Hypokalemia and Hyperkalemia in Infants and Children: Pathophysiology and Treatment

DEPARTMENT

Pharmacology Continuing Education

Hypokalemia and Hyperkalemia in Infants and Children: Pathophysiology and Treatment Kayleen Daly, PharmD, & Elizabeth Farrington, PharmD, FCCP, FCCM, FPPAG, BCPS

ABSTRACT Section Editors Teri Moser Woo, PhD, RN, ARNP, CNL, CPNP, FAANP Corresponding Editor Pacific Lutheran University Tacoma, Washington Elizabeth Farrington, PharmD, FCCP, FCCM, FPPAG, BCPS University of North Carolina, Eshelman School of Pharmacy Chapel Hill, North Carolina New Hanover Regional Medical Center Wilmington, North Carolina Brady S. Moffett, PharmD, MPH Clinical Pharmacy Specialist-Pediatric Cardiology Texas Children’s Hospital, Department of Pharmacy Houston, Texas Kayleen Daly, Pharmacist II, New Hanover Regional Medical Center, Wilmington, NC. Elizabeth Farrington, Pharmacist III, Pediatrics, New Hanover Regional Medical Center, Wilmington, NC. Conflicts of interest: None to report. Correspondence: Kayleen Daly, PharmD, New Hanover Regional Medical Center, 2131 S 17th St, Wilmington, NC 28401; e-mail: [email protected]. 0891-5245/$36.00 Copyright Q 2013 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pedhc.2013.08.003

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Potassium is the second most abundant cation in the body. About 98% of potassium is intracellular and that is particularly in the skeletal muscle. Electrical disturbances associated with disorders of potassium homeostasis are a function of both the extracellular and intracellular potassium concentrations. Clinical disorders of potassium homeostasis occur with some regularity, especially in hospitalized patients receiving many medications. This article will review the pathophysiology of potassium homeostasis, symptoms, causes, and treatment of hypo- and hyperkalemia. J Pediatr Health Care. (2013) 27, 486-496.

KEY WORDS Hypokalemia, hyperkalemia, treatment

OBJECTIVES 1. Describe the pathophysiology of potassium homeostasis. 2. Explain the role of potassium in the human body. 3. List the symptoms of hypokalemia and hyperkalemia. 4. Recommend the treatment for hyperkalemia and explain why one treatment regimen might be preferred over another. 5. Recommend the treatment for hypokalemia and explain when one would use intravenous versus oral replacement.

Healthy persons are in potassium balance, which means that the daily intake of potassium is equal to the amount excreted. In children, normal daily potassium requirements vary by age. However, they are estimated at approximately 2 mEq per 100 kcal of energy Journal of Pediatric Health Care

BOX 1. Foods high in potassium Fruits Bananas, oranges (citrus), cantaloupe, watermelon, apricots, raisins, prunes, pineapples, cherries, and tomatoes Vegetables Green and leafy, potatoes, avocados, artichokes, lentils, beets, white mushrooms, and onions Meats/Fish All contain potassium (the lowest levels are in chicken liver, shrimp, and crab) Breads/Flours Pumpernickel, buckwheat, and soy Miscellaneous Chocolate, cocoa, brown sugar, molasses, nuts, peanut butter, French fries, and whole milk Data from Potassium content of selected foods per common measure, sorted by nutrient content (USDA National Nutrient Database for Standard Reference, Released 2012). Retrieved from http://lpi.oregonstate. edu/infocenter/minerals/potassium/ and Bakris, G. L., & Olendzki, B. (2012). Patient information: Low potassium diet. Retrieved from http://www.uptodate.com/contents/ low-potassium-diet-beyond-the-basics.

requirement throughout most of childhood (Linshaw, 1987). An adult’s dietary intake varies from approximately 50 to 150 mEq per day. Potassium is present in sufficient quantities in most fruits, vegetables, meat, and fish (Box 1 and Table 1). Nutrition labels typically do not list the amount of potassium that is present in foods. In this article we will review a clinical approach to the treatment of both hyperkalemia and hypokalemia in the pediatric population. Treatment of hyperkalemia in newborns is the same as for infants and children but may be initiated at a slightly higher serum potassium level because of differences in normal serum potassium values in newborns. PHYSIOLOGY OF POTASSIUM Potassium is the second most abundant cation in the body. About 98% of potassium is intracellular, particularly in skeletal muscle, where the concentration ranges from 140 to 150 mEq/L. Only about 2% of the body’s potassium is in the extracellular fluid, where the concentration is tightly regulated at 3.5 to 5.5 mEq/L (Kraft, Btaiche, Sacks, & Kudsk, 2005). Therefore a gradient exists for the diffusion of potassium from intracellular to extracellular fluid. The gradient is the reverse of that for sodium, which is present in high extracellular concentration and low intracellular concentration. Diffusion occurring along both the sodium and potassium gradients is mainly controlled by the sodium– potassium–adenosine triphosphate (ATP) pump. This ion pump uses ATP to pump three sodium ions out of the cell and two potassium ions into the cell, which crewww.jpedhc.org

TABLE 1. Potassium content in popular foods and beverages Food/beverage

Potassium content (mEq)

French fries Small banana White mushrooms Orange juice (200 ml) Whole milk (200 ml) Broccoli Potato chips Green beans Milk chocolate bar (20 g) Onions, cooked Coca-Cola (200 ml)

