Acid-Base Disorders

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12 Acid-Base Disorders

Conventional wisdom posits that acid-base disorders are more important for what they tell the clinician about the patient than for any harm that happens to the patient as a direct consequence of abnormal blood (or tissue) pH. This view is reasonable because most acid-base disorders are mild and well tolerated, but they allow the astute clinician to recognize underlying disorders that might be difficult to diagnose or even suspect otherwise. However, there are certain circumstances in which acid-base derangements are themselves dangerous, such as when the disorders are extreme (e.g., pH <7.0 or >7.7), especially when the acid-base derangement develops quickly. Such severe abnormalities can be the direct cause of organ dysfunction and can manifest as cerebral edema, seizures, decreased myocardial contractility, pulmonary vasoconstriction, and/or systemic vasodilation. Even less extreme derangements can produce harm because of the patient’s response to the abnormality. For example, a spontaneously breathing patient with metabolic acidosis will attempt to compensate by increasing minute ventilation. The workload imposed by increasing minute ventilation can lead to respiratory muscle fatigue, with respiratory failure or diversion of blood flow from vital organs to the respiratory muscles, resulting in organ injury. Acidemia can promote the development of cardiac dysrhythmias in critically ill patients or increase myocardial oxygen demand in patients with myocardial ischemia. In such cases, one must treat the underlying disorder and also provide treatment for the acid-base disorder itself. Finally, emerging evidence suggests that changes in acid-base status influence immune effector cell function. Thus, avoiding acid-base derangements could influence outcome by modulating systemic inflammation and/or host defenses against infection.

General Principles

Three widely accepted methods are used to analyze and classify acid-base disorders, yielding mutually compatible results. The approaches differ only in assessment of the metabolic component (i.e., all three treat PCO₂ as an independent variable): (1) HCO₃⁻ concentration ([HCO₃⁻]); (2) standard base-excess; (3) strong ion difference. All three yield virtually identical results when used to quantify the acid-base status of a given blood sample.¹^–⁴ For the most part, the differences among these three approaches are conceptual; in other words, they differ in how they approach the understanding of mechanism.⁵^–⁷

There are three mathematically independent determinants of blood pH:

1 The difference between the sum of the concentrations of strong cations (e.g., Na⁺, K⁺) and the sum of the concentrations of strong anions (e.g., Cl⁻, lactate); this difference is called the strong ion difference (SID).

2 The total weak acid “buffers” concentration (A_TOT), which is mostly composed of the concentrations of albumin and phosphate.

3 PCO₂.

Only these three variables (SID, A_TOT, and PCO₂) can independently affect blood pH. [H⁺] and [HCO₃⁻] are dependent variables, being functions of SID, A_TOT, and PCO₂.

Changes in plasma [H⁺] result from dissociation of A_TOT and possibly water itself. The standard base-excess is mathematically equivalent to the change in SID required to restore pH to 7.4, given a PCO₂ of 40 mm Hg and the prevailing A_TOT. Thus, a standard base-excess of −10 mEq/L means that the SID is 10 mEq/L less than the SID that is associated with a pH of 7.4 when PCO₂ is 40 mm Hg.

Assessing Acid-Base Balance

Acid-base homeostasis is defined by the pH of blood plasma and by the conditions of the acid-base pairs that determine it. Because blood plasma is an aqueous solution containing both volatile (carbon dioxide) and fixed acids, its pH will be determined by the net effects of all these components. The determinants of blood pH can be grouped into two broad categories, respiratory and metabolic. Respiratory acid-base disorders are disorders of carbon dioxide (CO₂) tension, and metabolic acid-base disorders comprise all other conditions affecting the pH. This latter category includes disorders of both weak acids (often referred to as “buffers,” although the term is imprecise) and strong acids and bases (including both organic and inorganic acids). Acid-base disorders can be recognized by any of the following:

1 An alteration in the pH of the arterial blood (normally 7.35-7.45). If the pH is <7.35, acidemia is said to be present; if the pH is >7.45, alkalemia is said to be present.

2 An arterial partial pressure of CO₂ (PaCO₂) outside the normal range (35 to 45 mm Hg).

3 A plasma bicarbonate concentration outside the normal range (22-26 mEq/L).

4 An arterial standard base-excess of 3 or −3 mEq/L.

Although these criteria are useful in identifying an acid-base disorder, the absence of all four cannot exclude a mixed acid-base disorder—that is, alkalosis and acidosis that are completely matched. Fortunately, such conditions are quite rare.

Metabolic Acid-Base Disorders

Metabolic acid-base derangements are associated with a greater number of underlying conditions than are respiratory acid-base disorders and tend to be more difficult to treat. Metabolic acidosis is produced by a decrease in SID, which in turn generates an electrochemical force that increases [H⁺]. The SID decreases when the concentration of organic anions (e.g., lactate, β-hydroxybutyrate) increases. The SID also decreases when there is a loss of sodium bicarbonate (e.g., due to diarrhea or renal tubular acidosis) or there is a gain of exogenous anions (e.g., iatrogenic acidosis, poisonings). Metabolic alkaloses occur when SID is inappropriately wide, although it need not be greater than the “normal” 40 to 42 mEq/L. Widening of SID can be brought about by the loss of strong anions in excess of strong cations (e.g., vomiting, diuretics), or (rarely) by administration of strong cations in excess of strong anions (e.g., transfusion of large volumes of banked blood containing sodium citrate).

Pathophysiology of Metabolic Acid-Base Disorders

Disorders of metabolic acid-base balance occur as a result of:

1 Dysfunction of the primary regulating organs.

2 Exogenous administration of drugs or fluids that alter the body’s ability to maintain normal acid-base balance.

3 Abnormal metabolism that overwhelms the normal defense mechanisms.

The organs responsible for regulating SID in both health and disease are the kidneys and, to a lesser extent, the gastrointestinal (GI) tract.

The Kidneys

Normal plasma flow to the kidneys is approximately 600 mL/min in adults. The glomeruli filter the plasma to yield about 120 mL/min of filtrate. Normally, more than 99% of the filtrate is reabsorbed and returned to the plasma. Thus, the kidney can only excrete a very small amount of strong ions into the urine each minute, and several minutes to hours are required to achieve a significant impact on SID. The handling of strong ions by the kidney is extremely important because every Cl⁻ ion that is filtered but not reabsorbed decreases SID. Accordingly, “acid handling” by the kidney is generally mediated through changes in Cl⁻ balance. The purpose of renal ammoniagenesis is to allow the excretion of Cl⁻ without Na⁺ or K⁺. Viewed this way, renal tubular acidosis can be regarded as an abnormality of Cl⁻ handling rather than of H⁺ or HCO₃⁻ handling.³

Renal-Hepatic Interaction

Ammonium ion (NH₄⁺) is important to systemic acid-base balance not because it stores H⁺ or has a direct action in the plasma (normal plasma NH₄⁺ concentration is <0.01 mEq/L). NH₄⁺ is important because it is “co-excreted” with Cl⁻. Of course, NH₄⁺ is not only produced in the kidney. Hepatic ammoniagenesis (and, as we shall see, glutaminogenesis) is also important for systemic acid-base balance and is tightly controlled by mechanisms sensitive to plasma pH.⁸ This reinterpretation of the role of NH₄⁺ in acid-base balance is supported by the evidence that hepatic glutaminogenesis is stimulated by acidosis.⁹ Glutamine is used by the kidney to generate NH₄⁺ and thus facilitates the excretion of Cl⁻. The production of glutamine, therefore, can be seen as having an alkalinizing effect on plasma pH because of the way the kidney utilizes it.

