Published: August 2010
Potassium (K+) is the most abundant cation in the body. About 90% of total body potassium is intracellular and 10% is in extracellular fluid, of which less than 1% is composed of plasma. The ratio of intracellular to extracellular potassium determines neuromuscular and cardiovascular excitability, which is why serum potassium is normally regulated within a narrow range of 3.5 to 5.0 mmol/L. Dietary K+ intake is highly variable, ranging from as low as 40 mmol/day to more than 100 mmol/day.1, 2 Homeostasis is maintained by two systems. One regulates K+ excretion, or external balance through the kidneys and intestines, and the second regulates K+ shifts, or internal balance between intracellular and extracellular fluid compartments. Internal balance is mainly mediated by insulin and catecholamines.
Ingested K+ is absorbed rapidly and enters the portal circulation, where it stimulates insulin secretion. Insulin increases Na+,K+-ATPase activity and facilitates potassium entry into cells, thereby averting hyperkalemia. β2-Adrenergic stimulation also promotes entry of K+ into cells through increased cyclic adenosine monophosphate (cAMP) activation of Na+,K+-ATPase.
An increase in extracellular potassium concentration also stimulates aldosterone secretion (via angiotensin II), and aldosterone increases K+ excretion. In the steady state, K+ excretion matches intake, and approximately 90% is excreted by the kidneys and 10% in the stool. Renal K+ excretion is mediated by aldosterone and sodium (Na+) delivery (glomerular filtration rate [GFR]) in principal cells of the collecting ducts.3 K+ is freely filtered by the glomerulus, and almost all the filtered K+ is reabsorbed in the proximal tubule and loop of Henle (Fig. 1). This absorption in the proximal part of the nephron passively follows that of Na+ and water, whereas reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na+,K+,2Cl- carrier (NKCC2) in the luminal membrane. K+ is secreted by the connecting segment, the principal cells (see Fig. 1) in the cortical and outer medullary collecting tubule, and the papillary (or inner medullary) collecting duct via luminal potassium channels (ROMK). Secretion in these segments varies according to physiologic requirements, and is responsible for most of the urinary potassium excretion. Secretion in the distal segments is also balanced by K+ reabsorption through the intercalated cells (see Fig. 1) in the cortical and outer medullary collecting tubules. This process is mediated by an active H+,K+-ATPase pump in the luminal membrane and results in both proton secretion and K+ reabsorption. The kidneys are better at increasing K+ excretion than decreasing excretion. As a result, K+ depletion and hypokalemia can occur from inadequate intake. Hyperkalemia usually occurs when renal excretion is impaired (GFR <20 mL/min).
Hypokalemia is defined as a serum potassium concentration below 3.5 mmol/L. Hypokalemia can be further arbitrarily graded by severity.
Relative severity is defined as:
This applies to certain high-risk patient populations with cardiac disease, such as ischemic or scarred myocardium, left ventricular hypertrophy, congestive heart failure, or myocardial infarction).
Moderate severity is defined as:
Severe hypokalemia is defined as:
Hypokalemia is found in about 20% of hospitalized patients, but it occurs in less than 1% of otherwise healthy adults.
Hypokalemia can result from transcellular shifts (from extracellular into intracellular spaces), or when potassium losses are increased; these losses can be from renal or nonrenal causes (Box 1). Transcellular shifts can occur in pathologic conditions associated with a catecholamine surge, such as chest pain syndromes, or mediated by acid-base disturbances. Loop or thiazide diuretic use, aldosteronism, or other renal diseases (e.g., postobstructive diuresis, cortical necrosis) can cause excessive renal potassium losses. The renal and nonrenal causes of K+ loss can be determined by laboratory tests (Fig. 2).
|Box 1 Causes of Hypokalemia|
|Nonrenal losses (urine K+ < 20 mmol/L)
|Renal losses (urine K+ >?20 mmol/L)
|Hypokalemia with hypertension
|Hypokalemia with normal blood pressure
|β-Adrenergic agonists (bronchodilators, decongestants, tocolytic agents)- theophylline, caffeine|
|Acute catecholamine surge from stress (e.g., acute myocardial infarction)|
|Thyrotoxic hypokalemic paralysis|
|Familial hypokalemic periodic paralysis|
|Barium poisoning-metabolic alkalosis|
Normal individuals with hypokalemia are usually asymptomatic. Manifestations of hypokalemia include generalized muscle weakness, ileus, and cardiac arrhythmias. In patients with ischemic or scarred myocardium, left ventricular hypertrophy, congestive heart failure, or myocardial infarction, hypokalemia is associated with an increased incidence of ventricular ectopy, ventricular tachycardia, and ventricular fibrillation. In those patients with heart disease at risk for serious ventricular tachyarrhythmias, even relative hypokalemia ([K+] =3.5 to 4.0 mmol/L) may require potassium supplementation to prevent development of overt hypokalemia. More severe hypokalemia (<2.5 mmol/L) can cause myopathy that can progress to rhabdomyolysis, and ascending paralysis with respiratory arrest (<2.0 mmol/L; see Box 1).
When hypokalemia is reported, the initial step is to ascertain whether it is associated with clinical symptoms or arrhythmias that would require prompt intervention. In the absence of compelling indications for immediate therapy, a careful history and physical examination should be performed. Important clinical clues such as medication, vomiting, and hypertension should be specifically sought. Factitious or spurious hypokalemia, which can occur in patients with leukemia or elevated white cell counts because K+ is taken up by these metabolically active cells in the test tube, should be ruled out. If true hypokalemia is present, then determine whether it was caused by a transcellular shift or a decrease in total body potassium. Hypokalemia from transcellular shift is managed by treating the underlying condition or removing the offending agent. Decreased total body K+ require further diagnostic workup. Urine potassium, chloride, creatinine, and serum aldosterone levels are determined to distinguish the causes of extrarenal and renal losses of K+ so that the primary condition can be treated, in addition to replacement therapy (see Fig. 2).
The spot urine potassium concentration, fractional excretion of potassium (FEK), and transtubular potassium gradient (TTKG) can be used to help differentiate between renal and nonrenal causes of hypokalemia and hyperkalemia.4-7 The spot urine K+ level is helpful for determining renal and nonrenal causes of hypokalemia; a urinary potassium (UK) level higher than 20 mmol/L is suggestive of renal causes and a UK level lower than 20 mmol/L suggestive of nonrenal causes. Accuracy is improved with a 24-hour urine collection for K+ because K+ secretion and water reabsorption affect K+ excretion.7, 8
When serum and urine creatinine levels are known, FEK can be calculated.4, 5 FEK is the percentage of filtered potassium that appears in the urine; it represents the K+ clearance (ClK) corrected for the GFR, as determined by creatinine clearance (ClCr): ClK/ClCr. Because clearance for any substance is UV/P, where U is the concentration of that substance in urine, V is the volume per unit time, and P is the plasma concentration, then:
Or, to simplify, because V cancels out,
In a person with normal renal function and average potassium intake, FEK is approximately 10%. Hypokalemic patients with a lower FEK would suggest extrarenal loss of K+, whereas hypokalemia from renal losses would be associated with an elevated FEK.
where UOsm and POsm are the urine and plasma osmolalities, respectively. The numerator is an estimate of the luminal potassium concentration, and the osmolality ratio is used to correct for the increase in UK caused by water extraction. In normal individuals under normal conditions, the TTKG is about 6 to 8. Hypokalemia associated with a high TTKG (>10) suggests excessive renal potassium loss, whereas a low TTKG (<2) would suggest nonrenal losses. A value of 5 to 7 suggests aldosterone deficiency or resistance. In hyperkalemic patients, a value greater than 10 suggests normal aldosterone action and an extrarenal cause of hyperkalemia.
The usefulness of the FEK and TTKG is limited by their variability with diet and chronic kidney disease. These indices increase and decrease with dietary K+ accordingly. Moreover, in patients with chronic kidney disease (lower GFR), adaptive responses increase K+ excretion, with resultant increases in FEK and TTKG. Therefore, the normal values will vary, making the interpretation of significance difficult.
Intravenous potassium administration is rarely indicated because of the risk of hyperkalemia, except for cardiac arrhythmias (rapid ventricular response), severe myopathy, and paralysis (usually [K+] lower than 2.0 mmol/L, or with familial periodic paralysis). Continuous cardiac monitoring is preferred, with no more than 20 mmol/hr administered, and reassessment of the serum potassium level after 60 mmol is given. For every 0.3-mmol/L decrease in serum potassium concentration, the total body potassium deficit is approximately 100 mmol/L. Patients with relative hypokalemia (e.g., congestive heart failure [CHF] patients on diuretics or digoxin), should be counseled about adequate K+ intake with fruits and vegetables to prevent overt hypokalemia. Because almost all dietary potassium is coupled with phosphate, hypokalemia associated with chloride depletion (e.g., diuretic use, vomiting, nasogastric drainage) can only be effectively corrected with potassium chloride administration. Concomitant hypomagnesemia has to be corrected as well to correct hypokalemia fully. Magnesium depletion reduces the intracellular potassium concentration and causes renal potassium wasting; it appears to be caused by an impairment of cell membrane Na+, K+-ATPase (Box 2).
|Box 2 Treatment for Hypokalemia|
|Cause of hypokalemia should be addressed (remove drug, change diet, stop gastric drainage).|
|Indications for IV potassium (20 mmol/hr with cardiac monitoring, reassess after 60 mmol):|
|Cardiac arrhythmias with rapid ventricular response
|Indications for oral potassium chloride (20-80 mmol/day in divided doses):
Hyperkalemia is defined as a serum potassium concentration higher than 5.0 mmol/L, and severe hyperkalemia is defined as a serum potassium concentration higher than 6.5 mmol/L. An elevated potassium level occurs when potassium homeostasis is disrupted. Pseudohyperkalemia can occur with thrombocytosis, hemolysis, and extremely high white cell counts. In these cases, lysis of the cells in the test tube releases potassium into the serum and increases potassium concentrations. Repeated fist clenching with a tourniquet can also release K+ from muscle cells and increase potassium concentrations factitiously.
The reported incidence of hyperkalemia is from 1.1% to 10% of all hospitalized patients. Mortality data caused by hyperkalemia are unavailable for the general population but accounted for 1.9% of patients with end-stage renal disease in the United States in 1993.
More than 80% of hyperkalemic episodes are caused by impaired potassium excretion from renal insufficiency.1 Usually, another event that prevents or overcomes the renal adaptation precipitates the hyperkalemia. Supplemental potassium chloride administration is commonly the second event and this added potassium can be from exogenous (e.g., diet, salt substitutes) or endogenous sources (e.g., tumor lysis, gastrointestinal bleed, rhabdomyolysis). Impaired K+ excretion or impaired potassium entry into cells accounts for all other causes of hyperkalemia. Drugs such as potassium-sparing diuretics (e.g., spironolactone, triamterene), or drugs that block aldosterone production or receptors (e.g., eplerenone, angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs], heparin) impair the excretion of K+. Potassium entry into cells is impaired with insulin deficiency, hypertonicity, or drugs (e.g., beta blockers, digoxin; Box 3).
|Box 3 Causes of Hyperkalemia|
|Impaired potassium excretion
|Impaired transcellular shift-insulin deficiency|
|Hypertonicity (uncontrolled diabetes): familial hyperkalemic periodic paralysis
|Excessive potassium load|
|Massive tissue breakdown (rhabdomyolysis, burns, trauma)|
ACE, angiotensin-converting enzyme; COX-2, Cyclooxygenase-2; NSAID, nonsteroidal anti-inflammatory drug.
