Background: Metabolic acidosis is a clinical disturbance characterized by a relative increase in total body acid. The condition should be considered a sign of an underlying disease process affecting the body. Identification of this underlying condition is essential to initiate appropriate therapy.
This article discusses the differential diagnosis of metabolic acidosis. It also presents a scheme for identifying the underlying cause of acidosis by using laboratory tests that are available to emergency department physicians. Clinical strategies for treating metabolic acidosis are reviewed.
Pathophysiology: Metabolic acidosis can be induced by 2 basic mechanisms, as follows: an inability of the kidneys to excrete the dietary hydrogen (H+) load, and an increase in the generation of H+ that is due to the addition of H+ (lactic acid or ketoacids) or to the loss of bicarbonate (HCO3-) due to inappropriate wasting by the kidney or the gastrointestinal tract.
The response of the body to an increase in the H+ concentration involves several processes. The first and most readily available process is extracellular buffering. The most readily measured extracellular buffer is carbonic acid (H2CO3). This buffer is considered an open buffering system because compensatory mechanisms in respiratory carbon dioxide (CO2) (increase or decrease in ventilation) and renal HCO3- (increase or decrease in kidney reclamation of HCO3-) serve to maintain equilibrium.
H+ + HCO3- = H2CO3 = CO2 + H20
The Henderson-Hasselbalch equation mathematically describes the relationship between blood pH and the components of the H2CO3 buffering system.
pH = 6.1 + log (HCO3/H2CO3)
In clinical practice, H2CO3 can be calculated by using the following equation: H2CO3 = PCO2 X 0.03
Metabolic acidosis most commonly stimulates the central and peripheral chemoreceptors that control respiration, resulting in an increase in alveolar ventilation, which results in a compensatory respiratory alkalosis.
In addition to the extracellular buffering provided by the lungs and the kidneys, intracellular and bone buffering also provide limited buffering capacity. H+ ions can enter cells and be taken up by the cell and the bone buffers (eg, proteins, phosphate, bone carbonate).
Renal excretion of the H+ ion is an important process to regenerate HCO3-. H+ ions combine with the urinary buffers, particularly HPO4 and NH3, and are excreted in the distal tubule. In this process of H+ excretion, HCO3 is regenerated and added into the intravascular space.
Renal tubular acidosis (RTA) refers to those conditions in which metabolic acidosis results from diminished net tubular H+ secretion or HCO3 reabsorption. Three major types of RTA exist.
Type 1 (distal) RTA is characterized by a decrease in net H+ excretion in the collecting tubules. The urine pH remains above 5.5. This defect in acidification diminishes the NH4+ and titratable acid excretion, thereby preventing complete excretion of the dietary acid load. As a result, there is continued H+ retention, which leads to a progressive reduction in the plasma HCO3- concentration.
In type 2 (proximal) RTA, proximal HCO3- reabsorption is reduced, as is the total HCO3- reabsorptive capacity. Type 2 RTA essentially is a self-limiting disorder in which the plasma HCO3- concentration usually is 14-20 mEq/L.
Type 4 RTA is a metabolic acidosis that results from aldosterone deficiency or resistance. Aldosterone normally promotes distal potassium (K+) and H+ secretion, as well as sodium (Na+) reabsorption. Hypoaldosteronism results in hyperkalemia with a concomitant metabolic acidosis. This type of RTA can also occur from potassium-sparing diuretics or collecting duct dysfunction from renal insufficiency.
Refer to specific articles concerning the pathophysiology of individual types of metabolic acidosis.
Mixed acid-base disorders
Mixed acid-base disorders are defined as combinations of 2-3 primary disorders occurring contemporaneously. Common examples of mixed acid-base disorders include the following:
A respiratory disorder (alkalosis/acidosis) complicates a metabolic disorder (acidosis/alkalosis).
A metabolic disorder (alkalosis/acidosis) complicates another metabolic disorder (alkalosis/acidosis).
Mixed respiratory/metabolic disorders, which involve inappropriate respiratory compensations for metabolic disorders, are diagnosed by comparing the observed PCO2 with the expected (calculated) changes in PCO2 for that observed change in HCO3. When the observed PCO2 is higher that the expected PCO2, a primary respiratory acidosis is complicating the metabolic disturbance. Conversely, when the observed PCO2 is lower than the expected PCO2, a primary respiratory alkalosis is complicating the metabolic disturbance.
