Introdution
Hypermagnesemia is an uncommon clinical finding, and symptomatic hypermagnesemia is even less common. This disorder has a low incidence of occurrence, because the kidney is able to eliminate excess magnesium by rapidly reducing its tubular reabsorption to almost negligible amounts.
In healthy adults, plasma magnesium ranges from 1.7-2.3 mg/dL. Approximately 30% of total plasma magnesium is protein-bound and approximately 70% is filterable through artificial membranes (15% complexed, 55% free Mg2+ ions). With a glomerular filtration rate (GFR) of approximately 150 L/d and an ultrafiltrable magnesium concentration of 14 mg/L, the filtered magnesium load is approximately 2,100 mg/d. Normally, only 3% of filtered magnesium appears in urine; thus, 97% is reabsorbed by the renal tubules. In contrast to sodium and calcium, only approximately 25-30% of filtered magnesium is reabsorbed in the proximal tubule. Approximately 60-65% of filtered magnesium is reabsorbed in the thick ascending loop of Henle and 5% is reabsorbed in the distal nephron. Relatively little is known about cellular magnesium transport mechanisms.
The most common cause of hypermagnesemia is renal failure. Other causes include the following:
Excessive intake
Lithium therapy
Hypothyroidism
Addison disease
Familial hypocalciuric hypercalcemia
Milk alkali syndrome
Depression
RENAL FAILURE Section 3 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography
Patients with end-stage renal disease often have mild hypermagnesemia, and the ingestion of magnesium-containing medications (eg, antacids, cathartics) can exacerbate the condition. In patients undergoing regular dialysis, the serum magnesium level directly relates to the dialysate-magnesium concentration.
In patients with acute renal failure, hypermagnesemia usually presents during the oliguric phase; the serum magnesium level returns to normal during the diuretic phase. If a patient receives exogenous magnesium during the oliguric phase, severe hypermagnesemia can result, especially if the patient is acidotic. OTHER CAUSES Section 4 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography
People often take magnesium-containing medications (eg, antacids, laxatives, rectal enemas). Hypermagnesemia can develop after treatment of drug overdoses with magnesium-containing cathartics, and it also occurs in patients taking magnesium-containing medications for therapeutic purposes; however, most of these patients have normal renal function. If the patient does not ingest a large amount of magnesium but has a gastrointestinal disorder (eg, gastritis, colitis, gastric dilation), absorption may increase. In any case, monitoring serum magnesium levels in patients taking magnesium-containing medications is prudent.
In the treatment of eclampsia, hypermagnesemia is induced deliberately and sometimes can be symptomatic. Occasionally, hypermagnesemia also can occur in the unborn infant. Maternal magnesium therapy can cause neurobehavioral disorders in the unborn child.
Severe hypermagnesemia was described in patients who nearly drowned in the Dead Sea in Jordan, where magnesium levels average 400 mg/dL.
Lithium therapy causes hypermagnesemia by supposedly decreasing urinary excretion, although the mechanism for this is not completely clear.
Familial hypocalciuric hypercalcemia may cause modest elevations in serum magnesium. This autosomal dominant disorder is characterized by very low excretion of calcium and magnesium, and the increase in magnesium reabsorption appears to occur from an abnormal sensitivity of the loop of Henle to magnesium ions.
Hypothyroidism, adrenal insufficiency, and milk alkali syndrome occasionally produce mild elevations of serum magnesium.
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Effects Of Hypermagnesemia
Treatment Of Hypermagnesemia
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EFFECTS OF HYPERMAGNESEMIA Section 5 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography
Symptoms of hypermagnesemia usually are not apparent unless the serum magnesium level is greater than 2 mmol/L. Concomitant hypocalcemia, hyperkalemia, or uremia exaggerate the symptoms of hypermagnesemia at any given level.
Neuromuscular symptoms
These are the most common presenting problems. Hypermagnesemia causes blockage of neuromuscular transmission by preventing presynaptic acetylcholine release and by competitively inhibiting calcium influx into the presynaptic nerve channels via the voltage-dependent calcium channel.
One of the earliest symptoms of hypermagnesemia is deep-tendon reflex reduction. Facial paresthesias also may occur at moderate serum levels.
Muscle weakness is a more severe manifestation, occurring at levels greater than 5 mmol/L. This manifestation can proceed to flaccid paralysis, then to depressed respiration, and, eventually, to apnea.
Conduction system symptoms
Hypermagnesemia depresses the conduction system of the heart and sympathetic ganglia. A moderate increase in serum magnesium can lead to a mild decrease in blood pressure, and a greater concentration may cause severe symptomatic hypotension. Magnesium also is cardiotoxic and, in high concentrations, can cause bradycardia. Occasionally, complete heart block and cardiac arrest may occur at levels greater than 7 mmol/L.
Hypocalcemia
Apparently, this occurs because the secretion of parathyroid hormone (PTH) decreases or because end-organ resistance to PTH occurs. Paralytic ileus develops from smooth-muscle paralysis, and mothers being treated with magnesium for preterm labor suppression are at risk.
Hypermagnesemia may interfere with blood clotting through interference with platelet adhesiveness, thrombin generation time, and clotting time.
Nonspecific symptoms
These symptoms include nausea, vomiting, and cutaneous flushing.
TREATMENT OF HYPERMAGNESEMIA Section 6 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography
Prevention of hypermagnesemia is usually possible. Anticipate hypermagnesemia in patients who are receiving magnesium treatment, especially in those with reduced renal function. Initially, withdraw magnesium therapy, which often is enough in patients with mild-to-moderate hypermagnesemia.
In patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress, antagonize the effects by infusing calcium gluconate. Calcium antagonizes the toxic effect of magnesium, and these ions electrically oppose each other at their sites of action. This treatment usually leads to prompt symptomatic improvement.
Drug Name Calcium gluconate (Kalcinate) - Calcium directly antagonizes neuromuscular and cardiovascular effects of magnesium. Use for patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress.
Adult Dose Suggested dosing: 100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium/kg/h
Pediatric Dose Suggested dosing: 2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)
Contraindications Renal calculi, hypercalcemia, hypophosphatemia, renal or cardiac disease, digitalis toxicity
Interactions May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; high intake of dietary fiber may decrease calcium absorption and levels
Pregnancy B- Usually safe but benefits must outweigh the risks
Precautions Caution in digitalized patients, respiratory failure, acidosis, or severe hyperphosphatemia
Drug Name Glucose and insulin - May help promote magnesium entry into cells. Glucose should be administered with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.
Adult Dose Suggested dosing: 10 U IV and 50 mL D50W bolus or 500 mL D10W over 1 h
Pediatric Dose Suggested dosing: 0.5-1 g/kg IV followed by 1 U of regular insulin per 3 g glucose
Contraindications Documented hypersensitivity, hypoglycemia
Interactions Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines,cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone
Pregnancy B- Usually safe but benefits must outweigh the risks
Precautions Hyperthyroidism may increase renal clearance of insulin, and more insulin may be required to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal and hepatic dysfunction
Drug Name Furosemide (Lasix) - May promote excretion of magnesium. Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.
Adult Dose Suggested dosing: 20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states
Pediatric Dose Suggested PO dosing: 1-2 mg/kg/dose; not to exceed 6 mg/kg/dose; do not administer more often than q6h
Suggested IV/IM dosing: 1 mg/kg slowly under close supervision; not to exceed 6 mg/kg
Contraindications Documented hypersensitivity; hepatic coma, anuria, and state of severe electrolyte depletion
Interactions Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently
Pregnancy C- Safety for use during pregnancy has not been established
Precautions Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter
Thứ Sáu, 14 tháng 12, 2007
Hyperkalemia
Background
Potassium homeostasis
Potassium, the most abundant intracellular cation, is essential for the life of the organism. Potassium is obtained through the diet. Common potassium-rich foods include meats, beans, fruits, and potatoes. Gastrointestinal absorption is complete, resulting in daily excess intake of about 1 mEq/kg/d (60-100 mEq). This excess is excreted through the kidneys (90%) and the gut (10%). Potassium homeostasis is maintained predominantly through the regulation of renal excretion. The most important site of regulation is the cortical collecting tubule where aldosterone receptors are present.
Excretion is increased by the following:
Aldosterone
High sodium delivery to the distal tubule (eg, diuretics)
High urine flow (eg, osmotic diuresis)
High serum potassium level
Delivery of negatively charged ions to the distal tubule (eg, bicarbonate)
Excretion is decreased by the following:
Absence of aldosterone
Low sodium delivery to the distal tubule
Low urine flow
Low serum potassium level
Renal failure
Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion also is increased. In the absence of potassium intake, obligatory renal losses are 10-15 mEq/d. Thus, chronic losses occur in the absence of any ingested potassium. The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min. Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases.
The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load. An excess of only 100-200 mEq will increase the serum potassium concentration by about 1 mEq/L.1
Serum potassium level
Potassium is predominantly an intracellular cation; thus, serum potassium levels can be a very poor indicator of total body stores. Potassium moves easily across cell membranes; therefore, serum potassium levels reflect the movement of potassium between intracellular and extracellular fluid compartments as well as total-body potassium homeostasis. Several factors regulate the distribution of potassium between the intracellular and extracellular space.
Glucoregulatory hormones
Insulin enhances potassium entry into cells.
Glucagon impairs potassium entry into cells.
Adrenergic stimuli
Beta-adrenergic stimuli enhance potassium entry into cells, whereas beta-blocking drugs inhibit potassium entry into cells.
Alpha-adrenergic stimuli impair potassium entry into cells.
pH
Alkalosis enhances potassium entry into cells.
Acidosis causes shift of potassium from intracellular space into extracellular space. Inorganic or mineral acid acidoses are more likely to cause a shift of potassium out of the cells than organic acidoses.
Shift from intracellular pool
Acute increase in osmolality, such as hyperglycemia, causes potassium to exit from cells.
Acute cell-tissue breakdown releases potassium into extracellular space.
The 2 sets of regulatory factors, those that regulate total-body homeostasis and those that regulate the distribution of potassium between intracellular and extracellular space, meld to create smooth control of potassium levels throughout the day. For example, a high-protein meal, such as a steak, may contain enough potassium to raise the serum potassium acutely to lethal levels if the potassium remained in the extracellular space. Although renal potassium excretion can increase fairly rapidly, this mechanism easily is overwhelmed by such an acute potassium load.
The acute hyperkalemic effect of an extremely potassium-rich meal is blunted substantially by the release of insulin, which causes potassium to be taken up into cells. The excessive potassium then can be excreted by the kidneys, allowing serum potassium levels to return to normal. This integrated regulatory process is manifested in the diurnal rhythm for renal potassium excretion. The highest excretion occurs at midday, approximately 18 hours after peak potassium ingestion at the evening meal.
Pathophysiology
Any of 3 pathogenetic mechanisms can cause hyperkalemia.
Excessive intake: Excessive potassium intake alone is an uncommon cause of hyperkalemia. The mechanisms for shifting potassium intracellularly and for renal excretion allow a person with normal potassium homeostatic mechanisms to ingest virtually unlimited quantities of potassium. Even parenteral administration of as much as 60 mEq/h for several hours creates only a minimal increase in serum potassium concentration in healthy individuals. Most often, hyperkalemia is caused by a relatively high potassium intake in a patient with impaired mechanisms for the intracellular shift of potassium or renal potassium excretion.
Decreased excretion: Decreased excretion of potassium, especially coupled with excessive intake, is the most common cause of hyperkalemia. The most common causes of decreased renal potassium excretion include renal failure, ingestion of drugs that interfere with potassium excretion (eg, potassium-sparing diuretics, angiotensin-convening enzyme inhibitors, nonsteroidal anti-inflammatory drugs), or impaired responsiveness of the distal tubule to aldosterone (eg, type IV renal tubular acidosis observed with diabetes mellitus, sickle cell disease, chronic partial urinary tract obstruction).
Shift from intracellular to extracellular space: This pathogenetic mechanism alone is a relatively uncommon cause of hyperkalemia but can exacerbate hyperkalemia produced by a high intake or impaired renal excretion. Clinical situations in which this mechanism is the major cause of hyperkalemia include hyperosmolality, rhabdomyolysis, tumor lysis, and succinylcholine administration, which depolarizes the cell membrane and, thus, permits potassium to leave the cells.2 However, more often, mild-to-moderate impairment of intracellular shifting of potassium occurs with insulin deficiency or acute acidosis.
Hyperkalemia may also be caused by IV administration of epsilon amino caproic acid (EACA), a synthetic amino acid. EACA has been found to cause hyperkalemia in studies conducted in dogs. The mechanism of action is presumed to be because of a similarity in structure of EACA to arginine and lysine. These latter amino acids enter the muscle cell in exchange for potassium, thereby leading to an increase in extracellular potassium.3, 4
Regardless of the cause, hyperkalemia produces similar signs and symptoms. Because potassium overwhelmingly is an intracellular cation and various factors can regulate the actual serum potassium concentration, an individual can ingest a substantial potassium load without exhibiting frank hyperkalemia. Conversely, hyperkalemia does not always reflect a true increase in total body potassium stores.
Frequency
United States
Hyperkalemia, defined as serum potassium greater than 5.3 mEq/L, is rare in the general population of healthy individuals. However, certain groups definitely exhibit a higher incidence of hyperkalemia. In patients who are hospitalized, the incidence of hyperkalemia has ranged from 1-10%, depending on the definition of hyperkalemia. Patients at the extremes of life, either premature or elderly, are at high risk. The presence of decreased renal function, genitourinary disease, cancer, severe diabetes, and polypharmacy also predisposes patients to hyperkalemia. Generally, with patients who are hospitalized, drugs are implicated in the development of hyperkalemia in as many as 75% of cases.
Military recruits, individuals with sickle cell traits, and people who abuse drugs are at risk for hyperkalemia due to acute rhabdomyolysis. These cases disproportionately occur in males, probably reflecting the higher muscle mass of males, though an underlying hormonal predisposition cannot be excluded absolutely.
Patients with diabetes constitute a unique high-risk group. They develop defects in all aspects of potassium metabolism. The typical healthy diabetic diet often is high in potassium and low in sodium. Diabetic persons frequently have underlying renal disease and often develop hyporeninemic hypoaldosteronism, impairing renal excretion of potassium. They frequently are placed on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for treatment of diabetic nephropathy, exacerbating the defect in potassium excretion. Finally, persons with diabetes have both insulin deficiency and/or resistance to insulin action, limiting their ability to shift potassium intracellularly. All of these factors combine to render people with diabetes particularly prone to hyperkalemia.
One review of the incidence of hyperkalemia in people with diabetes found that, in an unselected group of diabetic persons treated in a clinic, hyperkalemia (defined as a serum potassium level >5 mEq/L) was found in 15% (270 out of 1764 patients).5 However, fewer than 4% had potassium levels more than 5.4 mEq/L. Clinical risk factors significant in predicting the occurrence of hyperkalemia included renal insufficiency, duration of diabetes mellitus, age, glycosylated hemoglobin levels, and retinopathy. Interestingly, neither the serum glucose level nor the agent for diabetes treatment was significantly correlated.
Significant concern also has been raised about the potential for hyperkalemia in patients taking angiotensin-converting enzyme inhibitors, particularly because the indications for their use in high-risk populations, such as diabetic persons, are broadening rapidly. In one series, the incidence of hyperkalemia in an outpatient clinic was 11%.6 Hyperkalemia occurred in less than 6% of patients with normal renal function. Risk factors for hyperkalemia in patients using angiotensin-converting enzyme inhibitors included elevated BUN and serum creatinine, severe diabetes mellitus, congestive heart failure, peripheral vascular disease, and the use of a long-acting drug.
As the therapy of congestive heart failure has evolved, this growing group of patients also constitute a high-risk group. The factors promoting the development of hyperkalemia in heart failure patients include underlying renal insufficiency due to poor cardiac output and reduced renal blood flow, the high prevalence of diabetes mellitus in the population of heart failure patients, and the growing use of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone inhibitors, such as spironolactone. The initial studies examining the risk of hyperkalemia in heart failure patients treated with aldosterone inhibitors revealed only a minor increase in hyperkalemia, but later studies showed that as the practice became more widespread, the morbidity and mortality from hyperkalemia have increased.7
International
As in the United States, the incidence of hyperkalemia in the general population has been reported in less than 5% of people. Patients who are hospitalized in countries as diverse as England, Australia, and Israel experience hyperkalemia approximately 10% of the time. Similar to what has been reported in the United States, risk factors include advanced age, significant prematurity, and the presence of renal failure, diabetes mellitus, and heart failure. Additionally, one series documented an increased incidence of hyperkalemia with cancer and gastrointestinal disease.8 Polypharmacy, particularly the use of potassium supplements and potassium-sparing diuretics, in patients with underlying renal insufficiency contributed to hyperkalemia in almost one half of the cases.
Mortality/Morbidity
Hyperkalemia in a patient who is hospitalized is an independent risk factor for death. In one series, 1.4% of patients who were hospitalized (406 out of 29,063 patients) developed hyperkalemia.8
The overall mortality rate in patients with hyperkalemia was 14.3% (58 out of 406 patients), with the risk increasing as potassium level increases.
Twenty-eight percent of patients with a serum potassium level greater than 7 mEq/L died, as opposed to 9% of those with a potassium level less than 6.5 mEq/L. In 7 out of 58 deaths, cause of death was directly attributable to hyperkalemia. Most cases resulting in death were complicated by renal failure.
Interestingly, all patients who died of hyperkalemia had normal potassium levels within the 36 hours prior to death.
Race
No racial predisposition to hyperkalemia appears to exist.
Sex
Men are significantly more prone to hyperkalemia than women. This difference has been noted in several series and stands in contrast to the increased incidence of hypokalemia in women. The reasons for this discrepancy are unknown.
Age
Several series document the increasing tendency for hyperkalemia in patients at the extremes of life, either small premature infants or elderly people, with renal insufficiency playing a significant role in both.
Premature infants are a high-risk group. Relative renal immaturity is likely to be a contributory factor; studies comparing small premature infants who developed hyperkalemia to those who did not indicate that incidence is increased in infants with a lower glomerular filtration rate as estimated by endogenous creatinine clearance. In these small infants, hyperkalemia often occurs within the first 48 hours of life.
Elderly patients are another high-risk group. In several series, an age older than 60 years was an independent risk factor for the development of hyperkalemia in the hospital. Several factors contribute to the increased propensity for elderly people to become hyperkalemic. Renal function tends to deteriorate with age, even in relatively healthy individuals. The glomerular filtration rate decreases by 1 mL/min/y in people older than 30 years. Renal blood flow also decreases. Oral intake declines, resulting in decreased urine flow rates. Plasma renin activity and aldosterone levels also tend to decrease with age, decreasing the ability of the distal nephron to secrete potassium.
Elderly patients are more likely to be taking medications that could interfere with potassium secretion, such as nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and potassium-sparing diuretics. Elderly individuals who are bedridden often are placed on subcutaneous heparin, which can decrease aldosterone production.
CLINICALSection 3 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
History
Symptoms are nonspecific and predominantly related to muscular or cardiac function. The most common complaints are weakness and fatigue. Occasionally, a patient may complain of frank muscle paralysis or shortness of breath. Patients also may complain of palpitations or chest pain.
When hyperkalemia is discovered, investigate potential pathophysiologic mechanisms.
For excessive potassium intake, query patients about the following:
Eating disorders - Very unusual diets consisting almost exclusively of high-potassium foods, such as fruits, dried fruits, juices, and vegetables with little to no sodium
Heart healthy diets - Very low-sodium and high-potassium diets recommended for patients with cardiac disease, hypertension, and diabetes mellitus
Use of potassium supplements in over-the-counter herbal supplements, salt substitutes, or prescribed pharmacologic agents - Many patients with renal insufficiency and hypertension have heard the advice to eat a banana a day because the potassium reduces blood pressure. They may not realize that in the case of renal insufficiency and hypertension, this is potentially a life-threatening therapy.
For decreased potassium excretion, query patients about the following:
Ingestion of medications that impair renal potassium excretion
Potassium-sparing diuretics, especially popular in the treatment of cirrhosis and congestive heart failure
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Cyclosporine or tacrolimus
Antibiotics, such as pentamidine or trimethoprim/sulfamethoxazole
EACA3
History of renal insufficiency or renal failure
History of diabetes mellitus, sickle cell disease or trait, or symptoms of lower urinary tract obstruction - These diseases predispose people to type IV renal tubular acidosis, also called hyperkalemic renal tubular acidosis. Type IV renal tubular acidosis also may accompany other tubulointerstitial disorders, such as polycystic kidney disease or amyloidosis. Often, patients with type IV renal tubular acidosis have Hyporeninemic Hypoaldosteronism (ie, decreased aldosterone secondary to suppressed renin levels). One example is diabetes mellitus, where the relative volume overload leads to low renin.
For a shift of potassium into the extracellular space, query patients about the following:
Recurrent episodes of flaccid paralysis
Presence of diabetes mellitus
Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
Risk factors for rhabdomyolysis, such as heat stroke, chronic alcoholism, seizures, sudden excessive exertion (eg, in military recruits undergoing basic training), or use of medications that interfere with heat dissipation (eg, tricyclic antidepressants or anesthesia)
Risk factors for tumor lysis syndrome, such as ongoing treatment for widespread lymphoma, leukemia, or other large tumors
Risk factors for hemolysis, such as blood transfusion and sickle cell disease
Other mechanisms
Drugs, such as cyclooxygenase-2 (COX-2) inhibitors9
Ingestion of toad venom (Bufo bufo gargarizans) in southeastern Asian countries
In Southeast Asia, toads are a common folk remedy for strengthening the heart. Bufadienolides, a form of cardiac glycoside that is present in toad venom, have a similar structure and biochemical activity to digitalis and cardenolides, the major plant-derived cardiac glycosides. Bufadienolides cause hyperkalemia via its binding to the alpha subunit of Na+–K+–ATPase, thus inhibiting the reuptake of potassium from the extracellular space.10
This compound has also turned up in some aphrodisiacs and Chinese medications (eg, chan su).
With regard to Western countries, at least 2 cases of poisoning by toad and eggs have been reported in the United States.11
Physical
Vital signs generally are normal, except occasionally in bradycardia due to heart block or tachypnea due to respiratory muscle weakness.
Muscle weakness and flaccid paralysis
Depressed or absent deep tendon reflexes
In general, the results of the physical examination alone do not alert the physician to the diagnosis, except when severe bradycardia is present or muscle tenderness accompanies muscle weakness, suggesting rhabdomyolysis.
Causes
Listed by pathophysiologic mechanisms, causes include increased potassium intake, decreased potassium excretion, or a shift of potassium from the intracellular to the extracellular space. The most common causes are due to decreased excretion. Alone, excessive intake or an extracellular shift is distinctly uncommon. Often, several disorders are present simultaneously.
Increased intake: Alone, this is a rare cause of hyperkalemia because the mechanisms for renal excretion and intracellular disposition are very efficient. In general, a relatively high potassium intake contributes to hyperkalemia in individuals who have impaired renal excretion, impaired intracellular shift, or both.
High-potassium, low-sodium diets
Ingestion of potassium supplements: Ingested amounts would have to be massive as the sole cause of hyperkalemia, but even relatively small amounts can produce hyperkalemia in a patient with impaired renal excretion.
High concentrations of potassium in intravenous fluid preparations, such as total parenteral nutrition
Dietary salt substitutes, penicillin potassium therapy
Decreased excretion: Impaired renal excretion almost always is present when a patient presents with persistent hyperkalemia. Mild degrees of renal failure generally do not result in resting hyperkalemia due to adaptive mechanisms in the kidneys and gastrointestinal tract. However, once the glomerular filtration rate falls below 15-20 mL/min, significant hyperkalemia can occur, even in the absence of an abnormally large potassium load. The simple lack of nephron mass prevents normal potassium homeostasis. Hyperkalemia due to decreased renal excretion can occur when a patient has normal or only mildly decreased renal function as a result of other mechanisms, such as drugs or renal tubular acidosis. Two other causes of decreased excretion of potassium include reduced distal sodium delivery and reduced tubular fluid flow rate.
Drugs
Potassium-sparing diuretics, spironolactone, triamterene, amiloride
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Cyclosporine or tacrolimus
Pentamidine
Trimethoprim/sulfamethoxazole
Heparin
Ketoconazole
Metyrapone
Herbs
Type IV renal tubular acidosis
Diabetes mellitus
Sickle cell disease or trait
Lower urinary tract obstruction
Adrenal insufficiency
Primary Addison syndrome due to autoimmune disease, tuberculosis, or infarct
Enzyme deficiencies
Disorders of steroid metabolism and mineralocorticoid receptors12, 13
21-hydroxylase deficiency in classical form and aldosterone synthase deficiency result in hyperkalemia due to low aldosterone levels.
11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and 17 alpha-hydroxylase/17,20-lyase deficiency are generally not characterized by the development of hyperkalemia.
Type 1 pseudohypoaldosteronism is caused by an inactivating mutation of the mineralocorticoid receptor, resulting in impaired potassium secretion due to impaired sodium reabsorption in the distal tubule.14
Gordon syndrome or pseudohypoaldosteronism Type II, characterized by hyperkalemia and hypertension, is caused by mutations in either WNK1 (with no lysine [K]) or WNK4, protein kinases that are localized to the distal tubule and that regulate ion transport in this nephron segment. WNK4 appears to have several roles in regulating sodium, potassium, and chloride transport through transcellular and paracellular pathways.15
Shift of potassium into the extracellular space: Like increased intake, this rarely is the sole cause of hyperkalemia because the mechanisms for renal excretion are very efficient. However, the inability to transport potassium intracellularly exacerbates hyperkalemia in individuals who have impaired renal excretion.
Hyperkalemic periodic paralysis
Insulin deficiency or insulin resistance (ie, type I or type II diabetes mellitus)
Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
Tissue breakdown
Rhabdomyolysis
Tumor lysis syndrome
Massive hemolysis
Drugs
Nonselective beta-blockers (inhibits Na-K-ATPase pump)
Digitalis toxicity (inhibits Na-K-ATPase pump)
Succinylcholine (membrane leak)
Inhibition of the sodium pump will impair K entry into the cells and facilitate K exit from the cells.
Hypertonicity may lead to hyperkalemia by 2 mechanisms: loss of intracellular water, resulting in an increased intracellular potassium concentration, favoring a gradient for potassium to move out of the cells; and, as water exits the cells, potassium is swept along with ‘‘solvent drag.' The most common cause of hyperosmolality is hyperglycemia in uncontrolled diabetes mellitus. Other conditions with hypertonicity are hypernatremia and hypertonic mannitol.
Aldosterone deficiency: This is somewhat controversial. Some evidence that long-term aldosterone deficiency impairs cell potassium uptake exists.
DIFFERENTIALSSection 4 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Other Problems to be Considered
Pseudohyperkalemia is the term applied to the clinical situation in which in vitro lysis of cellular contents leads to the measurement of a high serum potassium level not reflective of the true in vivo level. This condition occurs most commonly with red cell hemolysis during the blood draw (tourniquet too tight or the blood left sitting too long), severe thrombocytosis (platelet count >1,000,000/mL), or severe leukocytosis (WBC >70,000/mL). Recognizing that when true intravascular hemolysis has occurred, for example, with a transfusion reaction or a hemolytic sickle crisis or drug-induced hemolytic reaction, the measured potassium reflects the true potassium is important.
WORKUPSection 5 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Lab Studies
Assess renal function.
Check serum BUN and creatinine levels to determine whether renal insufficiency is present.
Check 24-hour urine for creatinine clearance or estimate the creatinine clearance using the Cockroft-Gault equation to assess whether the degree of renal insufficiency alone explains the hyperkalemia.
The Cockroft-Gault equation is (140 – age)(weight in kg)/(72)(serum creatinine). For women, the answer is multiplied by 0.8.
Estimate the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula, as follows: (GFR (mL/min/1.73 m2) = 186 X (serum creatinine) - 1.154 X (age) - 0.203 X (0.742 if female) X (1.210 if African American) (conventional units).16
Measure urine potassium and sodium concentrations and urine osmolality.
These tests are essential to determine whether impairment of renal excretion is contributing to the hyperkalemia. A urine potassium level less than 20 mEq/L suggests impaired renal excretion. A urine potassium level greater than 40 mEq/L suggests intact renal excretory mechanisms, implying that high intake or failure of cell uptake is the major mechanism for hyperkalemia. However, an isolated urine potassium level often is misleading because the concentration of potassium in the urine is influenced not only by secretion by the cortical collecting tubule but also by the degree of urinary concentration. If the urine osmolality is high (>700 mOsm/kg), then the absolute value of urine potassium concentration can be misleading and suggest that the kidneys are disposing of potassium appropriately.
For example, suppose serum potassium is 6 mEq/L and urine potassium 60 mEq/L. The high urine potassium level suggests appropriate renal potassium excretion. However, the final concentration of potassium in the urine not only is dependent on how much potassium is secreted in response to sodium reabsorption, but it also is dependent on how concentrated the urine is. In the above example, if urine osmolality is 300 mOsm/kg, that is, not concentrated relative to serum, then a measured urine potassium level of 60 mEq/L indeed suggests renal potassium loss. However, if the urine osmolality is 1200 mOsm/kg, that is, concentrated 4-fold relative to the serum, then the potassium concentration in the urine, in the absence of urinary concentration due to water reabsorption, is 15 mEq/L, which is very low.
The conclusion would then be that the kidneys are not appropriately excreting potassium. This adjustment in the evaluation of urinary potassium concentration for the degree of urinary concentration is called calculation of the transtubular potassium gradient (TTKG).
TTKG = (urine K x serum osmolarity)/(serum K x urine osmolarity)
A TTKG less than 3 suggests a lack of aldosterone effect on collecting tubules, that is, kidneys are not excreting potassium appropriately. A TTKG greater than 7 suggests an aldosterone effect, which would be appropriate in the setting of hyperkalemia.
These examples demonstrate that calculation of the TTKG is superior to using the urine potassium alone to assess contribution of decreased renal excretion to hyperkalemia. As useful as this test is, recognizing that it is valid only if 1) the urine osmolality is greater than the serum osmolality, that is, the urine is concentrated relative to the serum, and 2) the urine sodium is greater than 20 mEq/L, that is, distal delivery of sodium is adequate for potassium excretion, is important.
A 24-hour urine potassium measurement rarely is needed to assess renal potassium excretory ability.
Measure complete blood count.
A low hemoglobin and hematocrit (H/H) or abnormal red cell morphology may suggest hemolysis.
Severe leukocytosis or thrombocytosis raises the possibility of pseudohyperkalemia. When in doubt, measure the plasma potassium concentration. Plasma potassium is about the same as serum potassium.
Measure complete metabolic profile.
Low bicarbonate may suggest hyperkalemia due to metabolic acidosis.
Hyperglycemia suggests diabetes mellitus.
Elevated lactic dehydrogenase (LDH), uric acid, phosphate, and alanine aminotransferase (ALT) may suggest tissue breakdown such as in hemolysis, rhabdomyolysis, or tumor lysis.
A creatine kinase (CK) elevation suggests rhabdomyolysis.
Depending on the results of the above laboratory work, the following may be indicated:
Serum cortisol (reference range 8 am 5-25 µg/mL, 4 pm 3-12 µg/mL): Decrease may suggest adrenal insufficiency.
Serum renin and aldosterone (normal supine renin activity 3.2 ± 1 ng/mL/h; normal suppressed aldosterone 5-20 ng/mL): Decrease may suggest adrenal insufficiency.
Fasting blood sugar (reference range 75-115 mg/dL), glycosylated hemoglobin (normal 6.5%), or glucose tolerance test (normal 2 h postprandial value <140 mg/dL): Increase suggests underlying diabetes mellitus.
Assays of 11-beta hydroxylase or 21-hydroxylase: Deficiencies of these enzymes produce syndromes of virilization and generally are recognized in the neonatal period. 11-Beta hydroxylase deficiency is diagnosed by measurement of elevated plasma 11 deoxycortisol levels or increased urinary tetrahydro-ll-deoxycortisol levels. To detect mild cases, adrenocorticotropic hormone (ACTH) stimulation also may be performed to enhance synthesis of these products. 21-Hydroxylase deficiency is detected by the measurement of elevated 17-hydroxyprogesterone levels in blood, generally 90-1200 nmol/L.
Other Tests
Electrocardiogram: This test is vital to assess the physiologic significance of the hyperkalemia. However, ECG changes often do not correlate with the degree of hyperkalemia. ECG changes suggestive of an effect of hyperkalemia on cardiac conduction include (in order of appearance) the following17:
Peaked T waves
Prolongation of the PR interval
Widening of the QRS
Loss of the P wave
Sine wave pattern
Sinus arrest
In patients with organic heart disease and abnormal baseline ECG, bradycardia may be the only new ECG abnormality.18
TREATMENTSection 6 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medical Care
Orient the medical care of patients with hyperkalemia toward 5 different aims.
Evaluation for potential toxicities
Decreasing potassium intake
Increasing potassium uptake into cells
Increasing potassium excretion
Determining the cause to prevent future episodes
Although explicated below in a step-by-step format, these different aspects of hyperkalemia treatment generally are addressed simultaneously. The aggressiveness of therapy is directly related to the rapidity with which hyperkalemia has developed, the absolute level of hyperkalemia, and the evidence of toxicity. The faster the rise of potassium, the higher the level, and the greater the evidence of cardiotoxicity, the more aggressive therapy should be.
The first step is to determine whether the hyperkalemia is producing life-threatening toxicity.
Perform an ECG to look for cardiotoxicity.
Administer intravenous calcium to ameliorate cardiac toxicity, if present.
The second step is to identify and remove sources of potassium intake.
Discontinue oral and parenteral potassium supplements.
Remove potassium-containing salt substitutes.
Examine the patient's diet. Change the diet to a low-potassium tube feed or a 2-g potassium ad-lib diet.
The third step is to enhance potassium uptake by cells to decrease the serum concentration.
Parenteral glucose and insulin infusions are very effective in enhancing potassium uptake. Although glucose stimulates insulin secretion, administration of glucose alone often is not as effective in this clinical situation. The onset of action is within 20-30 minutes, and the duration is variable, from 2-6 hours. Continuous infusions of insulin and glucose-containing intravenous fluids can be used for prolonged effect. Measure glucose and potassium every 2 hours.
Correct metabolic acidosis with sodium bicarbonate. This therapeutic modality is both less effective and less predictable in producing a hypokalemic response due to the variable effect of different forms of metabolic acidosis on the serum potassium level. This particularly is true in patients with chronic renal failure. Nonetheless, if the acidosis is severe, then a trial of parenteral sodium bicarbonate therapy is warranted.
Beta-adrenergic agonists also are quite effective but, perhaps, somewhat more controversial and more likely to produce side effects. In the United States, the most commonly used preparation is nebulized albuterol. The dose for treating hyperkalemia, 10 mg, is substantially higher than the usual dose for the treatment of bronchospasm and requires the assistance of a respiratory therapist. This therapy is highly effective and preferred over alkali therapy in patients with renal failure. Parenteral isoproterenol or albuterol also decrease potassium. However, isoproterenol is not used commonly, and parenteral albuterol is not available in this country. Some investigators have reported tachycardia and chest discomfort using beta-agonist therapy for hyperkalemia. Discontinue beta-adrenergic antagonists.
The fourth step is to increase potassium excretion from the body.
Renal excretion is enhanced easily in the individual with normal kidney function by the administration of parenteral saline accompanied by a loop diuretic such as furosemide.
Discontinue potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other drugs that inhibit renal potassium excretion.
Monitor volume status and aim to maintain euvolemia.
Renal excretion can be enhanced by administration of aldosterone analogue such as 9-alpha fluorohydrocortisone acetate (Florinef). Florinef especially is helpful in those with hyporeninemia or hypoaldosteronism.
Gastrointestinal excretion can be increased by the use of cation exchange resins such as Kayexalate. Kayexalate can be administered orally or rectally as a retention enema. Because the major site of action for this drug is the colon, rectal administration is preferred for hyperkalemic emergencies.
The effectiveness of this drug is enhanced if the enema can be retained for an hour.
Repeated enemas can be used but, occasionally, cause colon perforation.
The onset of action occurs within 2 hours and is long lasting. The serum potassium level can be decreased by 2 mEq/L with a single enema. Kayexalate administered orally also is quite effective if it is suspended in 70% sorbitol.
Emergency dialysis is a final recourse for patients who are experiencing potentially lethal hyperkalemia that is unresponsive to more conservative measures or for patients who have complete renal failure. Initiation of dialysis often can take several hours; therefore, even if dialysis is contemplated, initiate the other modalities of therapy first.
The final step in the medical management of hyperkalemia is to determine the cause of hyperkalemia in order to prevent future episodes. This should include examination of the following:
Sources of potassium intake
Causes of decreased renal excretion
Causes for impaired cellular uptake
Surgical Care
Surgery generally is not needed for the care of a patient with hyperkalemia.
Patients with metabolic acidosis and consequent hyperkalemia due to ischemic gut obviously require exploration.
Patients with hyperkalemia due to rhabdomyolysis may need surgical decompression of swollen ischemic muscle compartments.
Patients without end-stage renal disease who require hemodialysis for control of hyperkalemia need placement of a hemodialysis catheter for emergent dialysis.
Consultations
For severe hyperkalemia, early consultation with a nephrologist for aid in efficient therapy and plans for dialysis is highly recommended.
For emergency pacemaker placement, the aid of a cardiologist may be required for patients with refractory heart block.
Diet
A low-potassium diet with 2 g of potassium is recommended to minimize potassium intake.
Activity
No restrictions on activity are required unless continuous monitoring for cardiotoxicity is required.
MEDICATIONSection 7 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
The goals of pharmacotherapy are to reduce potassium levels and morbidity and to prevent complications.
Drug Category: Beta-adrenergic agonists
Through an activation of cyclic adenosine monophosphate (AMP), these agonists stimulate the adenosine triphosphatase (ATPase) pump, thereby shifting potassium into the intracellular compartment.
Drug Name Isoproterenol (Dey-Dose, Isuprel, Arm-a-Med)
Description Has beta1-adrenergic and beta2-adrenergic receptor activity.
Adult Dose 5 mcg/min IV initial, titrate to response; not to exceed 20 mcg/min
Pediatric Dose 0.1 mcg/kg/min IV, titrate to response; not to exceed 2 mcg/min
Contraindications Documented hypersensitivity; tachyarrhythmias, tachycardia, or heart block caused by digitalis intoxication; ventricular arrhythmias that require inotropic therapy; angina pectoris
Interactions Bretylium increases action of vasopressors on adrenergic receptors, which may, in turn, result in arrhythmias; guanethidine may increase effect of direct-acting vasopressors, possibly resulting in severe hypertension; tricyclic antidepressants may potentiate pressor response of direct-acting vasopressors
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions By increasing myocardial oxygen requirements while decreasing effective coronary perfusion, isoproterenol may have a deleterious effect on the injured or failing heart; in some patients presumably with organic disease of the AV node and its branches, isoproterenol paradoxically may worsen heart blocks or precipitate Adams-Stokes attacks; caution in coronary artery disease, coronary insufficiency, diabetes, or hyperthyroidism; if heart rate >110 beats per min, decreasing infusion rate or temporarily discontinuing infusion may be advisable
Drug Name Albuterol (Proventil, Ventolin)
Description Adrenergic agonist that increases plasma insulin concentrations. Increase in insulin may shift potassium into intracellular space.
Adult Dose 10-20 mg nebulized or 0.5 mg IV over 15 min
Pediatric Dose 2.5 mg IV and repeat in 2 h prn
Contraindications Documented hypersensitivity
Interactions Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of
bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled
anesthetics, tricyclic antidepressants, and sympathomimetic agents
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders
Drug Category: Calcium salts
Calcium antagonizes cardiotoxicity of hyperkalemia by stabilizing cardiac cell membrane against undesirable depolarization. Has no effect on serum level of potassium. Onset of effect is rapid, within 15 min, but relatively short lived.
Drug Name Calcium gluconate (Kalcinate)
Description Moderates nerve and muscle performance and facilitates normal cardiac function.
Adult Dose 100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium per kg/h
Pediatric Dose 2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)
Contraindications Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Caution in patients who are digitalized; respiratory failure; acidosis; severe hyperphosphatemia
Drug Name Calcium chloride
Description Prevents deleterious effects caused by severe hyperkalemia as measured by ECG, pending correction of increased potassium in extracellular fluid. Generally, second choice to calcium gluconate due to irritating effects when administered parenterally.
Adult Dose Known or suspected hyperkalemia (K+ > 6 mEq/L): 2-4 mg/kg IV (10% solution)
Pediatric Dose 0.2 mL (20 mg)/kg of IV (10% solution)
Contraindications Ventricular fibrillation not associated with hyperkalemia; digitalis toxicity; hypercalcemia; renal insufficiency; cardiac disease
Interactions Coadministration with digoxin may cause arrhythmias; may antagonize effects of calcium channel blockers, atenolol, and sodium polystyrene sulfonate
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Administer slowly (not to exceed 0.5-1 mL/min) to avoid extravasation; hypercalcemia may occur in renal failure
Drug Category: Hormones
Insulin stimulates cellular uptake of potassium, lowering serum potassium level.
Drug Name Insulin (Novolin, Humulin)
Description Stimulates cellular uptake of potassium within 20-30 min. Administer glucose along with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.
Adult Dose 10 U IV and either 50 mL D50W bolus or 500 mL D10W over 1 h
Pediatric Dose 0.5-1 g/kg IV followed by 1 U of regular insulin per 3 g glucose
Contraindications Documented hypersensitivity; hypoglycemia
Interactions Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Hyperthyroidism may increase renal clearance of insulin and may need more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal and hepatic dysfunction
Drug Category: Diuretics
Loop diuretics markedly enhance renal potassium excretion, consequently lowering serum levels. Parenterally administered drug has a more rapid onset of action and is preferable in emergent situations. Simultaneous administration of saline can prevent severe volume depletion.
Drug Name Furosemide (Lasix)
Description Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle and distal renal tubule. Individualize dose to patient. Depending on the response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs. When treating infants, titrate with increments of 1 mg/kg per dose until a satisfactory effect is achieved. Oral absorption of furosemide is variable from person to person. If rapid and effective therapy is mandated, then IV route is preferred. Occasionally, a continuous infusion of furosemide, as high as 40 mg/h, is used for severe edema but rarely is required for the treatment of hyperkalemia.
Adult Dose 20-80 mg/d PO/IV/IM; titrate as high as 600 mg/d
Pediatric Dose 1-2 mg/kg per dose PO; not to exceed 6 mg/kg per dose; not to administer >q6h
1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
Contraindications Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Interactions Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of
antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter; profound diuresis may occur with fluid and electrolyte loss; caution in hepatic failure
Drug Name Bumetanide (Bumex)
Description Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle and distal renal tubule. Individualize dose to patient. Start at 1-2 mg IV; titrate to as high as 10 mg/d. Rarely, doses as high as 24 mg/d are used for edema but generally are not required for treatment of hyperkalemia.
Adult Dose 0.5-2 mg/dose PO qd/bid; not to exceed 10 mg/d
Alternatively, 0.5-1 mg/dose IV/IM; not to exceed 10 mg/d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; anuria; increasing azotemia
Interactions Decreases effects of indomethacin and probenecid; may increase lithium toxicity
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions Profound diuresis may occur with fluid and electrolyte loss; caution in hepatic failure; monitor serum sodium, bicarbonate, calcium, magnesium, phosphate, and potassium
Drug Category: Cation exchange resins
Stimulate the exchange of sodium for potassium in the colon, thus increasing intestinal excretion of potassium.
Drug Name Sodium polystyrene sulfonate (Kayexalate)
Description Exchanges sodium for potassium and binds it in the gut, primarily in the large intestine, and decreases total body potassium. Onset of action after oral administration ranges from 2-12 h and is longer when administered rectally.
Adult Dose 25-50 g PO in 25-50 mL sorbitol q6h
25-50 g PR in 25-50 mL sorbitol as retention enema q6h
Pediatric Dose 1 g/kg PO in sorbitol q6h
2 g/kg PR in sorbitol as retention enema q6h
Contraindications Documented hypersensitivity; hypernatremia
Interactions Systemic alkalosis may occur if administered concurrently with magnesium hydroxide, aluminum carbonate or similar antacids, and laxatives
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution when administering to patients who can be affected adversely by a small increase in sodium loads, such as severe hypertension, severe congestive heart failure, and marked edema; constipation, with the possibility of fecal impaction, may occur; treat constipation with 10-20 mL of 70% sorbitol every 2 h or as necessary to produce at least 1-2 watery stools daily
Drug Category: Electrolytes
Used to correct metabolic acidosis if acidosis is severe.
Drug Name Sodium bicarbonate (Neut)
Description Used only when patient is diagnosed with bicarbonate-responsive acidosis, hyperkalemia, tricyclic antidepressant overdose, or phenobarbital overdose. Routine use is not recommended.
To estimate the dose that should be administered may use the following formula: HCO3- (mEq) = 0.5 X weight in kg X (24 - serum HCO3- in mEq/L)
This formula has many limitations; however, the practitioner can determine roughly the amount of bicarbonate required and subsequently titrate against the pH and anion gap.
Adult Dose Generally for parenteral use, 1-2 amps of sodium bicarbonate containing a total of 50-100 mEq is adequate
650-1300 mg PO bid or tid
If the patient has a relatively normal serum bicarbonate level but severe ECG changes of hyperkalemia, then 1 ampule or 50 mEq may be infused q15min, monitoring serum bicarbonate and serum sodium to avoid severe alkalosis and hypernatremia
Alternatively, 2 ampules of sodium bicarbonate (100 mEq) may be added to 1 L 10% dextrose in water and infused at 250-500 mL/h if tolerated
Pediatric Dose Not established
Contraindications Documented hypersensitivity; alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain
Interactions Urinary alkalinization induced by increased sodium bicarbonate concentrations may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Only use sodium bicarbonate to treat documented metabolic acidosis and hyperkalemia-induced cardiac arrest; can cause alkalosis, decreased plasma potassium, hypocalcemia, and hypernatremia; caution in electrolyte imbalances, such as in patients with CHF, cirrhosis, edema, corticosteroid use, or renal failure; when administering, avoid extravasation because can cause tissue necrosis
FOLLOW-UPSection 8 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Further Inpatient Care
Once the potassium level is restored to normal, the potassium-lowering therapies can be discontinued and the serum potassium level can be monitored.
Determine and address the cause for hyperkalemia, including an evaluation of sources of potassium intake, causes for decreased renal excretion, and causes for decreased cell uptake of potassium. Most cases of hyperkalemia are multifactorial, with elements of all 3 causalities contributing to the final picture. In particular, reevaluate the use of potassium supplements (including salt substitutes) in patients with renal insufficiency or in patients taking medications that impair renal excretion of potassium.
Further Outpatient Care
For patients who have a defined and finite reason for hyperkalemia, such as acute exertional rhabdomyolysis or drug-induced hemolysis, serum potassium can be monitored on an infrequent basis. However, for patients who have conditions or medications predisposing them to hyperkalemia and in whom hyperkalemia has developed, monitor serum potassium levels more frequently. Once monthly measurements are indicated for patients at high risk.
For patients who have recurrent or constant hyperkalemia, such as patients with diabetic nephropathy and type IV renal tubular acidosis, chronic therapy with an oral loop diuretic and Kayexalate may be indicated.
In/Out Patient Meds
Loop diuretics often offset mild hyperkalemia without producing significant volume depletion. Once daily furosemide is effective in patients with moderate hyperkalemia and type IV renal tubular acidosis.
Oral Kayexalate is useful in patients with advanced renal failure who are not yet on dialysis or transplant candidates. One or more doses of 15 g/d can control mild-to-moderate hyperkalemia effectively with little inconvenience to patients.
Florinef 0.1 mg PO daily is a useful drug in hyperkalemia associated with mild-to-moderate renal impairment.
Transfer
Transfer patients with severe cardiac toxicity as recorded on ECG to the intensive care unit for continuous monitoring and aggressive therapy.
If a patient requires hemodialysis for hyperkalemia, transfer to a facility with this capability may be required.
Deterrence/Prevention
The most effective prevention of hyperkalemia is through education of patients on the potential causes of hyperkalemia, dietary sources, medical conditions predisposing to hyperkalemia, and contributing medications.
Additionally, repeated review of the patient's medications to identify potential interactions that can cause hyperkalemia is essential.
Some common clinical situations include the following:
Diabetic persons with mild nephropathy who are taking an angiotensin-converting enzyme inhibitor and are on a low-sodium diet
Patients with heart failure who are taking an angiotensin-converting enzyme inhibitor and spironolactone
Patients with chronic renal insufficiency placed on trimethoprim
Recipients of kidney transplants who are taking cyclosporin or tacrolimus and have an abnormal serum creatinine
Complications
Complications of hyperkalemia range from mild ECG changes to cardiac arrest. Weakness is common as well.
Complications of therapy include the following:
Failure to control hyperkalemia
Hypokalemia due to excessively aggressive therapy
Hypercalcemia due to excessive calcium administration
Hypocalcemia from excessive bicarbonate therapy
Chest discomfort or tachycardia due to beta-agonist therapy
Hypoglycemia or hyperglycemia complicating glucose and insulin administration
Metabolic alkalosis and tetany due to excessive sodium bicarbonate administration
Volume depletion, metabolic alkalosis, renal insufficiency, hypocalcemia, hypomagnesemia, and hypophosphatemia due to aggressive loop diuretic use
Colon perforation due to Kayexalate administration
Prognosis
For patients with a defined and transient cause of hyperkalemia, the prognosis is excellent. However, patients who have ongoing risk factors for hyperkalemia are likely to develop recurrent episodes.
Patient Education
Inform patients regarding the following:
Dietary sources of potassium, including salt substitutes
Medications that impair renal excretion, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and potassium-sparing diuretics
Clinical situations in which patients might be at risk for the development of hyperkalemia, which include volume depletion and acute renal insufficiency complicating gastrointestinal fluid losses; increasing doses of ACE inhibitors or potassium-sparing diuretics; and addition of a medication that decreases renal excretion or cellular uptake in patients who already are taking such drugs.
Potassium homeostasis
Potassium, the most abundant intracellular cation, is essential for the life of the organism. Potassium is obtained through the diet. Common potassium-rich foods include meats, beans, fruits, and potatoes. Gastrointestinal absorption is complete, resulting in daily excess intake of about 1 mEq/kg/d (60-100 mEq). This excess is excreted through the kidneys (90%) and the gut (10%). Potassium homeostasis is maintained predominantly through the regulation of renal excretion. The most important site of regulation is the cortical collecting tubule where aldosterone receptors are present.
Excretion is increased by the following:
Aldosterone
High sodium delivery to the distal tubule (eg, diuretics)
High urine flow (eg, osmotic diuresis)
High serum potassium level
Delivery of negatively charged ions to the distal tubule (eg, bicarbonate)
Excretion is decreased by the following:
Absence of aldosterone
Low sodium delivery to the distal tubule
Low urine flow
Low serum potassium level
Renal failure
Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion also is increased. In the absence of potassium intake, obligatory renal losses are 10-15 mEq/d. Thus, chronic losses occur in the absence of any ingested potassium. The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min. Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases.
The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load. An excess of only 100-200 mEq will increase the serum potassium concentration by about 1 mEq/L.1
Serum potassium level
Potassium is predominantly an intracellular cation; thus, serum potassium levels can be a very poor indicator of total body stores. Potassium moves easily across cell membranes; therefore, serum potassium levels reflect the movement of potassium between intracellular and extracellular fluid compartments as well as total-body potassium homeostasis. Several factors regulate the distribution of potassium between the intracellular and extracellular space.
Glucoregulatory hormones
Insulin enhances potassium entry into cells.
Glucagon impairs potassium entry into cells.
Adrenergic stimuli
Beta-adrenergic stimuli enhance potassium entry into cells, whereas beta-blocking drugs inhibit potassium entry into cells.
Alpha-adrenergic stimuli impair potassium entry into cells.
pH
Alkalosis enhances potassium entry into cells.
Acidosis causes shift of potassium from intracellular space into extracellular space. Inorganic or mineral acid acidoses are more likely to cause a shift of potassium out of the cells than organic acidoses.
Shift from intracellular pool
Acute increase in osmolality, such as hyperglycemia, causes potassium to exit from cells.
Acute cell-tissue breakdown releases potassium into extracellular space.
The 2 sets of regulatory factors, those that regulate total-body homeostasis and those that regulate the distribution of potassium between intracellular and extracellular space, meld to create smooth control of potassium levels throughout the day. For example, a high-protein meal, such as a steak, may contain enough potassium to raise the serum potassium acutely to lethal levels if the potassium remained in the extracellular space. Although renal potassium excretion can increase fairly rapidly, this mechanism easily is overwhelmed by such an acute potassium load.
The acute hyperkalemic effect of an extremely potassium-rich meal is blunted substantially by the release of insulin, which causes potassium to be taken up into cells. The excessive potassium then can be excreted by the kidneys, allowing serum potassium levels to return to normal. This integrated regulatory process is manifested in the diurnal rhythm for renal potassium excretion. The highest excretion occurs at midday, approximately 18 hours after peak potassium ingestion at the evening meal.
Pathophysiology
Any of 3 pathogenetic mechanisms can cause hyperkalemia.
Excessive intake: Excessive potassium intake alone is an uncommon cause of hyperkalemia. The mechanisms for shifting potassium intracellularly and for renal excretion allow a person with normal potassium homeostatic mechanisms to ingest virtually unlimited quantities of potassium. Even parenteral administration of as much as 60 mEq/h for several hours creates only a minimal increase in serum potassium concentration in healthy individuals. Most often, hyperkalemia is caused by a relatively high potassium intake in a patient with impaired mechanisms for the intracellular shift of potassium or renal potassium excretion.
Decreased excretion: Decreased excretion of potassium, especially coupled with excessive intake, is the most common cause of hyperkalemia. The most common causes of decreased renal potassium excretion include renal failure, ingestion of drugs that interfere with potassium excretion (eg, potassium-sparing diuretics, angiotensin-convening enzyme inhibitors, nonsteroidal anti-inflammatory drugs), or impaired responsiveness of the distal tubule to aldosterone (eg, type IV renal tubular acidosis observed with diabetes mellitus, sickle cell disease, chronic partial urinary tract obstruction).
Shift from intracellular to extracellular space: This pathogenetic mechanism alone is a relatively uncommon cause of hyperkalemia but can exacerbate hyperkalemia produced by a high intake or impaired renal excretion. Clinical situations in which this mechanism is the major cause of hyperkalemia include hyperosmolality, rhabdomyolysis, tumor lysis, and succinylcholine administration, which depolarizes the cell membrane and, thus, permits potassium to leave the cells.2 However, more often, mild-to-moderate impairment of intracellular shifting of potassium occurs with insulin deficiency or acute acidosis.
Hyperkalemia may also be caused by IV administration of epsilon amino caproic acid (EACA), a synthetic amino acid. EACA has been found to cause hyperkalemia in studies conducted in dogs. The mechanism of action is presumed to be because of a similarity in structure of EACA to arginine and lysine. These latter amino acids enter the muscle cell in exchange for potassium, thereby leading to an increase in extracellular potassium.3, 4
Regardless of the cause, hyperkalemia produces similar signs and symptoms. Because potassium overwhelmingly is an intracellular cation and various factors can regulate the actual serum potassium concentration, an individual can ingest a substantial potassium load without exhibiting frank hyperkalemia. Conversely, hyperkalemia does not always reflect a true increase in total body potassium stores.
Frequency
United States
Hyperkalemia, defined as serum potassium greater than 5.3 mEq/L, is rare in the general population of healthy individuals. However, certain groups definitely exhibit a higher incidence of hyperkalemia. In patients who are hospitalized, the incidence of hyperkalemia has ranged from 1-10%, depending on the definition of hyperkalemia. Patients at the extremes of life, either premature or elderly, are at high risk. The presence of decreased renal function, genitourinary disease, cancer, severe diabetes, and polypharmacy also predisposes patients to hyperkalemia. Generally, with patients who are hospitalized, drugs are implicated in the development of hyperkalemia in as many as 75% of cases.
Military recruits, individuals with sickle cell traits, and people who abuse drugs are at risk for hyperkalemia due to acute rhabdomyolysis. These cases disproportionately occur in males, probably reflecting the higher muscle mass of males, though an underlying hormonal predisposition cannot be excluded absolutely.
Patients with diabetes constitute a unique high-risk group. They develop defects in all aspects of potassium metabolism. The typical healthy diabetic diet often is high in potassium and low in sodium. Diabetic persons frequently have underlying renal disease and often develop hyporeninemic hypoaldosteronism, impairing renal excretion of potassium. They frequently are placed on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for treatment of diabetic nephropathy, exacerbating the defect in potassium excretion. Finally, persons with diabetes have both insulin deficiency and/or resistance to insulin action, limiting their ability to shift potassium intracellularly. All of these factors combine to render people with diabetes particularly prone to hyperkalemia.
One review of the incidence of hyperkalemia in people with diabetes found that, in an unselected group of diabetic persons treated in a clinic, hyperkalemia (defined as a serum potassium level >5 mEq/L) was found in 15% (270 out of 1764 patients).5 However, fewer than 4% had potassium levels more than 5.4 mEq/L. Clinical risk factors significant in predicting the occurrence of hyperkalemia included renal insufficiency, duration of diabetes mellitus, age, glycosylated hemoglobin levels, and retinopathy. Interestingly, neither the serum glucose level nor the agent for diabetes treatment was significantly correlated.
Significant concern also has been raised about the potential for hyperkalemia in patients taking angiotensin-converting enzyme inhibitors, particularly because the indications for their use in high-risk populations, such as diabetic persons, are broadening rapidly. In one series, the incidence of hyperkalemia in an outpatient clinic was 11%.6 Hyperkalemia occurred in less than 6% of patients with normal renal function. Risk factors for hyperkalemia in patients using angiotensin-converting enzyme inhibitors included elevated BUN and serum creatinine, severe diabetes mellitus, congestive heart failure, peripheral vascular disease, and the use of a long-acting drug.
As the therapy of congestive heart failure has evolved, this growing group of patients also constitute a high-risk group. The factors promoting the development of hyperkalemia in heart failure patients include underlying renal insufficiency due to poor cardiac output and reduced renal blood flow, the high prevalence of diabetes mellitus in the population of heart failure patients, and the growing use of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone inhibitors, such as spironolactone. The initial studies examining the risk of hyperkalemia in heart failure patients treated with aldosterone inhibitors revealed only a minor increase in hyperkalemia, but later studies showed that as the practice became more widespread, the morbidity and mortality from hyperkalemia have increased.7
International
As in the United States, the incidence of hyperkalemia in the general population has been reported in less than 5% of people. Patients who are hospitalized in countries as diverse as England, Australia, and Israel experience hyperkalemia approximately 10% of the time. Similar to what has been reported in the United States, risk factors include advanced age, significant prematurity, and the presence of renal failure, diabetes mellitus, and heart failure. Additionally, one series documented an increased incidence of hyperkalemia with cancer and gastrointestinal disease.8 Polypharmacy, particularly the use of potassium supplements and potassium-sparing diuretics, in patients with underlying renal insufficiency contributed to hyperkalemia in almost one half of the cases.
Mortality/Morbidity
Hyperkalemia in a patient who is hospitalized is an independent risk factor for death. In one series, 1.4% of patients who were hospitalized (406 out of 29,063 patients) developed hyperkalemia.8
The overall mortality rate in patients with hyperkalemia was 14.3% (58 out of 406 patients), with the risk increasing as potassium level increases.
Twenty-eight percent of patients with a serum potassium level greater than 7 mEq/L died, as opposed to 9% of those with a potassium level less than 6.5 mEq/L. In 7 out of 58 deaths, cause of death was directly attributable to hyperkalemia. Most cases resulting in death were complicated by renal failure.
Interestingly, all patients who died of hyperkalemia had normal potassium levels within the 36 hours prior to death.
Race
No racial predisposition to hyperkalemia appears to exist.
Sex
Men are significantly more prone to hyperkalemia than women. This difference has been noted in several series and stands in contrast to the increased incidence of hypokalemia in women. The reasons for this discrepancy are unknown.
Age
Several series document the increasing tendency for hyperkalemia in patients at the extremes of life, either small premature infants or elderly people, with renal insufficiency playing a significant role in both.
Premature infants are a high-risk group. Relative renal immaturity is likely to be a contributory factor; studies comparing small premature infants who developed hyperkalemia to those who did not indicate that incidence is increased in infants with a lower glomerular filtration rate as estimated by endogenous creatinine clearance. In these small infants, hyperkalemia often occurs within the first 48 hours of life.
Elderly patients are another high-risk group. In several series, an age older than 60 years was an independent risk factor for the development of hyperkalemia in the hospital. Several factors contribute to the increased propensity for elderly people to become hyperkalemic. Renal function tends to deteriorate with age, even in relatively healthy individuals. The glomerular filtration rate decreases by 1 mL/min/y in people older than 30 years. Renal blood flow also decreases. Oral intake declines, resulting in decreased urine flow rates. Plasma renin activity and aldosterone levels also tend to decrease with age, decreasing the ability of the distal nephron to secrete potassium.
Elderly patients are more likely to be taking medications that could interfere with potassium secretion, such as nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and potassium-sparing diuretics. Elderly individuals who are bedridden often are placed on subcutaneous heparin, which can decrease aldosterone production.
CLINICALSection 3 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
History
Symptoms are nonspecific and predominantly related to muscular or cardiac function. The most common complaints are weakness and fatigue. Occasionally, a patient may complain of frank muscle paralysis or shortness of breath. Patients also may complain of palpitations or chest pain.
When hyperkalemia is discovered, investigate potential pathophysiologic mechanisms.
For excessive potassium intake, query patients about the following:
Eating disorders - Very unusual diets consisting almost exclusively of high-potassium foods, such as fruits, dried fruits, juices, and vegetables with little to no sodium
Heart healthy diets - Very low-sodium and high-potassium diets recommended for patients with cardiac disease, hypertension, and diabetes mellitus
Use of potassium supplements in over-the-counter herbal supplements, salt substitutes, or prescribed pharmacologic agents - Many patients with renal insufficiency and hypertension have heard the advice to eat a banana a day because the potassium reduces blood pressure. They may not realize that in the case of renal insufficiency and hypertension, this is potentially a life-threatening therapy.
For decreased potassium excretion, query patients about the following:
Ingestion of medications that impair renal potassium excretion
Potassium-sparing diuretics, especially popular in the treatment of cirrhosis and congestive heart failure
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Cyclosporine or tacrolimus
Antibiotics, such as pentamidine or trimethoprim/sulfamethoxazole
EACA3
History of renal insufficiency or renal failure
History of diabetes mellitus, sickle cell disease or trait, or symptoms of lower urinary tract obstruction - These diseases predispose people to type IV renal tubular acidosis, also called hyperkalemic renal tubular acidosis. Type IV renal tubular acidosis also may accompany other tubulointerstitial disorders, such as polycystic kidney disease or amyloidosis. Often, patients with type IV renal tubular acidosis have Hyporeninemic Hypoaldosteronism (ie, decreased aldosterone secondary to suppressed renin levels). One example is diabetes mellitus, where the relative volume overload leads to low renin.
For a shift of potassium into the extracellular space, query patients about the following:
Recurrent episodes of flaccid paralysis
Presence of diabetes mellitus
Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
Risk factors for rhabdomyolysis, such as heat stroke, chronic alcoholism, seizures, sudden excessive exertion (eg, in military recruits undergoing basic training), or use of medications that interfere with heat dissipation (eg, tricyclic antidepressants or anesthesia)
Risk factors for tumor lysis syndrome, such as ongoing treatment for widespread lymphoma, leukemia, or other large tumors
Risk factors for hemolysis, such as blood transfusion and sickle cell disease
Other mechanisms
Drugs, such as cyclooxygenase-2 (COX-2) inhibitors9
Ingestion of toad venom (Bufo bufo gargarizans) in southeastern Asian countries
In Southeast Asia, toads are a common folk remedy for strengthening the heart. Bufadienolides, a form of cardiac glycoside that is present in toad venom, have a similar structure and biochemical activity to digitalis and cardenolides, the major plant-derived cardiac glycosides. Bufadienolides cause hyperkalemia via its binding to the alpha subunit of Na+–K+–ATPase, thus inhibiting the reuptake of potassium from the extracellular space.10
This compound has also turned up in some aphrodisiacs and Chinese medications (eg, chan su).
With regard to Western countries, at least 2 cases of poisoning by toad and eggs have been reported in the United States.11
Physical
Vital signs generally are normal, except occasionally in bradycardia due to heart block or tachypnea due to respiratory muscle weakness.
Muscle weakness and flaccid paralysis
Depressed or absent deep tendon reflexes
In general, the results of the physical examination alone do not alert the physician to the diagnosis, except when severe bradycardia is present or muscle tenderness accompanies muscle weakness, suggesting rhabdomyolysis.
Causes
Listed by pathophysiologic mechanisms, causes include increased potassium intake, decreased potassium excretion, or a shift of potassium from the intracellular to the extracellular space. The most common causes are due to decreased excretion. Alone, excessive intake or an extracellular shift is distinctly uncommon. Often, several disorders are present simultaneously.
Increased intake: Alone, this is a rare cause of hyperkalemia because the mechanisms for renal excretion and intracellular disposition are very efficient. In general, a relatively high potassium intake contributes to hyperkalemia in individuals who have impaired renal excretion, impaired intracellular shift, or both.
High-potassium, low-sodium diets
Ingestion of potassium supplements: Ingested amounts would have to be massive as the sole cause of hyperkalemia, but even relatively small amounts can produce hyperkalemia in a patient with impaired renal excretion.
High concentrations of potassium in intravenous fluid preparations, such as total parenteral nutrition
Dietary salt substitutes, penicillin potassium therapy
Decreased excretion: Impaired renal excretion almost always is present when a patient presents with persistent hyperkalemia. Mild degrees of renal failure generally do not result in resting hyperkalemia due to adaptive mechanisms in the kidneys and gastrointestinal tract. However, once the glomerular filtration rate falls below 15-20 mL/min, significant hyperkalemia can occur, even in the absence of an abnormally large potassium load. The simple lack of nephron mass prevents normal potassium homeostasis. Hyperkalemia due to decreased renal excretion can occur when a patient has normal or only mildly decreased renal function as a result of other mechanisms, such as drugs or renal tubular acidosis. Two other causes of decreased excretion of potassium include reduced distal sodium delivery and reduced tubular fluid flow rate.
Drugs
Potassium-sparing diuretics, spironolactone, triamterene, amiloride
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Cyclosporine or tacrolimus
Pentamidine
Trimethoprim/sulfamethoxazole
Heparin
Ketoconazole
Metyrapone
Herbs
Type IV renal tubular acidosis
Diabetes mellitus
Sickle cell disease or trait
Lower urinary tract obstruction
Adrenal insufficiency
Primary Addison syndrome due to autoimmune disease, tuberculosis, or infarct
Enzyme deficiencies
Disorders of steroid metabolism and mineralocorticoid receptors12, 13
21-hydroxylase deficiency in classical form and aldosterone synthase deficiency result in hyperkalemia due to low aldosterone levels.
11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and 17 alpha-hydroxylase/17,20-lyase deficiency are generally not characterized by the development of hyperkalemia.
Type 1 pseudohypoaldosteronism is caused by an inactivating mutation of the mineralocorticoid receptor, resulting in impaired potassium secretion due to impaired sodium reabsorption in the distal tubule.14
Gordon syndrome or pseudohypoaldosteronism Type II, characterized by hyperkalemia and hypertension, is caused by mutations in either WNK1 (with no lysine [K]) or WNK4, protein kinases that are localized to the distal tubule and that regulate ion transport in this nephron segment. WNK4 appears to have several roles in regulating sodium, potassium, and chloride transport through transcellular and paracellular pathways.15
Shift of potassium into the extracellular space: Like increased intake, this rarely is the sole cause of hyperkalemia because the mechanisms for renal excretion are very efficient. However, the inability to transport potassium intracellularly exacerbates hyperkalemia in individuals who have impaired renal excretion.
Hyperkalemic periodic paralysis
Insulin deficiency or insulin resistance (ie, type I or type II diabetes mellitus)
Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
Tissue breakdown
Rhabdomyolysis
Tumor lysis syndrome
Massive hemolysis
Drugs
Nonselective beta-blockers (inhibits Na-K-ATPase pump)
Digitalis toxicity (inhibits Na-K-ATPase pump)
Succinylcholine (membrane leak)
Inhibition of the sodium pump will impair K entry into the cells and facilitate K exit from the cells.
Hypertonicity may lead to hyperkalemia by 2 mechanisms: loss of intracellular water, resulting in an increased intracellular potassium concentration, favoring a gradient for potassium to move out of the cells; and, as water exits the cells, potassium is swept along with ‘‘solvent drag.' The most common cause of hyperosmolality is hyperglycemia in uncontrolled diabetes mellitus. Other conditions with hypertonicity are hypernatremia and hypertonic mannitol.
Aldosterone deficiency: This is somewhat controversial. Some evidence that long-term aldosterone deficiency impairs cell potassium uptake exists.
DIFFERENTIALSSection 4 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Other Problems to be Considered
Pseudohyperkalemia is the term applied to the clinical situation in which in vitro lysis of cellular contents leads to the measurement of a high serum potassium level not reflective of the true in vivo level. This condition occurs most commonly with red cell hemolysis during the blood draw (tourniquet too tight or the blood left sitting too long), severe thrombocytosis (platelet count >1,000,000/mL), or severe leukocytosis (WBC >70,000/mL). Recognizing that when true intravascular hemolysis has occurred, for example, with a transfusion reaction or a hemolytic sickle crisis or drug-induced hemolytic reaction, the measured potassium reflects the true potassium is important.
WORKUPSection 5 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Lab Studies
Assess renal function.
Check serum BUN and creatinine levels to determine whether renal insufficiency is present.
Check 24-hour urine for creatinine clearance or estimate the creatinine clearance using the Cockroft-Gault equation to assess whether the degree of renal insufficiency alone explains the hyperkalemia.
The Cockroft-Gault equation is (140 – age)(weight in kg)/(72)(serum creatinine). For women, the answer is multiplied by 0.8.
Estimate the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula, as follows: (GFR (mL/min/1.73 m2) = 186 X (serum creatinine) - 1.154 X (age) - 0.203 X (0.742 if female) X (1.210 if African American) (conventional units).16
Measure urine potassium and sodium concentrations and urine osmolality.
These tests are essential to determine whether impairment of renal excretion is contributing to the hyperkalemia. A urine potassium level less than 20 mEq/L suggests impaired renal excretion. A urine potassium level greater than 40 mEq/L suggests intact renal excretory mechanisms, implying that high intake or failure of cell uptake is the major mechanism for hyperkalemia. However, an isolated urine potassium level often is misleading because the concentration of potassium in the urine is influenced not only by secretion by the cortical collecting tubule but also by the degree of urinary concentration. If the urine osmolality is high (>700 mOsm/kg), then the absolute value of urine potassium concentration can be misleading and suggest that the kidneys are disposing of potassium appropriately.
For example, suppose serum potassium is 6 mEq/L and urine potassium 60 mEq/L. The high urine potassium level suggests appropriate renal potassium excretion. However, the final concentration of potassium in the urine not only is dependent on how much potassium is secreted in response to sodium reabsorption, but it also is dependent on how concentrated the urine is. In the above example, if urine osmolality is 300 mOsm/kg, that is, not concentrated relative to serum, then a measured urine potassium level of 60 mEq/L indeed suggests renal potassium loss. However, if the urine osmolality is 1200 mOsm/kg, that is, concentrated 4-fold relative to the serum, then the potassium concentration in the urine, in the absence of urinary concentration due to water reabsorption, is 15 mEq/L, which is very low.
The conclusion would then be that the kidneys are not appropriately excreting potassium. This adjustment in the evaluation of urinary potassium concentration for the degree of urinary concentration is called calculation of the transtubular potassium gradient (TTKG).
TTKG = (urine K x serum osmolarity)/(serum K x urine osmolarity)
A TTKG less than 3 suggests a lack of aldosterone effect on collecting tubules, that is, kidneys are not excreting potassium appropriately. A TTKG greater than 7 suggests an aldosterone effect, which would be appropriate in the setting of hyperkalemia.
These examples demonstrate that calculation of the TTKG is superior to using the urine potassium alone to assess contribution of decreased renal excretion to hyperkalemia. As useful as this test is, recognizing that it is valid only if 1) the urine osmolality is greater than the serum osmolality, that is, the urine is concentrated relative to the serum, and 2) the urine sodium is greater than 20 mEq/L, that is, distal delivery of sodium is adequate for potassium excretion, is important.
A 24-hour urine potassium measurement rarely is needed to assess renal potassium excretory ability.
Measure complete blood count.
A low hemoglobin and hematocrit (H/H) or abnormal red cell morphology may suggest hemolysis.
Severe leukocytosis or thrombocytosis raises the possibility of pseudohyperkalemia. When in doubt, measure the plasma potassium concentration. Plasma potassium is about the same as serum potassium.
Measure complete metabolic profile.
Low bicarbonate may suggest hyperkalemia due to metabolic acidosis.
Hyperglycemia suggests diabetes mellitus.
Elevated lactic dehydrogenase (LDH), uric acid, phosphate, and alanine aminotransferase (ALT) may suggest tissue breakdown such as in hemolysis, rhabdomyolysis, or tumor lysis.
A creatine kinase (CK) elevation suggests rhabdomyolysis.
Depending on the results of the above laboratory work, the following may be indicated:
Serum cortisol (reference range 8 am 5-25 µg/mL, 4 pm 3-12 µg/mL): Decrease may suggest adrenal insufficiency.
Serum renin and aldosterone (normal supine renin activity 3.2 ± 1 ng/mL/h; normal suppressed aldosterone 5-20 ng/mL): Decrease may suggest adrenal insufficiency.
Fasting blood sugar (reference range 75-115 mg/dL), glycosylated hemoglobin (normal 6.5%), or glucose tolerance test (normal 2 h postprandial value <140 mg/dL): Increase suggests underlying diabetes mellitus.
Assays of 11-beta hydroxylase or 21-hydroxylase: Deficiencies of these enzymes produce syndromes of virilization and generally are recognized in the neonatal period. 11-Beta hydroxylase deficiency is diagnosed by measurement of elevated plasma 11 deoxycortisol levels or increased urinary tetrahydro-ll-deoxycortisol levels. To detect mild cases, adrenocorticotropic hormone (ACTH) stimulation also may be performed to enhance synthesis of these products. 21-Hydroxylase deficiency is detected by the measurement of elevated 17-hydroxyprogesterone levels in blood, generally 90-1200 nmol/L.
Other Tests
Electrocardiogram: This test is vital to assess the physiologic significance of the hyperkalemia. However, ECG changes often do not correlate with the degree of hyperkalemia. ECG changes suggestive of an effect of hyperkalemia on cardiac conduction include (in order of appearance) the following17:
Peaked T waves
Prolongation of the PR interval
Widening of the QRS
Loss of the P wave
Sine wave pattern
Sinus arrest
In patients with organic heart disease and abnormal baseline ECG, bradycardia may be the only new ECG abnormality.18
TREATMENTSection 6 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medical Care
Orient the medical care of patients with hyperkalemia toward 5 different aims.
Evaluation for potential toxicities
Decreasing potassium intake
Increasing potassium uptake into cells
Increasing potassium excretion
Determining the cause to prevent future episodes
Although explicated below in a step-by-step format, these different aspects of hyperkalemia treatment generally are addressed simultaneously. The aggressiveness of therapy is directly related to the rapidity with which hyperkalemia has developed, the absolute level of hyperkalemia, and the evidence of toxicity. The faster the rise of potassium, the higher the level, and the greater the evidence of cardiotoxicity, the more aggressive therapy should be.
The first step is to determine whether the hyperkalemia is producing life-threatening toxicity.
Perform an ECG to look for cardiotoxicity.
Administer intravenous calcium to ameliorate cardiac toxicity, if present.
The second step is to identify and remove sources of potassium intake.
Discontinue oral and parenteral potassium supplements.
Remove potassium-containing salt substitutes.
Examine the patient's diet. Change the diet to a low-potassium tube feed or a 2-g potassium ad-lib diet.
The third step is to enhance potassium uptake by cells to decrease the serum concentration.
Parenteral glucose and insulin infusions are very effective in enhancing potassium uptake. Although glucose stimulates insulin secretion, administration of glucose alone often is not as effective in this clinical situation. The onset of action is within 20-30 minutes, and the duration is variable, from 2-6 hours. Continuous infusions of insulin and glucose-containing intravenous fluids can be used for prolonged effect. Measure glucose and potassium every 2 hours.
Correct metabolic acidosis with sodium bicarbonate. This therapeutic modality is both less effective and less predictable in producing a hypokalemic response due to the variable effect of different forms of metabolic acidosis on the serum potassium level. This particularly is true in patients with chronic renal failure. Nonetheless, if the acidosis is severe, then a trial of parenteral sodium bicarbonate therapy is warranted.
Beta-adrenergic agonists also are quite effective but, perhaps, somewhat more controversial and more likely to produce side effects. In the United States, the most commonly used preparation is nebulized albuterol. The dose for treating hyperkalemia, 10 mg, is substantially higher than the usual dose for the treatment of bronchospasm and requires the assistance of a respiratory therapist. This therapy is highly effective and preferred over alkali therapy in patients with renal failure. Parenteral isoproterenol or albuterol also decrease potassium. However, isoproterenol is not used commonly, and parenteral albuterol is not available in this country. Some investigators have reported tachycardia and chest discomfort using beta-agonist therapy for hyperkalemia. Discontinue beta-adrenergic antagonists.
The fourth step is to increase potassium excretion from the body.
Renal excretion is enhanced easily in the individual with normal kidney function by the administration of parenteral saline accompanied by a loop diuretic such as furosemide.
Discontinue potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other drugs that inhibit renal potassium excretion.
Monitor volume status and aim to maintain euvolemia.
Renal excretion can be enhanced by administration of aldosterone analogue such as 9-alpha fluorohydrocortisone acetate (Florinef). Florinef especially is helpful in those with hyporeninemia or hypoaldosteronism.
Gastrointestinal excretion can be increased by the use of cation exchange resins such as Kayexalate. Kayexalate can be administered orally or rectally as a retention enema. Because the major site of action for this drug is the colon, rectal administration is preferred for hyperkalemic emergencies.
The effectiveness of this drug is enhanced if the enema can be retained for an hour.
Repeated enemas can be used but, occasionally, cause colon perforation.
The onset of action occurs within 2 hours and is long lasting. The serum potassium level can be decreased by 2 mEq/L with a single enema. Kayexalate administered orally also is quite effective if it is suspended in 70% sorbitol.
Emergency dialysis is a final recourse for patients who are experiencing potentially lethal hyperkalemia that is unresponsive to more conservative measures or for patients who have complete renal failure. Initiation of dialysis often can take several hours; therefore, even if dialysis is contemplated, initiate the other modalities of therapy first.
The final step in the medical management of hyperkalemia is to determine the cause of hyperkalemia in order to prevent future episodes. This should include examination of the following:
Sources of potassium intake
Causes of decreased renal excretion
Causes for impaired cellular uptake
Surgical Care
Surgery generally is not needed for the care of a patient with hyperkalemia.
Patients with metabolic acidosis and consequent hyperkalemia due to ischemic gut obviously require exploration.
Patients with hyperkalemia due to rhabdomyolysis may need surgical decompression of swollen ischemic muscle compartments.
Patients without end-stage renal disease who require hemodialysis for control of hyperkalemia need placement of a hemodialysis catheter for emergent dialysis.
Consultations
For severe hyperkalemia, early consultation with a nephrologist for aid in efficient therapy and plans for dialysis is highly recommended.
For emergency pacemaker placement, the aid of a cardiologist may be required for patients with refractory heart block.
Diet
A low-potassium diet with 2 g of potassium is recommended to minimize potassium intake.
Activity
No restrictions on activity are required unless continuous monitoring for cardiotoxicity is required.
MEDICATIONSection 7 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
The goals of pharmacotherapy are to reduce potassium levels and morbidity and to prevent complications.
Drug Category: Beta-adrenergic agonists
Through an activation of cyclic adenosine monophosphate (AMP), these agonists stimulate the adenosine triphosphatase (ATPase) pump, thereby shifting potassium into the intracellular compartment.
Drug Name Isoproterenol (Dey-Dose, Isuprel, Arm-a-Med)
Description Has beta1-adrenergic and beta2-adrenergic receptor activity.
Adult Dose 5 mcg/min IV initial, titrate to response; not to exceed 20 mcg/min
Pediatric Dose 0.1 mcg/kg/min IV, titrate to response; not to exceed 2 mcg/min
Contraindications Documented hypersensitivity; tachyarrhythmias, tachycardia, or heart block caused by digitalis intoxication; ventricular arrhythmias that require inotropic therapy; angina pectoris
Interactions Bretylium increases action of vasopressors on adrenergic receptors, which may, in turn, result in arrhythmias; guanethidine may increase effect of direct-acting vasopressors, possibly resulting in severe hypertension; tricyclic antidepressants may potentiate pressor response of direct-acting vasopressors
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions By increasing myocardial oxygen requirements while decreasing effective coronary perfusion, isoproterenol may have a deleterious effect on the injured or failing heart; in some patients presumably with organic disease of the AV node and its branches, isoproterenol paradoxically may worsen heart blocks or precipitate Adams-Stokes attacks; caution in coronary artery disease, coronary insufficiency, diabetes, or hyperthyroidism; if heart rate >110 beats per min, decreasing infusion rate or temporarily discontinuing infusion may be advisable
Drug Name Albuterol (Proventil, Ventolin)
Description Adrenergic agonist that increases plasma insulin concentrations. Increase in insulin may shift potassium into intracellular space.
Adult Dose 10-20 mg nebulized or 0.5 mg IV over 15 min
Pediatric Dose 2.5 mg IV and repeat in 2 h prn
Contraindications Documented hypersensitivity
Interactions Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of
bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled
anesthetics, tricyclic antidepressants, and sympathomimetic agents
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders
Drug Category: Calcium salts
Calcium antagonizes cardiotoxicity of hyperkalemia by stabilizing cardiac cell membrane against undesirable depolarization. Has no effect on serum level of potassium. Onset of effect is rapid, within 15 min, but relatively short lived.
Drug Name Calcium gluconate (Kalcinate)
Description Moderates nerve and muscle performance and facilitates normal cardiac function.
Adult Dose 100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium per kg/h
Pediatric Dose 2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)
Contraindications Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Caution in patients who are digitalized; respiratory failure; acidosis; severe hyperphosphatemia
Drug Name Calcium chloride
Description Prevents deleterious effects caused by severe hyperkalemia as measured by ECG, pending correction of increased potassium in extracellular fluid. Generally, second choice to calcium gluconate due to irritating effects when administered parenterally.
Adult Dose Known or suspected hyperkalemia (K+ > 6 mEq/L): 2-4 mg/kg IV (10% solution)
Pediatric Dose 0.2 mL (20 mg)/kg of IV (10% solution)
Contraindications Ventricular fibrillation not associated with hyperkalemia; digitalis toxicity; hypercalcemia; renal insufficiency; cardiac disease
Interactions Coadministration with digoxin may cause arrhythmias; may antagonize effects of calcium channel blockers, atenolol, and sodium polystyrene sulfonate
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Administer slowly (not to exceed 0.5-1 mL/min) to avoid extravasation; hypercalcemia may occur in renal failure
Drug Category: Hormones
Insulin stimulates cellular uptake of potassium, lowering serum potassium level.
Drug Name Insulin (Novolin, Humulin)
Description Stimulates cellular uptake of potassium within 20-30 min. Administer glucose along with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.
Adult Dose 10 U IV and either 50 mL D50W bolus or 500 mL D10W over 1 h
Pediatric Dose 0.5-1 g/kg IV followed by 1 U of regular insulin per 3 g glucose
Contraindications Documented hypersensitivity; hypoglycemia
Interactions Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Hyperthyroidism may increase renal clearance of insulin and may need more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal and hepatic dysfunction
Drug Category: Diuretics
Loop diuretics markedly enhance renal potassium excretion, consequently lowering serum levels. Parenterally administered drug has a more rapid onset of action and is preferable in emergent situations. Simultaneous administration of saline can prevent severe volume depletion.
Drug Name Furosemide (Lasix)
Description Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle and distal renal tubule. Individualize dose to patient. Depending on the response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs. When treating infants, titrate with increments of 1 mg/kg per dose until a satisfactory effect is achieved. Oral absorption of furosemide is variable from person to person. If rapid and effective therapy is mandated, then IV route is preferred. Occasionally, a continuous infusion of furosemide, as high as 40 mg/h, is used for severe edema but rarely is required for the treatment of hyperkalemia.
Adult Dose 20-80 mg/d PO/IV/IM; titrate as high as 600 mg/d
Pediatric Dose 1-2 mg/kg per dose PO; not to exceed 6 mg/kg per dose; not to administer >q6h
1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
Contraindications Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Interactions Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of
antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter; profound diuresis may occur with fluid and electrolyte loss; caution in hepatic failure
Drug Name Bumetanide (Bumex)
Description Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle and distal renal tubule. Individualize dose to patient. Start at 1-2 mg IV; titrate to as high as 10 mg/d. Rarely, doses as high as 24 mg/d are used for edema but generally are not required for treatment of hyperkalemia.
Adult Dose 0.5-2 mg/dose PO qd/bid; not to exceed 10 mg/d
Alternatively, 0.5-1 mg/dose IV/IM; not to exceed 10 mg/d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; anuria; increasing azotemia
Interactions Decreases effects of indomethacin and probenecid; may increase lithium toxicity
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions Profound diuresis may occur with fluid and electrolyte loss; caution in hepatic failure; monitor serum sodium, bicarbonate, calcium, magnesium, phosphate, and potassium
Drug Category: Cation exchange resins
Stimulate the exchange of sodium for potassium in the colon, thus increasing intestinal excretion of potassium.
Drug Name Sodium polystyrene sulfonate (Kayexalate)
Description Exchanges sodium for potassium and binds it in the gut, primarily in the large intestine, and decreases total body potassium. Onset of action after oral administration ranges from 2-12 h and is longer when administered rectally.
Adult Dose 25-50 g PO in 25-50 mL sorbitol q6h
25-50 g PR in 25-50 mL sorbitol as retention enema q6h
Pediatric Dose 1 g/kg PO in sorbitol q6h
2 g/kg PR in sorbitol as retention enema q6h
Contraindications Documented hypersensitivity; hypernatremia
Interactions Systemic alkalosis may occur if administered concurrently with magnesium hydroxide, aluminum carbonate or similar antacids, and laxatives
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution when administering to patients who can be affected adversely by a small increase in sodium loads, such as severe hypertension, severe congestive heart failure, and marked edema; constipation, with the possibility of fecal impaction, may occur; treat constipation with 10-20 mL of 70% sorbitol every 2 h or as necessary to produce at least 1-2 watery stools daily
Drug Category: Electrolytes
Used to correct metabolic acidosis if acidosis is severe.
Drug Name Sodium bicarbonate (Neut)
Description Used only when patient is diagnosed with bicarbonate-responsive acidosis, hyperkalemia, tricyclic antidepressant overdose, or phenobarbital overdose. Routine use is not recommended.
To estimate the dose that should be administered may use the following formula: HCO3- (mEq) = 0.5 X weight in kg X (24 - serum HCO3- in mEq/L)
This formula has many limitations; however, the practitioner can determine roughly the amount of bicarbonate required and subsequently titrate against the pH and anion gap.
Adult Dose Generally for parenteral use, 1-2 amps of sodium bicarbonate containing a total of 50-100 mEq is adequate
650-1300 mg PO bid or tid
If the patient has a relatively normal serum bicarbonate level but severe ECG changes of hyperkalemia, then 1 ampule or 50 mEq may be infused q15min, monitoring serum bicarbonate and serum sodium to avoid severe alkalosis and hypernatremia
Alternatively, 2 ampules of sodium bicarbonate (100 mEq) may be added to 1 L 10% dextrose in water and infused at 250-500 mL/h if tolerated
Pediatric Dose Not established
Contraindications Documented hypersensitivity; alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain
Interactions Urinary alkalinization induced by increased sodium bicarbonate concentrations may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Only use sodium bicarbonate to treat documented metabolic acidosis and hyperkalemia-induced cardiac arrest; can cause alkalosis, decreased plasma potassium, hypocalcemia, and hypernatremia; caution in electrolyte imbalances, such as in patients with CHF, cirrhosis, edema, corticosteroid use, or renal failure; when administering, avoid extravasation because can cause tissue necrosis
FOLLOW-UPSection 8 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Further Inpatient Care
Once the potassium level is restored to normal, the potassium-lowering therapies can be discontinued and the serum potassium level can be monitored.
Determine and address the cause for hyperkalemia, including an evaluation of sources of potassium intake, causes for decreased renal excretion, and causes for decreased cell uptake of potassium. Most cases of hyperkalemia are multifactorial, with elements of all 3 causalities contributing to the final picture. In particular, reevaluate the use of potassium supplements (including salt substitutes) in patients with renal insufficiency or in patients taking medications that impair renal excretion of potassium.
Further Outpatient Care
For patients who have a defined and finite reason for hyperkalemia, such as acute exertional rhabdomyolysis or drug-induced hemolysis, serum potassium can be monitored on an infrequent basis. However, for patients who have conditions or medications predisposing them to hyperkalemia and in whom hyperkalemia has developed, monitor serum potassium levels more frequently. Once monthly measurements are indicated for patients at high risk.
For patients who have recurrent or constant hyperkalemia, such as patients with diabetic nephropathy and type IV renal tubular acidosis, chronic therapy with an oral loop diuretic and Kayexalate may be indicated.
In/Out Patient Meds
Loop diuretics often offset mild hyperkalemia without producing significant volume depletion. Once daily furosemide is effective in patients with moderate hyperkalemia and type IV renal tubular acidosis.
Oral Kayexalate is useful in patients with advanced renal failure who are not yet on dialysis or transplant candidates. One or more doses of 15 g/d can control mild-to-moderate hyperkalemia effectively with little inconvenience to patients.
Florinef 0.1 mg PO daily is a useful drug in hyperkalemia associated with mild-to-moderate renal impairment.
Transfer
Transfer patients with severe cardiac toxicity as recorded on ECG to the intensive care unit for continuous monitoring and aggressive therapy.
If a patient requires hemodialysis for hyperkalemia, transfer to a facility with this capability may be required.
Deterrence/Prevention
The most effective prevention of hyperkalemia is through education of patients on the potential causes of hyperkalemia, dietary sources, medical conditions predisposing to hyperkalemia, and contributing medications.
Additionally, repeated review of the patient's medications to identify potential interactions that can cause hyperkalemia is essential.
Some common clinical situations include the following:
Diabetic persons with mild nephropathy who are taking an angiotensin-converting enzyme inhibitor and are on a low-sodium diet
Patients with heart failure who are taking an angiotensin-converting enzyme inhibitor and spironolactone
Patients with chronic renal insufficiency placed on trimethoprim
Recipients of kidney transplants who are taking cyclosporin or tacrolimus and have an abnormal serum creatinine
Complications
Complications of hyperkalemia range from mild ECG changes to cardiac arrest. Weakness is common as well.
Complications of therapy include the following:
Failure to control hyperkalemia
Hypokalemia due to excessively aggressive therapy
Hypercalcemia due to excessive calcium administration
Hypocalcemia from excessive bicarbonate therapy
Chest discomfort or tachycardia due to beta-agonist therapy
Hypoglycemia or hyperglycemia complicating glucose and insulin administration
Metabolic alkalosis and tetany due to excessive sodium bicarbonate administration
Volume depletion, metabolic alkalosis, renal insufficiency, hypocalcemia, hypomagnesemia, and hypophosphatemia due to aggressive loop diuretic use
Colon perforation due to Kayexalate administration
Prognosis
For patients with a defined and transient cause of hyperkalemia, the prognosis is excellent. However, patients who have ongoing risk factors for hyperkalemia are likely to develop recurrent episodes.
Patient Education
Inform patients regarding the following:
Dietary sources of potassium, including salt substitutes
Medications that impair renal excretion, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and potassium-sparing diuretics
Clinical situations in which patients might be at risk for the development of hyperkalemia, which include volume depletion and acute renal insufficiency complicating gastrointestinal fluid losses; increasing doses of ACE inhibitors or potassium-sparing diuretics; and addition of a medication that decreases renal excretion or cellular uptake in patients who already are taking such drugs.
hypercalcemia
Background: Calcium (Ca) plays an important role in intracellular and extracellular metabolism that controls processes, such as nerve conduction, muscle contraction, coagulation, electrolyte and enzyme regulation, and hormone release. Calcium metabolism, in turn, is tightly regulated by a series of hormones that affect not only the entry of calcium into the extracellular space from bone and the GI tract but also control its excretion from the kidneys. Hypercalcemia can be the result of excess entry of calcium into the extracellular fluid (ECF) or of insufficient excretion.
Calcium hemostasis
Ninety-eight percent of body calcium is found in the skeleton; this is closely related to the extracellular concentration of calcium. Intracellular calcium is less than extracellular calcium by a factor of 100,000. Intracellular processes, including the activity of many enzymes, cell division, and exocytosis, are controlled by intracellular calcium. The primary mediator of the intracellular effects of calcium is the calcium-binding regulatory protein, calmodulin.
Plasma calcium is maintained despite its large movements across the gut, bone, kidney, and cells. Changes in calcium ions usually are accompanied by changes in total calcium in the ECF. In plasma, calcium exists in 3 different forms, (1) 50% as ionized or the biologically active form, (2) 45% bound to plasma proteins (mainly albumin), and (3) 5% complexed to phosphate and citrate. Because the proportion of bound calcium varies little within individuals, in the absence of severe acidosis or alkalosis, the amount of albumin is the major factor determining the amount of calcium that is bound.
Very little evidence suggests that intracellular stores of calcium contribute in any way towards plasma calcium homeostasis. An exception is in the parathyroid gland, in which the intracellular concentration increases in response to changes in extracellular concentration, which, in turn, alters the rate of parathyroid hormone (PTH) secretion. Any decrease in extracellular calcium ion concentration leads to an increase in PTH secretion. PTH increases distal renal tubular reabsorption of calcium within minutes and stimulates osteoclast activity, with release of calcium from the skeleton within 1-2 hours. More prolonged PTH elevation stimulates 1alpha-hydroxylase activity in the proximal tubular cells, which leads to 1,25-dihydroxyvitamin D (1,25(OH)2 D3) production. All these mechanisms help to maintain the serum calcium level within normal limits.
A normal serum calcium level is 8-10 mg/dL (2-2.5 mmol/L) with some interlaboratory variation in the reference range, and hypercalcemia is defined as a serum calcium level greater than 10.5 mg/dL (>2.5 mmol/L). Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:
Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or Ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L)
Moderate: Total Ca 12-13.9 mg/dL (3-3.5 mmol/L) or Ionized Ca 5.6-8 mg/dL (2-2.5 mmol/L)
Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or Ionized Ca 10-12 mg/dL (2.5-3 mmol/L)
Only 1-2% of total body calcium is in the exchangeable form in circulation, and the rest forms part of the skeleton. Only one half of the exchangeable calcium is in the active ionized form with the remainder bound to albumin, globulin, and other inorganic molecules. Protein binding of calcium is influenced by pH with metabolic acidosis leading to increased ionized calcium from reduced protein binding, and alkalosis leading to reduced ionized calcium from increased protein binding. Because calcium binds to albumin and only the unbound (free or ionized) calcium is biologically active, the serum level must be adjusted for abnormal albumin levels.
For every 1-g/dL drop in serum albumin below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL. Therefore, to correct for an albumin level of less than 4 g/dL, one should add 0.8 to the measured value of calcium for each 1-g/dL decrease in albumin. Without this correction, an abnormally high serum calcium level may appear to be normal.
A patient with a serum calcium level of 10.3 mg/dL but an albumin level of 3 g/dL appears to have a normal serum calcium level. However, when corrected for the low albumin, the real serum calcium value is 11.1 mg/dL (10.3 + 0.8), a more obviously abnormal level. Alternatively, serum free (ionized) calcium levels can be directly measured, negating the need for correction for albumin. Corrected calcium can be calculated using the following formula:
Corrected Ca = ([4 - plasma albumin in g/dL] X 0.8 + serum calcium)
Mild cases of hypercalcemia can be asymptomatic and are more often diagnosed incidentally from routine blood tests. Because calcium metabolism normally is tightly controlled by the body, even mild persistent elevations above normal signal disease and should be investigated.
Calcium is controlled by 2 mechanisms. These are (1) controlling or major regulatory hormones and (2) influencing hormones. Controlling or major regulatory hormones include PTH, calcitonin, and vitamin D. Image 1 shows a review of vitamin D metabolism. In the kidney, vitamin D and PTH stimulate the activity of the epithelial calcium channel and the calcium-binding protein (ie, calbindin) to increase active transcellular calcium absorption in the distal convoluted tubule. Influencing hormones include thyroid hormones, growth hormone, and adrenal and gonadal steroids.
Role of the calcium-sensing receptor
The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, which allows the parathyroid chief cells, the thyroidal C cells, and the ascending limb of the loop of Henle (renal tubular epithelial cells) to respond to changes in the extracellular calcium concentration. The ability of the CaSR to sense the serum Ca++ is essential for the appropriate regulation of PTH secretion by the parathyroid glands and for the regulation of passive paracellular calcium absorption in the loop of Henle. Calcitonin secretion and renal tubular calcium reabsorption also are directly regulated by the action of Ca++ on the calcium receptor.
The CaSR gene is located on band 3q13-q21 and encodes a 1078 amino acid protein. CaSR is expressed in many tissues. Three uncommon human disorders are due to abnormalities of the CaSR gene, (1) familial benign hypocalciuric hypercalcemia, (2) neonatal severe hyperparathyroidism, and (3) autosomal dominant hypocalcemia with hypercalciuria.
Pathophysiology: Hypercalcemia affects nearly every organ system in the body, but it particularly affects the CNS and kidneys. Mild hypercalcemia may not produce any symptoms. With modest hypercalcemia, most patients begin to feel fatigued. With higher levels, patients may have anxiety, depression, personality changes, and confusion. With very high levels, somnolence, coma, and death may ensure. The CNS effects are thought to be due to the direct depressant effect of hypercalcemia.
Renal effects include nephrolithiasis from the hypercalciuria. Distal renal tubular acidosis may be observed, and the increase in urine pH and hypocitraturia also may contribute to stone disease. Nephrogenic diabetes insipidus occurs from medullary calcium deposition and inhibition of aquaporin-2, the arginine-vasopressin–regulated water channel. Renal function may decrease due to hypercalcemia-induced renal vasoconstriction or if hypercalcemia is prolonged from calcium deposition (nephrocalcinosis) and interstitial renal disease.
High calcium levels also affect the conducting system of the heart and cause cardiac arrhythmias. Calcium has a positive inotropic effect. Hypercalcemia also causes hypertension, presumably from renal dysfunction and direct vasoconstriction.
The GI manifestations of hypercalcemia include anorexia, nausea, vomiting, and constipation. Prolonged hypercalcemia tends to cause high gastrin levels, which may contribute to peptic ulcer disease and may lead to pancreatitis or the deposition of calcium in any soft tissue. This deposition of calcium is especially prevalent if phosphorous levels also are elevated, as in renal failure.
The severity of symptoms is related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred. Serum calcium levels greater than approximately 15 mg/dL usually are considered to be a medical emergency and must be treated aggressively.
Frequency:
In the US: Hypercalcemia is relatively common and often is mild but of long duration. The incidence of hyperparathyroidism alone is approximately 1-2 cases per 1000 adults. Mild cases are often not diagnosed.
Internationally: Screenings of large groups of patients have found prevalence rates as high as 39 cases per 1000 persons in Scandinavia. Similar screenings in South Africa showed a prevalence of 8 cases per 1000 persons. These higher incidences may reflect underdiagnosis in the United States rather than a true difference in prevalence.
Mortality/Morbidity: Morbidity and mortality from hypercalcemia depend entirely on the cause.
Hypercalcemia from hyperparathyroidism tends to be mild and prolonged. Morbidity is related to the resultant bone disease. Because this condition is underdiagnosed so often, actual morbidity is unknown. Mild hypercalcemia rarely, if ever, leads directly to death.
Hypercalcemia caused by a neoplasm tends to be much more serious. The mechanism of hypercalcemia in malignancy can be from the ectopic production of a PTH-like factor, PTH-related protein (PTHrP), or osteolytic metastases. Often, the hypercalcemia is the immediate cause of death in patients with ectopic PTHrP production. These patients rarely survive more than a few weeks or months. Osteolytic metastases tend to cause morbidity and mortality from nerve compression and other orthopedic complications. These patients may live longer but still have a poor prognosis, especially if their serum calcium levels are very high.
Morbidity and mortality associated with hypercalcemia from other causes are directly related to the underlying cause and tend to be less serious. In these patients, hypercalcemia is a reflection of their disease state and morbidity and mortality depend on control of the underlying disease.
Sex: Some studies show a higher incidence in men compared to women, but this difference tends to diminish with increasing age. One study found the highest incidence to be in women aged 60-63 years.
Age: Hypercalcemia from nearly all causes increases with advancing age, especially the 2 most common causes, malignancy and hyperparathyroidism. However, hypercalcemia may occur in persons of any age.
CLINICAL Section 3 of 11
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History: The mnemonic “stones,” “bones,” “abdominal moans,” and “psychic groans” describes the constellation of symptoms and signs of hypercalcemia. These may be due directly to the hypercalcemia, to increased calcium and phosphate excretion, or to skeleton changes. The history of hypercalcemia is dependent on its cause and the sensitivity of the individual to higher calcium levels. Individuals with mild prolonged hypercalcemia may have mild or no symptoms, or, they may have recurring problems such as kidney stones. Those with more sudden onset and severe hypercalcemia may experience dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death.
Central nervous system effects include the following:
Lethargy
Weakness
Confusion
Coma
Renal effects include the following:
Polyuria
Nocturia
Dehydration
Renal stones
Renal failure
Gastrointestinal effects include the following:
Constipation
Nausea
Anorexia
Pancreatitis
Gastric ulcer
Cardiac effects include syncope from arrhythmias.
Physical: Most patients with hypercalcemia do not have any specific findings upon physical examination. Those with higher calcium levels may have findings that are more striking. Evidence of the underlying cause may be found, such as a suggestive breast mass in someone with hypercalcemia secondary to malignancy.
Nervous system findings include the following:
Confusion
Hypotonia
Hyporeflexia
Paresis
Coma
Renal findings include the following:
Volume depletion
Signs of renal failure
Gastrointestinal findings include the following:
Fecal impaction (from constipation)
Signs of pancreatitis
Signs of malignancy (eg, enlarged liver or masses)
Cardiac findings include the following:
Arrhythmias
Hypotension
Shortened QT interval
General findings may include band keratopathy, which is calcium precipitation in a horizontal band across the cornea in the palpebral aperture.
Causes: Approximately 90% of cases of hypercalcemia are caused by malignancy or hyperparathyroidism. About 20-30% of patients with cancer have hypercalcemia during the course of the disease, and its detection may signify an unfavorable prognosis. Of the cases due to malignancy, approximately 80% are due to bony metastases, while the other 20% are due to PTHrP effects. Hypercalcemia secondary to malignancy may be classified into 4 types based on the mechanism involved, as follows:
Humoral hypercalcemia of malignancy (HHCM) from an increased secretion of PTHrP. This is the most common form, accounting for up to 80% of cases.
Osteolytic hypercalcemia from osteoclastic activity and bone resorption surrounding the tumor tissue. This is the second most common mechanism, accounting for about 20% of cases.
Secretion of active vitamin D by some lymphomas may be seen.
Ectopic PTH secretion is very rarely seen.
The remaining 10% of cases of hypercalcemia are caused by many different conditions, including vitamin D–related problems, disorders associated with rapid bone turnover, thiazides or renal failure, and, in rare cases, familial causes.
Those related to malignancy (lung, breast, and myeloma are the most common tumors) include the following:
Solid tumor metastases
Solid tumors with humoral effects
Hematologic malignancies
Those related to the parathyroid include the following:
Primary hyperparathyroidism
Solitary adenoma
Generalized hyperplasia
Multiple endocrine neoplasia type 1 or type 2A
Lithium-related release of PTH
Familial cases of high PTH
Those related to vitamin D include the following:
Vitamin D toxicity
Granulomatous disease (especially sarcoidosis)
Those related to high bone turnover include the following:
Hyperthyroidism
Immobilization (especially in Paget disease)
Thiazides
Vitamin A intoxication
Renal failure (milk-alkali syndrome)
Other causes related to particular mechanisms are as follows:
Increased intestinal calcium absorption
Idiopathic infantile hypercalcemia (Williams syndrome)
Vitamin D intoxication
Vitamin A intoxication
Granulomatous disorders, eg, sarcoidosis
Decreased renal calcium excretion
Hyperparathyroidism
Familial hypocalciuric hypercalcemia
Thiazide diuretics
Increased bone resorption
Immobilization
Hyperparathyroidism
Malignancy
Mutations of the calcium-sensing receptor
Familial benign hypocalciuric hypercalcemia
Neonatal severe hyperparathyroidism
Uncertain mechanism
Hypophosphatasia
Subcutaneous fat necrosis
Blue diaper syndrome
Dietary phosphate deficiency
DIFFERENTIALS Section 4 of 11
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Hyperkalemia
Hypermagnesemia
Hypernatremia
Hyperparathyroidism
Hyperphosphatemia
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WORKUP Section 5 of 11
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Lab Studies:
Malignancy is one of the most common causes and must be excluded. Hyperparathyroidism and other causes of hypercalcemia can coexist with malignancy. If calcium levels have been mildly elevated for months or years, malignancy is an unlikely cause. If calcium levels have been elevated for an unknown duration, the patient should be evaluated for the presence of malignancy. Breast, lung, and kidney cancers should be considered, as should multiple myeloma, lymphoma, and leukemia. Hypercalcemia from malignancy usually is rapidly progressive; thus, rapidly rising calcium levels should increase suspicion of malignancy.
Hyperparathyroidism is the most common cause of hypercalcemia in the population at large and usually is mild, asymptomatic, and sustained for years. Immunoreactive PTH and ionized calcium should be simultaneously measured. PTH levels should be suppressed in hypercalcemia; thus, the presence of normal PTH levels with elevated calcium levels suggests mild hyperparathyroidism. Hyperparathyroidism may be part of multiple endocrine neoplasia type 1, ie, Wermer syndrome.
Other causes of hypercalcemia usually can be distinguished or at least considered on the basis of history and physical examination findings. Measurement of serum phosphate, alkaline phosphatase, serum chloride, serum bicarbonate, and urinary calcium may be useful in some cases. Renal function should be evaluated and thyroid-stimulating hormone should be checked to help rule out hyperthyroidism. In rare cases, measurement of vitamin D and its metabolites and measurement of PTHrP may be necessary.
Imaging Studies:
Chest radiographs always should be performed to help rule out lung cancer or sarcoidosis. Other radiographs should be considered to help evaluate for possible malignancies, metastases, or Paget disease.
Mammograms should be considered to help rule out breast cancer, and CT scan and ultrasound should be considered to help rule out renal cancer.
When a biochemical diagnosis of primary hyperparathyroidism is made, CT scan, ultrasound, MRI, and radionuclide imaging of the parathyroid gland may be helpful to assist with preoperative localization.
Other Tests:
Miscellaneous
Peripheral smear
Serum and urine immunofixation electrophoresis
Procedures:
Tissue histology
Biopsy of solid tumor
Biopsy of bone marrow
TREATMENT Section 6 of 11
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Medical Care: Treatment depends on the severity of symptoms and the underlying cause.
Volume expansion and saline diuresis
Volume depletion results from uncontrolled symptoms leading to decreased intake and enhanced renal sodium loss. This tends to exacerbate or perpetuate the hypercalcemia by increasing Na+ reabsorption in the thick ascending limb of the loop of Henle (TALH). Thus, appropriate volume repletion with isotonic sodium chloride solution is an effective short-term treatment for hypercalcemia.
Once volume is restored, simultaneous administration of loop diuretics blocks Na+ and calcium reabsorption in the TALH.
Replacing ongoing sodium, potassium, chloride, and magnesium losses is important if prolonged sodium chloride and loop diuretic therapy is contemplated.
Mobilization
Immobilization aggravates hypercalcemia.
Whenever possible, weightbearing mobilization should be encouraged.
Reduction of gastrointestinal calcium absorption
Reduction of dietary calcium and vitamin D intake is effective for treating hypercalcemia due to increased intestinal calcium absorption (eg, in idiopathic infantile hypercalcemia, ie, Williams syndrome).
In vitamin D toxicity or extrarenal synthesis of 1,25(OH) D3 (eg, in sarcoidosis), prednisone may help reduce plasma calcium levels by reducing intestinal calcium absorption.
Oral phosphate also can be used to form insoluble calcium phosphate in the gut.
Inhibition of bone resorption
Bisphosphonates inhibit osteoclastic bone resorption and are effective in the treatment of hypercalcemia due to conditions causing increased bone resorption and malignancy-related hypercalcemia.
Pamidronate and etidronate can be given intravenously, while risedronate and alendronate may be effective as oral therapy.
Calcitonin can be given intramuscularly or subcutaneously, but it becomes less effective after several days of use.
Mithramycin blocks osteoclastic function and can be given for severe malignancy-related hypercalcemia. It has significant hepatic, renal, and marrow toxicity.
Dialysis: Peritoneal or hemodialysis against calcium-free or lower calcium concentration dialysate solution is highly effective in lowering plasma calcium levels.
Surgical Care: Surgical care is directed toward reversing the underlying cause of hypercalcemia or repairing the orthopedic damage.
Prolonged hypercalcemia due to hyperparathyroidism may warrant surgical neck exploration and removal of one or more parathyroid glands. This is particularly appropriate if evidence of nephrolithiasis, osteoporosis, reduction of renal function, neuromuscular symptoms, or radiographic bone disease is present.
Hypercalcemia due to malignancy, especially if due to a tumor that is producing PTHrP, may require surgical resection of the tumor.
Orthopedic complications of prolonged hypercalcemia (eg, osteoporosis), complications of Paget disease, or complications of bony metastases may require orthopedic or neurosurgical intervention.
Consultations: Consultation with a surgeon or orthopedist may be required, as indicated.
MEDICATION Section 7 of 11
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The first therapy for symptomatic hypercalcemia is volume repletion. More severe cases require saline infusion with concomitant loop diuretics (eg, furosemide) to increase calcium excretion and lower levels rapidly. Other therapies, outlined below, are for longer-term management. Note, however, that no current therapies generally are effective for long-term outpatient therapy. Definitive treatment often requires surgical management.
Clodronate (not available in the United States) can be given either IV or PO and may represent a better alternative in the future at a dose 1600-2400 mg/d. Ibandronate (not available in the United States) is approximately 50 times more potent than pamidronate and may be given as a single bolus rather than an infusion. Zoledronic acid is 100-850 times more potent than pamidronate and may be given as a bolus rather than an infusion.
Drug Category: Bisphosphonates -- Inhibit bone reabsorption.Drug Name
Pamidronate (Aredia) -- Used after initial hydration to inhibit bone reabsorption and maintain low serum calcium levels, especially in hypercalcemia of malignancy and Paget disease.
Adult Dose Severe hypercalcemia: 90 mg IV over 24 h
Moderate hypercalcemia: 60 mg IV over 4 h or 90 mg IV over 24 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium) once treatment begins; adequate intake of calcium and vitamin D are necessary to prevent severe hypocalcemia; caution when administering bisphosphonates in patients with active upper GI problems; do not coadminister with alendronate for osteoporosis in postmenopausal women
Drug Name
Etidronate (Didronel) -- Reduces bone formation and does not alter renal tubular reabsorption of calcium. Does not affect hypercalcemia in patients with hyperparathyroidism.
Adult Dose 7.5 mg/kg/d IV for 3 consecutive d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia, renal impairment
Interactions Coadministration with calcium-containing products and other multivalent cations decrease absorption
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; do not administer with alendronate for osteoporosis in postmenopausal women
Drug Name
Alendronate (Fosamax) -- Available in the United States, but not yet indicated for treatment of hypercalcemia; alendronate probably is useful for long-term prevention of recurrence of hypercalcemia following use of more conventional therapy (ie, hydration and pamidronate). Useful in preventing and treating osteoporosis, which is a complication of prolonged mild hypercalcemia.
Adult Dose Not established; usual starting dose is 40 mg PO qam
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia; abnormalities of the esophagus; inability to stand upright for 30 min
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Must be taken at least 30 min before first food, beverage, or medication of the day and should be taken with large amounts of water; caution in renal impairment
Drug Category: Antineoplastic drugs -- Some agents in this drug class can reduce bone turnover.Drug Name
Gallium nitrate (Ganite) -- Available in the United States. Use should be limited to those with extensive experience in this field (ie, oncologists).
Adult Dose 200 mg/m2 IV infused over 24 h and repeated qd for 5 d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; renal failure
Interactions Nephrotoxic effects increase when administered with amphotericin B or aminoglycosides
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in renal failure
Drug Name
Plicamycin (Mithracin) -- No longer manufactured and distributed in the United States. Inhibits bone resorption. Used only in cases of hypercalcemia due to malignancy; treatment can be repeated if necessary.
Adult Dose 25 mcg/kg IV over 4-6 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; thrombocytopenia, coagulation disorders, impairment of bone marrow function
Interactions Coadministration with glucagon, calcitonin, and etidronate may increase toxicity
Pregnancy X - Contraindicated in pregnancy
Precautions Monitor platelets, prothrombin, and bleeding times periodically during therapy and for several days after last dose; discontinue therapy if significant prolongation of bleeding times occurs and thrombocytopenia is observed; correct any electrolyte imbalance (especially hypokalemia, hypocalcemia, and hypophosphatemia) prior to treatment
Drug Category: Antidote, hypercalcemia agents -- Inhibit bone resorption and increase renal calcium excretion.Drug Name
Calcitonin (Miacalcin, Osteocalcin) -- Lowers elevated serum calcium in patients with multiple myeloma, carcinoma, or primary hyperparathyroidism. Expect higher response when serum calcium levels are high.
Onset of action is approximately 2 h following injection, and activity lasts for 6-8 h. May lower calcium levels for 5-8 d by approximately 9% if given q12h. IM route is preferred at multiple injection sites with dose >2 mL.
Adult Dose 4-8 IU/kg IM/SC q6-12h
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Hypocalcemia may occur; examine urine sediment during prolonged therapy
Drug Category: Glucocorticoids -- Inhibit cytokine release and have a direct cytolytic effect on some tumor cells.Drug Name
Prednisone (Deltasone, Orasone, Sterapred) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Adult Dose 20-50 mg PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Interactions Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use
Drug Category: Minerals -- Phosphate inhibits calcium absorption and promotes calcium deposition. Theorized to help bind dietary calcium, thus rendering it an unabsorbable calcium-phosphorous product, but used rarely.Drug Name
Potassium phosphate (Neutra-Phos-K) -- Increases urinary pyrophosphate and complexes with calcium, thus decreasing urinary calcium level, while pyridoxine results in a reduction of urinary oxalate excretion. All dosage forms must be mixed in 6-8 oz of water. Never give IV. Never give if renal function is abnormal or if serum phosphorous levels are >3 mg/dL.
Adult Dose 250-500 mg phosphorus/8-16 mmol PO tid
Pediatric Dose Not established
Contraindications Abnormal renal function, renal failure, serum phosphorous >4.5 mg/dL; IV administration
Interactions Magnesium-containing and aluminum-containing antacids or sucralfate can act as phosphate binders and decrease serum phosphate levels; potassium-sparing diuretics, ACE inhibitors, and salt substitutes may increase serum phosphate levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in patients with renal insufficiency and metabolic alkalosis; admixture of phosphate and calcium in IV fluids can result in calcium phosphate precipitation
Drug Category: Calcimimetic agent -- Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.Drug Name
Cinacalcet (Sensipar) -- Directly lowers parathyroid hormone (PTH) levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and in hypercalcemia with parathyroid carcinoma.
Adult Dose Secondary hyperparathyroidism: 30 mg PO qd initially; titrate upward slowly (no more frequent than q2-4wk intervals) by 30-mg increments to target iPTH of 150-300 pg/mL
Take with meals or immediately following; do not crush, chew, or cut tablets
Hypercalcemia with parathyroid carcinoma: 30 mg PO qd initially; titrate q2-4wk as needed to normalize calcium levels by sequential doses of 30 mg bid, 60 mg bid, 90 mg bid, and 90 mg tid/qid
Take with meals or immediately following; do not crush, chew, or cut tablets
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Strong CYP450 2D6 inhibitor; may increase serum levels of CYP 2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP450 3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole) may decrease clearance
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2 mo (parathyroid carcinoma); do not initiate treatment if serum calcium level below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting
FOLLOW-UP Section 8 of 11
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Further Outpatient Care:
In most cases, follow-up care is dictated by the etiology of hypercalcemia.
If the hypercalcemia is related to malignancy, the cause may be obvious in most cases and efforts are directed towards treating the neoplasm.
The role of oral phosphates in the treatment of hypercalcemia is limited and now is increasingly replaced by bisphosphonates. However, when phosphates are used, especially for treating chronic hypercalcemia, attention should be paid to hyperphosphatemia and the calcium and phosphate product because this tends to increase the risk of metastatic calcification.
Dietary restriction of calcium and glucocorticoid administration remains the preferred treatment for hypercalcemia due to sarcoidosis and vitamin D intoxication.
Calcium hemostasis
Ninety-eight percent of body calcium is found in the skeleton; this is closely related to the extracellular concentration of calcium. Intracellular calcium is less than extracellular calcium by a factor of 100,000. Intracellular processes, including the activity of many enzymes, cell division, and exocytosis, are controlled by intracellular calcium. The primary mediator of the intracellular effects of calcium is the calcium-binding regulatory protein, calmodulin.
Plasma calcium is maintained despite its large movements across the gut, bone, kidney, and cells. Changes in calcium ions usually are accompanied by changes in total calcium in the ECF. In plasma, calcium exists in 3 different forms, (1) 50% as ionized or the biologically active form, (2) 45% bound to plasma proteins (mainly albumin), and (3) 5% complexed to phosphate and citrate. Because the proportion of bound calcium varies little within individuals, in the absence of severe acidosis or alkalosis, the amount of albumin is the major factor determining the amount of calcium that is bound.
Very little evidence suggests that intracellular stores of calcium contribute in any way towards plasma calcium homeostasis. An exception is in the parathyroid gland, in which the intracellular concentration increases in response to changes in extracellular concentration, which, in turn, alters the rate of parathyroid hormone (PTH) secretion. Any decrease in extracellular calcium ion concentration leads to an increase in PTH secretion. PTH increases distal renal tubular reabsorption of calcium within minutes and stimulates osteoclast activity, with release of calcium from the skeleton within 1-2 hours. More prolonged PTH elevation stimulates 1alpha-hydroxylase activity in the proximal tubular cells, which leads to 1,25-dihydroxyvitamin D (1,25(OH)2 D3) production. All these mechanisms help to maintain the serum calcium level within normal limits.
A normal serum calcium level is 8-10 mg/dL (2-2.5 mmol/L) with some interlaboratory variation in the reference range, and hypercalcemia is defined as a serum calcium level greater than 10.5 mg/dL (>2.5 mmol/L). Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:
Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or Ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L)
Moderate: Total Ca 12-13.9 mg/dL (3-3.5 mmol/L) or Ionized Ca 5.6-8 mg/dL (2-2.5 mmol/L)
Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or Ionized Ca 10-12 mg/dL (2.5-3 mmol/L)
Only 1-2% of total body calcium is in the exchangeable form in circulation, and the rest forms part of the skeleton. Only one half of the exchangeable calcium is in the active ionized form with the remainder bound to albumin, globulin, and other inorganic molecules. Protein binding of calcium is influenced by pH with metabolic acidosis leading to increased ionized calcium from reduced protein binding, and alkalosis leading to reduced ionized calcium from increased protein binding. Because calcium binds to albumin and only the unbound (free or ionized) calcium is biologically active, the serum level must be adjusted for abnormal albumin levels.
For every 1-g/dL drop in serum albumin below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL. Therefore, to correct for an albumin level of less than 4 g/dL, one should add 0.8 to the measured value of calcium for each 1-g/dL decrease in albumin. Without this correction, an abnormally high serum calcium level may appear to be normal.
A patient with a serum calcium level of 10.3 mg/dL but an albumin level of 3 g/dL appears to have a normal serum calcium level. However, when corrected for the low albumin, the real serum calcium value is 11.1 mg/dL (10.3 + 0.8), a more obviously abnormal level. Alternatively, serum free (ionized) calcium levels can be directly measured, negating the need for correction for albumin. Corrected calcium can be calculated using the following formula:
Corrected Ca = ([4 - plasma albumin in g/dL] X 0.8 + serum calcium)
Mild cases of hypercalcemia can be asymptomatic and are more often diagnosed incidentally from routine blood tests. Because calcium metabolism normally is tightly controlled by the body, even mild persistent elevations above normal signal disease and should be investigated.
Calcium is controlled by 2 mechanisms. These are (1) controlling or major regulatory hormones and (2) influencing hormones. Controlling or major regulatory hormones include PTH, calcitonin, and vitamin D. Image 1 shows a review of vitamin D metabolism. In the kidney, vitamin D and PTH stimulate the activity of the epithelial calcium channel and the calcium-binding protein (ie, calbindin) to increase active transcellular calcium absorption in the distal convoluted tubule. Influencing hormones include thyroid hormones, growth hormone, and adrenal and gonadal steroids.
Role of the calcium-sensing receptor
The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, which allows the parathyroid chief cells, the thyroidal C cells, and the ascending limb of the loop of Henle (renal tubular epithelial cells) to respond to changes in the extracellular calcium concentration. The ability of the CaSR to sense the serum Ca++ is essential for the appropriate regulation of PTH secretion by the parathyroid glands and for the regulation of passive paracellular calcium absorption in the loop of Henle. Calcitonin secretion and renal tubular calcium reabsorption also are directly regulated by the action of Ca++ on the calcium receptor.
The CaSR gene is located on band 3q13-q21 and encodes a 1078 amino acid protein. CaSR is expressed in many tissues. Three uncommon human disorders are due to abnormalities of the CaSR gene, (1) familial benign hypocalciuric hypercalcemia, (2) neonatal severe hyperparathyroidism, and (3) autosomal dominant hypocalcemia with hypercalciuria.
Pathophysiology: Hypercalcemia affects nearly every organ system in the body, but it particularly affects the CNS and kidneys. Mild hypercalcemia may not produce any symptoms. With modest hypercalcemia, most patients begin to feel fatigued. With higher levels, patients may have anxiety, depression, personality changes, and confusion. With very high levels, somnolence, coma, and death may ensure. The CNS effects are thought to be due to the direct depressant effect of hypercalcemia.
Renal effects include nephrolithiasis from the hypercalciuria. Distal renal tubular acidosis may be observed, and the increase in urine pH and hypocitraturia also may contribute to stone disease. Nephrogenic diabetes insipidus occurs from medullary calcium deposition and inhibition of aquaporin-2, the arginine-vasopressin–regulated water channel. Renal function may decrease due to hypercalcemia-induced renal vasoconstriction or if hypercalcemia is prolonged from calcium deposition (nephrocalcinosis) and interstitial renal disease.
High calcium levels also affect the conducting system of the heart and cause cardiac arrhythmias. Calcium has a positive inotropic effect. Hypercalcemia also causes hypertension, presumably from renal dysfunction and direct vasoconstriction.
The GI manifestations of hypercalcemia include anorexia, nausea, vomiting, and constipation. Prolonged hypercalcemia tends to cause high gastrin levels, which may contribute to peptic ulcer disease and may lead to pancreatitis or the deposition of calcium in any soft tissue. This deposition of calcium is especially prevalent if phosphorous levels also are elevated, as in renal failure.
The severity of symptoms is related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred. Serum calcium levels greater than approximately 15 mg/dL usually are considered to be a medical emergency and must be treated aggressively.
Frequency:
In the US: Hypercalcemia is relatively common and often is mild but of long duration. The incidence of hyperparathyroidism alone is approximately 1-2 cases per 1000 adults. Mild cases are often not diagnosed.
Internationally: Screenings of large groups of patients have found prevalence rates as high as 39 cases per 1000 persons in Scandinavia. Similar screenings in South Africa showed a prevalence of 8 cases per 1000 persons. These higher incidences may reflect underdiagnosis in the United States rather than a true difference in prevalence.
Mortality/Morbidity: Morbidity and mortality from hypercalcemia depend entirely on the cause.
Hypercalcemia from hyperparathyroidism tends to be mild and prolonged. Morbidity is related to the resultant bone disease. Because this condition is underdiagnosed so often, actual morbidity is unknown. Mild hypercalcemia rarely, if ever, leads directly to death.
Hypercalcemia caused by a neoplasm tends to be much more serious. The mechanism of hypercalcemia in malignancy can be from the ectopic production of a PTH-like factor, PTH-related protein (PTHrP), or osteolytic metastases. Often, the hypercalcemia is the immediate cause of death in patients with ectopic PTHrP production. These patients rarely survive more than a few weeks or months. Osteolytic metastases tend to cause morbidity and mortality from nerve compression and other orthopedic complications. These patients may live longer but still have a poor prognosis, especially if their serum calcium levels are very high.
Morbidity and mortality associated with hypercalcemia from other causes are directly related to the underlying cause and tend to be less serious. In these patients, hypercalcemia is a reflection of their disease state and morbidity and mortality depend on control of the underlying disease.
Sex: Some studies show a higher incidence in men compared to women, but this difference tends to diminish with increasing age. One study found the highest incidence to be in women aged 60-63 years.
Age: Hypercalcemia from nearly all causes increases with advancing age, especially the 2 most common causes, malignancy and hyperparathyroidism. However, hypercalcemia may occur in persons of any age.
CLINICAL Section 3 of 11
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History: The mnemonic “stones,” “bones,” “abdominal moans,” and “psychic groans” describes the constellation of symptoms and signs of hypercalcemia. These may be due directly to the hypercalcemia, to increased calcium and phosphate excretion, or to skeleton changes. The history of hypercalcemia is dependent on its cause and the sensitivity of the individual to higher calcium levels. Individuals with mild prolonged hypercalcemia may have mild or no symptoms, or, they may have recurring problems such as kidney stones. Those with more sudden onset and severe hypercalcemia may experience dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death.
Central nervous system effects include the following:
Lethargy
Weakness
Confusion
Coma
Renal effects include the following:
Polyuria
Nocturia
Dehydration
Renal stones
Renal failure
Gastrointestinal effects include the following:
Constipation
Nausea
Anorexia
Pancreatitis
Gastric ulcer
Cardiac effects include syncope from arrhythmias.
Physical: Most patients with hypercalcemia do not have any specific findings upon physical examination. Those with higher calcium levels may have findings that are more striking. Evidence of the underlying cause may be found, such as a suggestive breast mass in someone with hypercalcemia secondary to malignancy.
Nervous system findings include the following:
Confusion
Hypotonia
Hyporeflexia
Paresis
Coma
Renal findings include the following:
Volume depletion
Signs of renal failure
Gastrointestinal findings include the following:
Fecal impaction (from constipation)
Signs of pancreatitis
Signs of malignancy (eg, enlarged liver or masses)
Cardiac findings include the following:
Arrhythmias
Hypotension
Shortened QT interval
General findings may include band keratopathy, which is calcium precipitation in a horizontal band across the cornea in the palpebral aperture.
Causes: Approximately 90% of cases of hypercalcemia are caused by malignancy or hyperparathyroidism. About 20-30% of patients with cancer have hypercalcemia during the course of the disease, and its detection may signify an unfavorable prognosis. Of the cases due to malignancy, approximately 80% are due to bony metastases, while the other 20% are due to PTHrP effects. Hypercalcemia secondary to malignancy may be classified into 4 types based on the mechanism involved, as follows:
Humoral hypercalcemia of malignancy (HHCM) from an increased secretion of PTHrP. This is the most common form, accounting for up to 80% of cases.
Osteolytic hypercalcemia from osteoclastic activity and bone resorption surrounding the tumor tissue. This is the second most common mechanism, accounting for about 20% of cases.
Secretion of active vitamin D by some lymphomas may be seen.
Ectopic PTH secretion is very rarely seen.
The remaining 10% of cases of hypercalcemia are caused by many different conditions, including vitamin D–related problems, disorders associated with rapid bone turnover, thiazides or renal failure, and, in rare cases, familial causes.
Those related to malignancy (lung, breast, and myeloma are the most common tumors) include the following:
Solid tumor metastases
Solid tumors with humoral effects
Hematologic malignancies
Those related to the parathyroid include the following:
Primary hyperparathyroidism
Solitary adenoma
Generalized hyperplasia
Multiple endocrine neoplasia type 1 or type 2A
Lithium-related release of PTH
Familial cases of high PTH
Those related to vitamin D include the following:
Vitamin D toxicity
Granulomatous disease (especially sarcoidosis)
Those related to high bone turnover include the following:
Hyperthyroidism
Immobilization (especially in Paget disease)
Thiazides
Vitamin A intoxication
Renal failure (milk-alkali syndrome)
Other causes related to particular mechanisms are as follows:
Increased intestinal calcium absorption
Idiopathic infantile hypercalcemia (Williams syndrome)
Vitamin D intoxication
Vitamin A intoxication
Granulomatous disorders, eg, sarcoidosis
Decreased renal calcium excretion
Hyperparathyroidism
Familial hypocalciuric hypercalcemia
Thiazide diuretics
Increased bone resorption
Immobilization
Hyperparathyroidism
Malignancy
Mutations of the calcium-sensing receptor
Familial benign hypocalciuric hypercalcemia
Neonatal severe hyperparathyroidism
Uncertain mechanism
Hypophosphatasia
Subcutaneous fat necrosis
Blue diaper syndrome
Dietary phosphate deficiency
DIFFERENTIALS Section 4 of 11
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Hyperkalemia
Hypermagnesemia
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Hyperparathyroidism
Hyperphosphatemia
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WORKUP Section 5 of 11
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Lab Studies:
Malignancy is one of the most common causes and must be excluded. Hyperparathyroidism and other causes of hypercalcemia can coexist with malignancy. If calcium levels have been mildly elevated for months or years, malignancy is an unlikely cause. If calcium levels have been elevated for an unknown duration, the patient should be evaluated for the presence of malignancy. Breast, lung, and kidney cancers should be considered, as should multiple myeloma, lymphoma, and leukemia. Hypercalcemia from malignancy usually is rapidly progressive; thus, rapidly rising calcium levels should increase suspicion of malignancy.
Hyperparathyroidism is the most common cause of hypercalcemia in the population at large and usually is mild, asymptomatic, and sustained for years. Immunoreactive PTH and ionized calcium should be simultaneously measured. PTH levels should be suppressed in hypercalcemia; thus, the presence of normal PTH levels with elevated calcium levels suggests mild hyperparathyroidism. Hyperparathyroidism may be part of multiple endocrine neoplasia type 1, ie, Wermer syndrome.
Other causes of hypercalcemia usually can be distinguished or at least considered on the basis of history and physical examination findings. Measurement of serum phosphate, alkaline phosphatase, serum chloride, serum bicarbonate, and urinary calcium may be useful in some cases. Renal function should be evaluated and thyroid-stimulating hormone should be checked to help rule out hyperthyroidism. In rare cases, measurement of vitamin D and its metabolites and measurement of PTHrP may be necessary.
Imaging Studies:
Chest radiographs always should be performed to help rule out lung cancer or sarcoidosis. Other radiographs should be considered to help evaluate for possible malignancies, metastases, or Paget disease.
Mammograms should be considered to help rule out breast cancer, and CT scan and ultrasound should be considered to help rule out renal cancer.
When a biochemical diagnosis of primary hyperparathyroidism is made, CT scan, ultrasound, MRI, and radionuclide imaging of the parathyroid gland may be helpful to assist with preoperative localization.
Other Tests:
Miscellaneous
Peripheral smear
Serum and urine immunofixation electrophoresis
Procedures:
Tissue histology
Biopsy of solid tumor
Biopsy of bone marrow
TREATMENT Section 6 of 11
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Medical Care: Treatment depends on the severity of symptoms and the underlying cause.
Volume expansion and saline diuresis
Volume depletion results from uncontrolled symptoms leading to decreased intake and enhanced renal sodium loss. This tends to exacerbate or perpetuate the hypercalcemia by increasing Na+ reabsorption in the thick ascending limb of the loop of Henle (TALH). Thus, appropriate volume repletion with isotonic sodium chloride solution is an effective short-term treatment for hypercalcemia.
Once volume is restored, simultaneous administration of loop diuretics blocks Na+ and calcium reabsorption in the TALH.
Replacing ongoing sodium, potassium, chloride, and magnesium losses is important if prolonged sodium chloride and loop diuretic therapy is contemplated.
Mobilization
Immobilization aggravates hypercalcemia.
Whenever possible, weightbearing mobilization should be encouraged.
Reduction of gastrointestinal calcium absorption
Reduction of dietary calcium and vitamin D intake is effective for treating hypercalcemia due to increased intestinal calcium absorption (eg, in idiopathic infantile hypercalcemia, ie, Williams syndrome).
In vitamin D toxicity or extrarenal synthesis of 1,25(OH) D3 (eg, in sarcoidosis), prednisone may help reduce plasma calcium levels by reducing intestinal calcium absorption.
Oral phosphate also can be used to form insoluble calcium phosphate in the gut.
Inhibition of bone resorption
Bisphosphonates inhibit osteoclastic bone resorption and are effective in the treatment of hypercalcemia due to conditions causing increased bone resorption and malignancy-related hypercalcemia.
Pamidronate and etidronate can be given intravenously, while risedronate and alendronate may be effective as oral therapy.
Calcitonin can be given intramuscularly or subcutaneously, but it becomes less effective after several days of use.
Mithramycin blocks osteoclastic function and can be given for severe malignancy-related hypercalcemia. It has significant hepatic, renal, and marrow toxicity.
Dialysis: Peritoneal or hemodialysis against calcium-free or lower calcium concentration dialysate solution is highly effective in lowering plasma calcium levels.
Surgical Care: Surgical care is directed toward reversing the underlying cause of hypercalcemia or repairing the orthopedic damage.
Prolonged hypercalcemia due to hyperparathyroidism may warrant surgical neck exploration and removal of one or more parathyroid glands. This is particularly appropriate if evidence of nephrolithiasis, osteoporosis, reduction of renal function, neuromuscular symptoms, or radiographic bone disease is present.
Hypercalcemia due to malignancy, especially if due to a tumor that is producing PTHrP, may require surgical resection of the tumor.
Orthopedic complications of prolonged hypercalcemia (eg, osteoporosis), complications of Paget disease, or complications of bony metastases may require orthopedic or neurosurgical intervention.
Consultations: Consultation with a surgeon or orthopedist may be required, as indicated.
MEDICATION Section 7 of 11
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The first therapy for symptomatic hypercalcemia is volume repletion. More severe cases require saline infusion with concomitant loop diuretics (eg, furosemide) to increase calcium excretion and lower levels rapidly. Other therapies, outlined below, are for longer-term management. Note, however, that no current therapies generally are effective for long-term outpatient therapy. Definitive treatment often requires surgical management.
Clodronate (not available in the United States) can be given either IV or PO and may represent a better alternative in the future at a dose 1600-2400 mg/d. Ibandronate (not available in the United States) is approximately 50 times more potent than pamidronate and may be given as a single bolus rather than an infusion. Zoledronic acid is 100-850 times more potent than pamidronate and may be given as a bolus rather than an infusion.
Drug Category: Bisphosphonates -- Inhibit bone reabsorption.Drug Name
Pamidronate (Aredia) -- Used after initial hydration to inhibit bone reabsorption and maintain low serum calcium levels, especially in hypercalcemia of malignancy and Paget disease.
Adult Dose Severe hypercalcemia: 90 mg IV over 24 h
Moderate hypercalcemia: 60 mg IV over 4 h or 90 mg IV over 24 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium) once treatment begins; adequate intake of calcium and vitamin D are necessary to prevent severe hypocalcemia; caution when administering bisphosphonates in patients with active upper GI problems; do not coadminister with alendronate for osteoporosis in postmenopausal women
Drug Name
Etidronate (Didronel) -- Reduces bone formation and does not alter renal tubular reabsorption of calcium. Does not affect hypercalcemia in patients with hyperparathyroidism.
Adult Dose 7.5 mg/kg/d IV for 3 consecutive d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia, renal impairment
Interactions Coadministration with calcium-containing products and other multivalent cations decrease absorption
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; do not administer with alendronate for osteoporosis in postmenopausal women
Drug Name
Alendronate (Fosamax) -- Available in the United States, but not yet indicated for treatment of hypercalcemia; alendronate probably is useful for long-term prevention of recurrence of hypercalcemia following use of more conventional therapy (ie, hydration and pamidronate). Useful in preventing and treating osteoporosis, which is a complication of prolonged mild hypercalcemia.
Adult Dose Not established; usual starting dose is 40 mg PO qam
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia; abnormalities of the esophagus; inability to stand upright for 30 min
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Must be taken at least 30 min before first food, beverage, or medication of the day and should be taken with large amounts of water; caution in renal impairment
Drug Category: Antineoplastic drugs -- Some agents in this drug class can reduce bone turnover.Drug Name
Gallium nitrate (Ganite) -- Available in the United States. Use should be limited to those with extensive experience in this field (ie, oncologists).
Adult Dose 200 mg/m2 IV infused over 24 h and repeated qd for 5 d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; renal failure
Interactions Nephrotoxic effects increase when administered with amphotericin B or aminoglycosides
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in renal failure
Drug Name
Plicamycin (Mithracin) -- No longer manufactured and distributed in the United States. Inhibits bone resorption. Used only in cases of hypercalcemia due to malignancy; treatment can be repeated if necessary.
Adult Dose 25 mcg/kg IV over 4-6 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; thrombocytopenia, coagulation disorders, impairment of bone marrow function
Interactions Coadministration with glucagon, calcitonin, and etidronate may increase toxicity
Pregnancy X - Contraindicated in pregnancy
Precautions Monitor platelets, prothrombin, and bleeding times periodically during therapy and for several days after last dose; discontinue therapy if significant prolongation of bleeding times occurs and thrombocytopenia is observed; correct any electrolyte imbalance (especially hypokalemia, hypocalcemia, and hypophosphatemia) prior to treatment
Drug Category: Antidote, hypercalcemia agents -- Inhibit bone resorption and increase renal calcium excretion.Drug Name
Calcitonin (Miacalcin, Osteocalcin) -- Lowers elevated serum calcium in patients with multiple myeloma, carcinoma, or primary hyperparathyroidism. Expect higher response when serum calcium levels are high.
Onset of action is approximately 2 h following injection, and activity lasts for 6-8 h. May lower calcium levels for 5-8 d by approximately 9% if given q12h. IM route is preferred at multiple injection sites with dose >2 mL.
Adult Dose 4-8 IU/kg IM/SC q6-12h
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Hypocalcemia may occur; examine urine sediment during prolonged therapy
Drug Category: Glucocorticoids -- Inhibit cytokine release and have a direct cytolytic effect on some tumor cells.Drug Name
Prednisone (Deltasone, Orasone, Sterapred) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Adult Dose 20-50 mg PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Interactions Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use
Drug Category: Minerals -- Phosphate inhibits calcium absorption and promotes calcium deposition. Theorized to help bind dietary calcium, thus rendering it an unabsorbable calcium-phosphorous product, but used rarely.Drug Name
Potassium phosphate (Neutra-Phos-K) -- Increases urinary pyrophosphate and complexes with calcium, thus decreasing urinary calcium level, while pyridoxine results in a reduction of urinary oxalate excretion. All dosage forms must be mixed in 6-8 oz of water. Never give IV. Never give if renal function is abnormal or if serum phosphorous levels are >3 mg/dL.
Adult Dose 250-500 mg phosphorus/8-16 mmol PO tid
Pediatric Dose Not established
Contraindications Abnormal renal function, renal failure, serum phosphorous >4.5 mg/dL; IV administration
Interactions Magnesium-containing and aluminum-containing antacids or sucralfate can act as phosphate binders and decrease serum phosphate levels; potassium-sparing diuretics, ACE inhibitors, and salt substitutes may increase serum phosphate levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in patients with renal insufficiency and metabolic alkalosis; admixture of phosphate and calcium in IV fluids can result in calcium phosphate precipitation
Drug Category: Calcimimetic agent -- Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.Drug Name
Cinacalcet (Sensipar) -- Directly lowers parathyroid hormone (PTH) levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and in hypercalcemia with parathyroid carcinoma.
Adult Dose Secondary hyperparathyroidism: 30 mg PO qd initially; titrate upward slowly (no more frequent than q2-4wk intervals) by 30-mg increments to target iPTH of 150-300 pg/mL
Take with meals or immediately following; do not crush, chew, or cut tablets
Hypercalcemia with parathyroid carcinoma: 30 mg PO qd initially; titrate q2-4wk as needed to normalize calcium levels by sequential doses of 30 mg bid, 60 mg bid, 90 mg bid, and 90 mg tid/qid
Take with meals or immediately following; do not crush, chew, or cut tablets
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Strong CYP450 2D6 inhibitor; may increase serum levels of CYP 2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP450 3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole) may decrease clearance
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2 mo (parathyroid carcinoma); do not initiate treatment if serum calcium level below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting
FOLLOW-UP Section 8 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Further Outpatient Care:
In most cases, follow-up care is dictated by the etiology of hypercalcemia.
If the hypercalcemia is related to malignancy, the cause may be obvious in most cases and efforts are directed towards treating the neoplasm.
The role of oral phosphates in the treatment of hypercalcemia is limited and now is increasingly replaced by bisphosphonates. However, when phosphates are used, especially for treating chronic hypercalcemia, attention should be paid to hyperphosphatemia and the calcium and phosphate product because this tends to increase the risk of metastatic calcification.
Dietary restriction of calcium and glucocorticoid administration remains the preferred treatment for hypercalcemia due to sarcoidosis and vitamin D intoxication.
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