26 ELECTROLYTES/ACID-BASE BALANCE
Harrison’s Manual of Medicine
In most cases, disturbances of sodium concentration [Na+] result from abnormalities of water homeostasis. Disorders of Na+ balance usually lead to hypo- or hypervolemia. Attention to the dysregulation of volume (Na+ balance) and osmolality (water balance) must be considered separately for each pt (see below).
HYPONATREMIA This is defined as a serum [Na+] < 135 mmol/L and is among the most common electrolyte abnormalities encountered in hospitalized pts. Symptoms include confusion, lethargy, and disorientation; if severe (<120 mmol/L) and abrupt, seizures or coma may develop. Hyponatremia is often iatrogenic and almost always the result of an abnormality in the action of antidiuretic hormone (ADH), deemed either “appropriate” or “inappropriate,” depending on the associated clinical conditions. The serum [Na+] by itself does not yield diagnostic information regarding the total-body Na+ content. Therefore, a useful way to categorize pts with hyponatremia is to place them into three groups, depending on the volume status (i.e., hypovolemic, euvolemic, and hypervolemic hyponatremia) (Fig. 26-1).
FIGURE 26-1. Evaluation of hyponatremia. RTA, renal tubular acidosis; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
Hypovolemic Hyponatremia Mild to moderate degrees of hyponatremia ([Na+] = 125–135 mmol/L) complicate GI fluid or blood loss for two reasons. First, there is activation of the three major “systems” responsive to reduced organ perfusion: the renin-angiotensin-aldosterone axis, the sympathetic nervous system, and ADH. This sets the stage for enhanced renal absorption of solutes and water. Second, replacement fluid before hospitalization or other intervention is usually hypotonic (e.g., water, fruit juices). The optimal treatment of hypovolemic hyponatremia is volume administration, either in the form of colloid or isotonic crystalloid (e.g., 0.9% NaCl or lactated Ringer’s solution).
Hypervolemic Hyponatremia The edematous disorders (CHF, hepatic cirrhosis, and nephrotic syndrome) are often associated with mild to moderate degrees of hyponatremia ([Na+] = 125–135 mmol/L); occasionally, pts with severe CHF or cirrhosis may present with serum [Na+] <120 mmol/L. The pathophysiology is similar to that in hypovolemic hyponatremia, except that perfusion is decreased due to (1) reduced cardiac output, (2) arteriovenous shunting, and (3) severe hypoproteinemia, respectively, rather than true volume depletion. The scenario is sometimes referred to as reduced “effective circulating arterial volume.” The evolution of hyponatremia is the same: increased water reabsorption due to ADH, complicated by hypotonic fluid replacement. This problem may be compounded by increased thirst in pts with CHF. Pts with a variety of causes of chronic renal disease may also develop hypervolemic hyponatremia, due principally to salt and water retention due to reduced GFR, and to the diseased kidneys’ inability to osmoregulate.
Management consists of treatment of the underlying disorder (e.g., afterload reduction in heart failure, large-volume paracentesis in cirrhosis, glucocorticoid therapy in some forms of nephrotic syndrome), Na+ restriction, diuretic therapy, and, in some pts, H2O restriction. This approach is quite distinct from that applied to hypovolemic hyponatremia.
Euvolemic Hyponatremia The syndrome of inappropriate ADH secretion (SIADH) characterizes most cases of euvolemic hyponatremia. Common causes of the syndrome are pulmonary (e.g., pneumonia, tuberculosis, pleural effusion) and CNS diseases (e.g., tumor, subarachnoid hemorrhage, meningitis); SIADH also occurs with malignancies (e.g., small cell carcinoma of the lung) and drugs (e.g., chlorpropamide, carbamazepine, narcotic analgesics, cyclophosphamide). Optimal treatment of euvolemic hyponatremia is H2O restriction to <1 L/d, depending on the severity of the syndrome.
The rate of correction should be relatively slow (0.5 mmol/L per h of Na+). A useful “rule of thumb” is to limit the change in mmol/L of Na+ to half of the total difference within the first 24 h. More rapid correction has been associated with central pontine myelinolysis, especially if the hyponatremia has been of long standing. More rapid correction (with the potential addition of hypertonic saline to the above-recommended regimens) should be reserved for pts with very severe degrees of hyponatremia and ongoing neurologic compromise (e.g., a pt with Na+ <105 mmol/L in status epilepticus).