The Gastrointestinal Tract

Different parts of the GI tract handle strong ions in distinct ways. In the stomach, Cl⁻ is pumped out of the plasma and into the lumen, thereby reducing the SID and pH of gastric juice. The pumping action of the gastric parietal cells increases SID of the plasma by promoting the loss of Cl⁻; this effect produces the so-called alkaline tide at the beginning of a meal when gastric acid secretion is maximal.¹⁰ In the duodenum, Cl⁻ is reabsorbed and the plasma pH is restored. Normally, only slight changes in plasma pH are evident because Cl⁻ is returned to the circulation almost as soon as it is removed. However, if gastric secretions are removed from the patient, either through a suction catheter or as a result of vomiting, Cl⁻ is lost and SID increases. It is important to realize that it is the Cl⁻ loss, not the H⁺ loss, that is the cause for widening of the SID and the development of metabolic alkalosis. Although H⁺ is “lost” as HCl, it is also lost with every molecule of water removed from the body.

In contrast to the stomach, the pancreas secretes fluid into the small intestine that has a SID much greater than that of plasma; the [Cl⁻] of pancreatic secretions is quite low. Thus, SID in the plasma perfusing the pancreas decreases, a phenomenon that peaks about an hour after a meal and helps counteract the alkaline tide. If large amounts of pancreatic fluid are lost, for example from surgical drainage, acidosis develops as a consequence of decreased plasma SID. Fluid in the lumen of the large intestine has a wide SID because most of the Cl⁻ has been removed in the small intestine, and the remaining electrolytes are mostly Na⁺ and K⁺ and HCO₃⁻. The body normally reabsorbs much of the water and electrolytes from this fluid, but when there is severe diarrhea, large amounts of this HCO₃⁻-rich and Cl⁻-poor fluid can be lost. If these losses are persistent, plasma SID decreases and acidosis results.

In addition, the small intestine may contribute strong ions to the plasma. This effect is most apparent when mesenteric blood flow is compromised and lactate is produced, sometimes in large quantities, by the tissues of the small intestine.

Metabolic Acidosis

Traditionally, metabolic acidoses are categorized according to the presence or absence of unmeasured anions. The presence of unmeasured anions is routinely inferred by measuring the concentrations of electrolytes in plasma and calculating the anion gap, as described later. The differential diagnosis for a positive–anion gap (AG) acidosis is shown in Box 12-1. Non–anion gap acidoses can be divided into three types: renal, GI, and iatrogenic (Figure 12-1). In the intensive care unit (ICU), the most common types of metabolic acidosis include lactic acidosis, ketoacidosis, iatrogenic acidosis, and acidosis secondary to toxins.

Figure 12-1 Differential diagnosis for a hyperchloremic metabolic acidosis. GI, gastrointestinal; SID, Strong ion difference.

The potential effects of metabolic acidosis and alkalosis on vital organ function are shown in Table 12-1. Metabolic and respiratory acidosis may have different implications with respect to survival, an observation that suggests that the underlying disorder is perhaps more important than the absolute degree of acidemia.¹¹

TABLE 12-1 Potential Clinical Effects of Metabolic Acid-Base Disorders

Metabolic Acidosis	Metabolic Alkalosis
Cardiovascular	Cardiovascular
Decreased inotropy	Decreased inotropy (Ca⁺⁺ entry)
Conduction defects	Altered coronary blood flow*
Arterial vasodilation	Digoxin toxicity
Venous vasoconstriction
Oxygen Delivery	Neuromuscular
Decreased oxy-Hb binding	Neuromuscular excitability
Decreased 2,3-DPG (late)	Encephalopathy seizures
Neuromuscular	Metabolic Effects
Respiratory depression	Hypokalemia
Decreased sensorium	Hypocalcemia
	Hypophosphatemia
	Impaired enzyme function
Metabolism	Oxygen Delivery
Protein wasting	Increased oxy-Hb affinity
Bone demineralization	Increased 2,3-DPG (delayed)
Catecholamine, PTH, and aldosterone stimulation
Insulin resistance
Free radical formation
Gastrointestinal
Emesis
Gut barrier dysfunction
Electrolytes
Hyperkalemia
Hypercalcemia
Hyperuricemia

2,3-DPG, 2,3-diphosphoglycerate; oxy-Hb, oxyhemoglobin; PTH, parathyroid hormone.

* Animal studies have shown both increased and decreased coronary artery blood flow.

If metabolic acidemia is to be treated, consideration should be given to the likely duration of the disorder. If it is expected to be short lived (e.g., diabetic ketoacidosis), maximizing respiratory compensation is usually the safest approach. Once the disorder resolves, ventilation can be quickly reduced to normal, and there will be no lingering effects of therapy. However, if the disorder is likely to be more chronic (e.g., renal failure), therapy aimed at restoring SID is indicated. In all cases, the therapeutic target can be quite accurately determined from the standard base-excess. As discussed, the standard base-excess corresponds to the amount SID must change in order to restore the pH to 7.4, assuming a PCO₂ of 40 mm Hg. Thus, if the SID is 30 mEq/L and the standard base-excess is −10 mEq/L, the target SID would be 40 mEq/L. Accordingly, the plasma Na⁺ concentration would have to increase by 10 mEq/L for NaHCO₃ administration to completely repair the acidosis. If increasing the plasma Na⁺ concentration is inadvisable for other reasons (e.g., hypernatremia), then NaHCO₃ administration is also inadvisable. Importantly, NaHCO₃ administration has not been shown to improve outcome in patients with lactic acidosis.¹²

In addition, NaHCO₃ administration is associated with certain disadvantages. Large (hypertonic) doses given rapidly can lead to hypotension ¹³ and have the potential to cause a sudden marked increase in PaCO₂.¹⁴ Accordingly, it is important to assess the patient’s ventilatory status before NaHCO₃ is administered, particularly in the absence of mechanical ventilation. NaHCO₃ infusion also affects circulating [K⁺] and [Ca⁺⁺] concentrations, which need to be monitored closely.

Tromethamine (Tris-buffer or Tham) is an organic buffer that readily penetrates cells.¹⁵ It is a weak base (pK = 7.9) that does not alter SID and does not affect plasma [Na⁺]. Accordingly, it is often used when administration of NaHCO₃ is contraindicated because of hypernatremia. This agent has been available since the 1960s, but limited data are available on its use in humans with acid-base disorders. In small uncontrolled studies, tromethamine appears to be effective in reversing metabolic acidosis secondary to ketoacidosis or renal failure without obvious toxicity.¹⁶ However, adverse reactions have been reported, including hypoglycemia, respiratory depression, and even fatal hepatic necrosis when concentrations exceeding 0.3 M are used. In Europe, a mixture of tromethamine, acetate, NaHCO₃, and disodium phosphate is available (Tribonate). This mixture seems to have fewer side effects than tromethamine alone, but experience with Tribonate is still quite limited.

Anion Gap and Strong Ion Gap

For more than 30 years, AG has been used by clinicians, and it has evolved into a major tool to evaluate acid-base disorders.¹⁷ AG is estimated from the differences between the routinely measured concentrations of serum cations (Na⁺ and K⁺) and anions (Cl⁻ and HCO₃⁻). Normally this difference, or “gap,” is made up by albumin and, to a lesser extent, by phosphate. Sulfate and lactate also contribute a small amount, normally less than 2 mEq/L. However, there are also unmeasured cations, such as Ca⁺⁺ and Mg⁺⁺, and these tend to offset the effects of sulfate and lactate, except when the concentration of sulfate or lactate is abnormally increased (Figure 12-2). Plasma proteins other than albumin can be positively or negatively charged, but in the aggregate tend to be neutral except in rare cases of abnormal paraproteins, such as in cases of multiple myeloma.¹⁸ In practice, AG is calculated as follows:

Figure 12-2 Charge balance in blood plasma. “Other cations” include Ca⁺⁺ and Mg⁺⁺. The strong ion difference (SID) is always positive (in plasma) and SID − SIDe (effective strong ion difference) must equal zero. Any difference between apparent SID (SIDa) and SIDe is the strong ion gap (SIG) and must represent unmeasured anions.

Because of its low and narrow extracellular concentration range, K⁺ is often omitted from the calculation. The normal value for AG is 12 ± 4 (if [K⁺] is considered) or 8 ± 4 mEq/L (if [K⁺] is not considered). The normal range has decreased in recent years following the introduction of more accurate methods for measuring Cl⁻ concentration.^19,²⁰ However, the various measurement techniques available mandate that each institution reports its own expected “normal anion gap.”

The AG is useful because this parameter can limit the differential diagnosis for patients with metabolic acidosis. If AG is increased, the explanation almost invariably will be found among five disorders: ketosis, lactic acidosis, poisoning, renal failure, or sepsis.²¹ However, several conditions can alter the accuracy of AG estimation, and these conditions are particularly prevalent among patients with critical illness^22,²³:

• Dehydration can widen the apparent AG by increasing the concentration of all the ions used for the calculation.

• Hypoalbuminemia decreases AG, and it has been recommended to “correct” AG for changes in albumin concentration, because for every 1 g/dL decrease in serum albumin concentration, the apparent AG narrows by 2.5 to 3 mEq/L.²⁴

• Respiratory and metabolic alkaloses are associated with an increase of up to 3 to 10 mEq/L in the apparent AG. The basis for this effect is enhanced lactate production (from stimulated phosphofructokinase enzymatic activity), reduction in the concentration of ionized weak acids (A⁻), and possibly the additional effect of dehydration.

Other factors that can increase AG are low Mg⁺⁺ concentration and administration of the sodium salts of poorly reabsorbable anions (e.g., beta-lactam antibiotics).²⁵ Certain parenteral nutrition formulations, such as those containing acetate, can increase AG. Citrate-based anticoagulants rarely can have the same effect after administration of multiple blood transfusions.²⁶ None of these rare causes, however, increases AG significantly,²⁷ and they are usually easily identified. In recent years, some additional causes of an increased AG have been reported. It is sometimes widened in patients with nonketotic hyperosmolar states induced by diabetes mellitus; the biochemical basis for this effect remains unexplained.²⁸ In recent years, unmeasured anions have been reported in the blood of patients with sepsis^29,³⁰ and liver disease^31,³² and in experimental animals injected with endotoxin.³³ These anions may be the source of much of the unexplained acidosis seen in patients with critical illness.³⁴

Additional doubt has been cast on the diagnostic value of AG in certain situations, however.^22,³⁰ Salem and Mujais²² found routine reliance on AG to be “fraught with numerous pitfalls.” The primary problem with the AG is its reliance on the use of a “normal” range that depends on normal circulating levels of albumin and to a lesser extent phosphate, as discussed earlier. Plasma concentrations of albumin or phosphate are often grossly abnormal in patients with critical illness, leading to changes in the “normal” range for AG. Moreover, because these anions are not strong anions, their charge is affected by pH.

These considerations have prompted some authors to adjust the “normal range” for AG according to the albumin concentration ²⁴ or phosphate concentration.⁶ Each g/dL of albumin has a charge of 2.8 mEq/L at pH 7.4 (2.3 mEq/L at pH 7.0 and 3.0 mEq/L at pH 7.6). Each mg/dL of phosphate has a charge of 0.59 mEq/L at pH 7.4 (0.55 mEq/L at pH 7.0 and 0.61 mEq/L at pH 7.6). Thus, the “normal” AG can be estimated using this formula⁶:

Or for international units:

These formulas only should be used when the pH is less than 7.35, and even then they are only accurate within 5 mEq/L. When more accuracy is needed, a slightly more complicated method of estimating [A⁻] is required.^31,³⁵

Another alternative to using the traditional AG is to use the SID. By definition, SID must be equal and opposite to the negative charges contributed by [A⁻] and total CO₂. The sum of the charges from [A⁻] and total CO₂ concentration has been termed the effective strong ion difference (SIDe).¹⁸ The apparent strong ion difference (SIDa) is obtained by measurement of each individual ion. Both the SIDa and the SIDe should equal the true strong ion difference. If the SIDa and SIDe differ, unmeasured ions must exist. If the SIDa is greater than SIDe, these ions are anions; if the SIDa is less than SIDe, the unmeasured ions are cations. This difference has been termed the strong ion gap to distinguish it from AG.³¹ Unlike the AG, the strong ion gap is normally zero and does not change with changes in pH or albumin concentration.

Positive–Anion Gap Acidoses

Lactic Acidosis

In many forms of critical illness, lactate is the most important cause of metabolic acidosis.³⁶ Blood lactate concentration has been shown to correlate with outcome in patients with hemorrhagic³⁷ and septic shock.³⁸ Lactic acid has been viewed as the predominant source of metabolic acidosis due to sepsis.³⁹ In this view, lactic acid is released primarily from the musculature and the gut as a consequence of tissue hypoxia. Moreover, the amount of lactate produced is believed to correlate with the total oxygen debt, the magnitude of hypoperfusion, and the severity of shock.³⁶ In recent years, this view has been challenged by the observation that during sepsis, even with profound shock, resting muscle does not produce lactate. Indeed, studies by various investigators have shown that the musculature actually may consume lactate during endotoxemia.⁴⁰^–⁴² Data concerning the gut are less clear. There is little question that underperfused gut can release lactate; however, it does not appear that the gut releases lactate during sepsis if mesenteric perfusion is maintained. Under such conditions, the mesenteric circulation can even become a net consumer of lactate.^40,⁴¹ Perfusion is likely to be a major determinant of mesenteric lactate metabolism. In a canine model of sepsis, gut lactate production could not be shown when flow was maintained with dopexamine hydrochloride.⁴²

Studies in animals as well as humans have shown that the lung may be a prominent source of lactate in the setting of acute lung injury.^40,⁴³^–⁴⁵ While studies such as these do not address the underlying pathophysiologic mechanisms of hyperlactatemia in sepsis, they suggest that using blood lactate concentration as evidence for tissue dysoxia is an oversimplification at best. Indeed, many investigators have begun to offer alternative interpretations of hyperlactatemia in this setting.⁴⁴^–⁴⁸ Box 12-2 lists several alternative sources of hyperlactatemia. In particular, pyruvate dehydrogenase, the enzyme responsible for moving pyruvate into the Krebs cycle, is inhibited by endotoxemia.⁴⁹ However, data from recent studies suggest that increased aerobic metabolism may be more important than metabolic defects or anaerobic metabolism.⁵⁰ Finally, administration of epinephrine promotes lactic acidosis, presumably by stimulating cellular metabolism (e.g., increased glycolysis in skeletal muscle).

Administration of epinephrine may be a common cause of lactic acidosis in patients with critical illness.^51,⁵² Interestingly, this phenomenon does not occur when dobutamine or norepinephrine is infused⁵³ and does not appear to be related to decreased tissue perfusion.

Although controversy exists as to the source and interpretation of lactic acidosis in critically ill patients, there is no question about the ability of lactate accumulation to produce acidemia. Lactate is a strong ion by virtue of the fact that at a pH within the physiologic range, it is almost completely dissociated; for instance, the pK_a for lactic acid is 3.9. Thus, at pH 7.4, 3162 lactic acid molecules are dissociated for every one that is not. Because the body can produce and dispose of lactate rapidly, it functions as one of the most dynamic components of SID.

Plasma lactate concentration may be increased without an increase in [H⁺]. There are two possible explanations for this phenomenon. First, if lactate is added to the plasma, not as lactic acid but rather as the salt of a strong acid (e.g., sodium lactate), there will be little change in the SID. The SID does not change because a strong cation (Na⁺) is being added along with a strong anion. However, only if a very large amount of lactate is infused rapidly will there be an appreciable increase in the plasma lactate concentration. For example, the use of lactate-based hemofiltration fluid can result in hyperlactatemia with an increased plasma HCO₃⁻ concentration and pH.

A more important mechanism whereby hyperlactatemia exists without acidemia (or with less acidemia than expected) is when the SID is corrected by the elimination of another strong anion from the plasma.⁵⁴ In the setting of sustained lactic acidosis induced by lactic acid infusion, Cl⁻ moves out of the plasma space, thus normalizing pH. Under these conditions, hyperlactatemia may persist but base-excess may be normalized by compensatory mechanisms to restore the SID.

Traditionally, lactic acidosis is subdivided into type A, in which the mechanism is tissue hypoxia, and type B, in which there is no hypoxia.⁵⁵ However, this distinction may be artificial. Some disorders, such as sepsis, may be associated with lactic acidosis owing to a variety of mechanisms (see Box 12-2), some of the “A” type and some of the “B” type. A potentially useful method of distinguishing anaerobically produced lactate from other sources is to measure the blood pyruvate concentration. The normal lactate to pyruvate ratio is 10 : 1.⁵⁶ A lactate-to-pyruvate ratio greater than 25 : 1 is considered to be evidence of anaerobic metabolism.⁴⁸ This approach makes biochemical sense, because pyruvate is reduced to lactate during anaerobic metabolism, thereby increasing the lactate-to-pyruvate ratio. Unfortunately, pyruvate is very unstable in solution and, therefore, is difficult to measure accurately in the clinical setting, greatly reducing the clinical utility of lactate/pyruvate determinations.

Treatment of lactic acidosis remains controversial. The only noncontroversial approach is to treat the underlying cause. The use of sodium bicarbonate (NaHCO₃) is equally controversial and remains of unproven value.¹²

Ketoacidosis

Another common cause of a metabolic acidosis with a positive AG is ketoacidosis. Ketones are formed by beta-oxidation of fatty acids, a process that is inhibited by insulin. In insulin-deficient states, ketone formation increases substantially. The accumulation of ketone bodies (acetone, β-hydroxybutyrate, and acetoacetate) in the plasma is exacerbated because elevated blood glucose concentrations promote an osmotic diuresis, leading to intravascular volume contraction. This state is associated with elevated circulating cortisol and catecholamine levels, which further stimulates free fatty acid production.⁵⁷ In addition, increased glucagon levels relative to insulin levels decreases intracellular concentrations of malonyl coenzyme A and increases the activity of carnitine palmitoyl acyl transferase, effects that promote ketogenesis.

Both acetoacetate and β-hydroxybutyrate are strong anions (pK_a 3.8 and 4.8, respectively).⁵⁸ Thus, like lactate, the presence of these ions decreases the SID and increases [H⁺]. Ketoacidosis may result from diabetes (diabetic ketoacidosis) or excessive alcohol consumption (alcoholic ketoacidosis). The diagnosis is established by measuring serum ketone levels. However, it is important to understand that the nitroprusside reaction only measures acetone and acetoacetate, and not β-hydroxybutyrate. Thus, the state of measured ketosis is dependent on the ratio of acetoacetate to β-hydroxybutyrate. This ratio is low when lactic acidosis coexists with ketoacidosis, because the reduced redox state of lactic acidosis favors production of β-hydroxybutyrate.⁵⁹ In this circumstance, the apparent level of ketosis is small relative to the amount of acidosis and the elevation of AG. There is also a risk of confusion during treatment of ketoacidosis, because ketones as measured by the nitroprusside reaction can increase despite resolving acidosis. This effect occurs as a result of rapid clearance of β-hydroxybutyrate, improving acid-base balance without changing the measured level of ketosis. Furthermore, circulating ketone levels can even appear to increase as β-hydroxybutyrate is converted to acetoacetate. Hence, it is better to monitor therapy by measuring blood pH and AG than by assaying levels of serum ketones.

Treatment of diabetic ketoacidosis includes infusing insulin and large amounts of fluid; 0.9% saline is usually recommended. Potassium replacement is often required as well. Fluid resuscitation reverses the hormonal stimuli for ketone body formation, as discussed earlier, and insulin promotes metabolism of ketones and glucose. Administration of NaHCO₃ may produce a more rapid rise in pH by increasing SID, but there is little evidence that this effect is desirable. Furthermore, because increasing the plasma Na⁺ concentration increases the SID, the SID will be too high once the ketosis is cleared (“overshoot” alkalosis). In any case, administration of NaHCO₃ is rarely necessary and should be avoided except in extreme cases.⁶⁰

A more common problem in the treatment of diabetic ketoacidosis is persistence of acidemia after resolution of ketosis. This hyperchloremic metabolic acidosis occurs as Cl⁻ replaces ketoacids, thus maintaining decreases in SID and pH. This effect appears to occur for two reasons. First, exogenous Cl⁻ is often provided in the form of 0.9% saline, which, if given in large enough quantities, results in a so-called dilutional acidosis (see later discussion). Second, renal Cl⁻ reabsorption increases as ketones are excreted in the urine. Increases in the tubular Na⁺ load produce electrical-chemical forces favoring Cl⁻ reabsorption.⁶¹

The acidosis seen in patients with alcoholic ketoacidosis is usually less severe. Treatment consists of intravenous (IV) fluid administration and infusion of glucose instead of insulin, as would be the case with diabetic ketoacidosis.⁶² Indeed, insulin is contraindicated because it may cause precipitous hypoglycemia.⁶³ Thiamine also must be given to avoid precipitating Wernicke encephalopathy.

Renal Failure

Renal failure, especially when chronic, leads to accumulation of sulfates and other acids, widening AG, although this increase usually is not large.⁶⁴ Similarly, uncomplicated renal failure rarely produces severe acidosis, except when it is accompanied by a high rate of acid generation, such as occurs during hypermetabolism.⁶⁵ In all cases, SID is decreased and remains so unless some therapy is provided. Hemodialysis removes sulfate and other ions and allows normal Na⁺ and Cl⁻ balance to be restored, thus returning SID to normal (or near normal). However, patients not yet requiring dialysis and those who are between treatments often require some other therapy to increase SID. NaHCO₃ is used as long as the plasma Na⁺ concentration is not already elevated.

Toxins

Metabolic acidosis with an increased AG is a major feature of various types of drug and substance intoxications (see Box 12-1).

Other and Unknown Causes

In the nonketotic hyperosmolar state associated with poorly controlled diabetes, AG widens for unexplained reasons.²⁸ Even when very careful methods are applied using the strong ion gap or similar strategies, unmeasured anions have been detected in the blood of patients with sepsis^29,³⁰ and liver disease³¹ and in experimental animals given endotoxin.³² Furthermore, unknown cations also appear in the blood of some critically ill patients.³⁰ The significance of these findings remains to be determined.

Non–Anion Gap (Hyperchloremic) Acidoses

Hyperchloremic metabolic acidosis occurs as a result of either the increase in [Cl⁻] relative to strong cations, especially Na⁺, or the loss of cations with retention of Cl⁻. As seen in Figure 12-1, these disorders can be separated by history and by measurement of urinary Cl⁻ concentration. When acidosis occurs, the normal response by the kidney is to increase Cl⁻ excretion. If the kidney fails to increase Cl⁻ excretion appropriately, impaired renal function is at least part of the problem causing acidosis. Extrarenal causes of hyperchloremic acidosis are exogenous Cl⁻ loads (iatrogenic acidosis) or loss of cations from the lower GI tract without proportional losses of Cl⁻.

Renal Tubular Acidosis

Examination of the urine and plasma electrolytes and pH and calculation of the urine apparent SID allow one to correctly diagnose most cases of renal tubular acidosis (see Figure 12-1).⁶⁶ However, caution must be exercised when the plasma pH is greater than 7.35, because urinary Cl⁻ excretion is normally decreased when pH is this high. In such circumstances, it may be necessary to infuse sodium sulfate or furosemide. These agents stimulate Cl⁻ and K⁺ excretion and can be used to unmask the defect and probe K⁺ secretory capacity.

The defect in all types of renal tubular acidosis is an inability to excrete Cl⁻ in proportion to Na⁺, although the reasons vary by type. Treatment largely depends on whether the kidney responds to mineralocorticoid replacement or whether there are losses of Na⁺ that can be replaced as NaHCO₃.

Classic distal (type I) renal tubular acidosis responds to NaHCO₃ replacement; typically, only 50 to 100 mEq/day are required. Defects in K⁺ reabsorption are also common in this type of renal tubular acidosis, and K⁺ replacement is also required. A variant of the classic distal renal tubular acidosis is a hyperkalemic form that actually is more common than the classic type. The central defect here appears to be impaired Na⁺ transport in the cortical collecting duct. These patients also respond to NaHCO₃ replacement. Proximal (type II) renal tubular acidosis is characterized by both Na⁺ and K⁺ reabsorption defects. The disorder is uncommon and usually appears as a component of Fanconi syndrome, which also is characterized by defects in the reabsorption of glucose, phosphate, urate, and amino acids.

Treatment of this disorder with NaHCO₃ is ineffective because increased ion delivery merely results in increased excretion. Thiazide diuretics have been used to treat this disorder, with varying success.

Type IV renal tubular acidosis is caused by aldosterone deficiency or resistance. These disorders are diagnosed by the presence of high serum [K⁺] concentration and low urine pH (<5.5). Treatment is usually most effective if the cause can be removed; most commonly, drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), heparin, or potassium-sparing diuretics are responsible. Occasionally, mineralocorticoid replacement is required.

Gastrointestinal Acidosis

Fluid secreted into the gut lumen contains higher amounts of Na⁺ than Cl⁻. Large losses of these fluids, particularly if volume is replaced with fluids containing equal amounts of Na⁺ and Cl⁻, results in a decrease in the plasma Na⁺ concentration relative to the Cl⁻ concentration and a decrease in SID. Such a scenario can be avoided if formulations such as lactated Ringer’s solution are used instead of normal saline to replace GI losses.

Iatrogenic Acidosis

Two of the most common causes of a hyperchloremic metabolic acidosis are iatrogenic, and both are due to administration of Cl⁻. Modern parenteral nutrition formulas contain weak anions such as acetate in addition to Cl⁻. The proportions of each anion can be adjusted depending on the acid-base status of the patient. If an insufficient amount of weak anions is provided, the plasma Cl⁻ concentration increases, decreasing SID and resulting in acidosis. A similar condition can arise when normal saline is used for fluid resuscitation, resulting in the development of “dilutional acidosis.” Dilutional acidosis was first described more than 40 years ago,^67,⁶⁸ although some authors have argued that this problem is rarely clinically significant.⁶⁹ This view pertains because large doses of NaCl produce only minor degrees of hyperchloremic acidosis in healthy animals.⁷⁰ This line of reasoning cannot be applied to critically ill patients, who often require infusion of a very large volume of resuscitation fluid. Furthermore, acid-base balance is often already deranged in critically ill patients, and these patients may not be able to compensate normally by increasing ventilation or may have abnormal buffer capacity due to hypoalbuminemia. In ICU and surgical patients,⁷¹^–⁷³ as well as in animals with experimental sepsis,⁷⁴ saline-induced acidosis clearly occurs.

Administration of normal saline causes acidosis because this solution contains equal amounts of Na⁺ and Cl⁻, whereas the normal Na⁺ concentration in plasma is 35 to 45 mEq/L greater than the normal Cl⁻ concentration. Administration of 0.9% saline increases the Cl⁻ concentration relatively more than the Na⁺ concentration. Many critically ill patients have a significantly lower SID than do healthy individuals, even when there is no evidence of a metabolic acid-base derangement.⁷⁵ The lower SID in critical illness is not surprising given that the positive charge of SID is balanced by the negative charges of A⁻ and total CO₂. Since many critically ill patients are hypoalbuminemic, A⁻ tends to be reduced. Because the body defends PCO₂ for other reasons, a reduction in A⁻ leads to a reduction in SID to maintain normal pH. Thus, a typical ICU patient might have a SID of 30 mEq/L rather than 40 to 42 mEq/L. If this same patient then develops a metabolic acidosis (e.g., lactic acidosis), SID decreases further. If the patient is resuscitated with a large volume of 0.9% saline, metabolic acidosis is exacerbated. This relationship is illustrated in Figure 12-3, which shows that a patient with a lower baseline SID is more susceptible to a subsequent acid load.

Figure 12-3 Plot of pH versus strong ion difference (SID). For this plot, A_TOT and PCO₂ were held constant at 18 mEq/L and 40 mm Hg, respectively. This plot assumes a water dissociation constant for blood of 4.4 × 10⁻¹⁴ (Eq/L). Note how steep the pH curve becomes at SID < 20 mEq/L.

One alternative to using normal saline to resuscitate patients is to use Ringer’s lactate solution. This fluid contains a more physiologic difference between [Na⁺] and [Cl⁻], so its SID is closer to normal (28 mEq/L as compared to 0 mEq/L for normal saline). Morgan and colleagues recently showed that a solution with a SID of approximately 24 mEq/L results in a neutral effect on the pH as blood is progressively diluted.⁷⁶

Unexplained Hyperchloremic Acidosis

Critically ill patients sometimes manifest hyperchloremic metabolic acidosis for unclear reasons. Often these patients have other coexisting types of metabolic acidosis, making the precise diagnosis difficult. Patients with sepsis and acidosis frequently have normal circulating lactate levels.⁷⁷ Often, unexplained anions are the cause,²⁹^–³¹ but hyperchloremic acidosis also can be a contributing factor.

Metabolic Alkalosis

Metabolic alkalosis occurs as a result of an increase in SID or a decrease in A_TOT. These changes can occur secondary to the loss of anions (e.g., Cl⁻ from the stomach, albumin from the plasma) or the retention of cations (rare). Sometimes the loss of Cl⁻ is temporary and can be treated effectively by replacing the anion; metabolic alkalosis in this category is said to be “chloride responsive.” In other cases, hormonal mechanisms produce ongoing losses of Cl⁻. Thus, at best, the Cl⁻ deficit can be offset only temporarily by Cl⁻ administration; this form of metabolic alkalosis is said to be “chloride resistant” (Box 12-3). Similar to hyperchloremic acidosis, these disorders can be distinguished by measurement of the urine Cl⁻ concentration.

Box 12-3

Differential Diagnosis of Metabolic Alkalosis (Increased Strong Ion Difference)

Exogenous Sodium Load (>Chloride)

Sodium salt administration (acetate, citrate)

Massive blood transfusions

Parenteral nutrition

Plasma volume expanders

Sodium lactate (Ringer’s solution)

Other

Severe deficiency of intracellular cations

Magnesium, potassium

GI, Gastrointestinal.

Chloride-Responsive Disorders

The chloride-responsive disorders usually occur as a result of Cl⁻ losses from the stomach, such as from vomiting or gastric drainage. The treatment is to replace the Cl⁻, which can be achieved slowly with NaCl or more rapidly with KCl or even HCl. Saline plus KCl is the treatment of choice because volume depletion and K⁺ usually coexist with the acid-base disturbance in patients with chloride-responsive metabolic alkalosis. Dehydration in turn stimulates aldosterone secretion, leading to increased tubular Na⁺ reabsorption and increased urinary losses of K⁺. Administration of normal saline is effective because the administration of equal amounts of Na⁺ and Cl⁻ result in larger relative increases in Cl⁻ concentration compared to Na⁺ concentration. In rare circumstances, when neither K⁺ nor intravascular volume depletion is a problem, it may be desirable to give back Cl⁻ as HCl.

Diuretics and other forms of volume contraction produce metabolic alkalosis predominantly by stimulating aldosterone secretion, as discussed earlier. However, diuretics also induce K⁺ and Cl⁻ excretion directly, further complicating the problem and inducing metabolic alkalosis more rapidly.

Chloride-Resistant Disorders

The chloride-resistant disorders (see Box 12-3) are characterized by an increased urine Cl⁻ concentration (>20 mEq/L) and are said to be “chloride resistant” because of ongoing Cl⁻ losses. Most commonly, excessive chloride excretion occurs as a result of excessive mineralocorticoid activity. Treatment requires that the underlying disorder be addressed (Table 12-2).

TABLE 12-2 Treatment of Metabolic Alkalosis

Condition	Treatment
Primary aldosteronism	Spironolactone or other agents that block distal tubular sodium reabsorption improve alkalosis, hypokalemia, and hypertension. Large doses may be necessary. Restriction of sodium intake and potassium supplementation may be necessary. When an adenoma can be identified, surgery is curative. When the cause is bilateral adrenal cortical hyperplasia, therapy is medical. Dexamethasone is effective in long-term therapy of familial dexamethasone-responsive aldosteronism.
Secondary aldosteronism	ACE inhibitors are usually effective. Repair of the underlying lesion, if feasible, may be required.
Cushing’s syndrome	Due to pituitary oversecretion of ACTH: surgery or radiation.
Due to adrenal adenoma or carcinoma: adrenalectomy.
Due to secondary or ectopic ACTH production: address the underlying malignancy.
Liddle’s syndrome	Triamterene may be effective.
Bartter’s syndrome	Treatment often unsatisfactory long-term. Potassium-sparing diuretics, potassium and magnesium supplementation, ACE inhibitors, COX inhibitors are partially effective.
Exogenous corticoids	Discontinuation of the offending agent(s) and vigorous initial potassium replacement.
Severe potassium or magnesium depletion	Replacement of these electrolytes (may require very large amounts).

ACE, Angiotensin-converting enzyme, COX, Cyclooxygenase.

From Spital A, Garella S. Correction of acid-base derangments. In Ronco C, Bellomo R (eds) Critical Care Nephrology. Kluwer Academic Publishers, Dordrecht, The Netherlands, 1998; pp. 311-328. Used with permission.

Other Causes of Metabolic Alkalosis

Rarely, an increased SID and therefore metabolic alkalosis occurs secondary to cation administration rather than anion depletion. Examples of these disorders include milk-alkali syndrome and IV administration of strong cations without strong anions. The latter occurs with massive blood transfusion because Na⁺ is given with citrate (a weak anion) instead of Cl⁻. Similar results occur when parenteral nutrition formulations contain too much acetate and not enough Cl⁻ to balance the Na⁺ load.

Respiratory Acid-Base Disorders

Respiratory disorders are far easier to diagnose and treat than metabolic disorders because the mechanism is always the same, although the underlying disease process may vary. CO₂ is produced by cellular metabolism or by the titration of HCO₃⁻ by metabolic acids. Normally, alveolar ventilation is adjusted to maintain PaCO₂ between 35 and 45 mm Hg. When alveolar ventilation is increased or decreased out of proportion to CO₂ production, a respiratory acid-base disorder exists.