17.7 8.6 8.1 7.9 7.7 5.8 5.1 3.9 2.4 1.5 0.1

Data from Potassium content of selected foods per common measure, sorted by nutrient content (USDA National Nutrient Database for Standard Reference, Released 2012). Retrieved from http://lpi.oregonstate.edu/infocenter/minerals/potassium/

ates an electrochemical gradient over the cell membrane (Nyirenda, Tang, Padfield, & Seck, 2009). Many factors affect the activity of this pump, such as insulin, glucagon, catecholamine, aldosterone, acid-base status, plasma osmolality, and intracellular potassium levels (Baumgartner, Bailey, & Caudill, 1997). The presence of these pumps and the concentration of potassium inside the cell are critical because potassium performs an essential role in numerous physiologic and metabolic processes, including regulation of cell volume; influencing osmotic balance between cells and the interstitial fluid; renal function; carbohydrate metabolism; contraction of cardiac muscle; and the regulation of the electrical action potential across cell membranes, especially in the myocardium (Schaefer & Wolford, 2005). Under normal physiological conditions, 80% of potassium is excreted through the kidneys, with at least 90% actively reabsorbed along the kidney tubule. About 15% of potassium is excreted in feces, and 5% is lost in sweat. The balance of both cations, sodium and potassium, is maintained by the kidneys. The kidneys can adjust to increased intake by increasing potassium excretion, but they cannot prevent depletion in the absence of potassium ingestion. Most drugs that induce hyperkalemia/hypokalemia alter the renal elimination or reabsorption of potassium, and therefore the kidney is unable to prevent the electrolyte imbalance. The kidneys of a healthy person usually reabsorb all but 10% of filtered potassium (Greger & G€ ogelein, 1987). However, during osmotic diuresis, the kidney reabsorbs less potassium, and thus hypokalemia may occur. This mechanism of hypokalemia is seen in persons with diabetic ketoacidosis. Clinical disorders of potassium homeostasis occur with some regularity, especially in hospitalized patients receiving many medications. Clinically significant symptoms caused by disturbances in potassium November/December 2013

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BOX 2. Causes of hyperkalemia

BOX 3. Drug-induced hyperkalemia

Pseudo hyperkalemia

Increased potassium input

 Use of tourniquet when drawing blood  Hemolysis of drawn blood  Leukocytosis (white blood cell count >50,000/mm3 or thrombocytosis [platelets >1,000,000/mm3])

 Potassium chloride supplements (including salt substitutes)  Potassium penicillin

Increased efflux from intracellular fluid  Due to redistribution: acidosis, especially inorganic  Hyperkalemic familial periodic paralysis

Increased potassium load endogenous      

Extensive tissue injury, burns, heat stroke, or trauma Hemolysis Rhabdomyolysis Tumor lysis syndromes Tissue necrosis Hemolytic uremic syndrome

Decreased potassium output  Potassium sparing diuretics (e.g., spironolactone, triamterine, and amiloride)  Cyclosporine  Angiotensin-converting enzyme inhibitors  Nonsteroidal antiinflammatory drugs  Heparin  Tacrolimus  Pentamidine  Trimethoprim Data from Lehnhardt & Kemper (2011).

Increased potassium load exogenous    

Diet, dietary salt substitutes Banked blood transfusions Gastrointestinal hemorrhage Poisoning

Decreased excretion with or without increased intake  Acute renal failure and severe chronic renal failure  Mineralocorticoid deficiency — Addison’s disease — Selective aldosterone deficiency  Hyporeninemic hypoaldosteronism  Hereditary enzyme deficiencies  Tubulo-interstitial disease  Type IV renal tubular acidosis  Obstruction  Sickle cell disease  Systemic lupus erythematosus Data from Lehnhardt & Kemper (2011).

balance are due to potassium’s role in regulating ‘‘biologic electricity.’’ An alteration in electrical conduction within a nerve or muscle can cause signs and symptoms that range from subtle muscle weakness to more obvious cardiac arrhythmias. It is important to point out that the electrical disturbances associated with disorders of potassium homeostasis are a function of both the extracellular and intracellular potassium concentrations. In clinical conditions leading to chronic potassium depletion, both the extracellular and intracellular potassium concentrations will be decreased. In addition, in persons with chronic potassium depletion, potassium shifts out of the cells, and thus the alteration in electrical conduction is minimized; therefore, disturbances commonly associated with disorders in potassium balance are less noticeable or absent. In contrast, acute changes in potassium homeostasis are much more likely to pro488

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duce clinically significant signs and symptoms (Lehnhardt & Kemper, 2011). Hypokalemia, defined as a serum potassium level 3.5 mEq/L or lower, is perhaps the most common electrolyte abnormality encountered by clinicians (Smellie et al., 2007). Hyperkalemia is defined in children and adults as a potassium level greater than 5.5 mEq/L. In newborns, hyperkalemia is defined as a serum potassium level more than 6 mEq/L. Although hyperkalemia is less common than hypokalemia, it is equally important by virtue of its inherent dangers. HYPERKALEMIA Although hyperkalemia is defined as a serum potassium concentration of > 5.5 mEq/L, it is moderate (6 to 7 mEq/L) and severe (> 7 mEq/L) cases of hyperkalemia that are life threatThe most common ening and require immediate therapy. cause of The most common hyperkalemia in cause of hyperkalemia infants and children in infants and children is ‘‘pseudo hyperkaleis ‘‘pseudo mia’’ from hemolysis hyperkalemia’’ of the blood sample from hemolysis of when the sample is obtained from a heel stick the blood sample or a small bore intravewhen the sample is nous line. When obtained from pseudo hyperkalemia is suspected, the test a heel stick or to determine the serum a small bore potassium level should intravenous line. be repeated from a free-flowing venous sample before any treatment is administered. Otherwise, hyperkalemia is most commonly seen in patients with end-stage renal disease or in those who Journal of Pediatric Health Care