HYPERNATREMIA This is rarely associated with hypervolemia, and this association is always iatrogenic, e.g., administration of hypertonic sodium bicarbonate. Rather, hypernatremia is almost always the result of a combined water and volume deficit, with losses of H2O in excess of Na+. The most common causes are osmotic diuresis secondary to hyperglycemia, azotemia, or drugs (radiocontrast, mannitol, etc.) or central or nephrogenic diabetes insipidus (DI) (see “Polyuria,” Chap. 25). The evaluation of hypernatremia is outlined in Fig. 26-2.
FIGURE 26-2. Evaluation of hypernatremia.
The approach to correction of hypernatremia is outlined in Fig. 26-2 and Table 26-1. As with hyponatremia, it is advisable to correct the water deficit slowly to avoid neurologic compromise. In addition to the water replacement formula provided, other forms of therapy may be helpful in selected cases of hypernatremia. Pts with central DI may respond well to the administration of intranasal desmopressin or to the use of chlorpropamide (if the risk of drug- induced hypoglycemia is not excessive). Pts with nephrogenic DI due to lithium may reduce their polyuria with amiloride (2.5–10 mg/d) or hydrochlorothiazide (12.5–50 mg/d) or both in combination. Paradoxically, the use of diuretics may decrease distal nephron filtrate delivery, thereby reducing free-water losses and polyuria. Occasionally, NSAIDs have also been used to treat polyuria associated with nephrogenic DI; however, their nephrotoxic potential makes them a less attractive therapeutic option.
Table 26-1 Correction of Hypernatremia
Since potassium (K+) is the major intracellular cation, discussion of disorders of K+ balance must take into consideration changes in the exchange of intra- and extracellular K+ stores (extracellular K+ constitutes <2% of total-body K+ content). Insulin, b2-adrenergic agonists, and alkalosis tend to promote K+ uptake by cells; acidosis promotes shifting of K+.
HYPOKALEMIA Major causes of hypokalemia are outlined in Table 26-2. Atrial and ventricular arrhythmias are the major health consequences of hypokalemia. Pts with concurrent magnesium deficit (e.g., after diuretic therapy) and/or digoxin therapy are at particularly increased risk. Other clinical manifestations include muscle weakness, which may be profound at serum [K+] <2.5 mmol/L, and, if prolonged, ileus and polyuria. Clinical history and urinary [K+] are most helpful in distinguishing causes of hypokalemia.
Table 26-2 Causes of Hypokalemia
Hypokalemia is most often managed by correction of the acute underlying disease process (e.g., diarrhea) or withdrawal of an offending medication (e.g., loop or thiazide diuretic), along with oral K+ supplementation with KCl, or, in rare cases, KHCO3, or K-acetate. Hypokalemia may be refractory to correction in the presence of magnesium deficiency; both cations may need to be supplemented in selected cases (e.g., cisplatin nephrotoxicity). If loop or thiazide diuretic therapy cannot be discontinued, a distal tubular K-sparing agent, such as amiloride or spironolactone, can be added to the regimen. ACE inhibition in pts with CHF attenuates diuretic-induced hypokalemia and protects against cardiac arrhythmia. If hypokalemia is severe (<2.5 mmol/L) and/ or if oral supplementation is not tolerated, intravenous KCl can be administered through a central vein at rates which must not exceed 20 mmol/h, with telemetry and skilled monitoring.
HYPERKALEMIA Causes are outlined in Table 26-3. In most cases, hyperkalemia is due to decreased K+ excretion. Drugs can be implicated in many cases. Where the diagnosis is uncertain, calculation of the transtubular K gradient (TTKG) can be helpful. TTKG = UKPOSM/PKUOSM (U, urine; P, plasma). TTKG < 10 suggests decreased K+ excretion due to (1) hypoaldosteronism, or (2) renal resistance to the effects of mineralocorticoid. These can be differentiated by the administration of fludrocortisone (florinef) 0.2 mg, with the former increasing K+ excretion (and decreasing TTKG).
