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Critical Care Clinics

Volume 18 • Number 2 • April 2002
Copyright © 2002 W. B. Saunders Company

Disorders of potassium
homeostasis:  Hypokalemia and
hyperkalemia
F. John Gennari, MD

University of Vermont College of Medicine

Rehab 308
University Health Center Campus
Fletcher Allen Health Care
Burlington, VT 05401, USA

E-mail address:  fgennari@zoo.uvm.edu

PII S0749-0704(01)00009-4

Hypo-and hyperkalemia are the most commonly encountered electrolyte abnormalities

in hospitalized patients [1] [15] [16] [29] . Although no data are available concerning their
specific prevalence in critically ill patients, one might expect these abnormalities to
occur frequently because of the disruption in normal homeostasis inherent in critical
illness and the multiple interventions necessary for care. Hypo-and hyperkalemia are
more likely to contribute to morbidity and mortality in this group of patients. Although
recognition is simple, requiring only measurement of serum [K+], appropriate
management requires an understanding of normal K+ homeostasis and the ways it can
be disrupted. In this article, normal K+ homeostasis and the pathophysiology and
management of hypo-and hyperkalemia are discussed with special attention to
critically ill patients.

Normal homeostasis

Potassium intake is unregulated and varies according to diet, from as little as 40 to over
100 mEq/d. Normally, excretion matches intake on a day-to-day basis, and little
attention is paid to the nature of the diet. Ingested K+ is absorbed rapidly and must be
moved quickly into cells to prevent hyperkalemia. Fig. 1 [Not Available] illustrates the
homeostatic mechanisms that exist to achieve transcellular and total body K+ balance.
As ingested K+ is absorbed and enters the portal circulation, it stimulates insulin release
[27]
. Insulin in turn facilitates entry of K+ into cells by stimulating cell membrane Na+/K+
ATPase activity [11] . β2-adrenergic stimulation also promotes entry of K+ into cells, but a
feedback regulatory system has not been identified. A rise in extracellular [K+] also
stimulates aldosterone secretion (facilitated by angiotensin II), and aldosterone increases
K+ excretion within 30 minutes of ingestion [15] . Although aldosterone has been
implicated to have a role in transcellular K+ homeostasis, such a role is unlikely because
skeletal muscle cells, the major reservoir for intracellular K+, lack receptors for this
hormone [3] . In the steady state, K+ excretion matches intake; approximately 90% of
ingested K+ is excreted by the kidney, and the remaining 10% is excreted in the stool.
Renal K+ excretion occurs primarily by K+ secretion into the urine as it traverses the
collecting ducts (see Fig. 1 [Not Available]), a process regulated by aldosterone and Na+
delivery [20] . The kidney is better adapted to increase K+ excretion than to decrease
excretion. As a result, K+ depletion and hypokalemia can occur from inadequate intake.
Hyperkalemia, by contrast, occurs primarily when renal K+ excretion is impaired. Hypo-
and hyperkalemia can result from disruptions in transcellular homeostasis or in the renal
regulation of K+ excretion.
Fig. 1.  (Figure not Available)  Regulation of extracellular fluid potassium concentration (ECF [K+]). An
increase in ECF [K+] stimulates both aldosterone and insulin secretion. Insulin stimulates K+ entry into
cells, and aldosterone secretion stimulates K+ secretion into the collecting duct urine, promoting its
excretion by the kidney. Reprinted with permission from [Ref. 15] .

Hypokalemia

Hypokalemia is defined at various values, but most commonly is defined as a serum

[K+] < 3.6 mEq/L. Hypokalemia reflects a disruption in normal homeostasis, with one
rare exception: In some patients with leukemia and markedly elevated white cell counts,
K+ is taken up by the abnormal cells in the test tube, causing factitious hypokalemia [28] .
More commonly, these abnormal white cells release K+, causing factitious hyperkalemia
(see later in article).

Effects of hypokalemia
Patients with hypokalemia are usually asymptomatic. The disorder is identified in most
instances by the presence of a low serum [K+]. Although hypokalemia is well tolerated
in otherwise normal individuals, it is associated with an increased incidence of life-
threatening cardiac arrhythmias in patients with ischemic or scarred cardiac muscle [16] [35]
. Severe hypokalemia ([K+] < 2.5 mEq/L) can cause rhabdomyolysis and, when the
value is less than 2.0 mEq/L, can cause an ascending paralysis with eventual respiratory
arrest.

