Step 1: Classify pH

The normal limits for arterial pH in humans are 7.35 to 7.45. This range is not affected by age or gender. An arterial pH greater than 7.45 is called alkalemia, and a pH less than 7.35 is called acidemia. If the pH is classified as abnormal, one determines whether the abnormality is of respiratory or nonrespiratory (metabolic) origin.

Step 2: Analyze Respiratory Involvement (PaCO₂)

The PaCO₂ is controlled by alveolar ventilation and is thus the indicator of respiratory involvement. The normal range for PaCO₂ in humans is 35 to 45 mm Hg and is not affected by age or gender; high and low PaCO₂ values are called hypercapnia and hypocapnia. The PaCO₂ is analyzed, keeping the pH (step 1) in mind. A PaCO₂ greater than 45 mm Hg means blood H⁺ levels (from dissociated carbonic acid) are abnormally high; this is compatible with acidemia and hypoventilation. A PaCO₂ less than 35 mm Hg has the opposite meaning; it is compatible with alkalemia and hyperventilation. If the pH is abnormal, the following question should be asked: Could the observed PaCO₂ help explain the pH abnormality? For example, if the pH is 7.50 (alkalemia) and the PaCO₂ is 30 mm Hg (hyperventilation), the respiratory system must be at least partly, if not entirely, responsible for the alkalemia.

Step 3: Analyze Nonrespiratory (Metabolic) Involvement ([HCO₃⁻])

Because it is primarily determined by nonrespiratory, or so-called metabolic factors, plasma bicarbonate concentration is the logical indicator of nonrespiratory involvement in acid-base disturbances. The normal range for arterial plasma [HCO₃⁻] in humans is 22 to 26 mEq/L and is unaffected by age or gender. Bicarbonate is a chemical base; high plasma bicarbonate (>26 mEq/L) is compatible with alkalemia, and low plasma bicarbonate (<22 mEq/L) is compatible with acidemia.

Plasma [HCO₃⁻] is not as specific and accurate in indicating metabolic acid-base disturbances as PaCO₂ is in indicating respiratory disturbances. The reason is that plasma bicarbonate responds slightly to pure respiratory (i.e., PCO₂) changes. The carbon dioxide hydration reaction explains this phenomenon. As explained in Chapter 10, an acute increase in PaCO₂ of 10 mm Hg increases [HCO₃⁻] by about 1 mEq/L. Thus, the plasma [HCO₃⁻] must be evaluated with caution; if it falls outside of the normal range but the abnormality can be explained by the effect of the carbon dioxide hydration reaction, the [HCO₃⁻] level is not responsible for any existing acid-base disorder.

Keeping the foregoing limitation in mind, the [HCO₃⁻] is inspected and compared with the pH. If the pH is abnormal, one must ask: Can the observed [HCO₃⁻] explain the pH abnormality? For example, if the arterial pH is 7.25 (acidemia) and [HCO₃⁻] is low (18 mEq/L), this is compatible with acidemia. Therefore, metabolic (nonrespiratory) factors are at least partly, if not entirely, responsible for the acidosis.

Step 4: Assess for Compensation

When the acid-base abnormality has been identified as either respiratory or metabolic, the degree of compensation present, if any, must be determined. In other words, if a respiratory acidosis exists (increased PaCO₂), have the kidneys compensated by elevating the plasma [HCO₃⁻]? Conversely, if a metabolic acidosis exists (decreased HCO₃⁻), have the lungs compensated by hyperventilating and lowering the PaCO₂?

If the pH has been restored to the normal range (7.35 to 7.45), full compensation has occurred even though pH remains on the acid or alkaline side of the range. Compensation is partial if the pH is still outside of the normal range but the noncausative component (either PaCO₂ or HCO₃⁻) is also abnormal in a way that brings the pH back toward the normal range. A compensated acid-base disturbance is sometimes referred to as a chronic acidemia or chronic alkalemia because a certain amount of time is required to bring about compensation. Partial compensation means compensatory activity has begun but has not had enough time to restore the pH to normal. The term uncompensated means the acid-base disturbance is of such recent origin that compensatory activity has not yet started. Therefore, an uncompensated condition is sometimes called an acute acidemia or acute alkalemia.

It is assumed that compensation for a primary acid-base disorder is never truly complete in the sense of restoring arterial pH all the way to 7.40.³ In a compensated disorder, the pH is on the acid or alkaline side of the normal range, depending on whether the primary causative disorder created an acidosis or an alkalosis. That is, if the pH is on the acid side of normal (<7.40 but at least ≥7.35), the main cause of the original acid-base imbalance is the component (PaCO₂ or HCO₃⁻) that, by itself, would cause an acidosis. For example, if the pH is 7.36, PaCO₂ is 80 mm Hg, and HCO₃⁻ is 44 mEq/L, compensation is present because the pH is in the normal range, although it is on the acid side of normal. The primary cause of the original acid-base disturbance (before compensatory activity started) must be the factor that would produce acidemia (i.e., the increased PaCO₂ of 80 mm Hg). Thus, this set of blood gases would be classified as compensated (chronic) respiratory acidosis. The primary disturbance is of respiratory origin, and the increased [HCO₃⁻] is a secondary metabolic compensatory response. The reason the pH is on the acid side of the normal range is that the body generally does not overcompensate; it does not increase the [HCO₃⁻] so much that it converts the previously acidotic environment to one with a pH on the alkaline side of normal. Conversely, if the pH is 7.15, PaCO₂ is 80 mm Hg, and HCO₃⁻ is 26 mEq/L, no compensation has occurred; that is, HCO₃⁻ is still normal, not elevated as would be expected if compensatory action were underway.

Compensatory activity does not correct the primary acid-base disturbance; the primary defect is still present. Compensatory activity merely works to restore the pH to the normal range. Table 13-1 summarizes acid-base and ventilatory classification. Table 13-2 classifies the degree of compensation for acid-base disturbances.

Causes

Hypoventilation causes hypercapnia, which implies inadequate ventilation. Any process that hinders alveolar ventilation can

cause respiratory acidosis. Chronic obstructive pulmonary disease (COPD) is the most frequent cause of respiratory acidosis, mostly because the airways resistance of a patient with severe COPD is so high that the patient cannot sustain the ventilatory work required to maintain a normal PaCO₂.³ Central nervous system depression (drug-induced), extreme obesity (impaired diaphragmatic movement), and neuromuscular disorders (spinal cord lesions, paralytic neuromuscular diseases) are other causes of hypoventilation and respiratory acidosis. Hypercapnia may occur in different ways. A person may have an absolute decrease in ventilation because of drug-induced central nervous system depression, or a patient with COPD and a limited ventilatory reserve may sustain a normal PaCO₂ at rest but may not accommodate the increased carbon dioxide production associated with increased physical activity.

Uncompensated hypercapnia implies the presence of acute ventilatory failure; the resulting respiratory acidosis is manifested by a low arterial pH, increased PaCO₂, and normal or slightly high [HCO₃⁻]. In this situation, a slightly increased [HCO₃⁻] is not a sign that the kidneys have started compensatory activity; it merely reflects the effect of the carbon dioxide hydration reaction on [HCO₃⁻] (see Chapter 10).