Pathophysiology of Respiratory Acid-Base Disorders

Normal CO₂ production by the body (about 220 mL/min) is equivalent to 15,000 mM/day of carbonic acid.⁷⁸ This amount compares to less than 500 mM/day for all nonrespiratory acids that are handled by the kidney and gut. Pulmonary ventilation is adjusted by the respiratory center in response to changes in PaCO₂, blood pH, and PaO₂ as well as other factors (e.g., exercise, anxiety, wakefulness). Normal PaCO₂ (40 mm Hg) is maintained by precise matching of alveolar minute ventilation to metabolic CO₂ production. PaCO₂ changes in compensation for alterations in arterial pH produced by metabolic acidosis or alkalosis in predictable ways (Table 12-3).

TABLE 12-3 Observational Acid-Base Patterns

Respiratory Acidosis

When CO₂ elimination is inadequate relative to the rate of tissue production, PaCO₂ increases to a new steady state determined by the new relationship between alveolar ventilation and CO₂ production. Acutely, the increase in PaCO₂ increases both the [H⁺] and the [HCO₃⁻] in blood according to the carbonic acid equilibrium equation. Thus, the change in [HCO₃⁻] is mediated simply by the dissociation of H₂CO₃ into H⁺ and HCO₃⁻, not by an active physiologic adaptation response. Similarly, the increase in [HCO₃⁻] does not “buffer” the increase in [H⁺]. There is no change in SID and hence no change in standard base-excess. Cellular acidosis always occurs in respiratory acidosis, since CO₂ builds up in the tissues. If the PaCO₂ remains increased, active compensatory mechanisms are activated, and SID increases to restore [H⁺] toward normal.

Primarily, compensation is accomplished by removal of Cl⁻ from the plasma space. Since movement of Cl⁻ into the tissues or red blood cells results in intracellular acidosis, Cl⁻ must be removed from the body to achieve a lasting effect on the SID. The kidney is the primary organ for Cl⁻ removal, although the adaptive capacity of the GI tract for Cl⁻ elimination has not been fully explored. Accordingly, patients with renal disease have a difficult time adapting to chronic respiratory acidosis. When renal function is intact, Cl⁻ is eliminated in the urine, and after a few days, the SID increases to the level necessary to return blood pH to about 7.35. It is unclear whether this amount of time is required by the physiologic constraints of the system or to avoid being overly sensitive to transient changes in alveolar ventilation. In any case, this adaptation results in an increased pH for any degree of hypercarbia. According to the Henderson-Hasselbalch equation, the increased pH will result in an increased [HCO₃⁻] for a given PCO₂. Thus, the “adaptive” increase in [HCO₃⁻] results from the increase in pH and is not the cause for the increase in pH.

Although the change in HCO₃⁻ concentration is a convenient and reliable marker for the metabolic compensation, it is not the mechanism. This point is more than semantic because only changes in the independent variables of acid base balance (PCO₂, A_TOT, SID) can affect the plasma [H⁺], and [HCO₃⁻] is not an independent variable.

Diseases of Ventilatory Impairment

As for virtually all acid-base disorders, treatment begins with addressing the underlying disorder. Acute respiratory acidosis can be caused by central nervous system (CNS) suppression, neuromuscular disease or impairment (e.g., myasthenia gravis, hypophosphatemia, hypokalemia), or airway and parenchymal lung disease (e.g., asthma, acute respiratory distress syndrome). This last category of conditions also produces primary hypoxia, not just alveolar hypoventilation. The two can be distinguished by the alveolar gas equation:

where R is the respiratory exchange coefficient (generally assumed to be 0.8), and PIO₂ is the inspired oxygen tension (room air is approximately 150). Thus, as PaCO₂ increases, the PaO₂ will decrease in a predictable fashion. If the PAO₂ is reduced further, there is a defect in gas exchange.

Chronic respiratory acidosis is most often caused by chronic lung disease (e.g., chronic obstructive lung disease) or chest wall disease (e.g., kyphoscoliosis). Rarely, its cause is central hypoventilation or chronic neuromuscular disease.

When and How to Treat

The primary threat to life in cases of respiratory acidosis comes not from acidosis but from hypoxemia. If the patient is breathing room air, PaCO₂ cannot exceed 80 mm Hg before life-threatening hypoxemia results. Accordingly, supplemental oxygen is always required, although unfortunately, oxygen administration alone is almost never sufficient treatment, and the defect in ventilation must be addressed directly. When the underlying cause can be addressed quickly (e.g., reversal of narcotics with naloxone), it may be possible to avoid endotracheal intubation. More often, however, mechanical ventilation must be initiated. Mechanical support is indicated when the patient is unstable or at risk for instability or when CNS function deteriorates. Furthermore, in patients who are exhibiting signs of respiratory muscle fatigue, mechanical ventilation should be instituted before overt respiratory failure occurs. Thus, it is not the absolute PaCO₂ value that is important but rather the clinical condition of the patient.

Chronic hypercapnia requires treatment when there is an acute deterioration. In this setting, it is important to recognize that the goal of therapy is not a normal value for PaCO₂ (35-45 mm Hg) but rather restoration of the patient’s baseline PaCO₂ (if known). If the baseline PaCO₂ is not known, a target PaCO₂ of 60 mm Hg is reasonable. Overventilation has two undesirable consequences. First, life-threatening alkalemia can occur if the PaCO₂ is rapidly normalized in a patient with chronic respiratory acidosis and an appropriately large SID. Second, even if the PaCO₂ is corrected slowly, the patient will reduce the plasma SID over time, making it impossible to wean the patient from mechanical ventilation.

Noninvasive ventilation is another treatment option that is useful in selected patients, particularly those with normal sensorium.⁷⁹ Rapid infusion of NaHCO₃ in patients with respiratory acidosis can induce acute respiratory failure if alveolar ventilation is not increased to adjust for the increased CO₂ load. Thus, if NaHCO₃ is used, it must be administered slowly and alveolar ventilation adjusted appropriately. Furthermore, as discussed previously, NaHCO₃ works by increasing the plasma [Na⁺]. If this is not possible or not desirable, NaHCO₃ should be avoided.

Occasionally it is useful to reduce CO₂ production, which can be achieved by reducing the carbohydrate load in the nutritional support regimen, lowering the temperature in febrile patients, and providing adequate sedation for anxious or combative patients. Treatment of shivering in the postoperative period can reduce CO₂ production. However, it is unusual to control hypercarbia with these techniques alone.

Permissive Hypercapnia

In recent years, there has been increased recognition of ventilator-associated lung injury. Accordingly, a strategy designed to reduce minute ventilation and hence increase PaCO₂, so-called permissive hypercapnia or controlled hypoventilation, has been increasingly employed.¹¹ However, permissive hypercapnia is not without risks. Sedation is mandatory and the use of neuromuscular blocking agents is frequently required. Hypercapnia is associated with increased intracranial pressure and pulmonary hypertension, making this technique unusable in patients with brain injury or right ventricular dysfunction. Controversy exists as to how low to allow the pH to go. While some authors have reported good results with pH values less than 7.0,¹¹ most authors advocate more modest pH reductions (>7.25).

