Disorders of water, electrolytes, and acid-base metabolism

Hypo-osmotic hyponatremia.

Typically, when plasma Na ⁺ concentration is low, calculated, or measured, osmolality will also be low. This type of hyponatremia can be due to excess loss of Na ⁺ (depletional hyponatremia) or increased ECF volume (dilutional hyponatremia). Differentiating these initially requires clinical assessment of TBW and ECF volume by history and physical examination.

Depletional hyponatremia results from a loss of Na ⁺ from the ECF space that exceeds the concomitant loss of water. Hypovolemia is apparent in the physical examination (orthostatic hypotension, tachycardia, decreased skin turgor). If urine Na ⁺ is low (<10 mmol/L), the kidneys are properly retaining filtered Na ⁺ and the loss is extrarenal, most commonly from the gastrointestinal tract or skin (see Fig. 50.3 ). Preventing ongoing loss and restoring ECF volume with isotonic fluid is sufficient to correct hyponatremia in these situations.

Alternatively, if urine Na ⁺ is increased in this setting (generally >20 mmol/L), renal loss of Na ⁺ is likely. Renal loss of Na ⁺ occurs with (1) osmotic diuresis, (2) use of diuretics (which inhibit reabsorption of Cl ⁻ and Na ⁺ in the ascending loop), (3) adrenal insufficiency (no aldosterone or cortisone prevents distal tubule reabsorption of Na ⁺ ), or (4) salt-wasting nephropathies, as can occur with interstitial nephritis and tubular recovery after acute tubular necrosis or obstructive nephropathy. Hypo-osmotic hyponatremia has also been attributed to cerebral salt wasting, a controversial diagnosis associated with subarachnoid hemorrhage (SAH) and other intracranial diseases/trauma. Despite being described in literature for ≈70 years, the condition remains controversial because the mechanism of the condition remains undefined. If it is a physiologic condition, it is exceedingly rare as evidenced in a publication detailing a series of 100 patients with SAH. Of this population of 100 patients, 49 developed hyponatremia and the cause of the hyponatremia was ascribed to syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 71.4% patients. Of the remaining hyponatremic patients, 10.2% were incorrectly treated with hypotonic saline (0.45% saline), 10.2% were hypovolemic, and the remaining 8.2% had acute cortisol deficiency.

Renal loss of Na ⁺ in excess of H ₂ O can also occur in metabolic alkalosis from prolonged vomiting, because increased renal HCO ₃ ⁻ excretion is accompanied by Na ⁺ ions. In this case, urine sodium is increased (>20 mmol/L), but urine chloride remains low. In proximal renal tubular acidosis (RTA) type 2, bicarbonate is lost because of a defect in HCO ₃ ⁻ reabsorption, and Na ⁺ is co-excreted to maintain electrical neutrality. As with extrarenal Na ⁺ loss, management of hyponatremia attributable to renal Na ⁺ loss is centered on the reversal of underlying cause and restoration of ECF volume.

Dilutional hyponatremia is a result of excess H ₂ O retention and often can be detected during the physical examination as edema. In advanced renal failure, water is retained because of decreased filtration and H ₂ O excretion. When ECF is increased but the circulating blood volume is decreased, as occurs in hepatic cirrhosis, heart failure, and nephrotic syndrome, a vicious cycle is established. The decreased blood volume is sensed by baroreceptors and results in increased aldosterone and vasopressin, even though ECF volume is excessive. The kidneys reabsorb Na ⁺ and H ₂ O in response to increased aldosterone and vasopressin in an attempt to restore the blood volume, resulting in further increases in ECF and further dilution of Na ⁺ . In dilutional hyponatremia, the low serum sodium concentrations reflect the severity of the underlying disease process. Management should be focused on the treatment of the underlying disease, as correction of Na ⁺ concentrations alone have no effect on overall morbidity or mortality.