Compensation

Renal (kidney) compensation for respiratory acidosis begins as soon as PaCO₂ increases. The kidney reclaims HCO₃⁻ from the renal tubular filtrate, returning it to the blood. The arterial pH is brought into the normal range because the [HCO₃⁻]-dissolved carbon dioxide ratio is restored near its normal 20:1 range (see Chapter 10). However, this process cannot keep pace with an acutely increasing PaCO₂. Full compensation may take several days.

Over the course of developing COPD, a person’s PaCO₂ increases gradually, allowing the compensatory process enough time to keep pace with the rising PaCO₂. The arterial pH is thus maintained in the normal range. Partly compensated respiratory acidosis is characterized by increased PaCO₂, increased [HCO₃⁻], and an acid pH still not quite in the normal range. A compensated respiratory acidosis is characterized by a pH on the acid side of the normal range (<7.40 but at least ≥7.35), increased PaCO₂, and increased [HCO₃⁻]. The high [HCO₃⁻] in the presence of a high PaCO₂ is a sign that the PaCO₂ has been elevated for a considerable time (i.e., the kidneys have had sufficient time to compensate). Thus, compensated respiratory acidosis is synonymous with chronic ventilatory inadequacy. Although the pH is in the normal range, the underlying pathological process that produces hypercapnia is still present; the kidneys simply mask the problem by maintaining a normal pH range. Because hypercapnia persists, the term acidosis is retained in classifying this condition (compensated respiratory acidosis). This term emphasizes that lung function is still abnormal and has the potential to produce an acidosis.

Clinical Manifestations

Patients with neuromuscular weakness or mechanical breathing difficulties usually breathe shallowly and rapidly and are short of breath; they are often anxious and in obvious distress. Drug-induced central nervous system depression produces slow, shallow breathing and possibly apnea. Acute respiratory acidosis produces more serious physiological consequences than chronic respiratory acidosis. Rapidly increasing PaCO₂ causes cerebral vasodilation and increased intracranial pressure (ICP), possibly leading to retinal venous distention and retinal hemorrhages; in addition, the patient may develop myoclonus (spasmodic muscle jerks), asterixis (a hand-flapping tremor in which the patient cannot keep the wrists flexed with the arms extended), and mental confusion.³ An abrupt onset of hypercapnia in which PaCO₂ rises beyond 70 mm Hg can lead to coma, although patients with chronic hypercapnia can tolerate much higher PaCO₂ values.³ Hypercapnia increases the cardiac output and dilates peripheral vessels, often resulting in a bounding pulse and warm, flushed skin.

Correction

The corrective action in acute respiratory acidosis is to restore alveolar ventilation. Various respiratory therapy modalities ranging from secretion mobilization and bronchodilator drugs to endotracheal intubation and mechanical ventilation may be

needed to restore ventilation. However, if hypoventilation is chronic and compensation has restored arterial pH to the normal range, corrective action aimed at reducing the PaCO₂ is inappropriate and possibly harmful. In this situation, a rapidly decreasing PaCO₂ induces a sudden alkalosis because of renal compensation and elevated blood HCO₃⁻ levels.

Causes

Hyperventilation causes hypocapnia. Any process in which ventilatory elimination of carbon dioxide exceeds its production causes respiratory alkalosis. Causes can be divided into three categories: (1) hypoxia, (2) pulmonary diseases, and (3) central nervous system diseases. Probably the most common cause of hyperventilation in patients with pulmonary disease is arterial hypoxemia, mediated through the peripheral chemoreceptors.³ Hypoxia-induced respiratory alkalosis can be caused by high altitude or pulmonary diseases characterized by intrapulmonary shunting (e.g., pneumonia, pulmonary edema). Other pulmonary diseases associated with hyperventilation and respiratory alkalosis include interstitial fibrosis, pulmonary embolism, and acute asthma. J-receptor stimulation in the lung parenchyma may be involved in interstitial diseases, pneumonia, and pulmonary edema. The feeling of dyspnea from high airways resistance and resulting anxiety is a probable mechanism for respiratory alkalosis in acute asthma. General anxiety, fever, stimulating drugs, pain, and injuries of the central nervous system are other possible causes of hyperventilation.

Hyperventilation and respiratory alkalosis also may be iatrogenically induced (i.e., induced by health care personnel). Iatrogenic hyperventilation is most commonly associated with overly aggressive mechanical ventilation; it may also be associated with aggressive deep breathing and lung-expanding respiratory therapy procedures. Acute respiratory alkalosis is characterized by decreased PaCO₂, a high pH, and normal-range [HCO₃⁻]. An extremely slight decrease in [HCO₃⁻] is expected to be present as a result of the hydration reaction’s effect.

Clinical Manifestations

An early sign of acute respiratory alkalosis (hypocapnia) is paresthesia, a numb or tingling sensation in the extremities; light-headedness may also occur. Severe hyperventilation and alkalosis is associated with hyperactive reflexes, muscle

cramping of the hands or feet (carpopedal spasm), and possibly tetanic convulsions (a fusion of many muscle spasms producing a sustained contraction without relaxation). The low PaCO₂ level may constrict cerebral vessels enough to impair cerebral circulation, causing light-headedness, dizziness, and syncope (fainting). If respiratory alkalosis is anxiety-induced, the patient may show signs of panic and express feelings of impending doom. Vision may become impaired (tunnel vision), and speaking may become difficult.³

Compensation

The kidneys compensate for respiratory alkalosis by excreting HCO₃⁻ in the urine (bicarbonate diuresis). This activity brings the arterial pH down toward the normal range because the [HCO₃⁻]-dissolved carbon dioxide ratio is restored near its normal 20:1 range. However, renal compensation rarely causes [HCO₃⁻] to fall below 18 mEq/L.³ Renal compensation is a relatively slow process; it may take days until the compensation process is finally completed.

Partially compensated respiratory alkalosis is characterized by decreased PaCO₂, decreased [HCO₃⁻], and an alkaline pH that is still not quite down in the normal range. Compensated respiratory alkalosis is characterized by decreased PaCO₂, decreased [HCO₃⁻], and pH on the alkaline side of normal (pH >7.40 but ≤7.45). Compensated respiratory alkalosis is sometimes called chronic respiratory alkalosis or chronic alveolar hyperventilation. The underlying hyperventilation and hypocapnia are still present. Thus, the term alkalosis is used in classifying this condition, although the pH is in the normal range.

Correction

Respiratory alkalosis is corrected by removing the stimulus causing the hyperventilation. If hypoxemia is the stimulus, oxygen therapy is administered. If the cause is iatrogenic, the therapy causing the hyperventilation is reduced or eliminated. In patients with severe anxiety, reassurance and rebreathing exhaled air (breathing into a paper bag) to increase PaCO₂ may be effective.

Alveolar Hyperventilation Superimposed on Compensated Respiratory Acidosis

A patient with advanced but stable COPD and compensated respiratory acidosis may exhibit the following arterial blood gas values:

The HCO₃⁻ level is high because of renal compensatory activity. If the person now experiences an acute exacerbation of disease and becomes severely hypoxic, this may stimulate the peripheral chemoreceptors enough to increase alveolar ventilation and acutely decrease PaCO₂ despite the patient’s deranged lung mechanics.

