Metabolic Acidosis

Practice Essentials

Metabolic acidosis is a clinical disturbance characterized by an increase in plasma acidity. Metabolic acidosis should be considered a sign of an underlying disease process. Identification of this underlying condition is essential to initiate appropriate therapy. (See Etiology, DDx, Workup, and Treatment.)

Understanding the regulation of acid-base balance requires appreciation of the fundamental definitions and principles underlying this complex physiologic process.

Go to Pediatric Metabolic Acidosis and Emergent Management of Metabolic Acidosis for complete information on those topics.

• References

Background

Basic definitions

An acid is a substance that can donate hydrogen ions (H⁺). A base is a substance that can accept H⁺ ions. The ion exchange occurs regardless of the substance's charge.

Strong acids are those that are completely ionized in body fluids, and weak acids are those that are incompletely ionized in body fluids. Hydrochloric acid (HCl) is considered a strong acid because it is present only in a completely ionized form in the body, whereas carbonic acid (H₂ CO₃) is a weak acid because it is ionized incompletely, and, at equilibrium, all three reactants are present in body fluids. See the reactions below.

H₂ CO₃ (acid)↔H⁺ + HCO₃^- (base)

HCl↔H⁺ + Cl^-

The law of mass action states that the velocity of a reaction is proportional to the product of the reactant concentrations. On the basis of this law, the addition of H⁺ or bicarbonate (HCO₃^-) drives the reaction shown below to the left.

H₂ CO₃ (acid)↔H⁺ + HCO₃^- (base)

In body fluids, the concentration of hydrogen ions ([H⁺]) is maintained within very narrow limits, with the normal physiologic concentration being 40 nEq/L. The concentration of HCO₃^- (24 mEq/L) is 600,000 times that of [H⁺]. The tight regulation of [H⁺] at this low concentration is crucial for normal cellular activities because H⁺ at higher concentrations can bind strongly to negatively charged proteins, including enzymes, and impair their function.

Under normal conditions, acids and, to a lesser extent, bases are being added constantly to the extracellular fluid compartment, and for the body to maintain a physiologic [H⁺] of 40 nEq/L, the following three processes must take place:

• Buffering by extracellular and intracellular buffers
• Alveolar ventilation, which controls PaCO₂
• Renal H⁺ excretion, which controls plasma HCO₃^-

Buffers

Buffers are weak acids or bases that are able to minimize changes in pH by taking up or releasing H⁺. Phosphate is an example of an effective buffer, as in the following reaction:

HPO₄^2- + (H⁺)↔H₂ PO₄^-

Upon addition of an H⁺ to extracellular fluids, the monohydrogen phosphate binds H⁺ to form dihydrogen phosphate, minimizing the change in pH. Similarly, when [H⁺] is decreased, the reaction is shifted to the left. Thus, buffers work as a first-line of defense to blunt the changes in pH that would otherwise result from the constant daily addition of acids and bases to body fluids.

HCO

The major extracellular buffering system is HCO₃^-/H₂ CO₃; its function is illustrated by the following reactions:

H₂ O + CO₂ ↔H₂ CO₃ ↔H⁺ + HCO₃^-

One of the major factors that makes this system very effective is the ability to control PaCO₂ by changes in ventilation. As can be noted from this reaction, increased carbon dioxide (CO₂) concentration drives the reaction to the right, whereas a decrease in CO₂ concentration drives it to the left. Put simply, adding an acid load to the body fluids results in consumption of HCO₃^- by the added H⁺, and the formation of carbonic acid; the carbonic acid, in turn, forms water and CO₂. CO₂ concentration is maintained within a narrow range via the respiratory drive, which eliminates accumulating CO₂. The kidneys regenerate the HCO₃^- consumed during this reaction.

This reaction continues to move to the left as long as CO₂ is constantly eliminated or until HCO₃^- is significantly depleted, making less HCO₃^- available to bind H⁺. That HCO₃^- and PaCO₂ can be managed independently (kidneys and lungs, respectively) makes this a very effective buffering system. At equilibrium, the relationship between the 3 reactants in the reaction is expressed by the Henderson-Hasselbalch equation, which relates the concentration of dissolved CO₂ (ie, H₂ CO₃) to the partial pressure of CO₂ (0.03 x PaCO₂) in the following way:

pH = 6.10 + log ([HCO₃^-]/0.03 x PaCO₂)

Alternatively, [H⁺] = 24 x PaCO₂/[HCO₃^-]

Note that changes in pH or [H⁺] are a result of relative changes in the ratio of PaCO₂ to [HCO₃^-] rather than to absolute change in either one. In other words, if both PaCO₂ and [HCO₃^-] change in the same direction, the ratio stays the same and the pH or [H⁺] remains relatively stable. To diminish the alteration in pH that occurs when either HCO₃^- or PaCO₂ changes, the body, within certain limits, changes the other variable in the same direction.

In chronic metabolic acidosis, intracellular buffers (eg, hemoglobin, bone) may be more important than HCO₃^- when the extracellular HCO₃^- level is low.

Renal acid handling

Acids are added daily to the body fluids. These include volatile (eg, carbonic) and nonvolatile (eg, sulfuric, phosphoric) acids. The metabolism of dietary carbohydrates and fat produces approximately 15,000 mmol of CO₂ per day, which is excreted by the lungs. Failure to do so results in respiratory acidosis.

The metabolism of proteins (ie, sulfur-containing amino acids) and dietary phosphate results in the formation of nonvolatile acids, H₂ SO₄ and H₃ PO₄. These acids first are buffered by the HCO₃^-/H₂ CO₃ system as follows:

H₂ SO₄ + 2NaHCO₃ ↔Na₂ SO₄ + 2H₂ CO₃ ↔2H₂ O + CO₂

The net result is buffering of a strong acid (H₂ SO₄) by 2 molecules of HCO₃^- and production of a weak acid (H₂ CO₃), which minimizes the change in pH. The lungs excrete the CO₂ produced, and the kidneys, to prevent progressive HCO₃^- loss and metabolic acidosis, replace the consumed HCO₃^- (principally by H⁺ secretion in the collecting duct). Some amino acids (ie, glutamate, aspartate) result in the formation of citrate and lactate, which, in turn, will be converted to HCO₃^-. The net result, in a typical American diet, is an acid load in the range of 50-100 mEq of H⁺ per day.

To maintain normal pH, the kidneys must perform two physiologic functions. The first is to reabsorb all the filtered HCO₃^- (any loss of HCO₃^- is equal to the addition of an equimolar amount of H⁺), a function principally of the proximal tubule. The second is to excrete the daily H⁺ load (loss of H⁺ is equal to addition of an equimolar amount of HCO₃^-), a function of the collecting duct.

HCO

With a serum HCO₃^- concentration of 24 mEq/L, the daily glomerular ultrafiltrate of 180 L, in a healthy subject, contains 4300 mEq of HCO₃^-, all of which has to be reabsorbed. Approximately 90% of the filtered HCO₃^- is reabsorbed in the proximal tubule, and the remainder is reabsorbed in the thick ascending limb and the medullary collecting duct.

The 3Na⁺ -2K⁺/ATPase (sodium-potassium/adenosine triphosphatase) provides the energy for this process, which maintains a low intracellular Na⁺ concentration and a relative negative intracellular potential. The low Na⁺ concentration indirectly provides energy for the apical Na⁺/H⁺ exchanger, NHE3 (gene symbol SLC9A3), which transports H⁺ into the tubular lumen. H⁺ in the tubular lumen combines with filtered HCO₃^- in the following reaction:

HCO₃^- + H⁺ ↔H₂ CO₃ ↔H₂ O + CO₂

Carbonic anhydrase (CA IV isoform) present in the brush border of the first 2 segments of the proximal tubule accelerates the dissociation of H₂ CO₃ into H₂ O + CO₂, which shifts the reaction shown above to the right and keeps the luminal concentration of H⁺ low. CO₂ diffuses into the proximal tubular cell perhaps via the aquaporin-1 water channel, where carbonic anhydrase (CA II isoform) combines CO₂ and water to form HCO₃^- and H⁺. The HCO₃^- formed intracellularly returns to the pericellular space and then to the circulation via the basolateral Na⁺/3HCO₃^- cotransporter, NBCe1-A (gene symbol SLC4A4).

In essence, the filtered HCO₃^- is converted to CO₂ in the lumen, which diffuses into the proximal tubular cell and is then converted back to HCO₃^- to be returned to the systemic circulation, thus reclaiming the filtered HCO₃^-.

Acid excretion

Excretion of the daily acid load (50-100 mEq of H⁺) occurs principally through H⁺ secretion by the apical H⁺/ATPase in α intercalated cells of the collecting duct.

HCO₃^- formed intracellularly is returned to the systemic circulation via the basolateral Cl^-/HCO₃^- exchanger, AE1 (gene symbol SLC4A1), and H⁺ enters the tubular lumen via 1 of 2 apical proton pumps, H⁺/ATPase or H⁺ -K⁺/ATPase. The secretion of H⁺ in these segments is influenced by Na⁺ reabsorption in the adjacent principal cells of the collecting duct. The reabsorbed Na⁺ creates a relative lumen negativity, which decreases the amount of secreted H⁺ that back-diffuses from the lumen.

Hydrogen ions secreted by the kidneys can be excreted as free ions but, at the lowest achievable urine pH of 5.0 (equal to free H⁺ concentration of 10 µEq/L), would require excretion of 5000-10,000 L of urine a day. Urine pH cannot be lowered much below 5.0 because the gradient against which H⁺/ATPase has to pump protons (intracellular pH 7.5 to luminal pH 5) becomes too steep. A maximally acidified urine, even with a volume of 3 L, would thus contain a mere 30 µEq of free H⁺. Instead, more than 99.9% of the H⁺ load is excreted buffered by the weak bases NH₃ or phosphate.

