Metabolic Acidosis

ByJames L. Lewis III, MD, Brookwood Baptist Health and Saint Vincent’s Ascension Health, Birmingham

Reviewed/Revised Jul 2023

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Metabolic acidosis is primary reduction in bicarbonate (HCO), typically with compensatory reduction in carbon dioxide partial pressure (P); 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 gastrointestinal or renal HCO

Etiology|
Symptoms and Signs|
Diagnosis|
Treatment|
Key Points|

(See also Acid-Base Regulation and Acid-Base Disorders.)

Overview of Metabolic Acidosis

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With metabolic acidosis, “acidosis” refers to a process that lowers blood pH below 7.35, and “metabolic” refers to the fact that it’s a problem caused by a decrease in the bicarbonate HCO3− concentration in the blood. Normally, blood pH depends on the balance or ratio between the concentration of bases, mainly bicarbonate HCO3−, which increases the pH, and acids, mainly carbon dioxide CO2, which decrease the pH. The blood pH needs to be constantly between 7.35 and 7.45, and in addition the blood needs to remain electrically neutral, which means that the total cations, or positively charged particles, equals the total anions, or negatively charged particles. Now, not all of the ions are easy or convenient to measure, so typically the dominant cation, sodium Na+, which is typically around 137 mEq/L and the two dominant anions, chloride Cl−, which is about 104 mEq/L, and bicarbonate HCO3−, which is around 24 mEq/L, are measured. The rest are unmeasured. So just counting up these three ions, there’s usually a difference, or “gap” between the sodium Na+ concentration and the sum of bicarbonate HCO3− and chloride Cl− concentrations in the plasma, which is 137 minus 128 (104 plus 24) or 9 mEq/L. This is known as the anion gap, and normally it ranges between 3 and 11 mEq/L. The anion gap largely represents unmeasured anions like organic acids and negatively charged plasma proteins, like albumin. So, basically, metabolic acidosis arises either from the buildup of acid in our blood, which could be because it’s produced or ingested in increased amounts, or because the body can’t get rid of it, or from excessive bicarbonate HCO3− loss from the kidneys or gastrointestinal tract. The main problem with all of this is that they lead to a primary decrease in the concentration of bicarbonate HCO3− in the blood. They can be broken down to two categories, based on whether the anion gap is high or normal. So, the first category of metabolic acidosis is a high anion gap metabolic acidosis. In this case, the bicarbonate HCO3− ion concentration decreases by binding of bicarbonate HCO3− ions and protons H+, which results in the formation of H2CO3 carbonic acid, which subsequently breaks down into carbon dioxide CO2 and water H2O. These protons can come from organic acids which have accumulated in the blood, but they can also come from increased production in our body. One such example is lactic acidosis, which is where decreased oxygen delivery to the tissues leads to increased anaerobic metabolism and the buildup of lactic acid. Another example is diabetic ketoacidosis, which can occurs in uncontrolled diabetes mellitus, where the lack of insulin forces cells to use fats as primary energy fuel instead of glucose. Fats are then converted to ketoacids, such as acetoacetic acid and β-hydroxybutyric acid. Another way acids can build up in our blood is due to an inability of the kidneys to throw them away, although they are produced in normal amounts. This can happen in cases of chronic renal failure, in which organic acids such as uric acid or sulfur- containing amino acids can accumulate because they aren’t excreted normally. In other cases, organic acids don’t come from inside our bodies at all, but, instead, they are accidentally ingested. These include oxalic acid which can build up after an accidental ingestion of ethylene glycol, which is a common antifreeze, formic acid, which is a metabolite of methanol, a highly toxic alcohol, or hippuric acid, which comes from toluene, which is found in paint and glue. All of these organic acids have protons, and at a physiologic pH, these organic acids dissociate into protons H+ and corresponding organic acid anions. The protons H+ attach to bicarbonate HCO3− ions floating around, decreasing its plasma concentration and shifting the pH towards the acidic range. The key is that the plasma maintains its electroneutrality, because for each new negatively charged organic acid anions, there’s one less bicarbonate HCO3− ion, and because the organic acid anions are not part of the anion gap equation, the anion gap will be high. In contrast, in other cases of metabolic acidosis, the decrease in bicarbonate HCO3− ions is offset by the buildup of Cl- ions which are part of the anion gap equation, so the anion gap remains normal. The most common cause is severe diarrhea, where bicarbonate- rich intestinal and pancreatic secretions rush through the gastrointestinal tract before they can be reabsorbed. Another cause is type 2 renal tubular acidosis, which is the most common type of renal tubular acidosis, and develops because the proximal convoluted tubule, a part of the nephron, is unable to reabsorb bicarbonate HCO3−. Other types of renal tubular acidosis also result in normal anion gap metabolic acidosis, but the underlying mechanism is an inability to excrete protons H+ in the urine. The excessive loss of bicarbonate HCO3− results in a low plasma bicarbonate HCO3− concentration, which lowers the pH. In response, the kidneys start reabsorbing more chloride Cl- anions, so for each bicarbonate HCO3− ion that’s lost, there’s a new chloride Cl- anion. This is why normal anion gap metabolic acidosis is sometimes called a hyperchloremic metabolic acidosis. Now, if there’s a decrease in the HCO3− concentration in the blood, threatening to decrease blood pH, the body has a number of important mechanisms to help keep the pH in balance. One of them is moving hydrogen ions out of the blood and into cells. To accomplish this, cells usually need to exchange the hydrogen ion for a potassium ion, using a special ion transporter located across the cell membrane. So, in order to help compensate for an acidosis, hydrogen ions enter cells and potassium ions leave the cells and enter the blood. This might help with the acidosis, but it results in hyperkalemia. In cases, though, when there’s a metabolic acidosis from excess organic acids, like lactic acid and ketoacids, protons can enter cells with the organic anion rather than having to be exchanged for potassium ions. Another important regulatory mechanism involves the respiratory system, and begins with chemoreceptors that are located in the walls of the carotid arteries and in the wall of the aortic arch. These chemoreceptors start to fire when the pH falls, and that notifies the respiratory centers in the brainstem that they need to increase the respiratory rate and depth of breathing. As the respiratory rate and depth of each breath increase, the minute ventilation increases - that’s the volume of air that moves in and out of the lungs in a minute. The increased ventilation, helps move more carbon dioxide CO2 out of the body, reducing the PCO2 in the body, which increases the pH. An additional mechanism, is that if metabolic acidosis is not caused by some renal problem, then several days later, the kidneys usually correct the imbalance. The kidneys excrete more hydrogen ions, while also, reabsorbing bicarbonate HCO3− so that it’s not lost in the urine. All right, as a quick recap, metabolic acidosis caused by a decreased bicarbonate HCO3− concentration in the blood. It can be classified into high anion gap cases, which are caused by the accumulation of organic acids, either due to their increased production in the body, decreased excretion or exogenous ingestion, and normal anion gap cases, which are caused directly by a loss of bicarbonate HCO3−, as in diarrhea or type 2 renal tubular acidosis.