In this case, let us assume that the patient was incapable of hyperventilating enough to decrease PaCO₂ all the way down into the normal range. Although PaCO₂ is still above normal, the acute lowering of the PaCO₂ coupled with the preexisting high compensatory level of HCO₃⁻ causes the pH to swing from the acidic to the alkalotic side of normal, as the following values illustrate:

If one pays attention to only the blood gas data and applies the strict criteria for interpretation as outlined earlier in this chapter, one would arrive at the completely incorrect interpretation of compensated metabolic alkalosis. This interpretation would lead the novice to conclude that the patient is hypoventilating to compensate for a preexisting primary metabolic alkalosis; in light of this patient’s medical history, this would be an absurd conclusion. This example illustrates the fact that blood gas data alone are an insufficient basis for rational acid-base assessment. The patient’s medical history, the physical examination, and the nature of the current problem are vital in accurately evaluating blood gas abnormalities. The above-listed blood gases are correctly described as acute

hyperventilation superimposed on compensated respiratory acidosis.

Causes

Metabolic acidosis can occur in two general ways: (1) the accumulation of fixed (nonvolatile) acid in the blood or (2) an excessive loss of HCO₃⁻ from the body. For example, a lack of blood flow leads to tissue hypoxia, anaerobic metabolism, and production of lactic acid (a fixed acid). The resulting accumulation of hydrogen ions reacts with bicarbonate ions, lowering the blood [HCO₃⁻], producing nonrespiratory or metabolic acidosis. Another example is severe diarrhea, in which large stores of HCO₃⁻ are lost from the bowel, again producing nonrespiratory acidosis.

Because of their different causative mechanisms, these two types of metabolic acidosis are treated differently; the identification of the underlying mechanism is necessary to treat metabolic acidosis effectively. The analysis of plasma electrolytes—specifically, the so-called anion gap—is helpful in determining whether metabolic acidosis was caused by a gain of fixed acids or by a loss of base.

Anion Gap

The law of electroneutrality states that the total number of positive charges in the body fluids must equal the total number of negative charges. Plasma cations (positively charged ions) are exactly balanced by anions (negatively charged ions); that is, the plasma has no net electrical charge. The routinely measured plasma electrolytes (cations and anions) in clinical medicine include only Na⁺, K⁺, Cl⁻, and HCO₃⁻, although body fluids contain many other cations and anions. The normal plasma concentrations of these routinely measured electrolytes are such that the cations (Na⁺ and K⁺) outnumber the anions (Cl⁻ and HCO₃⁻), causing what seems to be an anion gap. Generally, K⁺ is ignored in calculating the anion gap because of its very low concentration:

Aniongap(mEq/L)=[Na+]−([Cl−]+[HCO3−])

The “anion gap” can be thought of as a measure of the concentrations of other anions in the plasma besides Cl⁻ and HCO₃⁻. Figure 13-2, A, shows that normal concentrations of the routinely measured electrolytes in the plasma are about 140 mEq/L for Na⁺, 105 mEq/L for Cl⁻, and 24 mEq/L for HCO₃⁻, producing an apparent anion gap of 11 mEq/L (140 − [105 + 24] = 11). The normal range for the anion gap is 8 to 16 mEq/L.³ Because [Na⁺] exceeds ([Cl⁻] + [HCO₃⁻]), the unmeasured anions must outnumber the unmeasured cations (see Figure 13-2, A). Therefore, the anion gap also can be thought of as the difference between the unmeasured anions and unmeasured cations:

Aniongap=unmeasuredanions−unmeasuredcations

If total anion and cation concentrations each equal 154 mEq/L (see Figure 13-2, A), there are normally 14 mEq/L of unmeasured cations and 25 mEq/L of unmeasured anions. Figure 13-2, A, shows that the anion gap is 11 mEq/L:

Aniongap=25(unmeasuredanions)−14(unmeasuredcations)=11mEq/L

Metabolic acidosis caused by an accumulation of fixed acids in the body increases the anion gap (>16 mEq/L). The hydrogen ions of these fixed acids react with HCO₃⁻, lowering its concentration in the plasma. This leads to an increased number of unmeasured anions; that is, when HCO₃⁻ buffers the fixed acid’s H⁺, the anion portion of the fixed acid remains in the plasma, increasing the unmeasured anion concentration (see Figure 13-2, B). Therefore, a high anion gap indicates the fixed acid concentration has increased in the body. The patient’s clinical history and current status help clarify which type of acid this may be. For example, in severe shock, tissue hypoxia may generate lactic acid. A history of diabetes is consistent with ketoacid formation. A history of kidney failure is consistent with uremic acidosis.

Metabolic acidosis caused by HCO₃⁻ loss from the body does not produce an increased anion gap because HCO₃⁻ loss is accompanied by Cl⁻ gain, keeping the anion gap within normal limits (see Figure 13-2, C). The law of electroneutrality helps explain the reciprocal nature of [HCO₃⁻] and [Cl⁻] in this situation. With a constant cation concentration, the loss of HCO₃⁻ means another anion must be gained to maintain electroneutrality. In this situation, the kidney increases its reabsorption of the most abundant anion in the tubular filtrate, Cl⁻. (This disturbance in electroneutrality does not occur when fixed acids accumulate and are buffered by HCO₃⁻ because no anions are actually lost from the body in that situation.) The type of metabolic acidosis in which HCO₃⁻ is lost from the body is sometimes called hyperchloremic acidosis because of the characteristic increase in plasma [Cl⁻] that occurs. Examples of conditions in which HCO₃⁻ is lost or Cl⁻ is gained include severe diarrhea and pancreatic fistulas. A fistula is an abnormal tubelike channel connecting one body cavity to another (in this situation, abnormally connecting the pancreas to the intestinal tract). Pancreatic juice is fairly alkaline, as are all intestinal fluids below the stomach.² Thus much bicarbonate can be lost during prolonged diarrhea. Box 13-2 summarizes causes of anion gap and non–anion gap metabolic acidosis.

Compensation

Hyperventilation is the essential compensatory mechanism for metabolic acidosis. Plasma HCO₃⁻ buffers the increased plasma [H⁺] of metabolic acidosis, depleting the plasma [HCO₃⁻]. In response, HCO₃⁻ diffuses out of the cerebrospinal fluid (CSF) into the blood, lowering the CSF pH, which stimulates the central chemoreceptors. Peripheral chemoreceptors are also directly stimulated by increased plasma [H⁺]. The end result is increased ventilation and lowered volatile acid (H₂CO₃) and dissolved carbon dioxide levels in the blood. The [HCO₃⁻]-dissolved carbon dioxide ratio is thus restored toward a normal 20:1 ratio, normalizing the pH. The peripheral chemoreceptor response to metabolic acidosis is rapid. Uncompensated metabolic acidosis is therefore rare, and its presence implies a ventilatory defect; that is, metabolic acidosis accompanied by a normal PaCO₂ means the lungs are unable to respond appropriately to chemoreceptor stimulation. The defect may lie in nerve impulse transmission, the respiratory muscles, or the lungs.