Titratable acidity

The amount of secreted H⁺ that is buffered by filtered weak acids is called titratable acidity. Phosphate as HPO₄^2- is the main buffer in this system, but other urine buffers include uric acid and creatinine.

H₂ PO₄ ↔H⁺ + HPO₄^2-

The amount of phosphate filtered is limited and relatively fixed, and only a fraction of the secreted H⁺ can be buffered by HPO₄^2-.

Ammonia

A more important urine-buffering system for secreted H⁺ than phosphate, ammonia (NH₃) buffering occurs via the following reaction:

NH₃ + H⁺ ↔NH₄⁺

Ammonia is produced in the proximal tubule from the amino acid glutamine, and this reaction is enhanced by an acid load and by hypokalemia. Ammonia is converted to ammonium (NH₄⁺) by intracellular H⁺ and is secreted into the proximal tubular lumen by the apical Na⁺/H⁺ (NH₄⁺) antiporter.

The apical Na⁺/K⁺ (NH₄⁺)/2Cl^- cotransporter in the thick ascending limb of the loop of Henle then transports NH₄⁺ into the medullary interstitium, where it dissociates back into NH₃ and H⁺. The NH₃ enters the collecting duct epithelial cells via the basolateral ammonia transporters, RhBG and RhCG, and then is transported into the lumen of the collecting duct via apical RhCG, where it is available to buffer H⁺ ions and becomes NH₄⁺. NH₄⁺ is trapped in the lumen and excreted as the Cl salt, and every H⁺ ion buffered is an HCO₃^- gained to the systemic circulation.

The increased secretion of H⁺ in the collecting duct shifts the equation to the right and decreases the NH₃ concentration, facilitating continued diffusion of NH₃ from the interstitium down its concentration gradient into the collecting duct lumen, allowing more H⁺ to be buffered. The kidneys can adjust the amount of NH₃ synthesized to meet demand, making this a powerful system to buffer secreted H⁺ in the urine.^[1]

Acidosis and alkalosis

In healthy people, blood pH is maintained at 7.39-7.41, and because pH is the negative logarithm of [H⁺] (pH = - log₁₀ [H⁺]), an increase in pH indicates a decrease in [H⁺] and vice versa. An increase in [H⁺] and a fall in pH are termed acidemia, and a decrease in [H⁺] and an increase in pH are termed alkalemia. The underlying disorders that lead to acidemia and alkalemia are acidosis and alkalosis, respectively. Metabolic acidosis is a primary decrease in serum HCO₃ - concentration and, in its pure form, manifests as acidemia (pH < 7.40).

Rarely, metabolic acidosis can be part of a mixed or complex acid-base disturbance in which two or more separate metabolic or respiratory derangements occur together. In these instances, pH may not be reduced or the HCO₃^- concentration may not be low.

As a compensatory mechanism, metabolic acidosis leads to alveolar hyperventilation with a fall in PaCO₂. Normally, PaCO₂ falls by 1-1.3 mm Hg for every 1-mEq/L fall in serum HCO₃^- concentration, a compensatory response that can occur fairly quickly. If the change in PaCO₂ is not within this range, then a mixed acid-base disturbance is present. For example, if the decrease in PaCO₂ is less than the expected change, then a primary respiratory acidosis also is present.

The only definitive way to diagnose metabolic acidosis is by simultaneous measurement of serum electrolytes and arterial blood gases (ABGs), which shows both pH and PaCO₂ to be low; calculated HCO₃^- also is low. (See Metabolic Alkalosis for a discussion of the difference between measured and calculated HCO₃^- concentrations.)

A normal serum HCO₃^- level does not rule out the presence of metabolic acidosis, because a drop in HCO₃^- from a high baseline (ie, preexisting metabolic alkalosis) can result in a serum HCO₃^- level that is within the reference range, concealing the metabolic acidosis.

In general, patients with renal failure tend to have a serum HCO₃^- level greater than 12 mEq/L, and buffering by the skeleton prevents further decline in serum HCO₃^-. Note that patients with hypobicarbonatemia from renal failure cannot compensate for additional HCO₃^- loss from an extrarenal source (eg, diarrhea), and severe metabolic acidosis can develop rapidly.

In persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum HCO₃^- level usually remains greater than 12 mEq/L. This bone buffering can lead to significant loss of bone calcium, with resulting osteopenia and osteomalacia.

Anion gap

Plasma, like any other body fluid compartment, is neutral; total anions match total cations. The major plasma cation is Na⁺, and major plasma anions are Cl^- and HCO₃^-. Extracellular anions present in lower concentrations include phosphate, sulfate, and some organic anions, while other cations present include K⁺, Mg²⁺, and Ca²⁺. The anion gap (AG) is the difference between the concentration of the major measured cation Na⁺ and the major measured anions Cl^- and HCO₃^-.

An increase in the AG can result from either a decrease in unmeasured cations (eg, hypokalemia, hypocalcemia, hypomagnesemia) or an increase in unmeasured anions (eg, hyperphosphatemia, high albumin levels). In certain forms of metabolic acidosis, other anions accumulate; by recognizing the increasing AG, the clinician can formulate a differential diagnosis for the cause of that acidosis.^[2]

The reaction below indicates that the addition of an acid (HA, where H⁺ is combined with an unmeasured anion A^-) results in the consumption of HCO₃^- with an addition of anions that will account for the increase in the AG. Metabolic acidosis is classified on the basis of AG into normal- (also called non-AG or hyperchloremic metabolic acidosis^[3] ) and high-AG metabolic acidosis.

HA + NaHCO₃ ↔NaA + H₂ CO₃ ↔CO₂ + H₂ O

Urinary AG

Calculating the urine AG is helpful in evaluating some cases of non-AG metabolic acidosis. The major measured urinary cations are Na⁺ and K⁺, and the major measured urinary anion is Cl^-.

Urine AG = ([Na⁺] + [K⁺]) - [Cl^-]

The major unmeasured urinary anions and cations are HCO₃^- and NH₄⁺, respectively. HCO₃^- excretion in healthy subjects is usually negligible, and average daily excretion of NH₄⁺ is approximately 40 mEq/L, which results in a positive or near-zero gap. In the face of metabolic acidosis, the kidneys increase the amount of NH₃ synthesized to buffer the excess H⁺ and NH₄ Cl excretion increases. The increased unmeasured NH₄⁺ thus increases the measured anion Cl^- in the urine, and the net effect is a negative AG, representing a normal response to systemic acidification. Thus, the finding of a positive urine AG in the face of non-AG metabolic acidosis points toward a renal acidification defect (eg, renal tubular acidosis [RTA]).

Caveats to urinary AG

The presence of ketonuria makes this test unreliable because the negatively charged ketones are unmeasured and urine AG will be positive or zero despite the fact that renal acidification and NH₄⁺ levels are increased. Moreover, severe volume depletion from extrarenal NaHCO₃ loss causes avid proximal Na⁺ reabsorption, with little Na⁺ reaching the lumen of the collecting duct to be reabsorbed in exchange for H⁺. Limiting H⁺ excretion reduces NH₄⁺ excretion and may make the urine AG become positive.

Potassium and renal acid secretion

Renal acid secretion is influenced by serum K⁺ and may result from the transcellular shift of K⁺ when intracellular K⁺ is exchanged for extracellular H⁺ or vice versa. In hypokalemia, an intracellular acidosis can develop; in hyperkalemia, an intracellular alkalosis can develop. HCO₃^- reabsorption is increased secondary to relative intracellular acidosis. The increase in intracellular H⁺ concentration promotes the activity of the apical Na⁺/H⁺ exchanger.

Renal production of NH₃ is increased in hypokalemia, resulting in an increase in renal acid excretion. The increase in NH₃ production by the kidneys may be significant enough to precipitate hepatic encephalopathy in patients who have advanced liver disease. Correcting the hypokalemia can reverse this process.

Patients with hypokalemia may have relatively alkaline urine because hypokalemia increases renal ammoniagenesis. Excess NH₃ then binds more H⁺ in the lumen of the distal nephron and urine pH increases, which may suggest RTA as an etiology for non-AG acidosis. However, these conditions can be distinguished by measuring urine AG, which will be negative in patients who have normal NH₄⁺ excretion and positive in patients with RTA. The most common cause for hypokalemia and metabolic acidosis is GI loss (eg, diarrhea, laxative use). Other less common etiologies include renal loss of potassium secondary to RTA or salt-wasting nephropathy. The urine pH, the urine AG, and the urinary K⁺ concentration can distinguish these conditions.

Hyperkalemia has an effect on acid-base regulation opposite to that observed in hypokalemia. Hyperkalemia impairs NH₄⁺ excretion through reduction of NH₃ synthesis in the proximal tubule and reduction of NH₄⁺ reabsorption in the thick ascending limb, resulting in reduced medullary interstitial NH₃ concentration. This leads to a decrease in net renal acid secretion and is a classic feature of primary or secondary hypoaldosteronism. Consistent with the central role of hyperkalemia in the generation of the acidosis, lowering the serum K⁺ concentration can correct the associated metabolic acidosis.

• References

Etiology

Causes and diagnostic considerations

Metabolic acidosis is typically classified as having a normal AG (ie, non-AG) or a high AG. Non-AG metabolic acidosis is also characterized by hyperchloremia and is sometimes referred to as hyperchloremic acidosis. Calculation of the AG is thus helpful in the differential diagnosis of metabolic acidosis.^{[2, 18]}

Hyperchloremic or non-AG metabolic acidosis occurs principally when HCO₃^- is lost from either the GI tract or the kidneys or because of a renal acidification defect. Some of the mechanisms that result in a non-AG metabolic acidosis are the following:

• Addition of HCl to body fluids: H⁺ buffers HCO₃^- and the added Cl^- results in a normal AG.
• Loss of HCO₃^- from the kidneys or the GI tract: The kidneys reabsorb sodium chloride to maintain volume.
• Rapid volume expansion with normal saline: This results in an increase in the chloride load that exceeds the renal capacity to generate equal amounts of HCO₃^-.

