(See also Acid-Base Regulation Acid-Base Regulation Metabolic processes continually produce acid and, to a lesser degree, base. Hydrogen ion (H+) is especially reactive; it can attach to negatively charged proteins and, in high concentrations... read more and Acid-Base Disorders Acid-Base Disorders Acid-base disorders are pathologic changes in carbon dioxide partial pressure (Pco2) or serum bicarbonate (HCO3−) that typically produce abnormal arterial pH values. Acidemia is serum pH 7... read more .)
Metabolic acidosis is acid accumulation due to
Increased acid production or acid ingestion
Decreased acid excretion
Gastrointestinal 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 Calculation of the anion gap Acid-base disorders are pathologic changes in carbon dioxide partial pressure (Pco2) or serum bicarbonate (HCO3−) that typically produce abnormal arterial pH values. Acidemia is serum pH 7... read more (see table Causes of Metabolic Acidosis Causes of Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly subnormal... read more ).
High anion gap acidosis
The most common causes of a high anion gap metabolic acidosis are
Ketoacidosis is a common complication of type 1 diabetes mellitus (see diabetic ketoacidosis Diabetic Ketoacidosis (DKA) Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis. Hyperglycemia causes an osmotic diuresis with... read more ), but it also occurs with chronic alcohol use disorder (see alcoholic ketoacidosis Alcoholic Ketoacidosis Alcoholic ketoacidosis is a metabolic complication of alcohol use and starvation characterized by hyperketonemia and anion gap metabolic acidosis without significant hyperglycemia. Alcoholic... read more ), undernutrition Overview of Undernutrition Undernutrition is a form of malnutrition. (Malnutrition also includes overnutrition.) Undernutrition can result from inadequate ingestion of nutrients, malabsorption, impaired metabolism, loss... read more , and, to a lesser degree, fasting. In these conditions, the body converts from glucose metabolism to free fatty acid (FFA) metabolism; FFAs are converted by the liver into ketoacids, acetoacetic acid, and beta-hydroxybutyrate (all unmeasured anions). Ketoacidosis is also a rare manifestation of congenital isovaleric acidemia Isovaleric acidemia Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more or congenital methylmalonic acidemia Methylmalonic acidemia Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more .
Lactic acidosis Lactic Acidosis Lactic acidosis is a high anion gap metabolic acidosis due to elevated blood lactate. Lactic acidosis results from overproduction of lactate, decreased metabolism of lactate, or both. (See also... read more is the most common cause of metabolic acidosis in hospitalized patients. Lactate accumulation results from a combination of excess formation and decreased metabolism of lactate. Excess lactate production occurs during states of anaerobic metabolism. The most serious form occurs during the various types of shock. Decreased metabolism generally occurs with hepatocellular dysfunction from decreased liver perfusion or as a part of generalized shock. Diseases and drugs that impair mitochondrial function can cause lactic acidosis.
Renal failure Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more causes high 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 Rhabdomyolysis Rhabdomyolysis is a clinical syndrome involving the breakdown of skeletal muscle tissue. Symptoms and signs include muscle weakness, myalgias, and reddish-brown urine, although this triad is... read more 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
Gastrointestinal (GI) or renal HCO3− loss
Impaired renal acid excretion
Normal anion gap metabolic acidosis is also called hyperchloremic acidosis because the kidneys reabsorb chloride (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 chloride (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 Renal Tubular Acidosis Renal tubular acidosis (RTA) is acidosis and electrolyte disturbances due to impaired renal hydrogen ion excretion (type 1), impaired bicarbonate resorption (type 2), or abnormal aldosterone... read more impair either 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) are taken.
Symptoms and Signs
Symptoms and signs (see table Clinical Consequences of Acid-Base Disorders Clinical Consequences of Acid-Base Disorders Acid-base disorders are pathologic changes in carbon dioxide partial pressure (Pco2) or serum bicarbonate (HCO3−) that typically produce abnormal arterial pH values. Acidemia is serum pH 7... read more ) 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 occur 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.
Pearls & Pitfalls
Severe, acute acidemia predisposes to cardiac dysfunction with hypotension and shock Shock Shock is a state of organ hypoperfusion with resultant cellular dysfunction and death. Mechanisms may involve decreased circulating volume, decreased cardiac output, and vasodilation, sometimes... read more , ventricular arrhythmias Overview of Arrhythmias The normal heart beats in a regular, coordinated way because electrical impulses generated and spread by myocytes with unique electrical properties trigger a sequence of organized myocardial... read more , and coma. Chronic acidemia causes bone demineralization disorders (eg, rickets, osteomalacia Vitamin D Deficiency and Dependency Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more , osteopenia).
