Approach to the adult with metabolic acidosis

Authors:
Michael Emmett, MD
Harold Szerlip, MD, FACP, FCCP, FASN, FNKF
Section Editor:
Richard H Sterns, MD
Deputy Editor:
John P Forman, MD, MSc
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2021. | This topic last updated: Jun 09, 2020.

INTRODUCTION On a typical Western diet, approximately 15,000 mmol of

carbon dioxide (which can generate carbonic acid as it combines with water) and 50 to
100 mEq of nonvolatile acid (mostly sulfuric acid derived from the metabolism of sulfur-
containing amino acids) are produced each day. Acid-base balance is maintained by
pulmonary and renal excretion of carbon dioxide and nonvolatile acid, respectively.
Renal excretion of acid involves the combination of hydrogen ions with urinary titratable
acids, particularly phosphate (HPO42- + H+ → H2PO4-), and ammonia to form ammonium
(NH3 + H+ → NH4+) [1]. The latter is the primary adaptive response since ammonia
production from the metabolism of glutamine can be appropriately increased in
response to an acid load [2].

Acid-base balance is usually assessed in terms of the bicarbonate-carbon dioxide buffer

system:

Dissolved CO2 + H2O ↔ H2CO3 ↔ HCO3- + H+

The ratio between these reactants can be expressed by the Henderson-Hasselbalch
equation. By convention, the pKa of 6.10 is used when the denominator is the
concentration of dissolved CO2, and this is proportional to the pCO2 (the actual
concentration of the acid H2CO3 is very low):
[HCO3]
pH = 6.10 + log ————————
[0.03 x pCO2]
In this equation, the pH is equal to (-log[H+]), 6.10 is the pKa (equal to the -log of the
dissociation constant for the reaction), 0.03 is equal to the solubility constant for CO 2 in
the extracellular fluid, and pCO2 is equal to the partial pressure of carbon dioxide in the
extracellular fluid [3].
The definition, pathogenesis, and approach to the adult with metabolic acidosis will be
reviewed here. An overview of simple and mixed acid-base disorders and the approach
in children with metabolic acidosis are discussed separately. (See "Simple and mixed
acid-base disorders" and "Approach to the child with metabolic acidosis".)

DEFINITION AND PATHOGENESIS

Definition — Metabolic acidosis is defined as a pathologic process that, when
unopposed, increases the concentration of hydrogen ions in the body and reduces the
HCO3 concentration. Acidemia (as opposed to acidosis) is defined as a low arterial pH
(<7.35), which can result from a metabolic acidosis, respiratory acidosis, or both. Not all
patients with metabolic acidosis have a low arterial pH; the pH and hydrogen ion
concentration also depend upon the coexistence of other acid-base disorders. Thus, the
pH in a patient with metabolic acidosis may be low, high, or normal.
Pathogenesis — Metabolic acidosis can be produced by three major mechanisms. The
most important individual etiologies are discussed in detail elsewhere (table 1):
●Increased acid generation
●Loss of bicarbonate
●Diminished renal acid excretion
In addition to classifying metabolic acidosis by the primary pathogenic mechanism, the
serum anion gap can be used to categorize the metabolic acidoses into two groups:
high anion gap metabolic acidosis and normal anion gap metabolic acidoses (table 1).
The normal anion gap metabolic acidoses must, by definition, manifest relative
hyperchloremia (a high chloride relative to the sodium concentration). Thus, the two
groups can also be labeled high anion gap metabolic acidosis and hyperchloremic
metabolic acidosis. (See 'Physiologic interpretation of the serum anion gap' below.)
Increased acid generation — Increased acid generation leading to metabolic acidosis
occurs in a variety of clinical settings, which are discussed in detail in separate topics
dealing with each of these specific disorders (links to those topics are provided
throughout this review).
●Lactic acidosis (see "Causes of lactic acidosis")
●Ketoacidosis due to uncontrolled diabetes mellitus, excess alcohol intake
(generally in a malnourished patient), or fasting (see "Diabetic ketoacidosis and
hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and
diagnosis" and "Fasting ketosis and alcoholic ketoacidosis")
●Ingestions or infusions
•Methanol, ethylene glycol, diethylene glycol, or propylene glycol
(see "Methanol and ethylene glycol poisoning: Pharmacology, clinical
manifestations, and diagnosis")
•Aspirin poisoning (see "Salicylate (aspirin) poisoning in adults")
•Chronic acetaminophen ingestion, especially in malnourished women
•D-lactic acid, generated from carbohydrates by gastrointestinal bacteria
•Toluene (see "Inhalant abuse in children and adolescents" and "The delta
anion gap/delta HCO3 ratio in patients with a high anion gap metabolic
acidosis")
Loss of bicarbonate — Metabolic acidosis due to loss of bicarbonate occurs in the
following settings:
●Severe diarrhea (see "Acid-base and electrolyte abnormalities with diarrhea")
●When urine is exposed to gastrointestinal mucosa, which occurs after ureteral
implantation into the sigmoid colon or the creation of replacement urinary bladder
using a segment of the gastrointestinal tract (see "Acid-base and electrolyte
abnormalities with diarrhea")
 ●Proximal (type 2) renal tubular acidosis (RTA), in which proximal bicarbonate
reabsorption is impaired (see "Overview and pathophysiology of renal tubular
acidosis and the effect on potassium balance", section on 'Proximal (type 2) RTA')
In addition, in several conditions, such as ketoacidosis, which would be expected to
generate an anion gap acidosis, the renal excretion of organic acid anions (for example,
ketoacid anions) in the urine with sodium or potassium represents the loss of "potential
bicarbonate" and the anion gap shrinks or normalizes. With the onset of ketoacidosis,
bicarbonate levels fall and ketoacid anion concentrations increase. As ketoacidosis
resolves, metabolism of the ketoacid anions results in regeneration of the bicarbonate
that was lost in the initial buffering reaction. However, if these ketoacid anions are lost
into the urine before they can be metabolized (as sodium or potassium salts), this
represents lost potential bicarbonate. The effect of these urinary losses is that most
patients with diabetic ketoacidosis develop a normal anion gap metabolic acidosis
during their recovery phase. Similarly, the loss of sodium and potassium lactate into the
urine also represents loss of potential bicarbonate and partially converts an anion gap
acidosis to a hyperchloremic acidosis. (See "The delta anion gap/delta HCO3 ratio in
patients with a high anion gap metabolic acidosis".)
Diminished renal acid excretion — A regular Western diet generates a daily
nonvolatile metabolic acid load of approximately 50 to 100 mEq/day that must be
excreted by the kidneys. Acid-base balance is maintained by excreting the hydrogen
ions and the acid anions in the urine. Metabolic acidosis due to diminished renal acid
excretion can be divided into two general types of disorders:
●Reduced acid excretion that occurs in conjunction with a reduction in glomerular
filtration rate (ie, the acidosis of kidney failure) (see "Pathogenesis, consequences,
and treatment of metabolic acidosis in chronic kidney disease", section on
'Development of metabolic acidosis')
●Distal (type 1) RTA and type 4 RTA, in which tubular dysfunction is the primary
problem and glomerular filtration is initially preserved (see "Overview and
pathophysiology of renal tubular acidosis and the effect on potassium balance",
section on 'Distal (type 1) RTA')
Dilution acidosis — Dilution acidosis refers to a fall in serum bicarbonate
concentration that is primarily due to expansion of the extracellular fluid volume with
large volumes of intravenous fluids containing neither bicarbonate nor the sodium salts
of organic anions that can be metabolized to bicarbonate (such as lactate or acetate)
[4]. The degree of metabolic acidosis is generally quite moderate. However, concern
has been raised that hyperchloremia and metabolic acidosis generated by volume
expansion with normal saline may contribute to acute kidney injury and affect patient
outcomes [5]. Although initial studies did not confirm any clinical benefit of "balanced
solutions" (eg, Lactated Ringer) compared with normal saline [6], subsequent studies
have suggested a modest potential survival benefit of balanced solutions in both
critically ill and non-critically ill patients [7,8].