Causes of non-AG metabolic acidosis can be remembered with the mnemonic ACCRUED (acid load, chronic renal failure, carbonic anhydrase inhibitors, renal tubular acidosis, ureteroenterostomy, expansion/extra-alimentation, diarrhea).

The conditions that may cause a non-AG metabolic acidosis are as follows:

• GI loss of HCO₃^- - Diarrhea
• Enterocutaneous fistula (eg, pancreatic) - Enteric diversion of urine (eg, ileal loop bladder), pancreas transplantation with bladder drainage
• Renal loss of HCO₃^- - Proximal RTA (type 2), carbonic anhydrase inhibitor therapy (including topiramate^[4] )
• Failure of renal H⁺ secretion - Distal RTA (type 1), hyperkalemic RTA (type 4), renal failure
• Acid infusion - Ammonium chloride, hyperalimentation
• Other - Rapid volume expansion with normal saline

Causes of non-AG metabolic acidosis are discussed in more detail below.

High AG warrants consideration of the following:

• Lactic acidosis – L-Lactate, D-lactate
• Ketoacidosis - Beta-hydroxybutyrate, acetoacetate
• Renal failure - Sulfate, phosphate, urate, and hippurate
• Ingestions - Salicylate, methanol or formaldehyde (formate), ethylene glycol (glycolate, oxalate), paraldehyde (organic anions), phenformin/metformin^[5]
• Infusions - Propylene glycol (D-lactate, L-lactate)
• Pyroglutamic acidemia (5-oxoprolinemia)
• Massive rhabdomyolysis (release of H⁺ and organic anions from damaged muscle)

Several mnemonics are used to help recall of the differential diagnosis of high anion gap acidosis. Three are as follows:

• MUDPILES: M-methanol; U-uremia; D-DKA, AKA; P-paraldehyde, phenformin; I-iron, isoniazid; L-lactic (ie, CO, cyanide); E-ethylene glycol; S-salicylates
• DR. MAPLES: D-DKA; R-renal; M-methanol; A-alcoholic ketoacidosis; P-paraldehyde, phenformin; L-lactic (ie, CO, HCN); E-ethylene glycol; S-salicylates
• SLUMPED (S-salicylate, L-lactate, U-uremia, M-methanol, P-paraldehyde, E-ethylene glycol, D-diabetes)

A more current mnemonic is GOLD MARK, which incorporates newly recognized forms of metabolic acidosis and eliminates P for paraldehyde as this is now rarely seen.^[6]

• GOLD MARK: G-Glycols (ethylene and propylene), O-Oxoproline, L-lactate, D-lactate, M-Methanol, A-Aspirin, R-Renal failure, and K-Ketoacidosis

Plasma osmolality and the osmolar gap can be helpful in determining the cause of high AG acidosis. Plasma osmolality can be calculated using the following equation:

P_osm = [2 X Na⁺]+[glucose in mg/dL]/18+[BUN in mg/dL]/2.8

P_osm can also be measured in the laboratory, and because other solutes normally contribute minimally to serum osmolality, the difference between the measured and the calculated value (osmolar gap) is no more than 10-15 mOsm/kg. In certain situations, unmeasured osmotically active solutes in the plasma can raise the osmolar gap (eg, mannitol, radiocontrast agents).

The osmolar gap can also be a clue to the nature of the anion in high-AG acidosis because some osmotically active toxins also cause a high-AG acidosis. Methanol, ethylene glycol, and acetone are classic poisons that increase the osmolar gap and AG; measuring the osmolar gap can help narrow the differential diagnosis of high-AG acidosis.

Causes of AG metabolic acidosis are discussed in more detail below.

Specific causes of hyperchloremic or non-AG metabolic acidosis

Loss of HCO₃^- via the GI tract

The secretions of the GI tract, with the exception of the stomach, are relatively alkaline, with high concentrations of base (50-70 mEq/L). Significant loss of lower GI secretions results in metabolic acidosis, especially when the kidneys are unable to adapt to the loss by increasing net renal acid excretion.

Such losses can occur in diarrheal states, fistula with drainage from the pancreas or the lower GI tract, and sometimes vomiting if it occurs as a result of intestinal obstruction. When pancreatic transplantation is performed, the pancreatic duct is sometimes diverted into the recipient bladder, from where exocrine pancreatic secretions are lost in the final urine. Significant loss also occurs in patients who abuse laxatives, which should be suspected when the etiology for non-AG metabolic acidosis is not clear.

Urine pH will be less than 5.3, with a negative urine AG reflecting normal urine acidification and increased NH₄⁺ excretion. However, if distal Na⁺ delivery is limited because of volume depletion, the urine pH cannot be lowered maximally.

Replacing the lost HCO₃^- on a daily basis can treat this form of metabolic acidosis.

Distal RTA (type 1) (see the Table below)

The defect in this type of RTA is a decrease in net H⁺ secreted by the A-type intercalated cells of the collecting duct. As mentioned previously, H⁺ is secreted by the apical H⁺ –ATPase and, to a lesser extent, by the apical K⁺/H⁺ –ATPase. The K⁺/H⁺ –ATPase seems to be more important in K⁺ regulation than in H⁺ secretion. The secreted H⁺ is then excreted as free ions (reflected by urine pH value) or titrated by urinary buffers, phosphate, and NH₃. A decrease in the amount of H⁺ secreted results in a reduction in its urinary concentration (ie, increase in urine pH) and a reduction in total H⁺ buffered by urinary phosphate or NH₃.

Type 1 RTA should be suspected in any patient with non-AG metabolic acidosis and a urine pH greater than 5.0. Patients have a reduction in serum HCO₃^- to various degrees, in some cases to less than 10 mEq/L. They are able to reabsorb HCO₃^- normally, and their FE of HCO₃^- is less than 3%. The disorder has been classified into 4 types—secretory, rate dependent, gradient, and voltage dependent—based on the nature of the defect.

Several different mechanisms are implicated in the development of distal RTA. These include a defect in 1 of the 2 proton pumps, H⁺ –ATPase or K⁺ -H⁺ –ATPase, that can be acquired or congenital. This may lead to loss of function (ie, secretory defect) or a reduction in the rate of H⁺ secretion (ie, rate-dependent defect).

Another mechanism is a defect in the basolateral Cl^-/HCO₃^- exchanger, AE1, or the intracellular carbonic anhydrase that can be acquired or congenital. This also causes a secretory defect.

Back-diffusion of the H⁺ from the lumen via the paracellular or transcellular space is another mechanism; this occurs if the integrity of the tight junctions is lost or permeability of the apical membrane is increased (ie, permeability or gradient defect). With a urine pH of 5.0 and an interstitial fluid pH of 7.4, the concentration gradient facilitating back-diffusion of free H⁺, under conditions of increased permeability of the collecting duct epithelia, is approximately 250-fold.

A defect in Na⁺ reabsorption in the collecting duct would decrease the electrical gradient favoring the secretion of H⁺ into the tubular lumen (ie, voltage-dependent defect). This can occur, for instance, in severe volume depletion with decreased luminal Na⁺ delivery to this site.

The serum potassium level typically is low in patients with distal RTA because defects in H⁺ secretion or back-diffusion of H⁺ tend to increase urinary K⁺ wasting. Potassium wasting occurs from one or more of the following factors:

• Decreased net H⁺ secretion results in more Na⁺ reabsorption in exchange for K⁺ secretion.
• The drop in serum HCO₃^- and, therefore, filtered HCO₃^-, reduces the amount of Na⁺ reabsorbed by the Na⁺/H⁺ exchanger in the proximal tubule, leading to mild volume depletion. The associated activation of the renin-angiotensin-aldosterone system increases K⁺ secretion in the collecting duct.
• A possible defect in K⁺/H⁺ –ATPase results in decreased H⁺ secretion and decreased K⁺ reabsorption.

The serum K⁺ level can be high if the distal RTA is secondary to decreased luminal Na⁺ in the distal nephron. Na⁺ reabsorption in the principal cells of the collecting duct serves as the driving force for K⁺ secretion. In this case, the patient has hyperkalemia and acidosis; the disorder is also called voltage-dependent or hyperkalemic type 1 acidosis.

Urine AG is positive and urine pH is high secondary to the renal acid secretion defect. Urine pH also can be high in patients with type 2 RTA if their serum HCO₃^- level is higher than the renal threshold for reabsorption, typically when a patient with type 2 RTA is on HCO₃^- replacement therapy. Administration of an HCO₃^- load leads to a marked increase in urine pH in those who have type 2 RTA, while those with type 1 RTA have a constant urine pH unless their acidosis is overcorrected.

Patients with type 1 RTA may develop nephrocalcinosis and nephrolithiasis. This is thought to occur for the following reasons:

• Patients have a constant release of calcium phosphate from bones to buffer the extracellular H⁺.
• Patients have decreased reabsorption of calcium and phosphate, leading to hypercalciuria and hyperphosphaturia.
• Patients have relatively alkaline urine, which promotes calcium phosphate precipitation.
• Metabolic acidosis and hypokalemia lead to hypocitraturia, a risk factor for stones. Citrate in the urine complexes calcium and inhibits stone formation.

The causes of distal RTA are shown as follows. Type 1 RTA occurs sporadically, although genetic forms have been reported.

