The diagnosis and treatment of fluid and electrolyte disorders are based on (1) careful history, (2) physical examination and assessment of total body water and its distribution, (3) serum electrolyte concentrations, (4) urine electrolyte concentrations, and (5) serum osmolality. The pathophysiology of electrolyte disorders is rooted in basic principles of total body water and its distribution across fluid compartments.
Total body water is different in men than in women, and it decreases with aging (Table 21–1). Approximately 50–60% of total body weight is water; two-thirds (40% of body weight) is intracellular, while one-third (20% of body weight) is extracellular. One-fourth of extracellular fluid (5% of body weight) is intravascular. Water may be lost from either or both compartments (intracellular and extracellular). Changes in total body water content are best evaluated by documenting changes in body weight. Effective circulating volume may be assessed by physical examination (eg, blood pressure, pulse, jugular venous distention). Quantitative measurements of effective circulating volume and intravascular volume may be invasive (ie, central venous pressure or pulmonary wedge pressure) or noninvasive (ie, inferior vena cava diameter and right atrial pressure by echocardiography) but still require careful interpretation.
Table 21–1. Total body water (as percentage of body weight) in relation to age and sex.
The cause of electrolyte disorders may be determined by reviewing the history, underlying diseases, and medications.
The urine concentration of an electrolyte indicates renal handling of the electrolyte and whether the kidney is appropriately excreting or retaining the electrolyte. A 24-hour urine collection for daily electrolyte excretion is the gold standard for renal electrolyte handling, but it is slow and onerous. A more convenient method is the fractional excretion (FE) of an electrolyte X (FEX) calculated from a spot urine sample:
A low fractional excretion indicates renal reabsorption (high avidity or electrolyte retention), while a high fractional excretion indicates renal wasting (low avidity or electrolyte excretion). Thus, the fractional excretion helps the clinician determine whether the kidney’s response is appropriate for a specific electrolyte disorder.
Solute concentration is measured by osmolality in millimoles per kilogram. Osmolarity is measured in millimoles of solute per liter of solution. At physiologic solute concentrations (normally 285–295 mmol/kg), the two measurements are clinically interchangeable. Tonicity refers to osmolytes that are impermeable to cell membranes. Differences in osmolyte concentration across cell membranes lead to osmosis and fluid shifts, stimulation of thirst, and secretion of antidiuretic hormone (ADH). Substances that easily permeate cell membranes (eg, urea, ethanol) are ineffective osmoles that do not cause fluid shifts across fluid compartments.
Serum osmolality can be estimated using the following formula:
(1 mosm/L of glucose equals 180 mg/L or 18 mg/dL and 1 mosm/L of urea nitrogen equals 28 mg/L or 2.8 mg/dL). Sodium is the major extracellular cation; doubling the serum sodium in the formula for estimated osmolality accounts for counterbalancing anions. A discrepancy between measured and estimated osmolality of > 10 mmol/kg suggests an osmolal gap, which is the presence of unmeasured osmoles such as ethanol, methanol, isopropanol, and ethylene glycol (see Table 38–5).
ESSENTIALS OF DIAGNOSIS
Volume status and serum osmolality are essential to determine etiology.
Hyponatremia usually reflects excess water retention relative to sodium rather than sodium deficiency. The sodium concentration is not a measure of total body sodium.
Hypotonic fluids commonly cause hyponatremia in hospitalized patients.
Defined as a serum sodium concentration < 135 mEq/L (or < 135 mmol/L), hyponatremia is the most common electrolyte abnormality in hospitalized patients. The clinician should be wary about hyponatremia since mismanagement can result in neurologic catastrophes from cerebral osmotic demyelination. Indeed, iatrogenic complications from aggressive or inappropriate therapy can be more harmful than hyponatremia itself.
A common misconception is that the sodium concentration is a reflection of total body sodium or total body water. In fact, total body water and sodium can be low, normal, or high in hyponatremia since the kidney independently regulates sodium and water homeostasis. Most cases of hyponatremia reflect water imbalance and abnormal water handling, not sodium imbalance, indicating the primary role of ADH in the pathophysiology of hyponatremia. A diagnostic algorithm using serum osmolality and volume status separates the causes of hyponatremia into therapeutically useful categories (Figure 21–1).
Figure 21–1. Evaluation of hyponatremia using serum osmolality and extracellular fluid volume status. ACE, angiotensin-converting enzyme; SIADH, syndrome of inappropriate antidiuretic hormone. (Adapted, with permission, from Narins RG et al. Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am J Med. 1982 Mar;72(3):496–520.)
Serum osmolality identifies isotonic and hypertonic hyponatremia, although these cases can often be identified by careful history or previous laboratory tests.
Isotonic hyponatremia is seen with severe hyperlipidemia and hyperproteinemia. Lipids (including chylomicrons, triglycerides, and cholesterol) and proteins (> 10 g/dL [> 100 g/L], eg, paraproteinemias and intravenous immunoglobulin therapy) interfere with the measurement of serum sodium, causing pseudohyponatremia. Serum osmolality is isotonic because lipids and proteins do not affect osmolality measurement. Newer sodium assays using ion-specific electrodes on undiluted serum specimens (ie, the direct assay method) will not result in pseudohyponatremia.
Hypertonic hyponatremia occurs with hyperglycemia and mannitol administration for increased intracranial pressure. Glucose and mannitol osmotically pull intracellular water into the extracellular space. The translocation of water lowers the serum sodium concentration. Translocational hyponatremia is not pseudohyponatremia or an artifact of sodium measurement. The sodium concentration falls 2 mEq/L (or 2 mmol/L) for every 100 mg/dL (or 5.56 mmol/L) rise in glucose when the glucose concentration is between 200 mg/dL and 400 mg/dL (11.1 mmol/L and 22.2 mmol/L). If the glucose concentration is > 400 mg/dL, the sodium concentration falls 4 mEq/L for every 100 mg/dL rise in glucose. There is some controversy about the correction factor for the serum sodium in the presence of hyperglycemia. Many guidelines recommend a correction factor, whereby the serum sodium concentration decreases by 1.6 mEq/L (or 1.6 mmol/L) for every 100 mg/dL (5.56 mmol/L) rise in plasma glucose above normal, but there is evidence that the decrease may be greater when patients have more severe hyperglycemia (> 400 mg/dL or 22.2 mmol/L) or volume depletion, or both. One group has suggested (based on short-term exposure of normal volunteers to markedly elevated glucose levels) that when the serum glucose is > 200 mg/dL, the serum sodium concentration decreases by at least 2.4 mEq/L (or 2.4 mmol/L).
Most cases of hyponatremia are hypotonic, highlighting sodium’s role as the predominant extracellular osmole. The next step is classifying hypotonic cases by the patient’s volume status.
1. Hypovolemic hypotonic hyponatremia—Hypovolemic hyponatremia occurs with renal or extrarenal volume loss and hypotonic fluid replacement (Figure 21–1). Total body sodium and total body water are decreased. To maintain intravascular volume, the pituitary increases ADH secretion, causing free water retention from hypotonic fluid replacement. The body sacrifices serum osmolality to preserve intravascular volume. In short, losses of water and salt are replaced by water alone. Without ongoing hypotonic fluid intake, the renal or extrarenal volume loss would produce hypovolemic hypernatremia.
Cerebral salt wasting is a distinct and rare subset of hypovolemic hyponatremia seen in patients with intracranial disease (eg, infections, cerebrovascular accidents, tumors, and neurosurgery). Clinical features include refractory hypovolemia and hypotension, often requiring continuous infusion of isotonic or hypertonic saline and ICU monitoring. The exact pathophysiology is unclear but includes renal sodium wasting possibly through B-type natriuretic peptide, ADH release, and decreased aldosterone secretion.
2. Euvolemic hypotonic hyponatremia—Euvolemic hyponatremia has the broadest differential diagnosis. Most causes are mediated directly or indirectly through ADH, including hypothyroidism, adrenal insufficiency, medications, and the syndrome of inappropriate ADH (SIADH). The exceptions are primary polydipsia, beer potomania, and reset osmostat.
A. HORMONAL ABNORMALITIES—Hypothyroidism and adrenal insufficiency can cause hyponatremia. Exactly how hypothyroidism induces hyponatremia is unclear but may be related to ADH. Adrenal insufficiency may be associated with the hyperkalemia and metabolic acidosis of hypoaldosteronism. Cortisol provides feedback inhibition for ADH release.
B. THIAZIDE DIURETICS AND OTHER MEDICATIONS—Thiazides induce hyponatremia typically in older female patients within days of initiating therapy. The mechanism appears to be a combination of mild diuretic-induced volume contraction, ADH effect, and intact urinary concentrating ability resulting in water retention and hyponatremia. Loop diuretics do not cause hyponatremia as frequently because of disrupted medullary concentrating gradient and impaired urine concentration.
Nonsteroidal anti-inflammatory drugs (NSAIDs) increase ADH by inhibiting prostaglandin formation. Prostaglandins and selective serotonin reuptake inhibitors (eg, fluoxetine, paroxetine, and citalopram) can cause hyponatremia, especially in geriatric patients. Enhanced secretion or action of ADH may result from increased serotonergic tone. Angiotensin-converting enzyme (ACE) inhibitors do not block the conversion of angiotensin I to angiotensin II in the brain. Angiotensin II stimulates thirst and ADH secretion. Hyponatremia during amiodarone loading has been reported; it usually improves with dose reduction.
Abuse of 3,4-methylenedioxymethamphetamine (MDMA, also known as Ecstasy) can lead to hyponatremia and severe neurologic symptoms, including seizures, cerebral edema, and brainstem herniation. MDMA and its metabolites increase ADH release from the hypothalamus. Primary polydipsia may contribute to hyponatremia since MDMA users typically increase fluid intake to prevent hyperthermia.
C. NAUSEA, PAIN, SURGERY, AND MEDICAL PROCEDURES—Nausea and pain are potent stimulators of ADH release. Severe hyponatremia can develop after elective surgery in healthy patients, especially premenopausal women. Hypotonic fluids in the setting of elevated ADH levels can produce severe, life-threatening hyponatremia. Medical procedures such as colonoscopy have also been associated with hyponatremia.
D. HIV INFECTION—Hyponatremia is seen in up to 50% of hospitalized HIV-infected patients and 20% of ambulatory HIV-infected patients. The differential diagnosis is broad: medication effect, adrenal insufficiency, hypoaldosteronism, central nervous system or pulmonary disease, SIADH, malignancy, and volume depletion.
E. EXERCISE-ASSOCIATED HYPONATREMIA—Hyponatremia after exercise, especially endurance events such as triathlons and marathons, may be caused by a combination of excessive hypotonic fluid intake and continued ADH secretion. Reperfusion of the exercise-induced ischemic splanchnic bed causes delayed absorption of excessive quantities of hypotonic fluid ingested during exercise. Sustained elevation of ADH prevents water excretion in this setting. Current guidelines suggest that endurance athletes drink water according to thirst rather than according to specified hourly rates of fluid intake. Specific universal recommendations for fluid replacement rates are not possible given the variability of sweat production, renal water excretion, and environmental conditions. Electrolyte-containing sport drinks do not protect against hyponatremia since they are markedly hypotonic relative to serum.
F. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION—Under normal circumstances, hypovolemia and hyperosmolality stimulate ADH secretion. ADH release is inappropriate without these physiologic cues. Normal regulation of ADH release occurs from both the central nervous system and the chest via baroreceptors and neural input. The major causes of SIADH (Table 21–2) are disorders affecting the central nervous system (structural, metabolic, psychiatric, or pharmacologic processes) or the lungs (infectious, mechanical, oncologic). Medications commonly cause SIADH by increasing ADH or its action. Some carcinomas, especially small cell lung carcinoma, can autonomously secrete ADH.
Table 21–2. Causes of syndrome of inappropriate ADH secretion (SIADH).
G. PSYCHOGENIC POLYDIPSIA AND BEER POTOMANIA—Marked free water intake (generally > 10 L/d) may produce hyponatremia. Euvolemia is maintained through renal excretion of sodium. Urine sodium is therefore generally elevated (> 20 mEq/L), and ADH levels are appropriately suppressed. As the increased free water is excreted, the urine osmolality approaches the minimum of 50 mosm/kg (or 50 mmol/kg). Polydipsia occurs in psychiatric patients. Psychiatric medications may interfere with water excretion or increase thirst through anticholinergic side effects, further increasing water intake. The hyponatremia of beer potomania occurs in patients who consume large amounts of beer. Free water excretion is decreased because of decreased solute consumption and production; muscle wasting and malnutrition are contributing factors. Without enough solute, these patients have decreased free water excretory capacity even if they maximally dilute the urine.
