Abnormal Electrolytes (Case 15)
Case: A 76-year-old woman with a history of hypertension and coronary artery disease presents to the ED with complaints of weakness, nausea, and muscle cramps. Her daughter states that she has been mildly confused over the past 2 days. She reports that her primary-care physician prescribed hydrochlorothiazide for elevated BP 2 weeks ago. The patient claims to be more thirsty than usual and, as a result, has been drinking more water. She denies any fevers, chills, vomiting, or diarrhea. Her other medications include metoprolol, aspirin, and simvastatin. On physical examination, the patient appears mildly lethargic and is oriented to name and place, but not to date. Her BP is 149/65 mm Hg without orthostatic changes, with a HR of 68 bpm. The cardiac and chest examinations are normal. No lower extremity edema is present. Neurologic examination reveals no focal deficits. Laboratory studies reveal a serum sodium 118 mEq/L, serum potassium 2.8 mEq/L, serum chloride 80 mEq/L, serum bicarbonate 29 mEq/L, BUN 34 mg/dL, serum creatinine 0.9 mg/dL, and serum calcium 11.2 mg/dL.
Electrolyte disorders are common clinical problems, especially among hospitalized patients. Fluids and electrolytes are normally very carefully maintained within narrow parameters to allow the cells of the body to function normally. Electrolyte abnormalities can affect the resting membrane potential, resulting in cardiac, neurologic, and musculoskeletal symptoms. Serum sodium concentration is a major determinant of extracellular osmolality, and abnormalities in sodium concentration lead to changes in intracranial pressure. The severity of the symptoms usually depends on how quickly the electrolyte disturbance occurs. The electrolytes that may be affected include sodium, potassium, and calcium. Since these disorders are accompanied by significant morbidity and mortality, appropriate diagnosis and treatment are essential.
• Search for causes of volume depletion, such as vomiting, diarrhea, GI bleeding, and decreased oral intake, or conditions associated with a low effective arterial blood volume, such as congestive heart failure (CHF), renal failure, and cirrhosis.
• Review the patient’s medications and their side effect profile, as many medications can cause sodium disturbance. For example, thiazide diuretics can cause hyponatremia by interfering with the ability of the kidneys to dilute the urine.
• Assess whether the patient has neurologic symptoms related to hyponatremia, such as nausea, vomiting, headaches, mental status changes, or seizures. These symptoms are related to brain swelling and require immediate treatment.
• Polyuria and polydipsia are common in patients with hypercalcemia and hypokalemia, as these disturbances interfere with the action of ADH in the distal tubule, resulting in nephrogenic diabetes insipidus.
The diagnosis and treatment of fluid and electrolyte disorders are based on serum electrolyte concentrations, urine electrolyte concentrations, and serum and urine osmolality. Once the specific electrolyte abnormality has been diagnosed, additional tests can be done to aid in determining the etiology.
$45, $334, $334
|Clinical Entities||Medical Knowledge|
Hyponatremia is defined as a serum sodium concentration < 135 mEq/L. Hyponatremia may be hypertonic, hypotonic, or isotonic, associated with a high, low, or normal serum osmolality, respectively. Isotonic hyponatremia is the result of laboratory artifact due to a decreased aqueous component of plasma such as may be seen in patients with hyperlipidemia and hyperproteinemia. Hypertonic hyponatremia results from the presence of solutes, such as mannitol and glucose, which do not freely cross cell membranes, and represents a hyperosmolar state. Most hyponatremia is hypotonic, representing an excess of total-body water relative to total-body sodium, and is caused by impaired renal water excretion combined with continued water intake. Reasons for impaired water excretion include renal failure, volume depletion, high-ADH states, hypothyroidism, adrenal insufficiency, and low osmolar intake. Thiazides impair the ability of the kidneys to excrete free water, and, if the patient maintains a high water intake, as in the case illustrated above, a positive water balance ensues and hyponatremia results.
The symptoms of hyponatremia reflect cerebral edema and range from headache, nausea, vomiting, and mental status changes to seizures, coma, brainstem herniation, and death. The majority of patients present with mild symptoms such as nausea, weakness, and confusion. On exam they may have signs of hypovolemia, hypervolemia, or euvolemia.
Most patients with hyponatremia will have a low serum osmolality and a urine osmolality > 100 mOsm/kg, reflecting an impaired renal diluting ability (the normal renal response should be to dilute the urine to 60 mOsm/kg). The urine sodium concentration will vary depending on the source of volume loss (renal or nonrenal) and the amount of sodium intake.