Patients with hyperkalemia are usually asymptomatic, although some patients may present with generalized muscle weakness, and cardiac conduction may be impaired. The earliest electrocardiographic changes are tenting of T waves, followed by widening of the QRS complex, atrioventricular conduction block, ventricular fibrillation, and then asystole. The serum potassium concentrations are poorly correlated to the electrocardiographic and conduction abnormalities. However, the toxic effects of hyperkalemia are enhanced by hypocalcemia, hyponatremia, and acidemia.9
The initial step with reported hyperkalemia is to ascertain whether it is associated with clinical symptoms or arrhythmias that would require prompt intervention. If no compelling indication for immediate therapy exists, a careful history and physical examination should be performed, with particular emphasis on medication, diet, and chronic kidney disease. Spurious hyperkalemia should be excluded. This can occur with hemolysis in vitro, fist clenching during blood draw, leukocytosis (>50,000/mm3), or severe thrombocytosis (>1,000,000/mm3). A plasma K+ determination, instead of serum determination, is sometimes necessary in addition, spurious hyperkalemia will not be associated with abnormalities on the electrocardiogram (ECG). If hyperkalemia is indeed present, then determine whether it occurred with a transcellular shift or reduction in potassium excretion, or in the setting of preserved renal function.
Hyperkalemia from transcellular shift occurs with insulin deficiency, hypertonicity (e.g., uncontrolled diabetes), massive tissue breakdown (e.g., rhabdomyolysis, burns, trauma), or familial hyperkalemic periodic paralysis. Impaired renal function (usually, estimated GFR from stable serum creatinine level <20 mL/min) can cause hyperkalemia. In the setting of preserved renal function (GFR >20 mL/min), serum aldosterone, renin, and cortisol levels can distinguish other causes (Fig. 3).
The urine potassium concentration, FEK, and TTKG can also be used to help distinguish between renal and nonrenal causes of hyperkalemia. Renal causes will be associated with a low TTKG (see earlier, “Urine Potassium, Fractional Excretion, and Transtubular Potassium Gradient”).
We believe that therapy should be initiated regardless of the cause of hyperkalemia when potassium levels are higher than 6.5 mmol/L or if there are conduction abnormalities on the ECG. Intravenous calcium is required for rapid reversal of conduction abnormalities that are present. An exception to this is hyperkalemia caused by digoxin toxicity because acute hypercalcemia can potentiate the toxic effects of digoxin. Acute therapy is also directed at rapidly moving potassium into cells with intravenous dextrose and insulin. This moves potassium into cells within 10 to 20 minutes and lowers the potassium level by 0.5 to 1.0 mmol/L, with the effect lasting for about 2 to 3 hours. Longer term therapy for hyperkalemia without conduction abnormalities should be directed toward minimizing intake and increasing excretion of potassium. Medications that affect potassium homeostasis should be stopped, if possible. Although there are no prospective studies on inpatient versus outpatient management of hyperkalemia, it would seem intuitive that patients with hyperkalemia associated with abnormalities on the ECG, or rapid increases in or large changes from baseline potassium concentrations, should be admitted for therapy under continuous cardiac monitoring.9 Patients with less severe hyperkalemia (lower than 6.0 mmol/L) and without cardiac conduction abnormalities can probably be safely managed in an outpatient setting (Table 1).
|Clinical Situation||Treatment||Response Time||Duration of Effect|
|Electrocardiographic abnormalities||IV calcium gluconate or chloride (10 mL of 10% solution)||Immediate||15-30 min|
|[K+]> 6.5 mmol/L or rising||IV Glucose (50 mL of 50%) + IV regular insulin, 10 U||10-20 min||2-3 hr|
|Albuterol (10-20 mg) by inhaler over 10 min||20-30 min||2-3 hr|
|IV sodium bicarbonate (only if metabolic acidosis)||Delayed|
|Kayexalate (sodium polystyrene), 15-30 g, with sorbitol||4-6 hr (PO); 1 hr (as retention enema)|
|Loop diuretic (IV)||1 hr|
|Dietary potassium restriction, 2-3 g/day|
|Discontinue supplemental potassium (salt substitutes)|
|Discontinue drugs that interfere with potassium homeostasis|
|Augment potassium excretion with loop diuretics, thiazide diuretics, fludrocortisone, if hypoaldosteronism present|
|Chronic Kayexalate therapy|
Management of Hypokalemia
Treatment of Hyperkalemia