Disorders of potassium homeostasis are common in hospitalized patients and may be associated with severe adverse clinical outcomes, including death. Prevention and proper treatment of hyper- and hypokalemia depend on an understanding of the underlying physiology.
The total body potassium content of a 70-kg adult is about 3500 mmol (136.5 g), of which only 2% (about 70 mmol / 2.73 g) is extracellular. It is not surprising that the extracellular potassium concentration is tightly regulated. In fact, two separate and cooperative systems participate in potassium homeostasis. One system regulates external potassium balance: the total body parity of potassium elimination with potassium intake. The other system regulates internal potassium balance: the distribution of potassium between the intracellular and extracellular fluid compartments. This latter system provides a short-term defense against changes in the plasma potassium concentration that might otherwise result from total body potassium losses or gains.
Disorders of Potassium Homeostasis
Disorders of potassium homeostasis may be conveniently divided according to the duration of the disturbance: acute (<48 hours’ duration) or chronic.
Excessive potassium intake. Given an acute potassium load, a normal individual will excrete about 50% in the urine and transport about 90% of the remainder into cells over 4 to 6 hours. It is possible to overwhelm this adaptive mechanism such that if too much potassium is taken in too quickly, significant hyperkalemia will result. Such events are almost always iatrogenic. One’s ability to tolerate a potassium load declines with disordered internal balance and impaired renal potassium excretory capacity. In such circumstances, an otherwise tolerable increase in potassium intake may cause clinically significant hyperkalemia: Doses of oral potassium supplements as small as 30 to 45 mmol have resulted in severe hyperkalemia in patients with impaired external or internal potassium homeostasis.
KCl, used as a supplement, is the drug most commonly implicated in acute hyperkalemia. Banked blood represents a trivial potassium load under most circumstances, because a unit of fresh banked blood, either whole or packed cells, contains only 7 mmol (273 mg) of potassium. Thus, severe hyperkalemia would result only from massive transfusion of compatible blood. However, the potassium concentration in banked blood does increase substantially as the blood ages.
Patients undergoing open heart surgery are exposed to cardioplegic, solutions containing KCl typically at about 16 mmol/L, which may lead to clinically significant hyperkalemia in the postoperative period, especially in patients with diabetes mellitus with or without renal failure.
Abnormal potassium distribution. Acute hyperkalemia may result from sudden redistribution of intracellular potassium to the extracellular space. If only 2% of intracellular potassium were to leak unopposed from cells, serum potassium level would immediately double. Fortunately, such dramatic circumstances are rarely encountered. Nevertheless, smaller degrees of potassium redistribution commonly result in clinically significant hyperkalemia.
Among the most impressive syndromes associated with acute hyperkalemia are those involving rapid cell lysis. The tumor lysis syndrome results from treatment of chemosensitive bulky tumors with release of intracellular contents, including potassium, into the ECF. Extreme hyperkalemia even causing sudden death has featured prominently in some series of patients. Most of such patients were in renal failure from acute uric acid nephropathy, thus impairing their ability to excrete the potassium load. Rhabdomylosis, either traumatic or nontraumatic, may result in sudden massive influx of potassium to the extracellular space. Other circumstances that may result in redistributive hyperkalemia include severe extensive burns, hemolytic transfusion reactions, and mesenteric ischemia or infarction.
Pharmacologic agents. Two drugs may rarely cause acute hyperkalemia by redistribution: digitalis glycosides and succinylcholine. Massive digitalis overdose has been associated with extreme hyperkalemia. Succinylcholine depolarizes the motor end plate and in normal individuals causes a trivial amount of potassium leak from muscle, resulting in an increase in serum potassium level by about 0.5 mmol/L. In patients with neuromuscular disorders, muscle damage, or prolonged immobilization, however, muscle depolarization may be more widespread, causing severe hyperkalemia. Prolonged use of nondepolarizing non depolarizing neuromuscular blockers in critically ill patients may predispose to succinylcholine-induced hyperkalemia.
Hyperkalemic periodic paralysis. This rare syndrome of episodic hyperkalemia and paralysis is caused by a mutation of the skeletal muscle sodium channel, inherited in an autosomal dominant pattern. Attacks may be precipitated by exercise, fasting, exposure to cold, and potassium administration, and prevented by frequent carbohydrate snacks. Attacks are usually brief and treatment consists of carbohydrate ingestion. Severe attacks may require intravenous glucose infusion.
Acute renal failure. Hyperkalemia accompanies acute renal failure in 30% to 50% of cases. It is seen most commonly in oliguric renal failure. Contributing factors include tissue destruction and increased catabolism.