Potassium depletion
The most common cause of hypokalemia is K+ depletion, caused by inadequate intake
or abnormal losses (Table 1 ). In critically ill patients, abnormal losses are usually the
primary culprit. Such losses may occur in the stool, from diarrhea or laxative abuse, or
in the urine, most commonly secondary to chloride depletion (metabolic alkalosis). K+ is
secreted into the stool only by the colonic epithelium; thus, an increase in stool output
in patients with ileostomies does not cause K+ depletion. Upper gastrointestinal losses
(vomiting or nasogastric drainage) also contain only small amounts of K+. These losses,
however, cause significant chloride depletion, altering the renal signals for K+ secretion
and promoting renal K+ losses despite the development of hypokalemia (see later in
article).

Table 1.   Causes of hypokalemia

Inadequate intake (<40 mEq/d)
Increased excretion
     Diarrhea, laxative abuse
     Renal losses
          Loop, thiazide diuretics
          Metabolic alkalosis (vomiting, nasogastric drainage)
          Osmotic diuresis (uncontrolled diabetes)
          Nonreabsorbable anions (penicillins)
          Mineralocorticoid excess
               Primary hyperaldosteronism
               Glucocorticoid responsive aldosteronism
               Congenital adrenal hyperplasia
     Apparent mineralocorticoid excess
          Liddle's syndrome
          11β-hydroxysteroid dehydrogenase deficiency
          Licorice
     Glucocorticoids (high dose)
     Bartter's and Gitelman's syndromes
     Magnesium depletion
     Renal tubular acidosis (types 1 and 2)

Diuretics
The most common cause of K+ depletion and hypokalemia is the use of diuretics [15] [29] .
The loop diuretics (furosemide, bumetanide, torsemide) block chloride-coupled sodium
reabsorption in the loop of Henle, and the thiazide diuretics block chloride-coupled
sodium reabsorption in the early distal tubule. As a result, both classes of drugs increase
Na+ and Cl− delivery to the collecting duct, stimulating K+ secretion and causing
chloride depletion. In critically ill patients, loop diuretics often are given in large doses
and sometimes by a continuous regimen. The combination of loop and thiazide diuretics
(most commonly, furosemide and metolazone) often is used to promote diuresis. This
intense diuretic regimen almost invariably causes K+ depletion and hypokalemia. Both
classes of diuretics also increase magnesium excretion, causing depletion of this cation.
Magnesium depletion itself promotes renal K+ losses and contributes to K+ depletion
(see later in article).

Other drugs
Fludrocortisone, an oral agent with mineralocorticoid activity, stimulates K+ secretion
directly. High-dose glucocorticoid administration promotes K+ excretion indirectly [32] .
Penicillin and its synthetic derivatives can cause excessive K+ losses when given
intravenously in large doses, by increasing distal Na+ delivery [15] . Aminoglycoside
antibiotics, cisplatin, foscarnet, and amphotericin B cause renal K+ wasting indirectly by
causing magnesium depletion [15] [16] . Amphotericin inhibits collecting duct H+ secretion,
providing an additional stimulus for K+ excretion.

Metabolic alkalosis
Potassium depletion and hypokalemia are almost invariable consequences of metabolic
alkalosis [16] [17] [32] . This acid-base disorder is most commonly the result of selective
chloride losses induced by upper gastrointestinal losses or by diuretic administration. In
either case, chloride-linked Na+ reabsorption is impaired, increasing delivery of Na+ to
the collecting duct where it serves to stimulate K+ secretion. In most critically ill
patients, the chloride depletion is coupled with a decrease in renal perfusion (caused by
extracellular volume depletion or by heart or liver failure), promoting aldosterone
secretion and further stimulating K+ secretion. More rarely, chloride depletion occurs
secondary to genetic abnormalities in chloride-linked Na+ reabsorption (Bartter's or
Gitelman's syndrome), causing refractory hypokalemia [15] [16] .
Metabolic alkalosis also can occur independent of chloride depletion, most commonly
caused by primary hyperaldosteronism, or more rarely by other states of
mineralocorticoid excess (see Table 1 ). In this form of metabolic alkalosis, K+ depletion
and the resultant hypokalemia are typically more severe, because the
hypermineralocorticoid state causes a sustained increase in distal Na+ delivery coupled
with an abnormal stimulus for K+ secretion. Two rare genetic abnormalities, Liddle's
syndrome and 11β-hydroxysteroid dehydrogenase deficiency, can produce the same
syndrome by stimulating K+ secretion independent of aldosterone secretion [16] [38] .

Other causes
Potassium depletion and hypokalemia occur in type 1 and in some forms of type 2 renal
tubular acidosis [16] . Magnesium depletion, regardless of its cause, can cause renal K+
wasting [16] . Osmotic diuresis, most commonly in the setting of uncontrolled diabetes
mellitus, increases distal Na+ delivery and causes renal K+ losses.