DIAGNOSIS AND EVALUATION

Diagnosis — A metabolic acidosis is diagnosed when the serum pH is reduced and the
serum bicarbonate concentration is abnormally low (often defined as <23 mEq/L, but the
threshold may vary across clinical laboratories) [9].

When a simple metabolic acidosis exists, the serum pH and bicarbonate concentration
will both be reduced. Although both measurements may be needed, in most patients,
the diagnosis can be made on the basis of a reduced bicarbonate concentration alone
(provided that chronic respiratory alkalosis can be ruled out on clinical grounds).

However, if metabolic acidosis coexists with respiratory acidosis or metabolic alkalosis,

then the serum bicarbonate may be normal or elevated. The bicarbonate concentration,
serum pH, and other electrolyte measurements will be required to correctly diagnose
such complicated mixed acid-base disorders. In such patients, a metabolic acidosis is
diagnosed when the serum bicarbonate is lower than it should be, even if the value falls
within the normal range. This issue is discussed in detail elsewhere but can be
illustrated here. Suppose a patient with chronic respiratory acidosis, characterized by
hypercapnia and a compensatory rise in the serum bicarbonate concentration, develops
watery diarrhea. The loss of alkali in the stool will lower the serum bicarbonate
concentration and produce a metabolic acidosis, but the serum bicarbonate
concentration may still be within or above the "normal" range since the baseline value
may have been very high (figure 1). (See "Simple and mixed acid-base disorders",
section on 'Response to respiratory acidosis'.)
It is important to recognize that the evaluation of an acid-base disorder often occurs at a
single point in time. If the previous (or "baseline") acid-base parameters are not known,
then the single set of values can be misinterpreted. Whenever a series of laboratory
results are available, the analysis should consider the changes that occurred over time.
(See "Simple and mixed acid-base disorders".)
Evaluation — Serum or plasma electrolytes, calculation of the anion gap, and a
detailed history and physical examination are usually sufficient to determine the cause
of the metabolic acidosis and guide therapy. However, in complicated patients, a
definitive evaluation of metabolic acidosis usually requires the following:
●Measurement of the arterial pH and pCO2. (See 'Measurement of the arterial pH
and pCO2' below.)
●Determine whether respiratory compensation is appropriate. (See 'Determination
of whether respiratory compensation is appropriate' below.)
●Assessment of the serum anion gap to help identify the clinical etiology of the
acidosis (table 1) and calculation of the delta anion gap/delta HCO3 ratio in patients
who have an elevated anion gap. (See 'Assessment of the serum anion
gap' below.)
The strong ion difference analysis is a complex alternative to the serum anion gap
methodology for analyzing acid-base disorders [10]. Although some believe that
this analysis may be helpful in certain unusual settings, we and others prefer an
approach based upon the serum pH, HCO3, pCO2, and anion gap (corrected for
albumin concentration) because we believe it is much simpler to understand and
utilize and it generates the correct clinical diagnosis in the vast majority of
circumstances [11]. (See "Strong ions and the analysis of acid-base disturbances
(Stewart approach)".)
 Although the serum anion gap is most often utilized in the evaluation of metabolic
acidosis, an abnormally high or low anion gap may be a valuable clue to the
presence of many conditions other than metabolic acidosis. These issues are
discussed elsewhere. (See "Serum anion gap in conditions other than metabolic
acidosis".)
Measurement of the arterial pH and pCO2 — Measurement of the serum bicarbonate
concentration alone may not be sufficient to establish a clinical diagnosis since a low
serum bicarbonate concentration can be generated by metabolic acidosis or,
alternatively, reflect the compensatory response to a primary respiratory alkalosis. If the
patient has a simple metabolic acidosis, then the arterial pH should be low. If the patient
has respiratory alkalosis, the pH should be elevated. If the patient has a mixed disorder
consisting of a metabolic acidosis plus a respiratory alkalosis, metabolic alkalosis, or all
three disorders, then the arterial pH can be low, normal, or high.
However, blood gas measurement is not mandatory in all cases. In the appropriate
clinical setting, the diagnosis of metabolic acidosis may be readily apparent (ie, lactic
acidosis with shock, hyperchloremic acidosis with diarrhea, ketoacidosis with
uncontrolled type 1 diabetes, etc). If a blood gas measurement is needed, then a
venous pH may often be adequate (see "Venous blood gases and other alternatives to
arterial blood gases"). However, an arterial blood gas is necessary to determine the
presence of a primary respiratory disorder or to accurately determine the degree of
respiratory compensation for metabolic disorders. (See "Simple and mixed acid-base
disorders".)
Determination of whether respiratory compensation is appropriate — The
complete evaluation of a patient with metabolic acidosis requires determination of the
appropriateness of the compensatory response.
Metabolic acidosis should generate a compensatory respiratory response. The
reduction in the serum bicarbonate and pH caused by the metabolic acidosis is
expected to increase ventilation and reduce the pCO2. The Henderson-Hasselbalch
equation displayed above shows that a fall in pCO2 will mitigate the fall in pH caused by
a reduced HCO3.
In all simple acid-base disorders, the primary abnormality generates a compensatory
response that results in both the HCO3 concentration and pCO2 moving in the same
direction (either both will increase or both will decrease). These directional changes
always push the pH toward the normal range [3,12,13]. The compensatory responses
are mediated, at least in part, by parallel alterations in pH within cells of the renal
tubules or respiratory center [14]. (See "Simple and mixed acid-base disorders".)
The respiratory compensation for metabolic acidosis generates a reproducible and
relatively linear relationship between the arterial pCO2 and bicarbonate concentration.
This respiratory response to metabolic acidosis begins within 30 minutes and is
complete by 12 to 24 hours. Respiratory compensation for metabolic acidosis is very
similar across all forms of metabolic acidosis (eg, lactic acidosis, ketoacidosis,
hyperchloremic acidosis caused by diarrhea, etc). In order to determine whether an
appropriate compensatory response exists, a variety of acid-base diagrams, charts,
nomograms, and mathematical relations have been published. These are discussed in
greater detail elsewhere. (See "Simple and mixed acid-base disorders", section on
'Response to metabolic acidosis'.)
Several relatively simple acid-base "rules" for metabolic acidosis are acceptable for
clinical use. They include:

