RENAL FAILURE Acute renal failure and chronic renal failure are common causes of elevated anion-gap acidosis.

The metabolic acidosis of renal failure is the result of the inability to excrete the acid load. The anions contributing to the elevated anion gap are predominantly sulfate, phosphate, and other unmeasured ions. In chronic renal failure, the anion gap usually is normal until the glomerular filtration rate decreases to below 30 mL/min and is accompanied by an anion-gap increase to 17 to 23 mEq/L. Drug-induced causes of acute renal failure are discussed in Chapter 12.

LACTIC ACIDOSIS Conversion of lactic acid back to pyruvate and in turn to glucose (via the Cori cycle) or to carbon dioxide (via the Krebs cycle) is the metabolic fate of lactic acid. However, conversion of lactic acid to pyruvate would release extracellular bicarbonate initially consumed during the generation of lactic acidosis. The normal serum lactic acid level is 1 mEq/L (range, 0.5 to 1.5 mEq/L). In most cases of lactic acidosis, there are components of increased production and decreased catabolism of lactic acid. It results most often from anaerobic metabolism whereby the cellular delivery of oxygen or its utilization is impaired, and anaerobic glycolysis with production of lactic acid results. Lactic acidosis is a common feature of severely poisoned patients and may be seen alone or superimposed on other forms of acidosis, such as alcoholic ketoacidosis, methanol intoxication, and salicylate poisoning. Lactic acidosis is associated with a profoundillness that includes weakness, anorexia, impaired mentation, hypotension, tachycardia, and hyperventilation. Blood lactate levels are uniformly elevated, and the higher they are, the worse the prognosis. In the absence of renal failure, lactic acidosis is accompanied by a phosphate-to-creatinine ratio in blood greater than 3 and may be associated with hyperuricemia because lactate and urate compete for the same secretory pathways in the renal tubule. As mentioned earlier, potassium shifts from intracellular to extracellular compartments do not occur, and any associated hyperkalemia is due to another cause. Drug-induced causes of lactic acidosis are shown in Table 6-1 along with the proposed mechanisms responsible for the lactic acid production. n the treatment of lactic acidosis, attention should be directed toward the underlying cause. In addition, cardiovascular function and ventilation must be improved, and hypovolemia and hypoxemia corrected. Although intravenous sodium bicarbonate has been standard therapy, its use in the treatment of lactic acidosis is controversial. Dichloroacetate, which stimulates pyruvate dehydrogenase, the catalyst for oxidation of lactate to pyruvate, may be helpful in its treatment, particularly if volume overload or renal failure is present.

KETOACIDOSIS Alcohol ketoacidosis is a common clinical entity and must be considered in the differential diagnosis of elevated anion-gap metabolic acidosis in the alcoholic. Depleted glycogen storage,

poor caloric intake, and the direct effect of alcohol in suppressing gluconeogenesis can lead to hypoglycemia. Hypoglycemia along with volume depletion suppresses insulin release and stimulates the release of glucagon, which predisposes to ketosis. In addition, alcohol can stimulate lipolysis to produce acetaldehyde and, ultimately, acetate, which allows for increased keto production. Alcohol increases the NADH/NAD ratio in its metabolism; this, in turn, favors the conversion of acetoacetate to -hydroxybutyrate, and an increase in the -hydroxybutyrate-toacetoacetate ratio is a characteristic feature of alcoholic ketoacidosis. Lactic acidosis also may accompany the ketoacidosis as a result of hypotension, sepsis, or gastrointestinal bleeding or as a consequence of ethanol intoxication. Blood glucose level usually is normal; however, if it is in the hyperglycemic range, it suggests the presence of diabetes mellitus. The treatment is volume resuscitation, and this treatment usually effects reversal of ketosis within hours. Any accompanying electrolyte abnormalities should be corrected; also, the administration of bicarbonate is required, as is the use of insulin.

SALICYLATE INTOXICATION The metabolic acid base disturbance characteristic of salicylate intoxication typically is a primary mild to moderate metabolic acidosis accompanied by a primary (not compensatory) respiratory alkalosis, the result of the drug's potent respiratory stimulant action. These findings are invariable in severe aspirin toxicity unless the victim has ingested an agent that depresses respiratory drive. The origin of the acidosis is multifactorial but includes uncoupling of oxidative metabolism and salicylate stimulation of organic acid (lactic acid and ketoacid) production. Ketone products may be found in 25% of cases and may contribute to false elevations in serum creatinine.

