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Metabolic acidosis is primary reduction in HCO₃ ⁻, typically with compensatory reduction in Pco₂; pH may be markedly low or slightly subnormal. Metabolic acidoses are categorized as high or normal anion gap based on the presence or absence of unmeasured anions in serum. Causes include accumulation of ketones and lactic acid, renal failure, and drug or toxin ingestion (high anion gap) and GI or renal HCO₃ ⁻ loss (normal anion gap). Symptoms and signs in severe cases include nausea and vomiting, lethargy, and hyperpnea. Diagnosis is clinical and with ABG and serum electrolytes. The underlying cause is treated; IV NaHCO₃ may be indicated when pH is very low.

Etiology and Pathophysiology

Metabolic acidosis is acid accumulation from increased acid production or acid ingestion; decreased acid excretion; or GI or renal HCO₃ ⁻ loss. Acidemia (arterial pH < 7.35) results when acid load overwhelms respiratory compensation. Causes are classified by their effect on the anion gap (see Sidebar 1: Acid-Base Regulation and Disorders: The Anion Gap and Table 3: Acid-Base Regulation and Disorders: Causes of Metabolic Acidosis).

Table 3
Causes of Metabolic Acidosis High anion gap Ketoacidosis (diabetes, chronic alcoholism, malnutrition, fasting) Lactic acidosis Renal failure Toxins metabolized to acids Methanol (formate) Ethylene glycol (oxalate) Paraldehyde (acetate, chloracetate) Salicylates Toxins causing lactic acidosis CO2 Cyanide Iron Isoniazid Some Trade Names INH NYDRAZID Click for Drug Monograph Toluene (initially high gap, subsequent excretion of metabolites normalizes gap) Rhabdomyolysis (rare) Normal anion gap (hyperchloremic acidosis) GI HCO3 − loss (diarrhea, ileostomy, colostomy, enteric fistulas, use of ion-exchange resins) Ureterosigmoidostomy, ureteroileal conduit Renal HCO3 − loss Tubulointerstitial renal disease Renal tubular acidosis, types 1, 2, 4 Hyperparathyroidism Ingestions ( acetazolamide Some Trade Names DIAMOX Click for Drug Monograph , CaCl2, MgSO4) Others Hypoaldosteronism Hyperkalemia Parenteral infusion of arginine Some Trade Names R-GENE Click for Drug Monograph , lysine, NH4Cl Rapid NaCl infusion Toluene (late)

High anion gap acidosis: The most common causes of a high anion gap metabolic acidosis are ketoacidosis, lactic acidosis (see Acid-Base Regulation and Disorders: Lactic Acidosis), renal failure, and toxic ingestions.

Ketoacidosis is a common complication of type 1 diabetes mellitus, but it also occurs with chronic alcoholism, malnutrition, and, to a lesser degree, fasting. In these conditions, the body converts from glucose to free fatty acid (FFA) metabolism; FFAs are converted by the liver into ketoacids, acetoacetic acid, and β-hydroxybutyrate (all unmeasured anions). Ketoacidosis is also a rare manifestation of congenital isovaleric and methylmalonic acidemia.

Renal failure causes anion gap acidosis by decreased acid excretion and decreased HCO₃ ⁻ reabsorption. Accumulation of sulfates, phosphates, urate, and hippurate accounts for the high anion gap.

Toxins may have acidic metabolites or trigger lactic acidosis. Rhabdomyolysis is a rare cause of metabolic acidosis thought to be due to release of protons and anions directly from muscle.

Normal anion gap acidosis: The most common causes of normal anion gap acidosis are GI or renal HCO₃ ⁻ loss and impaired renal acid excretion. Normal anion gap metabolic acidosis is also called hyperchloremic acidosis, because instead of reabsorbing HCO₃ ⁻ with Na, the kidney reabsorbs Cl⁻.