●pCO2 = 1.5 x HCO3 + 8 ± 2. This equation, which is called Winter's formula, was
derived in children (many less than 2 years of age).
●pCO2 = HCO3 + 15.
●The pCO2 should approximate the decimal digits of the arterial pH. As an example,
if the pH is 7.25, then the pCO2 should be approximately 25 mmHg [15].
These rules work well for mild to moderately severe metabolic acidosis (HCO3 between
7 and 22 mEq/L). For more severe metabolic acidosis (HCO3 less than 7 mEq/L), the
pCO2 should be maximally reduced to the 8 to 12 mmHg range. As an example, assume
the following results are obtained in a patient with metabolic acidosis: pH = 7.30; pCO 2 =
30 mmHg (4.0 kPa); HCO3 = 15 mEq/L. This is consistent with a simple metabolic
acidosis with appropriate respiratory compensation; all three of the compensation rules
presented above are satisfied. It should be noted that these rules should not be used for
determining the compensatory response for other acid-base disorders. The pCO2 cannot
be reduced to less than 8 to 12 mmHg. (See "Simple and mixed acid-base disorders",
section on 'Response to metabolic acidosis'.)
An inability to generate an appropriate hyperventilatory response is generally indicative
of significant underlying neurologic or respiratory disorder and represents a mixed acid-
base disorder: metabolic acidosis and respiratory acidosis. Conversely, excessive
hyperventilation, which reduces the pCO2 below the expected range, is indicative of
mixed metabolic acidosis and respiratory alkalosis. (See "Simple and mixed acid-base
disorders".)
Assessment of the serum anion gap — Disorders that produce metabolic acidosis by
increasing organic acid generation and severe chronic kidney disease, which leads to
the accumulation of multiple acids such as phosphoric and sulfuric acid, usually result in
an increased serum anion gap. Other disorders typically result in a hyperchloremic
metabolic acidosis. Thus, the serum anion gap helps narrow the differential diagnosis in
a patient with metabolic acidosis (table 1). (See 'Physiologic interpretation of the serum
anion gap' below.)
In patients with an elevated serum anion gap metabolic acidosis, the rise in anion gap is
generally similar to the fall in bicarbonate. This relationship can be defined as the delta
anion gap/delta HCO3. However, the expected 1:1 relationship between the decrease in
HCO3 and the increase in anion gap is not always observed in some forms of anion gap
acidosis, such as ketoacidosis and D-lactic acidosis. The reasons for the disruption of
the 1:1 relationship are discussed elsewhere. (See "The delta anion gap/delta HCO3
ratio in patients with a high anion gap metabolic acidosis".)
Physiologic interpretation of the serum anion gap — The serum anion gap can be
helpful in narrowing the differential diagnosis in patients with metabolic acidosis (table
1) [1,3,12,13,16]. For purposes of the following discussion about the anion gap, all non-
sodium cations will be referred to as "unmeasured cations," and all anions other than
chloride and bicarbonate will be designated "unmeasured anions." Of course, all of
these ions can be and often are "measured," but they are not utilized for these anion
gap calculations. (The issue related to potassium is discussed below.)

The serum anion gap is typically calculated using the following formula:
Serum anion gap = Na - (Cl + HCO3)

In some countries other than the United States, the serum potassium is also included in
the formula; when this formula is used, the normal range for the anion gap increases by
approximately 4 mEq/L:

Serum anion gap = (Na + K) - (Cl + HCO3)

The normal value of the serum anion gap is dependent upon the specific chemical
analyzers used to measure each analyte and therefore will vary from laboratory to
laboratory and over time. In general the normal range is approximately 4 to 12 mEq/L
[14,16], but it is best for each laboratory to determine its own local normal range.

Interpretation of the serum anion gap is most helpful when an individual's usual, or
baseline, anion gap is known and serial measurements are available from the same
laboratory. As an example, if a patient's baseline anion gap is 4 mEq/L and is found to
be 12 mEq/L, then this 8 mEq/L increase in the anion gap is probably clinically
significant despite the fact that the anion gap is still within the "normal" range.
Unfortunately, baseline data are often unavailable.

When all ions in any solution are measured in units of electric charge, or valence (ie,
mEq/L), then:

The sum of all anions = The sum of all cations

This relationship allows the derivation of another formulation for the anion gap, as
follows:

Total serum anions = Total serum cations

Therefore:

Na + All unmeasured cations = Cl + HCO3 + All unmeasured anions

Re-arranging:

Na - (Cl + HCO3) = All unmeasured anions - All unmeasured cations = Serum anion
gap

This formulation indicates that the anion gap will increase if unmeasured anions
increase or unmeasured cations decrease. Conversely, the anion gap will decrease if
unmeasured anions decrease or unmeasured cations increase.