Clinical Manifestations

Metabolic acidosis generally causes a great increase in minute ventilation. Patients may complain of dyspnea and, in extreme acidosis, may descend into a stupor and coma.³ Hyperpnea (increased tidal volume depth) is a common finding on physical examination. In severe metabolic acidosis (e.g., diabetic ketoacidosis), an extremely deep, gasping type of breathing develops, called Kussmaul’s respiration.

Arterial pH values less than 7.00 to 7.10 predispose the heart to potentially fatal ventricular arrhythmias and can reduce not only heart muscle contractility but also the heart’s ability to increase its contractile force in response to the body’s secretion of catecholamines, such as epinephrine.³ Neurological symptoms range from lethargy to coma in severe metabolic acidosis (see Figure 13-1).

Correction

The initial goal in treating severe acidemia is to raise the arterial pH above 7.2, a level at which serious cardiac arrhythmias are less likely, contractility is restored, and responsiveness to catecholamines improves.² If increased ventilation maintains the pH at or above this level, immediate corrective action is usually not indicated. Treatment should be focused on correction of the underlying metabolic disorder. For example, in diabetic acidosis, insulin is given; in shock-induced lactic acidosis, measures are taken to improve blood pressure and cardiac output.

Historically, sodium bicarbonate (NaHCO₃) was routinely infused during cardiac arrest to combat the lactic acidosis of tissue hypoxia; this practice has generally been discontinued. The 2010 American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend against the routine use of NaHCO₃ in cardiac arrest because of the lack of evidence showing improved survival, and because of the negative side effects of NaHCO₃, which include intracellular acidosis, cardiac arrhythmias, and inhibited hemoglobin release of oxygen.⁴ The AHA maintains that rapid return of spontaneous circulation (ROSC) through effective cardiopulmonary resuscitation is the mainstay of restoring acid-base balance during cardiac arrest. Rapid correction of arterial pH to values greater than 7.20 by NaHCO₃ infusion can be harmful for the following reasons: when HCO₃⁻ buffers H⁺, the hydration reaction moves to the left, rapidly producing carbon dioxide, which quickly diffuses across the blood-brain barrier into the CSF. Because blood HCO₃⁻ cannot follow carbon dioxide across the blood-brain barrier, the CSF rapidly becomes more acidic, possibly aggravating the neurological symptoms (coma) of metabolic acidosis.² The decreased CSF pH increases central chemoreceptor stimulation, causing the successfully resuscitated patient to hyperventilate, which coupled with the prior NaHCO₃ infusion may rapidly swing the previously acidotic arterial pH into an alkalotic range. In the same way, carbon dioxide produced by the buffering action of NaHCO₃ diffuses rapidly across all cell membranes, including the cell membranes of the heart; this may precipitate cardiac arrhythmias.³ Intracellular pH generally tends to decrease with the rapid infusion of NaHCO₃ because carbon dioxide diffuses across cell membranes into the cell much more rapidly than bicarbonate ions.³ The 2010 AHA Guidelines list special circumstances in which NaHCO₃ infusion may be beneficial during cardiac arrest such as in patients with preexisting metabolic acidosis, and in patients with severe hyperkalemia (high plasma potassium concentration).

Causes

Metabolic alkalosis can occur in two general ways: (1) loss of fixed acids or (2) gain of blood buffer base. Both processes produce an increased plasma [HCO₃⁻]. It is easy to understand why plasma [HCO₃⁻] increases if it is ingested or administered intravenously. It is not as apparent why [HCO₃⁻] increases when fixed acids are lost from the body. For an explanation of this phenomenon, consider a situation in which vomiting or nasogastric suction removes gastric hydrochloric acid (HCl) from the body (Figure 13-3). In response to HCl loss, H⁺ diffuses out of the gastric cell, accompanied by Cl⁻ from the blood. The loss of H⁺ forces the carbon dioxide hydration reaction in the gastric cell to the right, which generates HCO₃⁻; the HCO₃⁻ ion diffuses into the blood in exchange for Cl⁻. Thus, the plasma gains a bicarbonate ion for each chloride ion (or hydrogen ion) lost (see Figure 13-3).⁵

Box 13-3 summarizes the causes of metabolic alkalosis. Increased HCO₃⁻ ingestion rarely causes metabolic alkalosis because the normal kidney can rapidly excrete large amounts of HCO₃⁻ in the urine.² Metabolic alkalosis is most often caused by the loss of gastric acid through protracted vomiting or continuous nasogastric suctioning.³ It is also caused by hypochloremia (low plasma [Cl⁻]) and hypokalemia (low plasma [K⁺]). Metabolic alkalosis is quite common in acutely ill patients and probably the most complicated acid-base imbalance to treat because it involves fluid and electrolyte imbalances. Many causes of metabolic alkalosis are iatrogenic, resulting from the use of diuretics, low-salt diets, and nasogastric drainage.

The mechanisms by which volume depletion, hypokalemia, and hypochloremia produce alkalosis are discussed in Chapter 22. Briefly, the kidney’s strong stimulus to reabsorb Na⁺ from the renal tubule filtrate is predominant over its need to maintain chloride, potassium, or acid-base balance. A low plasma [Cl⁻] (hypochloremia) produces a low tubular filtrate Cl⁻ concentration; this presents a special problem because chloride ions must accompany sodium ions when they are reabsorbed from the tubular filtrate. If chloride ions are scarce (as may be induced by diuretic therapy, low-salt diets, or gastric HCl loss), the kidney reabsorbs Na⁺ by secreting abnormally large amounts of H⁺ and K⁺ into the filtrate. In other words, these ions are secreted in exchange for Na⁺ to maintain electroneutrality of the filtrate. This process leads to alkalosis (H⁺ loss) and hypokalemia

(K⁺ loss). Volume depletion (hypovolemia) induced by diuretics exaggerates alkalosis and hypokalemia because hypovolemia profoundly increases the kidney’s Na⁺ reabsorption stimulus.

Compensation

The expected respiratory response to metabolic alkalosis is hypoventilation and carbon dioxide retention. This response

occurs because alkalemia eventually leads to CSF alkalosis, decreasing the stimulation of central chemoreceptors. During hypoventilation, the increase in PaCO₂ increases the plasma carbonic acid concentration, offsetting the metabolically generated alkalosis. On average, the PaCO₂ increases about 0.7 mm Hg for every 1-mEq/L increase in plasma [HCO₃⁻].⁶

Traditionally, the belief was that the hypoxemia induced by hypoventilation limited respiratory compensation for metabolic alkalosis. In other words, as P_ACO₂ increases during hypoventilation, P_AO₂ decreases, leading to hypoxemia, which would stimulate peripheral chemoreceptors and counteract compensatory hypoventilation. However, more recent evidence contradicts this theory; alkalosis blunts the sensitivity of the carotid bodies to hypoxemia (see Chapter 11). Alkalemic patients with PaO₂ values less than 50 mm Hg may hypoventilate to PaCO₂ values much greater than 60 mm Hg.⁶

Underlying pulmonary disease may also limit compensatory hypoventilation in metabolic alkalosis. Pulmonary edema, fibrosis, vascular congestion, and inflammatory processes such as pneumonia stimulate intrapulmonary irritant receptors in airway walls and J-receptors in the alveolar interstitium. Such stimulation causes tachypnea and hyperventilation, which may limit compensatory hypoventilation and carbon dioxide retention.2,6 Other factors that tend to limit compensatory hypoventilation for metabolic alkalosis include anxiety, pain, infection, and fever.

