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Nephro Flash 2017 › Nephro Flash Vol-3, No-2, 2017

Potassium Replacement in Clinical Practice

Overview of Hypokalemia

Hypokalemia is defined as a plasma K+ concentration lower than 3.5 mEq/L.1Hoskote SS, Joshi SR, Ghosh AK. Disorders of Potassium Homeostasis: Pathophysiology and Management. JAPI 2008; 56: 685–693.   It occurs in up to 21% of hospitalised patients and 2% to 3% of outpatients.2Viera AJ, Wouk N. Potassium Disorders: Hypokalemia and Hyperkalemia. American Family Physician 2015; 92(6):487–495.

Diuretic therapy is the most common cause of potassium deficiency. Although the extent of potassium deficiency usually does not exceed 200 or 300 mEq, under appropriate circumstances such modest deficiency may have important consequences. Factors that tend to increase the incidence or severity of potassium deficiency in patients who take diuretics include high salt diets, large urine volumes, metabolic alkalosis, increased aldosterone production, and the simultaneous use of two diuretics that act on different sites in the renal tubule.3Knochel JP. Diuretic-induced hypokalemia. Am J Med. 1984; 77(5A):18–27.

Hypokalemia results in hyperpolarisation of the cell membrane, which impairs the ability of the cell to generate action potentials in excitable tissues such as muscles and nerves. Mild hypokalemia (3–3.5 mmol/L) is often asymptomatic. Moderate hypokalemia (2.5–3.0 mmol/L) may result in muscle weakness, fatigue and paraesthesia as well as ileus and constipation, because the smooth muscle of the gastrointestinal tract may be affected. In rare instances, severe Hypokalemia may precipitate rhabdomyolysis. Hypokalemia may also interfere with the ability of the kidney to concentrate the urine, thereby resulting in nephrogenic diabetes insipidus with polyuria and polydipsia.4Hughes. Disorders of potassium balance, In. p 21-37. Available from http://booksite.elsevier.com/samplechapters/9780443071973/9780443071973.pdf [Accessed 5th June 2017].

In patients with cardiac disease, hypokalaemia is associated with a greatly increased risk of ventricular arrhythmias. Severe hypokalaemia (< 2.5 mmol/L) can lead to weakness of respiratory muscles and ventilatory failure.4Hughes. Disorders of potassium balance, In. p 21-37. Available from http://booksite.elsevier.com/samplechapters/9780443071973/9780443071973.pdf [Accessed 5th June 2017].

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Causes of Hypokalemia

Potential causes include diuretic therapy, inadequate dietary potassium intake, high dietary sodium intake, and hypomagnesemia (Table 1). In most cases, hypokalemia is secondary to drug treatment, particularly diuretic therapy (Table 2).5Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.

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Diuretics inhibit chloride-associated sodium reabsorption in the kidney, creating a favourable electrochemical gradient for potassium secretion. The degree of hypokalemia is directly related to the dose and half-life of the diuretic administered. Hypokalemia occurs infrequently in patients with uncomplicated hypertension who take a diuretic but is more common in patients with congestive heart failure (CHF), nephrotic syndrome, or cirrhosis of the liver, who take an equivalent dose of a diuretic and consume approximately the same amount of potassium from food.5Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.

Gitelman’s Syndrome

Gitelman syndrome (GS) is a heritable renal disorder characterised by hypomagnesemia, hypokalemia and hypocalciuria.6Gjata M, Tase M, Gjata A, et al. Gitelman’s Syndrome (Familial hypokalemia- hypomagnesemia). Hippokratia. 2007, 11, 3: 150–153   The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders.7Knoers N VAM, Levtchenko EN. Gitelman syndrome. Orphanet Journal of Rare Diseases. 2008, 3:22 doi:10.1186/1750-1172-3-22.   It is usually caused by mutations in the SLC12A3 and CLCNKB genes. The proteins produced from these genes are involved in the kidneys’ reabsorption of salt (sodium chloride or NaCl) from urine back into the bloodstream. Mutations in either gene impair the kidneys’ ability to reabsorb salt, leading to the loss of excess salt in the urine (salt wasting). Abnormalities of salt transport also affect the reabsorption of other ions, including ions of potassium, magnesium and calcium. The resulting imbalance of ions in the body underlies the major features of Gitelman syndrome.8NIH. NLM. Gitelman syndrome. Available from: https://ghr.nlm.nih.gov/condition/ gitelman-syndrome [Accessed on 24th June 2017]   Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria).7Knoers N VAM, Levtchenko EN. Gitelman syndrome. Orphanet Journal of Rare Diseases. 2008, 3:22 doi:10.1186/1750-1172-3-22.   Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulphate) is recommended. All GS patients are encouraged to maintain a high-sodium and high potassium diet.7Knoers N VAM, Levtchenko EN. Gitelman syndrome. Orphanet Journal of Rare Diseases. 2008, 3:22 doi:10.1186/1750-1172-3-22.   Long term prognosis in terms of maintaining growth, preserving renal function and life expectancy is excellent.6Gjata M, Tase M, Gjata A, et al. Gitelman’s Syndrome (Familial hypokalemia- hypomagnesemia). Hippokratia. 2007, 11, 3: 150–153