In hypo-osmotic hyponatremia with a normal or euvolemic volume status, the most common causes are the syndrome of inappropriate ADH (vasopressin) (SIADH), primary polydipsia, and endocrine disorders such as adrenal insufficiency and hypothyroidism (see Fig. 50.3 ). Adrenal insufficiency causes hyponatremia through increased cortisol-releasing hormone, which stimulates vasopressin release, while hypothyroidism impairs free H ₂ O excretion. SIADH describes hyponatremia attributable to “inappropriate” vasopressin release, as from a malignancy, which stimulates excessive H ₂ O retention and increased urine osmolality. Free water restriction is the mainstay of therapy in SIADH. However, in severe or symptomatic hyponatremia from any cause, the use of hypertonic saline solutions may be required to correct serum Na ⁺ concentrations. In such cases, the hyponatremia must be corrected cautiously because too rapid correction can lead to brain demyelination (a condition known as osmotic demyelination syndrome). The pons is particularly sensitive to this, and rapid correction can lead to central pontine myelinolysis, a devastating condition characterized by dysarthria, dysphagia, weakness, and paralysis of the appendages, and, in the most serious cases, coma, paralysis of all voluntary muscles except those controlling the eye (locked-in syndrome), and death. Current recommendations are to increase Na ⁺ by 0.5 to 2.0 mmol/L per hour and not to exceed a total increase in Na ⁺ greater than 18 over 48 hours. For patients with severe symptoms, an easy-to-remember strategy called the “rule of sixes” is recommended (using the abbreviations six’s for symptoms): “six a day makes sense for safety; so six [mmol/L] in 6 hours for severe sx’s and stop.”

Finally, euvolemic hyponatremia also can be found in primary polydipsia when water intake is greater than the renal capacity to excrete excess H ₂ O. This can be the result of psychiatric illness, but diseases that cause hypothalamic disorders, such as sarcoidosis, also may cause polydipsia by altering the thirst reflex (see Fig. 50.3 ).

Hyperosmotic hyponatremia.

Hyponatremia in the presence of increased quantities of other solutes in the ECF is the result of an extracellular shift of water or an intracellular shift of Na ⁺ to maintain osmotic balance between ECF and ICF compartments. The most common cause of this type of hyponatremia is severe hyperglycemia (see Fig. 50.3 ). As a general rule, Na ⁺ is decreased by ≈1.6 to 2.0 mmol/L for every 100-mg/dL (5.6-mmol/L) increase in glucose greater than 100 mg/dL (5.6 mmol/L). Correction of hyperglycemia alone will restore normal blood Na ⁺ . It also may occur when unmeasured solutes, such as mannitol, radiographic contrast agents, and glycine (surgical irrigant solutions), enter the intravascular fluid compartment. In these circumstances, plasma osmolality cannot be calculated accurately and it must be ascertained by direct measurement.

Isosmotic hyponatremia.

If the measured Na ⁺ concentration in plasma is decreased, but measured plasma osmolality, glucose, and urea are normal, the most likely explanation is pseudohyponatremia caused by the electrolyte exclusion effect (see Chapter 37 ). This occurs when Na ⁺ is measured by an indirect ion-selective electrode (ISE) in patients with severe hyperlipidemia or, less commonly, hyperproteinemia. Hyperlipidemia, manifested primarily as hypertriglyceridemia, although a more common cause of pseudohyponatremia, is typically detected by visual or spectrophotometric screening of samples prior to analysis. Hypercholesterolemia, which in contrast, is not reliably detected by visual or spectrophotometric screening, may produce pseudohyponatremia. The common culprit in hypercholesterolemia-induced pseudohyponatremia is lipoprotein X, an abnormal lipid particle arising in the setting of cholestasis. However, it is worth noting that high cholesterol concentrations are less likely to produce pseudohyponatremia, because the molecular mass of cholesterol is approximately 2.5 times lower than triglycerides and thus displaces a smaller amount of plasma water than triglycerides.

Hyperproteinemia, the other common cause of pseudohyponatremia, also cannot be detected by visual or spectrophotometric inspection. As shown in a recent study, only 10.9% of sodium test orders included an order for total protein, and the prevalence of pseudohyponatremia due to hyperproteinemia (>7.9 g/dL) at a large academic medical center was 5.3%. Of note, 36.6% of high total protein results in that study came from the hematology and oncology clinics, and many of the patients had restricted protein bands consistent with monoclonal disorders such as multiple myeloma or waldenstrom macroglobulinemia. Given that a high proportion of those patients with high total protein also had restricted peaks consistent with a plasma cell disorder, it is important to raise awareness of the potential for these patients to be at risk for pseudohyponatremia.

For laboratories serving a population with a high percentage of plasma cell disorders, the availability of a direct ISE method to help with the investigation of potential pseudohyponatremia cases is important because direct ISE methods are not subject to pseudohyponatremia.