Expected PCO2 for any metabolic (alkalosis/acidosis) can be calculated as follows:
Metabolic acidosis: PCO2 falls 1.2 mm Hg for every 1 mEq/L fall in HCO3.
Another formula:
PCO2 = 1.5 X (observed HCO3) + 8±2
A quick rule of thumb: The PCO2 should approximate the last two digits of pH. For example, pH 7.25, PCO2 should be close to 25 mm Hg.
Metabolic alkalosis: PCO2 rises 0.7 mm Hg for every 1 mEq/L rise in HCO3.
Inappropriate metabolic compensation for respiratory disorders are diagnosed by comparing the observed HCO3 with the expected (calculated) changes in HCO3 for that observed change in PCO2.
When the observed HCO3 is higher than the expected HCO3, a primary metabolic alkalosis is complicating the respiratory disturbance. Conversely, when the observed HCO3 is lower than the expected HCO3, a primary metabolic acidosis is complicating the respiratory disturbance.
Expected HCO3 for any respiratory (alkalosis/acidosis) can be calculated as follows:
Respiratory alkalosis
Acute: 2 mEq/L drop in HCO3 for every drop of 10 mm Hg PCO2.
Chronic: 4 mEq/L drop in HCO3 for every drop of 10 mm Hg PCO2.
Respiratory acidosis
Acute: 1 mEq/L increase in HCO3 for every increase of 10 mm Hg PCO2. Chronic: 3.5 mEq/L increase in HCO3 for every increase of 10 mm Hg PCO2.
Mixed metabolic acidosis and metabolic alkalosis are diagnosed when the change in the anion gap (AG) does not equal the change in HCO3. Because the AG is an indirect measure of the acid added to the body, the HCO3 should fall by an amount paralleling the rise in AG. When the HCO3 is greater than the rise of the AG, a primary metabolic alkalosis is complicating the metabolic acidosis. Conversely, when the HCO3 is less than the rise of the AG, a non-AG metabolic acidosis should be assumed to be complicating an AG acidosis.
Mortality/Morbidity: The mortality and morbidity of patients with metabolic acidosis is dependent upon the nature of the underlying cause and the ability to correct it.
History: Metabolic acidosis can result in a variety of nonspecific changes in several organ systems, including, but not limited to neurologic, cardiovascular, pulmonary, gastrointestinal, and musculoskeletal dysfunction. Symptoms are often specific to and a result of the underlying etiology of the metabolic acidosis.
Head, eyes, ears, nose, throat (HEENT) Tinnitus, blurred vision, and vertigo can occur with salicylate poisoning. Visual disturbances, dimming, photophobia, scotomata, and frank blindness can be seen in methanol intoxication. Cardiovascular Palpitations Chest pain Neurologic Headache Visual changes Mental confusion Pulmonary: Subjective dyspnea from the patient's observation of hyperventilation. Gastrointestinal Nausea and vomiting Abdominal pain Diarrhea Polyphagia Musculoskeletal Generalized muscle weakness Bone pain
Physical: Neurologic Cranial nerve palsies may occur with ethylene glycol intoxication. Retinal edema may be seen in methanol ingestions. Lethargy, stupor, and coma may occur in severe metabolic acidosis, particularly when it is associated with a toxic ingestion. Cardiovascular: Severe acidemia (ie, pH Pulmonary Patients with acute metabolic acidosis demonstrate tachypnea and hyperpnea as prominent physical signs. Kussmaul respiration, an extremely intense respiratory effort, may be present. Hyperventilation, in the absence of obvious lung disease, should alert the clinician to the possibility of an underlying metabolic acidosis. Musculoskeletal: Chronic metabolic acidosis (eg, uremia, RTA) is associated with substantial bone disease from bone buffering of calcium carbonate. Long bone malformations in pediatric patients (eg, vitamin D resistant, rickets) Fractures in adult patients
Causes: Inability to excrete the dietary H+ load Renal failure - Diminished NH4+ production Hypoaldosteronism - Type 4 RTA Diminished H+ secretion - Type 1 (distal) RTA Increased H+ load Lactic acidosis - Numerous causes, including circulatory failure, drugs and toxins, and hereditary causes (see Lactic Acidosis) Ketoacidosis - Diabetes, alcoholism, and starvation Ingestions - Salicylates, methanol, ethylene glycol, isoniazid, iron, paraldehyde, sulfur, toluene, ammonium chloride, phenformin/metformin, and hyperalimentation fluids GI HCO3- loss Diarrhea Pancreatic, biliary, or intestinal fistulas Ureterosigmoidostomy Cholestyramine Renal HCO3- loss Type 2 (proximal) RTA Acetazolamide