Arterial blood gas (ABG) and serum electrolyte measurement
Anion gap and delta gap calculated
Winters formula for calculating compensatory changes
Testing for cause
Recognition of metabolic acidosis and appropriate respiratory compensation are discussed in Diagnosis of Acid-Base Disorders Diagnosis Acid-base disorders are pathologic changes in carbon dioxide partial pressure (Pco2) or serum bicarbonate (HCO3−) that typically produce abnormal arterial pH values. Acidemia is serum pH 7... read more . 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
BUN (blood urea nitrogen)
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 [sodium] + [glucose]/18 + BUN/2.8 + blood alcohol/5, based on conventional units) 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 sole 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 [sodium] + [potassium] – [chloride]. A normal urinary anion gap (including in patients with gastrointestinal losses) is 30 to 50 mEq/L (30 to 50 mmol/L) ; an elevation suggests renal HCO3− loss (evaluation of renal tubular acidosis Diagnosis Renal tubular acidosis (RTA) is acidosis and electrolyte disturbances due to impaired renal hydrogen ion excretion (type 1), impaired bicarbonate resorption (type 2), or abnormal aldosterone... read more is discussed elsewhere).
In addition, when metabolic acidosis is present, a delta gap Calculation of the anion gap Acid-base disorders are pathologic changes in carbon dioxide partial pressure (Pco2) or serum bicarbonate (HCO3−) that typically produce abnormal arterial pH values. Acidemia is serum pH 7... read more is calculated to identify concomitant metabolic alkalosis Metabolic Alkalosis Metabolic alkalosis is primary increase in bicarbonate (HCO3−) with or without compensatory increase in carbon dioxide partial pressure (Pco2); pH may be high or nearly normal. Common causes... read more , and Winters formula is applied to determine whether respiratory compensation is appropriate or reflects a second acid-base disorder.
Sodium bicarbonate (NaHCO3) primarily for severe acidemia—give with caution
Treatment is directed at the cause. Hemodialysis Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more is required for renal failure and sometimes for ethylene glycol, methanol, and salicylate poisoning.
Treatment of acidemia with sodium bicarbonate (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), bicarbonate therapy is generally safe and appropriate. However, when acidosis results from organic acid accumulation (ie, high anion gap acidosis), bicarbonate 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, sodium bicarbonate may also cause sodium 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 carbon dioxide (CO2), which does cross into the cell and is hydrolyzed to H+ and HCO3−.
Despite these and other controversies, most experts still recommend giving bicarbonate IV for severe metabolic acidosis (pH < 7.0).
Treatment requires 2 calculations (same for both conventional and SI units). The first is the level to which HCO3− must be raised, calculated by the Kassirer-Bleich equation, using a target value for [H+] of 79 nEq/L (79 nmol/L), which corresponds to a pH of 7.10:
79 = 24 × Pco2/HCO3−
Desired HCO3−= 0.30 × Pco2
The amount of sodium bicarbonate needed to achieve that level is
NaHCO3 required (mEq/mmol) = (desired [HCO3−] − observed [HCO3−]) × 0.4 × body weight (kg)
For example, a 70-kg man has severe metabolic acidosis with a pH of 6.92, PCO2 40 mmHg and HCO3− of 8 mEq/L (8 mmol/L). The target bicarbonate level needed to achieve a pH of 7.10 is 0.30 × 40 = 12 mEq/L (12 mmol/L). This level is 4 mEq/L (4 mmol/L) more than his current bicarbonate level of 8. To increase bicarbonate by 4, multiply 4 by 0.4 times 70 (the body weight), giving a result of 112 mEq (112 mmol) of HCO3−. This amount of sodium bicarbonate is given over several hours. Blood pH and HCO3−levels can be checked 30 minutes to 1 hour after administration, which allows for equilibration with extravascular HCO3−.
Alternatives to sodium bicarbonate include
Lactate, either in the form of lactated Ringer's solution or sodium lactate (is metabolized mEq for mEq to bicarbonate when liver function is normal)
Sodium acetate (metabolized mEq for mEq to bicarbonate when liver function is normal)
Tromethamine, an amino alcohol that buffers both metabolic (H+) and respiratory (carbonic acid [H2CO3]) acid
Carbicarb, an equimolar mixture of sodium bicarbonate and carbonate (the latter consumes CO2 and generates HCO3−)
Dichloroacetate, which enhances oxidation of lactate
These alternatives do not offer a proven benefit over sodium bicarbonate alone and can cause complications of their own.
Potassium (K+) depletion, common in metabolic acidosis, should be identified through frequent serum K+ monitoring and treated as needed with oral or parenteral potassium chloride.
Metabolic acidosis can be caused by acid accumulation due to increased acid production or acid ingestion; decreased acid excretion; or gastrointestinal or renal bicarbonate (HCO3−) 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, chronic kidney disease, or certain toxic ingestions.
Normal anion gap acidoses are most often due to gastrointestinal or renal HCO3− loss.
Calculate delta gap to identify concomitant metabolic alkalosis, and apply Winters formula to see whether respiratory compensation is appropriate or reflects a 2nd acid-base disorder.
Treat the cause.
Intravenous sodium bicarbonate (NaHCO3) is indicated when acidosis is due to a change in HCO3− level (normal anion gap acidosis).
Intravenous sodium bicarbonate is controversial in high anion gap acidosis (but may be considered when pH < 7.00, with a target pH of ≥ 7.10).