Hypovolemic hypernatremia.

Hypernatremia in the setting of decreased ECF is caused by renal or extrarenal loss of hypo-osmotic fluid, leading to dehydration. Thus once hypovolemia is established by physical examination, measurement of urine Na ⁺ and osmolality is used to determine the source of fluid loss. Patients who have large extrarenal losses will have concentrated urine (often >800 mOsmol/kg) with low urine Na ⁺ (<20 mmol/L), reflecting a proper renal response to conserve Na ⁺ and water to restore ECF volume. Extrarenal causes include diarrhea, skin losses (burns, fever, or excessive sweating), and respiratory losses coupled with failure to replace the water. When gastrointestinal loss is excluded, and the patient has normal mental status and access to H ₂ O, a hypothalamic disorder (tumor or granuloma) inducing diabetes insipidus (DI) should be suspected.

In patients with poorly controlled diabetes with glucose values greater than 600 mg/dL (33.3 mmol/L), an osmotic diuresis can occur that results in extreme dehydration and hypernatremia. This condition is referred to as hyperosmolar hyperglycemic nonketotic syndrome and occurs most commonly in elderly individuals with type 2 diabetes.

Normovolemic hypernatremia.

Hypernatremia in the presence of normal ECF volume is often a prelude to hypovolemic hypernatremia. Insensible losses through the lung or skin must be suspected and are characterized by concentrated urine as the kidneys conserve water. Another cause of normovolemic hypernatremia is water diuresis, which is manifested by polyuria (see Fig. 50.4 ). The differential for polyuria (generally defined as greater than 3 L urine output/day) is a water or solute diuresis. Solute diuresis is exemplified by the osmotic diuresis of diabetes mellitus and generally is characterized by urine osmolality greater than 300 mOsmol/kg and hyponatremia (see previous discussion in this chapter). Water diuresis, a manifestation of DI, is characterized by dilute urine (osmolality <250 mOsmol/kg) and hypernatremia. DI can be central or nephrogenic. Central DI is due to decreased or absent vasopressin secretion resulting from head trauma, hypophysectomy, pituitary tumor, or granulomatous disease. Nephrogenic DI is due to renal resistance to vasopressin as a result of drugs (e.g., lithium, demeclocycline, amphotericin, propoxyphene); electrolyte disorders (e.g., hypercalcemia, hypokalemia); sickle cell anemia or Sjögren syndrome, which affect collecting duct responsiveness to vasopressin; or, more rarely, mutant vasopressin receptors. When thirst and access to water are uncompromised, many patients with DI will remain normonatremic because their free water losses are offset by intake. Such patients display symptoms of only polyuria and polydipsia. However, overt hypernatremia can manifest with progression of underlying causes, impaired thirst, or restricted access to water. Administration of vasopressin can be used to treat central DI, although patients with nephrogenic DI may be resistant to it. Correction of underlying disorders or discontinuation of offending drugs may be required to normalize Na ⁺ concentrations in nephrogenic DI.

Hypervolemic hypernatremia.

The presence of excess TBW and hypernatremia indicates a net gain of water and Na ⁺ , with Na ⁺ gain in excess of water (see Fig. 50.4 ). This rare condition is observed most commonly in hospitalized patients receiving hypertonic saline or sodium bicarbonate. It affects acute kidney injury (AKI) patients in the ICU at a high rate because these patients are often given large quantities of physiologic saline, leading to sodium and water retention (as evidenced by edema and substantial weight gain). Hypernatremia then develops during the recovery of their renal function due to loss of water in excess of sodium and potassium. This type of hypernatremia can be prevented by paying close attention to the water and sodium balance in patients with large urine or stool outputs.

Rarely, hypervolemic hypernatremia may also be the result of the intentional or accidental ingestion of large quantities of sodium rich fluids, otherwise known as salt poisoning. Ingestion of a concentrated salt (NaCl) solution may induce vomiting and had previously been used as an emetic. However, because a salt water solution may also produce life-threatening hyponatremia, the use of salt water as an emetic should be strongly discouraged.

The causes of salt poisoning also include inappropriately reconstituted oral rehydration solutions and infant formula, as well as the intentional ingestion of high-sodium solutions such as soy sauce, in suicide attempts.

