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Matthew McGuire

, and Subramaniam Pennathur

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date: 29 June 2022

  1. A. Introduction

    1. a. Definition. Hypokalemia refers to serum potassium concentration <3.5 mEq/L.

    2. b. Maintenance of plasma potassium

      1. i. More than 95% of potassium is intracellular.

      2. ii. Plasma potassium is maintained in a narrow range primarily by two mechanisms:

        1. 1. Intracellular and extracellular shifts of potassium

        2. 2. Renal potassium excretion

      3. iii. Increased intracellular shifts and increased renal and gastrointestinal potassium losses lead to hypokalemia.

  2. B. Clinical Manifestations of Hypokalemia. The clinical manifestation of hypokalemia arise from alterations in membrane polarization and are organ specific:

    1. a. Cardiac. Altered cardiac conduction is the most life-threatening abnormality. An electrocardiogram may display flattened T waves and emergence of new or prominent U waves. Patients are at risk for ventricular ectopy, which may not always correlate with potassium levels. Hypokalemia also predisposes patients to digoxin toxicity; therefore, this should be considered in patients on digoxin treatment.

      Hot Key

      Hypokalemia predisposes patients to digoxin toxicity.

    2. b. Neuromuscular. Patients can experience a range of abnormalities from mild weakness to paralysis. Paralysis is uncommon with potassium levels >2 mEq/L. Muscle cramps, muscle weakness, respiratory failure, and ileus can occur. Hypokalemia also predisposes patients to rhabdomyolysis.

      Hot Key

      Hypokalemia predisposes patients to rhabdomyolysis.

    3. c. Renal. Hypokalemia leads to a urinary concentrating defect (nephrogenic diabetes insipidus), which leads to polydipsia and polyuria. Additionally, hypokalemia can both initiate and maintain a metabolic alkalosis. Prolonged hypokalemia can lead to renal tubular damage and interstitial fibrosis.

    4. d. Endocrine. Aldosterone levels are depressed, and pancreatic insulin release is inhibited.

  3. C. Causes of Hypokalemia

    1. a. Hypokalemia with transcellular redistribution

      1. i. Alkalosis stimulates transcellular H+/K+ exchange in an attempt to restore normal pH.

      2. ii. Insulin excess indirectly stimulates the transcellular Na+, K+-ATPase pump, which leads to muscle and liver cellular potassium uptake.

      3. iii. β‎-Adrenergic agonists cause direct stimulation of the Na+, K+-ATPase pump.

      4. iv. Hypokalemic periodic paralysis is a rare hereditary disorder leading to rapid recurrent attacks of flaccid paralysis, lasting from 4–24 hours, due to intracellular potassium shifts. Patients of Asian descent and those with thyroid disease are particularly vulnerable to this entity.

      5. v. Pseudohypokalemia occurs in patients with very high white blood cell counts (>105) such as in those with acute leukemia. Redistribution can occur with leukocyte uptake of potassium after phlebotomy if the sample is kept at room temperature.

    2. b. Hypokalemia due to true potassium depletion. Urinary potassium excretion can only be interpreted in a euvolemic patient. Otherwise, volume contraction may reduce urinary potassium excretion and obscure a state of hyperaldosteronism.

      1. i. Extrarenal potassium loss. If the kidney is not the source of potassium loss in a hypokalemic patient, the urinary potassium excretion should be <25 mEq/day (spot urine potassium-to-creatinine ratio <13 mEq/g). Diarrhea, fistula drainage, and villous adenomas are usually easily diagnosed based on clinical presentation and this rule. However, laxative use or abuse may be more difficult to diagnose and may require stool electrolyte measurement. Potassium loss through the skin in the form of severe burns or sweat is best diagnosed by history and examination. Inadequate potassium intake is a rare cause but can be seen in patients with eating disorders.

      2. ii. Renal potassium loss. Urinary potassium excretion is >25 mEq/day (spot urine potassium-to-creatinine ratio >13 mEq/g). Another method to assess renal potassium handling is the transtubular potassium gradient (TTKG). This calculation adjusts for concentrating effects in the distal nephron.