Transcellular shifts
A wide variety of β2-adrenergic agonist drugs shift K+ into cells and cause transient
hypokalemia (Table 2 ). These drugs include decongestants, bronchodilators, and
tocolytic agents [16] . Theophylline and caffeine stimulate cell membrane Na+/K+ ATPase
and promote K+ entry into cells. Severe hypokalemia is a characteristic feature of
theophylline toxicity [9] [36] . The caffeine in a few cups of coffee can decrease serum [K+]
by as much as 0.4 mEq/L [30] . Accidental ingestion of barium salts blocks K+ exit from
cells and causes hypokalemia. In addition to drugs and toxins, hypokalemia rarely
occurs as a complication of hyperthyroidism, presumably from stimulation of activity of
Na+/K+ ATPase by thyroid hormone [15] [16] . Endogenous β2-adrenergic stimulation in
delirium tremens can cause a shift of K+ into cells [15] . Familial hypokalemic periodic
paralysis is a rare autosomal dominant hereditary disorder caused by a mutation in a cell
membrane Ca++ channel that causes paroxysmal severe episodes of hypokalemia
brought on a by high-carbohydrate or high-sodium intake or by exercise [37] .
Table 2.   Hypokalemia caused by shift of K+ into cells
Drugs
     β-Adrenergic agonists
          Bronchodilators
          Decongestants
          Tocolytic agents
     Theophylline
     Caffeine
     Insulin
Delirium tremens
Hyperthyroidism
Familial hypokalemic periodic paralysis
Barium poisoning

Treatment of hypokalemia
Because of the risk of hyperkalemia, intensive intravenous K+ administration rarely is
indicated (Table 3 ). Situations that warrant this intervention include cardiac arrhythmias
characterized by a rapid ventricular response (particularly in the setting of digoxin
toxicity), severe myopathy, and paralysis (the latter usually is associated with a serum
[K+] of less than 2.0 mEq/L or with familial periodic paralysis). When K+ is given
intravenously, the patient should have cardiac monitoring, and the rate should be no
more than 20 mEq/h with a break in the infusion after 60 mEq to reassess serum [K+].

Table 3.   Treatment of hypokalemia

Intravenous KCl: Maximum rate, 20 mEq/h with cardiac monitoring; pause and reassess
after 60 mEq
Cardiac arrhythmias with rapid ventricular response
Cardiac arrhythmias due to digoxin toxicity
Severe diarrhea
Severe myopathy with muscle necrosis
Paralysis
     Oral KCl: 20–80 mEq/d in divided doses
          All other settings except renal tubular acidosis
     Oral KHCO3, citrate, acetate or gluconate
          Renal tubular acidosis

With the exception of these settings, oral replacement therapy should be the rule. The
cause of the hypokalemia should be sought and addressed, whether it be to remove an
offending drug, change the diet, or intervene to minimize losses. Potassium replacement
should be part of the therapy if the cause is uncertain or if the hypokalemia is not
rapidly reversed when caused by an abnormal shift into cells. In the absence of
abnormalities in transcellular homeostasis, serum [K+] falls by approximately 0.3
mEq/L for every 100 mEq decrement in total body K+ stores [39] . This formula should be
regarded only as a general estimate (e.g., a patient with a serum [K+] of 3.0 mEq/L may
have a deficit ranging from 100 to 400 mEq).
When initiating K+ replacement therapy, one should keep in mind that the most common
cause of hyperkalemia is physician-ordered K+ supplements (Fig. 2 ; discussed later in
article). The risk of this complication is greatest with intravenous KCl administration.
As a result, the first approach to treatment should be oral supplementation, if possible.
The preferred salt for replacement is KCl, because most causes of hypokalemia require
repletion of chloride and K+. Magnesium depletion, when present, impairs the ability to
replace K+ losses, and hypomagnesemia should be treated in hypokalemic patients. Oral
KCl should be given in divided doses (10–40 mEq per dose) and most commonly is
given twice daily. If the patient is unable to take the supplement by mouth, similar doses
can be given intravenously (see earlier for maximum rate of administration). There is no
indication to correct the losses more urgently in most instances; typically, replacement
therapy should extend over several days.

Fig. 2.  Medications, serum potassium and creatinine concentrations, and events during a 10-day period
in a critically ill patient with congestive heart failure. The complicating events on days 4 and 9 both
occurred in association with an increase in serum creatinine concentration, while the patient was receiving
both KCl and several drugs that impair K+ homeostasis. On the first occasion, these included captopril,
propanolol and heparin; on the second, captopril and heparin.