Table 26-3 Major Causes of Hyperkalemia
The most important consequence of hyperkalemia is altered cardiac conduction, leading to bradycardic cardiac arrest in severe cases. Hypocalcemia and acidosis accentuate the cardiac effects of hyperkalemia. Figure 26-3 shows serial ECG patterns of hyperkalemia. Stepwise treatment of hyperkalemia is summarized in table 26-4.
FIGURE 26-3. Diagrammatic ECGs at normal and high serum K. Peaked T waves (precordial leads) are followed by diminished R wave, wide QRS, prolonged P-R, loss of P wave, and ultimately a sine wave.
Table 26-4 Management of Hyperkalemia
ACID-BASE DISORDERS (See Fig. 26-4)
FIGURE 26-4. Nomogram, showing bands for uncomplicated respiratory or metabolic acid- base disturbances in intact subjects. Each “confidence” band represents the mean ±2 SD for the compensatory response of normal subjects or patients to a given primary disorder. Ac, acute; chr, chronic; resp, respiratory; met, metabolic; acid, acidosis; alk, alkalosis. (From Levinsky NG: HPIM-12, p. 290; modified from Arbus GS: Can Med Assoc J 109:291, 1973.)
Regulation of normal pH (7.35–7.45) depends on both the lungs and kidneys. By the Henderson-Hasselbalch equation, pH is a function of the ratio of HCO3 (regulated by the kidney) to PCO2 (regulated by the lungs). The HCO3/PCO2 relationship is useful in classifying disorders of acid-base balance. Acidosis is due to gain of acid or loss of alkali; causes may be metabolic (fall in serum HCO3) or respiratory (rise in PCO2). Alkalosis is due to loss of acid or addition of base and is either metabolic (
serum HCO3) or respiratory (¯ PCO2).
To limit the change in pH, metabolic disorders evoke an immediate compensatory response in ventilation; compensation to respiratory disorders by the kidneys takes days. Simple acid-base disorders consist of one primary disturbance and its compensatory response. In mixed disorders, a combination of primary disturbances is present. Mixed disorders should be suspected when the change in anion gap is significantly higher or lower than the change in serum HCO3 (see below).
METABOLIC ACIDOSIS The low HCO3– results from the addition of acids (organic or inorganic) or loss of HCO3–. The causes of metabolic acidosis are categorized by the anion gap, which equals Na+ – (Cl– + HCO3–) (Table 26-5). Increased anion gap acidosis (>12 mmol/L) is due to addition of acid (other than HCl) and unmeasured anions to the body. Causes include ketoacidosis (diabetes mellitus, starvation, alcohol), lactic acidosis, poisoning (salicylates, ethylene glycol, and ethanol) and renal failure.
Table 26-5 Metabolic Acidosis
Diagnosis may be made by measuring BUN, creatinine, glucose, lactate, serum ketones, and serum osmolality and obtaining a toxic screen. Certain commonly prescribed drugs (e.g., metformin, antiretroviral agents) are occasionally associated with lactic acidosis.
Normal anion gap acidoses result from HCO3– loss from the GI tract or from the kidney, e.g., renal tubular acidosis, urinary obstruction, rapid volume expansion with saline-containing solutions, and administration of NH4Cl, lysine HCl. Calculation of urinary anion gap may be helpful in evaluation of hyperchloremic metabolic acidosis. A negative anion gap suggests GI losses; a positive anion gap suggests altered urinary acidification.
Clinical features include hyperventilation, cardiovascular collapse, and nonspecific symptoms ranging from anorexia to coma.
Depends on cause and severity. Always correct the underlying disturbance. Administration of alkali is controversial. It may be reasonable to treat lactic acidosis with intravenous HCO3– at a rate sufficient to maintain a plasma HCO3– of 8–10 mmol/L and pH > 7.10. Lactic acidosis associated with cardiogenic shock may be worsened by bicarbonate administration.
Chronic acidosis should be treated when HCO3– < 18–20 mmol/L or symptoms of anorexia or fatigue are present. In pts with renal failure, there is some evidence that acidosis promotes protein catabolism and may worsen bone disease. Na citrate may be more palatable than oral NaHCO3, although the former should be avoided in pts with advanced renal insufficiency, as it augments aluminum absorption. Oral therapy with NaHCO3 usually begins with 650 mg tid and is titrated upward to maintain desired serum [HCO3–]. Other therapies for lactic acidosis (e.g., dichloroacetate) remain unproven.