In normal individuals, the major unmeasured anion responsible for the existence of a
serum anion gap is albumin. This circulating protein has a significant net negative
charge in the physiologic pH range. As a result, the expected baseline value for the
anion gap must be adjusted downward in patients with hypoalbuminemia. The serum
anion gap falls by approximately 2.5 mEq/L for every 1 g/dL (10 g/L) reduction below
normal (4.5 g/L) in the serum albumin concentration [1,16,17]:
Corrected serum anion gap = (Serum anion gap measured) + (2.5 x [4.5 - Observed
serum albumin])

In addition to hypoalbuminemia, marked hyperkalemia may affect the interpretation of

the anion gap. Potassium is an "unmeasured" cation when the anion gap equation that
does not include the serum potassium is utilized. Thus, a serum potassium of 6 mEq/L
will reduce the anion gap by 2 mEq/L. Marked hypercalcemia and/or hypermagnesemia
can similarly reduce the anion gap. Another cause of a reduced or negative anion gap is
immunoglobulin G (IgG) multiple myeloma. Many of these abnormal proteins circulate
as cations. Other monoclonal proteins such as immunoglobulin A (IgA) are anions and
therefore can raise the anion gap [16,18]. (See "Serum anion gap in conditions other
than metabolic acidosis".)

An anion gap metabolic acidosis develops when an accumulating acid is any strong
acid other than hydrogen chloride. Under these conditions, the bicarbonate
concentration falls; the chloride concentration, the other "measured" anion, remains
relatively unchanged; and the acid anion increases, raising the anion gap. As an
example, when lactic acidosis develops, the following reaction occurs:

HLactate + NaHCO3 → NaLactate + H2CO3 → CO2 + H2O

Note that, in this oversimplified schema, the magnitude of decrease in HCO3 matches
the magnitude of increase in the lactate concentration and the anion gap. However, this
1:1 relationship between the fall in HCO3 and rise in serum anion gap is not always
found; the reasons for this are discussed elsewhere. (See "The delta anion gap/delta
HCO3 ratio in patients with a high anion gap metabolic acidosis", section on
'Determinants'.)
Although the specific organic acid anions responsible for anion gap metabolic acidosis
can often be characterized using a variety of analytic techniques, a significant
component sometimes remains unidentified. These unidentified anions may include a
number of organic acids generated by the Krebs cycle (citrate, isocitrate, alpha-
ketoglutarate, succinate, and malate) [19-22].
Normal anion gap (hyperchloremic) metabolic acidoses are caused by loss of
bicarbonate or a disorder that reduces renal acid excretion in the setting of a relatively
normal glomerular filtration rate (ie, type 1, 3, or 4 renal tubular acidosis) [RTA]. A rare
form of normal anion gap metabolic acidosis is due to the ingestion or infusion of
hydrogen chloride or compounds which generate hydrogen chloride (NH4Cl, arginine
HCl, CaCl2). (See 'Definition and pathogenesis' above.)

When hydrogen chloride is added to the extracellular fluid space, bicarbonate is

replaced on an equimolar basis by chloride. Thus, there is no change in the serum
anion gap. The terms "normal anion gap metabolic acidosis" and "hyperchloremic
metabolic acidosis" are therefore interchangeable names for this disorder.

Loss of sodium bicarbonate, or other potential alkali salts (such as sodium acetate,
sodium butyrate, etc), from the body generates hyperchloremia because the lost fluid
has a relatively high HCO3, or alkali, concentration and a relatively low chloride
concentration. The loss of such fluid (urine, pancreatic secretions, stool) will contract the
extracellular fluid volume "around" a relatively stable quantity of chloride. Also, the
hypovolemia that develops will favor retention of any chloride that is ingested or infused
(eg, isotonic saline).
Causes of elevated anion gap metabolic acidosis — The major causes of a high
anion gap metabolic acidosis include (table 1) [1,3,16]:
●Lactic acidosis – There are numerous conditions that cause L-lactic acidosis (L-
lactate is the dominant mammalian isomer of lactate). Lactic acidosis commonly
occurs with tissue hypoperfusion that may be secondary to systemic hypotension.
Microcirculatory hypoperfusion without overt systemic hypotension, called
"cryptogenic shock," can also generate lactic acidosis. In addition, numerous
medications may cause an increase in the production of lactic acid. (See "Causes
of lactic acidosis".)
●Ketoacidosis – Ketoacidosis results from uncontrolled diabetes mellitus or in
association with chronic alcohol abuse. (See "Fasting ketosis and alcoholic
ketoacidosis" and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Clinical features, evaluation, and diagnosis", section on 'Anion gap
metabolic acidosis'.)
●Acute or chronic kidney disease – Patients with severe kidney failure may develop
a high anion gap acidosis, resulting from the retention of both hydrogen ions and
anions such as sulfate, phosphate, and urate [3,23]. (See "Pathogenesis,
consequences, and treatment of metabolic acidosis in chronic kidney disease".)
●Toxic alcohol ingestion – Ingestion of methanol or ethylene glycol produces high
anion gap metabolic acidosis. These alcohols are metabolized to various organic
acids; methanol is metabolized to formic acid, and ethylene glycol to glycolic and
oxalic acid. Diethylene and propylene glycol may also produce an elevated anion
gap acidosis. (See "Methanol and ethylene glycol poisoning: Pharmacology, clinical
manifestations, and diagnosis".)
●Salicylate (aspirin) poisoning – Salicylate poisoning impairs oxidative
phosphorylation and causes the accumulation of multiple acids including lactic acid
and ketoacids. (See "Salicylate (aspirin) poisoning in adults".)
●Acetaminophen – Chronic acetaminophen use at therapeutic doses can result in
an elevated anion gap metabolic acidosis [24-29]. The accumulating acid is
pyroglutamic acid (also called 5-oxoproline). Affected patients are usually women
with chronic illness and malnutrition. The pathogenesis is probably related to
chronic glutathione and cysteine deficiency. This disorder is distinct from acute
acetaminophen overdose, which can generate severe acute liver disease and, in
some cases, lactic acidosis.
●D-lactic acidosis – D-lactic acid is generated by bacterial fermentation of ingested,
but unabsorbed, carbohydrates. D-lactic acidosis results from excessive absorption
of D-lactic acid from the lumen of the gastrointestinal tract, usually in patients with
jejunoileal bypass or short bowel syndrome. Several other causes of D-lactic
acidosis have been described. The metabolism of propylene glycol (which is used
as the solvent for intravenous preparations of several medications, such
as lorazepam, and as a less toxic alternative to ethylene glycol in automotive
antifreeze) can generate D-lactic acid. Elevated D-lactate acid levels have also
 been identified in some patients with diabetic ketoacidosis [30,31]. (See "D-lactic
acidosis".)
There are other, much less common causes of a high anion gap acidosis. As an
example, inherited glutathione synthetase deficiency may result in an acidosis caused
by the accumulation of pyroglutamic acid (5-oxoproline), a metabolic product of gamma-
glutamylcysteine. This is discussed separately. (See "Disorders of the hexose
monophosphate shunt and glutathione metabolism other than glucose-6-phosphate
dehydrogenase deficiency", section on 'Glutathione synthetase deficiency'.)