The importance of recognizing the complex acid base disturbances of salicylate intoxication cannot be overemphasized. Salicylate overdose is prominent among the agents and conditions that produce a mixed metabolic acidosis and respiratory alkalosis. In patients with a Pco2 less than 30 to 35 mm Hg and/or a serum bicarbonate level of 18 mEq/L or less, a serum salicylate level should be obtained if these abnormal findings are unexplained. Salicylates are discussed further in Chapter 48.

METHANOL Methanol intoxication is accompanied by the production of formaldehyde and formic acid; production of the latter leads to a profoundly elevated anion gap, which usually develops 12 to 24 hours after ingestion. Although controversial, formic acid seems to be the earliest cause of aniongap elevation, although lactic and other organic acids may contribute to this disturbance. Additionally, multiple-organ failure results in decreased hepatic lactate utilization. In untreated patients, as methanol is metabolized, an early osmolal gap and normal or slightly elevated anion

gap is followed by a decrease in the osmolal gap with an increase in the anion gap. Treatment includes correction of the profound academia with bicarbonate administration, use of fomepizole or ethanol to inhibit the metabolism of methanol, and hemodialysis to correct the profound acidemia and remove the toxic compounds. Methanol is further discussed in Chapter 32.

ETHYLENE GLYCOL Ethylene glycol intoxication leads to serious, life-threatening anion-gap acidosis. The decrease in serum bicarbonate level is due to buffering of excess glycolic acid, which contributes primarily to the elevation of the anion gap. However, increases in lactic acid and -hydroxybutyrate also occur with ethylene glycol intoxication, adding to the metabolic acidosis. Lactic acidosis usually occurs in the later stages of ethylene glycol intoxication; its etiology is not completely understood. Hyperchloremic metabolic acidosis may occur also from accompanying proximal renal tubular dysfunction. As with methanol, ethylene glycol is associated with an increased osmolal gap; also like methanol, the metabolism of ethylene glycol produces a reciprocal change in the osmolal and anion gaps. Treatment includes aggressive correction of metabolic acidosis and administration of fomepizole or ethanol. Hemodialysis removes ethylene glycol and its breakdown products in addition to correcting the acidosis. Ethylene glycol is further discussed in Chapter 32B.

PARALDEHYDE Paraldehyde is a pungent, colorless liquid used primarily for the treatment of seizures; it has been supplanted by safer and more effective agents and rarely is used today. Paraldehyde is metabolized predominantly to acetaldehyde and acetic acid and ultimately to carbon dioxide and water. The drug produces an elevated anion-gap metabolic acidosis by ill-defined mechanisms, possibly by increasing the NADH/NAD ratio, which favors the conversion of acetoacetate to hydroxybutyrate.

TOLUENE Toluene is metabolized to benzoic acid and hippuric acid, which accumulate to yield an elevated anion-gap metabolic acidosis accompanied by hepatic and renal failure. Long-term toluene exposure can lead to type I distal tubular acidosis and type II proximal tubular acidosis associated with Fanconi's syndrome with a normal anion gap.

MISCELLANEOUS CAUSES OF ELEVATED ANION-GAP METABOLIC ACIDOSIS

The miscellaneous causes of elevated anion-gap metabolic acidosis include ingestion of formaldehyde, ibuprofen, cocaine, theophylline, phencyclidine, cyanide, or iron.

Historically, the commonly used mnemonic for metabolic acidosis has been MUDPILES (methanol, uremia, diabetic ketoacidosis, phenformin or paraldehyde, lactate, ethanol or ethylene glycol, and salicylates). However, this mnemonic has four shortcomings: not all of its elements are toxic agents; the toxins phenformin and paraldehyde rarely are used clinically, if at all; newer agents are associated with metabolic acidosis (e.g., metformin); and common and important agents (e.g., cyanide and ibuprofen) are not included. The mnemonic therefore no longer has great clinical value.

METABOLIC ACIDOSIS WITH A NORMAL ANION GAP (HYPERCHLOREMIC METABOLIC ACIDOSIS) Metabolic acidosis with normal anion gap results from a loss of fluid with a bicarbonate concentration greater than chloride concentration, the addition of acids with chloride as their associated anion, or the transient dilution of extracellular bicarbonate with nonbicarbonate solutions. To maintain electroneutrality, the decrease in serum bicarbonate is associated with a proportionate increase in the serum chloride level. For example, in diarrhea, bicarbonate loss is greater than chloride loss; thus, hyperchloremia develops. Accompanying this is extracellular volume contraction, which stimulates renal retention of sodium with chloride, rather than of bicarbonate, because of the increased availability of chloride. This, in turn, leads to the development of hyperchloremic metabolic acidosis. Normal anion-gap metabolic acidosis can be divided into hypochloremic and hyperchloremic forms. Box 6-2 lists the causes of normal aniongap metabolic acidosis.