• Primary - Genetic or sporadic
• Drug-related - Amphotericin B, lithium, analgesics, ifosfamide, topiramate, toluene
• Autoimmune disease - Systemic lupus erythematosus, chronic active hepatitis, Sjögren syndrome, rheumatoid arthritis, primary biliary cirrhosis
• Related to other systemic disease - Sickle cell disease, hyperparathyroidism, light chain disease, cryoglobulinemia, Wilson disease, Fabry disease
• Tubulointerstitial disease - Obstructive uropathy, transplant rejection, medullary cystic kidney disease, hypercalciuria

The genetic forms of type 1 RTA are the following:

• Autosomal dominant: Heterozygous mutations in the basolateral Cl^-/HCO₃^- exchanger, AE1 (gene symbol SLC4A1), cause a dominant form of distal RTA with nephrocalcinosis and osteomalacia. Some patients with this disorder can be relatively asymptomatic and present in later years, while others present with severe disease in childhood. The disorder is allelic with one form of hereditary spherocytosis, but each disease is caused by distinct mutations in the same gene.
• Autosomal recessive: This form of the disease may occur with or without sensorineural deafness. The type that occurs with deafness involves homozygous mutations in the B subunit of H⁺ –ATPase (gene symbol ATP6B1) in the A-type intercalated cells. The type that occurs without deafness involves homozygous mutations in the accessory N1 subunit of H⁺ –ATPase (gene symbol ATP6N1B). Homozygous or compound heterozygous mutations in AE1 also cause a recessive form of distal RTA that manifests in childhood with growth retardation and nephrocalcinosis that may lead to renal insufficiency. Heterozygous carriers have autosomal dominant ovalocytosis but normal renal acidification.

Proximal (type 2) RTA

The hallmark of type 2 RTA is impairment in proximal tubular HCO₃^- reabsorption. In the euvolemic state and in the absence of elevated levels of serum HCO₃^-, all filtered HCO₃^- is reabsorbed, 90% of which is in the proximal tubule. Normally, HCO₃^- excretion occurs only when serum HCO₃^- exceeds 24-28 mEq/L. Patients with type 2 RTA, however, have a lower threshold for excretion of HCO₃^-, leading to a loss of filtered HCO₃^- until the serum HCO₃^- concentration reaches the lower threshold. At this point, bicarbonaturia ceases and the urine appears appropriately acidified. Serum HCO₃^- typically does not fall below 15 mEq/L because of the ability of the collecting duct to reabsorb some HCO₃^-.

Type 2 RTA can be found as a solitary proximal tubular defect, in which reabsorption of HCO₃^- is the only abnormality (rare) such as with homozygous mutations in SLC4A4. More commonly, it is part of a more generalized defect of the proximal tubule characterized by glucosuria, aminoaciduria, and phosphaturia, also called Fanconi syndrome.

Dent disease or X-linked hypercalciuric nephrolithiasis is one example of a generalized proximal tubular disorder characterized by an acidification defect, hypophosphatemia, and hypercalciuria and arises from mutations in the renal chloride channel gene (CLCN5). Homozygous mutations in SCL34A1 also cause a genetic form of Fanconi syndrome.

The proximal tubule is the site where bulk reabsorption of ultrafiltrate occurs, driven by the basolateral Na⁺/K⁺ –ATPase. Any disorder that leads to decreased ATP production or a disorder involving Na⁺ -K⁺ –ATPase can result in Fanconi syndrome. In principle, loss of function of the apical Na⁺/H⁺ antiporter or the basolateral Na⁺/3HCO₃^- cotransporter or the intracellular carbonic anhydrase results in selective reduction in HCO₃^- reabsorption.

Patients with type 2 RTA typically have hypokalemia and increased urinary K⁺ wasting. This is thought, in part, to be due to an increased rate of urine flow to the distal nephron caused by the reduced proximal HCO₃^- reabsorption and, in part, to be due to activation of the renin-angiotensin-aldosterone axis with increased collecting duct Na⁺ reabsorption from the mild hypovolemia induced by bicarbonaturia. Administration of alkali in those patients leads to more HCO₃^- wasting and can worsen hypokalemia unless K⁺ is replaced simultaneously.

The diagnosis of type 2 RTA should be suspected in patients who have a normal-AG metabolic acidosis with a serum HCO₃^- level usually greater than 15 mEq/L and acidic urine (pH < 5.0). Those patients have an FEHCO₃^- less than 3% when their serum HCO₃^- is low. However, raising serum HCO₃^- above their lower threshold and closer to normal levels results in significant HCO₃^- wasting and an FEHCO₃ exceeding 15%.

FEHCO₃^- = (urine [HCO₃^-] X plasma [creatinine] / plasma [HCO₃^-]) X urine [creatinine] X 100

Some patients with type 2 RTA tend to have osteomalacia, a condition that can be observed in any chronic acidemic state, although it is more common in persons with type 2 RTA. The traditional explanation is that the proximal tubular conversion of 25(OH)-cholecalciferol to the active 1,25(OH)2-cholecalciferol is impaired. Patients with more generalized defects in proximal tubular function (as in Fanconi syndrome) may have phosphaturia and hypophosphatemia, which also predispose to osteomalacia.

The following are causes of proximal RTA:

• Primary - Genetic or sporadic
• Inherited systemic disease - Wilson disease, glycogen storage disease, tyrosinemia, Lowe syndrome, cystinosis, fructose intolerance
• Related to other systemic disease - Multiple myeloma, amyloidosis, hyperparathyroidism, Sjögren syndrome
• Drug- and toxin-related - Carbonic anhydrase inhibitors, ifosfamide, gentamicin, valproic acid, lead, mercury, streptozotocin

Isolated proximal RTA occurs sporadically, although an inherited form has recently been described. Homozygous mutations in the apical Na⁺/3HCO₃^- cotransporter have been found in 2 kindred with proximal RTA, band keratopathy, glaucoma, and cataracts. A form of autosomal recessive osteopetrosis with mental retardation is associated with a mixed RTA with features of both proximal and distal disease (called type 3). The mixed defect is related to the deficiency of carbonic anhydrase (CA II isoform) normally found in the cytosol of the proximal tubular cells and the intercalated cells of the collecting duct. The most common cause of acquired proximal RTA in adults follows the use of carbonic anhydrase inhibitors.

Type 4 RTA

This is the most common form of RTA in adults and results from aldosterone deficiency or resistance. The collecting duct is a major site of aldosterone action; there it stimulates Na⁺ reabsorption and K⁺ secretion in the principal cells and stimulates H⁺ secretion in the A-type intercalated cells. Hypoaldosteronism, therefore, is associated with decreased collecting duct Na⁺ reabsorption, hyperkalemia, and metabolic acidosis.

Hyperkalemia also reduces proximal tubular NH₄⁺ production and decreases NH₄⁺ absorption by the thick ascending limb, leading to a reduction in medullary interstitial NH₃ concentration. This diminishes the ability of the kidneys to excrete an acid load and worsens the acidosis.

Because the function of H⁺ –ATPase is normal, the urine is appropriately acidic in this form of RTA. Correction of hyperkalemia leads to correction of metabolic acidosis in many patients, pointing to the central role of hyperkalemia in the pathogenesis of this acidosis.

Almost all patients with type 4 RTA manifest varying degrees of hyperkalemia, which commonly is asymptomatic. The etiology of hyperkalemia is multifactorial and related to the presence of hypoaldosteronism in conjunction with a degree of renal insufficiency. The acidosis and hyperkalemia, however, are out of proportion to the degree of renal failure.

The following findings are typical of type 4 RTA:

• Mild-to-moderate chronic kidney disease (stages 2-3) in most patients, with a creatinine clearance of 30-60 mL/min
• Hyperkalemia
• Hypoaldosteronism
• Diabetes mellitus (in approximately 50% of patients)

Type 4 RTA should be suspected in any patient with a mild non-AG metabolic acidosis and hyperkalemia. The serum HCO₃^- level is usually greater than 15 mEq/L, and the urine pH is less than 5.0 because these patients have a normal ability to secrete H⁺. The primary problem is hyperkalemia from aldosterone deficiency or end organ (collecting duct) resistance to the action of aldosterone. This can be diagnosed by measuring the transtubular potassium gradient (TTKG).

TTKG = urine K⁺ X serum osmolality/serum K⁺ X urine osmolality

A TTKG greater than 8 indicates that aldosterone is present and the collecting duct is responsive to it. A TTKG less than 5 in the presence of hyperkalemia indicates aldosterone deficiency or resistance. For the test to be interpretable, the urine Na⁺ level should be greater than 10 mEq/L and the urine osmolality should be greater than or equal to serum osmolality.

The hyperkalemia suppresses renal ammoniagenesis, leading to a lack of urinary buffers to excrete the total H⁺ load. The urine AG will be positive. Note that patients with hyperkalemic type 1 RTA have a urine pH greater than 5.5 and a low urine Na⁺.

The following are causes of type 4 RTA:

• Hypoaldosteronism (low renin) - Hyporeninemic hypoaldosteronism (diabetes mellitus/mild renal impairment, chronic interstitial nephritis, nonsteroidal anti-inflammatory drugs, beta-blockers)
• Hypoaldosteronism (high renin) - Primary adrenal defect (isolated: congenital hypoaldosteronism; generalized: Addison disease, adrenalectomy, AIDS), inhibition of aldosterone secretion (heparin, ACE inhibitors, AT1 receptor blockers)
• Aldosterone resistance (drugs) - Diuretics (amiloride, triamterene, spironolactone), calcineurin inhibitors (cyclosporine, tacrolimus), antibiotics (trimethoprim, pentamidine)
• Aldosterone resistance (genetic) - Pseudohypoaldosteronism (PHA) types I and II

Although type 4 RTA occurs sporadically, familial forms have been reported. The genetic forms are called PHA; PHA type 1 is characterized by hypotension with hyperkalemia and acidosis and includes an autosomal recessive and autosomal dominant form. PHA type 2 is characterized by hypertension with hyperkalemia and acidosis and is also known as Gordon syndrome and familial hyperkalemic hypertension. Note the following:

• Autosomal recessive PHA type 1: Homozygous mutations in the alpha, beta, or gamma subunits (gene symbols SCNN1A, SCNN1B, and SCNN1G) of the collecting duct epithelial sodium channel cause a syndrome that manifests in infancy with severe salt wasting, hypotension, hyperkalemia, and acidosis. A pulmonary syndrome characterized by recurrent respiratory infections, chronic cough, and increased respiratory secretions has also been noted in some individuals.
• Autosomal dominant PHA type 1: Heterozygous mutations in the mineralocorticoid receptor lead to a milder phenotype that is restricted to the kidneys. Unlike the autosomal recessive form, the clinical symptoms improve with age.
• Gordon syndrome (PHA type 2): This disorder is characterized by hypertension and hyperkalemia with variable degrees of metabolic acidosis. There are at least 5 genetic loci associated with this disease. Heterozygous mutations in 1 of 2 kinases, WNK1 or WNK4, or in the CUL3 gene cause this syndrome. Heterozygous or homozygous mutations in the KLHL3 genecause an autosomal dominant or recessive form of this syndrome. A fifth locus on band 1q has been described, but the genetic defect at this locus has not yet been identified.