H. RESET OSMOSTAT—Reset osmostat is a rare cause of hyponatremia characterized by appropriate ADH regulation in response to water deprivation and fluid challenges. Patients with reset osmostat regulate serum sodium and serum osmolality around a lower set point, concentrating or diluting urine in response to hyperosmolality and hypo-osmolality. The mild hypo-osmolality of pregnancy is a form of reset osmostat.
3. Hypervolemic hypotonic hyponatremia—Hypervolemic hyponatremia occurs in the edematous states of cirrhosis, heart failure, nephrotic syndrome, and advanced kidney disease (Figure 21–1). In cirrhosis and heart failure, effective circulating volume is decreased due to peripheral vasodilation or decreased cardiac output. Increased renin-angiotensin-aldosterone system activity and ADH secretion result in water retention. Note the pathophysiologic similarity to hypovolemic hyponatremia—the body sacrifices osmolality in an attempt to restore effective circulating volume.
The pathophysiology of hyponatremia in nephrotic syndrome is not completely understood, but the primary disturbance may be renal sodium retention, resulting in overfilling of the intravascular space and secondary edema formation as fluid enters the interstitial space. Previously, it was thought that the decreased oncotic pressure of hypoalbuminemia caused fluid shifts from the intravascular space to the interstitial compartment. Intravascular underfilling led to secondary renal sodium retention. However, patients receiving therapy for glomerular disease and nephrotic syndrome often have edema resolution prior to normalization of the serum albumin.
Patients with advanced kidney disease typically have sodium retention and decreased free water excretory capacity, resulting in hypervolemic hyponatremia.
Whether hyponatremia is symptomatic depends on its severity and acuity. Chronic disease can be severe (sodium concentration < 110 mEq/L), yet remarkably asymptomatic because the brain has adapted by decreasing its tonicity over weeks to months. Acute disease that has developed over hours to days can be severely symptomatic with relatively modest hyponatremia. Mild hyponatremia (sodium concentrations of 130–135 mEq/L) is usually asymptomatic.
Mild symptoms of nausea and malaise progress to headache, lethargy, and disorientation as the sodium concentration drops. The most serious symptoms are respiratory arrest, seizure, coma, permanent brain damage, brainstem herniation, and death. Premenopausal women are much more likely than menopausal women to die or suffer permanent brain injury from hyponatremic encephalopathy, suggesting a hormonal role in the pathophysiology.
Evaluation starts with a careful history for new medications, changes in fluid intake (polydipsia, anorexia, intravenous fluid rates and composition), fluid output (nausea and vomiting, diarrhea, ostomy output, polyuria, oliguria, insensible losses). The physical examination should help categorize the patient’s volume status into hypovolemia, euvolemia, or hypervolemia.
Laboratory assessment should include serum electrolytes, creatinine, and osmolality as well as urine sodium. The etiology of most cases of hyponatremia will be apparent from the history, physical, and basic laboratory tests. Additional tests of thyroid and adrenal function will occasionally be necessary.
SIADH is a clinical diagnosis characterized by (1) hyponatremia; (2) decreased osmolality (< 280 mosm/kg [< 280 mmol/kg]); (3) absence of heart, kidney, or liver disease; (4) normal thyroid and adrenal function (see Chapter 26); and (5) urine sodium usually over 20 mEq/L. In clinical practice, ADH levels are not measured. Patients with SIADH may have low blood urea nitrogen (BUN) (< 10 mg/dL [or < 3.6 mmol/L]) and hypouricemia (< 4 mg/dL [or < 238 mcmol/L]), which are not only dilutional but result from increased urea and uric acid clearances in response to the volume-expanded state. Azotemia may reflect volume contraction, ruling out SIADH, which is seen in euvolemic patients.
The most serious complication of hyponatremia is iatrogenic cerebral osmotic demyelination from overly rapid sodium correction. Also called central pontine myelinolysis, cerebral osmotic demyelination may occur outside the brainstem. Demyelination may occur days after sodium correction or initial neurologic recovery from hyponatremia. Hypoxic episodes during hyponatremia may contribute to demyelination. The neurologic effects are generally catastrophic and irreversible.
Regardless of the patient’s volume status, another common feature is to restrict free water and hypotonic fluid intake, since these solutions will exacerbate hyponatremia. Free water intake from oral intake and intravenous fluids should generally be < 1–1.5 L/d.
Hypovolemic patients require adequate fluid resuscitation from isotonic fluids (either normal saline or lactated Ringer solution) to suppress the hypovolemic stimulus for ADH release. Patients withcerebral salt wasting may require hypertonic saline to prevent circulatory collapse; some may respond to fludrocortisone. Hypervolemic patients may require loop diuretics or dialysis, or both, to correct increased total body water and sodium. Euvolemic patients may respond to free water restriction alone.
Pseudohyponatremia from hypertriglyceridemia or hyperproteinemia requires no therapy except confirmation with the clinical laboratory. Translocational hyponatremia from glucose or mannitol can be managed with glucose correction or mannitol discontinuation (if possible). No specific therapy is necessary in patients with reset osmostat since they successfully regulate their serum sodium with fluid challenges and water deprivation.
Symptomatic and severe hyponatremia generally require hospitalization for careful monitoring of fluid balance and weights, treatment, and frequent sodium checks. Inciting medications should be discontinued if possible.
There is no consensus about the optimal rate of sodium correction in symptomatic hyponatremic patients. Recent guidelines have introduced new recommendations. First, a relatively small increase of 4–6 mEq/L in the serum sodium may be all that is necessary to reverse the neurologic manifestations of symptomatic hyponatremia. Second, acute hyponatremia (eg, exercise-associated hyponatremia) with severe neurologic manifestations can be reversed rapidly with 100 mL of 3% hypertonic saline infused over 10 minutes (repeated twice as necessary). Third, lower correction rates for chronic hyponatremia have been introduced, as low as 4–8 mEq/L per 24 hours in patients at high risk for demyelination. Fourth, chronic hyponatremic patients at high risk for demyelination who are corrected too rapidly are candidates for treatment with a combination of DDAVP and intravenous dextrose 5% to relower the serum sodium.
In severely symptomatic patients, the clinician should calculate the sodium deficit and deliver 3% hypertonic saline. The sodium deficit can be calculated by the following formula:
where TBW is typically 50% of total mass in women and 55% of total mass in men. For example, a nonedematous, severely symptomatic 70 kg woman with a serum sodium of 124 mEq/L should have her serum sodium corrected to approximately 132 mEq/L in the first 24 hours. Her sodium deficit is calculated as:
3% hypertonic saline has a sodium concentration of 514 mEq/1000 mL. The delivery rate for hypertonic saline can be calculated as:
In general, the 3% hypertonic saline infusion rate should not exceed 0.5 mL/kg body weight/h; higher rates may represent a miscalculated sodium deficit or a mathematical error. Hypertonic saline in hypervolemic patients can be hazardous, resulting in worsening volume overload, pulmonary edema, and ascites.
For patients who cannot adequately restrict free water or have an inadequate response to conservative measures, demeclocycline (300–600 mg orally twice daily) inhibits the effect of ADH on the distal tubule. Onset of action may require 1 week, and urinary concentrating ability may be permanently impaired, resulting in nephrogenic diabetes insipidus (DI) and even hypernatremia. Cirrhosis may increase the nephrotoxicity of demeclocycline.
Vasopressin antagonists may revolutionize the treatment of euvolemic and hypervolemic hyponatremia, especially in heart failure. Tolvaptan, lixivaptan, and satavaptan are oral selective vasopressin-2 receptor antagonists; conivaptan is an intravenous agent. Tolvaptan and conivaptan are available in the United States, but lixivaptan and satavaptan are not yet approved by the US Food and Drug Administration (FDA).
V2 receptors mediate the diuretic effect of ADH and V2 receptor antagonists are recommended for use in hospital. For hospitalized patients with euvolemic SIADH, tolvaptan is begun as 15 mg orally daily and can be increased to 30 mg daily and 60 mg daily at 24 hour intervals if hyponatremia persists or if the increase in sodium concentration is < 5 mEq/L over the preceding 24 hours. Conivaptan is given as an intravenous loading dose of 20 mg delivered over 30 minutes, then as 20 mg continuously over 24 hours. Subsequent infusions may be administered every 1–3 days at 20–40 mg/d by continuous infusion. The standard free water restriction for hyponatremic patients should be lifted for patients receiving vasopressin antagonists since the aquaresis can result in excessive sodium correction in a fluid-restricted patient. Frequent monitoring of the serum sodium is necessary.
• Nephrology or endocrinology consultation should be considered in severe, symptomatic, refractory, or complicated cases of hyponatremia.
• Aggressive therapies with hypertonic saline, demeclocycline, vasopressin antagonists, or dialysis mandate specialist consultation.
• Consultation may be necessary with end-stage liver or heart disease.
Hospital admission is necessary for symptomatic patients or those requiring aggressive therapies for close monitoring and frequent laboratory testing.
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ESSENTIALS OF DIAGNOSIS
Increased thirst and water intake is the first defense against hypernatremia.
Urine osmolality helps differentiate renal from nonrenal water loss.
Hypernatremia is defined as a sodium concentration > 145 mEq/L. All patients with hypernatremia have hyperosmolality, unlike hyponatremic patients who can have a low, normal, or high serum osmolality. The hypernatremic patient is typically hypovolemic due to free water losses, although hypervolemia is frequently seen, often as an iatrogenic complication in hospitalized patients with impaired access to free water. Rarely, excessive sodium intake may cause hypernatremia. Hypernatremia in primary aldosteronism is mild and usually does not cause symptoms.
An intact thirst mechanism and access to water are the primary defense against hypernatremia. The hypothalamus can sense minimal changes in serum osmolality, triggering the thirst mechanism and increased water intake. Thus, whatever the underlying disorder (eg, dehydration, lactulose or mannitol therapy, central and nephrogenic DI), excess water loss can cause hypernatremia only when adequate water intake is not possible.
When the patient is dehydrated, orthostatic hypotension and oliguria are typical findings. Because water shifts from the cells to the intravascular space to protect volume status, these symptoms may be delayed. Lethargy, irritability, and weakness are early signs. Hyperthermia, delirium, seizures, and coma may be seen with severe hypernatremia (ie, sodium > 158 mEq/L). Symptoms in the elderly may not be specific; a recent change in consciousness is associated with a poor prognosis. Osmotic demyelination is an uncommon but reported consequence of severe hypernatremia.
1. Urine osmolality > 400 mosm/kg—Renal water-conserving ability is functioning.
A. NONRENAL LOSSES—Hypernatremia will develop if water intake falls behind hypotonic fluid losses from excessive sweating, the respiratory tract, or bowel movements. Lactulose causes an osmotic diarrhea with loss of free water.
B. RENAL LOSSES—While severe hyperglycemia can cause translocational hyponatremia, progressive volume depletion from glucosuria can result in hypernatremia. Osmotic diuresis can occur with the use of mannitol or urea.
2. Urine osmolality < 250 mosm/kg—Hypernatremia with a dilute urine (osmolality < 250 mosm/kg) is characteristic of DI. Central DI results from inadequate ADH release. Nephrogenic DI results from renal insensitivity to ADH; common causes include lithium, demeclocycline, relief of urinary obstruction, interstitial nephritis, hypercalcemia, and hypokalemia.
Treatment of hypernatremia includes correcting the cause of the fluid loss, replacing water, and replacing electrolytes (as needed). In response to increases in plasma osmolality, brain cells synthesize solutes called idiogenic osmoles, which cause intracellular fluid shifts. Osmole production begins 4–6 hours after dehydration and takes several days to reach steady state. If hypernatremia is rapidly corrected, the osmotic imbalance may cause cerebral edema and potentially severe neurologic impairment. Fluids should be administered over a 48-hour period, aiming for serum sodium correction of approximately 1 mEq/L/h (1 mmol/L/h). There is no consensus about the optimal rates of sodium correction in hypernatremia and hyponatremia.