Lab Studies: Arterial blood gas A low HCO3 level found on an automated sequential multiple analyzer (SMA) (eg, serum chemistries) is often the first clue to the presence of a metabolic acidosis; however, it cannot be the only consideration in the diagnosis of metabolic acidosis. A low HCO3 level can be caused by metabolic acidosis, a metabolic compensation of a respiratory alkalosis, or a laboratory error. The HCO3 level that is calculated by the arterial blood gas (ABG) machine, which uses the Henderson-Hasselbalch equation, represents a more accurate measure of the plasma HCO3 than the SMA measurement. It is suggested that the HCO3 level that is determined from the ABG be used in the anion gap calculation instead of the HCO3 level found using the SMA. Measurement of pH and PCO2 by ABG in a patient with a low HCO3 level allows a physician to differentiate a metabolic compensation of a respiratory alkalosis from a primary metabolic acidosis. Measurement of PCO2 also allows a physician to judge the appropriateness of respiratory compensation of a metabolic acidosis (see formulae later in chapter), and it allows a physician to detect respiratory acidosis, which is signified by an elevated PCO2. Oxygenation does not affect the acid-base status of a patient and generally should not be part of the discussion unless severe hypoxia is leading to ischemia. In that case, measurement of PO2 can identify severe hypoxia as a precipitant of lactic acidosis. 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 degrees Celsius. BE/BD is a more accurate reflection of the body's state, and it is recommended over calculations using the HCO3 level. Serum chemistry Sodium, potassium, chloride, and bicarbonate levels are used in the calculation of anion gap. Hyperkalemia often complicates metabolic acidosis. It commonly is seen with inorganic acidosis (ie, non-AG). Diabetic ketoacidosis (DKA) often presents with hyperkalemia that does not parallel the acidosis; in this case, hyperkalemia results from insulin deficiency and the effects of hyperosmolality. Lactic acidosis and other forms of organic acidosis generally do not present with a significant potassium shift. Glucose commonly is elevated in DKA, and it may be low, normal, or mildly elevated in alcoholic ketoacidosis. The BUN and creatinine levels are elevated in uremic acidosis. Complete blood count An elevation of the WBC count is a nonspecific finding, but it should prompt consideration of septicemia, which causes lactic acidosis. Severe anemia with compromised O2 delivery may cause lactic acidosis. Urinalysis A urine pH is normally acidic at Ethylene glycol toxicity may present with calcium oxalate crystals, which appear needle shaped, in the urine.
Imaging Studies:
If iron ingestion is suspected, perform imaging studies on the abdominal area, including the kidneys, ureters, and bladder.
Other Tests:
Anion gap: Calculation of the AG is often helpful in the differential diagnosis of metabolic acidosis. The AG is equal to the difference between the plasma concentrations of the measured plasma cation (ie, Na+) and the measured anions (ie, chloride [Cl-], HCO3-). It exists because standard electrolyte panels do not measure all the anions present in the serum.
AG calculation = (Na+) - ([Cl-] + [HCO3-])
A normal AG is traditionally listed as 8-16 mEq/L, with an average value of 12. This value may vary, depending on the instrumentation used to measure electrolyte levels, and recent data suggests a normal range of 5-11 mEq/L. Some authors add K+ to measured cations; then, the traditional normal range is 12-20 mEq/L. The anion gap allows for the differentiation of 2 groups of metabolic acidosis. Metabolic acidosis with a high AG is associated with the addition of endogenously- or exogenously-generated acids. Metabolic acidosis with a normal AG is associated with the loss of HCO3 or the failure to excrete H+ from the body. High AG
Lactic acidosis - 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), sulfur (SO4-), phenformin/metformin
Pyroglutamic acidemia (5-oxoprolinemia)
Massive rhabdomyolysis (release of H+ and organic anions from damaged muscle) There are several mnemonics used to prompt recall of the differential diagnosis of high anion gap acidosis. Two, neither of which is completely comprehensive, 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 Normal AG (ie, hyperchloremic acidosis)
GI loss of HCO3-, diarrhea
Pancreatic fistula
Renal HCO3- loss - Type 2 (proximal) RTA
Renal dysfunction
Some cases of renal failure
Hypoaldosteronism (ie, type 4 RTA)
Hyperventilation
Ingestions - Ammonium chloride, acetazolamide, hyperalimentation fluids, some cases of ketoacidosis, particularly during treatment with fluid and insulin The AG can rise because of increases in unmeasured anions or decreases in unmeasured cations (eg, hypokalemia, hypocalcemia, hypomagnesemia). AG also can increase, secondary to an increase in albumin or an increase in negative charges on albumin, which is caused by alkalosis.