Symptoms

Symptoms directly related to metabolic alkalemia are most likely related to causative factors (e.g., volume depletion [weakness and dizziness on standing] and hypokalemia [muscle weakness and high urine output]). As with respiratory alkalosis, patients may exhibit hyperactive reflexes, muscle cramping, and possibly tetanic convulsions.³ Similar to acidosis, severe alkalosis may also induce cardiac arrhythmias. Alkalosis, whether of respiratory or metabolic origin, promotes the movement of K⁺ into the cells, creating a hypokalemia that also can contribute to cardiac arrhythmias.

Correction

Corrective action is aimed at the underlying causes of metabolic alkalosis (e.g., restoring normal fluid volume, potassium, and chloride levels). After these fluids and electrolytes are restored to normal levels, the kidney can reabsorb Na⁺ normally (i.e., Cl⁻ can be reabsorbed with Na⁺). The kidney does not need to reabsorb HCO₃⁻ with Na⁺ as it did when Cl⁻ was scarce; this allows excess HCO₃⁻ to be excreted in the urine. Restoring plasma K⁺ levels causes K⁺ to diffuse into the red blood cells in exchange for H⁺, which moves out of the cell into the plasma. This reciprocal shift of K⁺ and H⁺ helps bring the plasma pH back toward normal.²

In extremely severe metabolic alkalosis (pH >7.55), acidifying agents such as dilute HCl or ammonium chloride may be infused intravenously.³ (The liver metabolizes NH₄Cl, producing HCl.)

Standard Bicarbonate

The standard bicarbonate (SB) laboratory procedure was developed to eliminate the respiratory component’s (PaCO₂) effect on [HCO₃⁻]. SB is defined as the plasma [HCO₃⁻] measured at 37° C after a laboratory blood sample has been exposed to and equilibrated with a gas having a PCO₂ of 40 mm Hg; this eliminates the effect of an abnormal PaCO₂ on [HCO₃⁻]. If an abnormal [HCO₃⁻] (<22 mEq/L or >26 mEq/L) persists in the presence of a PCO₂ of 40 mm Hg, a metabolic acid-base disturbance is theoretically present.

SB has shortcomings as a purely metabolic index. The laboratory (in vitro) process of bringing the blood sample’s PCO₂ to 40 mm Hg creates an artificial condition not present in the patient’s body (in vivo conditions). For example, if a patient has an increased PaCO₂, this would increase plasma [HCO₃⁻] slightly as a result of the hydration reaction. This increased plasma [HCO₃⁻] would establish equilibrium with the fluid outside of the blood capillaries (extravascular fluid). The fluid outside of the capillaries would develop an equally increased [HCO₃⁻]. If the patient increased the alveolar ventilation, bringing the PaCO₂ back down to 40 mm Hg, the hydration reaction would reverse directions, and the plasma [HCO₃⁻] would decrease slightly. Consequently, the extravascular HCO₃⁻ would diffuse back into the capillary until equilibrium is reestablished between intravascular and extravascular [HCO₃⁻]. These exchanges between intravascular and extravascular fluid cannot take place in laboratory conditions. When PCO₂ of a laboratory blood sample is artificially lowered to 40 mm Hg, plasma [HCO₃⁻] decreases, as it would in the body, but extravascular HCO₃⁻ is not present and cannot diffuse into the plasma as it does in the body; this in vivo–in vitro discrepancy is a limitation of the SB measurement.

Base Excess

Similar to the SB measurement, the base excess (BE) is also obtained by exposing a blood sample in the laboratory to a gas with a constant PCO₂ of 40 mm Hg at 37° C. When the blood sample PCO₂ is brought to 40 mm Hg, the sample pH changes. In the next step of the procedure, the blood gas machine calculates the milliequivalents of acid or base needed to bring the blood sample pH to 7.40, holding the pH constant at 40 mm Hg. The first step (bringing the blood sample PCO₂ to 40 mm Hg) theoretically eliminates any respiratory contribution to the acid-base imbalance, whereas the second step quantifies the amount of base that must be removed or added to the blood to bring its pH to 7.40. If the pH of the original blood sample rose above 7.40 (became alkalotic) after the sample PCO₂ was brought to 40 mm Hg, a nonrespiratory (metabolic) process must be responsible for the alkalosis. The milliequivalents of strong acid required to bring the blood pH to 7.40 is exactly equal to the milliequivalents of excess base the original blood sample contained. This calculated BE is reported in milliequivalents per liter (mEq/L). If the blood sample pH fell after it was exposed to a PCO₂ of 40 mm Hg, the blood gas machine computes the quantity of strong base needed to bring the blood pH up to 7.40, which would be exactly equal to the amount of base the original blood sample lacked (base deficit).

By convention, BE is reported as either a positive or a negative number; a positive BE indicates an alkalosis of metabolic origin, and a negative BE indicates an acidosis of metabolic origin. Normal BE is ±2 mEq/L. The BE determination has the same limitations as the SB; in vitro conditions differ from in vivo conditions, and the same discrepancy occurs.

The use of BE to determine whether acid-base disturbances are metabolic in origin can be easily misinterpreted. For example, in a patient with compensated respiratory acidosis, the arterial blood has a high PaCO₂, which is compensated by a high [HCO₃⁻] that keeps arterial pH in the normal range. In determining the BE, high PaCO₂ of this patient’s blood sample is abruptly reduced to 40 mm Hg in the laboratory, which produces an alkalotic pH because the blood [HCO₃⁻] is still high; large amounts of acid must be titrated to bring the blood sample pH to 7.40. This process may lead some clinicians to believe that too much base is present in the blood, which might be incorrectly interpreted as a primary metabolic alkalosis that requires treatment. The high BE in this case would simply be a reflection of secondary renal compensation, not a primary metabolic alkalosis.

Expected pH Relationships

Table 13-3 illustrates acute PaCO₂ and pH relationships. If PaCO₂ changes suddenly as a result of an acute ventilatory change, the subsequent change in pH must be caused by the change in PaCO₂ (i.e., a respiratory change). The expected pH for a given acute change in PaCO₂ can be precisely predicted using the Henderson-Hasselbalch equation. Table 13-3 illustrates this relationship. If PCO₂ acutely increases by 20 mm Hg, the pH should decrease by (20 × 0.006), or 0.12 units, producing an expected pH of 7.28 (i.e., [7.40 − 0.12] = 7.28). This calculated expected pH differs from the actual measured blood pH only if a metabolic acid-base disturbance is present. For example, if the actual measured pH is more acidic than the calculated expected pH, nonrespiratory metabolic factors are causing the acidosis. Likewise, if the actual measured pH is more alkalotic than the expected pH, the alkalosis must be of metabolic origin. The following pH formulas can be derived from Table 13-3 and used to determine whether a measured abnormal pH is strictly due to the abnormal PCO₂ or whether the abnormal pH is partly due to nonrespiratory (metabolic) factors:

ExpectedpH=7.40+(40mmHg−measuredPaCO2)0.01

ExpectedpH=7.40−(measuredPaCO2−40mmHg)0.006

If expected and measured pH values are identical, the metabolic status must be normal. If the two pH values are not equal, metabolic factors must be involved in the acid-base imbalance. A normal metabolic status is present if the measured and calculated pH values are within ±0.03 units of each other.