1. Hypernatremia with hypovolemia—Hypovolemic patients should receive isotonic 0.9% normal saline to restore euvolemia and to treat hyperosmolality because normal saline (308 mosm/kg or 308 mmol/kg) is hypo-osmolar compared with plasma. After adequate volume resuscitation with normal saline, 0.45% saline or 5% dextrose (or both) can be used to replace any remaining free water deficit. Milder volume deficits may be treated with 0.45% saline and 5% dextrose.
2. Hypernatremia with euvolemia—Water ingestion or intravenous 5% dextrose will result in the excretion of excess sodium in the urine. If the glomerular filtration rate (GFR) is decreased, diuretics will increase urinary sodium excretion but may impair renal concentrating ability, increasing the quantity of water that needs to be replaced.
3. Hypernatremia with hypervolemia—Treatment includes 5% dextrose solution to reduce hyperosmolality. Loop diuretics may be necessary to promote natriuresis and lower total body sodium. In severe rare cases with kidney disease, hemodialysis may be necessary to correct the excess total body sodium and water.
Fluid replacement should include the free water deficit and additional maintenance fluid to replace ongoing and anticipated fluid losses.
1. Acute hypernatremia—In acute dehydration without much solute loss, free water loss is similar to the weight loss. Initially, a 5% dextrose solution may be used. As correction of water deficit progresses, therapy should continue with 0.45% saline with dextrose.
2. Chronic hypernatremia—The water deficit is calculated to restore normal sodium concentration, typically 140 mEq/L. Total body water (TBW) (Table 21–1) correlates with muscle mass and therefore decreases with advancing age, cachexia, and dehydration and is lower in women than in men. Current TBW equals 40–60% current body weight.
Patients with refractory or unexplained hypernatremia should be referred for subspecialist consultation.
• Patients with symptomatic hypernatremia require hospitalization for evaluation and treatment.
• Significant comorbidities or concomitant acute illnesses, especially if contributing to hypernatremia, may necessitate hospitalization.
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ESSENTIALS OF DIAGNOSIS
Disorder of excessive sodium retention in the setting of low arterial underfilling (eg, heart failure or cirrhosis).
Hyponatremia from water retention in edematous states is associated with sodium retention.
The hallmark of a volume overloaded state is sodium retention. Abnormally low arterial filling, such as from heart failure or cirrhosis, activates the neurohumoral axis, which stimulates the renin-angiotensin-aldosterone system, the sympathetic nervous system, and ADH (vasopressin) release. The result is sodium retention with edema. The stimulus for vasopressin release is nonosmotic. Released in response to baroreceptor activation, vasopressin stimulates renal V2 receptors, resulting in water reabsorption, edema formation, and hyponatremia.
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Urea and alcohol readily cross cell membranes and can produce hyperosmolality. Urea is an ineffective osmole with little effect on osmotic water movement across cell membranes. Alcohol quickly equilibrates between the intracellular and extracellular compartments, adding 22 mosm/L for every 100 mg/dL (or 21.7 mmol/L) of ethanol. Ethanol ingestion should be considered in any case of stupor or coma with an elevated osmol gap (measured osmolality – calculated osmolality > 10 mosm/kg [> 10 mmol/kg]). Other toxic alcohols such as methanol and ethylene glycol cause an osmol gap and a metabolic acidosis with an increased anion gap (see Chapter 38). The combination of an increased anion gap metabolic acidosis and an osmol gap exceeding 10 mosm/kg (or 10 mmol/kg) is not specific for toxic alcohol ingestion and may occur with alcoholic ketoacidosis or lactic acidosis (see Metabolic Acidosis).
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Increased concentrations of solutes that do not readily enter cells cause a shift of water from intracellular to extracellular. Hyperosmolality of effective osmoles such as sodium and glucose causes symptoms, primarily neurologic. The severity of symptoms depends on the degree of hyperosmolality and rapidity of development. In acute hyperosmolality, somnolence and confusion can appear when the osmolality exceeds 320–330 mosm/kg (320–330 mmol/kg); coma, respiratory arrest, and death can result when osmolality exceeds 340–350 mosm/kg (340–350 mmol/kg).
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ESSENTIALS OF DIAGNOSIS
Serum potassium level < 3.5 mEq/L (< 3.5 mmol/L)
Severe hypokalemia may induce dangerous arrhythmias and rhabdomyolysis.
Transtubular potassium concentration gradient (TTKG) can distinguish renal from nonrenal loss of potassium.
Hypokalemia can result from insufficient dietary potassium intake, intracellular shifting of potassium from the extracellular space, extrarenal potassium loss, or renal potassium loss (Table 21–3). Cellular uptake of potassium is increased by insulin and beta-adrenergic stimulation and blocked by alpha-adrenergic stimulation. Aldosterone is an important regulator of total body potassium, increasing potassium secretion in the distal renal tubule. The most common cause of hypokalemia, especially in developing countries, is gastrointestinal loss from infectious diarrhea. The potassium concentration in intestinal secretion is ten times higher (80 mEq/L) than in gastric secretions. Hypokalemia in the presence of acidosis suggests profound potassium depletion and requires urgent treatment. Self-limited hypokalemia occurs in 50–60% of trauma patients, perhaps related to enhanced release of epinephrine.
Table 21–3. Causes of hypokalemia.
Hypokalemia increases the likelihood of digitalis toxicity. In patients with heart disease, hypokalemia induced by beta-2-adrenergic agonists and diuretics may substantially increase the risk of arrhythmias. Numerous genetic mutations affect fluid and electrolyte metabolism, including disorders of potassium metabolism (Table 21–4).
Table 21–4. Genetic disorders associated with electrolyte metabolism disturbances.
Magnesium is an important cofactor for potassium uptake and maintenance of intracellular potassium levels. Loop diuretics (eg, furosemide) cause substantial renal potassium and magnesium losses. Magnesium depletion should be considered in refractory hypokalemia.
Muscular weakness, fatigue, and muscle cramps are frequent complaints in mild to moderate hypokalemia. Gastrointestinal smooth muscle involvement may result in constipation or ileus. Flaccid paralysis, hyporeflexia, hypercapnia, tetany, and rhabdomyolysis may be seen with severe hypokalemia (< 2.5 mEq/L). The presence of hypertension may be a clue to the diagnosis of hypokalemia from aldosterone or mineralocorticoid excess (Table 21–4). Renal manifestations include nephrogenic DI and interstitial nephritis.
Urinary potassium concentration is low (< 20 mEq/L) as a result of extrarenal loss (eg, diarrhea, vomiting) and inappropriately high (> 40 mEq/L) with renal loss (eg, mineralocorticoid excess, Bartter syndrome, Liddle syndrome) (Table 21–3).
The transtubular [K+] gradient (TTKG) is a simple and rapid evaluation of net potassium secretion. TTKG is calculated as follows:
Hypokalemia with a TTKG > 4 suggests renal potassium loss with increased distal K+ secretion. In such cases, plasma renin and aldosterone levels are helpful in differential diagnosis. The presence of nonabsorbed anions, such as bicarbonate, increases the TTKG.
The electrocardiogram (ECG) shows decreased amplitude and broadening of T waves, prominent U waves, premature ventricular contractions, and depressed ST segments.
Oral potassium supplementation is the safest and easiest treatment for mild to moderate deficiency. Dietary potassium is almost entirely coupled to phosphate—rather than chloride—and is therefore not effective in correcting potassium loss associated with chloride depletion from diuretics or vomiting. In the setting of abnormal kidney function and mild to moderate diuretic dosage, 20 mEq/d of oral potassium is generally sufficient to prevent hypokalemia, but 40–100 mEq/d over a period of days to weeks is needed to treat hypokalemia and fully replete potassium stores.
Intravenous potassium is indicated for patients with severe hypokalemia and for those who cannot take oral supplementation. For severe deficiency, potassium may be given through a peripheral intravenous line in a concentration up to 40 mEq/L and at rates up to 10 mEq/h. Concentrations of up to 20 mEq/h may be given through a central venous catheter. Continuous ECG monitoring is indicated, and the serum potassium level should be checked every 3–6 hours. Avoid glucose-containing fluid to prevent further shifts of potassium into the cells. Magnesium deficiency should be corrected, particularly in refractory hypokalemia.
Patients with unexplained hypokalemia, refractory hyperkalemia, or clinical features suggesting alternative diagnoses (eg, aldosteronism or hypokalemic periodic paralysis) should be referred for endocrinology or nephrology consultation.
Patients with symptomatic or severe hypokalemia, especially with cardiac manifestations, require cardiac monitoring, frequent laboratory testing, and potassium supplementation.
Asmar A et al. A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis. 2012 Sep;60(3):492–7. [PMID: 22901631]
Marti G et al. Etiology and symptoms of severe hypokalemia in emergency department patients. Eur J Emerg Med. 2014 Feb;21(1):46–51. [PMID: 23839104]
Pepin J et al. Advances in diagnosis and management of hypokalemic and hyperkalemic emergencies. Emerg Med Pract. 2012 Feb;14(2):1–18. [PMID: 22413702]
Rastegar A. Attending rounds: patient with hypokalemia and metabolic acidosis. Clin J Am Soc Nephrol. 2011 Oct;6(10): 2516–21. [PMID: 21921151]
ESSENTIALS OF DIAGNOSIS
Serum potassium level > 5.0 mEq/L (> 5.0 mmol/L).
Hyperkalemia may develop in patients taking ACE inhibitors, angiotensin-receptor blockers, potassium-sparing diuretics, or their combination, even with no or only mild kidney dysfunction.
The ECG may show peaked T waves, widened QRS and biphasic QRS–T complexes, or may be normal despite life-threatening hyperkalemia.
Measurement of plasma potassium level differentiates potassium leak from blood cells in cases of clotting, leukocytosis, and thrombocytosis from elevated serum potassium.
Rule out extracellular potassium shift from the cells in acidosis and assess renal potassium excretion.
Hyperkalemia usually occurs in patients with advanced kidney disease but can also develop with normal kidney function (Table 21–5). Acidosis causes intracellular potassium to shift extracellularly. Serum potassium concentration rises about 0.7 mEq/L for every decrease of 0.1 pH unit during acidosis. Fist clenching during venipuncture may raise the potassium concentration by 1–2 mEq/L by causing acidosis and potassium shift from cells. In the absence of acidosis, serum potassium concentration rises about 1 mEq/L when there is a total body potassium excess of 1–4 mEq/kg. However, the higher the serum potassium concentration, the smaller the excess necessary to raise the potassium levels further.
Table 21–5. Causes of hyperkalemia.
Mineralocorticoid deficiency from Addison disease or chronic kidney disease (CKD) is another cause of hyperkalemia with decreased renal excretion of potassium. Mineralocorticoid resistance due to genetic disorders, interstitial kidney disease, or urinary tract obstruction also leads to hyperkalemia.
ACE inhibitors or angiotensin-receptor blockers (ARBs), commonly used in patients with heart failure or CKD, may cause hyperkalemia. The concomitant use of spironolactone, eplerenone, or beta-blockers further increases the risk of hyperkalemia. Thiazide or loop diuretics and sodium bicarbonate may minimize hyperkalemia. Persistent mild hyperkalemia in the absence of ACE inhibitor or ARB therapy is usually due to type IV renal tubular acidosis (RTA). Heparin inhibits aldosterone production in the adrenal glands, causing hyperkalemia.
Trimethoprim is structurally similar to amiloride and triamterene, and all three drugs inhibit renal potassium excretion through suppression of sodium channels in the distal nephron.
Cyclosporine and tacrolimus can induce hyperkalemia in organ transplant recipients, especially kidney transplant patients, partly due to suppression of the basolateral Na+–K+-ATPase in principal cells. Hyperkalemia is commonly seen in HIV patients and has been attributed to impaired renal excretion of potassium due to pentamidine or trimethoprim-sulfamethoxazole or to hyporeninemic hypoaldosteronism.
Hyperkalemia impairs neuromuscular transmission, causing muscle weakness, flaccid paralysis, and ileus. Electrocardiography is not a sensitive method for detecting hyperkalemia, since nearly half of patients with a serum potassium level > 6.5 mEq/L will not manifest ECG changes. ECG changes in hyperkalemia include bradycardia, PR interval prolongation, peaked T waves, QRS widening, and biphasic QRS–T complexes. Conduction disturbances, such as bundle branch block and atrioventricular block, may occur. Ventricular fibrillation and cardiac arrest are terminal events.