AG can be decreased by an increase in unmeasured cations (eg, hyperkalemia, hypercalcemia, hypermagnesemia, lithium intoxication, high immunoglobulin G [igG] levels) or by a decrease in unmeasured anions (eg, hypoalbuminemia).
Finally, laboratory errors can also affect the AG. Hyperproteinemia, hyperlipidemia, and hyperglycemia resulting in underestimation of serum sodium level can falsely depress AG. In addition, bromide intoxication can be mistaken for Cl-, which can result in an inappropriate depression of the AG. The osmolal gap is the measured plasma osmolality minus calculated osmolality. The serum osmolality is composed of all osmotically active substances including ionic and nonionic substances such as serum ions, glucose, and BUN. Other substances such as alcohols, excess serum lipids and proteins, and delivered substances such as mannitol all contribute to the serum osmolality. The calculated osmolality is 2 X plasma [Na+] + [glucose]/18 + BUN/2.8.
Normal osmolal gap is 10-15
Metabolic acidosis with elevated osmolal gap indicates methanol and ethylene glycol ingestions. Ketones: 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 only measures 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. Serum lactate: For a complete discussion of the differentials of lactic acidosis, refer to Lactic Acidosis.
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. Salicylate 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 levels
Iron toxicity is associated with lactic acidosis.
Iron levels greater than 300 mg/dL are considered toxic. Electrocardiogram: An ECG may be used to detect abnormalities that result from the effects of electrolyte imbalances (eg, hyperkalemia
Many drugs may be employed in the management of a patient with metabolic acidosis. They range from antibiotics for septic shock to toxin antidotes. These agents are discussed in detail under the specific chapters for the disease. Bicarbonate is an agent that is considered across the numerous differentials of metabolic acidosis. As discussed above, its use generally is limited to severe cases of acidosis (pH
Drug Category: Alkalinizing agent -- Used in the treatment of metabolic acidosis. Drug Name
Sodium bicarbonate (Neut) -- Bicarbonate ion is produced when it dissociates and neutralizes the hydrogen ions and raises urinary and blood pH. Adult DoseTotal bicarbonate deficit = Base deficit X bicarbonate (0.5-0.8) X body weight (kg)
Although this represents total bicarbonate deficit, replacement of this amount is never necessary since the unmeasured anions will be converted back to bicarbonate once the underlying condition is treated; the goal of IV bicarbonate is only to emergently raise the pH above 7.1-7.2; this generally can be accomplished by small boluses of IV bicarbonate equalling 50-100 mEq; continuous monitoring of pH and electrolytes is required to judge the adequacy of bicarbonate therapy Pediatric DoseThe following formula may be used to estimate dose to be administered in children: HCO3- (mEq) = 0.5 X weight (kg) X [24 - serum HCO3- (mEq/L)]
Formula has many limitations but practitioner can roughly determine amount of bicarbonate required and subsequently titrate against pH and anion gap ContraindicationsAlkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain Interactions Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; Increases levels of amphetamines pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine PregnancyC - Safety for use during pregnancy has not been established. PrecautionsSodium bicarbonate should only be used to treat documented metabolic acidosis and hyperkalemia-induced cardiac arrest; can cause alkalosis, decreased plasma potassium, hypocalcemia and hypernatremia; caution in electrolyte imbalances (eg, CHF, cirrhosis, edema, corticosteroid use, or renal failure); when administering, avoid extravasation because can cause tissue necrosis
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