Hypokalemia and Hyperkalemia

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Chapter 44 Hypokalemia and Hyperkalemia

Stuart L. Linas, MD , Shailendra Sharma, MD

Hypokalemia

1 Is serum potassium level an accurate estimate of total body potassium?

No. The majority of potassium is distributed in the intracellular fluid (ICF) compartment, with only approximately 2% of the total body potassium in the extracellular fluid (ECF) compartment. Alterations in serum potassium can result from transcellular potassium shift between ECF and ICF compartments or from actual changes in total body potassium.

2 When does serum potassium level falsely estimate total body potassium?

Transcellular potassium shifts between ECF and ICF compartments can have profound effects on serum potassium. Buffering of the ECF compartment, with reciprocal movement of potassium and hydrogen across the cell membrane, can result in a rise in serum potassium in the case of acidemia and a fall in serum potassium in the case of alkalemia. Two important hormones that are known to drive potassium into the ICF compartment are insulin and catecholamines.

The classic example of how serum potassium falsely estimates total body potassium is a patient with diabetic ketoacidosis. Insulin deficiency and acidemia cause potassium to shift to the ECF compartment so that serum potassium may be normal or high despite profound total body potassium depletion (due to osmotic diuresis and hyperaldosteronemic state). Only after proper treatment of insulin deficiency and acidosis does the total body potassium depletion become apparent.

3 Why is tight regulation of serum potassium concentrations so critical?

Although a small fraction of total body potassium is in the ECF compartment, changes in ECF potassium, either by compartmental shifts or by net gain or loss, significantly alter the ratio of ECF to ICF potassium, which determines the cellular resting membrane potential. As a consequence, small fluctuations in ECF potassium can have profound effects on cardiac and neuromuscular excitability.

4 How do you estimate the total body potassium deficit?

It is difficult to predict accurately the total body potassium deficit on the basis of serum potassium, but in uncomplicated potassium depletion a useful rule of thumb is as follows: For each 100 mEq potassium deficit, the fall in serum potassium level is 0.27 mEq/L. Thus, for a 70-kg patient, serum potassium of 3 mEq/L reflects a 300- to 400-mEq deficit, whereas potassium of 2 mEq/L reflects a 500- to 700-mEq deficit. In patients with acid-base disorders, this rule of thumb is not accurate because of shifts in compartmental potassium.

5 What is the relationship between potassium and magnesium?

Magnesium depletion typically occurs after diuretic use, sustained alcohol consumption, or diabetic ketoacidosis. Magnesium depletion can cause hypokalemia that is refractory to oral or intravenous (IV) potassium chloride therapy because severe magnesium depletion causes renal potassium wasting through undefined mechanisms. In the setting of severe magnesium and potassium depletion, magnesium and potassium must be replaced simultaneously.

Magnesium regulates activity of the renal outer medullary potassium (ROMK) channel. Intracellular magnesium is inversely proportional to the open ROMK channel pore. Therefore low intracellular magnesium causes more ROMK channels to open, allowing more K+ efflux into the urine.

Magnesium is also closely related to sodium-potassium–adenosine triphosphatase (Na+,K+-ATPase), possibly explaining failure to retain intracellular potassium in hypomagnesemia.

6 What factors are important in K+ balance?

K+ is mostly intracellular cation. Of 3500 mEq of total body potassium only approximately 60 mEq is in the extracellular compartment. Dietary K+ must be rapidly shifted from the vascular space into cells (internal K+ balance) before excretion by kidneys and GI tract (external balance). Internal balance is primarily regulated by insulin, whereas external balance is regulated by kidneys (85%) and gastrointestinal (GI) tract (15%).

7 What are the factors that dictate urine potassium excretion?

Key factors influencing potassium secretion include adequate sodium delivery to the distal nephron and increased aldosterone action.

8 What are the causes of hypokalemia?

image Redistribution: Intracellular potassium redistribution or shift can be caused by metabolic alkalosis, increased insulin availability, increased β2-adrenergic activity, and periodic paralysis (classically associated with thyrotoxicosis).

image GI loss: Diarrhea or poor K+ intake.

image Renal loss: Diuretics, vomiting, and states of mineralocorticoid excess (e.g., primary hyperaldosteronism, Cushing disease, European licorice ingestion, and hyperreninemia). Increases in distal sodium delivery in the setting of high plasma aldosterone levels (due to lower blood volume) result in increases in urinary potassium and subsequent hypokalemia. Other causes include hypomagnesemia and familial hypokalemic alkalosis syndromes (Bartter and Gitelman syndromes)

image Low intake: Poor oral intake or total parenteral nutrition with inadequate potassium supplement.