Inhibitors of the renin-angiotensin-aldosterone axis (ie, ACE inhibitors, ARBs, and spironolactone) and potassium-sparing diuretics (eplerenone, triamterene) should be used cautiously in patients with heart failure, liver failure, and kidney disease. Laboratory monitoring should be performed within 1 week of drug initiation or dosage increase.
The diagnosis should be confirmed by repeat laboratory testing to rule out spurious hyperkalemia, especially in the absence of medications that cause hyperkalemia or in patients without kidney disease or a previous history of hyperkalemia. Plasma potassium concentration can be measured to avoid hyperkalemia due to potassium leakage out of red cells, white cells, and platelets. Kidney dysfunction should be ruled out at the initial assessment.
Treatment consists of withholding exogenous potassium, identifying the cause, reviewing the patient’s medications and dietary potassium intake, and correcting the hyperkalemia. Emergent treatment is indicated when cardiac toxicity, muscle paralysis, or severe hyperkalemia (potassium > 6.5 mEq/L) is present, even in the absence of ECG changes. Insulin, bicarbonate, and beta-agonists shift potassium intracellularly within minutes of administration (Table 21–6). Intravenous calcium may be given to antagonize the cell membrane effects of potassium, but its use should be restricted to life-threatening hyperkalemia in patients taking digitalis because hypercalcemia may cause digitalis toxicity. Hemodialysis may be required to remove potassium in patients with acute or chronic kidney injury.
Table 21–6. Treatment of hyperkalemia.
• Patients with hyperkalemia from kidney disease and reduced renal potassium excretion should see a nephrologist.
• Transplant patients may need adjustment of their immunosuppression regimen by transplant specialists.
Patients with severe hyperkalemia > 6 mEq/L, any degree of hyperkalemia associated with ECG changes, or concomitant illness (eg, tumor lysis, rhabdomyolysis, metabolic acidosis) should be sent to the emergency department for immediate treatment.
Kamel KS et al. Asking the question again: are cation exchange resins effective for the treatment of hyperkalemia? Nephrol Dial Transplant. 2012 Dec;27(12):4294–7. [PMID: 22989741]
Palmer BF. A physiologic-based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis. 2010 Aug;56(2):387–93. [PMID: 20493606]
Pepin J et al. Advances in diagnosis and management of hypokalemic and hyperkalemic emergencies. Emerg Med Pract. 2012 Feb;14(2):1–18. [PMID: 22413702]
Shingarev R et al. A physiologic-based approach to the treatment of acute hyperkalemia. Am J Kidney Dis. 2010 Sep;56(3): 578–84. [PMID: 20570423]
The normal total plasma (or serum) calcium concentration is 8.5–10.5 mg/dL (or 2.1–2.6 mmol/L). Ionized calcium (normal: 4.6–5.3 mg/dL [or 1.15–1.32 mmol/L]) is physiologically active and necessary for muscle contraction and nerve function.
The calcium-sensing receptor, a transmembrane protein that detects the extracellular calcium concentration, has been identified in the parathyroid gland and the kidney. Functional defects in this protein are associated with diseases of abnormal calcium metabolism such as familial hypocalcemia and familial hypocalciuric hypercalcemia (Table 21–4).
ESSENTIALS OF DIAGNOSIS
Often mistaken as a neurologic disorder.
Check for decreased serum parathyroid hormone (PTH), vitamin D, or magnesium levels.
If the ionized calcium level is normal despite a low total serum calcium, calcium metabolism is usually normal.
The most common cause of low total serum calcium is hypoalbuminemia. When serum albumin concentration is lower than 4 g/dL (40 g/L), serum Ca2+ concentration is reduced by 0.8–1 mg/dL (0.20–0.25 mmol/L) for every 1 g/dL (10 g/L) of albumin.
The most accurate measurement of serum calcium is the ionized calcium concentration. True hypocalcemia (decreased ionized calcium) implies insufficient action of PTH or active vitamin D. Important causes of hypocalcemia are listed in Table 21–7.
Table 21–7. Causes of hypocalcemia.
The most common cause of hypocalcemia is advanced CKD, in which decreased production of active vitamin D3 (1, 25 dihydroxyvitamin D3) and hyperphosphatemia both play a role (see Chapter 22). Some cases of primary hypoparathyroidism are due to mutations of the calcium-sensing receptor in which inappropriate suppression of PTH release leads to hypocalcemia (see Chapter 26). Magnesium depletion reduces both PTH release and tissue responsiveness to PTH, causing hypocalcemia. Hypocalcemia in pancreatitis is a marker of severe disease. Elderly hospitalized patients with hypocalcemia and hypophosphatemia, with or without an elevated PTH level, are likely vitamin D deficient.
Hypocalcemia increases excitation of nerve and muscle cells, primarily affecting the neuromuscular and cardiovascular systems. Spasm of skeletal muscle causes cramps and tetany. Laryngospasm with stridor can obstruct the airway. Convulsions, perioral and peripheral paresthesias, and abdominal pain can develop. Classic physical findings include Chvostek sign (contraction of the facial muscle in response to tapping the facial nerve) and Trousseau sign (carpal spasm occurring with occlusion of the brachial artery by a blood pressure cuff). QT prolongation predisposes to ventricular arrhythmias. In chronic hypoparathyroidism, cataracts and calcification of basal ganglia may appear (see Chapter 26).
Serum calcium concentration is low (< 8.5 mg/dL [or < 2.1 mmol/L]). In true hypocalcemia, the ionized serum calcium concentration is also low (< 4.6 mg/dL [or < 1.15 mmol/L]). Serum phosphate is usually elevated in hypoparathyroidism or in advanced CKD, whereas it is suppressed in early CKD or vitamin D deficiency.
Serum magnesium concentration is commonly low. In respiratory alkalosis, total serum calcium is normal but ionized calcium is low. The ECG shows a prolonged QT interval.
In the presence of tetany, arrhythmias, or seizures, intravenous calcium gluconate is indicated. Because of the short duration of action, continuous calcium infusion is usually required. Ten to 15 milligrams of calcium per kilogram body weight, or six to eight 10-mL vials of 10% calcium gluconate (558–744 mg of calcium), is added to 1 L of D5W and infused over 4–6 hours. By monitoring the serum calcium level frequently (every 4–6 hours), the infusion rate is adjusted to maintain the serum calcium level at 7–8.5 mg/dL.
Oral calcium (1–2 g) and vitamin D preparations, including active vitamin D sterols, are used. Calcium carbonate is well tolerated and less expensive than many other calcium tablets. A check of urinary calcium excretion is recommended after the initiation of therapy because hypercalciuria (urine calcium excretion > 300 mg or > 7.5 mmol per day) or urine calcium:creatinine ratio > 0.3 may impair kidney function in these patients. The low serum calcium associated with hypoalbuminemia does not require replacement therapy. If serum Mg2+ is low, therapy must include magnesium replacement, which by itself will usually correct hypocalcemia.
Patients with complicated hypocalcemia from hypoparathyroidism, familial hypocalcemia, or CKD require referral to an endocrinologist or nephrologist.
Patients with tetany, arrhythmias, seizures, or other symptoms of hypocalcemia require immediate evaluation and therapy.
Al-Azem H et al. Hypoparathyroidism. Best Pract Res Clin Endocrinol Metab. 2012 Aug;26(4):517–22. [PMID: 22863393]
Fong J et al. Hypocalcemia: updates in diagnosis and management for primary care. Can Fam Physician. 2012 Feb;58(2):158–62. [PMID: 22439169]
Kelly A et al. Hypocalcemia in the critically ill patient. J Intensive Care Med. 2013 May–Jun;28(3):166–77. [PMID: 21841146]
Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol. 2010 Jan;5(Suppl 1):S23–30. [PMID: 20089499]
ESSENTIALS OF DIAGNOSIS
Primary hyperparathyroidism and malignancy-associated hypercalcemia are the most common causes.
Hypercalciuria usually precedes hypercalcemia.
Most often, asymptomatic, mild hypercalcemia (≥ 10.5 mg/dL [or 2.6 mmol/L]) is due to primary hyperparathyroidism, whereas the symptomatic, severe hypercalcemia (≥ 14 mg/dL [or 3.5 mmol/L]) is due to hypercalcemia of malignancy.
Important causes of hypercalcemia are listed in Table 21–8. Primary hyperparathyroidism and malignancy account for 90% of cases. Primary hyperparathyroidism is the most common cause of hypercalcemia (usually mild) in ambulatory patients. Chronic hypercalcemia (over 6 months) or some manifestation such as nephrolithiasis also suggests a benign cause. Tumor production of PTH-related proteins (PTHrP) is the most common paraneoplastic endocrine syndrome, accounting for most cases of hypercalcemia in inpatients (see Table 39–2). The neoplasm is clinically apparent in nearly all cases when the hypercalcemia is detected, and the prognosis is poor. Granulomatous diseases, such as sarcoidosis and tuberculosis, cause hypercalcemia via overproduction of active vitamin D3 (1,25 dihydroxyvitamin D3).
Table 21–8. Causes of hypercalcemia.
Milk-alkali syndrome has had a resurgence due to calcium ingestion for prevention of osteoporosis. Heavy calcium carbonate intake causes hypercalcemic acute kidney injury, likely from renal vasoconstriction. The decreased GFR impairs bicarbonate excretion, while hypercalcemia stimulates proton secretion and bicarbonate reabsorption. Metabolic alkalosis decreases calcium excretion, maintaining hypercalcemia.
Hypercalcemia causes nephrogenic DI through activation of calcium-sensing receptors in collecting ducts, which reduces ADH-induced water permeability. Volume depletion further worsens hypercalcemia.
The history and physical examination should focus on the duration of hypercalcemia and evidence for a neoplasm. Hypercalcemia may affect gastrointestinal, kidney, and neurologic function. Mild hypercalcemia is often asymptomatic. Symptoms usually occur if the serum calcium is > 12 mg/dL (or > 3 mmol/L) and tend to be more severe if hypercalcemia develops acutely. Symptoms include constipation and polyuria, except in hypocalciuric hypercalcemia, in which polyuria is absent. Other symptoms include nausea, vomiting, anorexia, peptic ulcer disease, renal colic, and hematuria from nephrolithiasis. Polyuria from hypercalciuria-induced nephrogenic DI can result in volume depletion and acute kidney injury. Neurologic manifestations range from mild drowsiness to weakness, depression, lethargy, stupor, and coma in severe hypercalcemia. Ventricular ectopy and idioventricular rhythm occur and can be accentuated by digitalis.
The ionized calcium exceeds 1.32 mmol/L. A high serum chloride concentration and a low serum phosphate concentration in a ratio > 33:1 (or > 102 if SI units are utilized) suggests primary hyperparathyroidism where PTH decreases proximal tubular phosphate reabsorption. A low serum chloride concentration with a high serum bicarbonate concentration, along with elevated BUN and creatinine, suggests milk-alkali syndrome. Severe hypercalcemia (> 15 mg/dL [or > 3.75 mmol/L]) generally occurs in malignancy. More than 300 mg (or > 7.5 mmol) per day of urinary calcium excretion suggests hypercalciuria; < 100 mg (or < 2.5 mmol) per day suggests hypocalciuria. Hypercalciuric patients—such as those with malignancy or those receiving oral active vitamin D therapy—may easily develop hypercalcemia in case of volume depletion. Serum phosphate may or may not be low, depending on the cause. Hypocalciuric hypercalcemia occurs in milk-alkali syndrome, thiazide diuretic use, and familial hypocalciuric hypercalcemia.
The chest radiograph may reveal malignancy or granulomatous disease. The ECG shows a shortened QT interval. Measurements of PTH and PTHrP help distinguish between hyperparathyroidism (elevated PTH) and malignancy-associated hypercalcemia (suppressed PTH, elevated PTHrP).
Until the primary cause can be identified and treated, renal excretion of calcium is promoted through aggressive hydration and forced calciuresis. The tendency in hypercalcemia is hypovolemia from nephrogenic DI. In dehydrated patients with normal cardiac and kidney function, 0.45% saline or 0.9% saline can be given rapidly (250–500 mL/h). A meta-analysis questioned the efficacy and safety profile of intravenous furosemide for hypercalcemia. Thiazides can worsen hypercalcemia.
Bisphosphonates are the treatment of choice for hypercalcemia of malignancy. Although they are safe, effective, and normalize calcium in > 70% of patients, bisphosphonates may require up to 48–72 hours before reaching full therapeutic effect. Calcitonin may be helpful in the short-term until bisphosphonates reach therapeutic levels. In emergency cases, dialysis with low calcium dialysate may be needed. The calcimimetic agent cinacalcet hydrochloride suppresses PTH secretion and decreases serum calcium concentration and holds promise as a treatment option. (See Chapters 26 and 39.)