Independent Variables That Affect [H⁺]: [SID], [A_TOT], and [CO₂]

Stewart distinguished between independent and dependent variables involved in [H⁺] regulation. He showed through a series of complex equations that the [H⁺] of a solution is a dependent variable determined solely by three independent variables:⁹ (1) strong ion difference [SID]; (2) total concentration of nonvolatile weak acids [A_TOT]; and (3) dissolved [CO₂], which is a function of PCO₂. The [SID] is the summative difference between the concentrations of all strong cations (positively charged ions) and all strong anions (negatively charged ions) in body fluids; for clinical purposes, [SID] = ([Na⁺] + [K⁺] + [Ca⁺⁺] + [Mg⁺⁺]) − ([Cl⁻] + [unidentified strong anions]).^8,9 Normal body fluids contain more strong cations than strong anions⁸; the [SID] thus represents a net positive charge that must be balanced by weak anions in solution, as explained in the following paragraphs. The kidneys are responsible for maintaining a normal [SID] of about 40 to 42 mEq/L, primarily by excreting or reabsorbing Na⁺, K⁺, and Cl⁻ ions.

Stewart’s theory of acid-base assessment rests on three basic assumptions about physiological solutions:³ (1) All solutions must obey the powerful principle of electrical neutrality; that is, the sum of all strong and weak cations must equal the sum of all strong and weak anions. (2) All weak nonvolatile acids in body fluids attain equilibrium with their dissociated ions according to their equilibrium constants (law of mass action). (3) The total amount of a substance in solution must remain constant unless it is added, removed, generated, or destroyed (conservation of mass).

The principle of electrical neutrality demands that the normal [SID] of body fluids, which represents a net positive charge, must be equal to the net negative charge of all weak anions in solution, that is, anions contributed by volatile and nonvolatile weak acids.⁸ This principle means that normally the [SID] is equal to [HCO₃⁻] + [A⁻], or, stated differently, the [SID] is equal to the sum of the bicarbonate [HCO₃⁻] and nonbicarbonate [A⁻] buffers, or the total buffer base (see Chapter 10). The number of weak anions supplied by volatile acid (i.e., HCO₃⁻ originating from H₂CO₃) is determined by the independent variable, PCO₂, which is controlled by ventilation. The number of weak anions supplied by all nonvolatile weak acids is determined by the dissociation constant (temperature dependent) of the independent variable [A_TOT]. The total amount of nonvolatile weak acid present ([A_TOT]) at any given time is constant, such that [A_TOT] = [H⁺] + [A⁻], where the universal symbols H⁺ and A⁻ represent dissociated weak acid molecules. All weak acids in the plasma can be treated as a single acid because they are in equilibrium with the same solution; the dissociation of this combined weak acid group is represented by HA H⁺ + A⁻, which has an apparent dissociation constant that determines the number of weak anions contributed by [A_TOT] in balancing the positive [SID].

At any given time, PaCO₂ is determined by ventilation, and the dissociation of [A_TOT] is determined by its apparent dissociation constant. With these two independent variables predetermined, a change in the [SID] generates powerful electrochemical forces that cause H₂O molecules to dissociate or reassociate in a way that maintains electrical neutrality. In this way, changes in the [SID] affect the solution’s [H⁺]; a decrease in the [SID] (a decrease in net positive charges) increases H₂O dissociation, liberating more H⁺ to maintain electrical neutrality, whereas an increase in the [SID] (an increase in net positive charges) has the opposite effect.⁸ (This is consistent with a decrease or increase in total buffer base.)

Determinants of Metabolic Acid-Base Balance: [SID] and [A_TOT]

In Stewart’s system, metabolic (nonrespiratory) acid-base disturbances can be caused only by changes in [SID] and nonvolatile weak acid concentration [A_TOT], not by changes in [HCO₃⁻]. Stewart asserts that [HCO₃⁻] and [H⁺] are dependent variables, that is, dependent on the [SID], [A_TOT], and PCO₂. In this scheme, the kidneys manipulate the [SID] to change the plasma [H⁺] by excreting or reabsorbing Na⁺, K⁺, and Cl⁻. The kidneys place priority on keeping [Na⁺] constant to maintain intravascular volume. [K⁺], [Ca⁺⁺], and [Mg⁺⁺] do not vary enough to affect the [SID] significantly; the kidneys change the [SID] primarily by excreting or reabsorbing Cl⁻ ions.⁸ With a constant [Na⁺], an increase in plasma [Cl⁻] reduces the [SID], causing hyperchloremic acidosis, whereas a decrease in plasma [Cl⁻] causes hypochloremic alkalosis; these changes cause equal magnitude losses and gains in [HCO₃⁻]. Thus, in responding to metabolic acid-base disturbances, the kidney does not manipulate the HCO₃⁻ ion; instead it regulates the [SID], primarily by controlling [Cl⁻].

This perspective is a departure from the Henderson-Hasselbalch concept of acid-base balance in which [HCO₃⁻] is treated as though it varies independently of dissolved [CO₂], independently influencing pH or [H⁺]. However, in reality, [HCO₃⁻] and [CO₂] cannot vary independently of each other as the CO₂ hydration reaction clearly shows; instead, both [HCO₃⁻] and [H⁺] depend on [CO₂]:⁹

Changes in [HCO₃⁻] cannot cause changes in [H⁺]; changes in [HCO₃⁻] and [H⁺] are merely correlated with each other. Therefore, it would seem that [HCO₃⁻] cannot be a valid indicator of metabolic acid-base disturbances.

Clinical Practicality of Strong Ion Approach

The complex nature of the equations involved in Stewart’s strong ion approach make this method clinically unwieldy; knowledge of protein and phosphate concentrations is required for accurate acid-base assessment. PCO₂ and pH can be easily and directly measured in the clinical setting, and [HCO₃⁻] can be calculated with sufficient precision using the Henderson-Hasselbalch equation; there is no need to calculate [HCO₃⁻] and pH from the concentrations of electrolytes and weak acids, which are often unknown.³ Although the strong ion approach is a more conceptually correct approach, it is not sufficiently superior to the Henderson-Hasselbalch approach in the clinical context to merit its universal adoption. It is reasonable and clinically appropriate to explain metabolic acid-base physiology in terms of [H⁺] and [HCO₃⁻] from the Henderson-Hasselbalch perspective.^3,8,10 Hence, the traditional approach is retained in this book.