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Diagnosis of Hypokalemia

In most cases, the cause of hypokalemia is apparent from the history and physical examination. First-line studies include measurement of urine potassium, a serum magnesium assay, and an electrocardiogram (ECG).9Lederer E. Hypokalemia. Available from http://emedicine.medscape.com/article/ 240903-overview

Depending on history, physical examination findings, clinical impressions, and urine potassium results, the following tests may be appropriate, but they should not be first-line tests unless the clinical index of suspicion for the disorder is high:9Lederer E. Hypokalemia. Available from http://emedicine.medscape.com/article/ 240903-overview

  • Drug screen in urine and/or serum for diuretics, amphetamines, and other sympathomimetic stimulants
  • Serum renin, aldosterone, and cortisol
  • 24-hour urine aldosterone, cortisol, sodium, and potassium
  • Pituitary imaging to evaluate for Cushing syndrome
  • Adrenal imaging to evaluate for adenoma
  • Evaluation for renal artery stenosis
  • Enzyme assays for 17-beta hydroxylase deficiency
  • Thyroid function studies in patients with tachycardia, especially Asians
  • Serum anion gap (e.g., to detect toluene toxicity)

Epidemiology

The occurrence of hypokalemia is strongly dependent on the patient population. In otherwise healthy adults not receiving any medications, less than 1% will develop hypokalemia, as defined by a serum potassium level of less than 3.5 mEq/liter. This very low frequency of hypokalemia is a testament to two factors: the adequacy of potassium in the typical Western diet, and potent mechanisms for renal potassium conservation in states of potassium depletion.10Weiner D, Wingo CS. Hypokalemia-Consequences , Causes , and Correction. Journal of the American Society of Nephrology 1997; 8(7): 1179–1188.

Most cases of hypokalemia occur in the setting of specific disease states. Patients receiving diuretics are at the highest risk. Individuals with secondary hyperaldosteronism, whether due to congestive heart failure, hepatic insufficiency, or nephrotic syndrome, constitute a second group at high risk. Finally, those patients with diseases that alter renal potassium conservation through interaction with salt delivery to the cortical collecting duct (CCD) are also at high risk for hypokalemia.10Weiner D, Wingo CS. Hypokalemia-Consequences , Causes , and Correction. Journal of the American Society of Nephrology 1997; 8(7): 1179–1188.

Clinical implications of hypokalaemia

The clinical estimation of potassium balance generally depends on the level of serum potassium. Since the extracellular fluid contains only 2 percent of the total body potassium, it must be recognized that potassium deficits are usually large before significant hypokalemia occurs. The total body potassium is regulated by the kidney in which distal nephron secretion of potassium into the urine is enhanced by aldosterone, alkalosis, adaptation to a high potassium diet, and delivery of increased sodium and tubular fluid to the distal tubule. However, the distribution of potassium between the intracellular and extracellular fluids can markedly affect the serum potassium level without a change in total body potassium. Cellular uptake of potassium is regulated by insulin, acid-base status, aldosterone, and adrenergic activity. Hypokalemia, therefore, may be caused by redistribution of potassium into cells due to factors that increase cellular potassium uptake, in addition to total body depletion of potassium due to renal, gastrointestinal, or sweat losses. An understanding of the drugs that affect potassium homeostasis, either by altering the renal excretion of potassium or by modifying its distribution, is essential to the proper assessment of many clinical potassium abnormalities. Hypokalemia may cause asymptomatic electrocardiographic changes, serious arrhythmias, muscle weakness, and death. Hypokalemia has also been associated with several other consequences, including postural hypotension, potentiation of digitalis toxicity, confusional states, glucose intolerance, polyuria, metabolic alkalosis, sodium retention, rhabdomyolysis, intestinal ileus, and decreased gastric motility and acid secretion.11Brown RS. Potassium homeostasis and clinical implications. Am J Med. 1984;77(5A):3–10.