In both ketoacidosis and lactic acidosis, the unmeasured anions that accumulate in the
body represent "potential bicarbonate" because metabolism of these anions generates
bicarbonate. This occurs when the underlying abnormality is corrected (eg, restoration
of tissue perfusion in lactic acidosis and volume expansion and insulin therapy in
diabetic ketoacidosis). However, the accumulation of unmeasured "potential
bicarbonate" anions in these two disorders differs in the following way:

●In patients with ketoacidosis, a large amount of the potential bicarbonate is

excreted in the urine as sodium and potassium beta-hydroxybutyrate and
acetoacetate The renal loss of ketoacids increases during therapy because volume
expansion with intravenous saline restores the extracellular fluid volume and
improves kidney function. This increases the renal loss of potential bicarbonate.
The net effect is that most patients with diabetic ketoacidosis convert their anion
gap acidosis into a normal anion gap (hyperchloremic) acidosis in response to
successful therapy [32]. (See "Diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section
on 'Anion gap metabolic acidosis' and "The delta anion gap/delta HCO3 ratio in
patients with a high anion gap metabolic acidosis".)
●By contrast, in patients with hypoperfusion-induced lactic acidosis, the renal loss
of potential bicarbonate is much less marked because kidney function is typically
reduced. Thus, lactate anions are not excreted, and, after adequate perfusion is
restored, a normal anion gap acidosis does not usually develop.
Causes of hyperchloremic (normal anion gap) metabolic acidosis — As noted
above, normal anion gap (hyperchloremic) metabolic acidoses usually result from a loss
of bicarbonate or an isolated reduction in renal acid excretion. Loss of bicarbonate-rich
fluid can occur in several clinical settings including:
●Diarrhea (see "Acid-base and electrolyte abnormalities with diarrhea", section on
'Acid-base, electrolyte, and volume abnormalities associated with diarrhea')
●Prolonged exposure of urine to colonic or ileal mucosa (in patients who have had
ureteral implants into the colon or have a malfunctioning ileal loop bladder)
(see "Acid-base and electrolyte abnormalities with diarrhea")
●Proximal (type 2) RTA (table 1) (see "Etiology and diagnosis of distal (type 1) and
proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA')
Impairment of renal acid excretion also produces a normal anion gap metabolic
acidosis. Each day, the metabolism of dietary proteins generates 50 to 100 mEq of acid,
mainly sulfuric acid and phosphoric acid [3]. Excretion of these acids can be considered
a two-step process. The anions (sulfate and phosphate) are filtered by the glomeruli and
excreted as sodium salts. The hydrogen ions are excreted by the distal nephron via the
acid secretory process (figure 2). When kidney function is intact, these two processes
successfully excrete both the anions and the hydrogen ions of sulfuric and phosphoric
acid. However, impaired acid excretion, and therefore metabolic acidosis, can develop
in the following settings:
●Acute or chronic kidney disease can, if severe, produce an elevated anion gap
metabolic acidosis. Tubular dysfunction decreases hydrogen ion excretion while a
pronounced reduction in glomerular filtration rate results in accumulation of anions
(such as sulfate and phosphate) that elevate the anion gap. However, a normal
anion gap acidosis may develop in patients with mild or moderate renal
insufficiency whose defect in distal tubular function is considerably worse than the
reduction in glomerular filtration rate. In such patients, glomerular filtration is
adequate to permit excretion of the anions as sodium or potassium salts, but the
tubular defect impairs acid excretion, and a hyperchloremic acidosis ensues
[23,33]. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in
chronic kidney disease".)
●Similar considerations apply when hydrogen ions are retained because of
impaired renal acid excretion due to distal (type 1) or type 4 RTA or
hypoaldosteronism. In these conditions, a normal anion gap acidosis develops
since there is no retention of unmeasured anions [1,3]. (See "Etiology and
diagnosis of distal (type 1) and proximal (type 2) renal tubular
acidosis" and "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4
RTA)".)
Combined elevated anion gap and hyperchloremic acidoses — Normal and high
anion gap metabolic acidosis can coexist. Two settings in which this can occur are:
●Diarrhea – Diarrhea typically generates a normal anion gap acidosis. However,
with severe diarrhea (as can occur in cholera), the development of marked
hypovolemia can generate an anion gap metabolic acidosis. This is due to
hypoperfusion-induced lactic acidosis, hyperalbuminemia (albumin is negatively
charged and accounts for most of the anion gap in normal individuals), and a
reduced glomerular filtration rate, which generates hyperphosphatemia and
retention of other organic ions [34]. (See "Overview of the causes and treatment of
hyperphosphatemia", section on 'Acute extracellular shift of phosphate' and "Acid-
base and electrolyte abnormalities with diarrhea", section on 'Serum anion gap in
patients with metabolic acidosis due to diarrhea'.)
●Ketoacidosis – The reasons why ketoacidosis can produce both a high anion gap
and normal anion gap acidosis are presented above. (See 'Causes of elevated
anion gap metabolic acidosis' above.)
●Progression of kidney disease – Early kidney disease generates a non-anion gap,
hyperchloremic metabolic acidosis, and this may gradually evolve into an anion gap
uremic acidosis [33]. (See "Pathogenesis, consequences, and treatment of
metabolic acidosis in chronic kidney disease".)
Similar considerations apply to D-lactic acidosis and toluene-induced metabolic
acidosis. These conditions will increase the anion gap if the acid anions (D-lactate or
hippurate) are retained, but a normal anion gap acidosis will evolve if these anions are
excreted. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap
metabolic acidosis".)
 OVERVIEW OF THERAPY The treatment of metabolic acidosis varies

depending upon the underlying disorder. The general principles of treatment of

metabolic acidosis will be reviewed here, including issues related to estimation of the
bicarbonate deficit.