METABOLIC ALKALOSIS A primary increase in serum [HCO3–]. Most cases originate with volume concentration and loss of acid from the stomach or kidney. Less commonly, HCO3– administered or derived from endogenous lactate is the cause and is perpetuated when renal HCO3– reabsorption continues. In vomiting, Cl– loss reduces its availability for renal reabsorption with Na+. Enhanced Na+ avidity due to volume depletion then accelerates HCO3– reabsorption and sustains the alkalosis. Urine Cl– is typically low (<10 mmol/L) (Table 26-6). Alkalosis may also be maintained by hyperaldosteronism, due to enhancement of H+ secretion and HCO3– reabsorption. Severe K+ depletion also causes metabolic alkalosis by increasing HCO3– reabsorption; urine Cl– >20 mmol/L.
Table 26-6 Metabolic Alkalosis
Vomiting and nasogastric drainage cause HCl and volume loss, kaliuresis, and alkalosis. Diuretics are a common cause of alkalosis due to volume contraction, Cl– depletion, and hypokalemia. Pts with chronic pulmonary disease and high PCO2 and serum HCO3– levels whose ventilation is acutely improved may develop alkalosis.
Excessive mineralocorticoid activity due to Cushing’s syndrome (worse in ectopic ACTH or primary hyperaldosteronism) causes metabolic alkalosis not associated with volume or Cl– depletion and not responsive to NaCl.
Severe K+ depletion also causes metabolic alkalosis.
Diagnosis The [Cl–] from a random urine sample is useful (Table 26-6) unless diuretics have been administered. Determining the fractional excretion of Cl–, rather than the fractional excretion of Na+, is the best way to identify an alkalosis responsive to volume expansion.
Correct the underlying cause. In cases of Cl– depletion, administer NaCl; and in hypokalemia, add KCl. Pts with adrenal hyperfunction require treatment of the underlying disorder. Severe alkalosis may require, in addition, treatment with acidifying agents such as NaCl, HCl, or acetazolamide. The initial amount of H+ needed (in mmol) should be calculated from 0.5 × (body wt in kg) × (serum HCO3– – 24).
RESPIRATORY ACIDOSIS Characterized by CO2 retention due to ventilatory failure. Causes include sedatives, stroke, chronic pulmonary disease, airway obstruction, severe pulmonary edema, neuromuscular disorders, and cardiopulmonary arrest. Symptoms include confusion, asterixis, and obtundation.
The goal is to improve ventilation through pulmonary toilet and reversal of bronchospasm. Intubation may be required in severe acute cases. Acidosis due to hypercapnia is usually mild.
RESPIRATORY ALKALOSIS Excessive ventilation causes a primary reduction in CO2 and
pH in pneumonia, pulmonary edema, interstitial lung disease, asthma. Pain and psychogenic causes are common; other etiologies include fever, hypoxemia, sepsis, delirium tremens, salicylates, hepatic failure, mechanical overventilation, and CNS lesions. Pregnancy is associated with a mild respiratory alkalosis. Severe respiratory alkalosis may cause seizures, tetany, cardiac arrhythmias, or loss of consciousness.
Should be directed at the underlying disorders. In psychogenic cases, sedation or a rebreathing bag may be required.
“MIXED” DISORDERS In many circumstances, more than a single acid- base disturbance exists. Examples include combined metabolic and respiratory acidosis with cardiogenic shock; metabolic alkalosis and acidosis in pts with vomiting and diabetic ketoacidosis; metabolic acidosis with respiratory alkalosis in pts with sepsis. The diagnosis may be clinically evident or suggested by relationships between the PCO2 and HCO3– that are markedly different from those found in simple disorders.
In simple anion-gap acidosis, anion gap increases in proportion to fall in [HCO3–]. When increase in anion gap occurs despite a normal [HCO3–], simultaneous anion-gap acidosis and metabolic alkalosis are suggested. When fall in [HCO3–] due to metabolic acidosis is proportionately larger than increase in anion gap, mixed anion-gap and non-anion-gap metabolic acidosis is suggested.
For a more detailed discussion, see Singer GG, Brenner BM: Fluids and Electrolyte Disturbances, Chap. 49, p. 271; and DuBose TD Jr: Acidosis and Alkalosis, Chap. 50, p. 283, in HPIM-15.