TABLE 2. Electrocardiographic manifestations for hypokalemia and hyperkalemia Serum potassium concentration < 3.5 mEq/L; does not correlate with specific potassium levels

Hypokalemia

Serum potassium concentration

Increased P wave amplitude

5.5-6.5 mEq/L

Prolonged PR interval, ST segment depression QT prolongation, reduction in T wave amplitude T wave inversion, U waves

6.5-7.5 mEq/L 7.0-8.0 mEq/L > 8 mEq/L

Hyperkalemia Tall, peaked, ‘‘tented’’ T waves, normal or decreased QT, PR interval shortening Widening of QRS complex, increased PR interval Broad, low-amplitude P waves, QT prolongation, ST elevation or depression P waves disappear, marked widening of QRS + ‘‘sine wave’’ pattern, high risk for ventricular fibrillation or asystole

Note. Data from Taketomo, Hodding, & Kraus (2013) and Sood, Sood, & Richardson. (2007). Emergency management and commonly encountered outpatient scenarios in patients with hyperkalemia. Mayo Clinic Proceedings, 82(12), 1553-1561.

experience acute renal failure (Masilamani & Van der Voort, 2012). The causes of hyperkalemia are summarized in Boxes 2 and 3. Identification of potential causes of hyperkalemia will be beneficial when determining optimal treatment. Clinical manifestations of hyperkalemia include weakness, confusion, and muscular or respiratory paralysis (Kleinman et al., 2010). Early electrocardiographic (ECG) changes seen with an increase in the potassium level include peaked T waves followed by a decrease in R wave amplitude, widened QRS complex, and a prolonged PR interval. This scenario may ultimately progress to complete heart block with absent P waves and finally a sine wave. Ventricular arrhythmias or cardiac arrest may ensue if no effort is made to lower the serum potassium level. Although the sequences of ECG abnormalities correlate with the serum potassium concentrations, the potassium levels at which specific ECG abnormalities are seen vary widely from patient to patient. Treatment of hyperkalemia depends on the serum potassium level, as well as the presence or absence of symptoms and ECG changes. Table 2 includes a list of ECG changes based on hypokalemia and hyperkalemia serum concentrations. Treatment is recommended when ECG changes are present or when serum potassium levels are greater than 6 to 6.5 mEq/L, regardless of the ECG findings. The first step is to identify and remove all sources of oral or parenteral potassium intake (oral potassium supplements and intravenous maintenance fluids or parenteral nutrition must be considered) and evaluate drugs that can increase the serum potassium level (e.g., potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and nonsteroidal antiinflammatory agents). A list of commonly used medications that can increase serum potassium is provided in Box 3. The goals of hyperkalemia treatment are to antagonize the cardiac effects of potassium, reverse symptoms, and return the serum potassium level to normal www.jpedhc.org

while avoiding overcorrection. Three principle methods are used to treat hyperkalemia. First, calcium is administered to counteract the effects of excess potassium on the heart. Second, medications can be used to shift potassium from extracellular to intracellular fluid compartments. Third, exchange resins, diuretics, or dialysis are used to remove potassium from the body (Farrington, 1991). Table 3 lists treatment options for hyperkalemia. CALCIUM Calcium increases the cellular threshold potential, thereby restoring the normal difference between the resting membrane potential and the firing threshold, which is elevated abnormally in persons with hyperkalemia. This type of treatment is temporary to antagonize the effects of hyperkalemia on cardiac muscle and will not remove potassium from the body (Schaefer & Wolford, 2005). Calcium should be administered intravenously to symptomatic patients or those with ECG changes. In the presence of a lifethreatening arrhythmia, 20 mg/kg of calcium chloride (with a maximum dose of 1 g) or 100 mg/kg of calcium gluconate (with a maximum dose of 1 g) may be given intravenously over 2 to 5 minutes to reduce the effects of potassium at the myocardial cell membrane (Taketomo, Hodding, & Kraus, 2013). The dose may be repeated in 5 minutes; continuous monitoring of the ECG is mandatory. The cardiac response to an injection of calcium is seen within 5 minutes and may last for up to 1 hour (Farrington, 1991). Calcium must be administered with caution to patients receiving digitalis glycosides because the cardiac glycosides are synergistic with parenteral calcium salts and thus the combination of digitalis and calcium may increase the risk of precipitating hypokalemia-related arrhythmias (Taketomo et al., 2013). Because the administration of calcium does not lower serum potassium, other modes of treatment must be initiated. November/December 2013

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TABLE 3. Treatment of hyperkalemia Drug

Pediatric dose (max: adult dose)

Adult dose

Route

Administration time

Onset

Length of effect

Calcium chloride 10% Calcium gluconate 10% Sodium bicarbonate

20 mg/kg/ dose

1-2 g

IV, IO

2-5 min

5 min

30-60 min

60-100 mg/kg/dose

1-2 g

IV, IO

2-5 min

5 min

30-60 min

1-2 mEq/kg/dose

50-100 mEq

IV, IO

2-5 min

Various

50% dextrose

102 ml/kg

50 ml

IV, IO

5 min

15-60 min depending on acid base status of the patient 20 min

10% dextrose

5-10 ml/kg

250 ml

IV, IO

5 min

Regular insulin

0.2 units/kg

5-10 units

IV, IO

Kayexalate

1 g/kg

60 g

Albuterol

10-20 mg (use concentrated form, 5 mg/ml) 1 mg/kg

10-20 mg (use concentrated form, 5 mg/ml) 40 mg

Furosemide

Journal of Pediatric Health Care

Hemodialysis

Notes

Adverse effects

May repeat in 5 min if necessary May repeat in 5 min if necessary May repeat every 5-10 min

Burning at the infusion site

6 hr

Administer with insulin

20 min

6 hr

Administer with insulin

5 min

20 min

2-6 hr

Administer with glucose

Oral or rectal

N/A

4-6 hr

Effective but slow

Inhale by nebulizer

10 min

Oral: 1-2 hr Rectal: < 30 min 30 min

Hypoglycemia, hyperosmolarity, volume overload Hypoglycemia, hyperosmolarity, volume overload Hypoglycemia, hyperosmolarity, volume overload Nausea and vomiting

2 hr

IV

1-2 min

5-30 min

4 hr

N/A

N/A

N/A

N/A

Efficacy demonstrated in patients with renal insufficiency Amount of potassium excretion is unreliable and does not correlate to furosemide dose Hypotension

Note. IO = interosseous; IV = intravenous; N/A = not applicable. Data from Taketomo, Hodding, & Kraus (2013).

Burning at the infusion site Hypernatremia, metabolic alkalosis

Tachycardia, vasomotor flushing, mild tremor Volume depletion

Volume depletion

TREATMENT THAT SHIFTS POTASSIUM INTO CELLS Increasing the Serum pH of the Acidotic Patient The most rapid treatment for hyperkalemia in an acidotic patient is hyperventilation. However, the decrease in serum potassium level seen with acute increases in pH resulting from decreases in partial pressure of carbon dioxide (PCO2) may be less than that seen with comparable improvements in pH obtained with intravenously administered sodium bicarbonate (NaHCO3; Lehnhardt & Kemper, 2011). Classically, it has been taught that for every 0.1 increase in serum pH, serum potassium will decrease by approximately 0.6 mEq/L. However, observed changes in serum potassium concentrations vary widely, depending, in part, on the origin of the acid or base load. Hyperventilation, or a decrease in the PCO2 (respiratory alkalosis), is associated with a decrease in serum potassium of only 0.1 to 0.3 mEq/L for each 0.1 pH unit change (Lehnhardt & Kemper, 2011). Sodium Bicarbonate NaHCO3 is used because the alkaline systemic pH it produces favors the shift of potassium intracellularly, and the sodium load enhances distal tubular potassium secretion (Galla, 2000). Thus the administration of sodium bicarbonate is most effective in a patient who is acidotic and will have less of an effect on a nonacidotic hyperkalemic patient. In addition, NaHCO3 administration can cause an ‘‘overshoot’’ alkalosis in an oliguric patient who is unable to excrete the administrated NaHCO3. The dose of NaHCO3 is 1 to 2 mEq/kg injected intravenously over 1 to 5 minutes (with a maximum dose of 50 to 100 mEq; Taketomo et al., 2013). This treatment may be repeated every 5 to 10 minutes as needed to reverse ECG abnormalities (Farrington, 1991). Administration of NaHCO3 can have a rapid effect; however, it only causes a temporary redistribution of potassium into the intracellular space and does not change total body potassium levels (Masilamani & Van der Voort, 2012). Therefore additional therapy should be administered to remove serum potassium. Patients with coexisting respiratory failure should not be given NaHCO3. Because patients with respiratory failure cannot eliminate the increase of CO2 production that results from NaHCO3 metabolism, respiratory acidosis will develop. For each 1 mEq of NaHCO3 that is administered, the patient receives 1 mEq of sodium. Therefore NaHCO3 should be used with caution in patients with heart failure or renal failure because of its sodium content, which could exacerbate fluid retention. Glucose Plus Insulin Glucose plus insulin infusions shift potassium intracellularly. Insulin stimulates cellular uptake of glucose with potassium following, thus lowering its serum conwww.jpedhc.org

centration (Palmer, 2010). However, if the patient is hyperglycemic, only the administration of insulin is recommended to treat the hyperkalemia. Remember that the effects of intravenously administered insulin frequently extend several hours after the dextrose has been consumed, which may result in delayed hypoglycemia. Glucose, 500 mg/kg (maximum dose 25 g), and insulin, 0.2 units/kg (5 to 10 units), are administered over a 5-minute period (Farrington, 1991; Taketomo et al., 2013). The hypokalemic effect of this treatment can be seen within 20 minutes, peaks between 30 and 60 minutes, and may last for up to 6 hours. A continuous infusion of glucose and insulin may be initiated after the initial glucose/insulin bolus (10 units of regular insulin in 500 ml dextrose 10%). This is a ratio of 0.2 units of regular insulin per 1.0 g of glucose (Parham, Mehdirad, Biermann, & Fredman, 2006). It is recommended that finger-stick tests for blood glucose levels be checked hourly for at least 6 hours after insulin and dextrose have been administered. b-Adrenergic Agonists Albuterol and other b-adrenergic agents induce the intracellular movement of potassium via the stimulation of the sodium/potassium–adenosine triphosphate pump. Inhaled b2 agonists have a rapid onset of action. The effect of b2 agonists is additive to that of insulin or NaHCO3 administration, and they can be administered concurrently. The majority of published data concerning the efficacy of albuterol in persons with hyperkalemia has been in patients with chronic renal failure. Intravenous administration of salbutamol at a dose of 5 mg/ kg over 15 minutes has demonstrated a predictable decrease in serum potassium with a mean decrease of 1.6 to 1.7 mEq/L after 2 hours (Kember, Harps, Hellwege, & Mueller-Wiefel, 1996). Injectable salbutamol is not available in the United States; however, nebulized albuterol has demonstrated efficacy (Weisberg, 2008). Studies show that a nebulization of 10 mg of albuterol leads to a decline in serum potassium of 0.6 mmol/kg and a nebulized dose of albuterol 20 mg demonstrates a decline in pharmacokinetics (about 1 mmol/L; Weisberg, 2008). Note that the effective dose of albuterol for hyperkalemia is at least four times higher than that typically used for bronchodilation. The clinical effect of high-dose albuterol is apparent at 30 minutes and persists for at least 2 hours (Weisberg, 2008). A single study demonstrated that the administration of subcutaneous terbutaline (7 mg/kg) reduces serum potassium in patients undergoing dialysis by an average of 1.3 mEq/L within 60 minutes (Sowinski, Cronin, Mueller, & Kraus, 2005). Mild tachycardia is the most common reported adverse effect of high-dose nebulized albuterol or terbutaline. It is unlikely that patients who take nonselective November/December 2013

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b-blockers will have a hypokalemic effect from nebulized albuterol. Approximately 40% of patients who do not take b-blockers seem to be resistant to the hypokalemic effect of albuterol. The mechanism for this resistance is currently unknown, and there is no basis for predicting which patients will respond. Because of this uncertainty, albuterol should never be used as a single agent for the treatment of urgent hyperkalemia in patients with renal failure (Nissenson & Fine, 2005). TREATMENT THAT REMOVES POTASSIUM Exchange Resins Sodium polystyrene sulfonate or Kayexalate mixed in sorbitol is a cation-exchange resin that binds potassium in the gastrointestinal tract and eliminates it from the body. Each gram of resin will bind approximately 1 mEq of potassium and release 2 to 3 mEq of sodium. It should be given at a dose of 1 g/kg orally or per rectum (maximum dose: 60 g) and repeated every 1 to 2 hours until the serum potassium level is lowered (Taketomo et al., 2013). The onset of action of sodium polystyrene sulfonate administered orally is at least 2 hours, and the maximal effect may take 6 hours (Hollander-Rodriguez & Calvert, 2006). Although the oral administration of Kayexalate is often considered unpalatable, it should not be mixed with citrus juices or solutions that contain high concentrations of potassium because doing so will reduce the effectiveness of the resin. Because this resin exchanges sodium for potassium, consideration should be given to patients with congestive heart failure, elevated blood pressure, or severe hepatic disease (Farrington, 1991). Lastly, because of complications of hypernatremia and necrotizing enterocolitis, Kayexalate use in neonates should be reserved for refractory cases (Taketomo et al., 2013). Diuretics For patients who are not experiencing renal failure, the administration of furosemide, a loop diuretic, will produce an increase in the renal excretion of potassium. The onset of action of parenteral furosemide is within 5 minutes; the peak effect is observed within 30 minutes. The furosemide dose for children is 1 mg/kg/ dose (maximum 40 mg/dose; Taketomo et al., 2013). The amount of potassium excreted is unreliable and does not correlate with the diuretic dose; therefore, the administration of diuretics should only be used as an adjunct to other modes of therapy (Lehnhardt & Kemper, 2011). Renal Replacement Therapy Renal replacement therapy is used when conservative methods fail or for patients with life-threatening hyperkalemia. Hemodialysis (or continuous venovenous hemofiltration in hemodynamically unstable patients) is 492

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more effective than peritoneal dialysis and is the preferred method when hyperkalemia is the result of cell breakdown (Weisberg, 2008). To be most effective, peritoneal dialysis must be started early, Hemodialysis is because potassium much more clearance rates by the efficient at peritoneal membrane are limited by the limiremoving tations on dialysate potassium from the flow rates inherent to patient than all the peritoneal dialysis system. Hemodialysis other treatment is much more efficient modalities at removing potassium from the patient than all other treatment modalities. In patients with lifethreatening levels of hyperkalemia, hemodialysis should be the treatment of choice (Lehnhardt & Kemper, 2011). Prevention of Recurrence After hyperkalemia is treated, it is essential to determine the cause and implement measures to prevent recurrence. In patients with renal dysfunction, management for sustained hyperkalemia is to reduce the overall total dietary potassium intake, which includes restriction in the use of salt substitutes because they contain potassium chloride (KCl). In some studies it has been found that fludrocortisone, an oral mineralocorticoid, is effective in lowering serum potassium levels in patients with hyporenin hypoaldosteronism (Hollander-Rodriguez & Calvert, 2006; Kim, Chung, Yoon, & Kim, 2007). Fludrocortisone, an endogenous mineralocorticoid, mimics the actions of aldosterone, and hence hyperkalemia is reversed. The patient’s medication regimen should be evaluated to see if it is causing hyperkalemia, including over-the-counter medications and herbal and dietary supplements. In patients with renal dysfunction, it may not be prudent to discontinue therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker because they slow progression of renal dysfunction. Instead, it may be in the patient’s best interest to use oral Kayexalate daily, which is effective in reducing the incidence of severe hyperkalemia (Gennari, 2002). Monitoring In the acute management of hyperkalemia, the frequency of monitoring depends on the potassium level, any underlying comorbidities experienced by the patient, and the physician’s preference. Once initial interventions have been made, the serum potassium level should be rechecked within 1 to 2 hours to ensure the effectiveness of the correction. Depending on the underlying cause of the hyperkalemia and the level when the potassium is rechecked, the physician may Journal of Pediatric Health Care

BOX 4. Causes of hypokalemia Intracellular shifts of potassium  Metabolic alkalosis (respiratory and metabolic)  b-Adrenergic agonists: albuterol, insulin, theophylline, caffeine, and epinephrine  Hyperthyroidism  Delirium tremens  Barium poisoning  Therapy of hyperglycemia

Increased losses of potassium  Sodium polystyrene sulfonate, corticosteroids, and magnesium depletion  Renal replacement therapy  Hemodialysis  Continuous renal replacement therapy

Decreased intake/gastrointestinal losses    

Diarrhea Vomiting Increased colostomy output Nasogastric drainage

Inadequate potassium intake (< 40 mEq/L)  Eating disorders  Alcoholism

Urinary loss  Diuretics: loop and thiazide  Antimicrobials: amphotericin B, cisplatin, aminoglycoside—piperacillin, ticarcillin  Diabetic ketoacidosis  Osmotic dieresis (diabetic ketoacidosis, mannitol)  Hypomagnesemia  Cushing syndrome  Primary mineralocorticoid excess  Bartter syndrome or Gitelman syndrome Data from Gennari (2002) and Linshaw (1987).

choose to decrease or increase the frequency of potassium checks (Elliott et al., 2010). HYPOKALEMIA Hypokalemia occurs when a serum potassium concentration is < 3.5 mEq/L, and it can become lifethreatening when the serum potassium concentration falls below 2.5 mEq/L (Table 2). Hypokalemia can result from intracellular shifts of potassium, increased losses of potassium, or decreased ingestion or administration of potassium (Box 4). The main cause of hypokalemia in pediatric patients is excessive gastrointestinal losses such as diarrhea or vomiting. Because serum potassium levels do not correlate with intracellular potassium levels, hypokalemia does not reflect total body potassium stores. Clear cases of potassium deficiency, defined by symptoms, signs, and a low potassium level, are rare in healthy persons (Kleinman et al., 2010). www.jpedhc.org

The clinical manifestations of hypokalemia involve changes to muscle and cardiovascular function because hypokalemia results in membrane hyperpolarization and impairs muscle contraction. Mild hypokalemia (3 to 3.5 mEq/L) may not cause symptoms. Moderate hypokalemia, with serum potassium concentrations of 2.5 to 3 mEq/L, may cause muscular weakness, myalgia, muscle cramps (as a result of disturbed function of the skeletal muscles), and constipation (as a result of disturbed function of smooth muscles). With more severe hypokalemia, flaccid paralysis and hyporeflexia may result. Reports have been made of rhabdomyolysis occurring with profound hypokalemia with serum potassium levels less than 2 mEq/L. Respiratory depression from severe impairment of skeletal muscle may occur with severe potassium depletion (Schaefer & Wolford, 2005). TREATMENT OF HYPOKALEMIA Treatment depends on the serum level of potassium, as well as the presence or absence of symptoms and ECG changes (Table 2). Early ECG changes include ST segment depression, T wave flattening, and the presence of U waves. Like hyperkalemia, the sequence of ECG abnormalities correlates with serum conPatients with centrations, but the symptomatic potassium levels at hypokalemia which specific ECG abnormalities are seen should be treated vary widely from pawith tient to patient. The pharmacologic goals of therapy for hypokalemia include therapy, because avoidance or resoluincreasing the tion of symptoms and intake of return of the serum potassium concentration potassium-rich to normal (Gennari, foods only is 1998). unlikely to resolve If potassium were to be removed from symptoms in the diet, a minimum potassiumkidney excretion of depleted patients. about 200 mg per day would continue to occur. The serum potassium level would decline to 3.0 to 3.5 mEq/L in about 1 week. If the serum potassium was not supplemented, the patient would experience further depletion in serum potassium levels and could ultimately experience death. A potassium intake sufficient to support life can in general be guaranteed by eating a variety of foods. Patients with symptomatic hypokalemia should be treated with pharmacologic therapy, because increasing the intake of potassium-rich foods only is unlikely to resolve symptoms in potassium-depleted patients. November/December 2013

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TABLE 4. Oral potassium replacement products Potassium chloride preparations Tablets, controlled release/extended release Tablets, controlled release/extended release Tablets, extended release Tablets, controlled release/extended release Tablets, effervescent Capsules, controlled release Capsules, controlled release Liquid Liquid Powder packets Powder packets Potassium gluconate preparations Caplet Capsule Tablets Tablets, timed-release Liquid Liquid Potassium bicarbonate Tablets, effervescent Potassium bicarbonate and potassium citrate Tablets, effervescent Tablets, effervescent Tablets, effervescent

Potassium phosphate Tablet (K-Phos original) Powder packet (Neutral-Phos K) Powder packet (Neutral-Phos) Potassium citrate Tablet, extended release Tablet, extended release Tablet, extended release Potassium citrate and citric acid Liquid Powder packets

# mEq/mg potassium

Salt form (mg)/miscellaneous information

8

600 KCl

10

750 KCl

15 20

1125 KCl 1500 mg KCl

25 8 10 20 mEq/15 ml 40 mEq/15 ml 20 mEq/packet 25 mEq/packet

Chloride and bicarbonate salts 600 mg KCl 750 mg KCl 1125 mg/15 ml 2250 mg/15 ml 1500 mg KCl 1875 mg KCl

99 mg potassium 99 mg potassium 99 mg potassium/ 90 mg potassium 95 mg potassium 20 mEq/15 ml 20 mEq/15 ml

595 mg potassium gluconate 595 mg potassium gluconate 595 mg potassium gluconate/550 mg potassium gluconate As the gluconate salt A mixture of gluconate and citrate salts

25

Orange flavor

10 20 25

Unflavored and cherry vanilla flavor Unflavored and orange cream flavor Unflavored, orange, lemon citrus and cherry berry flavor AND sugar free; orange flavor

3.7 mEq 14 mEq KCl 7 mEq KCl

114 mg potassium and 114 mg phosphate per tablet 8 mmol phos 8 mmol phos, 7 mEq NaCl

5 mEq 10 mEq 15 mEq

540 mg potassium citrate 1080 mg potassium citrate 1620 mg potassium citrate

2 mEq/mL 30 mEq

2 mEq/mL NaHCO3 30 mEq NaHCO3

Note. KCl = potassium chloride; NaCl = sodium chloride; NaHCO3 = sodium bicarbonate. Data from Taketomo, Hodding, & Kraus (2013).

Dietary potassium is predominantly in the form of potassium phosphate or potassium citrate, which results in the retention of only 40% as much potassium as KCl (Sanguinetti & Jurkiewicz, 1992). Therefore pharmacotherapy of symptomatic hypokalemia should be with KCl. In the presence of cardiac arrhythmias, extreme muscle weakness, or respiratory distress, KCl should be administered intravenously with cardiac monitoring. The intravenous dose of KCl is 0.5 mEq/kg (maximum 20 mEq/dose) administered over 1 to 2 hours based on the severity of the patient’s symptoms (Taketomo et al., 2013). Once the serum potassium level is stabi-

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lized, the oral route of administration is preferable (Schaefer & Wolford, 2005). Oral potassium supplements are available as chloride, bicarbonate, citrate, gluconate, and phosphate salts. Potassium bicarbonate is preferred in patients with hypokalemia and metabolic acidosis because of their renal tubular acidosis or diarrhea. Administration of potassium phosphate should be considered only in patients with hypokalemia and hypophosphatemia, which might occur in patients with proximal renal tubular acidosis associated with Fanconi syndrome and phosphate wasting. Use of potassium chloride is preferred in patients with hypokalemia, hypochloremia, and metabolic

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TABLE 5. Intravenous potassium replacement products Infusion, premixed in water for injection

Central or peripheral line recommended

10 mEq/50 mL 10 mEq/100 mL 20 mEq/50 mL 20 mEq/100 mL 30 mEq/100 mL 40 mEq/100 mL Mixed by pharmacy # 0.1 mEq/mL > 0.1 mEq/mL with a maximum of 0.4 mEq/mL

Central Peripheral Central Central Central Central Peripheral Central

Note. Data from Taketomo, Hodding, & Kraus (2013).

alkalosis because of diuretic therapy or vomiting. Chloride depletion contributes to maintenance of the metabolic alkalosis by enhancing renal bicarbonate reabsorption and may contribute to potassium wasting as sodium is reabsorbed in exchange for secreted potassium rather than with chloride. Compared with potassium bicarbonate, KCL raises the serum potassium concentration more quickly (Schaefer &Wolford, 2005). Chloride is primarily an extracellular anion that does not enter cells to the same extent as bicarbonate, thereby promoting maintenance of the administered potassium in the extracellular fluid (Sanguinetti & Jurkiewicz, 1992). The single oral dose of KCl is 1 to 1.5 mEq/kg/dose (maximum 40 mEq/dose; Taketomo et al., 2013). If potassium deficits are severe or ongoing, scheduled potassium doses may be necessary (Gennari, 1998). Potassium salts available for potassium replacement are summarized in Tables 4 and 5. Patients with hypokalemia may also have hypomagnesemia as a result of concurrent loss of magnesium with diarrhea or diuretic therapy or medications such as cisplatin, carboplatin, and amphotericin B, which cause renal magnesium wasting. In addition, magnesium depletion may cause renal potassium wasting. Because the major site of potassium reabsorption occurs in the ascending loop of Henle and reabsorption at this site is driven by a magnesium-dependent, sodium–potassium–adenosine triphosphatase pump, cellular depletion of magnesium in these cells prevents potassium reabsorption (Schaefer & Wolford, 2005). Treating the hypokalemia without addressing the hypomagnesemia will be ineffective. The measurement of serum magnesium should be considered in patients with hypokalemia, and if hypomagnesemia is present, it should be treated prior to the administration of potassium. The recommended initial treatment is intravenous magnesium sulfate, 50 mg/kg/dose (maximum dose: 2 g) administered over 2 hours (Taketomo et al., 2013). This dose can be repeated if the hypomagnesemia persists.

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Monitoring The timing of a repeat serum potassium level depends on the severity of the initial value, the patient’s symptoms, and the form of potassium administered to the patient. In a symptomatic patient who receives an intravenous dose of KCl, the dose should be repeated without measuring a serum value if the patient’s symptoms persist. If the symptoms resolve, the serum potassium level can be obtained 1 hour after completion of an intravenous dose (Schaefer & Wolford, 2005). In clinical situations in which an oral dose is administered based on a low serum value, in the absence of clinical symptoms, the serum level can be repeated the next day. After hypokalemia is treated, it is essential to determine the cause and implement measures to prevent recurrence. Patients who receive diuretics or other medications that cause a depletion of serum potassium (Box 4) may need to begin taking a scheduled oral supplement. CONCLUSION Derangements in potassium homeostasis affect the body’s bioelectric process, including muscle contraction, nerve conduction, and myocardial electrical activity. Alterations in the potassium level, whether it be hyperkalemia or hypokalemia, may cause serious symptoms in the patient. Knowledge of the causes of hypokalemia and hyperkalemia and the therapeutic interventions recommended for their treatment can be lifesaving for the patient. REFERENCES Baumgartner, T., Bailey, L., & Caudill, M. (1997). Potassium. In T. G. Baumgartner (Ed.), Clinical guide to parenteral micronutrition (3rd ed.). Deerfield, IL: Fujisawa USA Inc. Elliott, M. J., Ronksley, P. E., Clase, C. M., Ahmed, S. B., & Hemmelgarn, B. R. (2010). Management of patients with acute hyperkalemia. Canadian Medical Association Journal, 182, 1631-1635. Farrington, E. (1991). Treatment of hyperkalemia. Pediatric Nursing, 17(2), 190-192. Galla, J. (2000). Metabolic alkalosis. Journal of American Society of Nephrology, 11(2), 369-375. Gennari, F. (1998). Hypokalemia. New England Journal of Medicine, 339, 451-458. Gennari, F. (2002). Disorders of potassium homeostasis hypokalemia and hyperkalemia. Critical Care Clinics, 18, 273-288. €gelein, H. (1987). Role of K+ conductive pathways in Greger, R., & Go the nephron. Kidney International, 31, 1055. Hollander-Rodriguez, J., & Calvert, J. (2006). Hyperkalemia. American Family Physician, 73(2), 283-290. Kember, M., Harps, E., Hellwege, H., & Mueller-Wiefel, D. E. (1996). Effective treatment of acute hyperkalemia in childhood by shortterm infusion of salbutamol. European Journal of Pediatrics, 155, 495-497. Kim, D., Chung, J., Yoon, S., & Kim, H. (2007). Effect of fludrocortisone acetate on reducing serum potassium levels in patients with end-stage renal disease undergoing hemodialysis. Nephrology Dialysis Transplantation, 7, 3273-3276. Kleinman, M., Chameides, L., Schexnayder, S., Samson, R. A., Hazinski, M. F., Atkins, D. L., . Zaritsky, A. L. (2010). Part 14:

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Pediatric advanced life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation, 122(18 suppl. 3), S876-S908. Kraft, M., Btaiche, I., Sacks, G., & Kudsk, K. A. (2005). Treatment of electrolyte disorders in adult patients in the intensive care unit. American Journal of Health-System Pharmacists, 62, 16631679. Lehnhardt, A., & Kemper, M. (2011). Pathogenesis, diagnosis and management of hyperkalemia. Pediatric Nephrology, 26, 377384. Linshaw, M. (1987). Potassium homeostasis and hypokalemia. Pediatric Clinics of North America, 34, 649-681. Masilamani, K., & Van der Voort, J. (2012). The management of acute hyperkalaemia in neonates and children. Archives of Disease in Childhood, 97(4), 376-380. Nissenson, A., & Fine, R. (2005). Clinical dialysis. New York, NY: Tim McGraw Companies, Inc. Nyirenda, M., Tang, J., Padfield, P., & Seck, J. (2009). Hyperkalemia. British Medical Journal, 339(B4824), 1019-1024.

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Palmer, B. F. (2010). A physiologic-based approach to the evaluation of a patient with hypokalemia. American Journal of Kidney Disease, 45(6), 578-584. Parham, W., Mehdirad, A., Biermann, K., & Fredman, C. (2006). Hyperkalemia revisited. Texas Heart Institute Journal, 33, 40-47. Sanguinetti, M., & Jurkiewicz, N. (1992). Role of external Ca2+ and K+ €gers Arin gating of cardiac delayed rectifier K+ currents. Pflu chive: European Journal of Physiology, 420(2), 180-186. Schaefer, T., & Wolford, R. (2005). Disorders of potassium. Emergency Medicine Clinics of North America, 23(3), 723-747. Smellie, S., Shaw, N., Bowlees, R., Taylor, A., Howell-Jones, R., & McNulty, C. A. (2007). Best practice in primary care pathology. Journal of Clinical Pathology, 60(9), 966-974. Sowinski, K., Cronin, D., Mueller, B., & Kraus, M. (2005). Subcutaneous terbutaline use in CKD to reduce potassium concentrations. American Journal of Kidney Diseases, 45, 1040-1045. Taketomo, C. K., Hodding, J. R., & Kraus, D. M. (2013). Pediatric and neonatal dosage handbook. Hudson, OH: Lexi-Comp. Weisberg, L. (2008). Management of severe hyperkalemia. Critical Care Medicine, 36(12), 1-6.

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