Table. Comparison of Types 1, 2, and 4 RTA

View Table

See Table

Early renal failure

Metabolic acidosis is usual in patients with renal failure, and, in early to moderate stages of chronic kidney disease (glomerular filtration rate of 20-50 mL/min), it is associated with a normal AG (hyperchloremic). In more advanced renal failure, the acidosis is associated with a high AG.

In hyperchloremic acidosis, reduced ammoniagenesis (secondary to loss of functioning renal mass) is the primary defect, leading to an inability of the kidneys to excrete the normal daily acid load. In addition, NH₃ reabsorption and recycling may be impaired, leading to reduced medullary interstitial NH₃ concentration.

In general, patients tend to have a serum HCO₃^- level greater than 12 mEq/L, and buffering by the skeleton prevents further decline in serum HCO₃^-.

Note that patients with hypobicarbonatemia from renal failure cannot compensate for additional HCO₃^- loss from an extrarenal source (eg, diarrhea) and severe metabolic acidosis can develop rapidly.

Urinary diversion

Hyperchloremic metabolic acidosis can develop in patients who undergo a urinary diversion procedure, such as a sigmoid bladder or an ileal conduit.

This occurs through 1 of the following 2 mechanisms:

The first is the intestinal mucosa has an apical Cl^-/HCO₃^- exchanger. When urine is diverted to a loop of bowel (as in patients with obstructive uropathy), the chloride in the urine is exchanged for HCO₃^-. Significant loss of HCO₃^- can occur, with a concurrent increase in serum Cl^- concentration.

The second is intestinal mucosa reabsorbs urinary NH₄⁺, and the latter is metabolized in the liver to NH₃ and H⁺. This is particularly likely to occur if urine contact time with the intestinal mucosa is prolonged, as when a long loop of bowel is used or when the stoma is obstructed and when sigmoid rather than ileal loop is used. Presumably, the creation of a continent bladder also increases HCO₃^- loss. This disorder is not observed very frequently anymore because short-loop incontinent ureteroileostomies are used now.

Infusion of acids

The addition of an acid that contains Cl^- as an ion (eg, NH₄ Cl) can result in a normal-AG acidosis because the drop in HCO₃^- is accompanied by an increase in Cl^-.

The use of arginine or lysine hydrochloride as amino acids during hyperalimentation can have the same result.

Specific causes of high-AG metabolic acidosis

Lactic acidosis

Briefly, L-lactate is a product of pyruvic acid metabolism in a reaction catalyzed by lactate dehydrogenase that also involves the conversion of nicotinamide adenine dinucleotide (NADH) to the oxidized form of nicotinamide adenine dinucleotide (NAD⁺). This is an equilibrium reaction that is bidirectional, and the amount of lactate produced is related to the reactant concentration in the cytosol (pyruvate, NADH/NAD⁺).

Daily lactate production in a healthy person is substantial (approximately 20 mEq/kg/d), and this is usually metabolized to pyruvate in the liver, the kidneys, and, to a lesser degree, in the heart. Thus, production and use of lactate (ie, Cori cycle) is constant, keeping plasma lactate low.

The major metabolic pathway for pyruvate is to acetyl coenzyme A, which then enters the citric acid cycle. In the presence of mitochondrial dysfunction, pyruvate accumulates in the cytosol and more lactate is produced.

Lactic acid accumulates in blood whenever production is increased or use is decreased. A value greater than 4-5 mEq/L is considered diagnostic of lactic acidosis.

Type A lactic acidosis occurs in hypoxic states, while type B occurs without associated tissue hypoxia.

D-lactic acidosis is a form of lactic acidosis that occurs from overproduction of D-lactate by intestinal bacteria. It is observed in association with intestinal bacterial overgrowth syndromes. D-lactate is not measured routinely when lactate levels are ordered and must be requested specifically when such cases are suspected.

Ketoacidosis

Free fatty acids released from adipose tissue have 2 principal fates. In the major pathway, triglycerides are synthesized in the cytosol of the liver. In the less common pathway, fatty acids enter mitochondria and are metabolized to ketoacids (acetoacetic acid and beta-hydroxybutyric acid) by the beta-oxidation pathway. Ketoacidosis occurs when delivery of free fatty acids to the liver or preferential conversion of fatty acids to ketoacids is increased.

This pathway is favored when insulin is absent (as in the fasting state), in certain forms of diabetes, and when glucagon action is enhanced.

Alcoholic ketoacidosis occurs when excess alcohol intake is accompanied by poor nutrition. Alcohol inhibits gluconeogenesis, and the fasting state leads to low insulin and high glucagon levels. These patients tend to have a mild degree of lactic acidosis. This diagnosis should be suspected in alcoholic patients who have an unexplained AG acidosis, and detection of beta-hydroxybutyric acid in the serum in the absence of hyperglycemia is highly suggestive. Patients may have more than one metabolic disturbance (eg, mild lactic acidosis, metabolic alkalosis secondary to vomiting).

Starvation ketoacidosis can occur after prolonged fasting and may be exacerbated by exercise.

DKA is usually precipitated in patients with type 1 diabetes by stressful conditions (eg, infection, surgery, emotional trauma), but it can also occur in patients with type 2 diabetes. Hyperglycemia, metabolic acidosis, and elevated beta-hydroxybutyrate confirm the diagnosis. The metabolic acidosis in DKA is commonly a high-AG acidosis secondary to the presence of ketones in the blood. However, after initiation of treatment with insulin, ketone production ceases, the liver uses ketones, and the acidosis becomes a non-AG type that resolves in a few days (ie, time necessary for kidneys to regenerate HCO₃^-, which was consumed during the acidosis).

Advanced renal failure

Patients with advanced chronic kidney disease (glomerular filtration rate of less than 20 mL/min) present with a high-AG acidosis. The acidosis occurs from reduced ammoniagenesis leading to a decrease in the amount of H⁺ buffered in the urine. The increase in AG is thought to occur because of the accumulation of sulfates, urates and phosphates from a reduction in glomerular filtration and from diminished tubular function.

In persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum HCO₃^- level usually remains greater than 12 mEq/L. This bone buffering can lead to significant loss of bone calcium with resulting osteopenia and osteomalacia.

Salicylate overdose

Deliberate or accidental ingestion of salicylates can produce a high-AG acidosis, although respiratory alkalosis is usually the more pronounced acid-base disorder.

The increase in AG is only partly from the unmeasured salicylate anion. Increased ketoacid and lactic acid levels have been reported in persons with salicylate overdose and are thought to account for the remainder of the AG.

Salicylic acid ionizes to salicylate and H⁺ ion with increasing pH; at a pH of 7.4, only 0.004% of salicylic acid is nonionized, as follows:

Salicylic acid (HS)↔salicylate (S) + H⁺ (H⁺)

HS is lipid soluble and can diffuse into the CNS; with a fall in pH, more HS is formed. The metabolic acidosis thus increases salicylate entry to the CNS, leading to respiratory alkalosis and CNS toxicity.

Methanol poisoning

Methanol ingestion is associated with the development of a high-AG metabolic acidosis. Methanol is metabolized by alcohol dehydrogenase to formaldehyde and then to formic acid.

Formaldehyde is responsible for the optic nerve and CNS toxicity, while the increase in AG is from formic acid and from lactic acid and ketoacid accumulation.

Clinical manifestations include optic nerve injury that can be appreciated by funduscopic examination as retinal edema, CNS depression, and unexplained metabolic acidosis with high anion and osmolar gaps.

Ethylene glycol poisoning

Ingestion of ethylene glycol, a component of antifreeze and engine coolants, leads to a high-AG acidosis. Ethylene glycol is converted by alcohol dehydrogenase first to glycoaldehyde and then to glycolic and glyoxylic acids. Glyoxylic acid then is degraded to several compounds, including oxalic acid, which is toxic, and glycine, which is relatively innocuous.

The high AG is primarily from the accumulation of these acids, although a mild lactic acidosis also may be present.

Patients present with CNS symptoms, including slurred speech, confusion, stupor or coma, myocardial depression, and renal failure with flank pain.

Oxalate crystals are usually observed in the urine and are an important clue to the diagnosis, as is an elevated osmolar gap.

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Prognosis

Morbidity and mortality in metabolic acidosis are primarily related to the underlying condition.

In a prospective, observational, cohort study, Maciel and Park looked at differences between survivors and nonsurvivors within a group of 107 patients suffering from metabolic acidosis on admission to an intensive care unit (ICU).^[7] The authors found that although acidosis was more severe in nonsurvivors than in survivors, the proportion of acidifying variables was similar on admission between the 2 groups (with hyperchloremia being the primary cause of the acidosis).

The investigators also found that in nonsurviving patients, the degree of metabolic acidosis was similar on the day of death to the level measured when they were admitted to the ICU, but that the proportion of anions had changed. Specifically, the chloride levels in the patients had decreased, and the lactate levels had increased.

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History

Symptoms of metabolic acidosis are not specific. The respiratory center in the brainstem is stimulated, and hyperventilation develops in an effort to compensate for the acidosis. As a result, patients may report varying degrees of dyspnea. Patients may also report chest pain, palpitations, headache, confusion, generalized weakness, and bone pain. Patients, especially children, also may present with nausea, vomiting, and decreased appetite.