Typically, if dialysis patients do not receive proper supplementation of calcium and active vitamin D, hypocalcemia and hyperphosphatemia develop. On the other hand, hypercalcemia can sometimes develop, particularly in the setting of severe secondary hyperparathyroidism, characterized by high PTH levels and subsequent release of calcium from bone. Therapy may include intravenous vitamin D, which further increases the serum calcium concentration. Another type of hypercalcemia occurs when PTH levels are low. Bone turnover is decreased, which results in a low buffering capacity for calcium. When calcium is administered in calcium-containing phosphate binders or dialysate, or when vitamin D is administered, hypercalcemia results. Hypercalcemia in dialysis patients usually occurs in the presence of hyperphosphatemia, and metastatic calcification may occur. Malignancy should be considered as a cause of the hypercalcemia.
• Patients may require referral to an oncologist or endocrinologist depending on the underlying cause of hypercalcemia.
• Patients with granulomatous diseases (eg, tuberculosis and other chronic infections, granulomatosis with polyangiitis [formerly Wegener granulomatosis], sarcoidosis) may require assistance from infectious disease specialists, rheumatologists, or pulmonologists.
• Patients with symptomatic or severe hypercalcemia require immediate treatment.
• Unexplained hypercalcemia with associated conditions, such as acute kidney injury or suspected malignancy, may require urgent treatment and expedited evaluation.
Bech A et al. Denosumab for tumor-induced hypercalcemia complicated by renal failure. Ann Intern Med. 2012 Jun 19;156(12):906–7. [PMID: 22711097]
Crowley R et al. How to approach hypercalcaemia. Clin Med. 2013 Jun;13(3):287–90. [PMID: 23760705]
Lindner G et al. Hypercalcemia in the ED: prevalence, etiology, and outcome. Am J Emerg Med. 2013 Apr;31(4):657–60. [PMID: 23246111]
Marcocci C et al. Clinical practice. Primary hyperparathyroidism. N Engl J Med. 2011 Dec 22;365(25):2389–97. [PMID: 22187986]
Rosner MH et al. Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol. 2012 Oct;7(10):1722–9. [PMID: 22879438]
Plasma phosphorus is mainly inorganic phosphate and represents a small fraction (< 0.2%) of total body phosphate.
Important determinants of plasma inorganic phosphate are renal excretion, intestinal absorption, and shift between the intracellular and extracellular spaces. The kidney is the most important regulator of the serum phosphate level. PTH decreases reabsorption of phosphate in the proximal tubule while 1,25-dihydroxyvitamin D3 increases reabsorption. Renal proximal tubular reabsorption of phosphate is decreased by volume expansion, corticosteroids, and proximal tubular dysfunction (as in Fanconi syndrome). Fibroblast growth factor 23 (FGF23) is a potent phosphaturic hormone. Intestinal absorption of phosphate is facilitated by active vitamin D. PTH stimulates phosphate release from bone and renal phosphate excretion; primary hyperparathyroidism can lead to hypophosphatemia and depletion of bone phosphate stores. By contrast, growth hormone augments proximal tubular reabsorption of phosphate. Cellular phosphate uptake is stimulated by various factors and conditions, including alkalemia, insulin, epinephrine, feeding, hungry bone syndrome, and accelerated cell proliferation.
Phosphorus metabolism and homeostasis are intimately related to calcium metabolism. See sections on metabolic bone disease in Chapter 26.
ESSENTIALS OF DIAGNOSIS
Severe hypophosphatemia may cause tissue hypoxia and rhabdomyolysis.
Renal loss of phosphate can be diagnosed by measuring urinary phosphate excretion and by calculating maximal tubular phosphate reabsorption rate (TmP/GFR).
PTH and FGF23 are the major factors that decrease TmP/GFR, leading to renal loss of phosphate.
The leading causes of hypophosphatemia are listed in Table 21–9. Hypophosphatemia may occur in the presence of normal phosphate stores. Serious depletion of body phosphate stores may exist with low, normal, or high serum phosphate concentrations.
Table 21–9. Causes of hypophosphatemia.
Serum phosphate levels decrease transiently after food intake, thus fasting samples are recommended for accuracy. Moderate hypophosphatemia (1.0–2.4 mg/dL [or 0.32–0.79 mmol/L]) occurs commonly in hospitalized patients and may not reflect decreased phosphate stores.
In severe hypophosphatemia (< 1 mg/dL [or < 0.32 mmol/L]), the affinity of hemoglobin for oxygen increases through a decrease in the erythrocyte 2,3-biphosphoglycerate concentration, impairing tissue oxygenation and cell metabolism and resulting in muscle weakness or even rhabdomyolysis. Severe hypophosphatemia is common and multifactorial in alcoholic patients. In acute alcohol withdrawal, increased plasma insulin and epinephrine along with respiratory alkalosis promote intracellular shift of phosphate. Vomiting, diarrhea, and poor dietary intake contribute to hypophosphatemia. Chronic alcohol use results in a decrease in the renal threshold of phosphate excretion. This renal tubular dysfunction reverses after a month of abstinence. Patients with chronic obstructive pulmonary disease and asthma commonly have hypophosphatemia, attributed to xanthine derivatives causing shifts of phosphate intracellularly and the phosphaturic effects of beta-adrenergic agonists, loop diuretics, xanthine derivatives, and corticosteroids. Refeeding or glucose administration to phosphate-depleted patients may cause fatal hypophosphatemia.
Acute, severe hypophosphatemia (< 1.0 mg/dL [or < 0.32 mmol/L]) can lead to rhabdomyolysis, paresthesias, and encephalopathy (irritability, confusion, dysarthria, seizures, and coma). Respiratory failure or failure to wean from mechanical ventilation may occur as a result of diaphragmatic weakness. Arrhythmias and heart failure are uncommon but serious manifestations. Hematologic manifestations include acute hemolytic anemia from erythrocyte fragility, platelet dysfunction with petechial hemorrhages, and impaired chemotaxis of leukocytes (leading to increased susceptibility to gram-negative sepsis).
Chronic severe depletion may cause anorexia, pain in muscles and bones, and fractures.
Urine phosphate excretion is a useful clue in the evaluation of hypophosphatemia. The normal renal response to hypophosphatemia is decreased urinary phosphate excretion to < 100 mg/d. The fractional excretion of phosphate (FEPO4) should be < 5%. The main factors regulating FEPO4 are PTH and phosphate intake. Increased PTH or phosphate intake decreases FEPO4 (ie, more phosphate is excreted into the urine).
Measurement of plasma PTH or PTHrP levels may be helpful. The clinical utility of serum FGF levels is undetermined except in uncommon diseases.
Other clinical features may be suggestive of hypophosphatemia, such as hemolytic anemia and rhabdomyolysis. Fanconi syndrome may present with any combination of uricosuria, aminoaciduria, normoglycemic glucosuria, normal anion gap metabolic acidosis, and phosphaturia. In chronic hypophosphatemia, radiographs and bone biopsies show changes resembling osteomalacia.
Hypophosphatemia can be prevented by including phosphate in repletion and maintenance fluids. A rapid decline in calcium levels can occur with parenteral administration of phosphate; oral replacement of phosphate is preferable. Moderate hypophosphatemia (1.0–2.5 mg/dL [or 0.32–0.79 mmol/L]) is usually asymptomatic and does not require treatment. The hypophosphatemia in patients with diabetic ketoacidosis (DKA) will usually correct with normal dietary intake. Chronic hypophosphatemia can be treated with oral phosphate repletion. Mixtures of sodium and potassium phosphate salts may be given to provide 0.5–1 g (16–32 mmol) of phosphate per day. For severe, symptomatic hypophosphatemia (< 1 mg/dL [or < 0.32 mmol/L]), an infusion should provide 279–310 mg/12 h (or 9–10 mmol/12 h) until the serum phosphorus exceeds 1 mg/dL and the patient can be switched to oral therapy. The infusion rate should be decreased if hypotension occurs. Monitoring of plasma phosphate, calcium, and potassium every 6 hours is necessary because the response to phosphate supplementation is not predictable. Magnesium deficiency often coexists and should be treated.
Contraindications to phosphate replacement include hypoparathyroidism, advanced CKD, tissue damage and necrosis, and hypercalcemia. When an associated hyperglycemia is treated, phosphate accompanies glucose into cells, and hypophosphatemia may ensue.
• Patients with refractory hypophosphatemia with increased urinary phosphate excretion may require evaluation by an endocrinologist (for such conditions as hyperparathyroidism and vitamin D disorders) or a nephrologist (for such conditions as renal tubular defects).
• Patients with decreased gastrointestinal absorption may require referral to a gastroenterologist.
Patients with severe or refractory hypophosphatemia will require intravenous phosphate.
Bacchetta J et al. Evaluation of hypophosphatemia: lessons from patients with genetic disorders. Am J Kidney Dis. 2012 Jan;59(1):152–9. [PMID: 22075221]
Carpenter TO. The expanding family of hypophosphatemic syndromes. J Bone Miner Metab. 2012 Jan;30(1):1–9. [PMID: 22167381]
Felsenfeld AJ et al. Approach to treatment of hypophosphatemia. Am J Kidney Dis. 2012 Oct;60(4):655–61. [PMID: 22863286]
Imel EA et al. Approach to the hypophosphatemic patient. J Clin Endocrinol Metab. 2012 Mar;97(3):696–706. [PMID: 22392950]
Suzuki S et al. Hypophosphatemia in critically ill patients. J Crit Care. 2013 Aug;28(4):536.e9–19. [PMID: 23265292]
ESSENTIALS OF DIAGNOSIS
Advanced CKD is the most common cause.
Hyperphosphatemia in the presence of hypercalcemia imposes a high risk of metastatic calcification.
Advanced CKD with decreased urinary excretion of phosphate is the most common cause of hyperphosphatemia. Other causes are listed in Table 21–10.
Table 21–10. Causes of hyperphosphatemia.
The clinical manifestations are those of the underlying disorder or associated condition.
In addition to elevated phosphate, blood chemistry abnormalities are those of the underlying disease.
Treatment is directed at the underlying cause. Exogenous sources of phosphate, including enteral or parenteral nutrition and medications, should be reduced or eliminated. Dietary phosphate absorption can be reduced by oral phosphate binders, such as calcium carbonate, calcium acetate, sevelamer carbonate, lanthanum carbonate, and aluminum hydroxide. Sevelamer, lanthanum, and aluminum may be used in patients with hypercalcemia, although aluminum use should be limited to a few days because of the risk of aluminum accumulation and neurotoxicity. In acute kidney injury and advanced CKD, dialysis will reduce serum phosphate.
Patients with acute severe hyperphosphatemia require hospitalization for emergent therapy, possibly including dialysis. Concomitant illnesses, such as acute kidney injury or cell lysis, may necessitate admission.
Howard SC et al. The tumor lysis syndrome. N Engl J Med. 2011 May 12;364(19):1844–54. [PMID: 21561350]
Leaf DE et al. A physiologic-based approach to the evaluation of a patient with hyperphosphatemia. Am J Kidney Dis. 2013 Feb;61(2):330–6. [PMID: 22938849]
Lee R et al. Disorders of phosphorus homeostasis. Curr Opin Endocrinol Diabetes Obes. 2010 Dec;17(6):561–7. [PMID: 20962635]
Orrego JJ et al. Hyperphosphatemia. Endocr Pract. 2010 May–Jun;16(3):524–5. [PMID: 20551010]
Prié D et al. Genetic disorders of renal phosphate transport. N Engl J Med. 2010 Jun 24;362(25):2399–409. [PMID: 20573928]
Normal plasma magnesium concentration is 1.8–3.0 mg/dL (or 0.75–1.25 mmol/L), with about one-third bound to protein and two-thirds existing as free cation. Magnesium excretion is via the kidney. Magnesium’s physiologic effects on the nervous system resemble those of calcium.
Altered magnesium concentration usually provokes an associated alteration of Ca2+. Both hypomagnesemia and hypermagnesemia can decrease PTH secretion or action. Severe hypermagnesemia (> 5 mg/dL [or 2.1 mmol/L]) suppresses PTH secretion with consequent hypocalcemia; this disorder is typically seen only in patients receiving magnesium therapy for preeclampsia. Severe hypomagnesemia causes PTH resistance in end-organs and eventually decreased PTH secretion in severe cases.