The specific approaches to therapy in the most common causes of metabolic acidosis
are discussed in detail separately. These include:

●Diabetic ketoacidosis (see "Diabetic ketoacidosis and hyperosmolar

hyperglycemic state in adults: Treatment")
●Lactic acidosis (see "Bicarbonate therapy in lactic acidosis")
●Chronic kidney disease (see "Pathogenesis, consequences, and treatment of
metabolic acidosis in chronic kidney disease")
●Diarrhea (see "Acid-base and electrolyte abnormalities with diarrhea")
●Renal tubular acidosis (RTA) (see "Treatment of distal (type 1) and proximal (type
2) renal tubular acidosis")
●Ingestions, such as aspirin, methanol, and ethylene glycol (see "Salicylate
(aspirin) poisoning in adults" and "Methanol and ethylene glycol poisoning:
Pharmacology, clinical manifestations, and diagnosis")
General approach and rationale — First, whenever possible, the primary focus of
therapy for metabolic acidosis should be directed at reversing the underlying
pathophysiologic process (see above). Second, it is important to consider acute and
chronic forms of metabolic acidosis separately:
Acute metabolic acidosis — We initiate bicarbonate therapy when acute metabolic
acidosis has generated severe acidemia (ie, pH less than 7.1). We also generally
suggest bicarbonate therapy for patients with less severe acidemia (eg, pH 7.1 to 7.2)
who have severe acute kidney injury (ie, a twofold or greater increase in serum
creatinine or oliguria); bicarbonate therapy in such patients can potentially prevent the
need for dialysis and may improve survival [35].
The clinical impact and treatment of severe acute metabolic acidosis remain
controversial. Experts disagree about the indications for the use of sodium
bicarbonate or other buffering agents. Some studies indicate that myocardial
depression, decreased catecholamine efficacy, and arrhythmias develop when the pH
falls below 7.1. However, these data come mainly from animal or tissue experiments.
Human studies of the cardiovascular effects of severe acidemia have
generally not supported the animal or tissue experimental results. As an example,
transient decreases in pH to 6.8 in individuals with diabetic ketoacidosis are not
associated with depressed cardiac function [36]. In addition, raising the pH may have
adverse consequences including a paradoxical fall in intracellular pH, increased lactate
production, and myocardial depression. It is, however, important to recognize that, at a
pH below 7.1, small changes in pCO2 or HCO3 can have very large pH effects. Thus,
many clinicians initiate treatment of metabolic acidosis when the bicarbonate level is
very low (eg, <5 mEq/L) and the pH is below 7.1.
We do not generally use bicarbonate therapy in patients with less severe acidosis (pH
7.1 or greater), unless the patient also has severe acute kidney injury. The best data
come from a randomized trial of critically ill patients with severe metabolic acidosis
(most patients had lactic acidosis, and the mean arterial pH was 7.15) [35]. In this trial,
bicarbonate therapy (to maintain a pH >7.3) had no overall effect on mortality or organ
failure, but, among the subgroup of patients with severe acute kidney injury (defined as
a twofold or greater increase in serum creatinine or oliguria), bicarbonate therapy
reduced 28-day mortality and the need for dialysis. (See "Bicarbonate therapy in lactic
acidosis", section on 'Which patients should receive bicarbonate therapy'.)
Severe and symptomatic acute acidemia can most rapidly be treated by the intravenous
administration of sodium bicarbonate. Despite its potential adverse effects, sodium
bicarbonate remains the most frequently used alkalinizing agent. Less severe acute
metabolic acidosis does not usually require bicarbonate treatment. This is especially the
case when "potential" bicarbonate (ie, lactate, ketoacid anions) has been retained and
can be converted to bicarbonate when the underlying pathologic derangement has been
alleviated or eliminated. Even if the "potential bicarbonate" has been excreted (and a
hyperchloremic metabolic acidosis exists), a patient with relatively intact kidney function
can restore normal acid-base status in several days by excreting ammonium
chloride into the urine.
An alternative alkalinizing agent is tris-hydroxymethyl aminomethane (tromethamine, or
THAM), although this drug is not continuously available for use. The potential
advantages and disadvantages of this agent are discussed below. (See 'Alternative
agent' below.)
Chronic metabolic acidosis — The most common causes of chronic metabolic
acidosis are diarrhea, advanced chronic kidney disease, and the various forms of RTA.
The indications for treating these disorders are fully discussed in the sections devoted
to these disorders. (See "Acid-base and electrolyte abnormalities with
diarrhea" and "Pathogenesis, consequences, and treatment of metabolic acidosis in
chronic kidney disease" and "Treatment of distal (type 1) and proximal (type 2) renal
tubular acidosis".)

Generally, if more normal acid-base parameters can be achieved with exogenous alkali
(eg, sodium or potassium bicarbonate, citrate, or analogous salts) without creating other
difficulties (such as potassium wasting in disorders such as type 2 or proximal RTA),
then such treatment may be helpful. The rational for alkali therapy is summarized here:

●Increasing the bicarbonate concentration reduces or eliminates the need for

compensatory hyperventilation and can alleviate the dyspnea experienced by some
patients.
●Chronic metabolic acidosis may have adverse effects on muscle function and
metabolism, skeletal integrity, hormone levels, and other physiologic parameters. In
children, for example, correction of chronic metabolic acidosis restores skeletal
growth. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular
acidosis" and "Approach to the child with metabolic acidosis".)
●Patients with chronic distal (type 1) RTA are likely to develop nephrocalcinosis and
calcium-containing kidney stones. This defect can be reversed with adequate
bicarbonate replacement. (See "Nephrocalcinosis".)
 ●Chronic metabolic acidosis in patients with kidney dysfunction may accelerate the
progression of their kidney damage, and reversal of the acidosis can slow this
process. (See "Pathogenesis, consequences, and treatment of metabolic acidosis
in chronic kidney disease".)
Dosing of alkali therapy (when given)
Bicarbonate — From a practical clinical perspective, the dose of bicarbonate to be
administered is determined empirically. When the decision to administer sodium
bicarbonate is made for a patient with severe acute metabolic acidosis, it is usually
accomplished with 50 mL vials of hypertonic sodium bicarbonate. They are generally
available as 8.4 percent (50 mEq/50 mL) or 7.2 percent (44.6 mEq/50 mL). If the virtual
bicarbonate space (see 'The virtual bicarbonate distribution space' below) is roughly 50
percent of lean body weight, then one vial will raise the serum HCO3 concentration by
approximately 1.3 to 1.5 mEq/L in a 70 kg patient. Note that this solution is hypertonic
(100 mEq/50 mL = 2000 mosm/L). Thus, it will raise the serum sodium concentration
and cause movement of water from the intracellular to the extracellular space. If more
than two vials are administered, additional free water should be considered to avoid
hypernatremia. Alternatively, three vials can be added to 1 liter of 5 percent dextrose to
generate an intravenous solution with approximately 150 mEq/L of sodium bicarbonate.

When chronic alkali treatment is required, options include the sodium or potassium salts
of either bicarbonate or a metabolizable anion such as citrate or lactate. The potassium
salts are indicated when hypokalemia and total body potassium deficits exist. In
general, the initial dose is 50 to 100 mEq per day, which is then titrated up, or down, as
required. If ongoing bicarbonate losses persist or accelerate, the dose will need to be
adjusted accordingly.

The virtual bicarbonate distribution space — After the infusion of sodium

bicarbonate into the intravascular space, it will rapidly distribute throughout the
extracellular fluid space. Some will enter the intracellular fluid space, some will be
titrated by hydrogen ions released from a variety of body acid-base buffers, and some
will be titrated by organic acids that can be produced both as a part of the original
pathologic process and in response to the bicarbonate load and increase of pH.
Together, the physical distribution of the bicarbonate into these spaces and the
disappearance of some bicarbonate as a result of its titration with hydrogen ions can be
considered a virtual "space" into which the infused HCO3 load distributes [37,38]. If the
bicarbonate distribution space can be determined, then the quantity of bicarbonate
required to elevate the serum bicarbonate concentration by any given amount can be
estimated from the bicarbonate deficit:
HCO3 deficit = HCO3 space x HCO3 deficit per liter

When the serum bicarbonate concentration is normal to moderately reduced, the

apparent bicarbonate space is approximately 55 percent of lean body weight.

However, for a number of complex reasons related to the body's bicarbonate buffering
mechanisms, and because the bicarbonate-CO2 acid-base pair is an "open" system (ie,
CO2 can be added or removed in great quantities through ventilation), the bicarbonate
space is not fixed but varies with the initial HCO3 concentration and the size and
potency of the other buffer pools with which it equilibrates. With severe metabolic
acidosis, the apparent bicarbonate buffer space expands markedly, reaching
approximately 70 percent of lean body weight when the serum bicarbonate falls below
10 mEq/L and potentially exceeding the body weight when the serum bicarbonate is
less than 5 mEq/L [38,39]. The bicarbonate space at a given serum bicarbonate
concentration can be estimated from the following formula [38]:
HCO3 space = [0.4 + (2.6 ÷ [HCO3])] x Lean body weight (in kg)
If, for example, a patient with a lean body weight (calculator 1 and calculator 2) of 60 kg
has a serum bicarbonate of 6 mEq/L and the initial aim of therapy is to raise this value
to 12 mEq/L, then the following calculations can be made: the bicarbonate space is
initially approximately 80 percent of lean body weight at a bicarbonate concentration of
6 mEq/L, and this space falls to approximately 60 percent of body weight at a
bicarbonate concentration of 12 mEq/L. Using the average value of 70 percent of lean
body weight, the amount of bicarbonate required to raise the level to 12 mEq/L is:
HCO3 deficit = 0.7 x 60 x (12 - 6) = 252 mEq
Thus, approximately 250 mEq of alkali (usually as intravenous sodium bicarbonate) can
be given over the first four to eight hours. In addition, the virtual bicarbonate space
expands dramatically when organic acids are rapidly generated.
Thus, these calculations are very rough estimates that can be used to provide an initial
guide to therapy. They must never replace serial measurements of the blood pH and
HCO3.
Alternative agent — Tromethamine (tris-hydroxymethyl aminomethane; also called
THAM, TRIS, and trometamol) is an alternative to sodium bicarbonate. The
manufacturer of THAM has not continuously produced the drug, and therefore it may
not be available.
It is an amino alcohol that buffers hydrogen ions by virtue of its amine (NH2) moiety (pKa
= 7.7) via the following reactions [40]:
THAM-NH2 + H+ = THAM-NH3+

or

THAM-NH2 + H2O + CO2 = THAM-NH3+ + HCO3-

Unlike bicarbonate, which generates carbon dioxide (CO2) when it reacts with hydrogen
ions (H+), THAM consumes carbon dioxide.
In addition, unlike sodium bicarbonate, THAM is not a sodium salt and therefore does
not provide a sodium load.

Renal clearance of protonated THAM salts is slightly greater than renal clearance of
creatinine. Thus, THAM can buffer hydrogen ions without generating carbon dioxide but
is less effective when kidney function is reduced. Toxicities include hyperkalemia,
hypoglycemia, and respiratory depression; the latter may be due to rapid alkalization of
the central nervous system.

THAM has been used to treat severe acidemia due to sepsis, permissive hypercapnia,
diabetic ketoacidosis, RTA, gastroenteritis, and drug intoxications [40-42]. However,
THAM has not been evaluated in clinical trials involving patients with lactic acidosis.
Because of its ability to decrease pCO2, THAM is an alternative to bicarbonate that may
be the preferred buffer in critically ill patients with mixed metabolic and respiratory
acidosis. THAM is dosed using the following formula:
0.3 M THAM (mL) = Body dry weight (kg) x (Desired HCO3 - Actual HCO3) x 1.1

SOCIETY GUIDELINE LINKS Links to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Acute kidney injury in adults".)