9 What are the clinical manifestations of hypokalemia?

By depressing neuromuscular excitability, hypokalemia leads to muscle weakness, which can include quadriplegia and hypoventilation. Severe hypokalemia disrupts cell integrity, leading to rhabdomyolysis. Among the most important manifestations of hypokalemia are cardiac arrhythmias, including paroxysmal atrial tachycardia with block, atrioventricular dissociation, first- and second-degree atrioventricular block with Wenckebach periods, and even ventricular tachycardia or fibrillation. Typical electrocardiographic (ECG) findings include ST-segment depression, flattened T waves, and prominent U waves.

10 Which drugs can cause hypokalemia?

The most common drugs are diuretics: loop diuretics, thiazides, and acetazolamide. Penicillin and penicillin analogs (e.g., carbenicillin, ticarcillin, piperacillin) also cause renal potassium wasting that is mediated by various mechanisms, including delivery of nonreabsorbable anions to the distal nephron, which results in potassium trapping in the urine. Drugs that damage renal tubular membranes such as amphotericin, cisplatin, and aminoglycosides cause renal potassium wasting even in the absence of decreases in glomerular filtration rate (GFR).

11 What is the diagnostic approach to a patient with hypokalemia?

After eliminating spurious causes (such as leukocytosis), the diagnosis of true hypokalemia can be approached on the basis of urine potassium concentration, systemic acid-base status, urine chloride level, and blood pressure (Fig. 44-1).

image

Figure 44-1 Algorithm for diagnosis of hypokalemia. ATN, Acute tubular necrosis; Cl, chloride; NG, nasogastric.

Urine potassium excretion is best measured by a 24-hour urine collection. A spot urine potassium concentration can also be measured (less accurate, but easier to obtain thus most commonly obtained) with a value of < 15 mEq/L indicating extrarenal loss (poor oral intake, GI loss, intracellular shift) and a value of > 15 mEq/L indicating renal potassium wasting. Low urine osmolality can interfere with interpretation of isolated urine potassium by diluting the urinary K+ concentration.

12 Why is serum K+ often low in patients with myocardial infarction or acute asthma?

Both conditions are associated with activation of the sympathetic nervous system. β2-Adrenergic activation results in transcellular shift of K+.

13 How do you treat hypokalemia in the setting of K+ depletion?

Oral replacement is the safest route, and administration of doses of up to 40 mEq multiple times daily is allowed. In most cases, potassium chloride is used because metabolic alkalosis and chloride depletion often accompany hypokalemia, such as in patients who are taking diuretics or who are vomiting. In these settings, coadministration of chloride is important for correction of both the metabolic alkalosis and hypokalemia. In other settings, potassium should be administered with other salt preparations. For example, in metabolic acidosis, replacement with potassium bicarbonate or bicarbonate equivalent (e.g., potassium citrate, acetate, or gluconate) is recommended to help alleviate the acidosis. Persons who abuse alcohol or who have diabetes with ketoacidosis often have concomitant phosphate deficiency and should receive some of the potassium in the form of potassium phosphate.

14 How do you treat hypokalemia in patients requiring loop diuretics?

Positive K+ balance is important in patients requiring loop diuretics because hypokalemia is arrhythmogenic. Increases in dietary K+ and or K+ supplements are often inadequate. Amiloride (Na+ channel inhibitor) and spironolactone or eplerenone (mineralocorticoid receptor antagonist) are used. Consider measuring 24-hour K+ excretion, then adjusting the dose of these agents to account for intake. The usual K+ intake is 40 to 80 mEq/day.

15 How do you treat hypokalemia in the setting of periodic paralysis?

In both familial and nonfamilial periodic paralysis (e.g., from thyrotoxicosis), hypokalemia can be life threatening. Oral propranolol (nonselective β-blocker) at the dose of 1-2 mg/kg is an effective treatment to treat an acute attack of thyrotoxic periodic paralysis.

16 When is IV potassium replacement necessary? What are the risks?

In life-threatening situations such as severe weakness, respiratory distress, cardiac arrhythmias, and rhabdomyolysis, or in situations when oral administration is not possible, potassium must be replaced intravenously. Infusion rates in the intensive care unit should be limited to 20 mEq/hr to prevent the potentially catastrophic effect of a potassium bolus to the heart.

17 What are the circumstances requiring special care in monitoring potassium replacement?

image Patients with defects in potassium excretion (e.g., renal failure, use of potassium-sparing diuretics or angiotensin-converting enzyme [ACE] inhibitors) must have their serum potassium concentrations monitored frequently when potassium is being replaced to prevent overcorrection.

image Patients who are receiving digitalis therapy and have hypokalemia are prone to having serious cardiac arrhythmias (especially in overdose situations) and must be treated urgently.

image Patients with significant magnesium deficiency have renal potassium wasting and often must have their magnesium levels corrected before therapy for hypokalemia is initiated.

