3↔ CO2 + NaB + H2O
where B- is beta-hydroxybutyrate or acetoacetate, the ketones responsible for the increased anion gap. DKA may be accompanied by an additional lactic acidosis from tissue hypoperfusion and increased anaerobic metabolism. The anion gap in DKA is often large (greater than 20 mEq/L) but is variable. The elevated serum glucose leads to a marked osmotic diuresis with sizeable losses of sodium, water, and potassium.
The correction of ketoacidosis via therapeutic maneuvers can be monitored by the measurement of serum beta-hydroxybutyrate, measuring the pH, or by normalization of the anion gap. Urine ketones are detected by nitroprusside testing, results of which are rapidly available. However, urinary nitroprusside tests detect both acetoacetate and acetone (albeit to a lesser extent) but do not detect beta-hydroxybutyrate. Direct measurement of serum beta-hydroxybutyrate is preferred and can be used to monitor response to therapy.
2. Fasting Ketoacidosis
Hepatic generation of ketones may occur as a normal response to fasting from relative hypoinsulinemia. Mild ketosis often occurs after 12-14 hours of fasting, peaking after 20-30 hours. The level of acidosis is generally small with fasting, albeit overt ketoacidosis can occur in patients who consume very low carbohydrate diets.
3. Alcoholic Ketoacidosis
Chronically malnourished patients who consume large quantities of alcohol may develop alcoholic ketoacidosis. Alcohol metabolism decreases gluconeogenesis, resulting in hepatic production of beta-hydroxybutyrate and, to a lesser degree, acetoacetate. Mixed acid-base disorders, such as a combination of metabolic alkalosis from vomiting and respiratory alkalosis from alcohol withdrawal, aspiration, or cirrhosis, are common.
With either fasting or alcohol ketoacidosis, insulin release is suppressed by hypoglycemia or stimulation of the sympathetic nervous system, allowing ketosis to occur. Patients with these disorders are able to sufficiently produce endogenous insulin and therefore do not require exogenous insulin administration. Treatment should commence with glucose administration to stimulate insulin release and suppress ketogenesis. Potassium should be repleted prior to glucose administration as insulin release will cause intracellular potassium shift, risking hypokalemia.
C. Toxins
(See also Part 40.) Multiple toxins and drugs increase the anion gap by increasing endogenous acid production. Common examples include methanol (metabolized to formic acid), ethylene glycol (glycolic and oxalic acid), and salicylates (salicylic acid and lactic acid). The latter can cause a mixed disorder of metabolic acidosis with respiratory alkalosis. In toluene poisoning, the metabolite hippurate is rapidly excreted by the kidney, resulting in a normal anion gap acidosis. Isopropanol, which is metabolized to acetone, increases the osmolar gap, but not the anion gap. Long-term acetaminophen use, even at therapeutic doses, can result in an elevated anion gap acidosis from accumulation of 5-oxoproline.
D. Uremic Acidosis
As the GFR drops below 15-30 mL/min/1.73 m2 , the kidneys are increasingly unable to synthesize ammonium (NH4). The reduced excretion of H+ (as NH4Cl) and accumulation of organic anions from decreased excretion (eg, phosphate and sulfate) results in an increased anion gap metabolic acidosis.