Potassium is the most common cation in the body. The ratio of the intracellular to extracellular potassium concentration is the primary determinant of the resting membrane potential (Em). Alterations in the Em disrupt the normal function of neural, cardiac, and muscular tissues. Normal serum potassium ranges from 3.5 to 5.2 mmol/L. The molecular weight of potassium is 39.1, so a daily potassium intake of 80 mmol is roughly equivalent to 3.1 g of potassium.
The normal physiologic handling of potassium can be viewed as a three-step process: ingestion, cellular distribution, and excretion. Irregularities at any of these steps can result in pathologic serum potassium concentrations.
Normal daily intake is roughly 40 to 80 mmol. Potassium is rapidly and completely absorbed by the small intestine. Net GI absorption (intake minus GI losses) is approximately 90%.29 Lower GI secretions have high concentrations of potassium, 80 to 90 mmol/L, but due to the limited amount of stool (80 to 120 g/d), daily GI excretion of potassium is only 10 mEq.30–32 The colonic epithelium is capable of actively excreting potassium, but this is not clinically significant. Patients with chronic renal failure have elevated stool potassium but total potassium excretion is still limited to about 12 mEq/d.29
Following absorption, potassium distributes among the intracellular and extracellular compartments. The intracellular compartment acts as the primary buffer to changes in serum potassium concentration.
The Na-K-ATPase pump, driven by a ubiquitous cell surface enzyme, moves potassium into cells while pumping sodium out of cells. The pump is stimulated by β2-adrenergic activity, while α-adrenergic activity results in potassium efflux.33 Insulin also stimulates the activity of this pump and is independent of its hypoglycemic activity.34
Extracellular pH can affect the cellular distribution of potassium. Various explanations have been proposed, including a direct effect of pH on the Na-K-ATPase, or a H+—K+ exchange to maintain electroneutrality. The effect of pH on potassium distribution varies depending on the nature of the acid-base disturbance. Respiratory acidosis, alkalosis, and organic acidosis all have minimal effect on potassium distribution. Inorganic acidosis can increase serum potassium, while metabolic alkalosis can lower potassium.
Renal Excretion of Potassium
Renal excretion of potassium can range from 5 to 500 mEq/d.35,36 Though 500 mmol of potassium is filtered by the glomerulus each day, essentially all of it is resorbed in the proximal tubule and loop of Henle. Any potassium that is ultimately excreted in the urine must be secreted by the distal nephron.37 Because of this phenomenon, the study of renal potassium handling can focus exclusively on the distal nephron.
The secretion of potassium in the distal tubule is governed by two phenomena: tubular flow and aldosterone activity (Fig. 76-9). Potassium secretion by the principal cells of the collecting duct depends on a favorable electrochemical gradient. Rapid tubular flow provides a continuous supply of potassium-depleted fluid, maintaining a favorable chemical gradient. Additionally, increased tubular flow occurs with high tubular sodium delivery. Resorption of sodium by the principal cells generates a negative charge in the tubular lumen. Some of this negative charge is lost by concurrent resorption of chloride. The luminal electronegativity enhances potassium secretion. Decreased distal chloride delivery, as occurs with metabolic alkalosis, reduces chloride resorption, increasing the tubule electronegativity and enhancing potassium secretion.38 Aldosterone is a steroid hormone produced in the zona glomerulosa of the adrenal gland. Its principal site of action is the connecting segment and collecting tubules of the distal nephron. In the principal cells of the cortical collecting duct (CCD), aldosterone increases the resorption of sodium and hence the secretion of potassium. Aldosterone stimulates the production and activity of Na-K-ATPase, sodium channels, and potassium channels.39 Aldosterone also has a small but measurable effect on increasing GI potassium excretion.29 Aldosterone is secreted in response to angiotensin II and elevated serum potassium.
Potassium handling in the cortical collecting duct. The resorption of sodium creates a negatively charged tubule lumen. This charge helps drive the secretion of potassium. Chloride resorption decreases the negative charge, so increased chloride resorption decreases potassium secretion. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate.
The fact that potassium secretion is dependent on both tubular flow and aldosterone means that renal potassium handling is independent of volume status, despite the fact that both tubular flow and aldosterone are intimately tied to volume status. With volume depletion, increased angiotensin II stimulates the release of aldosterone, which enhances potassium secretion; however, the simultaneous decrease in GFR and increased resorption by the proximal tubule decrease tubular flow, antagonizing potassium secretion. In the opposite case of volume overload, decreased aldosterone suppresses potassium secretion, but increased tubular flow enhances potassium secretion, maintaining potassium balance.
Hypokalemia is defined as a serum potassium concentration below 3.5 mmol/L, and is found among 20% of the hospitalized population. However, this high frequency probably does not reflect total body potassium depletion. In a review of 70 hospitalized patients with a potassium less than 2.8 mmol/L, the potassium rose toward normal regardless if they were given potassium or not. The authors suggested that hospitalization for acute illness was associated with increased adrenergic stimulation, resulting in intracellular movement of potassium and transient hypokalemia.40
Table 76–4. Causes of Hypokalemia ||Download (.pdf)
Table 76–4. Causes of Hypokalemia
|Decreased Potassium Intake||Cellular Shift||Increased Potassium Loss|
|Anorexia||β-Adrenergic activity||Extrarenal losses|
|Malnutrition/malabsorption|| Endogenous|| Chronic diarrhea|
|Alcoholism|| Albuterol|| Fistulas and ostomies|
|Ingestion of grey clay|| Dobutamine||Renal losses|
| Terbutaline|| Loop diuretics|
| Fenoterol|| Thiazide diuretics|
|Insulin|| Osmotic diuretics|
|Periodic paralysis|| Type I and II renal tubular|
| Thyrotoxicosis|| acidosis|
| Familial|| Metabolic alkalosis|
|Xanthines|| Bicarbonaturia (vomiting)|
| Theophylline toxicity|| Ketonuria|
| Caffeine|| Hypomagnesemia|
|Barium toxicity|| Carbenicillin|
|Treatment of anemia|| Bartter's and Gitelman's|
| (rapid cell proliferation)|| syndromes|
| Exogenous steroids|
| Adrenal adenoma|
| Adrenal hyperplasia (Conn's syndrome)|
| Syndrome of apparent mineralocorticoid excess|
| Liddle syndrome|
| Congenital adrenal hyperplasia|
| Renal artery stenosis|
| Renin-secreting tumor|
Potassium-poor diets usually are merely contributory to hypokalemia. Even among patients with severe malnutrition due to anorexia nervosa and/or bulimia, serum potassium less than 3 mmol/L occurred in less than 2%, and in all of those patients there was enhanced potassium loss from cathartics or vomiting.41
Activation of β-adrenergic receptors increases Na-K-ATPase activity. Any physiologic stress that releases epinephrine or norepinephrine can result in a transient decrease in serum potassium. Use of primarily β-adrenergic catecholamines, such as dobutamine, can cause transient hypokalemia.42 The β-agonists used for bronchodilation or as tocolytic agents can also acutely lower potassium.
Insulin reliably stimulates Na-K-ATPase and lowers serum potassium.34 Insulin-induced hypokalemia has been documented in the treatment of diabetic ketoacidosis, nonketotic hyperosmolar coma, and with the use of intravenous dextrose solutions.43 Refeeding syndrome occurs among patients given a carbohydrate-rich diet or parenteral nutrition following periods of starvation. Refeeding syndrome is associated with hypokalemia and hypophosphatemia.44
Metabolic alkalosis is associated with the intracellular movement of potassium and increased renal potassium excretion. Increased pH results in movement of hydrogen ions from the intracellular to the extracellular compartment. Potassium shifts into cells to maintain electroneutrality. Simultaneously, increased serum bicarbonate enhances renal potassium excretion. Studies in nephrectomized dogs show a modest but measurable decrease in serum potassium of less than 0.3 mmol/L for each increase in pH of 0.1 (though these data did not account for a significant increase in serum osmolality).45 The common association of alkalosis and hypokalemia is primarily due to enhanced renal excretion of potassium rather than a transmembrane shift.
Hypokalemic periodic paralysis is an unusual clinical entity in which transcellular shifts in potassium result in paralysis. These patients develop sudden, severe drops in serum potassium associated with skeletal muscle paralysis. Triggers include carbohydrate loads, exercise, and changes in body temperature. Acetazolamide may decrease the frequency and severity of symptoms in some families.46 Oral potassium can be used to treat acute paralysis but patients often develop rebound hyperkalemia.47
The cortical collecting duct is the critical site of renal potassium handling. Normally aldosterone activity and sodium delivery to the CCD are balanced so that when one is elevated the other is decreased. Excess renal potassium excretion only occurs when both aldosterone and distal sodium delivery are increased.
Most diuretics increase distal delivery of sodium and increase aldosterone, resulting in hypokalemia. Primary hyperaldosteronism causes hypertension and hypokalemia. The hypokalemia is due to the simultaneous increase in aldosterone activity and sodium delivery to the distal nephron. The increased sodium delivery is due to a spontaneous diuresis in response to the hypertension known as aldosterone escape. A full discussion of the causes of increased aldosterone activity is beyond the scope of this text; however, a list of causes is included in Table 76-4.
Normally, the primary anion in the tubular fluid is chloride. Various conditions can result in chloride being replaced by an unresorbable anion. Anions that are not resorbed prevent sodium from being resorbed and increase sodium and tubular fluid delivery to the distal nephron. Additionally, unresorbable anions increase tubule electronegativity, which enhances potassium secretion by the principal cells. The most common example of an unresorbable anion resulting in hypokalemia is bicarbonate. In metabolic alkalosis, increased serum bicarbonate is delivered to the distal nephron, resulting in increased renal potassium loss. Diabetic ketoacidosis increases delivery of the unresorbable anion β-hydroxybutyrate to the distal nephron.
Hypomagnesemia is associated with hypokalemia that is resistant to therapy. Decreased magnesium increases renal potassium losses and needs to be corrected prior to successful treatment of hypokalemia.48
Despite a high concentration of potassium in lower GI secretions, 85 to 95 mmol/L, GI potassium losses are typically modest, about 10 mEq/d.31 Chronic diarrhea can cause hypokalemia, but the mechanism appears to be more complex than simple GI loss of potassium. In cases of experimental diarrhea, daily GI potassium loss was never higher than 24 mEq/d, a level well below average daily potassium intake.49 In addition, studies on diarrhea show that as stool volume increases, stool potassium concentration falls, ultimately reaching a level similar to that of plasma in cases of severe cholera.29 Explanations for the commonly seen association of diarrhea and hypokalemia include: secondary hyperaldosteronism, diminished intake of potassium, or transcellular shifts of extracellular potassium.
Gastric secretions have potassium content similar to that of plasma, 5 to 8 mmol/L. Gastric losses result in severe metabolic alkalosis and secondary hyperaldosteronism, both of which enhance renal potassium loss.
Hypokalemia is a well-known risk factor for cardiac arrhythmia. Increased ectopy with hypokalemia has been documented in ambulatory hypertensive patients, in patients undergoing coronary artery bypass grafting, and during acute myocardial infarction (AMI).50,51 Following AMI, hypokalemia increases the risk for a number of arrhythmias; patients with hypokalemia are more than twice as likely to develop ventricular fibrillation.52 Hypokalemia enhances the risk of digitalis toxicity and associated arrhythmias. Digitalis-induced arrhythmias may occur despite normal digitalis levels in the presence of modest hypokalemia.53
A drop in extracellular potassium hyperpolarizes the muscle cells, which can prevent myocyte depolarization. Clinically, this can lead to weakness, fatigue, cramping, and myalgia. Severe cases can result in paralysis. Numerous case reports of respiratory muscle weakness and respiratory failure have been reported with hypokalemia due to diabetic ketoacidosis. Severe hypokalemia can cause rhabdomyolysis. Alcoholics may be particularly prone to proximal muscle weakness due to rhabdomyolysis.54,55
Hypokalemia can cause polyuria due to increased thirst and by inducing a mild and reversible renal concentrating defect.56,57 The etiology of the concentrating defect is multifactorial, but primarily represents decreased renal response to ADH.
Gastrointestinal complications are primarily related to decreased gut motility associated with hypokalemia. Serum potassium of less than 3.0 mmol/L is associated with constipation. Paralytic ileus can occur as potassium falls below 2.5 mmol/L.
Hypokalemia stimulates the proximal tubule to increase ammoniagenesis. Patients predisposed to hepatic encephalopathy can develop encephalopathy from this increased ammonia load.58
Hypokalemia is defined as a serum potassium concentration less than 3.5 mmol/L. Once hypokalemia has been established, the primary diagnostic goal is differentiating renal from extrarenal potassium loss. Urine studies are used to separate extrarenal losses, in which the kidneys are potassium avid, from renal losses, in which the kidney inappropriately wastes potassium. Three studies may be used to differentiate these states: spot urine potassium concentration, 24-hour urine potassium, and the transtubular potassium gradient (TTKG).
The spot urine is the simplest test to use. The urine potassium should be less than 20 mmol/L in the face of hypokalemia. If the spot potassium is greater than 40, renal potassium wasting should be suspected. Urine potassium of 20 to 40 mmol/L is considered nondiagnostic.59 There are two primary problems with this test; the first is it fails to control for changes in the water content of urine. Since hypokalemia is associated with decreased ADH sensitivity, increased water content will lower the urinary potassium concentration. The second problem is that spot samples provide information for only a single moment in time. Patients with diuretic-induced hypokalemia become potassium avid after the diuretic has cleared. One study on the diagnosis of hypokalemia (mean K = 2.0 mmol/L) found spot urine potassium to have a sensitivity of 40% and specificity of 100% for excess renal potassium loss.60
The 24-hour urine potassium test avoids both of the above problems at the expense of increased complexity and a 24-hour delay. Patients with hypokalemia should reduce urinary potassium losses to less than 15 mEq/d. Potassium losses greater than that indicate inappropriate renal losses. The 24-hour urine provides no information on the renal potassium handling prior to the urine collection (e.g., diuretic use that is stopped prior to collection will show an appropriately potassium-avid kidney).
The transtubular potassium gradient calculates the ratio of tubular potassium to venous potassium at the end of the CCD. The CCD is responsible for potassium excretion, so increases in the TTKG indicate renal wasting of potassium, while decreases indicate renal potassium conservation (Fig. 76-10 and Equation 76-5). When serum and renal potassium handling are normal, the TTKG runs from 5 to 8.61,59 In the face of hypokalemia, the CCD should minimize the potassium excretion, resulting in a reduced TTKG. The TTKG has been validated in patients with decreased dietary potassium, periodic paralysis, diuretic-induced hypokalemia, primary hyperaldosteronism and vomiting.61–62
Equation 76-5. The transtubular potassium gradient (TTKG). plasma Osm,
plasma osmolality; urine Osm, urine osmolality.
The transtubular potassium gradient measures the ratio of tubular potassium to interstitial potassium and quantifies the renal excretion of potassium. ADH, antidiuretic hormone; CCD, cortical collecting duct; DCT, distal convoluted tubule; TALH, the thick ascending limb of the loop of Henle.
The TTKG has two assumptions that must be met prior to using this formula:63
There must be ADH activity to ensure that the osmolality of the tubular fluid approximates the osmolality of blood by the end of the cortical collecting duct. ADH activity is assured by only using the formula when urine osmolality exceeds serum osmolality.
There must be adequate tubular sodium to allow the cortical collecting duct to secrete potassium. The test should only be done if the urine sodium concentration is greater than 25 mmol/L.
The treatment of hypokalemia can be broken down into three questions: when to treat, with which potassium salt, and with what quantity. The National Council on Potassium in Clinical Practice has published clinical practice guidelines on potassium replacement. The guidelines recommend correcting potassium in any patient with potassium below 3.0 mmol/L and select patients with serum potassium below 3.5 mmol/L. They specified the more aggressive treatment regimen for patients with hypertension, congestive heart failure, and increased risk for or history of cardiac arrhythmias or stroke.64
Determining the dose of potassium to correct hypokalemia is difficult because there is not a firm relationship between serum potassium and total body potassium. Balance studies have shown that potassium is disproportionately lost from the extracellular compartment rather than total body potassium (e.g., a 25% drop in serum potassium is due to less than a 25% drop in total body potassium). Sterns and colleagues analyzed the results of seven balance studies and found a linear relationship for potassium deficit and serum potassium (r = 0.893). The loss of 100 mmol of potassium lowered the serum potassium by 0.27 mmol/L, so a fall from 4 to 3 mmol/L represented a 370-mmol potassium deficit.65 In Scribner and Burnell's review, they estimated that a drop in potassium from 4 to 3 mmol/L represented a loss of 100 to 200 mmol of potassium, and a drop in serum potassium from 3 to 2 mmol/L represented an additional 200 to 400 mmol deficit.66 These estimates do not account for altered cellular distribution of potassium. In diabetic ketoacidosis for example, serum potassium overestimates total body potassium, while β-agonist–induced hypokalemia underestimates total body potassium. In most cases of hypokalemia due to cellular redistribution, experts advise against treatment, as the hypokalemia is transient and treatment predisposes the patient to hyperkalemia. One exception to this is symptomatic periodic paralysis in which respiratory arrest due to hypokalemia may occur, so emergent treatment is indicated. Caution should still be used, as rebound hyperkalemia is common.
The form of potassium used in repletion is most often potassium chloride. The chloride anion has some advantages over alternatives such as phosphate, bicarbonate, or citrate. The chloride anion is primarily an extracellular anion, which minimizes the movement of potassium into the cell, maximizing the change in serum potassium. Chloride also does not increase the secretion of potassium at the collecting duct. The use of alternate potassium salts should be reserved for specific clinical scenarios in which there is an indication for the anion (e.g., citrate in metabolic acidosis and phosphate in hypophosphatemia).
In patients who are asymptomatic, oral replacement is sufficient and doses from 40 to 100 mEq of KCl per day are typically sufficient to correct the hypokalemia over several days.64 Increasing intake of potassium-rich foods is less effective than potassium chloride supplements because the anions associated with dietary potassium are primarily phosphate and citrate.
Potassium chloride can be given as a liquid, powder (often marketed as a salt substitute), or pills with multiple formulations and coatings. The bioavailability of all these formulations is identical, with greater than 70% absorption.67 The liquid formulation has the fastest absorption and lowest patient compliance of all formulations (due to the bad taste).68 Wax-matrix extended-release tablets are associated with gastrointestinal tract ulcers and stenotic lesions. The microencapsulated extended-release formulations have the best compliance and low rates of GI side effects.68,64
Parenteral potassium should be used to correct symptomatic hypokalemia or when patients are unable to take oral medications. Twenty to forty millimoles of KCl in a liter of isotonic saline or 5% dextrose is a typical solution. Both saline and dextrose solutions can cause problems. Dextrose solutions stimulate insulin release that can result in acute worsening of the hypokalemia.43,69 The use of saline with dilute concentrations of potassium means that patients must get multiple liters of saline to correct even modest potassium deficits.
The use of concentrated potassium solutions has generated fears about the possibility of precipitating arrhythmias from local, transient hyperkalemia near the infusion site or by causing peripheral vein irritation from caustic potassium solutions. Despite these concerns, the use of concentrated potassium infusions, 200 mmol/L, at a rate of 20 mEq/h in the ICU was shown to be safe and efficacious in both a retrospective study of 495 infusions and a prospective study of 40 patients.70,71 Twenty milliequivalents of KCl increased the serum potassium by 0.25 mmol/L 1 hour after the infusion finished. The peak rise in serum potassium, 0.48 mmol/L, was at the end of the infusion. ECG monitoring showed no change except for decreased ventricular ectopy. Potassium was infused safely through both peripheral and central sites.
Hypomagnesemia is a common cause of treatment failure. Patients who are resistant to potassium supplementation should have serum magnesium measured, and if low, repleted. Patients with diuretic-induced hypokalemia often benefit from the initiation of a potassium-sparing diuretic. Amiloride has been shown to mitigate magnesium losses associated with loop and thiazide diuretics.
Patients on amphotericin B often become hypokalemic. Both spironolactone (100 mg twice a day) and amiloride (5 mg twice a day) have been shown to increase serum potassium and decrease the use of potassium supplements in randomized prospective trials.72,73
In patients with recalcitrant vomiting (i.e., bulimia) and associated hypokalemia, one treatment strategy is to decrease the loss of hydrogen ions with a proton pump inhibitor or H2-blocker. In one case a bulimic patient was started on lansoprazole and the patient's alkalosis and hypokalemia improved. In addition, the patient remained normokalemic for the following year despite continued vomiting.74 Proton pump inhibitors may have a similar role in ameliorating hypokalemia associated with gastric suction.
The ability of the kidney to excrete potassium is flexible and adaptable. If dietary ingestion of potassium is increased over a number of days, the kidney increases daily potassium excretion to match. Because of this, dietary loads of potassium do not result in hyperkalemia unless they are sudden, or paired with a defect in renal potassium handling. Likewise, conditions associated with the movement of intracellular potassium to the extracellular space are associated with only transient hyperkalemia because either the kidneys excrete or the cells reuptake the excess potassium. Decreases in the ability of the kidney to excrete potassium increase susceptibility to hyperkalemia from increased potassium intake or transcellular shifts (Table 76-5).
Table 76–5. Causes of Hyperkalemia ||Download (.pdf)
Table 76–5. Causes of Hyperkalemia
|Increased Potassium Intake||Cellular Shift||Decreased Potassium Excretion|
|Oral||β-Blockers||Decreased tubular flow|
|Dietary||Lack of insulin||Renal insufficiency|
|K supplements||Acidemia (inorganic)||Prerenal azotemia|
|Salt substitutes||Digitalis toxicity||Volume depletion|
|Ingestion of red clay||Succinylcholine||Congestive heart failure|
|Enternal feeding supplements||Periodic paralysis||Cirrhosis|
|Medical error||Hypertonicity||Decreased stimulation of aldosterone|
|TPN||Hyperglycemia||Type IV RTA (hyporeninism)|
|CVVH replacement fluid||Mannitol||ACE inhibitor use|
|Peritoneal dialysis fluid||Cell destruction||Angiotensin-receptor blocker|
|Old blood transfusions||Ischemia||Decreased synthesis of aldosterone|
|Treatment of hypokalemia||Necrosis||Adrenal insufficiency, primary|
|Tumor lysis syndrome||Congenital adrenal hyperplasia|
|Chemotherapy||Decreased aldosterone activity|
|Type I RTA, hyperkalemic variety|
|SLE, obstruction, sickle cell|
|Decreased GI excretion|
|Constipation in ESRD patients|
Increased Potassium Intake
Dietary potassium is typically in the range of 40 to 80 mEq/d. Hyperkalemia has been reported to follow the use of potassium chloride salt substitutes, even in the presence of normal renal function.75 One teaspoon of potassium chloride contains 50 to 65 mEq of potassium. Enteral nutrition supplements may be rich sources of potassium. Ensure Plus at 100 mL/h provides 130 mEq of potassium per day.
Red blood cell transfusions can have extracellular potassium concentrations as high as 70 mmol/L.76 The risk of hyperkalemia from transfusions rises as the age of the transfusions increases (Table 76-6). Use of “washed” packed red blood cells reduces the risk of transfusion-associated hyperkalemia.77
Table 76–6. Potassium Concentration in Red Blood Cell Transfusions ||Download (.pdf)
Table 76–6. Potassium Concentration in Red Blood Cell Transfusions
|Age (Days)||Plasma Potassium (mmol/L)a||Extracellular Potassium (mmol) per 250 mL of PRBC (Hematocrit 60%)|
Intracellular Redistribution of Potassium
Increases in plasma osmolality, most often due to hyperglycemia, causes an osmotic movement of water from the intracellular compartment. Potassium moves out of the cell with the water. Using mannitol to increase serum osmolality from 283 to 300 mmol/kg increased potassium from 4.4 to 5.2 mmol/L.78
The Na-K-ATPase is critical in preventing intracellular potassium from causing hyperkalemia. Any factor that decreases the activity of this enzyme will cause potassium to leak from cells. A lack of insulin slows the Na-K-ATPase. In diabetic ketoacidosis hyperkalemia is typical despite total body potassium depletion, and in this setting is largely related to the hyperglycemia.
β-Blockers inhibit the Na-K-ATPase activity and are associated with a mild increase in serum potassium. Uremia reduces Na-K-ATPase activity so that renal failure patients are less able to use the intracellular compartment to buffer potassium loads. Digitalis is a Na-K-ATPase antagonist. Digitalis toxicity can cause severe hyperkalemia. Removing digitalis with binding antibodies allows rapid correction of the hyperkalemia.79
Inorganic acids increase serum potassium. Attempts to predict the change in potassium from changes of pH have shown tremendous variability (0.3 to 1.1 mmol/L for a decrease in pH of 0.1) and are considered unreliable.78 Decreases in pH due to respiratory or organic acidosis have minimal effect on serum potassium.
Cell death results in release of intracellular potassium. Large-scale cell death can cause fatal hyperkalemia. Tissue necrosis and hyperkalemia can be seen with rhabdomyolysis of any etiology. Likewise, tissue ischemia can cause cell death and release large amounts of potassium. Bowel and limb ischemia are occult causes of hyperkalemia. Hemolysis causes hyperkalemia by releasing the intracellular potassium of red blood cells. Tumor destruction with chemotherapy results in release of intracellular contents. Tumor lysis syndrome is hyperphosphatemia, hyperuricemia, hyperkalemia, and hypocalcemia associated with acute renal failure. The prophylactic use of allopurinol has nearly eliminated acute renal failure, which is due to uric acid nephropathy. The syndrome most often occurs with poorly differentiated neoplasms such as Burkitt's lymphoma and acute leukemias, but it has been reported with breast cancer, medulloblastoma, and ovarian and lung cancer. In some rapidly-growing tumors, spontaneous lysis occurs prior to therapy. Hyperkalemia in tumor lysis syndrome is more common in patients with premorbid renal insufficiency.80
Succinylcholine is a depolarizing paralytic. It can cause hyperkalemia by two unique mechanisms. The first occurs after muscle damage from burns, trauma, or disuse (often from denervation, prolonged ICU stay, or central nervous system lesion such as stroke or Gullain-Barré syndrome). The muscle damage causes upregulation of the nicotinic acetylcholine receptors so that subsequent exposure to succinylcholine causes massive potassium efflux and hyperkalemia. The second mechanism is a drug-induced rhabdomyolysis. Nearly all of the reported cases of rhabdomyolysis occurred in patients with a preexisting myopathy, often a form of muscular dystrophy (Duchenne's or Becker's).81
Increased intake and cellular redistribution cause transient increases in potassium because the kidneys are so efficient at excreting potassium. Persistent hyperkalemia is almost always associated with a defect in renal potassium clearance. Renal potassium excretion is dependent on adequate tubular flow and adequate aldosterone activity. Besides dramatic decreases in renal function, defects in renal potassium clearance can always be traced back to one of these two problems.
Decreases in GFR from chronic renal insufficiency or prerenal azotemia reduce the flow through the distal tubule and can cause hyperkalemia. Decreases in renal function not associated with oliguria do not typically cause hyperkalemia. Examples of this include aminoglycoside toxicity (usually associated with hypokalemia) and chronic interstitial nephritis.
Inadequate aldosterone activity can be due to pathology at any point in the aldosterone axis. Inadequate renin production causes hypoaldosteronism and subsequently type IV renal tubular acidosis (RTA). Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers prevent angiotensin II from stimulating the release of aldosterone. Since serum potassium itself can directly stimulate aldosterone release, most patients can maintain potassium homeostasis despite the loss of angiotensin II. However, patients with other defects in potassium handling (e.g., renal insufficiency or decreased insulin) can become hyperkalemic.82
Ketoconazole and heparin cause hyperkalemia by blocking aldosterone synthesis. Spironolactone and eplerenone act as competitive inhibitors of aldosterone. Calcineurin inhibitors cause hyperkalemia in a subset of patients, possibly by inducing tubular insensitivity to aldosterone.83,84 Potassium-sparing diuretics such as amiloride and triamterene and the antibiotic trimethoprim all block collecting tubule sodium channels, decreasing potassium secretion.85 Distal RTA usually causes hypokalemia; however, one subtype causes hyperkalemia due to a defect in sodium resorption at the cortical collecting duct. This is different from type IV RTA and does not respond to supplemental mineralocorticoids. This defect has been reported in chronic urinary tract obstruction, lupus, and sickle cell anemia. 86,87
The potassium concentrations inside and outside of the cell are the primary determinants of the cellular resting membrane potential (Em). Changes in the extracellular concentration can have dramatic effects on the resting membrane potential and the cell's ability to depolarize. As extracellular potassium rises, the normally negative Em increases toward zero; this allows easier depolarization (i.e., increased excitability). However, this excitability is short-lived as chronic hyperkalemia ultimately inactivates the sodium channels critical to producing an action potential. Hyperkalemia shortens the refractory period following depolarization by facilitating faster potassium uptake.
In the myocardium, inactivated sodium channels slow conduction velocity, and high serum potassium speeds repolarization. On ECG, hyperkalemia causes widened QRS complexes (slowed conduction velocity) and shortened ST intervals with tented T waves (rapid repolarization). The slowed conduction associated with rapid repolarization predisposes the myocardium to ventricular fibrillation.
While animal models and experimental protocols document a stepwise progression of ECG changes from peaked T waves to widened QRS to disappearance of P waves, and ultimately a sinusoidal ECG, clinically patients may develop symptomatic arrhythmias without prior ECG changes.88 Rapid increases in potassium, hyponatremia, hypocalcemia, and metabolic acidosis all increase the likelihood of arrhythmia.89–92
Ascending paralysis mimicking Guillain-Barré syndrome has been documented with a serum potassium of 7 mmol/L. In a review of all published cases of hyperkalemic paralysis (excluding hereditary periodic paralysis) the average potassium was 9 mmol/L. The use of potassium-sparing diuretics was the etiology of the hyperkalemia in over half of the cases. Electromyograms showed the paralysis to be due to abnormal nerve depolarization rather than muscle pathology.93
The high intracellular potassium content results in frequent misdiagnosis of hyperkalemia. The most common cause is hemolysis following the blood draw. The lab should report this, as it is easy to detect. Increased platelets or white cells can also release potassium, especially if the specimen is allowed to clot. Thrombocytosis greater than 1,000,000 platelets or leukocytosis over 100,000 increase the likelihood of pseudohyperkalemia. Rarely, counts as low as 600,000 platelets or 70,000 leukocytes have been reported to cause the same phenomenon.94 The other major cause of pseudohyperkalemia is fist pumping prior to phlebotomy. Forearm exercise in the presence of a tourniquet can falsely elevate potassium by 1.4 mmol/L.95
In the diagnosis of hyperkalemia, urine chemistries have a limited role since they are primarily useful for differentiating decreased renal excretion from increased potassium loads. Increased potassium loads, whether endogenous or exogenous, rarely are an occult cause of persistent hyperkalemia, and so the urinary chemistries nearly always point to inappropriate renal handling of potassium.
The decision of when and how to treat hyperkalemia should be based on physical signs, the clinical situation, and serum potassium. Individual tolerances of hyperkalemia can vary dramatically and are influenced by pH, calcium concentration, rate of potassium rise, and underlying heart disease. Patients with rapid increases in serum potassium or hypocalcemia may have arrhythmias at serum potassium levels as low as 7 mmol/L, while newborns regularly tolerate potassium concentrations of that level. Patients with muscle weakness or ECG changes consistent with hyperkalemia should be urgently treated. Modestly elevated potassium in the absence of ECG or muscle weakness can be treated more conservatively (Table 76-7).
Table 76–7. Time Course, Expected Decrement of Potassium, and Side Effects of Each Therapy ||Download (.pdf)
Table 76–7. Time Course, Expected Decrement of Potassium, and Side Effects of Each Therapy
|Calciuma||1 g (10 mL) of 10% calcium gluconate or calcium chloride; may repeat||Immediate (documented normalization of ECG as early as 15 s)||30–60 min ||Caution/contraindicated in hypercalcemia and digoxin toxicity|
|Insulin and glucosea||10 U of regular insulin and 50 g of glucose; can omit the glucose if the patient is hyperglycemic||Significant reduction at 15 min;a peak action at 60 mind|| >6 h (potassium still decreased by 0.76 mmol/L at 6 h)e||1 mmol/L||Hypoglycemia and hyperglycemia; hyperglycemia may increase serum potassium through solute drag|
|Albuterol IVf||0.5% mg in 100 mL of 5% dextrose solution infused over 15 min ||Onset and peak action at 30 mins||6 h||1–1.5 mEq/L||Tachycardia, variable changes in BP, tremor; rise in blood glucose|
|Albuterol nebulizedg||10–20 mg in 5 mL of normal saline inhaled over 10–15 min||5–10 min with peak action at 30–120 min||3–6 h|| and insulin; rise in serum potassium in the first minute after MDI spacer use; rise|
|Albuterol MDI with spacerh||1200 μg via MDI||3–5 min with potassium falling at end of study||Only one study and test ended at 60 min; K was still trending down||≥0.4 mmol/L|| averaged only 0.15 mmol/L, but 59% had a rise of at least 0.1 mmol/L and two had a rise of >0.4 mmol/L|
|Sodium bicarbonate||4-mEq/min drip for a total of 400 mEq; note: lower doses, 50–100 mEq have been shown to be ineffective||240 min;i note: the prolonged time for onset of hypokalemic effect||Potassium was still falling at end of 6-h study||0.6 at 4 h 0.74 mmol/L at 6 h||May precipitate tetany by decreasing ionized calcium; may antagonize cardioprotective effect of calcium|
First-line therapy for hyperkalemia should be stopping any and all potassium sources. Total parenteral nutrition, potassium supplements, transfusions, and medications containing potassium should be stopped. Patients already on peritoneal dialysis with potassium added to the peritoneal fluid should be switched to potassium-free fluid. Patients on continuous renal replacement therapies need to have the replacement fluid potassium verified and removed.
Calcium reverses the ECG changes seen in hyperkalemia and decreases the risk of arrhythmia. Both calcium chloride and calcium gluconate can be used, but the chloride formulation has three times the elemental calcium (0.225 mmol/mL vs. 0.68 mmol/mL of a 10% solution). Since the cardioprotective effect of calcium has been shown to be dose dependent it is presumed that the chloride salt is more effective than the gluconate.96 The downside of calcium chloride is that it is more irritating to veins. Both compounds cause tissue necrosis if extravasated. The onset of action is immediate and duration is approximately 1 hour. If, following a dose of IV calcium, hyperkalemic ECG changes persist, the calcium should be repeated. In animal studies, calcium channel blockers ablate the cardioprotective effect of calcium.96,97
Calcium may be contraindicated in hyperkalemia due to digitalis toxicity.98 Digitalis toxicity is associated with intracellular hypercalcemia. Theoretically, additional calcium can worsen the toxicity and precipitate arrhythmias. Clinical data to support this are scant. Bower and Mengle reported two cases of cardiovascular collapse and death following the administration of calcium in digitalized patients, but no information on digitalis levels, serum calcium, or potassium concentrations was provided.99 Digitalis toxicity with hyperkalemia should be treated with digoxin FAB to rapidly remove the drug (improvement within 2 hours).