Metabolic Acidosis (https://www.youtube.com/watch?v=vf99lYkJRnE&list=PLY33uf2n4e6PT53f0Z5LmFHo7Vb0ljn5b&index=5&t=23s) by Osmosis (https://open.osmosis.org/) is licensed under CC-BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0/).

Etiology of Metabolic Acidosis

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 (see table Causes of Metabolic Acidosis).

Table

Causes of Metabolic Acidosis

Table

Causes of Metabolic Acidosis

Cause

Examples

High anion gap

Ketoacidosis

Alcohol (chronic abuse)

Diabetes

Fasting

Undernutrition

Lactic acidosis (due to physiologic processes)

Alcohol (chronic abuse)

Primary hypoxia due to lung disorders

Seizures

Shock

Lactic acidosis (due to exogenous toxins)

Biguanides (rare except with acute kidney injury)

Carbon monoxide

Cyanide

HIV nucleoside reverse transcriptase inhibitors

Iron

Toluene (initially high gap; subsequent excretion of metabolites normalizes gap)

D-Lactate generation

—

—

Toxins metabolized to acids

Ethylene glycol (oxalate)

Methanol (formate)

Paraldehyde (acetate, chloracetate)

Salicylates

Normal anion gap (hyperchloremic acidosis)

Gastrointestinal bicarbonate (HCO₃⁻) loss

₂)

Colostomy

Diarrhea

Enteric fistulas

Ileostomy

Magnesium sulfate (MgSO₄)