Significance of potassium

Potassium is present in most foods in varying amounts. Although the typical dietary intake averages 70 mEq/d, there is considerable variation, depending on the dietary preferences of the individual. In the absence of other factors, the body can adapt to a wide range of potassium intake without development of marked hypokalemia. Notably, African Americans commonly eat diets containing less potassium, which may induce a state of physiologic potassium deficiency and contribute to the incidence and severity of hypertension in this population.10Weiner D, Wingo CS. Hypokalemia-Consequences , Causes , and Correction. Journal of the American Society of Nephrology 1997; 8(7): 1179–1188.

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Potassium supplementation strategies

Increasing potassium intake should be considered when serum potassium levels are between 3.5 and 4.0 mmol. Efforts to increase potassium intake are appropriate in certain populations who are vulnerable to cardiac arrhythmias (such as patients with heart failure, those taking digoxin, and patients with a history of myocardial infarction or ischemic heart disease). When the serum potassium level is below 3.5 mmol, potassium supplementation may be warranted even in asymptomatic patients with mild-to-moderate hypertension.5Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.

Increasing dietary potassium is the most straightforward means of enhancing potassium intake, but the high content of some potassium-rich foods is a potential drawback to dietary potassium supplementation (Table 3).5Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.

Repletion strategies also should include eating foods high in potassium, using salt substitutes, or taking prescription potassium supplements.5Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.

Potassium salts include potassium chloride, potassium phosphate, and potassium bicarbonate. Potassium phosphate is found primarily in food, and potassium bicarbonate is typically recommended when potassium depletion occurs in the setting of metabolic acidosis (pH, 7.4). In all other settings, potassium chloride should be used because of its unique effectiveness against the most common causes of potassium depletion. Potassium chloride is available in either liquid or tablet formulations and all potassium formulations are readily absorbed. Although liquid forms may be less expensive, they have a strong, unpleasant taste and often are not well tolerated.5Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.

Potassium replacement therapy

For successful potassium replacement, one should consider the optimal potassium preparation, route of administration, and the appropriate speed of administration. In the absence of an independent factor causing transcellular potassium shifts, the plasma potassium concentration can be used as a rough index to estimate body potassium stores. Oral KCl replacement therapy is preferable if there are bowel sounds, except in the setting of life-threatening abnormalities such as ventricular arrhythmias, digitalis intoxication, or paralysis.12Kim GH, Han JS. Therapeutic Approach to Hypokalemia. Nephron. 2002;92(1):28–32.

Hypokalemia caused due to true potassium deficit should be treated with K+ replacement, though if serious complications are expected, hypokalemia resulting from transcellular shifts may also be treated similarly. Potassium chloride or acetate are used depending on coexistent alkalosis or acidosis, respectively.1Hoskote SS, Joshi SR, Ghosh AK. Disorders of Potassium Homeostasis: Pathophysiology and Management. JAPI 2008; 56: 685–693.  

The 2005 American Heart Association (AHA) guidelines recommend K+ replacement for serum levels below 2.5 mEq/L to avert risk of cardiac arrhythmias. Replacement should be carried out gradually, rather than rapidly, unless the patient’s severity so demands. It is difficult to estimate the K+ requirement because the ECF concentration does not reflect body stores. Hence, it is important to frequently monitor serum K+ while administering therapy. Response to treatment improves with co-administration of magnesium replacement, especially in hypokalemia that is refractory to therapy.1Hoskote SS, Joshi SR, Ghosh AK. Disorders of Potassium Homeostasis: Pathophysiology and Management. JAPI 2008; 56: 685–693.  

Replacement should be initiated with oral potassium chloride because a greater rise in ECF potassium can be achieved with this route at the expense of fewer adverse events and parenteral administration should be reserved for patients unable to take enteral doses. According to the AHA guidelines K+ replacement should be empiric, with a maximum intravenous potassium chloride infusion rate of 10-20 mEq/L, while continuously monitoring the ECG.1Hoskote SS, Joshi SR, Ghosh AK. Disorders of Potassium Homeostasis: Pathophysiology and Management. JAPI 2008; 56: 685–693.  

Guidelines for the use of replacement in clinical practice5Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.