Key Points Circumstances requiring special care in monitoring potassium replacement

1. Patients with defects in potassium excretion (e.g., renal failure, use of potassium-sparing diuretics or ACE inhibitors) must have their serum potassium concentration monitored (i.e., daily laboratory checks) when potassium is being replaced to prevent overcorrection.
2. Patients who are receiving digitalis therapy and have hypokalemia are prone to having serious cardiac arrhythmias (especially in overdose situations) and must be treated urgently.
3. Patients with significant magnesium deficiency have renal potassium wasting and often must have their magnesium level corrected before therapy for hypokalemia is initiated.

Hyperkalemia

18 What are the causes of hyperkalemia?

image High potassium intake (e.g., oral potassium replacement, total parenteral nutrition, and high-dose potassium penicillin) can cause hyperkalemia, usually in the setting of low renal potassium excretion.

image Extracellular potassium redistribution can be caused by metabolic acidosis, insulin deficiency, β-adrenergic blockade, rhabdomyolysis, massive hemolysis, tumor lysis syndrome, periodic paralysis (hyperkalemic form), and heavily catabolic states such as severe sepsis.

image Low renal potassium excretion can be caused by renal failure, decreased effective circulating volume (e.g., severe sepsis, congestive heart failure, cirrhosis), and states of hypoaldosteronism. States of hypoaldosteronism include decreased renin-angiotensin system activity (e.g., hyporeninemic hypoaldosteronism in diabetes, interstitial nephritis, ACE inhibitors, nonsteroidal antiinflammatory drugs [NSAIDs], cyclosporine), decreased adrenal synthesis (e.g., Addison disease, heparin), and aldosterone resistance (e.g., high-dose trimethoprim, potassium-sparing diuretic agents).

19 Which drugs can cause hyperkalemia?

Drugs that cause release of intracellular potassium include succinylcholine and, rarely, β-blockers. Drugs that block the renin-angiotensin-aldosterone axis will result in decreased renal potassium excretion; these include spironolactone, ACE inhibitors, cyclosporine, heparin (low molecular weight and unfractionated), and NSAIDs. Drugs that impair the process of sodium and potassium exchange include digitalis; drugs that block sodium and potassium exchange in the distal nephron include amiloride and trimethoprim.

20 How do states of decreased circulatory volume cause hyperkalemia?

Urinary K+ is primarily dependent on aldosterone action mediated through activation of the epithelial Na+ channel (ENaC). In states of volume deficiency, there is enhanced proximal nephron Na+ reabsorption, hence decreased Na+ availability to ENaC. Even in the setting of high aldosterone (e.g., congestive heart failure), insufficient Na+ reabsorption occurs to cause electrogenic K+ secretion.

21 What are the clinical manifestations of hyperkalemia?

Clinical manifestations of hyperkalemia are dependent on many other variables such as calcium, acid-base status, and chronicity.

The most serious manifestation of hyperkalemia involves the electrical conduction system of the heart. Profound hyperkalemia can lead to heart block and asystole. Initially, the ECG shows peaked T waves and decreased amplitude of P waves followed by prolongation of QRS waves. With severe hyperkalemia, QRS and T waves blend together into what appears to be a sine-wave pattern consistent with ventricular fibrillation. A good way to think about ECG changes in hyperkalemia is to imagine lifting the T wave, in which the T gets taller first followed by flattening of P and QRS. Other effects of hyperkalemia include weakness, neuromuscular paralysis (without central nervous system disturbances), and suppression of renal ammoniagenesis, which may result in metabolic acidosis.

22 What degree of chronic kidney disease causes hyperkalemia?

Chronic kidney disease per se is not associated with hyperkalemia until the GFR is reduced to approximately 75% of normal levels (serum creatinine level > 3 mg/dL). Although more than 85% of filtered potassium is reabsorbed in the proximal tubule, urinary excretion of potassium is determined primarily by potassium secretion along the cortical collecting tubule. Hyperkalemia disproportionate to reductions in GFR usually results from decreases in potassium secretion (due either to decreases in aldosterone, as may occur in Addison disease, or to diabetes with hyporeninemic hypoaldosteronism) or from marked decreases in sodium delivery to the distal nephron, as may occur in severe prerenal states.