Many GI secretions are rich in HCO₃ ⁻ (eg, biliary, pancreatic, and intestinal fluids); loss from diarrhea, tube drainage, or fistulas can cause acidosis. In ureterosigmoidostomy (insertion of ureters into the sigmoid colon after obstruction or cystectomy), the colon secretes and loses HCO₃ ⁻ in exchange for urinary Cl⁻ and absorbs urinary ammonium, which dissociates into NH₃ ⁺ and H⁺. Ion-exchange resin uncommonly causes HCO₃ ⁻ loss by binding HCO₃ ⁻.

The renal tubular acidoses (see Abnormal Renal Transport Syndromes: Renal Tubular Acidosis (RTA)) either impair H⁺ secretion (types 1 and 4) or HCO₃ ⁻ absorption (type 2). Impaired acid excretion and a normal anion gap also occur in early renal failure, tubulointerstitial renal disease, and when carbonic anhydrase inhibitors (eg, acetazolamide Some Trade Names
DIAMOX
Click for Drug Monograph
) are taken.

Symptoms and Signs

Symptoms and signs (see Table 2: Acid-Base Regulation and Disorders: Clinical Consequences of Acid-Base Disorders) are primarily those of the cause. Mild acidemia is itself asymptomatic. More severe acidemia (pH < 7.10) may cause nausea, vomiting, and malaise. Symptoms may appear at higher pH if acidosis develops rapidly. The most characteristic sign is hyperpnea (long, deep breaths at a normal rate), reflecting a compensatory increase in alveolar ventilation.

Severe, acute acidemia predisposes to cardiac dysfunction with hypotension and shock; ventricular arrhythmias; and coma. Chronic acidemia causes bone demineralization disorders (rickets, osteomalacia, osteopenia).

Diagnosis

Recognition of metabolic acidosis and appropriate respiratory compensation are discussed in Acid-Base Regulation and Disorders: Diagnosis. Determining the cause of metabolic acidosis begins with the anion gap.

The cause of an elevated anion gap may be clinically obvious (eg, hypovolemic shock, missed hemodialysis), but if not, blood testing should include glucose, BUN, creatinine, lactate, and tests for possible toxins. Salicylate levels can be measured in most laboratories, but methanol and ethylene glycol usually cannot; their presence may be suggested by presence of an osmolar gap. Calculated serum osmolarity (2 [Na] + [glucose]/18 + BUN/2.8 + blood alcohol/5) is subtracted from measured osmolarity. A difference > 10 implies the presence of an osmotically active substance, which in the case of a high anion gap acidosis is methanol or ethylene glycol. Although ingestion of ethanol may cause an osmolar gap and a mild acidosis, it should never be considered the cause of a significant metabolic acidosis.

If the anion gap is normal and no cause is obvious (eg, marked diarrhea), urinary electrolytes are measured and the urinary anion gap is calculated as [Na] + [K] – [Cl]. Normal (including patients with GI losses) is 30 to 50 mEq/L; an elevation suggests renal HCO₃ ⁻ loss (for evaluation of renal tubular acidosis, see Abnormal Renal Transport Syndromes: Diagnosis).

Treatment

Treatment is directed at the underlying cause. Hemodialysis is required for renal failure and sometimes for ethylene glycol, methanol, and salicylate poisoning.

Treatment of acidemia with NaHCO₃ is clearly indicated only in certain circumstances and is probably deleterious in others. When metabolic acidosis results from loss of HCO₃ ⁻ or accumulation of inorganic acids (ie, normal anion gap acidosis), HCO₃ ⁻ therapy is generally safe and appropriate. However, when acidosis results from organic acid accumulation (ie, high anion gap acidosis), HCO₃ ⁻ is controversial; it does not clearly improve mortality in these conditions, and there are several possible risks. With treatment of the underlying condition, lactate and ketoacids are metabolized back to HCO₃ ⁻; exogenous HCO₃ ⁻ loading may therefore cause an “overshoot” metabolic alkalosis. In any condition, HCO₃ ⁻ may also cause Na and volume overload, hypokalemia, and, by inhibiting respiratory drive, hypercapnia. Furthermore, because HCO₃ ⁻ does not diffuse across cell membranes, intracellular acidosis is not corrected and may paradoxically worsen because some of the added HCO₃ ⁻ is converted to CO₂, which does cross into the cell and is hydrolyzed to H⁺ and HCO₃ ⁻.

Despite these and other controversies, most experts still recommend HCO₃ ⁻ IV for severe metabolic acidosis (pH < 7.00), with a target pH of 7.20.

Treatment requires 2 calculations. The 1st is the level to which HCO₃ ⁻ must be raised, calculated by the Kassirer-Bleich equation, using a value for [H⁺] of 63 nmol/L at a pH of 7.2:

63 = 24 × Pco₂/HCO₃ ⁻

or

desired HCO3⁻ = 0.38 × Pco₂

The amount of HCO₃ ⁻ needed to achieve that level is:

NaHCO₃ required (mEq) = (desired [HCO₃ ⁻] − observed [HCO₃ ⁻]) × 0.4 × body weight (kg)

This amount of NaHCO₃ is given over several hours. Serum pH and HCO₃ ⁻ levels can be checked 30 min to 1 h after administration, which allows for equilibration with extravascular HCO₃ ⁻.

Alternatives to NaHCO₃ include tromethamine Some Trade Names
THAM
Click for Drug Monograph
, an amino alcohol that buffers both metabolic (H⁺) and respiratory (H₂CO₃) acid; carbicarb, an equimolar mixture of NaHCO₃ and carbonate (the latter consumes CO₂ and generates HCO₃ ⁻); and dichloroacetate, which enhances oxidation of lactate. These are all of unproven benefit and cause complications of their own.

K⁺ depletion, common in metabolic acidosis, should also be treated as needed with oral or parenteral KCl.

Lactic Acidosis

Lactic acidosis results from overproduction, decreased metabolism, or both, of lactate.

Lactate is a normal byproduct of glucose and amino acid metabolism. The most serious form of lactic acidosis, type A, occurs when lactic acid is overproduced in ischemic tissue to generate ATP during O₂ deficit. Overproduction typically occurs during tissue hypoperfusion in hypovolemic, cardiac, or septic shock and is worsened by decreased lactate metabolism in the poorly perfused liver. It may also occur with primary hypoxia from lung disease and with various hemoglobinopathies.

Type B lactic acidosis occurs in states of normal tissue perfusion (and hence ATP production) and is less ominous. Lactate production may be increased from vigorous muscle use (eg, exertion, seizures, hypothermic shivering), alcohol ingestion, cancer, drugs such as biguanides (eg, phenformin and, less so, metformin Some Trade Names
GLUCOPHAGE
Click for Drug Monograph
) and nucleoside reverse transcriptase inhibitors or by various toxins (see Table 3: Acid-Base Regulation and Disorders: Causes of Metabolic Acidosis). Metabolism may be decreased from hepatic insufficiency or thiamine deficiency.

d-Lactic acidosis is an unusual form of lactic acidosis in which d-lactic acid, the product of bacterial carbohydrate metabolism in the colon of patients with jejunoileal bypass or intestinal resection, is systemically absorbed. It persists in circulation because lactate dehydrogenase can metabolize only l-lactate.

Findings and treatment are as for other metabolic acidoses except for d-lactic acidosis. In d-lactic acidosis, the anion gap is lower than expected for the decrease in HCO₃ ⁻, and there may be a urinary osmolar gap (difference between calculated and measured urine osmolarity). Treatment is IV fluids, restriction of carbohydrates, and sometimes antibiotics (eg, metronidazole Some Trade Names
FLAGYL
Click for Drug Monograph
).

Last full review/revision November 2005

Content last modified November 2005