In contrast to other causes of hypernatremia, in which a rapid correction of hypernatremia may produce osmotic demyelination, the rapid correction of acute salt poisoning with hypotonic solutions can prevent intracranial hemorrhage and neurologic sequelae.

Redistribution.

Intracellular redistribution of K ⁺ is illustrated by the fall in plasma K ⁺ that occurs after insulin therapy for diabetic hyperglycemia. Insulin plays a crucial role in maintaining the intracellular distribution of K ⁺ through active cellular transport and glucose control. In alkalosis, redistribution hypokalemia occurs when K ⁺ moves from ECF into cells as H ⁺ ions are pumped out by the Na ⁺ -H ⁺ antiporter. The resulting increase in intracellular Na ⁺ concentration from the action of the Na ⁺ -H ⁺ antiporter increases the activity of the Na ⁺ /K ⁺ -ATPase, resulting in a decrease in ECF K ⁺ . In addition, renal conservation of H ⁺ in the distal tubule occurs at the expense of K ⁺ . Hypokalemia is not an uncommon condition in in patients with cancer, either due to effects of the tumor itself on adrenal or renal tissues or from side effects of the chemotherapeutic medications. However, it is important in this group to be sure that the hypokalemia is true hypokalemia and not due to pseudohypokalemia.

The risk of pseudohypokalemia is higher in patients with hematologic malignancies associated with acute leukemia. Pseudohypokalemia can arise when blood samples from patients with very high white blood cell counts are allowed to stand at room temperature prior to processing and analysis. Pseudohypokalemia arises in this setting due to a time-dependent redistribution of K ⁺ from the plasma fraction into leukemic cells after the blood sample is collected. In addition, use of myelopoietic growth factors after chemotherapy can lead to rapid K ⁺ uptake by new cells. In these settings, it is important to process the samples as quickly as possible. Other causes of intracellular redistribution are listed in Fig. 50.5 . Clinically, redistributive hypokalemia is generally a transient phenomenon that is reversed once underlying conditions are corrected. Therefore careful monitoring during treatment of these patients is essential to avoid overcorrection (termed “rebound hyperkalemia”), especially when considering that supplemental potassium is a common cause of hyperkalemia in hospitalized patients.

True potassium deficit.

Hypokalemia reflecting true total body deficits of K ⁺ because of potassium loss can be classified into renal and nonrenal losses, based on daily excretion of K ⁺ in the urine (see Fig. 50.5 ). If urine excretion of K ⁺ is less than 30 mmol/d, it can be concluded that the kidneys are functioning properly and are attempting to reabsorb K ⁺ . The cause may be decreased K ⁺ intake or extrarenal loss of K ⁺ -rich fluid. Causes of decreased intake include chronic starvation and postoperative intravenous fluid therapy with K ⁺ -poor solutions. Gastrointestinal loss of K ⁺ occurs most commonly with diarrhea and loss of gastric fluid through vomiting.

Urine excretion exceeding 25 to 30 mmol/day in a hypokalemic setting is inappropriate and indicates that the kidneys are the primary source of K ⁺ loss. Renal losses of K ⁺ may occur during the diuretic (recovery) phase of acute tubular necrosis and during states of excess mineralocorticoid (primary or secondary aldosteronism) or glucocorticoid (Cushing’s syndrome) production when the distal tubules increase Na ⁺ reabsorption and K ⁺ excretion. Renal loss of K ⁺ is also caused by thiazide and loop diuretics. In addition to redistribution of K ⁺ into cells in an alkalotic setting, K ⁺ can be lost from the kidneys in exchange for reclaimed H ⁺ ions. This cause of true hypokalemia will be evident in low urine Cl ⁻ and an alkaline urine. In patients with cancer, increased renal K ⁺ loss may be due to chemotherapy (e.g., cisplatin)-induced nephron and tubular damage. Magnesium deficiency also can lead to increased renal loss of K ⁺ , which is attributable to a reduction in the inhibitory effect of magnesium on luminal potassium channels.

True potassium deficit requires replacement of potassium. Although there are dietary sources of potassium, such as potatoes and tomatoes, significant K ⁺ losses may require oral or intravenous supplementation with potassium chloride. The oral route is generally preferred, although intravenous correction should be pursued in patients with severe or symptomatic hypokalemia and those who are unable to take oral medication. In individuals with ongoing sources of potassium losses, such as patients on diuretics, chronic supplementation with a daily regimen of oral potassium chloride is often used.