23 What is the transtubular potassium gradient (TTKG)? When should it be used?

TTKG was developed to account for the potentially confounding effect of urine concentration on the interpretation of the urine potassium concentration. The TTKG provides a better clinical approach to uncover defects in urinary potassium (UK) excretion as compared with UK alone because the latter fails to account for plasma potassium concentration and for medullary water abstraction. TTKG is calculated as follows:

image

It is most commonly used in patients with hyperkalemia, where a TTKG < 6 indicates an inappropriate renal response to hyperkalemia, that is, reduced renal potassium excretion. Two limitations exist to using the TTKG:

image Urinary sodium must be > 25 mEq/L (so that sodium delivery is not the limiting factor for K+ secretion). Na+ is reabsorbed by the cortical collecting tubule (epithelial Na channel), then removed from the cell (Na+,K+-ATPase), resulting in an increase in cellular K+ that then moves through a K+ channel into the urine.

image Urine must be hypertonic (because vasopressin is required for optimal potassium conductance in the distal nephron).

TTKG is of limited use in patients with a varying K+ diet or after acute diuretic use.

24 What is the diagnostic approach to hyperkalemia?

The cause is often apparent after a careful history and review of medications and basic laboratory values, including a chemistry panel with blood urea nitrogen and creatinine concentrations. Additional laboratory tests can be performed if clinical suspicion exists for any of the following:

image Pseudohyperkalemia (look for high white blood cell and platelet counts)

image Rhabdomyolysis (look for high creatinine kinase concentration)

image Tumor lysis syndrome (look for high lactate dehydrogenase, uric acid, and phosphorus and low calcium levels)

image Hypoaldosteronemic state (look for a TTKG < 5 in the setting of hyperkalemia)

25 What is the effect of heparin on K+?

Heparin can cause hyperkalemia by blocking aldosterone biosynthesis. Both low-molecular-weight heparin and unfractionated heparin can cause hyperkalemia.

26 What is pseudohyperkalemia?

Serum potassium measurements can be falsely elevated when potassium is released during the process of blood collection from the patient or during the process of clot formation in the specimen tube. These situations do not reflect true hyperkalemia. Potassium release from muscles distal to a tight tourniquet can artifactually elevate potassium level by as much as 2.7 mEq/L. Potassium release during the process of clot formation in the specimen tube from leukocytes (white blood cell counts > 70,000/mm3) or platelets (platelet count > 1,000,000/mm3) can also become quite significant and distort serum potassium measurement results. In these circumstances, an unclotted blood sample (i.e., plasma potassium determination) should be obtained.

27 What are the indications for emergent therapy?

image ECG changes. Because cardiac arrest can occur at any point during ECG progression, hyperkalemia with ECG changes constitutes a medical emergency.

image Severe weakness.

image Serum potassium level above 6 mEq/L. ECG changes may not always be present, although this level of hyperkalemia predisposes to rhythm abnormalities.

28 How do you treat hyperkalemia?

The general approach is to use therapy involving each of the following:

image Membrane stabilization: Calcium antagonizes the cardiac effects of hyperkalemia. It raises the cell depolarization threshold and reduces myocardial irritability. Calcium is given regardless of serum calcium levels. One or two ampules of IV calcium chloride result in improvement in ECG changes within seconds, but the beneficial effect lasts only approximately 30 minutes. The dose can be repeated in absence of obvious change in ECG or with recurrence of ECG changes after initial resolution.

image Shifting potassium into cells: IV insulin with glucose administration begins to lower serum potassium levels in approximately 2 to 5 minutes and lasts a few hours. Correction of acidosis with IV sodium bicarbonate has a similar duration and time of onset. Nebulized β-adrenergic agonists such as albuterol can lower serum potassium level by 0.5 to 1.5 mEq/L with an onset within 30 minutes and an effect lasting 2 to 4 hours. Albuterol, however, may be ineffective in a subset of patients with end-stage renal disease (from 20%-40%).

image Removal of potassium: Loop diuretics can sometimes cause enough renal potassium loss in patients with intact renal function, but usually a potassium-binding resin must be used (e.g., Kayexalate, 30 gm taken orally or 50 gm administered by retention enema). The effect of resin on potassium is slow, and the full effect may take up to 4 to 24 hours. Acute hemodialysis is quick and effective at removing potassium and must be used when the GI tract is nonfunctional or when serious fluid overload is already present. Rarely, when chronic hyperkalemia is secondary to hypoaldosteronism, mineralocorticoids can be of use.

29 Should glucose always be given with insulin?

Glucose elevation in the extravascular space (e.g., with administration of 50% dextrose) results in K+ movement from the intracellular to extracellular space. Thus hyperglycemia in diabetes may cause hyperkalemia, especially in the absence of insulin. After insulin therapy for hyperkalemia, glucose should not be administered if the serum glucose concentration is over 175 mg/dL.

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