One of the most common electrolyte disturbances seen in clinical practice is hypokalemia. Hypokalemia is more prevalent than hyperkalemia; however, most cases are mild. Although there is a slight variation, an acceptable lower limit for normal serum potassium is 3.5 mmol/L. Severity is categorized as mild when the serum potassium level is 3 to 3.4 mmol/L, moderate when the serum potassium level is 2.5 to 3 mmol/L, and severe when the serum potassium level is less than 2.5 mmol/L. Values obtained from plasma and serum may differ. Therefore, it is important to know the sampling source. Compared to plasma levels, serum levels are usually slightly higher due to delays in processing and/or the effect of clotting.
A variety of etiologies can result in hypokalemia. These etiologies can be placed into the following categories:
In general, hypokalemia is associated with diagnoses of cardiac disease, renal failure, malnutrition, and shock. Hypothermia and increased blood cell production (for example, leukemia) are additional risk factors for developing hypokalemia. There are subsets of patients that are susceptible to the development of hypokalemia. For instance, psychiatric patients are at risk for hypokalemia due to their drug therapy. Hypokalemia is also prevalent in hospitalized patients, in particular, pediatric patients, those who have a fever and those who are critically ill. Additionally, in developing countries, an increased risk of mortality is observed in children when severe hypokalemia is associated with diarrhea and severe malnutrition.
Potassium is predominantly intracellular where it is the most abundant cation and involved in cell regulation and several cellular processes. The fraction of potassium in the extracellular fluid is small. Therefore, plasma or serum levels are not a reliable indicator of total body potassium stores. Potassium homeostasis is maintained through a combination of adjustments in acute cellular shifts between the extracellular and intracellular fluid compartments, renal excretion and, to a lesser extent, gastrointestinal losses.
Hypokalemia can occur as a result of decreased potassium intake, transcellular shifts (increased intracellular uptake) or increased potassium loss (skin, gastrointestinal and renal losses). Decreased potassium intake, in isolation, rarely results in hypokalemia due to the ability of the kidneys to effectively minimize potassium excretion. However, reduced intake can be a contributor to hypokalemia in the presence of other causes, such as malnutrition or diuretic therapy. Cellular uptake of potassium is promoted by alkalemia, insulin, beta-adrenergic stimulation, aldosterone and xanthines, such as caffeine. Most cases of hypokalemia result from gastrointestinal (GI) or renal losses. Renal potassium losses are associated with increased mineralocorticoid-receptor stimulation such as occurs with primary hyperreninism and primary aldosteronism. Increased delivery of sodium and/or non-absorbable ions (diuretic therapy, magnesium deficiency, genetic syndromes) to the distal nephron can also result in renal potassium wasting. GI losses are a common cause of hypokalemia with severe or chronic diarrhea being the most common extrarenal cause of hypokalemia.
The cause of hypokalemia is evident from the patient’s history. Therefore, questioning should focus on the presence of GI losses (vomiting, diarrhea) and underlying cardiac comorbidities, as well as, a thorough review of medications (insulin, beta agonists, diuretic use). Clinical manifestations mainly involve the musculoskeletal and cardiovascular systems. Hence, the physical exam should focus on identifying neurologic manifestations and cardiac dysrhythmias.
Clinical symptoms of hypokalemia do not become evident until the serum potassium level is less than 3 mmol/L unless there is a precipitous fall or the patient has a process that is potentiated by hypokalemia. The severity of symptoms also tends to be proportional to the degree and duration of hypokalemia. Symptoms resolve with correction of the hypokalemia.
Significant muscle weakness occurs at serum potassium levels below 2.5 mmol/L but can occur at higher levels if the onset is acute. Similar to the weakness associated with hyperkalemia, the pattern is ascending in nature affecting the lower extremities, progressing to involve the trunk and upper extremities and potentially advancing to paralysis. Affected muscles can include the muscles of respiration which can lead to respiratory failure and death. Involvement of GI muscles can cause an ileus with associated symptoms of nausea, vomiting, and abdominal distension. Severe hypokalemia can also lead to muscle cramps, rhabdomyolysis, and resultant myoglobinuria. Periodic paralysis is a rare neuromuscular disorder, which is inherited or acquired, that is caused by an acute transcellular shift of potassium into the cells. It is characterized by potentially fatal episodes of muscle weakness or paralysis that can affect the respiratory muscles.
Hypokalemia can result in a variety of cardiac dysrhythmias. Although cardiac dysrhythmias or ECG changes are more likely to be associated with moderate to severe hypokalemia, there is a high degree of individual variability and can occur with even mild decreases in serum levels. This variability is dependent on concomitant factors such as magnesium depletion, digitalis therapy, among others. Moreover, characteristic ECG changes do not manifest in all patients. The ECG changes that occur are T-wave flattening initially, followed by ST depression and the appearance of a U wave that can be difficult to distinguish from the T wave. The U wave is often seen in the lateral precordial leads of V4 to V6. Prolongation of the PR and QT interval can also occur. Risk of arrhythmias is highest in older patients, those with heart disease and those receiving digoxin or antiarrhythmic drugs. Administration of anesthesia in the setting of hypokalemia is also a risk for dysrhythmias and impaired cardiac contractility but more so with acute rather than chronic hypokalemia.
Hypomagnesemia often occurs with and may worsen hypokalemia especially in the presence of chronic diarrhea, alcoholism, genetic disorders, diuretic use and chemotherapy. Both promote the development of cardiac dysrhythmias. The combination of hypokalemia and hypomagnesemia are associated with an increased risk of torsades de pointes, particularly in individuals receiving QT-prolonging medications. Additionally, hypomagnesemia can increase urinary potassium losses thus lowering the serum potassium level, as well as, prevent urinary potassium reabsorption thereby impeding potassium repletion.