Respiratory Alkalosis

Respiratory alkalosis may be the most frequently encountered acid-base disorder. It occurs in a number of pathologic conditions, including salicylate intoxication, early sepsis, hepatic failure, and hypoxic respiratory disorders. Respiratory alkalosis also occurs with pregnancy and with pain or anxiety. Hypocapnia appears to be a particularly bad prognostic indicator in patients with critical illness.⁸⁰ As in acute respiratory acidosis, acute respiratory alkalosis results in a small change in [HCO₃⁻] as dictated by the Henderson-Hasselbalch equation. If hypocapnia persists, the SID will begin to decrease as a result of renal Cl⁻ reabsorption. After 2 to 3 days, the SID assumes a new, lower steady state.⁸¹ Severe alkalemia is unusual in patients with respiratory alkalosis, and management is therefore directed to the underlying cause. Typically, these mild acid-base changes are clinically more important for what they can alert the clinician to, in terms of underlying disease, than for any threat they pose to the patient. In rare cases, respiratory depression with narcotics is necessary.

Pseudorespiratory Alkalosis

The presence of arterial hypocapnia in patients with profound circulatory shock has been termed pseudorespiratory alkalosis.⁸² This condition can be seen when alveolar ventilation is supported, but the circulation is grossly inadequate. In such conditions, the mixed venous PCO₂ is significantly elevated, but the arterial PCO₂ is normal or even decreased secondary to decreased CO₂ delivery to the lungs and increased pulmonary transit time. Overall CO₂ clearance is markedly decreased, and there is marked tissue acidosis, usually involving both metabolic and respiratory components. The metabolic component comes from tissue hypoperfusion and hyperlactatemia. Arterial oxygen saturation also may appear to be adequate despite tissue hypoxemia. This condition is rapidly fatal unless cardiac output is rapidly corrected.

Unified Approach to the Patient with Acid-Base Imbalance

Characterizing the Disorder

As described in greater detail in recent reviews,⁶^–⁷ the first step in the approach to a patient with an acid-base imbalance is to characterize the disorder. Acid-base imbalances are usually recognized by abnormalities in the venous plasma electrolyte concentrations, so it is useful to start there. Measurement of venous [HCO₃⁻] is the easiest way to screen for acid-base disorders. However, a normal [HCO₃⁻] does not exclude the possibility of an acid-base derangement, even a serious one. Therefore, if the history and physical examination findings lead one to suspect a disease process that results in an acid-base imbalance, more investigation is required. The normal [HCO₃⁻] is 22 to 26 mEq/L. Increases in [HCO₃⁻] occur with primary and compensatory metabolic alkaloses and decreases occur with primary or compensatory metabolic acidoses. Unfortunately, in mixed disorders, [HCO₃⁻] may be misleading, and the presence of any abnormality in [HCO₃⁻] requires further investigation. In addition to examining the [HCO₃⁻], venous blood can be used to calculate AG: ([Na⁺] + [K⁺]) − ([Cl⁻] − [HCO₃⁻]). If [HCO₃⁻] or AG are abnormal or if there is clinical suspicion for a mixed disorder, arterial blood should be sampled for blood gas analysis. This test will provide information on the pH, PaCO₂, and standard base-excess. Although simple disorders will conform to the equations presented in Table 12-3, “mixed” disorders are quite common.

In patients with acidemia, the next step is to examine AG. The AG should also be examined when there is suspicion of an occult metabolic acidosis, even in a patient with alkalemia. However, severe alkalemia will increase AG by 2 to 4 mEq/L, and hence wider “tolerance limits” should be used. If AG is calculated from an alkalemic blood sample, only significant abnormalities (>8-10 mEq/L above normal) should be considered important. More often, however, it is not excessive sensitivity but rather insensitivity that plagues AG calculation. The accuracy of AG can be improved easily by using a patient-specific normal range rather than a standard one. If unmeasured anions are detected, it is a good idea to compare their amounts to the abnormality in standard base-excess. For example, if the calculated AG is 5 mEq/L greater than expected and the standard base-excess is −15 mEq/L, a mixed metabolic acidosis is present. The unmeasured anions (e.g., ketones) are accounting for a standard base-excess of −5 mEq/L while some other process is responsible for another 10 mEq/L. This sort of abnormality can occur if very large amounts of 0.9% saline are used to treat a patient with diabetic ketoacidosis. As the ketosis resolves, the acidosis persists because SID has been decreased due to excessive Cl⁻ administration.

Determining the Cause

Once the disorder has been characterized, the clinician must integrate the information obtained from the history and physical examination to arrive at an accurate diagnosis. Mixed disorders continue to be problematic, as any acid-base disorder that fails to fit into the classification scheme shown in Table 12-2 can be considered a mixed disorder, but some mixed disorders appear to be simple disorders when first encountered. For example, a patient with chronic respiratory acidosis and a PaCO₂ of 60 mm Hg would be expected to have a standard base-excess of +8 mEq/L (see Table 12-3). If this patient develops a metabolic acidosis, the standard base-excess will decrease and may be 0 mEq/L. At this point, it may appear that the patient has a pure acute respiratory acidosis rather than a mixed disorder. If the metabolic acidosis causes an increase in AG, this abnormality may provide a clue. Another useful method is to obtain at least two blood gas analyses to examine for trends. In general, however, it is only by careful attention to history and physical examination that the true diagnosis can be made.

Annotated References

Kellum JA, Elbers PWG, editors. Stewart’s Textbook of Acid-Base, 2nd ed, Amsterdam: Acidbase.org, 2009.

An expanded 2nd edition to Stewart’s classic monograph. Additional chapter provided by leading experts covers clinical application.

Kellum JA. Disorders of acid-base balance. Crit Care Med. 2007;35(11):2630-2636.

A case-based review of acid-base using modern methods.

Forsythe SM, Schmidt GA. Sodium bicarbonate for the treatment of lactic acidosis. Chest. 2000;117(1):260-267.

A systematic review of the evidence for and against use of sodium bicarbonate for lactic acidosis.

Morgan TJ, Venkatesh B, Hall J. Crystalloid strong ion difference determines metabolic acid-base change during in vitro hemodilution. Crit Care Med. 2002;30(1):157-160.

In vitro studies of hemodilution using different crystalloid solution. The authors demonstrate that the SID of the diluent is the decisive factor in determining final pH.

References

1 Kellum JA, Bellomo R, Kramer DJ, et al. Splanchnic buffering of metabolic acid during early endotoxemia. J Crit Care. 1997;12:7-12.

2 Schlichtig R, Grogono AW, Severinghaus JW. Human PaCO₂ and standard base excess compensation for acid-base imbalance. Crit Care Med. 1998;26:1173-1179.