Pseudohyperkalemia. It refers to a measured potassium level that is higher than that circulating in the patient’s blood. It has a number of possible causes. First, it may be caused by efflux of potassium out of blood cells in the test tube after phlebotomy. This may be seen in a serum specimen in cases of thrombocytosis or leukocytosis, when the clot causes cell lysis in vitro. These days, many clinical laboratories measure electrolytes in plasma (unclotted) specimens. Even under these conditions, extreme leukocytosis may cause pseudohyperkalemia if the specimen is chilled for a long time before the plasma is separated, leading to passive potassium leak from cells. Hemolysis during specimen collection with false raise [K+] or plasma potassium concentration by liberating intraerythrocyte to potassium. Second, if the patient’s arm is exercised by fist clenching with a tourniquet in place before the specimen is drawn, the sampled blood potassium concentration will rise significantly as a result of local muscle release of intracellular potassium.
Treatment of diabetic ketoacidosis. It is well recognized that patients presenting in DKA are always severely depleted in total body potassium as a result of glucose-driven osmotic diuresis, poor nutrition, and vomiting during the development of DKA. Paradoxically, most patients in DKA have a normal serum potassium level upon admission. Insulin deficiency and hyperglycemia appear to account for the preservation of a normal [K+] despite severe total body potassium depletion. Once therapy for DKA is instituted, however, [K+] typically plummets as potassium is rapidly taken up by cells. Potassium replacement at rates up to 120 mmol (4.68 g) per hour have been reported, with total potassium supplementation of 600 to 800 mmol (23.5 to 31.2 g) within the first 24 hours of treatment. Hypokalemia in this setting may lead to respiratory arrest.
Refeeding. A situation analogous to DKA arises during aggressive refeeding after prolonged starvation or with aggressive “hyperalimentation” of chronically ill patients. The glucose-stimulated hyperinsulinemia and tissue anabolism shift potassium into cells, rapidly depleting extracellular potassium.
Pharmacologic agents. Specific beta2-adrenergic receptor agonists may cause electrophysiologically significant hypokalemia, especially when given to patients who are potassium depleted from the use of diuretic drugs. Epinephrine, given intravenously in a dose about 5% of that recommended for cardiac resuscitation, cause a fall in [K+] by about 1 mmol/L. A rare cause of severe hypokalemia is poisoning with soluble barium salts such as chloride, carbonate, hydroxide, and sulfide. Soluble barium salts are used in pesticides and some depilatories, which may be ingested accidentally or intentionally. Thiopentone, a barbiturate used to induce coma for refractory intracranial hypertension, is associated with redistributive hypokalemia in the majority of treated patients within 12 hours of initiating therapy.
Hypokalemic periodic paralysis. Three forms of this rare syndrome have been described: familial, sporadic, and thyrotoxic. All have in common attacks of muscle weakness accompanied by acute hypokalemia caused by cellular potassium uptake.
Pseudohypokalemia. Severe leukocytosis may cause spuriously low plasma potassium concentrations if blood cells are left in contact with the plasma for a long time at room temperature or higher. This phenomenon results from ongoing cell metabolism in vitro with glucose and potassium uptake. Unexpected hypokalemia and hypoglycemia in the setting of leukocytosis should alert the clinician to this phenomenon.
Potassium exchange between ECF and ICF: insulin, epinephrine, and [H+]
Potassium renal secretion: [K+], dietary intake of potassium, AngII, aldosterone, tubular sodium delivered to principal cells (at distal nephron).
EKG Changes of Potassium Disturbances
Hyperkalemia produces a progressive evaluation of changes in the EKG that can culminate in ventricular fibrillation and death. The presence of electrocardiographic changes is a better measure of clinically significant potassium toxicity than the serum potassium level. As the potassium begins to rise, the T waves across the entire 12-lead EKG begin to peak. This effect can easily be confused with the peaked T waves of an acute myocardial infarction. One difference is that the changes in an infarction are confined to those leads overlying the area of the infarct, whereas in hyperkalemia, the changes are diffuse. With a further increase in the serum potassium, the PR interval becomes prolonged, and the P wave gradually flattens and then disappears. Ultimately, the QRS complex widens until it merges with the T wave, forming a sine wave pattern. Ventricular fibrillation may eventually develop.
It is important to note that whereas these changes frequently do occur in the order described as the serum potassium rises, they do not always do so. Progression to ventricular fibrillation can occur with devastating suddenness. Any change in the EKG due to hyperkalemia mandates immediate clinical attention.
With hypokalemia, the EKG may again be a better measure of serious toxicity than the serum potassium level. Three changes can be seen, occurring in no particular order, including: ST-segment depression, flattening of the T wave with prolongation of the QT interval, and appearance of a U wave. The term U wave is given to a wave appearing after T wave in the cardiac cycle. It is usually has the same axis as the T wave and is often best seen in the anterior leads. Its precise physiologic meaning is not fully understood. Although U waves are the most characteristic feature of hypokalemia, they are not in and of themselves diagnostic. Other conditions can produce prominent U waves, and U waves can sometimes be seen in patients with normal hearts and normal serum potassium levels. Rarely, severe hypokalemia can cause ST-segment elevation. Whenever you see ST-segment elevation or depression on an EKG, you first instinct should always be to suspect some form of cardiac ischemia, but always keep hypokalemia in your differential diagnosis.