        TTKG = (Urine K/serum K)/(Urine osmolalrity/serum osmolalrity)

        Normal TTKG is about 8–9. Lower values indicate reduced excretion, and higher values indicate enhanced excretion.

        The causes of hypokalemia in this setting can be subdivided based on the patient’s blood pressure.

        1. 1. Patients with elevated blood pressure. Mineralocorticoid excess may be responsible for potassium loss and hypertension in this setting.

          • a. Hyperreninemic states include hypertensive emergencies, renal artery stenosis, and rare renin-producing tumors.

          • b. Hyporeninemic states include primary hyperaldosteronism, apparent mineralocorticoid excess (e.g. licorice ingestion, Liddle’s syndrome), Cushing’s syndrome, and congenital adrenal hyperplasia.

        1. 2. Patients with normal or low blood pressure. These disorders can be categorized based on serum bicarbonate concentration.

          • a. Low bicarbonate syndromes include renal tubular acidosis (see Chapter 40).

          • b. High bicarbonate syndromes can be genetic or acquired.

            • i. Genetic causes of normotensive renal potassium wasting include Bartter’s syndrome (defects in loop diuretic–sensitive transporter), Gitelman’s syndrome (defects in thiazide-sensitive transporter).

            • ii. Acquired causes of normotensive renal potassium wasting include diuretic therapy, an excess of non-reabsorbable anions (bicarbonate from supplementation or as a result of upper gastrointestinal losses, β‎-hydroxybutyrate excess from starvation/diabetic ketoacidosis, or hippurate from glue sniffing). Diuretics increase flow to the distal nephron and hence potassium elimination. An excess of non-reabsorbable anions typically causes polyuria and volume depletion, and potassium is eliminated with the anions preferentially over sodium.

          • c. Hypomagnesemia leads to opening of renal outer medullary potassium channels in the collecting tubule and allows intracellular potassium efflux into the filtrate.

  4. D. Treatment

    1. a. The underlying disorder, if known, should be treated. The serum potassium level should be corrected through oral or intravenous (IV) route.

      1. i. Oral repletion by pharmacologic potassium preparations and/or high-potassium diets is the preferred route. Oral potassium preparations include potassium chloride, potassium phosphate, and potassium bicarbonate (or organic anion precursor). In all but rare instances, potassium chloride is the favored form of potassium repletion.

      2. ii. IV administration can be considered with severe, symptomatic hypokalemia or if patients are unable to tolerate oral medication. Remember, IV potassium is highly phlebitic and can cause pain and burning during infusion. Consider central venous access in patients who will need high rates or extensive IV repletion.

      3. iii. Peripheral IV rates should not exceed 10 mEq/hr, and central IV rates should not exceed 20–40 mEq/hr.

        Hot Key

        High rates of potassium repletion require continuous electrocardiographic monitoring and may require central venous access because potassium is an irritant to peripheral veins.

    2. b. Hypomagnesemia, and glucose or alkali administration, can worsen hypokalemia and should be corrected before or during potassium administration.

      1. i. Hypomagnesemia, in particular, must be corrected before potassium repletion, or repletion will be ineffective (owing to ongoing renal wasting).

    3. c. Serum potassium levels should be followed closely when repletion is being performed. In general, for every 10 mEq of supplemental potassium given, serum potassium will rise by 0.1 mEq/L. However, this approximation is less valid when serum potassium levels are less than 3 mEq/L, at which point there is a significant potassium deficit and larger amounts of supplementation will likely be required.

Suggested Further Readings

Crop MJ, Hoorn EJ, Lindemans J, Zietse R. Hypokalaemia and subsequent hyperkalaemia in hospitalized patients. Nephrol Dial Transplant 2007;22:3471–7.Find this resource:

Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451–8. (Classic Article.)Find this resource:

Unwin RJ, Luft FC, Shirley DG. Pathophysiology and management of hypokalemia: a clinical perspective. Nat Rev Nephrol 2011;7:75.Find this resource:

Wu K-L, Cheng C-J, Sung C-C, et al. Identification of the causes for chronic hypokalemia: importance of urinary sodium and chloride excretion. Am J Med 2017;130:846–55.Find this resource: