Overview of Acid-Base Balance

To maintain extracellular pH within the normal range, the daily production of acid must be excreted from the body ( Fig. 13.1 ). The vast majority of acid production results from the metabolism of dietary carbohydrates and fats. Complete oxidation of these metabolic substrates produces CO ₂ and water. The 15,000 mmoles of CO ₂ produced daily are efficiently exhaled by the lungs and are therefore known as “volatile acid.” As long as ventilatory function remains normal, this volatile acid does not contribute to changes in acid-base balance. Nonvolatile or fixed acids are produced by the metabolism of sulfate-containing and phosphate-containing amino acids. In addition, incomplete oxidation of fats and carbohydrates results in the production of small quantities of lactate and other organic anions, which when excreted in the urine represent a loss of base. Individuals consuming a typical meat-based diet produce approximately 1 mmol/kg/day of hydrogen ions. Fecal excretion of a small amount of base also contributes to total daily acid production.

Maintenance of acid-base homeostasis requires that the addition of acid to the body is balanced by excretion of acid. Production of fixed nonvolatile acid occurs mainly through the metabolism of proteins. A small quantity of base also is lost in the stool and urine. Acid excretion occurs in the kidney through the secretion of H ⁺ buffered by titratable acids and NH ₃ . Bicarbonate filtration and reclamation by the kidney are normally a neutral process.

The kidney is responsible not only for the excretion of the daily production of fixed acid but also for the reclamation of the filtered bicarbonate. Bicarbonate reclamation occurs predominantly in the proximal tubule, mainly through the Na ⁺ -H ⁺ exchanger. Active transporters in the distal tubule secrete hydrogen ion against a concentration gradient. Although urinary pH can fall to as low as 4.5, if there were no urinary buffers, this would account for very little acid excretion. For example, to excrete 100 mmoles of H ⁺ into unbuffered urine at a minimum urine pH of 4.5 ([H ⁺ ] = 32 mmol/L) would require a daily urine volume of 3000 L. Fortunately, urinary phosphate and creatinine help buffer these protons, allowing the kidney to excrete approximately 40% to 50% of the daily fixed acid load as titratable acid (TA), so called because they are quantitated by titrating the urine pH back to that of plasma, 7.4. In addition to TA, renal excretion of acid is supported by ammoniagenesis. NH ₃ is generated in the proximal tubule by the deamidation of glutamine to glutamate, which is subsequently deaminated to yield α-ketoglutarate. The enzymes responsible for these reactions are upregulated by acidosis and hypokalemia. Hyperkalemia, on the other hand, reduces ammoniagenesis. NH ₃ builds up in the renal interstitium and passively diffuses into the tubule lumen along the length of the collecting duct, where it is trapped by H ⁺ as ammonium ( ).

Under conditions of increased acid production, the normal kidney can increase acid excretion primarily by augmenting NH ₃ production. Renal acid excretion varies directly with the rate of acid production. Net renal acid excretion (NAE) is equal to the sum of TA and , minus any secreted [NAE = (TA + ) – ]. Thus the etiology of a metabolic acidosis can be divided into four broad categories: (1) overproduction of fixed acids, (2) increased extrarenal loss of base, (3) decrease in the kidney’s ability to secrete hydrogen ions, and (4) inability of the kidney to reclaim the filtered bicarbonate ( Fig. 13.2 ).

Metabolic acidosis can result from increased acid production, increased loss of base in stool or urine, or decreased H ⁺ secretion in the distal tubule. The causes of these processes are shown. RTA , Renal tubular acidosis.

Evaluation of Urinary Acidification

The cause of metabolic acidosis often is evident from the clinical situation. However, because the kidney is responsible for both the reclamation of filtered and the excretion of the daily production of fixed acid, to evaluate a metabolic acidosis it may be necessary to assess whether the kidney is appropriately able to reabsorb , secrete H ⁺ against a gradient, and excrete ( Table 13.1 ). The simplest test is to measure the urine pH. Although urine pH can be measured using a dipstick, the lack of precision of this technique prevents it from being useful in making clinical decisions. Although it has been suggested that urine be collected under oil and the pH measured, using a pH electrode to prevent the loss of CO ₂ , in fact when the urine pH is less than 6.0, the amount of dissolved CO ₂ is minimal and the use of oil is unnecessary. Under conditions of acid loading, urine pH should be below 5.5. A pH of higher than 5.5 usually reflects impaired distal hydrogen ion secretion. Measuring the pH after challenging the patient with the loop diuretic furosemide will increase the sensitivity of this test by providing Na ⁺ to the distal tubule for reabsorption. The reabsorption of Na ⁺ creates a negative electrical potential in the lumen and enhances H ⁺ secretion. It is important, however, to rule out urinary infections with urea-splitting organisms, which will increase pH. An elevated urine pH may also be misleading in conditions associated with volume depletion and hypokalemia, as can occur in diarrhea. In contradistinction to furosemide, volume depletion with decreased sodium delivery to the distal tubule impairs distal H ⁺ secretion. Furthermore, hypokalemia, by enhancing ammoniagenesis, raises the urine pH.

Because renal excretion of accounts for the majority of acid excretion, measurement of urine provides important information. Urinary excretion can be decreased by a variety of mechanisms, including a primary decrease in ammoniagenesis by the proximal tubule, as seen in chronic kidney disease (CKD), or decreased trapping in the distal tubule either secondary to decreased H ⁺ secretion or an increased delivery of , which will preferentially buffer H ⁺ , making it unavailable to form . Although direct measurement of is becoming more readily available in clinical laboratories and is the gold standard, many laboratories still do not perform this assay. An estimate of excretion, however, is easily obtained by calculating the urine anion gap (UAG) or urine osmole gap. If, as is usual, the anion balancing the charge of the is Cl ⁻ , the UAG [(Na ⁺ + K ⁺ ) − Cl ⁻ ] should be negative because the chloride is greater than the sum of Na ⁺ and K ⁺ ( Fig. 13.3 ). Although the measurement of the UAG in conditions of acid loading is often reflective of excretion, the presence of anions other than Cl ⁻ (such as keto anions or hippurate) makes it a less reliable assessment of than the urine osmole gap (see Fig. 13.3 ). The urine osmole gap is calculated as follows: [measured urine osmolality − calculated urine osmolality], where calculated urine osmolality is [2(Na ⁺ + K ⁺ ) + (urea nitrogen/2.8) + (glucose/18)]. The osmole gap is made up primarily of salts. Thus half of the gap represents . An osmole gap of greater than 100 mmol/L signifies normal excretion.

In the presence of acidemia, the kidney increases excretion. The urine anion gap (UAG) is an indirect method for estimating urine . (A) If the accompanying anion is chloride, the UAG (Na ⁺ + K ⁺ − Cl ⁻ ) will be negative, reflecting the large quantity of in the urine. (B) A decrease in secretion occurs when ammoniagenesis is diminished, H ⁺ secretion is impaired, or there is delivery of to the distal tubule. In these cases, the UAG will be inappropriately positive. (C) If anions other than Cl are excreted (e.g., ketones, hippurate), the UAG will be positive despite increased excretion, because these anions are not used in calculation of the gap.

Another test of distal H ⁺ ion secretory ability is measurement of urine pCO ₂ during bicarbonate loading. Distal delivery of in the presence of normal H ⁺ secretory capacity results in elevated pCO ₂ in the urine. When there is a secretory defect, urine pCO ₂ does not increase. In this case, accurate measurement of urine pCO ₂ requires that the urine be collected under oil to prevent the loss of CO ₂ into the air.

Complications of Acidosis

Although it has been accepted that a decrease in extracellular pH has detrimental effects on numerous physiologic parameters and should be aggressively treated, this dogma has been challenged. The proponents of treatment argue that acidemia depresses cardiac contractility, blocks activation of adrenergic receptors, and inhibits the action of key enzymes. Uncontrolled clinical studies are not easy to interpret because of the difficulties in separating the effects of the acidosis from the effects of the underlying illness. Most controlled studies investigating the role of acidosis on cellular processes have been done in isolated cells or organs; therefore the effects of acidemia on whole-body physiology and their applicability to humans are unclear.

The effect of pH on cardiac function has been strongly debated. Cardiac output is determined by multiple components, and it is the sum of the effects on these individual components that determines the net effect of acidemia on cardiac function. Myocardial contractile strength and changes in vascular tone determine cardiovascular performance, and the relative contributions of each in the context of acidemia remain to be clarified. Because of differing effects of acidemia on contractile force, vascular tone, and sympathetic discharge, it is difficult to predict what happens to cardiac output from studies using isolated myocytes or perfused hearts.

During continuous infusion of lactic acid, it has been shown that cardiac output and the rate of development of left ventricular force increase. In addition, fractional shortening of the left ventricle as assessed by transthoracic echocardiography appears to be normal, even in cases of severe acidemia. The pH at which cardiac output and blood pressure fall remains unclear.

Approach to Acid-Base Disorders

Complete evaluation of acid-base status requires a routine electrolyte panel, measurement of serum albumin, and arterial blood gas analysis (see Chapter 12 ). The traditional approach to metabolic acidosis relies on the calculation of the anion gap (AG) and the subsequent separation of metabolic acidosis into those with an elevated AG and those in which the AG is normal, or so-called hyperchloremic metabolic acidosis (HCMA; Fig. 13.4 ). The AG is defined as the difference between the concentration of sodium, the major cation, and the sum of the concentrations of chloride and bicarbonate, the major anions: Na ⁺ -[Cl ⁻ – ]. Because the concentration of potassium changes minimally, its contribution is ignored for convenience. Obviously, electrical neutrality must exist, and the sum of the anions must equal the sum of the cations. The gap results because the unmeasured anions, such as sulfate, phosphate, organic anions, and especially the weak acid proteins, are greater than the unmeasured cations (i.e., magnesium). Thus it would seem upon examination of a basic chemistry panel that cations exceed anions, creating an AG. The normal AG is 10 ± 2 mEq/L. Any increase in the AG, even in the face of a normal or frankly alkalemic pH, represents the accumulation of acids and the presence of an acidosis. In many cases, the anions that make up the gap are not easily identifiable.

The anion gap (AG) is equal to [Na ⁺ ] + ([Cl ⁻ ] + [ ], which is equal to the unmeasured anions minus the unmeasured cations. (A) The normal anion gap is 10 ± 2. (B) In an AG acidosis there is a decrease in [ ] and an increase in organic anions (e.g., lactate), which results in an elevated anion gap. (C) In a hyperchloremic acidosis, there is a decrease in [ ] and an increase in [Cl], with no change in anion gap.

The one caveat in using the AG is to recognize that the normal gap is predominantly composed of the negative charge on albumin. When hypoalbuminemia is present, the AG must be corrected for the serum albumin. For each 1-g/dL decrease in the serum albumin, the calculated AG should be increased by 2.5 mEq/L. Thus the corrected AG can be estimated as AGc = AG + 2.5 (4 − serum albumin). If the AG is not corrected, the presence of a metabolic acidosis may be masked. This is especially true in critically ill patients, who typically have decreased serum albumin.

Anion Gap Acidosis

As previously described, an increased AG represents the accumulation of nonchloride acids. The mnemonic GOLDMARK is a useful tool that helps identify the causes of an AG acidosis ( Fig. 13.5 ). AG acidosis can be divided into four major categories ( Table 13.2 ): (1) lactic acidosis, (2) ketoacidosis, (3) toxin/drugs, and (4) severe kidney failure. In all but kidney failure, the accumulation of acids is caused by their overproduction. These acids dissociate into protons, which are quickly buffered by , and into their respective conjugate bases, the unmeasured anions. As long as these anions are retained in the body and not excreted, they contribute to the elevation in the AG.

GOLDMARK is a useful mnemonic to remember the common causes of an anion gap metabolic acidosis.

Lactic Acidosis

Lactic acidosis is a common AG acidosis and by far the most serious of all high-AG acidoses. Anaerobic metabolism of glucose (glycolysis) occurs in the extramitochondrial cytoplasm and produces pyruvate as an intermediary. If this were the end of the glycolytic process, there would be a net production of two protons and a metabolically unsatisfactory reduction of NAD to NADH. Fortunately, pyruvate rapidly undergoes one of two metabolic fates: (1) under anaerobic conditions, because of the high NADH/NAD ratio, pyruvate is quickly reduced by lactate dehydrogenase to lactate, releasing energy, consuming a proton, and decreasing the NADH/NAD ratio, thus allowing for continued glycolysis; or (2) in the presence of oxygen, pyruvate diffuses into the mitochondria and, after oxidation by the pyruvate dehydrogenase (PDH) complex, enters the tricarboxylic acid cycle, where it is completely oxidized to CO ₂ and water. Neither of these pathways results in the production of H ⁺ . During glycolysis, glucose metabolism produces two molecules of lactate and two molecules of adenosine triphosphate (ATP). It is the hydrolysis of ATP (ATP = ADP + H ⁺ + Pi) that releases protons. Therefore the acidosis does not occur because of the production of lactate but because under hypoxic conditions the hydrolysis of ATP is greater than ATP production. Thus the buildup of lactate is a surrogate marker for ATP consumption during hypoxic states.

Although lactate production averages about 1300 mmol/day, serum lactate levels are typically less than 1 mmol/L because lactate is either reoxidized to pyruvate and enters the tricarboxylic acid cycle or is used by the liver and kidney via the Cori cycle for gluconeogenesis. Increased concentration of lactate can therefore result from decreased oxidative phosphorylation, increased glycolysis, or decreased gluconeogenesis. Lactate levels between 2 and 3 mmol/L are frequently found in hospitalized patients. Some of these patients will go on to develop frank acidosis, but others will have no adverse events. Lactic acidosis is defined as the presence of a lactate level of greater than 5 mmol/L.

There is a poor correlation among arterial pH, uncorrected AG, and serum lactate levels, even in those patients with a serum lactic acid level greater than 5 mmol/L. Approximately 25% of patients with serum lactate levels between 5 and 9.9 mmol/L have a pH greater than 7.35, and as many as half have AGs of less than 12.

Lactic acidosis has been traditionally divided into types A and B ( Table 13.3 ). Type A, or hypoxic lactic acidosis, results from an imbalance between oxygen supply and oxygen demand. In type B lactic acidosis, oxygen delivery is normal, but oxidative phosphorylation is impaired. This is seen in patients who have inborn errors of metabolism or who have ingested drugs or toxins. It has become increasingly clear, however, that lactic acidosis is often caused by the simultaneous existence of both hypoxic and nonhypoxic factors, and in many cases it is difficult to separate one from the other. For example, hereditary partial defects in mitochondrial metabolism, as well as age-related declines in cytochrome IV complex activity, may result in lactic acidosis with a lesser degree of hypoxia than in patients without such defects. Even in cases of shock, in which tissue oxygen delivery is obviously inadequate, decreased portal blood flow and reduced hepatic clearance of lactate contribute to the acidosis. Similarly, in sepsis there is a decrease in both tissue perfusion and in the ability to use oxygen. Therefore this division based solely on cause is largely of historic and conceptual interest.

Table 13.3

Lactic Acidosis

Type A • Generalized seizure • Extreme exercise • Shock • Cardiac arrest • Low cardiac output • Severe anemia • Severe hypoxemia • Carbon monoxide poisoning Type B • Sepsis • Thiamine deficiency • Uncontrolled diabetes mellitus • Malignancy • Hypoglycemia • Drugs/toxins • Ethanol • Metformin • Zidovudine • Didanosine • Stavudine • Lamivudine • Zalcitabine • Salicylate • Linezolid • Propofol • Niacin • Isoniazid • Nitroprusside • Cyanide • Catecholamines • Cocaine • Acetaminophen • Streptozotocin • Pheochromocytoma • Sorbitol/fructose • Malaria • Inborn errors of metabolism Other • Hepatic failure • Respiratory or metabolic alkalosis • Propylene glycol • d -Lactic acidosis

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