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.

image 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.14 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.57

There are three mathematically independent determinants of blood pH:

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

Changes in plasma [H+] result from dissociation of ATOT 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 ATOT. 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.

image 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).

Similarly, the treatment of metabolic acid-base disorders requires a change in SID. Metabolic acidoses are repaired by increasing plasma Na+ concentration more than plasma Cl concentration (e.g., by infusing NaHCO3), and metabolic alkaloses are repaired by replacing Cl as NaCl (large volumes), KCl, or even HCl. Note that so-called chloride-resistant metabolic alkaloses are resistant to chloride only because of ongoing renal losses that increase in response to increased Cl replacement (e.g., hyperaldosteronism).

Pathophysiology of Metabolic Acid-Base Disorders

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

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

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.

image 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.

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 hypotension13 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:

image

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 illness22,23:

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 sepsis29,30 and liver disease31,32 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 concentration24 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:

image

Or for international units:

image

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.4042

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