The urgency of treatment is dictated by the severity of symptoms and the time course of development of the hyponatremia. In the presence of severe, symptomatic hyponatremia, an infusion of hypertonic 3% saline solution is the standard approach. For asymptomatic patients the treatment depends on the cause of hyponatremia. Hypovolemic hyponatremia should be corrected with isotonic saline. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), renal failure, and psychogenic polydipsia are treated primarily with fluid restriction. In cases of low osmolar intake, increase dietary solute and decrease water intake. Edematous states require water and sodium restriction. In addition, loop diuretics (e.g., furosemide) can be added to promote water loss in excess of sodium loss. The rate of correction should not exceed 0.5 mEq/L/hr to avoid osmotic demyelination (central pontine myelinolysis), the most feared consequence of overly rapid correction. See Cecil Essentials 28.
Hypernatremia is defined as serum sodium > 145 mEq/L and generally results from loss of water combined with a failure to adequately replace the water deficit. The causes of hypernatremia can be divided into three categories: (1) increased water loss, which may be renal losses (diabetes insipidus, osmotic diuresis, diuretic use) or extrarenal losses (diarrhea, vomiting, excessive sweating, burns), (2) decreased water intake due to impaired thirst mechanism or altered mental status, and (3) iatrogenic causes such as administration of hypertonic saline.
Diabetes insipidus (DI) results from the inability of the kidneys to concentrate the urine due to either a deficiency of ADH or lack of response to ADH. Central DI is characterized by decreased secretion of ADH and is most often due to brain tumors, head injuries, CNS infections, or inherited disorders. Nephrogenic DI is due to unresponsiveness of the kidney to the effects of ADH; it can be congenital or caused by certain medications such as lithium.
Patients typically present with neurologic symptoms such as altered mental status and lethargy, and occasionally seizures or coma if the hypernatremia is severe. They may complain of polyuria or excessive thirst. On exam, patients are usually volume depleted, but in certain instances they can be hypervolemic or euvolemic.
In most cases the etiology of the hypernatremia can be determined based on history and physical. Laboratory tests such as urine osmolality, urine sodium concentration, and blood glucose can provide further diagnostic clues. Hypovolemia with a urine sodium concentration < 20 mEq/L is consistent with extrarenal losses. The hallmark of DI is polyuria with low urine osmolality, whereas osmotic diuresis—as can be seen with hyperglycemia—is associated with polyuria and a daily solute excretion (urine volume × urine osmolality) in excess of 900 mOsm/kg.
The goals of treatment are (1) to stop ongoing loss of water and (2) to replace the water deficit. The water deficit can be estimated as follows:
Water deficit = 0.6 × body weight (kg) × [(Na/140) – 1]
In hypovolemic patients, especially those with hemodynamic compromise, replacement of volume with 0.9% saline is a first priority. Subsequently, free-water deficit can be replaced using hypotonic fluids. Using the oral or gastric route to replace free water is preferred; however, if not possible, IV fluids such as D5W or 0.45% saline can be used. The major complication of overly rapid correction is cerebral edema. To avoid this, the rate of increase of sodium should not exceed 0.5 mEq/L/hr. See Cecil Essentials 28.
Hypokalemia is defined as a serum potassium concentration <3.5 mEq/L. Hypokalemia is caused by decreased intake, increased excretion, or intracellular shifts. A typical American diet is rich in potassium, and the kidney is efficient at conserving potassium; thus, it is rare to see hypokalemia on the basis of low potassium intake. Intracellular shift of potassium can be stimulated in patients with metabolic alkalosis, insulin, and certain drugs such as theophylline and β-agonists. A strong clue for this mechanism is the lack of an associated acid-base abnormality. Increased potassium excretion occurs via the GI tract or the kidney. GI losses can occur in patients with diarrhea, as a result of loss of potassium in the stool, or with vomiting. Vomiting also leads to potassium loss in the urine through volume depletion and secondary hyperaldosteronism. Potassium loss via the kidneys can be further classified based on the associated acid-base abnormality and the presence of hypertension. Metabolic alkalosis accompanies vomiting, diuretic use (as in the case illustrated above), and distal tubular defects such as Bartter and Gitelman syndrome. Metabolic alkalosis with hypertension is associated with hypokalemia from primary mineralocorticoid excess, such as in patients with adrenal adenomas. Hypokalemia from RTA is associated with metabolic acidosis. Another cause of hypokalemia without acid-base disturbances, but with hypocalcemia, is hypomagnesemia.
Weakness, fatigue, and muscle cramps are the most frequent complaints in patients with mild to moderate hypokalemia. Smooth muscle involvement may result in constipation or ileus. Electrocardiographic (ECG) changes can occur and include flattening or inversion of T waves, prominent U waves, and ST-segment depression and arrhythmias. Severe hypokalemia can lead to flaccid paralysis, respiratory failure, arrhythmias, rhabdomyolysis, and nephrogenic DI.