SUMMARY AND RECOMMENDATIONS

●Metabolic acidosis is defined as a pathologic process that, when unopposed,

increases the concentration of hydrogen ions in the body and reduces the
HCO3 concentration. Acidemia (as opposed to acidosis) is defined as a low arterial
pH (<7.35), which can result from a metabolic acidosis, respiratory acidosis, or
both. Not all patients with metabolic acidosis have a low arterial pH; the pH and
hydrogen ion concentration also depend upon the coexistence of other acid-base
disorders. Thus, the pH in a patient with metabolic acidosis may be low, high, or
normal. (See 'Definition' above.)
●Metabolic acidosis can be produced by three major mechanisms (table 1)
(see 'Pathogenesis' above):
•Increased acid generation due, for example, to lactic acidosis or ketoacidosis
(see 'Increased acid generation' above)
•Loss of bicarbonate due, for example, to diarrhea (see 'Loss of
bicarbonate' above)
•Diminished renal acid excretion due, for example, to renal tubular acidosis
(RTA) (see 'Diminished renal acid excretion' above)
●A metabolic acidosis is diagnosed when the serum pH is reduced and the serum
bicarbonate concentration is abnormally low (often defined as <22 mEq/L, but the
threshold may vary across clinical laboratories). When a simple metabolic acidosis
exists, the serum pH and bicarbonate concentration will both be reduced. Although
both measurements may be needed, under many clinical circumstances the
diagnosis can be made on the basis of a reduced bicarbonate concentration alone
(provided that chronic respiratory alkalosis can be ruled out on clinical grounds).
The lower normal range limit for a peripheral venous bicarbonate measurement is
generally 22 mEq/L, but this may vary in different laboratories. However, if
metabolic acidosis coexists with respiratory acidosis or metabolic alkalosis, then
the serum bicarbonate may be normal or elevated. The bicarbonate concentration,
serum pH, and other electrolyte measurements will often be required to correctly
diagnose such complicated mixed acid-base disorders. In such patients, a
metabolic acidosis is diagnosed when the serum bicarbonate is lower than it should
be, even if the value falls within the normal range. (See 'Diagnosis' above.)
●Serum or plasma electrolytes, calculation of the anion gap, and a detailed history
and physical examination are frequently sufficient to determine the cause of the
metabolic acidosis and guide therapy. However, in complicated patients, a
definitive evaluation of metabolic acidosis usually requires the following
(see 'Evaluation' above):
•Measurement of the arterial pH and pCO2 (see 'Measurement of the arterial
pH and pCO2' above)
•Determining whether respiratory compensation is appropriate
(see 'Determination of whether respiratory compensation is appropriate' above)
•Assessment of the serum anion gap to help identify the cause of acidosis
(table 1) and calculation of the delta anion gap/delta HCO3 ratio in patients who
have an elevated anion gap (see 'Assessment of the serum anion gap' above)
●The treatment of metabolic acidosis varies depending upon the underlying
disorder. The specific approaches to therapy in the most common causes of
metabolic acidosis are discussed in detail separately. (See "Diabetic ketoacidosis
and hyperosmolar hyperglycemic state in adults: Treatment" and "Bicarbonate
therapy in lactic acidosis" and "Pathogenesis, consequences, and treatment of
metabolic acidosis in chronic kidney disease" and "Acid-base and electrolyte
abnormalities with diarrhea" and "Treatment of distal (type 1) and proximal (type 2)
renal tubular acidosis" and "Salicylate (aspirin) poisoning in adults" and "Methanol
and ethylene glycol poisoning: Pharmacology, clinical manifestations, and
diagnosis".)
●After addressing the underlying pathophysiologic process, the general approach to
treatment of adults with metabolic acidosis depends upon whether or not the
metabolic acidosis is acute or chronic (see 'General approach and
rationale' above):
•The appropriate treatment of severe acute metabolic acidosis is controversial,
and experts disagree about the indications for the use of sodium
bicarbonate or other buffering agents. Our general approach is as follows
(see 'Acute metabolic acidosis' above):
-In patients with acute metabolic acidosis that has generated severe
acidemia (arterial pH less than 7.1), we suggest sodium
bicarbonate therapy rather than no alkali therapy (Grade 2C). The goal of
bicarbonate therapy is to maintain the arterial pH above 7.1 until the
primary process causing the metabolic acidosis can be reversed.
-In patients with acute metabolic acidosis that has generated less severe
acidemia (ie, arterial pH 7.1 to 7.2), we suggest sodium
bicarbonate therapy, rather than no alkali therapy, if severe acute kidney
injury is also present (defined as a twofold or greater increase in serum
creatinine or oliguria) (Grade 2B). We generally target a pH of 7.3 or
higher in such patients. We do not typically give sodium bicarbonate to
patients with arterial pH 7.1 or higher if they do not have severe acute
kidney injury.
•The most common causes of chronic metabolic acidosis are diarrhea,
advanced chronic kidney disease, and the various forms of RTA. The
indications for treating these disorders are fully discussed in the sections
 devoted to these disorders. However, if more normal acid-base parameters
can be achieved with exogenous alkali (eg, sodium or potassium bicarbonate
or citrate) without creating other difficulties (such as potassium wasting in
disorders such as type 2 or proximal RTA), then such treatment may be
helpful. (See "Acid-base and electrolyte abnormalities with
diarrhea" and "Pathogenesis, consequences, and treatment of metabolic
acidosis in chronic kidney disease" and "Treatment of distal (type 1) and
proximal (type 2) renal tubular acidosis".)
●When the decision to administer sodium bicarbonate is made for a patient with
severe acute metabolic acidosis, it is usually accomplished with 50 mL vials of
hypertonic sodium bicarbonate. If the virtual bicarbonate space is roughly 50
percent of lean body weight, then one vial will raise the serum HCO3 concentration
by approximately 1.3 to 1.5 mEq/L in a 70 kg patient. Tromethamine (tris-
hydroxymethyl aminomethane; also called THAM, TRIS, and trometamol) is an
alternative to sodium bicarbonate. (See 'Bicarbonate' above and 'Alternative
agent' above.)
●When chronic alkali treatment is required, options include the sodium or potassium
salts of either bicarbonate or a metabolizable anion such as citrate or lactate. The
potassium salts are indicated when hypokalemia and total body potassium deficits
exist. In general, the initial dose is 50 to 100 mEq per day, which is then titrated up
or down as required. If ongoing bicarbonate losses persist or accelerate, the dose
will need to be adjusted accordingly. (See 'Bicarbonate' above.)

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