The clinical history in metabolic acidosis is helpful in establishing the etiology when symptoms relate to the underlying disorder. The age of onset and a family history of acidosis may point to inherited disorders, which usually start during childhood. Important points in the history include the following:

• Diarrhea - GI losses of HCO₃^-
• History of diabetes mellitus, alcoholism, or prolonged starvation - Accumulation of ketoacids
• Polyuria, increased thirst, epigastric pain, vomiting -Diabetic ketoacidosis (DKA)
• Nocturia, polyuria, pruritus, and anorexia - Renal failure^[8]
• Ingestion of drugs or toxins - Salicylates, acetazolamide, cyclosporine, ethylene glycol, methanol, metformin, topiramate
• Visual symptoms, including dimming, photophobia, scotomata - Methanol ingestion
• Renal stones - RTA or chronic diarrhea
• Tinnitus, blurred vision, and vertigo - Salicylate overdose

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Physical Examination

The best recognized sign of metabolic acidosis is Kussmaul respirations, a form of hyperventilation that serves to increase minute ventilatory volume. This is characterized by an increase in tidal volume rather than respiratory rate and is appreciated as deliberate, slow, deep breathing.

Chronic metabolic acidosis in children may be associated with stunted growth and rickets.

Coma and hypotension have been reported with acute severe metabolic acidosis.

Other physical signs of metabolic acidosis are not specific and depend on the underlying cause. Some examples include xerosis, scratch marks on the skin, pallor, drowsiness, fetor, asterixis, and pericardial rub for renal failure, as well as reduced skin turgor, dry mucous membranes, and fruity smell for DKA.

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Approach Considerations

Often the first clue to metabolic acidosis is a decreased serum HCO₃^- concentration observed when serum electrolytes are measured. Remember, however, that a decreased serum [HCO₃^-] level can be observed as a compensatory response to respiratory alkalosis. An [HCO₃^-] level of less than 15 mEq/L, however, almost always is due, at least in part, to metabolic acidosis.

The only definitive way to diagnose metabolic acidosis is by simultaneous measurement of serum electrolytes and arterial blood gases (ABGs), which shows pH and PaCO₂ to be low; calculated HCO₃^- also is low. (For more information, see Metabolic Alkalosis.)

A low serum HCO₃^- and a pH of less than 7.40 upon ABG analysis confirm metabolic acidosis.

Go to Pediatric Metabolic Acidosis and Emergent Management of Metabolic Acidosis for complete information on these topics.

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Laboratory Evaluation

The diagnosis is made by evaluating serum electrolytes and ABGs. A low serum HCO₃^- and a pH of less than 7.40 upon ABG analysis confirm metabolic acidosis. The anion gap (AG) should be calculated to help with the differential diagnosis of the metabolic acidosis and to diagnose mixed disorders. In general, a high-AG acidosis is present if the AG is greater than 10-12 mEq/L, and a non-AG acidosis is present if the AG is less than or equal to 10-12 mEq/L. It is important to note that the AG decreases by 2.5 mEq for every 1 g/dL decrease in serum albumin.

If the AG is elevated, the osmolar gap should be calculated by subtracting the calculated serum osmolality from the measured serum osmolality. Ethylene glycol and methanol poisoning increase the AG and the osmolar gap. Acetone, produced by decarboxylation of acetoacetate, can also raise serum osmolality. Other tests can be performed, including a screen for toxins (eg, ethylene glycol, salicylate) and tests for metabolic disorders (eg, ketoacidosis, lactic acidosis), that are known to elevate the AG.

If the AG is not elevated, then a urinalysis should be performed and a urine pH obtained with a pH electrode on a fresh sample of urine collected under oil or in a capped syringe. A urine AG is calculated from the measurement of urine Na⁺, K⁺, and Cl^-. This helps to differentiate between GI and renal losses of HCO₃^- in non-AG metabolic acidosis.

The change in AG (delta AG) helps in detecting the presence of a second acid-base disorder in patients with an elevated AG. It is calculated by the following equation:

(AG - 10)/(24 - HCO₃^-)

A value less than 1 indicates that the drop in serum HCO₃^- is not accompanied by a corresponding increase in the AG. This suggests that a portion of the H⁺ load is not accompanied by an unmeasured anion and indicates the presence of a mixed metabolic acidosis (eg, a non-AG acidosis and a high-AG acidosis).

A value greater than 1.6 indicates that the drop in serum HCO₃^- is associated with a larger-than-expected increase in the AG. This would occur if the serum HCO₃^- level was higher than normal prior to the onset of the metabolic acidosis and then dropped below normal with the addition of H⁺ coupled to an unmeasured anion. This indicates the presence of a mixed metabolic acidosis and metabolic alkalosis.

Special tests

Measuring the transtubular potassium gradient (TTKG) is useful in determining the etiology of hyperkalemia or hypokalemia associated with metabolic acidosis.

Plasma renin activity and plasma aldosterone levels are useful in determining the etiology of the hyperkalemia and hypokalemia that accompany metabolic acidosis.

FEHCO₃^- is useful in the diagnosis of proximal renal tubular acidosis (RTA).

The NH₄ Cl loading test is useful in patients with nephrocalcinosis and/or nephrolithiasis, who may have an incomplete form of distal RTA. These patients may not have a pH less than 7.35 or a drop in serum HCO₃^-; metabolic acidosis can be induced by administration of NH₄ Cl (0.1 g/kg for 3 d). Under these circumstances of induced acidemia, a urine pH greater than 5.3 indicates distal RTA.

A recently described alternative to the NH₄ Cl loading test involves the simultaneous oral administration of furosemide to increase distal Na⁺ delivery and fludrocortisone to increase collecting duct Na⁺ absorption and proton secretion.^[9] Under these circumstances, a urine pH greater than 5.3 indicates distal RTA.

Measuring the urine-blood PaCO₂ gradient following an HCO₃^- load is useful in some patients with classic distal RTA to differentiate a permeability defect from other defects. This test is useful in patients with nephrocalcinosis in whom distal RTA is suspected but urine is acidified appropriately in the face of metabolic acidosis. Some of these patients have a rate-dependent defect in proton secretion, revealed by a low urine-blood PaCO₂ gradient following HCO₃^- loading.

Abdominal radiographs (eg, kidneys, ureters, bladder), CT scans, and/or renal ultrasound images may show renal stones or nephrocalcinosis in patients with distal RTA.

Base excess/base deficit

ABGs also measure base excess/base deficit (BE/BD), which is the best indicator of the degree of acidosis/alkalosis. BE/BD is measured by gauging the amount of acid or base that is required to titrate the patient's blood sample to a pH of 7.40, given a PCO₂ level of 40 mm Hg at 37°C.

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Complete Blood Count

An elevation of the white blood cell (WBC) count is a nonspecific finding, but it should prompt consideration of septicemia, which causes lactic acidosis.

Severe anemia with compromised oxygen delivery may cause lactic acidosis.

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Urinalysis

A urine pH is normally acidic at less than 5.0. In acidemia, the urine normally becomes more acidic. If the urine pH is above 5.5 in the face of acidemia, this finding is consistent with a type I RTA. Alkaline urine is typical in salicylate poisoning.

Patients with ethylene glycol toxicity may present with calcium oxalate crystals, which appear needle shaped, in the urine.

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Urine Anion Gap

Calculating the urine AG is helpful in evaluating some cases of non-AG metabolic acidosis. The major measured urinary cations are Na⁺ and K⁺, and the major measured urinary anion is Cl^-:

Urine AG = ([Na⁺] + [K⁺]) - [Cl^-]

In the face of metabolic acidosis, the kidneys increase the amount of NH₃ synthesized to buffer the excess H⁺ and NH₄ Cl excretion increases. The increased unmeasured NH₄⁺ thus increases the measured anion Cl^- in the urine, and the net effect is a negative AG, representing a normal response to systemic acidification. The finding of a positive urine AG in the face of non-AG metabolic acidosis points toward a renal acidification defect (eg, RTA^[10] ). See earlier section on urine anion gap.

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Ketone Level

Elevations of ketones indicate diabetic, alcoholic, and starvation ketoacidosis.

The nitroprusside test is used to detect the presence of ketoacids in the blood and the urine. This test measures only acetoacetate and acetone; therefore, it may underestimate the degree of ketonemia and ketonuria, because it will not detect the presence of beta-hydroxybutyrate (BOH). This limitation of the test can be especially problematic in patients with ketoacidosis who cannot convert BOH to acetoacetate because of severe shock or liver failure.

An assay for BOH is unavailable in some hospitals. An indirect method to circumvent this problem is to add a few drops of hydrogen peroxide to a urine specimen. This enzymatically will convert BOH into acetoacetate, which will be detected by the nitroprusside test.

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Serum Lactate level

The normal plasma lactate concentration is 0.5-1.5 mEq/L. Lactic acidosis is considered present if the plasma lactate level exceeds 4-5 mEq/L in an acidemic patient.

Most cases of lactic acidosis are due to tissue hypoxia (eg, from shock). Less commonly, underlying disease (eg, diabetic ketoacidosis), drugs, or toxins may be the cause.^[19]

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Salicylate levels and Iron levels

Therapeutic salicylate levels range up to 20-35 mg/dL. Plasma levels exceeding 40-50 mg/dL are in the toxic range.

Plasma levels provide some information as to the severity of intoxication: 40-60 mg/dL is considered mild; 60-100 mg/dL is moderate; and greater than 100 mg/dL is considered severe.

Iron toxicity is associated with lactic acidosis. Iron levels greater than 300 mg/dL are considered toxic.

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Transtubular Potassium Gradient

Measuring the transtubular potassium gradient (TTKG; see the calculation below) is useful in determining the etiology of hyperkalemia or hypokalemia associated with metabolic acidosis.