Redistribution.

The transfer of intracellular K ⁺ into ECF invariably occurs in acidemia as K ⁺ shifts outward as the result of pH-induced changes in Na ⁺ /K ⁺ -ATPase activity. In general, K ⁺ concentrations can be expected to rise 0.2 to 0.5 mmol/L for every 0.1-unit drop in pH. When acidemia is corrected, normokalemia will be restored rapidly. Extracellular redistribution of K ⁺ also may occur in (1) tissue hypoxia; (2) insulin deficiency (e.g., diabetic ketoacidosis); (3) massive intravascular hemolysis; (4) severe burns; (5) violent muscular activity, as in status epilepticus; (6) rhabdomyolysis; and (7) tumor lysis syndrome. Finally, important iatrogenic causes of redistribution hyperkalemia include digoxin toxicity and β-adrenergic blockade, especially in patients with diabetes or on dialysis. Redistributive hyperkalemia can be corrected by reversing the aberrations that cause K ⁺ to shift out of cells. Insulin and sodium bicarbonate are commonly used and have a quick onset of action, particularly in the diabetic or acidemic setting. Drug-induced causes require cessation or dose reduction of the offending agent. Patients with digoxin toxicity should be given antibodies to digoxin as well, because of the high risk for mortality associated with hyperkalemia and supratherapeutic administration of digoxin.

Potassium retention.

When glomerular filtration rate (GFR) or renal tubular function is decreased, hyperkalemia will often occur. In the absence of severe renal failure, hyperkalemia is seldom prolonged and may not even occur in some cases. Decreased excretion of K ⁺ in moderate and acute renal disease and end-stage renal failure (with oliguria or anuria) are the most common causes of prolonged hyperkalemia (see Fig. 50.6 ). Hyperkalemia occurs along with Na ⁺ depletion in adrenocortical insufficiency (e.g., Addison disease) because diminished Na ⁺ reabsorption results in decreased tubular K ⁺ secretion. Drugs that block the production of aldosterone, such as inhibitors of angiotensin-converting enzyme (ACE inhibitors; e.g., lisinopril), nonsteroidal antiinflammatory drugs, and angiotensin II–receptor blockers, may also cause hyperkalemia. Excess administration of potassium-sparing diuretics that block distal tubular K ⁺ secretion (e.g., triamterene, spironolactone) may also cause hyperkalemia. In patients with cancer, hyperkalemia can be caused by adrenal insufficiency secondary to metastases to the adrenal glands, nephrotoxic chemotherapy agents (e.g., mitomycin-C, methotrexate, platinum compounds), postrenal obstruction, or tumor lysis syndrome. Treatment of hyperkalemia includes agents that increase cellular uptake of K ⁺ , such as glucose given with insulin, sodium bicarbonate, and β ₂ -adrenergic agonists. The rapid onset of these agents provides a quick reduction in ECF potassium concentrations, thus reducing the risk for immediate life-threatening cardiac effects of hyperkalemia.

In the setting of hyperkalemia, calcium salts are also frequently administered to counteract the depolarizing effects of high extracellular K ⁺ . High K ⁺ concentration increases the resting membrane potential of the myocyte from approximately −90 to −80 mV, which is close to the depolarization threshold of −75 mV. This results in a greater likelihood of myocyte depolarization and arrhythmia. Infusion of calcium, in the form of CaCl ₂ or calcium gluconate, rapidly increases extracellular Ca ²⁺ concentrations, which raise the depolarization threshold to approximately −65 mV. Raising the depolarization threshold to −65 mV re-establishes the interval between the normal resting potential and normal depolarization threshold, in effect decreasing myocyte excitability.

However, infusion of calcium does not contribute to the redistribution of extracellular potassium and should be combined with other treatment modalities. It is also important to note that treatments that increase intracellular redistribution of potassium are only temporizing measures when there is a true excess of potassium, and they need to be coupled with interventions that remove potassium from the circulation. To reduce the total body content of potassium, patients can be given K ⁺ -losing diuretics, cation-exchange resins, and, finally, hemodialysis. Stimulation of renal potassium excretion is preferred because the use of cation-exchange resins can be associated with bowel necrosis, particularly when given per rectum. Hemodialysis is an option of last resort, removing potassium through an extracorporeal circuit, which stimulates diffusion of potassium out of the circulating blood and into the discarded dialysate.