Hypoxic Hypoxia (Decreased P_AO₂)

Hypoxic hypoxia refers to mechanisms that decrease the alveolar PO₂ (see Table 13-4). These mechanisms (hypoventilation, shunt, V./Q. mismatch, and high-altitude breathing) were discussed in detail in Chapter 12. In shunt, the PO₂ of collapsed or otherwise airless alveoli is effectively 0 mm Hg, reducing the overall average P_AO₂. Likewise, in V./Q. mismatch, P_AO₂ of underventilated lung regions is low, reducing the mean P_AO₂. Alveolar hypoxia produces low PaO₂ values, leading to low arterial oxygen content and reduced oxygen delivery to the tissues. As discussed in Chapter 12, the effectiveness of oxygen therapy is limited in shunt because the added oxygen cannot reach collapsed alveoli. Treatment in this situation must be aimed at reopening and ventilating collapsed alveoli.

Anemic Hypoxia (Decreased Hemoglobin Concentration)

Anemia refers to low amounts of functional hemoglobin in the blood; this can be caused by the loss of hemoglobin (hemorrhage), decreased red blood cell production, abnormal hemoglobin production, or inability of the hemoglobin molecule to bind chemically with oxygen. All forms of anemia reduce the blood’s oxygen-carrying capacity and reduce oxygen delivery to the tissues. Carbon monoxide poisoning produces a functional anemia by aggressively binding with the hemoglobin molecule, rendering it unable to bind oxygen.

Carbon monoxide poisoning occurs in the setting of smoke inhalation from house fires, automobile exhaust, or poorly ventilated charcoal fires or gas furnaces. Oxygen therapy cannot add much oxygen to the blood because the available functional hemoglobin is already almost 100% saturated with room air breathing. Nevertheless, oxygen breathing hastens the displacement of carbon monoxide from the hemoglobin molecule, and the administration of 100% inspired oxygen is extremely important in treating carbon monoxide poisoning. The ideal treatment of this condition involves hyperbaric oxygen therapy, in which the individual’s body is placed in an oxygen-enriched environment pressurized above atmospheric pressure (i.e., a hyperbaric oxygen chamber). In this way, PaO₂ and the amount of oxygen dissolved in the plasma can be raised far above values achievable while breathing 100% oxygen at atmospheric pressure; this significantly increases the total amount of oxygen the blood can carry. In addition, the extremely high plasma oxygen pressure facilitates the release of carbon monoxide by the hemoglobin molecule, shortening the half-life of carbon monoxide. Severe anemia caused by blood loss or decreased red blood cell production may be treated by blood transfusion (see Chapter 8).

Stagnant Hypoxia (Decreased Blood Flow)

Low blood flow and blood pressure—that is, low oxygen-delivery rate—are general features of shock. Low blood flow may be caused by cardiac (pump) failure or by low blood volume (hypovolemia) caused by hemorrhage or severe dehydration. In such instances, lung function and arterial oxygen content may be completely normal, but reduced blood flow greatly decreases oxygen transport to the tissues. Oxygen therapy is of little benefit because arterial oxygen content is almost at its maximal level while the patient is breathing room air; that is, the only possible increase in blood oxygen content is the small additional amount that dissolves in the plasma. However, in patients with coronary artery disease and myocardial tissue hypoxia (ischemia), this small increase in dissolved oxygen may be critical in preventing myocardial tissue death (infarction); thus, oxygen therapy is always given to patients in cardiogenic shock. An extreme example of stagnant hypoxia is cardiac arrest. In cardiac arrest, even a small increase in arterial oxygen content is vitally important. Thus, 100% oxygen is routinely given during cardiopulmonary resuscitation. The focus in treating shock-induced tissue hypoxia is generally the restoration of adequate blood flow.

Histotoxic Hypoxia (Blocked Oxidative Metabolism)

Histotoxic hypoxia refers to poisoning of the cellular oxygen use mechanisms. Cyanide poisoning is the typical example of histotoxic hypoxia. Cyanide combines with and inactivates cellular enzymes necessary for oxidative metabolism. Cyanide poisoning often occurs with carbon monoxide poisoning in the setting of smoke inhalation from house fires.¹¹ High blood lactic acid levels with high mixed venous oxygen content are evidence that cellular oxygen consumption has been blocked and should raise the suspicion of cyanide poisoning. Treatment includes administration of 100% oxygen and inhaled amyl nitrite and intravenous sodium nitrite, which convert hemoglobin to methemoglobin; methemoglobin is an effective scavenger of free cyanide molecules.¹¹

Diffusion Defects

Conditions that increase the diffusion pathway distance across the alveolar capillary membrane include pulmonary edema and processes leading to interstitial alveolar fibrosis. Normally, capillary blood and alveolar gas PO₂ values equilibrate in the first one third of the time required to travel through the alveolar capillary. Thickened membranes require longer equilibrium times, and during exercise, equilibrium may not occur, leading to arterial hypoxemia (see Chapter 7). The contribution of diffusion defects to arterial hypoxemia when the patient is at rest is uncertain; the major mechanism is probably uneven ventilation-perfusion relationships caused by regional differences in lung compliance secondary to nonuniform distribution of lung disease.⁷ For this reason, some physiologists classify diffusion defects in the hypoxic hypoxia category. Increased F_IO₂ is helpful in treating diffusion defects because the increased diffusion gradient greatly enhances oxygen transfer across the alveolar capillary membrane into the blood.

Clinical Signs and Symptoms

If hemoglobin concentration and cardiac output are normal, PaO₂ must acutely decrease to less than 50 to 60 mm Hg before clinical manifestations appear.⁷ At this PaO₂, most people experience mild nausea, light-headedness, and dizziness. These symptoms do not necessarily occur in slowly progressing, chronic hypoxemia of equal severity. In chronic hypoxemia, the body compensates by producing more erythrocytes, increasing the CaO₂.

In acute hypoxemia in the range of 50 to 60 mm Hg, peripheral chemoreceptor stimulation increases minute ventilation, although dyspnea is generally not perceived. PaO₂ values from 35 to 50 mm Hg cause mental confusion; PaO₂ less than 35 mm Hg causes decreased renal blood flow and cardiac conduction disturbances. This level of hypoxemia causes maximal minute ventilation and severe lethargy. Loss of consciousness and respiratory center depression occur at PaO₂ values less than 25 mm Hg.¹² In the presence of anemia or cardiac insufficiency, these manifestations become apparent at higher PaO₂ values. Box 13-4 summarizes clinical signs and symptoms of acute hypoxemia from mild to severe conditions. Tissues with high oxygen consumption requirements, such as brain, heart, and kidney cells, are the most susceptible to hypoxia. A total lack of oxygen causes irreversible brain cell injury or death in minutes.

Normal PaO₂ at High Altitude

Altitude also affects normal, expected PaO₂. High altitude decreases barometric pressure and therefore it decreases inspired PO₂. Up to an altitude of 10,000 feet above sea level, barometric pressure decreases about 24 mm Hg per 1000 feet of elevation.¹ For example, in Denver, Colorado, where the elevation is 5280 feet, barometric pressure is about 633 mm Hg. At 10,000 feet elevation, barometric pressure is only 523 mm Hg.