ESSENTIALS OF DIAGNOSIS
Serum concentration of magnesium may not be decreased even in the presence of magnesium depletion. Check urinary magnesium excretion if renal magnesium wasting is suspected.
Causes neurologic symptoms and arrhythmias.
Impairs release of PTH.
Causes of hypomagnesemia are listed in Table 21–11. Normomagnesemia does not exclude magnesium depletion because only 1% of total body magnesium is in the extracellular fluid (ECF). Hypomagnesemia and hypokalemia share many etiologies, including diuretics, diarrhea, alcoholism, aminoglycosides, and amphotericin. Renal potassium wasting also occurs from hypomagnesemia, and is refractory to potassium replacement until magnesium is repleted. Hypomagnesemia also suppresses PTH release and causes end-organ resistance to PTH and low 1,25-dihydroxyvitamin D3 levels. The resultant hypocalcemia is refractory to calcium replacement until the magnesium is normalized. Molecular mechanisms of magnesium wasting have been revealed in some hereditary disorders. The FDA has issued a warning about hypomagnesemia for patients taking proton pump inhibitors. The presumed mechanism is decreased intestinal magnesium absorption, but it is not clear why this complication develops in only a small fraction of patients taking these medications.
Table 21–11. Causes of hypomagnesemia.
Common symptoms are those of hypokalemia and hypocalcemia, with weakness and muscle cramps. Marked neuromuscular and central nervous system hyperirritability may produce tremors, athetoid movements, jerking, nystagmus, Babinski response, confusion, and disorientation. Cardiovascular manifestations include hypertension, tachycardia, and ventricular arrhythmias.
Urinary excretion of magnesium exceeding 10–30 mg/d or a fractional excretion > 2% indicates renal magnesium wasting. Hypocalcemia and hypokalemia are often present. The ECG shows a prolonged QT interval, due to lengthening of the ST segment. PTH secretion is often suppressed (see Hypocalcemia).
Magnesium oxide, 250–500 mg orally once or twice daily, is useful for treating chronic hypomagnesemia. Symptomatic hypomagnesemia requires intravenous magnesium sulfate 1–2 g over 5–60 minutes mixed in either dextrose 5% or 0.9% normal saline. Torsades de pointes in the setting of hypomagnesemia can be treated with 1–2 g of magnesium sulfate in 10 mL of dextrose 5% solution pushed intravenously over 15 minutes. Severe, non–life-threatening deficiency can be treated at a rate to 1–2 g/h over 3–6 hours. Magnesium sulfate may also be given intramuscularly in a dosage of 200–800 mg/d (8–33 mmol/d) in four divided doses. Serum levels must be monitored daily and dosage adjusted to keep the concentration from rising above 3 mg/dL (1.23 mmol/L). Tendon reflexes may be checked for hyporeflexia of hypermagnesemia. K+ and Ca2+ replacement may be required, but patients with hypokalemia and hypocalcemia of hypomagnesemia do not recover without magnesium supplementation.
Patients with normal kidney function can excrete excess magnesium; hypermagnesemia should not develop with replacement dosages. In patients with CKD, magnesium replacement should be done cautiously to avoid hypermagnesemia. Reduced doses (50–75% dose reduction) and more frequent monitoring (at least twice daily) are indicated.
Ayuk J et al. How should hypomagnesaemia be investigated and treated? Clin Endocrinol (Oxf). 2011 Dec;75(6):743–6. [PMID: 21569071]
Blasco LM et al. Chronic cyclic nonnephrogenic magnesium depletion without losses. N Engl J Med. 2012 May 10;366(19):1845–6. [PMID: 22571217]
Danziger J et al. Proton-pump inhibitor use is associated with low serum magnesium concentrations. Kidney Int. 2013 Apr;83(4):692–9. [PMID: 23325090]
Dimke H et al. Evaluation of hypomagnesemia: lessons from disorders of tubular transport. Am J Kidney Dis. 2013 Aug;62(2):377–83. [PMID: 23201160]
ESSENTIALS OF DIAGNOSIS
Often associated with advanced CKD and chronic intake of magnesium-containing drugs.
Hypermagnesemia is almost always the result of advanced CKD and impaired magnesium excretion. Antacids and laxatives are underrecognized sources of magnesium. Pregnant patients may have severe hypermagnesemia from intravenous magnesium for preeclampsia and eclampsia. Magnesium replacement should be done cautiously in patients with CKD; dose reductions up to 75% may be necessary to avoid hypermagnesemia.
Muscle weakness, decreased deep tendon reflexes, mental obtundation, and confusion are characteristic manifestations. Weakness, flaccid paralysis, ileus, urinary retention, and hypotension are noted. Serious findings include respiratory muscle paralysis and cardiac arrest.
Serum Mg2+ is elevated. In the common setting of CKD, BUN, creatinine, potassium, phosphate, and uric acid may all be elevated. Serum Ca2+ is often low. The ECG shows increased PR interval, broadened QRS complexes, and peaked T waves, probably related to associated hyperkalemia.
Exogenous sources of magnesium should be discontinued. Calcium antagonizes Mg2+ and may be given intravenously as calcium chloride, 500 mg or more at a rate of 100 mg (4.1 mmol) per minute. Hemodialysis or peritoneal dialysis may be necessary to remove magnesium, particularly with severe kidney disease.
Long-term use of magnesium hydroxide and magnesium sulfate should be avoided in patients with advanced stages of CKD.
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Volpe SL. Magnesium in disease prevention and overall health. Adv Nutr. 2013 May 1;4(3):378S–83S. [PMID: 23674807]
Assessment of a patient’s acid–base status requires measurement of arterial pH, PCO2, and plasma bicarbonate (HCO3–). Blood gas analyzers directly measure pH and PCO2. The HCO3– value is calculated from the Henderson–Hasselbalch equation:
The total venous CO2 measurement is a more direct determination of HCO3–. Because of the dissociation characteristics of carbonic acid (H2CO3) at body pH, dissolved CO2 is almost exclusively in the form of HCO3–, and for clinical purposes the total carbon dioxide content is equivalent (± 3 mEq/L) to the HCO3– concentration:
Venous blood gases can provide useful information for acid–base assessment since the arteriovenous differences in pH and PCO2 are small and relatively constant. Venous blood pH is usually 0.03–0.04 units lower than arterial blood pH, and venous blood PCO2 is 7 or 8 mm Hg higher than arterial blood PCO2. Calculated HCO3– concentration in venous blood is at most 2 mEq/L higher than arterial blood HCO3–. Arterial and venous blood gases will not be equivalent during a cardiopulmonary arrest; arterial samples should be obtained for the most accurate measurements of pH and PCO2.
There are two types of acid–base disorders: acidosis and alkalosis. These disorders can be either metabolic (decreased or increased HCO3–) or respiratory (decreased or increased Pco2). Primary respiratory disorders affect blood acidity by changes in PCO2, and primary metabolic disorders are disturbances in HCO3– concentration. A primary disturbance is usually accompanied by a compensatory response, but the compensation does not fully correct the pH disturbance of the primary disorder. If the pH is < 7.40, the primary process is acidosis, either respiratory (Pco2 > 40 mm Hg) or metabolic (HCO3– < 24 mEq/L). If the pH is higher than 7.40, the primary process is alkalosis, either respiratory (Pco2 < 40 mm Hg) or metabolic (HCO3– > 24 mEq/L). One respiratory or metabolic disorder with its appropriate compensatory response is a simple acid-base disorder.
Two or three simultaneous disorders can be present in a mixed acid-base disorder, but there can never be two primary respiratory disorders. Uncovering a mixed acid-base disorder is clinically important, but requires a methodical approach to acid-base analysis (see box, Step-by-Step Analysis of Acid-Base Status). Once the primary disturbance has been determined, the clinician should assess whether the compensatory response is appropriate (Table 21–12). An inadequate or an exaggerated response indicates the presence of another primary acid-base disturbance.
Table 21–12. Primary acid-base disorders and expected compensation.
The anion gap should always be calculated for two reasons. First, it is possible to have an abnormal anion gap even if the sodium, chloride, and bicarbonate levels are normal. Second, a large anion gap (> 20 mEq/L) suggests a primary metabolic acid-base disturbance regardless of the pH or serum bicarbonate level because a markedly abnormal anion gap is never a compensatory response to a respiratory disorder. In patients with an increased anion gap metabolic acidosis, clinicians should calculate the corrected bicarbonate. In increased anion gap acidoses, there should be a mole for mole decrease in HCO3– as the anion gap increases. A corrected HCO3– value higher or lower than normal (24 mEq/L) indicates the concomitant presence of metabolic alkalosis or normal anion gap metabolic acidosis, respectively.
STEP-BY-STEP ANALYSIS OF ACID-BASE STATUS
Step 1: Determine the primary (or main) disorder—whether it is metabolic or respiratory—from blood pH, HCO3–, and Pco2 values.
Step 2: Determine the presence of mixed acid-base disorders by calculating the range of compensatory responses (Table 21–12).
Step 3: Calculate the anion gap (Table 21–13).
Step 4: Calculate the corrected HCO3– concentration if the anion gap is increased (see above).
Step 5: Examine the patient to determine whether the clinical signs are compatible with the acid-base analysis.
Table 21–13. Anion gap in metabolic acidosis.1
Adrogué HJ et al. Assessing acid-base disorders. Kidney Int. 2009 Dec;76(12):1239–47. [PMID: 19812535]
Adrogué HJ et al. Secondary responses to altered acid-base status: the rules of engagement. J Am Soc Nephrol. 2010 Jun;21(6):920–3. [PMID: 20431042]
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ESSENTIALS OF DIAGNOSIS
Decreased HCO3– with acidemia.
Classified into increased anion gap acidosis and normal anion gap acidosis.
Lactic acidosis, ketoacidosis, and toxins produce metabolic acidoses with the largest anion gaps.
Normal anion gap acidosis is mainly caused by gastrointestinal HCO3– loss or RTA. Urinary anion gap may help distinguish between these causes.
The hallmark of metabolic acidosis is decreased HCO3–. Metabolic acidoses are classified by the anion gap, usually normal or increased (Table 21–13). The anion gap is the difference between readily measured anions and cations.
Major unmeasured cations are calcium (2 mEq/L), magnesium (2 mEq/L), gamma-globulins, and potassium (4 mEq/L). Major unmeasured anions are albumin (2 mEq/L per g/dL), phosphate (2 mEq/L), sulfate (1 mEq/L), lactate (1–2 mEq/L), and other organic anions (3–4 mEq/L). Traditionally, the normal anion gap has been 12 ± 4 mEq/L. With current auto-analyzers, the reference range may be lower (6 ± 1 mEq/L), primarily from an increase in Cl– values. Despite its usefulness, the anion gap can be misleading. Non–acid-base disorders may cause errors in anion gap interpretation; these disorders including hypoalbuminemia, hypernatremia, or hyponatremia; antibiotics (eg, carbenicillin is an unmeasured anion; polymyxin is an unmeasured cation) may also cause errors in anion gap interpretation. Although not usually associated with metabolic acidosis, a decreased anion gap can occur because of a reduction in unmeasured anions or an increase in unmeasured cations. In hypoalbuminemia, a 2 mEq/L decrease in anion gap will occur for every 1 g/dL decline in serum albumin.
Normochloremic metabolic acidosis generally results from addition of organic acids such as lactate, acetoacetate, beta-hydroxybutyrate, and exogenous toxins. Other anions such as isocitrate, alpha-ketoglutarate, malate and D-lactate, may contribute to the anion gap of lactic acidosis, DKA, and acidosis of unknown etiology. Uremia causes an increased anion gap metabolic acidosis from unexcreted organic acids and anions.
Lactic acid is formed from pyruvate in anaerobic glycolysis, typically in tissues with high rates of glycolysis, such as gut (responsible for over 50% of lactate production), skeletal muscle, brain, skin, and erythrocytes. Normally, lactate levels remain low (1 mEq/L) because of metabolism of lactate principally by the liver through gluconeogenesis or oxidation via the Krebs cycle. The kidneys metabolize about 30% of lactate.
In lactic acidosis, lactate levels are at least 4–5 mEq/L but commonly 10–30 mEq/L. There are two basic types of lactic acidosis.