The source of potassium loss is very often evident upon careful history. When the cause is not apparent, the 24-hour urinary potassium can help distinguish between renal and extrarenal losses. Potassium excretion >20 mEq in 24 hours in the presence of hypokalemia implies renal potassium loss. Alternatively, measurement of the transtubular potassium gradient can be used. Assessment of the patient’s volume status, BP, and acid-base status provides additional diagnostic clues.
Each 1-mEq/L decrement in serum potassium concentration below a level of 4 mEq/L may represent a total-body deficit of 200–400 mEq. Mild to moderate deficiency (3.0–3.5 mEq/L) may best be treated with oral potassium chloride (KCl). Severe hypokalemia (<3.0 mEq/L) requires IV replacement with KCl. The maximum rate of KCl administration is 10 mEq/L/hr via a peripheral IV line and 20 mEq/L/hr via a central line. The latter requires continuous ECG monitoring. Serum potassium levels should be checked frequently during correction. When present, magnesium deficiency must be corrected to allow potassium correction. See Cecil Essentials 28.
Severe hyperkalemia is a life-threatening emergency, requiring immediate treatment. Hyperkalemia can be caused by increased intake, transcellular shift, decreased excretion, or some or all of these. Transcellular shift involves transient movement of potassium out of cells and into the extracellular space. This can be triggered by acidosis, hypertonic states, and insulin deficiency, as well as with drugs such as β-blockers and digoxin. Release of potassium from cells can also be caused by tissue breakdown as seen in patients with rhabdomyolysis and tumor lysis syndrome. Decreased renal excretion is the most common mechanism of hyperkalemia, due to (1) decreased renal function, (2) aldosterone deficiency or tubular unresponsiveness to aldosterone, or (3) decreased delivery of sodium to the distal tubule. Aldosterone acts on the principal cells of the collecting duct, where it causes increased sodium reabsorption and potassium excretion. Causes of true or functional hypoaldosterone states leading to hyperkalemia include adrenal insufficiency and drugs such as ACE inhibitors, ARBs, NSAIDs, aldosterone receptor blockers, and potassium-sparing diuretics. Conditions associated with low urinary sodium and decreased urine output, such as advanced liver cirrhosis or CHF, severely limit the ability of the kidneys to excrete potassium. Pseudo-hyperkalemia is a factitious elevation of serum potassium often seen in patients with hemolysis, thrombocytosis (platelet count > 1 million/μL), or leukocytosis (WBC count over 100,000/μL). In these instances the ECG is normal, and the patient has no apparent clinical reasons to be hyperkalemic.
Most patients with hyperkalemia are asymptomatic. When present, symptoms include muscle weakness, ascending paralysis, respiratory failure, and cardiac arrhythmias. ECG changes in patients with hyperkalemia are progressive and include peaked T waves, flattened P waves, prolonged PR interval, widened QRS complex, and, finally, a sine wave pattern.
The ECG is the most important tool to evaluate the severity of the hyperkalemia and to guide the therapeutic approach. If the ECG is normal and the patient has no clinical reason to be hyperkalemic, pseudo-hyperkalemia should be excluded. Careful venipuncture without using a tourniquet and measuring plasma instead of serum potassium usually clarifies the diagnosis. Hyperkalemia is often multifactorial, and the diagnostic approach is to systematically address the possible mechanism. Often an iatrogenic intervention such as the initiation of an ACE inhibitor or an aldosterone receptor antagonist will precipitate hyperkalemia in a predisposed patient. Heparin inhibits aldosterone synthesis and can cause hyperkalemia in hospitalized patients.
Severe hyperkalemia with ECG changes is a medical emergency and requires immediate treatment. The initial treatment is aimed at stabilizing the cardiac cell membrane to prevent cardiac death by giving intravenous calcium gluconate. Further measures aim to shift potassium intracellularly by administering insulin, D50W, sodium bicarbonate, and nebulized β2-adrenergic agonists. Finally patients are treated with diuretics, cation exchange resins, or even dialysis to decrease potassium. Dialysis should be reserved for patients with renal failure and those with severe life-threatening hyperkalemia unresponsive to more conservative measures. See Cecil Essentials 28.
Calcium homeostasis is maintained through the actions of parathyroid hormone (PTH) and vitamin D. PTH acts directly upon the bone to mobilize calcium and upon the kidneys to reabsorb calcium. PTH acts indirectly upon the GI tract by increasing the amount of active vitamin D. Vitamin D acts directly upon the GI tract to facilitate calcium absorption. Hypocalcemia is defined as a reduction in serum ionized calcium concentration and can be caused by decreased entry of calcium into the circulation or loss of calcium from the circulation. Conditions that result in a decreased entry of calcium into the circulation include vitamin D deficiency and hypoparathyroidism. Vitamin D deficiency is not uncommon in the elderly and is usually the result of malabsorption or poor oral intake. True hypoparathyroidism is rare and is usually the result of surgical removal, while a functional hypoparathyroid state can result from hypomagnesemia or bisphosphonate therapy. Loss of calcium from the circulation can be seen in patients with acute pancreatitis, rhabdomyolysis, or massive transfusions.