TTKG = urine K⁺ × serum osmolality/serum K⁺ × urine osmolality

A TTKG of greater than 8 indicates that aldosterone is present and that the collecting duct is responsive to it. A TTKG of less than 5 in the presence of hyperkalemia indicates aldosterone deficiency or resistance. For the test to be interpretable, the urine Na⁺ level should be greater than 10 mEq/L and the urine osmolality should be greater than or equal to serum osmolality.

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Plasma Renin Activity, Plasma Aldosterone levels, and FEHCO3-

Plasma renin activity and plasma aldosterone levels are useful in determining the etiology of the hyperkalemia and hypokalemia that accompany metabolic acidosis.

Measurement of the fractional excretion of bicarbonate (FEHCO₃^-) is useful in the diagnosis of proximal RTA.

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Ammonium Chloride Loading Test

The ammonium chloride (NH₄ Cl) loading test is useful in patients with nephrocalcinosis and/or nephrolithiasis, who may have an incomplete form of distal RTA. These patients may not have a pH of less than 7.35 or a drop in serum HCO₃^-; metabolic acidosis can be induced by administration of NH₄ Cl (0.1 g/kg for 3 d). Under these circumstances of induced acidemia, a urine pH of greater than 5.3 indicates distal RTA.

An alternative to the NH₄ Cl loading test involves the simultaneous oral administration of furosemide to increase distal Na⁺ delivery and fludrocortisone to increase collecting duct Na⁺ absorption and proton secretion.^[9] Under these circumstances, a urine pH greater than 5.3 indicates distal RTA.

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Urine-Blood PaCO2 Gradient Following HCO3- Loading

Measuring the urine-blood PaCO₂ gradient following an HCO₃^- load is useful in some patients with classic distal RTA to differentiate a permeability defect from other defects. This test is useful in patients with nephrocalcinosis in whom distal RTA is suspected but urine is acidified appropriately in the face of metabolic acidosis. Some of these patients have a rate-dependent defect in proton secretion, revealed by a low urine-blood PaCO₂ gradient following HCO₃^- loading.

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Imaging Studies and Electrocardiography

Abdominal radiographs (eg, kidneys, ureters, bladder), computed tomography (CT) scans, and/or renal ultrasonographic images may show renal stones or nephrocalcinosis in patients with distal RTA.

If iron ingestion is suspected, perform imaging studies on the abdominal area, including the kidneys, ureters, and bladder.

An electrocardiogram (ECG) may be used to detect abnormalities that result from the effects of electrolyte imbalances (eg, hyperkalemia).

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Approach Considerations

Treatment of acute metabolic acidosis by alkali therapy is usually indicated to raise and maintain the plasma pH to greater than 7.20. In the following two circumstances this is particularly important.

When the serum pH is below 7.20, a continued fall in the serum HCO₃^- level may result in a significant drop in pH. This is especially true when the PCO₂ is close to the lower limit of compensation, which in an otherwise healthy young individual is approximately 15 mm Hg. With increasing age and other complicating illnesses, the limit of compensation is likely to be less. A further small drop in HCO₃^- at this point thus is not matched by a corresponding fall in PaCO₂, and rapid decompensation can occur. For example, in a patient with metabolic acidosis with a serum HCO₃^- level of 9 mEq/L and a maximally compensated PCO₂ of 20 mm Hg, a drop in the serum HCO₃^- level to 7 mEq/L results in a change in pH from 7.28 to 7.16.

A second situation in which HCO₃^- correction should be considered is in well-compensated metabolic acidosis with impending respiratory failure. As metabolic acidosis continues in some patients, the increased ventilatory drive to lower the PaCO₂ may not be sustainable because of respiratory muscle fatigue. In this situation, a PaCO₂ that starts to rise may change the plasma pH dramatically even without a significant further fall in HCO₃^-. For example, in a patient with metabolic acidosis with a serum HCO₃^- level of 15 and a compensated PaCO₂ of 27 mm Hg, a rise in PaCO₂ to 37 mm Hg results in a change in pH from 7.33 to 7.20. A further rise of the PaCO₂ to 43 mm Hg drops the pH to 7.14. All of this would have occurred while the serum HCO₃^- level remained at 15 mEq/L.

In lactic acidosis and diabetic ketoacidosis, the organic anion can regenerate bicarbonate when the underlying disorder is corrected, and caution must be exercised in trying to correct the acidosis with bicarbonate therapy, unless the pH is less than 7.0-7.1.

Sodium bicarbonate (NaHCO₃) is the agent most commonly used to correct metabolic acidosis. The HCO₃^- deficit can be calculated by using the following equation:

HCO₃^- deficit = deficit/L (desired serum HCO₃^- - measured HCO₃^-) × 0.5 × body weight (volume of distribution for HCO₃^-)

This provides a crude estimate of the amount of HCO₃^- that must be administered to correct the metabolic acidosis; the serum HCO₃^- level or pH should be reassessed frequently.

HCO₃^- can be administered intravenously to raise the serum HCO₃^- level adequately to increase the pH to greater than 7.20. Further correction depends on the individual situation and may not be indicated if the underlying process is treatable or the patient is asymptomatic.

This is especially true in certain forms of metabolic acidosis. For example, in high anion gap acidosis secondary to accumulation of organic acids, lactate, and ketones, these anions are eventually metabolized to HCO₃^-. When the underlying disorder is treated, the serum pH corrects; thus, caution should be exercised in these patients when providing alkali to raise the pH much higher than 7.20, because an overshoot alkalosis may occur.

To minimize the risk of hypernatremia and hyperosmolality, two 50-mL ampules of 8.4% NaHCO₃ (containing 50 mEq each) are added to 1 L of 0.25 normal saline or three ampules are added to 1 L of 5% dextrose in water.

Volume overload can be a consequence of alkali therapy. Loop diuretics can be used in these circumstances.

Another consequence of treatment with NaHCO₃ is a rise in PaCO₂. This can become a very important factor in patients who have reduced ventilatory reserve.

In high anion gap acidosis secondary to accumulation of organic acids, lactate, and ketones, these anions are eventually metabolized to HCO₃^-. When the underlying disorder is treated, the serum pH corrects; thus, caution should be exercised in these patients when providing alkali to raise the pH much higher than 7.20, because an overshoot alkalosis may occur.

Potassium citrate can be useful when the acidosis is accompanied by hypokalemia but should be used cautiously in the presence of renal impairment and must be avoided in the presence of hyperkalemia.

Oral NaHCO₃ can be administered in some acute metabolic acidemic states in which correction of metabolic acidosis is unlikely to occur without exogenous alkali administration.

Oral alkali administration is the preferred route of therapy in persons with chronic metabolic acidosis. The most common alkali forms for oral therapy include NaHCO₃ tablets. These are available in 325 and 650 mg strengths (1 g of NaHCO₃ is equal to 11.5 mEq of HCO₃^-).

Citrate salts are available in a variety of formulations, as mixtures of citric acid with sodium citrate and/or potassium citrate. These solutions generally contain 1-2 mEq of HCO₃^- per mL. Potassium citrate is useful when the acidosis is accompanied by hypokalemia but should be used cautiously in persons with renal impairment and must be avoided in those with hyperkalemia.

In a 12-month controlled, randomized, interventional trial that included 30 renal transplant patients with metabolic acidosis, correction of metabolic acidosis with potassium citrate was found to be effective and well tolerated, and was associated with improvements in bone quality, suggesting a beneficial effect of both alkali treatment and restoration of acid/base balance. The researchers concluded that potassium citrate may be superior to sodium bicarbonate, because it lacks volume effects and the obligatory calcium excretion associated with sodium administration.^[11]

Go to Pediatric Metabolic Acidosis and Emergent Management of Metabolic Acidosis for complete information on these topics.

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Type 1 Renal Tubular Acidosis

Administration of an alkali is the mainstay of treatment for type 1 renal tubular acidosis (RTA). Adult patients should be given the amount required to buffer the daily acid load from the diet. This is usually approximately 1-3 mEq/kg/d and can be administered in any form, although the preferred form is as potassium citrate. Correction of acidosis usually corrects the hypokalemia, but K⁺ supplements may be necessary.

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Type 2 Renal Tubular Acidosis

Correcting this form of acidosis with alkali is difficult because a substantial proportion of the administered HCO₃^- is excreted in the urine, and large amounts are needed to correct the acidosis (10-30 mEq/kg/d). Potassium is also required when administering HCO₃^-. Correction is essential in children for normal growth, while in adults aggressive correction to a normal level may not be required. Thiazide diuretics can be administered to induce diuresis and mild volume depletion, which, in turn, raises the proximal tubule threshold for HCO₃^- wasting.

Patients with type 2 RTA typically have hypokalemia and increased urinary K⁺ wasting. Administration of alkali in those patients leads to more HCO₃^- wasting and can worsen hypokalemia unless K⁺ is replaced simultaneously.

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Type 4 Renal Tubular Acidosis

Because hyperkalemia is central to the etiology of this disorder,^[23] a major treatment goal is to lower the serum K⁺ level. This can be achieved by placing the patient on a low-K⁺ diet (1 mEq/kg K⁺/d) and by withdrawal of drugs that can cause hyperkalemia (eg, angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs). Loop diuretics can be helpful in reducing serum potassium levels as long as the patient is not hypovolemic.

In resistant cases, fludrocortisone, a synthetic mineralocorticoid, can be used to increase K⁺ secretion, but this may increase Na⁺ retention. Alkali therapy is not usually required, because, in many patients, the mild degree of acidosis is corrected by achieving normokalemia. Hyperkalemia and acidosis worsen as renal function declines further; eventually, the patient develops a high-AG renal acidosis. Renal replacement therapy should be considered once the measures described fail to control hyperkalemia or acidosis.

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Chronic Kidney Disease

Treatment of chronic metabolic acidosis in persons with chronic kidney disease (CKD) is indicated because it can help to prevent bone loss that can progress to osteopenia or osteoporosis. In children, growth retardation can occur. In addition, treatment slows the progression of hyperparathyroidism and helps to reduce the high-protein catabolic state associated with uremic acidosis, which leads to loss of muscle mass and malnutrition.