The fastest method to reduce serum potassium is to induce a transcellular shift. IV insulin with glucose (to prevent hypoglycemia) will reduce potassium within 15 minutes and the lower serum levels persist for up to 6 hours.100 This treatment can be repeated. The primary side effect is hypoglycemia.
Albuterol has been used to stimulate β2 receptors and produce a transcellular shift of potassium. Albuterol has been shown to be effective when given IV, by nebulizer, or by metered dose inhaler with spacer.101–103 One concern is the β-selectivity of albuterol. α-Agonists increase serum potassium. Two studies that looked at potassium immediately after administration of albuterol showed a brief increase in serum potassium.101,104 A short-lived predominance of α activity immediately following administration of albuterol may account for the increase in serum potassium.
Combining therapies is additive but not synergistic. Combining albuterol and insulin/glucose is particularly appealing, as albuterol decreases the incidence of hypoglycemia.105 In a well controlled trial the use of insulin and glucose with albuterol was twice as efficacious than either drug alone (1.2 mmol/L at 1 hour vs. 0.6 mmol/L).106
Bicarbonate has long been listed as a way to induce an intracellular potassium shift, based primarily on case reports and small trials.107,108 Recent data have shown bicarbonate to be an ineffective agent for the treatment of hyperkalemia. Blumberg and associates found an increase in potassium of 0.2 mmol/L following bicarbonate infusions, regardless whether isotonic or hypertonic bicarbonate was used.109 Sodium bicarbonate also was ineffective in patients with low serum bicarbonate. Additionally, increased pH lowers ionized calcium, increasing the risk of arrhythmia with hyperkalemia.
Other strategies to induce a transcellular shift include epinephrine infusions and aminophylline; however, both of these therapies are less effective than insulin and glucose.109,110
In patients with cardiac arrest, the ability to induce a transcellular shift is reduced.111 This may be due to decreased blood flow to skeletal muscle and the liver, which are the primary tissues involved in cellular redistribution.112
Enhanced GI Clearance of Potassium
In addition to inducing a transcellular shift of potassium, patients with increases in total body potassium must get specific therapy to remove potassium from the body. Cation exchange resins can enhance intestinal potassium excretion. Sodium polystyrene (SPS) resins bind approximately 1 mEq of potassium per gram of resin. SPS maximally absorbs potassium when given orally, but enemas are effective.113 When given at doses of 20 to 40 g, SPS resins can be effective at treating acute hyperkalemia after calcium and intracellular shift treatments have been initiated. Two recent studies have questioned the effectiveness of SPS resins, but until larger studies corroborate these findings, SPS resins remain part of the therapy for acute hyperkalemia.114,98 SPS and sorbitol usage have rarely been associated with intestinal necrosis.115–117
Enhanced Renal Clearance of Potassium
In patients with decreased renal excretion of potassium, but adequate GFR, the kidneys may be used to increase potassium excretion. The best way to increase renal potassium excretion is to increase distal delivery of sodium and increase tubular flow by increasing sodium intake and using loop diuretics. Potassium-sparing diuretics should be stopped.
In cases of severe hyperkalemia hemodialysis is the best method to remove potassium from the body. In a study comparing various therapeutic regimens for hyperkalemia, Blumberg and colleagues found hemodialysis to be faster than insulin and glucose, with 1-hour reductions of serum potassium of 1.34 mmol/L.109 Higher serum potassium concentrations enhance dialytic clearance of potassium. A 4-hour dialysis session with a potassium bath of 1 mmol/L can be expected to remove between 60 and 140 mmol of potassium.118 Following dialysis the serum concentration rises significantly. Therapies that shift potassium into cells decrease the effectiveness of dialysis and increase the post-rebound serum potassium.118 There is concern that dialyzing patients prone to cardiac arrhythmias against a low potassium dialysate may precipitate arrhythmias. In a randomized controlled trial, potassium modeling (stepwise lowering of the potassium bath during treatment) reduced premature ventricular contractions (PVCs) and PVC couplets during dialysis.119 The use of intermittent dialysis has been successful in the face of cardiac arrest. In one case of ventricular fibrillation due to hyperkalemia, CPR provided adequate blood pressure to dialyze the patient. Cardiac function was restored after 25 minutes of dialysis.120
Continuous renal replacement therapy (CRRT) is also effective at reducing potassium and is better tolerated than intermittent hemodialysis in unstable patients. CRRT has been used to successfully treat hyperkalemic asystole.121
Other Issues in the Treatment of Hypokalemia
An important factor to consider when adopting a treatment strategy for hyperkalemia is whether the source of potassium is transient (e.g., potassium overdose) or continuous (e.g., limb or gut ischemia). In the latter situation the use of intermittent hemodialysis will provide temporary correction followed by recurrent hyperkalemia. CRRT offers a unique advantage in this situation as it prevents rebound hyperkalemia. In cases of severe hyperkalemia from a continuous potassium leak, one should consider mixed modalities: initiating intermittent hemodialysis to rapidly correct the hyperkalemia, followed by CRRT to prevent rebound hyperkalemia.
There are multiple cases in the literature of patients with remarkable neurologic recovery despite prolonged resuscitative efforts.111,122,123 Patients with hyperkalemic cardiac arrest may have better outcomes than generally associated with cardiac arrest and deserve aggressive and prolonged resuscitative efforts.