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).