Physiological Effects of Acidemia
[H+] is strictly regulated in the nanomole/liter (36–43 nmol/L) range, 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. Biochemical reactions are very sensitive to changes in [H+]. The overall effects of acidemia seen in patients represent the balance between its direct biochemical effects and the effects of acidemia-induced sympathoadrenal activation. With severe acidosis (pH < 7.20), direct depressant effects predominate. 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 threshold for ventricular fibrillation is decreased. Progressive hyperkalemia as a result of the movement of K+ out of cells in exchange for extracellular H+ 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 CO2narcosis. 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
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. 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 50–3 Causes of Respiratory Acidosis. ||Download (.pdf)
Table 50–3 Causes of Respiratory Acidosis.
- Central nervous system depression
- Sleep disorders
- Obesity hypoventilation (Pickwickian) syndrome
- Cerebral ischemia
- Cerebral trauma
- Neuromuscular disorders
- Chest wall abnormalities
- Flail chest
- Pleural abnormalities
- Pleural effusion
- Airway obstruction
- Upper airway
- Foreign body
- Sleep disorders
- Lower airway
- Severe asthma
- Chronic obstructive pulmonary disease
- Parenchymal lung disease
- Pulmonary edema
- Pulmonary emboli
- Interstitial lung disease
- Ventilator malfunction
|Increased CO2 production|
- Large caloric loads
- Malignant hyperthermia
- Intensive shivering
- Prolonged seizure activity
- Thyroid storm
- Extensive thermal injury (burns)
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 above). 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
“Full” renal compensation characterizes chronic respiratory acidosis. Renal compensation is appreciable only after 12–24 hr and may not peak until 3–5 days. During that time, the sustained increase in Paco2 has been present long enough to permit maximal renal compensation.
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 tetanus, antithyroid medication for thyroid storm, and reduced caloric intake in patients receiving 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 (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 <7.10 and HCO3− is <15 mEq/L. Sodium bicarbonate therapy will transiently increase Paco2:
Buffers that do not produce CO2, such as CarbicarbTM 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 a baseline 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 below). 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 above) characteristically does not reduce Paco2 to a level that completely normalizes pH but 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 50–4 Causes of Metabolic Acidosis. ||Download (.pdf)
Table 50–4 Causes of Metabolic Acidosis.
|Increased anion gap|
- Increased production of endogenous nonvolatile acids
- Renal failure
- Lactic acidosis
- Nonketotic hyperosmolar coma
- Inborn errors of metabolism
- Ingestion of toxin
- Ethylene glycol
|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−
- Renal tubular acidosis
- Carbonic anhydrase inhibitors
- Large amount of bicarbonate-free fluids (eg, 0.9% NaCl)
- Total parenteral nutrition (Cl− salts of amino acids)
- Increased intake of chloride-containing acids
- Ammonium chloride
- Lysine hydrochloride
- Arginine hydrochloride
The anion gap in plasma is most commonly defined as the difference between the major measured cations and the major measured anions:
Anion gap = major plasma cations - major plasma anions
Some physicians include plasma K+ in the calculation. Using normal values,
Anion gap = 140 - (104 + 24) = 12 mEq/L × (normal range = 7 - 14 mEq/L)
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,
Anion gap = unmeasured anions - unmeasured cations
“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 (about 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 >30 mEq/L usually indicate the presence of a high anion gap acidosis (below). 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.
Failure to Excrete Endogenous Nonvolatile Acids
Endogenously produced organic acids are normally eliminated by the kidneys in urine (above). Glomerular filtration rates below 20 mL/min (renal failure) typically result in progressive metabolic acidosis from the accumulation of these acids.
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 0.3–1.3 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. Ketoacidosis may also be seen following starvation and alcoholic binges. The pathophysiology of the acidosis often associated with severe alcoholic intoxication and nonketotic hyperosmolar coma is complex and may represent a build-up 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.
Ingestion of Exogenous Nonvolatile Acids
Ingestion of large amounts of salicylates frequently results 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 visual disturbances (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 can be deposited in the renal tubules and result in renal failure.
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 renal failure or renal tubular acidosis (below), results in a positive urine anion gap in spite of systemic acidosis.
Increased Gastrointestinal Loss of HCO3−
Diarrhea is a common cause of hyperchloremic metabolic acidosis. Diarrheal fluid contains 20–50 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 loops 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. These nonabsorbable resins bind bicarbonate ions, whereas calcium and magnesium combine with bicarbonate to form insoluble salts within the intestines.
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 comprises a group of nonazotemic defects of H+ secretion by the renal tubules, resulting in a urinary pH that is too high for the systemic acidemia. These defects may be a result of a primary renal defect or may be secondary to a systemic disorder. The site of the H+-secreting defect may be in the distal (type 1) or proximal (type 2) renal tubule. Hyporeninemic hypoaldosteronism is commonly referred to as type 4 renal tubular acidosis. With distal renal tubular acidosis, the defect occurs at a site after most of the filtered HCO3− has been reclaimed. As a result, there is a failure to acidify the urine, so that net acid excretion is less than the daily net acid production. This disorder is frequently associated with hypokalemia, demineralization of bone, nephrolithiasis, and nephrocalcinosis. Alkali (NaHCO3) therapy (1–3 mEq/kg/d) is usually sufficient to reverse those side effects. With the less common proximal renal tubular acidosis, defective H+ secretion in the proximal tubule results in massive wasting of HCO3−. Concomitant defects in tubular reabsorption of other substances, such as glucose, amino acids, or phosphates, are common. The hyperchloremic acidosis results in volume depletion and hypokalemia. Treatment involves giving alkali (as much as 10–25 mEq/kg per day) and potassium supplements.
Other Causes of Hyperchloremic Acidosis
A dilutional hyperchloremic acidosis can occur when extracellular volume is rapidly expanded with a bicarbonate-free fluid, such as normal saline. This is a reason to prefer balanced salt solutions over 0.9% saline for fluid resuscitation. The plasma HCO3− decreases in proportion to the amount of fluid infused as extracellular HCO3− is diluted. 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 NaHCO3 (usually a 7.5% 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 (see below). 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 to >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 CarbicarbTM or tromethamine (THAM), may be theoretically preferable, but are unproven clinically.
Specific therapy for diabetic ketoacidosis includes replacement of the existing fluid deficit (as a result of 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 ethanol 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 it is given 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 (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 penetration of the opioid into the brain. Increased sedation and depression of airway reflexes may predispose to pulmonary aspiration. 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+].