Hypocalcemia increases excitation of nerve and muscle cells, primarily affecting the neuromuscular and cardiovascular systems. Patients with significant deficiency may complain of muscle cramps, tetany, and paresthesias of the lips and extremities. Severe hypocalcemia may cause lethargy, confusion, laryngospasm, or seizures. Prolongation of the QT interval may be present and predisposes to the development of ventricular arrhythmias.
Patients with hypocalcemia may exhibit Chvostek sign and Trousseau sign. The diagnosis is confirmed, however, by a low serum ionized calcium. Once hypocalcemia has been confirmed, further testing for PTH, vitamin D, magnesium, phosphorus, and creatinine should be performed. Additional testing for pancreatitis or rhabdomyolysis should be performed if clinically warranted.
Severe, symptomatic hypocalcemia should be corrected with IV calcium. Chronic treatment of hypocalcemia requires oral calcium supplementation of 1–2 g of elemental calcium daily, given with vitamin D. In patients with hypoparathyroidism, calcium should be supplemented to maintain serum calcium at the lower limit of normal (8.0 mg/dL) so as to minimize hypercalciuria and precipitation of renal stones. Hypomagnesemia should be corrected when it is present. See Cecil Essentials 74.
Together, primary hyperparathyroidism and malignancy account for the vast majority of cases of hypercalcemia. Primary hyperparathyroidism is the most common cause of hypercalcemia in ambulatory patients, whereas malignancy is the most common cause of hypercalcemia in hospitalized patients. Primary hyperparathyroidism causes hypercalcemia through two distinct mechanisms: PTH acts directly on the kidney resulting in calcium reabsorption, and PTH increases vitamin D synthesis, which results in increased calcium absorption through the GI tract. Hypercalcemia associated with malignancy is commonly caused by increased osteoclastic activity. Other causes of hypercalcemia include exogenous vitamin D intake, granulomatous disorders such as sarcoidosis and tuberculosis, milk-alkali syndrome, and immobilization. Thiazide diuretics increase renal calcium reabsorption; however, hypercalcemia rarely results from thiazide use alone and should raise the suspicion of the presence of an underlying hyperparathyroidism.
Hypercalcemia may affect GI, renal, and neurologic function. Mild hypercalcemia is often asymptomatic. Symptoms usually occur if the serum calcium is above 12 mg/dL and tend to be more severe if hypercalcemia develops acutely. Even mild elevation of calcium can induce symptoms in hypoalbuminemic patients, as less calcium is bound and more is free. Neurologic manifestations may range from mild drowsiness to weakness, lethargy, confusion, and coma. GI symptoms may include constipation, nausea, vomiting, anorexia, and peptic ulcer disease. The ECG shows a shortened QT interval. Hypercalcemia induces nephrogenic DI and polyuria. The ensuing dehydration has an important role in decreasing renal calcium excretion and increasing the serum calcium.
The serum calcium level should be corrected for serum albumin, or serum ionized calcium should be measured. Once hypercalcemia is confirmed, measurements of PTH, PTH-related protein (PTHrP), and vitamin D should be ordered. Hyperparathyroidism is diagnosed by finding a high PTH level. Patients with malignancy-induced hypercalcemia usually have a known malignancy and may have an elevated PTHrP. The vitamin D level will be high in patients taking exogenous vitamin D, as well in those with hypercalcemia from granulomatous disease.
Until the primary disease can be brought under control, acute treatment of hypercalcemia is directed at increasing calcium excretion and decreasing resorption of calcium from bone. The first step is volume repletion with 0.9% saline. After extracellular volume has been restored, a loop diuretic (such as furosemide) is added to increase calcium excretion and prevent volume overload. Thiazides should not be used because they will worsen hypercalcemia. Bisphosphonates and calcitonin can also be used to inhibit bone resorption, although may be required up to 3 days before the effect of bisphosphonates is seen. In certain cases, such as patients with CHF or renal failure, dialysis with low-calcium dialysate may be needed. See Cecil Essentials 74.
a. Familial hypokalemic periodic paralysis: This is an autosomal-dominant disorder that causes hypokalemia due to a transcellular shift of potassium. This disorder is associated with recurrent episodes of flaccid paralysis that begin in childhood. Episodes are usually triggered by high-carbohydrate meals (increased insulin) or after a period of exercise (catecholamine excess).