Type A (hypoxic) lactic acidosis is more common, resulting from decreased tissue perfusion; cardiogenic, septic, or hemorrhagic shock; and carbon monoxide or cyanide poisoning. These conditions increase peripheral lactic acid production and decrease hepatic metabolism of lactate as liver perfusion declines.
Type B lactic acidosis may be due to metabolic causes (eg, diabetes, ketoacidosis, liver disease, kidney disease, infection, leukemia, or lymphoma) or toxins (eg, ethanol, methanol, salicylates, isoniazid, or metformin). Propylene glycol can cause lactic acidosis from decreased liver metabolism; it is used as a vehicle for intravenous drugs, such as nitroglycerin, etomidate, and diazepam. Parenteral nutrition without thiamine causes severe refractory lactic acidosis from deranged pyruvate metabolism. Patients with short bowel syndrome may develop D-lactic acidosis with encephalopathy due to carbohydrate malabsorption and subsequent fermentation by colonic bacteria.
Nucleoside analog reverse transcriptase inhibitors can cause type B lactic acidosis due to mitochondrial toxicity.
Idiopathic lactic acidosis, usually in debilitated patients, has an extremely high mortality rate. (For treatment of lactic acidosis, see below and Chapter 27.)
DKA is characterized by hyperglycemia and metabolic acidosis with an increased anion gap:
where B– is beta-hydroxybutyrate or acetoacetate, the ketones responsible for the increased anion gap. The anion gap should be calculated from the measured serum electrolytes; correction of the serum sodium for the dilutional effect of hyperglycemia will exaggerate the anion gap. Diabetics with ketoacidosis may have lactic acidosis from tissue hypoperfusion and increased anaerobic metabolism.
During the recovery phase of DKA, a hyperchloremic non-anion gap acidosis can develop because saline resuscitation results in chloride retention, restoration of GFR, and ketoaciduria. Ketone salts (NaB) are formed as bicarbonate is consumed:
The kidney reabsorbs ketone anions poorly but can compensate for the loss of anions by increasing the reabsorption of Cl–.
Patients with DKA and normal kidney function may have marked ketonuria and severe metabolic acidosis but only a mildly increased anion gap. Thus, the size of the anion gap correlates poorly with the severity of the DKA; the urinary loss of Na+ or K+ salts of beta-hydroxybutyrate will lower the anion gap without altering the H+ excretion or the severity of the acidosis. Urine dipsticks for ketones test primarily for acetoacetate and, to a lesser degree, acetone but not the predominant ketoacid, beta-hydroxybutyrate. Dipstick tests for ketones may become more positive even as the patient improves due to the metabolism of beta-hydroxybutyrate. Thus, the patient’s clinical status and pH are better markers of improvement than the anion gap or ketone levels.
Chronically malnourished patients who consume large quantities of alcohol daily may develop alcoholic ketoacidosis. Most of these patients have mixed acid–base disorders (10% have a triple acid–base disorder). Although decreased HCO3– is usual, 50% of the patients may have normal or alkalemic pH. Three types of metabolic acidosis are seen in alcoholic ketoacidosis: (1) Ketoacidosis is due to beta-hydroxybutyrate and acetoacetate excess. (2) Lactic acidosis: Alcohol metabolism increases the NADH:NAD ratio, causing increased production and decreased utilization of lactate. Accompanying thiamine deficiency, which inhibits pyruvate carboxylase, further enhances lactic acid production in many cases. Moderate to severe elevations of lactate (> 6 mmol/L) are seen with concomitant disorders such as sepsis, pancreatitis, or hypoglycemia. (3) Hyperchloremic acidosis from bicarbonate loss in the urine is associated with ketonuria (see above). Metabolic alkalosis occurs from volume contraction and vomiting. Respiratory alkalosis results from alcohol withdrawal, pain, or associated disorders such as sepsis or liver disease. Half of the patients have hypoglycemia or hyperglycemia. When serum glucose levels are > 250 mg/dL (>13.88 mmol/L), the distinction from DKA is difficult. The absence of a diabetic history and normoglycemia after initial therapy support the diagnosis of alcoholic ketoacidosis.
(See also Chapter 38.) Multiple toxins and drugs increase the anion gap by increasing endogenous acid production. Common examples include methanol (metabolized to formic acid), ethylene glycol (glycolic and oxalic acid), and salicylates (salicylic acid and lactic acid). The latter can cause a mixed disorder of metabolic acidosis with respiratory alkalosis. In toluene poisoning, the metabolite hippurate is rapidly excreted by the kidney and may present as a normal anion gap acidosis. Isopropanol, which is metabolized to acetone, increases the osmolar gap, but not the anion gap.
As the GFR drops below 15–30 mL/min, the kidneys are increasingly unable to excrete H+ and organic acids, such as phosphate and sulfate, resulting in an increased anion gap acidosis. Hyperchloremic normal anion gap acidosis develops in earlier stages of CKD.
Table 21–14. Hyperchloremic, normal anion gap metabolic acidoses.
The two major causes are gastrointestinal HCO3– loss and defects in renal acidification (renal tubular acidoses). The urinary anion gap can differentiate between these causes (see below).
The gastrointestinal tract secretes bicarbonate at multiple sites. Small bowel and pancreatic secretions contain large amounts of HCO3–; massive diarrhea or pancreatic drainage can result in HCO3– loss. Hyperchloremia occurs because the ileum and colon secrete HCO3– in exchange for Cl– by countertransport. The resultant volume contraction causes increased Cl– retention by the kidney in the setting of decreased HCO3–. Patients with ureterosigmoidostomies can develop hyperchloremic metabolic acidosis because the colon secretes HCO3– in the urine in exchange for Cl–.
Hyperchloremic acidosis with a normal anion gap and normal (or near normal) GFR, and in the absence of diarrhea, defines RTA. The defect is either inability to excrete H+ (inadequate generation of new HCO3–) or inappropriate reabsorption of HCO3–. Three major types can be differentiated by the clinical setting, urinary pH, urinary anion gap (see below), and serum K+ level. The pathophysiologic mechanisms of RTA have been elucidated by identifying the responsible molecules and gene mutations.
1. Classic distal RTA (type I)—This disorder is characterized by selective deficiency in H+ secretion in alpha intercalated cells in the collecting tubule. Despite acidosis, urinary pH cannot be acidified and is above 5.5, which retards the binding of H+ to phosphate (H+ + HPO42– → H2PO4) and inhibits titratable acid excretion. Furthermore, urinary excretion of NH4+Cl– is decreased, and the urinary anion gap is positive (see below). Enhanced K+ excretion occurs probably because there is less competition from H+ in the distal nephron transport system. Furthermore, hyperaldosteronism occurs in response to renal salt wasting, which will increase potassium excretion. Nephrocalcinosis and nephrolithiasis are often seen in patients with distal RTA since chronic acidosis decreases tubular calcium reabsorption. Hypercalciuria, alkaline urine, and lowered level of urinary citrate cause calcium phosphate stones and nephrocalcinosis.
Distal RTA develops as a consequence of paraproteinemias, autoimmune disease, and drugs and toxins such as amphotericin.
2. Proximal RTA (type II)—Proximal RTA is due to a selective defect in the proximal tubule’s ability to reabsorb filtered HCO3–. Carbonic anhydrase inhibitors (acetazolamide) can cause proximal RTA. About 90% of filtered HCO3– is absorbed by the proximal tubule. A proximal defect in HCO3– reabsorption will overwhelm the distal tubule’s limited capacity to reabsorb HCO3–, resulting in bicarbonaturia and metabolic acidosis. Distal delivery of HCO3– declines as the plasma HCO3– level decreases. When the plasma HCO3– level drops to 15–18 mEq/L, the distal nephron can reabsorb the diminished filtered load of HCO3–. Bicarbonaturia resolves, and the urinary pH can be acidic. Thiazide-induced volume contraction can be used to enhance proximal HCO3– reabsorption, leading to the decrease in distal HCO3– delivery and improvement of bicarbonaturia and renal acidification. The increased delivery of HCO3– to the distal nephron increases K+ secretion, and hypokalemia results if a patient is loaded with excess HCO3– and K+ is not adequately supplemented. Proximal RTA can exist with other proximal reabsorption defects, such as Fanconi syndrome, resulting in glucosuria, aminoaciduria, phosphaturia, and uricosuria. Causes include multiple myeloma and nephrotoxic drugs.
3. Hyporeninemic hypoaldosteronemic RTA (type IV)—Type IV is the most common RTA in clinical practice. The defect is aldosterone deficiency or antagonism, which impairs distal nephron Na+reabsorption and K+ and H+ excretion. Renal salt wasting and hyperkalemia are frequently present. Common causes are diabetic nephropathy, tubulointerstitial renal diseases, hypertensive nephrosclerosis, and AIDS. In patients with these disorders, drugs, such as ACE inhibitors, spironolactone, and NSAIDs, can exacerbate the hyperkalemia.
Rapid dilution of plasma volume by 0.9% NaCl may cause hyperchloremic acidosis.
See Increased Anion Gap Acidosis (Increased Unmeasured Anion).
In prolonged respiratory alkalosis, HCO3– decreases and Cl– increases from decreased renal NH4+Cl– excretion. If the respiratory alkalosis is corrected quickly, HCO3– will remain low until the kidneys can generate new HCO3–, which generally takes several days. In the meantime, the increased Pco2 with low HCO3– causes metabolic acidosis.
Hyperalimentation fluids may contain amino acid solutions that acidify when metabolized, such as arginine hydrochloride and lysine hydrochloride.
Increased renal NH4+Cl– excretion to enhance H+ removal is the normal physiologic response to metabolic acidosis. The daily urinary excretion of NH4Cl can be increased from 30 mEq to 200 mEq in response to acidosis.
The urinary anion gap (Na+ + K+ – Cl–) reflects the ability of the kidney to excrete NH4Cl. The urinary anion gap differentiates between gastrointestinal and renal causes of hyperchloremic acidosis. If the cause is gastrointestinal HCO3– loss (diarrhea), renal acidification remains normal and NH4Cl excretion increases, and the urinary anion gap is negative. If the cause is distal RTA, the urinary anion gap is positive, since the basic lesion in the disorder is the inability of the kidney to excrete H+ as NH4Cl. In proximal (type II) RTA, the kidney has defective HCO3– reabsorption, leading to increased HCO3–excretion rather than decreased NH4Cl excretion; the urinary anion gap is often negative.
Urinary pH may not readily differentiate between the two causes. Despite acidosis, if volume depletion from diarrhea causes inadequate Na+ delivery to the distal nephron and therefore decreased exchange with H+, urinary pH may not be lower than 5.3. In the presence of this relatively high urinary pH, however, H+ excretion continues due to buffering of NH3 to NH4+, since the pK of this reaction is as high as 9.1. Potassium depletion, which can accompany diarrhea (and surreptitious laxative abuse), may also impair renal acidification. Thus, when volume depletion is present, the urinary anion gap is a better measure of ability to acidify the urine than urinary pH.
When large amounts of other anions are present in the urine, the urinary anion gap may not be reliable. In such a situation, NH4+ excretion can be estimated using the urinary osmolar gap.
NH4+ excretion (mmol/L) = 0.5 × Urinary osmolar gap = 0.5 [U osm – 2(U Na+ + U K+) + U urea + U glucose]
where urine concentrations and osmolality are in mmol/L.
Symptoms of metabolic acidosis are mainly those of the underlying disorder. Compensatory hyperventilation is an important clinical sign and may be misinterpreted as a primary respiratory disorder; Kussmaul breathing (deep, regular, sighing respirations) may be seen with severe metabolic acidosis.
Blood pH, serum HCO3–, and PCO2 are decreased. Anion gap may be normal (hyperchloremic) or increased (normochloremic). Hyperkalemia may be seen.
Treatment is aimed at the underlying disorder, such as insulin and fluid therapy for diabetes and appropriate volume resuscitation to restore tissue perfusion. The metabolism of lactate will produce HCO3–and increase pH. Supplemental HCO3– is indicated for treatment of hyperkalemia (Table 21–6) and some forms of normal anion gap acidosis but has been controversial for treatment of increased anion gap metabolic acidosis with respect to efficacy and safety. Large amounts of HCO3– may have deleterious effects, including hypernatremia, hyperosmolality, volume overload, and worsening of intracellular acidosis.
In addition, alkali administration stimulates phosphofructokinase activity, thus exacerbating lactic acidosis via enhanced lactate production. Ketogenesis is also augmented by alkali therapy.