Use of ion-exchange resins

Parenteral infusion

Arginine

Ammonium chloride (NH₄Cl)

Lysine

Renal HCO₃⁻ loss

Hyperparathyroidism

Renal tubular acidosis, types 1, 2, and 4

Tubulointerstitial renal disease

Urologic procedures

Ureteroileal conduit

Ureterosigmoidostomy

Other

Hypoaldosteronism

Hyperkalemia

Toluene (late)

Clinical Calculators

Anion Gap

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 (see diabetic ketoacidosis), but it also occurs with chronic alcohol use disorder (see alcoholic ketoacidosis), undernutrition, 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 or congenital methylmalonic acidemia, which are rare disorders that involve the abnormal metabolism of amino acids.

Lactic acidosis 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 resulting from decreased liver perfusion or as a part of generalized shock. Diseases and medications that impair mitochondrial function can cause lactic acidosis.

Renal failure 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 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 a section of 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 impair either H⁺ secretion (types 1 and 4) or HCO₃⁻

Symptoms and Signs of Metabolic Acidosis

Symptoms and signs (see table 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 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

The hyperpnea triggered by metabolic acidosis does not cause a sensation 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).

Clinical Calculators

Arterial Blood Gas Interpretation TreeCalc

Diagnosis of Metabolic Acidosis

Arterial blood gas (ABG) and serum electrolyte measurement
Anion gap and delta gap calculated
Winters formula for calculating compensatory changes
Evaluation for cause

Recognition of metabolic acidosis and appropriate respiratory compensation are discussed in Diagnosis of Acid-Base Disorders. 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)
Creatinine
Glucose
Lactate
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 [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 serum anion gap is normal, urinary electrolytes are measured and the urinary anion gap is calculated as [sodium] + [potassium] – [chloride]. A normal urinary anion gap in a person without acidosis has a value near zero. If the urinary anion gap becomes negative, there are excess unmeasured positively charged ions in the urine, typically ammonium (NH4+), which is normally secreted by the kidneys in response to volume depletion. If the urinary anion gap in a patient with non-anion gap metabolic acidosis is -30 to -50 mEq/L (-30 to -50 mmol/L), the kidneys are responding to extra-renal volume losses typically from the GI tract. An elevation in urinary anion gap in such patients (a positive calculated result) is due to the loss of unmeasured negatively charged ions in the urine and suggests renal HCO₃⁻ loss, which most commonly occurs in renal tubular acidosis (evaluation of renal tubular acidosis is discussed elsewhere).

In addition, when metabolic acidosis is present, a delta gap is calculated to identify concomitant metabolic alkalosis, and Winters formula is applied to determine whether respiratory compensation is appropriate or reflects a second acid-base disorder.

Clinical Calculators

Winter's Formula for Expected PCO2

Clinical Calculators

Urine anion gap

Treatment of Metabolic Acidosis

Cause treated
₃) primarily for severe acidemia—give with caution

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

₃) 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 HCO₃⁻₃⁻ 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⁻. Clearance of additional CO₂ also requires adequate minute ventilation. Patients with compromised respiratory status due to underlying pulmonary disease may not be able meet the increased minute ventilation. Patients requiring mechanical ventilatory support will need appropriate ventilator settings to account for increased minute ventilation.

Despite these and other controversies, most experts recommend giving bicarbonate IV for severe metabolic acidosis (pH < 7.0) primarily because of concerns about worsening cardiovascular instability at lower pH values.

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

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 of 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 HCO₃⁻₃⁻ levels can be checked 30 minutes to 1 hour after administration, which allows for equilibration with extravascular HCO₃⁻. There is no consensus regarding the concentration of bicarbonate solution to use, but it is important to realize that the typical 50-mL ampule of NaHCO₃₃ mixed with 1 L of 0.45% saline and 150 mEq NaHCO₃ mixed with 1 L of sterile water are also used.

⁺) and respiratory (carbonic acid [H₂CO₃]) acid
₂ and generates HCO₃⁻)
Dichloroacetate, which enhances oxidation of lactate

Potassium (K⁺) depletion, common in metabolic acidosis, should be identified through frequent serum K⁺

Key Points

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.
₃) is indicated when acidosis is due to a change in HCO₃⁻ level (normal anion gap acidosis).
< 7.00, with a target pH of ≥ 7.10).

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