PHYSIOLOGICAL EFFECTS OF ACIDEMIA
Biochemical reactions are very sensitive to changes in [H+]. [H+] is strictly regulated (36–43 nmol/L), as H+ ions have high charge densities and “large” electric fields that can affect the strength of hydrogen bonds that are present on most physiological molecules. The overall effects of acidemia represent the balance between the direct biochemical effects of H+ and the effects of acidemia-induced sympathoadrenal activation. With severe acidosis (pH <7.20), direct myocardial and smooth muscle depression reduces cardiac contractility and peripheral vascular resistance, resulting in progressive hypotension. Severe acidosis can lead to tissue hypoxia, despite a rightward shift in hemoglobin affinity for oxygen. Both cardiac and vascular smooth muscle become less responsive to endogenous and exogenous catecholamines, and the ventricular fibrillation threshold is decreased. The movement of K+ out of cells in exchange for increased extracellular H+ results in hyperkalemia that is also potentially lethal. Plasma [K+] increases approximately 0.6 mEq/L for each 0.10 decrease in pH.
Central nervous system depression is more prominent with respiratory acidosis than with metabolic acidosis. This effect is often termed CO2 narcosis. Unlike CO2, H+ ions do not readily penetrate the blood–brain barrier.
Respiratory acidosis is defined as a primary increase in PaCO2. This increase drives the reaction
H2O + CO2 ↔ H2CO3 ↔ H+ + HCO3−
to the right, leading to an increase in [H+] and a decrease in arterial pH. For the reasons described above, [HCO3−] is minimally affected.
PaCO2 represents the balance between CO2 production and CO2 elimination:
CO2 is a byproduct of fat and carbohydrate metabolism—and muscle activity, body temperature, and thyroid hormone activity can all have major influences on CO2 production. Because CO2 production does not appreciably vary under most circumstances, respiratory acidosis is usually the result of alveolar hypoventilation (Table 50–3). In patients with a limited capacity to increase alveolar ventilation, however, increased CO2 production can precipitate respiratory acidosis.
TABLE 50–3Differential diagnosis of respiratory acidosis. ||Download (.pdf) TABLE 50–3 Differential diagnosis of respiratory acidosis.
Increased CO2 production
Acute Respiratory Acidosis
The compensatory response to acute (6–12 h) elevations in PaCO2 is limited. Buffering is primarily provided by hemoglobin and the exchange of extracellular H+ for Na+ and K+ from bone and the intracellular fluid compartment (see earlier discussion). The renal response to retain more bicarbonate is acutely very limited. As a result, plasma [HCO3−] increases only about 1 mEq/L for each 10 mm Hg increase in PaCO2 above 40 mm Hg.
Chronic Respiratory Acidosis
Renal compensation in respiratory acidosis is appreciable only after 12 to 24 h and may not be maximal until 3 to 5 days have elapsed. During chronic respiratory acidosis, plasma [HCO3−] increases approximately 4 mEq/L for each 10 mm Hg increase in PaCO2 above 40 mm Hg.
Treatment of Respiratory Acidosis
Respiratory acidosis is treated by reversing the imbalance between CO2 production and alveolar ventilation. In most instances, this is accomplished by increasing alveolar ventilation. Measures aimed at reducing CO2 production are useful only in specific instances (eg, dantrolene for malignant hyperthermia, muscle paralysis for status epilepticus, antithyroid medication for thyroid storm, or reduced caloric intake in patients receiving excessive enteral or parenteral nutrition). Potential temporizing measures aimed at improving alveolar ventilation (in addition to controlled mechanical ventilation) include bronchodilation, reversal of narcosis, or improving lung compliance via diuresis. Severe acidosis (pH <7.20), CO2 narcosis, and respiratory muscle fatigue are indications for mechanical ventilation. An increased inspired oxygen concentration is also usually necessary, as coexistent hypoxemia is common. Intravenous NaHCO3 is rarely necessary, unless pH is less than 7.10 and HCO3− is less than 15 mEq/L. Sodium bicarbonate therapy will transiently increase PaCO2:
Buffers that do not produce CO2, such as Carbicarb or tromethamine (THAM), are theoretically attractive alternatives; however, there is almost no evidence showing that they have greater efficacy than bicarbonate. CarbicarbTM is a mixture of 0.3 M sodium bicarbonate and 0.3 M sodium carbonate; buffering by this mixture mainly produces sodium bicarbonate instead of CO2. Tromethamine has the added advantage of lacking sodium and may be a more effective intracellular buffer.