Lastly, prolonged hypokalemia can cause structural and functional changes in the kidney that include impairing concentrating ability, increased ammonia production, altered sodium reabsorption and increased bicarbonate absorption. Hypokalemia can also result in glucose intolerance by reducing insulin secretion.
As stated previously, the etiology for hypokalemia is evident from the patient’s history. On the rare occasion that the etiology is uncertain, then diagnostic evaluation should ensue. Diagnostic evaluation involves assessment of urinary potassium excretion and assessment of acid-base status. Assessment of urinary potassium excretion can help distinguish renal losses from other causes of hypokalemia. Measurement of potassium excretion is ideally done via a 24-hour urine collection. Excretion of more than 30 mEq of potassium per day indicates inappropriate renal potassium loss. Alternative methods for measurement include a spot urine potassium concentration or urine potassium-to-creatinine ratio. A urine potassium concentration of greater than 15 mmol/L or a ratio greater than 13 mEq/mmol of creatinine, respectively, also indicates inappropriate renal potassium loss. After determining the presence or lack of renal potassium wasting, assessment of acid-base status should then be determined. The existence of metabolic acidosis or alkalosis with or without renal potassium wasting can further narrow the differential diagnosis. Aside from diagnostic evaluation, assessment of serum magnesium level, muscle strength, and electrocardiographic changes is warranted as the latter two would warrant immediate intervention.
The overarching goals of therapy for hypokalemia are to prevent or treat life-threatening complications, replace the potassium deficit, and to diagnose and correct the underlying cause. Therapeutic urgency depends on the severity of hypokalemia, the existence of comorbid conditions and the rate of decline of serum potassium levels. Elucidating the cause of hypokalemia and understanding whether it is secondary to transcellular shifts or a potassium deficit is also essential. Regardless, potassium replacement is indicated in most cases of hypokalemia, especially in those related to renal or GI losses. The presence of concomitant hypomagnesemia should also be investigated and corrected if present. In the presence of hypomagnesemia, hypokalemia can be refractory to potassium replacement alone.
Clinical manifestations do not occur with mild to moderate hypokalemia; thus, repletion is not urgent. Mild to moderate hypokalemia is typically treated with oral potassium supplements. Providing 60 to 80 mmol/day in divided doses over days to weeks is usually sufficient. Oral supplementation can irritate GI mucosa leading to bleeding and/or ulceration but is associated with a lower risk of rebound hyperkalemia. It should be taken with plenty of fluids and food. Potassium chloride is the preferred formulation for replacement therapy in most cases. Increasing dietary potassium is not usually adequate to treat hypokalemia because most of the potassium contained in foods is coupled with phosphate. A majority of cases of hypokalemia involve chloride depletion and respond best to replacement with potassium chloride. Intravenous (IV) repletion is administered if oral therapy is not tolerated.
Replacement therapy must be given more rapidly with severe hypokalemia or when clinical symptoms are present. Potassium chloride of 40 mmol given every 3 to 4 hours for 3 doses is preferred. Rapid correction can be provided via oral and/or IV formulation. IV administration is preferred in the setting of cardiac dysrhythmias, digitalis toxicity and recent or ongoing cardiac ischemia. Pain and phlebitis usually occur with peripheral IV infusions when infusion rates exceed 10 mmol per hour. There is also a risk of rebound hyperkalemia when rates exceed a dose of 20 mmol per hour. In general, 20 mmol per hour of potassium chloride will increase serum potassium levels by an average of 0.25 mmol per hour. Potassium should not be given in dextrose-containing solutions because dextrose will stimulate insulin secretion which then exacerbates the hypokalemia. Serum potassium levels should be checked every 2 to 4 hours. Potassium repletion can occur more slowly once the serum potassium level is persistently above 3 mmol/L or clinical symptoms have resolved. Regardless of severity, careful monitoring of serum potassium levels is required as the development of hyperkalemia is common in hospitalized patients.
The potassium deficit varies directly with the severity of hypokalemia. Every decrease in serum concentration of 0.3 mmol/L accounts for a reduction of approximately 100 mmol in total body potassium stores. Accurate quantification is difficult, especially in instances where transcellular shifts are the cause of hypokalemia. Therefore, careful monitoring is required to prevent hyperkalemia from excessive supplementation.
The goal of potassium replacement in the context of renal or GI losses is to immediately raise serum potassium concentration to a safe level and then replace the remaining deficit over days to weeks. A potassium-sparing diuretic should also be considered when the etiology of hypokalemia involves renal potassium wasting as potassium replacement therapy alone may not suffice.
The presence of an acid-base disorder needs to be established as management may differ for etiologies of hypokalemia caused by redistribution of potassium from the extracellular fluid into cells (redistributive hypokalemia). When paralysis or cardiac dysrhythmias are present, in this setting, potassium repletion should be considered. Rebound hyperkalemia is a potential complication of potassium therapy when redistributive hypokalemia is the cause of hypokalemia. As the initial process causing redistribution resolves or is corrected, the transfer of potassium from intracellular to extracellular fluid in conjunction with potassium repletion can result in hyperkalemia. Potassium repletion in patients with periodic paralysis carries a high risk of rebound hyperkalemia. Regardless of etiology, careful monitoring of serum potassium levels is required due to an increased risk of hyperkalemia during replacement therapy.