Because of the multiple factors involved, guidelines therefore should be directed toward patients with specific disease states, such as those with cardiovascular conditions, and toward the general patient population. The following list encompasses the general practices for the use of potassium.

  1. Dietary consumption of potassium rich foods should be supplemented with potassium replacement therapy. Often, increasing dietary potassium intake is not completely effective in replacing the potassium loss associated with chloride depletion (eg, that which occurs in diuretic therapy, vomiting, or nasogastric drainage) because dietary potassium is almost entirely coupled with phosphate, rather than with chloride. In addition, the consumption of potassium-rich foods in amounts that are sufficient to increase the level of serum potassium level to acceptable concentrations may be costly, and it may lead to weight gain.
  2. Potassium replacement is recommended for individuals who are sensitive to sodium or who are unable or unwilling to reduce salt intake; it is especially effective in reducing blood pressure in such persons. A high-sodium diet often results in excessive urinary potassium loss.
  3. Potassium replacement is recommended for individuals who are subject to nausea, vomiting, diarrhoea, bulimia, or diuretic/laxative abuse. Potassium chloride has been shown to be the most effective means of replacing acute potassium loss.
  4. Potassium supplements are best administered orally in a moderate dosage over a period of days to weeks to achieve the full repletion of potassium.
  5. Although laboratory measurement of serum potassium is convenient, it is not always an accurate indicator of total body potassium. Measurement of 24-hour urinary potassium excretion is appropriate for patients who are at high risk (eg, those with CHF).
  6. Patient adherence to potassium supplementation may be increased with compliance-enhancing regimens. Microencapsulated formulations have no unpleasant taste and are associated with a relatively low incidence of gastrointestinal side effects.
  7. Potassium supplementation regimens should be as uncomplicated as possible to help optimize long term compliance.
  8. A dosage of 20 mmol/d of potassium in oral form is generally sufficient for the prevention of hypokalemia, and 40 to 100 mmol/d sufficient for its treatment.

Conclusion

Disorders of potassium homeostasis are common electrolyte abnormalities encountered in hospitalized patients. Hypokalemia and hyperkalemia have been estimated to occur in about 21% and 3% of hospitalized patients, respectively; though the morbidity and mortality associated with the latter is significantly higher. Potassium is a predominantly intracellular ion and the understanding of its dynamics between intra- and extracellular fluid milieus, along with its handling by the kidneys, is important in the diagnosis and treatment of potassium disorders. Amongst various potassium supplements, potassium chloride is the usual choice for supplementation in most cases of mild hypokalemia due to its unique effectiveness against the most common causes of potassium depletion.

References

  1. Hoskote SS, Joshi SR, Ghosh AK. Disorders of Potassium Homeostasis: Pathophysiology and Management. JAPI 2008; 56: 685–693.
  2. Viera AJ, Wouk N. Potassium Disorders: Hypokalemia and Hyperkalemia. American Family Physician 2015; 92(6):487–495.
  3. Knochel JP. Diuretic-induced hypokalemia. Am J Med. 1984; 77(5A):18–27.
  4. Hughes. Disorders of potassium balance, In. p 21-37. Available from http://booksite.elsevier.com/samplechapters/9780443071973/9780443071973.pdf [Accessed 5th June 2017].
  5. Cohn JN, Kowey PR, Whelton PK, Prisant M. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000;160:2429–2436.
  6. Gjata M, Tase M, Gjata A, et al. Gitelman’s Syndrome (Familial hypokalemia- hypomagnesemia). Hippokratia. 2007, 11, 3: 150–153
  7. Knoers N VAM, Levtchenko EN. Gitelman syndrome. Orphanet Journal of Rare Diseases. 2008, 3:22 doi:10.1186/1750-1172-3-22
  8. NIH. NLM. Gitelman syndrome. Available from: https://ghr.nlm.nih.gov/condition/ gitelman-syndrome [Accessed on 24th June 2017]
  9. Lederer E. Hypokalemia. Available from http://emedicine.medscape.com/article/ 240903-overview
  10. Weiner D, Wingo CS. Hypokalemia-Consequences , Causes , and Correction. Journal of the American Society of Nephrology 1997; 8(7): 1179–1188.
  11. Brown RS. Potassium homeostasis and clinical implications. Am J Med. 1984;77(5A):3–10.
  12. Kim GH, Han JS. Therapeutic Approach to Hypokalemia. Nephron. 2002;92(1):28–32.
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