Patients with chronic respiratory acidosis require special consideration. When such patients develop acute ventilatory failure, the goal of therapy should be to return PaCO2 to the patient’s “normal” baseline. Normalizing the patient’s PaCO2 to 40 mm Hg will produces the equivalent of a respiratory alkalosis (see later discussion). Oxygen therapy must also be carefully controlled, because the respiratory drive in these patients may be dependent on hypoxemia, not PaCO2. “Normalization” of PaCO2 or relative hyperoxia can precipitate severe hypoventilation.
Metabolic acidosis is defined as a primary decrease in [HCO3−]. Pathological processes can initiate metabolic acidosis by one of three mechanisms: (1) consumption of HCO3− by a strong nonvolatile acid, (2) renal or gastrointestinal wasting of bicarbonate, or (3) rapid dilution of the extracellular fluid compartment with a bicarbonate-free fluid.
A fall in plasma [HCO3−] without a proportionate reduction in PaCO2 decreases arterial pH. The pulmonary compensatory response in a simple metabolic acidosis (see preceding discussion) characteristically does not reduce PaCO2 to a level that completely normalizes pH but nevertheless can produce marked hyperventilation (Kussmaul’s respiration).
Table 50–4 lists disorders that can cause metabolic acidosis. Note that differential diagnosis of metabolic acidosis may be facilitated by calculation of the anion gap.
TABLE 50–4Differential diagnosis of metabolic acidosis. ||Download (.pdf) TABLE 50–4 Differential diagnosis of metabolic acidosis.
Increased anion gap
Normal anion gap (hyperchloremic)
Increased gastrointestinal losses of HCO3−
Anion exchange resins (cholestyramine)
Ingestion of CaCl2, MgCl2
Fistulas (pancreatic, biliary, or small bowel)
Ureterosigmoidostomy or obstructed ileal loop
Increased renal losses of HCO3−
Total parenteral nutrition (Cl− salts of amino acids)
Increased intake of chloride-containing acids
The anion gap in plasma is most commonly defined as the difference between the major measured cations and the major measured anions:
Anion gap = ([Na+] − ([Cl−] + [HCO3−])
Some practitioners also include plasma K+ in the calculation. Using normal values,
In reality, an anion gap cannot exist because electroneutrality must be maintained in the body; the sum of all anions must equal the sum of all cations. Therefore,
“Unmeasured cations” include K+, Ca2+, and Mg2+, whereas “unmeasured anions” include all organic anions (including plasma proteins), phosphates, and sulfates. Plasma albumin normally accounts for the largest fraction of the anion gap (approximately 11 mEq/L). The anion gap decreases by 2.5 mEq/L for every 1 g/dL reduction in plasma albumin concentration. Any process that increases “unmeasured anions” or decreases “unmeasured cations” will increase the anion gap. Conversely, any process that decreases “unmeasured anions” or increases “unmeasured cations” will decrease the anion gap.
Mild elevations of plasma anion gap up to 20 mEq/L may not be helpful diagnostically during acidosis, but values greater than 30 mEq/L usually indicate the presence of a high anion gap acidosis. Metabolic alkalosis can also produce a high anion gap because of extracellular volume depletion, an increased charge on albumin, and a compensatory increase in lactate production. A low plasma anion gap may be encountered with hypoalbuminemia, bromide or lithium intoxication, and multiple myeloma.
High Anion Gap Metabolic Acidosis
Metabolic acidosis with an increased anion gap is characterized by an increase in relatively strong nonvolatile acids. These acids dissociate into H+ and their respective anions; the H+ consumes HCO3− to produce CO2, whereas their anions (conjugate bases) accumulate and take the place of HCO3− in extracellular fluid (hence the anion gap increases). Nonvolatile acids can be endogenously produced or ingested.
A. Failure to Excrete Endogenous Nonvolatile Acids
Endogenously produced organic acids are normally eliminated by the kidneys in urine (as described earlier). Glomerular filtration rates below 20 mL/min (kidney injury or failure) typically result in progressive metabolic acidosis from the accumulation of these acids.
B. Increased Endogenous Nonvolatile Acid Production
Severe tissue hypoxia following hypoxemia, hypoperfusion (ischemia), or an inability to utilize oxygen (cyanide poisoning) can result in lactic acidosis. Lactic acid is the end product of the anaerobic metabolism of glucose (glycolysis) and can rapidly accumulate under these conditions. Decreased utilization of lactate by the liver, and, to a lesser extent by the kidneys, is less commonly responsible for lactic acidosis; causes include hypoperfusion, alcoholism, and liver disease. Lactate levels can be readily measured and are normally 0.3 to 1.3 mEq/L. Acidosis resulting from D-lactic acid, which is not recognized by α-lactate dehydrogenase (and not measured by routine assays), may be encountered in patients with short bowel syndromes; D-lactic acid is formed by colonic bacteria from dietary glucose and starch and is absorbed systemically.
An absolute or relative lack of insulin can result in hyperglycemia and progressive ketoacidosis from the accumulation of β-hydroxybutyric and acetoacetic acids (diabetic ketoacidosis). Ketoacidosis may also be seen following starvation or alcoholic binges. The pathophysiology of the acidosis often associated with severe alcoholic intoxication and nonketotic hyperosmolar coma is complex and may represent a buildup of lactic, keto, or other unknown acids.
Some inborn errors of metabolism, such as maple syrup urine disease, methylmalonic aciduria, propionic acidemia, and isovaleric acidemia, produce a high anion gap metabolic acidosis as a result of accumulation of abnormal amino acids.
C. Ingestion of Exogenous Nonvolatile Acids
Ingestion of large amounts of salicylates may result in metabolic acidosis. Salicylic acid and other acid intermediates rapidly accumulate and produce a high anion gap acidosis. Because salicylates also produce direct respiratory stimulation, most adults develop mixed metabolic acidosis with superimposed respiratory alkalosis. Ingestion of methanol (methyl alcohol) frequently produces acidosis and retinitis. Symptoms are typically delayed until the slow oxidation of methanol by alcohol dehydrogenase produces formic acid, which is highly toxic to the retina. The high anion gap represents the accumulation of many organic acids, including acetic acid. The toxicity of ethylene glycol is also the result of the action of alcohol dehydrogenase to produce glycolic acid. Glycolic acid, the principal cause of the acidosis, is further metabolized to form oxalic acid, which may be deposited in the renal tubules and produce acute kidney injury.
Normal Anion Gap Metabolic Acidosis
Metabolic acidosis associated with a normal anion gap is typically characterized by hyperchloremia. Plasma [Cl−] increases to take the place of the HCO3− ions that are lost. Hyperchloremic metabolic acidosis most commonly results from abnormal gastrointestinal or renal losses of HCO3−, or from excessive intravenous administration of 0.9% NaCl solution.
Calculation of the anion gap in urine can be helpful in diagnosing a normal anion gap acidosis.
Urine anion gap = ([Na+] + [K+]) – [Cl−]
The urine anion gap is normally positive or close to zero. The principal unmeasured urinary cation is normally NH4+, which should increase (along with Cl−) during a metabolic acidosis; the latter results in a negative urinary anion gap. Impairment of H+ or NH4+ secretion, as occurs in kidney failure or renal tubular acidosis (discussed below), results in a positive urine anion gap despite systemic acidosis.
A. Increased Gastrointestinal Loss of HCO3−
Diarrhea is a common cause of hyperchloremic metabolic acidosis. Diarrheal fluid contains 20 to 50 mEq/L of HCO3−. Small bowel, biliary, and pancreatic fluids are all rich in HCO3−. Loss of large volumes of these fluids can lead to hyperchloremic metabolic acidosis. Patients with ureterosigmoidostomies and those with ileal loop neobladders that are too long or that become partially obstructed frequently develop hyperchloremic metabolic acidosis. The ingestion of chloride-containing anion-exchange resins (cholestyramine) or large amounts of calcium or magnesium chloride can result in increased absorption of chloride and loss of bicarbonate ions. The nonabsorbable resins bind bicarbonate ions, whereas calcium and magnesium combine with bicarbonate to form insoluble salts within the intestines.
B. Increased Renal Loss of HCO3−
Renal wasting of HCO3− can occur as a result of failure to reabsorb filtered HCO3− or to secrete adequate amounts of H+ in the form of titratable acid or ammonium ion. These defects are encountered in patients taking carbonic anhydrase inhibitors, such as acetazolamide, and in those with renal tubular acidosis.
Renal tubular acidosis (RTA) is a disease of systemic acidosis resulting from inadequate renal compensation for systemic acid production. The kidneys are unable to adequately acidify the urine, and urinary pH is inappropriately high relative to the systemic acidemia. Kidney function is otherwise normal. RTA involves a defect in distal renal tubular H+ secretion (type 1 RTA), proximal renal tubular reabsorption of filtered HCO3− (type 2 RTA), or both (type 3 RTA). Type 4 RTA is the result of hypoaldosteronism or renal insensitivity to aldosterone.
C. Other Causes of Hyperchloremic Acidosis
Dilutional hyperchloremic acidosis may occur when extracellular volume is rapidly expanded with a bicarbonate-free, chloride-rich fluid such as normal saline. Plasma [HCO3−] decreases in proportion to the amount of fluid infused as extracellular HCO3− is diluted, and this fall in [HCO3−] is compensated by a rise in [Cl−]. This is a reason to prefer balanced salt solutions over 0.9% saline for fluid resuscitation. Amino acid infusions (parenteral hyperalimentation) contain organic cations in excess of organic anions and can produce hyperchloremic metabolic acidosis because chloride is commonly used as the anion for the cationic amino acids. Lastly, the administration of excessive quantities of chloride-containing acids, such as ammonium chloride or arginine hydrochloride (usually given to treat a metabolic alkalosis), can cause hyperchloremic metabolic acidosis.
Treatment of Metabolic Acidosis
Several general measures can be undertaken to control the severity of acidemia until the underlying processes are corrected. Any respiratory component of the acidemia should be corrected. Respiration should be controlled, if necessary; a PaCO2 in the low 30s may be desirable to partially return pH to normal. If arterial blood pH remains below 7.20, alkali therapy, usually in the form of a 7.5% NaHCO3 solution may be necessary. PaCO2 may transiently rise as HCO3− is consumed by acids, emphasizing the need to control ventilation in severe acidemia. The amount of NaHCO3 given is decided empirically as a fixed dose (1 mEq/kg) or is derived from the base excess and the calculated bicarbonate space (discussed next). In either case, serial blood gas measurements are mandatory to avoid complications (eg, overshoot alkalosis and sodium overload) and to guide further therapy. Raising arterial pH above 7.25 is usually sufficient to overcome the adverse physiological effects of the acidemia. Profound or refractory acidemia may require acute hemodialysis with a bicarbonate dialysate.
The routine use of large amounts of NaHCO3 in treating cardiac arrest and low flow states is not recommended. Paradoxical intracellular acidosis may occur, particularly when CO2 elimination is impaired, because the CO2 formed readily enters cells, but the bicarbonate ion does not. Alternate buffers that do not produce CO2, such as Carbicarb or tromethamine (THAM), may be theoretically preferable, but are unproven clinically.
Specific therapy for diabetic ketoacidosis includes replacement of the existing fluid deficit resulting from a hyperglycemic osmotic diuresis first, as well as insulin, potassium, phosphate, and magnesium. The treatment of lactic acidosis should be directed first at restoring adequate oxygenation and tissue perfusion. Alkalinization of the urine with NaHCO3 to a pH greater than 7.0 increases elimination of salicylate following salicylate poisoning. Treatment options for methanol or ethylene glycol intoxication include ethanol infusion or fomepizole administration, which competitively inhibit alcohol dehydrogenase and hemodialysis or hemofiltration.
The bicarbonate space is defined as the volume to which HCO3− will distribute when administered intravenously. Although this theoretically should equal the extracellular fluid space (approximately 25% of body weight), in reality, it ranges anywhere between 25% and 60% of body weight, depending on the severity and duration of the acidosis. This variation is at least partly related to the amount of intracellular and bone buffering that has taken place.
Example: Calculate the amount of NaHCO3 necessary to correct a base deficit (BD) of –10 mEq/L for a 70-kg man with an estimated HCO3− space of 30%:
NaHCO3 = BD × 30% × body weight in L
NaHCO3 = –10 mEq/L × 30% × 70 L = 210 mEq
In practice, only 50% of the calculated dose (eg., 105 mEq) is usually given, after which another blood gas is measured.
ANESTHETIC CONSIDERATIONS IN PATIENTS WITH ACIDOSIS
Acidemia can potentiate the depressant effects of most sedatives and anesthetic agents on the central nervous and circulatory systems. Because most opioids are weak bases, acidosis can increase the fraction of the drug in the nonionized form and facilitate opioid penetration into the brain, potentiating its sedative effect. The circulatory depressant effects of both volatile and intravenous anesthetics can also be exaggerated. Moreover, any agent that rapidly decreases sympathetic tone can potentially allow unopposed circulatory depression in the setting of acidosis. Halothane is more arrhythmogenic in the presence of acidosis. Succinylcholine should generally be avoided in acidotic patients with hyperkalemia to prevent further increases in plasma [K+].