In salicylate intoxication, alkali therapy must be started to decrease central nervous system damage unless blood pH is already alkalinized by respiratory alkalosis, since an increased pH converts salicylate to more impermeable salicylic acid. In alcoholic ketoacidosis, thiamine should be given with glucose to avoid Wernicke encephalopathy. The bicarbonate deficit can be calculated as follows:
HCO3– deficit = 0.5 × body weight in kg × (24 – HCO 3–)
Half of the calculated deficit should be administered within the first 3–4 hours to avoid overcorrection and volume overload. In methanol intoxication, inhibition of alcohol dehydrogenase by fomepizole is now standard care. Ethanol had previously been used as a competitive substrate for alcohol dehydrogenase, which metabolizes to formaldehyde.
Treatment of RTA is mainly achieved by administration of alkali (either as bicarbonate or citrate) to correct metabolic abnormalities and prevent nephrocalcinosis and CKD.
Large amounts of oral alkali (10–15 mEq/kg/d) (Table 21–14) may be required to treat proximal RTA because most of the alkali is excreted into the urine, which exacerbates hypokalemia. Thus, a mixture of sodium and potassium salts is preferred. Thiazides may reduce the amount of alkali required, but hypokalemia may develop. Treatment of type 1 distal RTA requires less alkali (1–3 mEq/kg/d) than proximal RTA. Potassium supplementation may be necessary.
For type IV RTA, dietary potassium restriction may be necessary and potassium-retaining drugs should be withdrawn. Fludrocortisone may be effective in cases with hypoaldosteronism, but should be used with care, preferably in combination with loop diuretics. In some cases, oral alkali supplementation (1–3 mEq/kg/d) may be required.
Most clinicians will refer patients with renal tubular acidoses to a nephrologist for evaluation and possible alkali therapy.
Patients will require emergency department evaluation or hospital admission depending on the severity of the acidosis and underlying conditions.
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ESSENTIALS OF DIAGNOSIS
High HCO3– with alkalemia.
Evaluate effective circulating volume by physical examination.
Check urinary chloride concentration to differentiate saline-responsive alkalosis from saline-unresponsive alkalosis.
Metabolic alkalosis is characterized by high HCO3–. Abnormalities that generate HCO3– are called “initiation factors,” whereas abnormalities that promote renal conservation of HCO3– are called “maintenance factors.” Thus, metabolic alkalosis may remain even after the initiation factors have resolved.
The causes of metabolic alkalosis are classified into two groups based on “saline responsiveness” using the urine Cl– as a marker for volume status (Table 21–15). Saline-responsive metabolic alkalosis is a sign of extracellular volume contraction, and saline-unresponsive alkalosis implies excessive total body bicarbonate with either euvolemia or hypervolemia. The compensatory increase in PCO2 rarely exceeds 55 mm Hg; higher PCO2 values imply a superimposed primary respiratory acidosis.
Table 21–15. Metabolic alkalosis.
Much more common than saline-unresponsive alkalosis, saline-responsive alkalosis is characterized by normotensive extracellular volume contraction and hypokalemia. Hypotension and orthostasis may be seen. In vomiting or nasogastric suction, loss of acid (HCl) initiates the alkalosis, but volume contraction from Cl– loss maintains the alkalosis because the kidney avidly reabsorbs Na+ to restore the ECF. Increased sodium reabsorption necessitates increased HCO3– reabsorption proximally, and the urinary pH remains acidic despite alkalemia (paradoxical aciduria). Renal Cl– reabsorption is high, and urine Cl– is low (< 10–20 mEq/L). In alkalosis, bicarbonaturia may force Na+ excretion as the accompanying cation even if volume depletion is present. Therefore, urine Cl– is preferred to urine Na+ as a measure of extracellular volume. Diuretics may limit the utility of urine chloride by increasing urine chloride and sodium excretion, even in the setting of volume contraction.
Metabolic alkalosis is generally associated with hypokalemia due to the direct effect of alkalosis on renal potassium excretion and secondary hyperaldosteronism from volume depletion. Hypokalemia exacerbates the metabolic alkalosis by increasing bicarbonate reabsorption in the proximal tubule and hydrogen ion secretion in the distal tubule. Administration of KCl will correct the disorder.
1. Contraction alkalosis—Diuretics decrease extracellular volume from urinary loss of NaCl and water. The plasma HCO3– concentration increases because the extracellular fluid volume contracts around a stable total body bicarbonate. Contraction alkalosis is the opposite of dilutional acidosis.
2. Posthypercapnia alkalosis—In chronic respiratory acidosis, the kidney decreases bicarbonate excretion, increasing plasma HCO3– concentration (Table 21–12). Hypercapnia directly affects the proximal tubule to decrease NaCl reabsorption, which can cause extracellular volume depletion. If PCO2 is rapidly corrected, metabolic alkalosis will exist until the kidney excretes the retained bicarbonate. Many patients with chronic respiratory acidosis receive diuretics, which further exacerbates the metabolic alkalosis.
1. Hyperaldosteronism—Primary hyperaldosteronism causes extracellular volume expansion and hypertension by increasing distal sodium reabsorption. Aldosterone increases H+ and K+ excretion, producing metabolic alkalosis and hypokalemia. In an attempt to decrease extracellular volume, high levels of NaCl are excreted resulting in a high urine Cl– (> 20 mEq/L). Therapy with NaCl will only increase volume expansion and hypertension and will not treat the underlying problem of mineralocorticoid excess.
2. Alkali administration with decreased GFR—The normal kidney has a substantial capacity for bicarbonate excretion, protecting against metabolic alkalosis even with large HCO3– intake. However, urinary excretion of bicarbonate is inadequate in CKD. If large amounts of HCO3– are consumed, as with intensive antacid therapy, metabolic alkalosis will occur. Lactate, citrate, and gluconate can also cause metabolic alkalosis because they are metabolized to bicarbonate. In milk-alkali syndrome, sustained heavy ingestion of absorbable antacids and milk causes hypercalcemic kidney injury and metabolic alkalosis. Volume contraction from renal hypercalcemic effects exacerbates the alkalosis.
There are no characteristic symptoms or signs. Orthostatic hypotension may be encountered. Concomitant hypokalemia may cause weakness and hyporeflexia. Tetany and neuromuscular irritability occur rarely.
The arterial blood pH and bicarbonate are elevated. With respiratory compensation, the arterial Pco2 is increased. Serum potassium and chloride are decreased. There may be an increased anion gap. The urine chloride can differentiate between saline-responsive (< 25 mEq/L) and unresponsive (> 40 mEq/L) causes.
Mild alkalosis is generally well tolerated. Severe or symptomatic alkalosis (pH > 7.60) requires urgent treatment.
Therapy for saline-responsive metabolic alkalosis is correction of the extracellular volume deficit with isotonic saline. Diuretics should be discontinued. H2-blockers or proton pump inhibitors may be helpful in patients with alkalosis from nasogastric suctioning. If pulmonary or cardiovascular disease prohibits adequate resuscitation, acetazolamide will increase renal bicarbonate excretion. Hypokalemia may develop because bicarbonate excretion may induce kaliuresis. Severe cases, especially those with reduced kidney function, may require dialysis with low-bicarbonate dialysate.
Therapy for saline-unresponsive metabolic alkalosis includes surgical removal of a mineralocorticoid-producing tumor and blockage of aldosterone effect with an ACE inhibitor or with spironolactone (seeChapter 26). Metabolic alkalosis in primary aldosteronism can be treated only with potassium repletion.
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Respiratory acidosis results from hypoventilation and subsequent hypercapnia. Pulmonary and extrapulmonary disorders can cause hypoventilation.
Acute respiratory failure is associated with severe acidosis and only a small increase in the plasma bicarbonate. After 6–12 hours, the primary increase in PCO2 evokes a renal compensation to excrete more acid and to generate more HCO3–; complete metabolic compensation by the kidney takes several days.
Chronic respiratory acidosis is generally seen in patients with underlying lung disease, such as chronic obstructive pulmonary disease. Renal excretion of acid as NH4Cl results in hypochloremia. When chronic respiratory acidosis is corrected suddenly, posthypercapnic metabolic alkalosis ensues until the kidneys excrete the excess bicarbonate over 2–3 days.
With acute onset, somnolence, confusion, mental status changes, asterixis, and myoclonus may develop. Severe hypercapnia increases cerebral blood flow, cerebrospinal fluid pressure, and intracranial pressure; papilledema and pseudotumor cerebri may be seen.
Arterial pH is low and PCO2 is increased. Serum HCO3– is elevated but does not fully correct the pH. If the disorder is chronic, hypochloremia is seen.
If opioid overdose is a possible diagnosis or there is no other obvious cause for hypoventilation, the clinician should consider a diagnostic and therapeutic trial of intravenous naloxone (see Chapter 38). In all forms of respiratory acidosis, treatment is directed at the underlying disorder to improve ventilation.
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Respiratory alkalosis occurs when hyperventilation reduces the PCO2, increasing serum pH. The most common cause of respiratory alkalosis is hyperventilation syndrome (Table 21–16), but bacterial septicemia and cirrhosis are other common causes. In pregnancy, progesterone stimulates the respiratory center, producing an average PCO2 of 30 mm Hg and respiratory alkalosis. Symptoms of acute respiratory alkalosis are related to decreased cerebral blood flow induced by the disorder.
Table 21–16. Causes of respiratory alkalosis.
Determination of appropriate metabolic compensation may reveal an associated metabolic disorder (see Mixed Acid–Base Disorders).
As in respiratory acidosis, the metabolic compensation is greater if the respiratory alkalosis is chronic (Table 21–12). Although serum HCO3– is frequently < 15 mEq/L in metabolic acidosis, such a low level in respiratory alkalosis is unusual and may represent a concomitant primary metabolic acidosis.
In acute cases (hyperventilation), there is light-headedness, anxiety, perioral numbness, and paresthesias. Tetany occurs from a low ionized calcium, since severe alkalosis increases calcium binding to albumin.
Arterial blood pH is elevated, and PCO2 is low. Serum bicarbonate is decreased in chronic respiratory alkalosis.
Treatment is directed toward the underlying cause. In acute hyperventilation syndrome from anxiety, the traditional treatment of breathing into a paper bag should be discouraged because it does not correct PCO2 and may decrease Po2. Reassurance may be sufficient for the anxious patient, but sedation may be necessary if the process persists. Hyperventilation is usually self-limited since muscle weakness caused by the respiratory alkalemia will suppress ventilation. Rapid correction of chronic respiratory alkalosis may result in metabolic acidosis as PCO2 is increased in the setting of a previous compensatory decrease in HCO3–.
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Daily parenteral maintenance fluids and electrolytes for an average adult would include at least 2 L of water in the form of 0.45% saline with 20 mEq/L of potassium chloride. Patients with hypoglycemia, starvation ketosis, or ketoacidosis being treated with insulin may require 5% dextrose-containing solutions. Guidelines for gastrointestinal fluid losses are shown in Table 21–17.
Table 21–17. Replacement guidelines for sweat and gastrointestinal fluid losses.
Weight loss or gain is the best indication of water balance. Insensible water loss should be considered in febrile patients. Water loss increases by 100–150 mL/d for each degree of body temperature over 37°C.
In patients requiring maintenance and possibly replacement of fluid and electrolytes by parenteral infusion, the total daily ration should be administered continuously over 24 hours to ensure optimal utilization.
If intravenous fluids are the only source of water, electrolytes, and calories for longer than a week, parenteral nutrition containing amino acids, lipids, trace metals, and vitamins may be indicated. (SeeChapter 29.)
For parenteral alimentation, 620 mg (20 mmol) of phosphorus is required for every 1000 nonprotein kcal to maintain phosphate balance and to ensure anabolic function. For prolonged parenteral fluid maintenance, a daily ration is 620–1240 mg (20–40 mmol) of phosphorus.
Excessive fluid resuscitation or maintenance is now viewed as a complication in hospitalized patients, especially those with critical illness or acute kidney injury, and has been associated with worsened outcomes such as prolonged mechanical ventilation, dependence on dialysis, and long duration of hospitalization with increased mortality.
Annane D et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013 Nov 6;310(17):1809–17. [PMID: 24108515]
Myburgh JA et al. Resuscitation fluids. N Engl J Med. 2013 Sep 26;369(13):1243–51. [PMID: 24066745]
1 See also Chapter 26 for discussion of the treatment of hypoparathyroidism.