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Metabolic Acidosis

by James L. Lewis, III, MD

Metabolic acidosis is primary reduction in HCO 3 , typically with compensatory reduction in P co 2 ; 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 HCO 3 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 NaHCO 3 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 HCO 3 loss. Acidemia (arterial pH < 7.35) results when acid load overwhelms respiratory compensation. Causes are classified by their effect on the anion gap (see The Anion Gap and Causes of Metabolic Acidosis).

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

Isoniazid

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 HCO 3 loss

Colostomy

Diarrhea

Enteric fistulas

Ileostomy

Use of ion-exchange resins

Urologic procedures

Ureterosigmoidostomy

Ureteroileal conduit

Renal HCO 3 loss

Tubulointerstitial renal disease

Renal tubular acidosis, types 1, 2, and 4

Hyperparathyroidism

Ingestions

Acetazolamide

CaCl 2

Mg sulfate (MgSO 4 )

Parenteral infusion

Arginine

Lysine

Ammonium Cl (NH 4 Cl)

Rapid NaCl infusion

Other

Hypoaldosteronism

Hyperkalemia

Toluene (late)

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 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 HCO 3 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 HCO 3 loss

  • Impaired renal acid excretion

Normal anion gap metabolic acidosis is also called hyperchloremic acidosis because the kidneys reabsorb Cl instead of reabsorbing HCO 3 .

Many GI secretions are rich in HCO 3 (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 HCO 3 in exchange for urinary Cl and absorbs urinary ammonium, which dissociates into ammonia (NH 3 + ) and hydrogen ion (H + ). Ion-exchange resin uncommonly causes HCO 3 loss by binding HCO 3 .

The renal tubular acidoses (see Renal Tubular Acidosis (RTA)) either impair H + secretion (types 1 and 4) or HCO 3 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) are taken.


Symptoms and Signs

Symptoms and signs (see 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; this hyperpnea is not accompanied by a feeling of dyspnea.

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 Acid-Base 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 HCO 3 loss (for evaluation of renal tubular acidosis, see Renal Tubular Acidosis (RTA) : Diagnosis). In addition, when metabolic acidosis is present, a delta gap is calculated (see The Anion Gap) to identify concomitant metabolic alkalosis, and Winter’s formula (see Diagnosis) is applied to see whether respiratory compensation is appropriate or reflects a 2nd acid-base disorder.

Treatment

  • Cause treated

  • NaHCO 3 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 NaHCO 3 is clearly indicated only in certain circumstances and is probably deleterious in others. When metabolic acidosis results from loss of HCO 3 or accumulation of inorganic acids (ie, normal anion gap acidosis), HCO 3 therapy is generally safe and appropriate. However, when acidosis results from organic acid accumulation (ie, high anion gap acidosis), HCO 3 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 HCO 3 ; exogenous HCO 3 loading may therefore cause an “overshoot” metabolic alkalosis. In any condition, HCO 3 may also cause Na and volume overload, hypokalemia, and, by inhibiting respiratory drive, hypercapnia. Furthermore, because HCO 3 does not diffuse across cell membranes, intracellular acidosis is not corrected and may paradoxically worsen because some of the added HCO 3 is converted to CO 2 , which does cross into the cell and is hydrolyzed to H + and HCO 3 .

Despite these and other controversies, most experts still recommend HCO 3 IV for severe metabolic acidosis (pH < 7.00), with a target pH of 7.10.

Treatment requires 2 calculations. The first is the level to which HCO 3 must be raised, calculated by the Kassirer-Bleich equation, using a value for [H + ] of 63 nmol/L at a pH of 7.20:

63 = 24 × P co 2 /HCO 3

or

desired HCO 3 = 0.38 × P co 2

The amount of HCO 3 needed to achieve that level is

NaHCO 3 required (mEq) = (desired [HCO 3 ] observed [HCO 3 ]) × 0.4 × body weight (kg)

This amount of NaHCO 3 is given over several hours. Serum pH and HCO 3 levels can be checked 30 min to 1 h after administration, which allows for equilibration with extravascular HCO 3 .

Alternatives to NaHCO 3 include

  • Tromethamine, an amino alcohol that buffers both metabolic (H + ) and respiratory (carbonic acid [H 2 CO 3 ]) acid

  • Carbicarb, an equimolar mixture of NaHCO 3 and carbonate (the latter consumes CO 2 and generates HCO 3 )

  • Dichloroacetate, which enhances oxidation of lactate

These alternatives are all of unproven benefit over NaHCO 3 alone 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.

Key Points

  • Metabolic acidosis can be caused by acid accumulation due to increased acid production or acid ingestion; decreased acid excretion; or GI or renal HCO 3 loss.

  • Metabolic acidoses are categorized based on whether the anion gap is high or normal.

  • High anion gap acidoses are most often due to ketoacidosis, lactic acidosis, renal failure, or certain toxic ingestions

  • Normal anion gap acidoses are most often due to GI or renal HCO 3 loss

  • Calculate delta gap to identify concomitant metabolic alkalosis, and apply Winter’s formula to see whether respiratory compensation is appropriate or reflects a 2nd acid-base disorder.

  • Treat the cause; NaHCO 3 is rarely indicated but may be safe to give when acidosis is due to a change in HCO 3 (normal anion gap acidosis); it is potentially dangerous in high anion gap acidosis (but may be considered when pH < 7.00, with a target pH of ≤ 7.10).

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. There are 2 main types of lactic acidosis, A and B, and an unusual form, d -lactic acidosis.

Type A lactic acidosis, the most serious form, occurs when lactic acid is overproduced in ischemic tissue to generate ATP during O 2 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 Causes of Metabolic Acidosis). Drugs include the nucleoside reverse transcriptase inhibitors and the biguanides phenformin and, less so, metformin; 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 HCO 3 , 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).

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