The general formula for changing observed sea-level PaO₂ values to PaO₂ values at a different barometric pressure is as follows:

ExpectedPO2athighaltitude=(highaltitudebarometricpressure/760mmHg)×sea−levelPO2

According to this calculation, if normal sea-level PaO₂ is 95 mm Hg, normal PaO₂ in Denver is about 79 mm Hg; at 10,000 feet elevation, normal PaO₂ is only 65 mm Hg.

Severity of Arterial Hypoxemia

Table 13-5 arbitrarily classifies the severity of arterial hypoxemia. Traditionally, only PaO₂ is classified in evaluating oxygenation. (Corresponding SaO₂ values are included in Table 13-5.) Both CaO₂ and cardiac output (i.e. oxygen delivery) are essential in evaluating oxygenation. (These factors are discussed later in this chapter.) Table 13-5 assumes a normal cardiac output and blood hemoglobin content.

Mild hypoxemia is generally well tolerated and not associated with tissue hypoxia; hemoglobin saturation is 90% or greater. Moderate hypoxemia requires an increased cardiac output to maintain adequate oxygen delivery to the tissues. A failing or compromised heart may be unable to meet this challenge, leading to tissue hypoxia. Even a normal heart and an increased cardiac output would probably not sustain adequate oxygen delivery to the tissues in severe hypoxemia (PaO₂ values <40 mm Hg). Hypoxemia in this range invariably leads to tissue hypoxia and lactic acidosis. Severe hypoxemia requires immediate therapy because at this level of PaO₂, heart and brain cells may be permanently injured within minutes.

Indicators of Oxygen Transfer Efficiency

P(A-a)O₂, PaO₂/P_AO₂, and PaO₂/F_IO₂ are indicators of the lung’s efficiency in transferring oxygen from alveolar gas to capillary blood. The advantages and disadvantages of these indicators are reviewed in Chapter 12. All of these indicators are sensitive to the degree of intrapulmonary shunt present, although PaO₂/P_AO₂ is the most stable and reliable in this regard. Calculating the intrapulmonary shunt fraction using the classic shunt equation is the most accurate way to quantify the degree of shunt present (see Chapter 12).

The greater the shunt, the less effective oxygen therapy will be. Shunting leads to refractory hypoxemia, which means therapy must be focused on reopening and oxygenating airless alveoli.

Through observation of the PaO₂ response to increased F_IO₂, shunt can be differentiated from V._A/Q._C mismatch as the major cause of hypoxemia (see Chapter 12). If PaO₂ is low but oxygenation efficiency indicators and shunt fraction are normal, overall hypoventilation may be the cause of hypoxemia; this would be confirmed by an increased PaCO₂, reciprocally related to PaO₂.

Effect of Cardiac Output on PaO₂

Changes in cardiac output do not significantly affect PaO₂ or CaO₂ of individuals with a normal intrapulmonary shunt fraction (3% to 5%). However, as mentioned in Chapter 12, a decrease in cardiac output can significantly lower CaO₂ and PaO₂ in persons with increased shunt fractions because it lowers Cv¯O₂ and Pv¯O₂. Likewise, an increase in cardiac output can mask the hypoxemic effects of shunt by increasing Cv¯O₂ and Pv¯O₂.

The foregoing becomes clear when one considers the fact that arterial blood is a mixture of blood draining both normally oxygenated alveoli and airless alveoli (shunt units) (Figure 13-4, A and B). Shunted blood is actually unoxygenated venous blood. This blood mixes directly with the oxygenated blood that leaves ventilated alveoli. Low cardiac output reduces the mixed venous oxygen content and lowers the oxygen content of the shunted blood (see Figure 13-4, B). In this way, a reduced cardiac output decreases CaO₂ and PaO₂ as the more profoundly hypoxemic shunted blood mixes with arterial blood.

However, the normal response to increased shunting is an increase, not a decrease, in cardiac output. This increase in cardiac output increases Cv¯O₂, preventing a more severe decrease in CaO₂ than would occur if cardiac output remains normal. A sudden decrease in PaO₂ with a stable pulmonary oxygenation status (e.g., shunt fraction remains constant) suggests a reduction in cardiac output.

CLINICAL FOCUS 13-11   Differentiating Pulmonary and Cardiovascular Oxygenation Defects

You are caring for two patients in the intensive care unit. Patient A is recovering from an emergency appendectomy and has a history of chronic bronchitis. Patient B has been admitted for management of an acute myocardial infarction (heart attack).

Patient A Data (Room Air)

PaO₂ = 50 mm Hg

PaCO₂ = 30 mm Hg

pH = 7.47

[HCO₃⁻] = 21 mEq/L

SaO₂ = 83%

Hb = 15 g/dL

CaO₂ = 16.8 mL oxygen/dL

P(A-a)O₂ = 63.7

CO = 4.8 L/min

Sv¯O₂ = 70%

Pv¯O₂ = 38 mm Hg

Cv¯O₂ = 14.2 mL oxygen/dL

Patient B Data (Room Air)

PaO₂ = 98 mm Hg

PaCO₂ = 40 mm Hg

pH = 7.38

[HCO₃⁻] = 23 mEq/L

SaO₂ = 99%

Hb = 15 g/dL

CaO₂ = 20.2 mL oxygen/dL

P(A-a)O₂ = 3.7

CO = 3.1 L/min

Sv¯O₂ = 55%

Pv¯O₂ = 29 mm Hg

Cv¯O₂ = 11.1 mL oxygen/dL

Discussion

At first glance, one notices that patient B has a higher PaO₂ and CaO₂ than patient A, breathing the same F_IO₂. Both patients have the same hemoglobin concentration. Pulmonary oxygenation defects are characterized by large P(A-a)O₂ differences, indicating impaired oxygen transfer from the lungs to the blood. Patient A has impaired oxygen transfer, whereas patient B’s oxygen transfer is normal. (Patient A’s hypoxemia is probably stimulating ventilation, creating a decreased PaCO₂ and respiratory alkalosis.) If the data are not examined further, the conclusion may be drawn (incorrectly) that patient B is better oxygenated than patient A.

The Fick equation is helpful in examining the amount of oxygen delivered to the tissues each minute by patient A and patient B:

Patient A:

O2DEL=(16.8mLoxygen/dL×10)×4.8L/min

O2DEL=806mLoxygen/min

Patient B:

O2DEL=(20.1mLoxygen/dL×10)×3.1L/min

O2DEL=623mL/min

Despite clearly superior PaO₂ and CaO₂, patient B delivers less oxygen to the tissues each minute than patient A. The key difference is the cardiac output. Although patient B does not have an oxygen-transfer problem in the lung, he has an oxygen-delivery problem. The low Pv¯O₂ of 29 mm Hg and high arterial venous oxygen content difference of 9 mL oxygen/dL are signs of low cardiac output. In patient B, blood spends more time in tissue capillary beds and gives up more oxygen than in patient A. The important clinical point is that oxygenation involves pulmonary and cardiovascular systems; the contribution of each must be critically evaluated to assess overall oxygenation.