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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 electrolyte measurement. The cause is treated; IV NaHCO₃ may be indicated when pH is very low.

Etiology

Metabolic acidosis is acid accumulation due to 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 Cause Examples High anion gap Ketoacidosis Diabetes Chronic alcoholism Undernutrition Fasting Lactic acidosis (due to physiologic processes) Shock Primary hypoxia due to lung disorders Seizures Lactic acidosis (due to exogenous toxins) Carbon monoxide Cyanide Iron IsoniazidSome Trade Names INH NYDRAZID Click for Drug Monograph Toluene (initially high gap; subsequent excretion of metabolites normalizes gap) Renal failure — Toxins metabolized to acids Alcohol Methanol (formate) Ethylene glycol (oxalate) Paraldehyde (acetate, chloracetate) Salicylates Rhabdomyolysis (rare) — Normal anion gap (hyperchloremic acidosis) GI HCO3− loss Colostomy Diarrhea Enteric fistulas Ileostomy Use of ion-exchange resins Urologic procedures Ureterosigmoidostomy Ureteroileal conduit Renal HCO3− loss Tubulointerstitial renal disease Renal tubular acidosis, types 1, 2, and 4 Hyperparathyroidism Ingestions AcetazolamideSome Trade Names DIAMOX Click for Drug Monograph CaCl2 Mg sulfate (MgSO4) Parenteral infusion ArginineSome Trade Names R-GENE Click for Drug Monograph Lysine Ammonium Cl (NH4Cl) Rapid NaCl infusion Other Hypoaldosteronism Hyperkalemia Toluene (late)

Clinical Calculator

High anion gap acidosis: The most common causes of a high anion gap metabolic acidosis are

• Ketoacidosis
• Lactic acidosis
• Renal failure
• Toxic ingestions

Ketoacidosis is a common complication of type 1 diabetes mellitus, but it also occurs with chronic alcoholism, undernutrition, 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.

Lactic acidosis (see Acid-Base Regulation and Disorders: Lactic Acidosis) is the most common cause of metabolic acidosis in hospitalized patients. Lactate accumulation results from a combination of excess formation and decreased utilization of lactate. Excess lactate production occurs during states of anaerobic metabolism. The most serious form occurs during the various types of shock. Decreased utilization generally occurs with hepatocellular dysfunction from decreased liver perfusion or as a part of generalized shock.

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
• Impaired renal acid excretion

Normal anion gap metabolic acidosis is also called hyperchloremic acidosis because the kidneys reabsorb Cl⁻ instead of reabsorbing HCO₃⁻.

Many GI secretions are rich in HCO₃⁻ (eg, biliary, pancreatic, and intestinal fluids); loss due to 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 ammonia (NH₃⁺) and hydrogen ion (H⁺). Ion-exchange resin uncommonly causes HCO₃⁻ loss by binding HCO₃⁻.

The renal tubular acidoses (see Renal Transport Abnormalities: 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, acetazolamideSome 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 (eg, rickets, osteomalacia, osteopenia).

Diagnosis

• ABG and serum electrolytes
• Anion gap and delta gap calculated
• Winter's formula for calculating compensatory changes
• Testing for cause

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 frequently 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]. A normal urinary anion gap (including in patients with GI losses) is 30 to 50 mEq/L; an elevation suggests renal HCO₃⁻ loss (for evaluation of renal tubular acidosis, see Renal Transport Abnormalities: Diagnosis). In addition, when metabolic acidosis is present, a delta gap is calculated (see Sidebar 1: Acid-Base Regulation and Disorders: The Anion Gap) to identify concomitant metabolic alkalosis, and Winter's formula (see Acid-Base Regulation and Disorders: Diagnosis) is applied to see whether respiratory compensation is appropriate or reflects a 2nd acid-base disorder.

Clinical Calculator

Treatment

• Cause treated
• NaHCO₃ rarely indicated

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⁻ therapy is controversial; it does not clearly decrease 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 first 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

• TromethamineSome Trade Names
  THAM
  Click for Drug Monograph
  , an amino alcohol that buffers both metabolic (H⁺) and respiratory (carbonic acid [H₂CO₃]) acid
• Carbicarb, an equimolar mixture of NaHCO₃ and carbonate (the latter consumes CO₂ and generates HCO₃⁻)
• Dichloroacetate, which enhances oxidation of lactate

These alternatives are all of unproven benefit and cause complications of their own.

K⁺ depletion, common in metabolic acidosis, should be identified through frequent serum K⁺ monitoring and treated as needed with oral or parenteral KCl.

Lactic Acidosis

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

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 due to lung disease and with various hemoglobinopathies.

Type B lactic acidosis occurs in states of normal global tissue perfusion (and hence ATP production) and is less ominous. Lactate production may be increased from local relative hypoxia as with vigorous muscle use (eg, exertion, seizures, hypothermic shivering) and with cancer and ingestion of certain drugs or toxins (see Table 3: Acid-Base Regulation and Disorders: Causes of Metabolic Acidosis). Drugs include the nucleoside reverse transcriptase inhibitors and the biguanides phenformin and, less so, metforminSome Trade Names
GLUCOPHAGE
Click for Drug Monograph
; although phenformin has been removed from the market in most of the world, it is still available from China (including as a component of some Chinese proprietary medicines). Metabolism may be decreased due to hepatic insufficiency or thiamin 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 human lactate dehydrogenase can metabolize only l-lactate.

Findings in and treatment of types A and B lactic acidosis are as for other metabolic acidoses. 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, metronidazoleSome Trade Names
FLAGYL
Click for Drug Monograph
).

Last full review/revision July 2008 by James L. Lewis, III, MD

Content last modified July 2008