Alkali treatment is suggested when the serum bicarbonate concentration falls below 22 mEq/L, as treatment may decrease muscle wasting, improve bone disease, and slow the progression of CKD.^[22] In patients with stages 3b and 4 CKD, treatment of metabolic acidosis with sodium bicarbonate has also been shown to significantly improve vascular endothelial function.^[21] The target serum bicarbonate concentration is unclear, however; concentrations above 24 mEq/L have been tentatively linked with worsening of cardiovascular disease, which complicates treatment decisions.^[12]

NaHCO₃ is the most frequently used agent. It is administered in an amount necessary to keep the serum HCO₃^- level greater than 20 mEq/L. The average requirement is approximately 1-2 mEq/kg/d. Sodium citrate should be avoided if the patient is taking aluminum as a phosphate binder, because citrate increases aluminum absorption and, hence, the risk for aluminum toxicity.

The choice of sodium bicarbonate dose remains unclear, and there are concerns over side effects, most notably fluid retention, especially with higher doses. Consequently, Abramowitz and colleagues conducted a single-blinded pilot study in 20 adults with stages 3 and 4 CKD and mild metabolic acidosis. Participants were treated during successive 2-week periods with placebo followed by escalating doses of oral sodium bicarbonate at 2-week intervals (0.3, 0.6, and 1.0 mEq/d per kg ideal body weight).^[13]

Sodium bicarbonate was well tolerated, even at high doses; produced a dose-dependent increase in serum bicarbonate; and was associated with an improvement in lower extremity muscle strength and reduced urinary nitrogen excretion. The authors caution, however, that the results require further study and confirmation from a large randomized placebo-controlled study.^[13]

In older persons with CKD, existing evidence is insufficient to show whether any benefits of sodium bicarbonate therapy outweigh the adverse effects and treatment burden in this population, which may include fluid retention and blood pressure from the additional sodium load, as well as gastrointestinal side effects. Trials of bicarbonate therapy for older persons with CKD are currently in progress.^[15]

Metabolic acidosis in patients with CKD can also be treated with dietary modification. Dietary acid reduction can be accomplished by limiting the intake of acid-producing foods such as animal protein and emphasizing base-producing foods such as fruits and vegetables.^[20]

In a year-long randomized study of 71 patients with stage 4 CKD, Goroya et al compared the effectiveness of daily oral sodium bicarbonate with that of base-producing fruits and vegetables for reduction of kidney injury and improvement of metabolic acidosis. Patients consuming fruits and vegetables dosed to reduce dietary acid by half had a reduction in kidney injury and improvement in metabolic acidosis comparable to that in the sodium bicarbonate group and did not experience hyperkalemia.^[14]

The investigators note that study patients were selected to be at low risk for hyperkalemia and advise that caution should be exercised in prescribing fruits and vegetables in patients with very low estimated glomerular filtration rates. Nevertheless, Goroya et al concluded that treating metabolic acidosis in individuals with stage 4 CKD due to hypertensive nephropathy with fruits and vegetables appeared to be an effective kidney-protective adjunct.^[14]

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Ketoacidosis

Starvation and alcohol use resulting in acidosis is treated with intravenous glucose, which is administered to stimulate insulin secretion and stop lipolysis and ketosis.

For diabetic ketoacidosis (DKA), insulin is administered, usually intravenously, to facilitate cellular uptake of glucose, reduce gluconeogenesis, and halt lipolysis and production of ketone bodies. In addition, normal saline is administered to restore extracellular volume; potassium and phosphate replacement also may be necessary. The acidosis is corrected partly by the metabolism of ketones to HCO₃^-, partly by increased H⁺ secretion by the collecting duct, and partly by H⁺ excretion as NH₄⁺.

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Lactic Acidosis

Correction of the underlying disorder is the mainstay of therapy.^[16] In patients with tissue hypoxia, restoration of tissue perfusion is essential.

The role of alkali therapy is controversial; some authors recommend raising the serum pH to 7.20 when possible. Some evidence suggests, however, that HCO₃^- therapy produces only a transient increase in the serum HCO₃^- level and that this can lead to intracellular acidosis and worsening of lactic acidosis. Furthermore, large amounts of NaHCO₃ are commonly required, and volume overload and hypernatremia can occur. In such situations, hemodialysis or continuous venovenous hemofiltration can be used to correct the metabolic abnormalities.

If the process leading to lactic acidosis is corrected, lactic acid can be used again by the liver to produce HCO₃^- on an equimolar basis. This is important, because rebound alkalosis can occur if the patient has received an excessive amount of alkali during the acidemia.

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Salicylate Poisoning

Alkali therapy is an important component of therapy in salicylate overdose for several reasons. Correcting the acidemia decreases the amount of salicylate crossing the blood-brain barrier. Care should be exercised to avoid inducing or worsening the alkalosis that may be present.

Increasing urine pH increases the excreted salicylate. Alkaline diuresis can be initiated by intravenous NaHCO₃ administration or by acetazolamide therapy. The goal is to maintain the urine pH at greater than 7.5 until the salicylate level falls below 30-50 mg/dL.

Multiple dosing of activated charcoal at 0.25-1 g/kg every 2-4 hours can also be used to increase the excretion of salicylate.

In acute intoxication, hemodialysis should be considered when the blood level is greater than 80 mg/dL or when renal failure or severe central nervous system (CNS) depression is present.

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Methanol or Ethylene Glycol Poisoning

Treatment should be started promptly to prevent any neurologic sequelae.

Fomepizole (4-methylpyrazole; Antizol) is a potent inhibitor of alcohol dehydrogenase and is now the preferred therapy, although it is much more expensive than ethanol. Fomepizole is given as a loading dose and continued over several doses until toxin levels decline substantially. Fomepizole levels do not need to be monitored.

Ethanol competes for alcohol dehydrogenase and can be used as an alternative to fomepizole. It is administered orally or intravenously to saturate alcohol dehydrogenase, to which it has a higher affinity, thus inhibiting metabolism of methanol or ethylene glycol to its toxic metabolites. The blood ethanol level should be maintained at 100-150 mg/dL.

HCO₃^- therapy can be administered to correct severe acidosis, but large amounts of HCO₃^- may be required and fluid overload can compromise therapy.

Patients with methanol overdose should receive folate to enhance the metabolism of formic acid. Patients with ethylene glycol overdose should receive thiamine and pyridoxine.

Hemodialysis should be considered in any patient with significant metabolic acidosis, renal failure, visual symptoms, a high blood toxin level, or a suspected large overdose. Hemodialysis is effective in clearing methanol and ethylene glycol, as well as their toxic metabolites; in correcting the acidosis; and in restoring extracellular volume.

A study by Zakarov et al of 31 patients involved in a mass outbreak of methanol poisoning determined that correction of acidemia was accomplished more rapidly with intermittent hemodialysis (IHD) than with continuous renal replacement therapy (CRRT). HCO₃^- increased by 1 mmol/L in a mean of 12 ± 2 min with IHD versus 34 ± 8 min withr CRRT (P <  0.001), while arterial blood pH increased 0.01 in a mean of 7 ± 1 mins with IHD versus 11 ± 4 min with CRRT (p = 0.024).^[17]

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Medication Summary

As previously stated, sodium bicarbonate (NaHCO₃) is the agent most commonly used to correct metabolic acidosis. Also as previously mentioned, the role of alkali therapy is controversial in the treatment of lactic acidosis, with some evidence suggesting that HCO₃^- therapy produces only a transient increase in the serum HCO₃^- level and that this can lead to intracellular acidosis and worsening of lactic acidosis.

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Sodium bicarbonate

• Dosing, Interactions, etc.

Clinical Context:  Sodium bicarbonate is a systemic and urinary alkalinizer used to increase serum or urinary HCO₃^- concentration and raise pH. Dosing is based on the clinical setting, blood pH, serum HCO₃^- level, and PaCO₂.

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Tromethamine (THAM)

• Dosing, Interactions, etc.

Clinical Context:  THAM combines with hydrogen ions to form a bicarbonate buffer. It is used to prevent and correct systemic acidosis. It is available as 0.3-mol/L IV solution containing 18 g (150 mEq) per 500 mL (0.3 mEq/mL).

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Class Summary

Acute metabolic acidosis is usually treated with alkali therapy to raise plasma pH and to maintain it at greater than 7.20.

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Acetazolamide (Diamox)

• Dosing, Interactions, etc.

Clinical Context:  This agent is used in the treatment of salicylate poisoning. It reduces the reduction of hydrogen ion secretion at the renal tubule and increases excretion of sodium, potassium, bicarbonate, and water. The goal is to maintain the urine pH at greater than 7.5 until the salicylate level falls below 30-50 mg/dL.

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Class Summary

Agents in this class may be used to induce alkaline diuresis.

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Insulin

Clinical Context:  Insulin is administered, to facilitate cellular uptake of glucose, reduce gluconeogenesis, and halt lipolysis and production of ketone bodies. In addition, normal saline is administered to restore extracellular volume; potassium and phosphate replacement also may be necessary.

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Class Summary

These agents are used for the treatment of ketoacidosis.

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Fomepizole (Antizol)

• Dosing, Interactions, etc.

Clinical Context:  Begin fomepizole treatment immediately upon suspicion of ethylene glycol ingestion based on patient history or anion gap metabolic acidosis, increased osmolar gap, oxalate crystals in urine, or documented serum methanol level.

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Activated charcoal (Actidose-Aqua, Requa Activated Charcoal)

• Dosing, Interactions, etc.

Clinical Context:  This agent can be used to increase the excretion of salicylate. It is used in the emergency treatment of poisoning caused by drugs and chemicals. The network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. It prevents absorption by adsorbing the drug in the intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of the drug from intestinal villous capillary blood into the intestine. It does not dissolve in water.

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Class Summary

These agents may be used in methanol or ethylene glycol poisoning.

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