Hyperkalemia

Hyperkalemia, defined as a serum [K+] greater than 5.0 mEq/L, is less common than
hypokalemia and can be life threatening when severe (serum [K+] >6.5 mEq/L). An
elevated serum [K+] is indicative of disordered K+ homeostasis, with the exception of
several situations in which K+ is released in the blood sample (factitious hyperkalemia;
Table 4 ). These settings include thrombocytosis, hemolysis, and extremely high white
cell counts. In all three settings, death or lysis of cells in the test tube release K+ into the
serum, increasing the measured value. Because platelets are lysed when the blood clots,
serum [K+] is always higher than plasma [K+], and the discrepancy is correlated directly
with the platelet count [22] . This collection artifact, however, does not increase serum
[K+] to notably abnormal levels unless the platelet count is greater than 1,000,000/mm3.
In addition to these settings, repeated fist clenching with a tourniquet tightly in place
can increase K+ release from muscle cells, factitiously increasing serum [K+] [42] .

Table 4.   Causes of hyperkalemia

Factitious
     Thrombocytosis (platelets >1,000,000/,mm3)
     Leukocytosis (white blood cell count >100,000/mm3)
     Hemolysis
     Repeated fist clenching with tourniquet in place
Impaired K+ excretion
Table 4.   Causes of hyperkalemia
     Renal insufficiency or failure
     Mineralocorticoid deficiency
          Addison's disease
          Hyporenin hypoaldosteronism (type 4 renal tubular acidosis)
          Heparin-induced inhibition of aldosterone synthesis
          Hereditary enzyme deficiencies
     Pseudohypoaldosteronism
     Drugs
          K+-sparing diuretics
          ACE inhibitors
          Angiotensin receptor blockers
          NSAIDs
          Heparin (see above)
          Cyclosporine, tacrolimus
          Trimephaprim
          Pentamidine

Effects of hyperkalemia
Hyperkalemia is characteristically asymptomatic, but it silently impairs normal cardiac
conduction, producing characteristic electrocardiogram (ECG) changes that are
progressive indicators of life-threatening arrhythmias (Fig. 3 [Not Available]). The earliest
sign is tenting of the T waves, followed by widening of the QRS complex, A-V
conduction blockade with a slow idioventricular rhythm, ventricular fibrillation, and
standstill. There is no clear correlation between the degree of hyperkalemia and the
likelihood of life-threatening arrhythmias, but arrhythmias are more likely to occur if
serum [K+] increases rapidly [24] . In the absence of a clear time course, all patients with a
serum [K+] >6.0 mEq/L should be considered at risk for life-threatening cardiac
arrhythmias. In patients with long-standing and severe hyperkalemia (usually >7.5
mEq/L), an ascending paralysis can occur.
Fig. 3.  (Figure not Available)  Characteristic effects of hypokalemia and hyperkalemia on the
electrocardiogram. Reprinted with permission from [Ref. 15] .

Causes
Impaired K+ excretion caused by renal insufficiency is responsible for over 80% of
clinical episodes of hyperkalemia, but a second event, which prevents renal adaptation,
is almost invariably present. In most instances, the second event is a physician-
prescribed medication, and the most common culprit is supplemental KCl [1] [15] [33] . Two
mechanisms, impaired K+ excretion or impaired K+entry into cells, account for all
causes of hyperkalemia (Table 5 ; see also Table 4 ).
Table 5.   Hyperkalemia caused by impaired K+ entry into cells
Insulin deficiency or resistance
Hypertonicity (uncontrolled diabetes)
Massive tissue breakdown (rhabdomyolysis, burns, trauma)
Familial hyperkalemic periodic paralysis
Drugs
     β-blockers
     Digoxin (at toxic levels)
     Succinylcholine
     Arginine
     Lysine

Impaired K+ excretion
Renal insufficiency
Most patients with stable chronic renal insufficiency have mild hyperkalemia (serum
[K+] ∼4.8–5.3 mEq/L) [41] . The initiating cause is decreased capacity to excrete K+, but
the reason for the persistent hyperkalemia is unclear. A subset of patients, most
commonly patients with diabetic nephropathy or tubulointerstitial disease, may have
more severe hyperkalemia, with serum [K+] sometimes rising above 6.0 mEq/L. This
subset of patients almost always has low renin and aldosterone levels (hyporenin
hypoaldosteronism) [13] [34] .

Mineralocorticoid deficiency
Impairment of aldosterone production for any reason almost invariably leads to
hyperkalemia, particularly when renal function is reduced or Na+ delivery to the distal
nephron is decreased. Acquired adrenal failure (Addison's disease) is associated with
hyperkalemia, even when renal function is normal. Addisonian crisis is characterized by
severe hyperkalemia and responds to mineralocorticoid replacement therapy.
Hyperkalemia is also the hallmark of hyporenin hypoaldosteronism, which often is
associated with metabolic acidosis (type 4 renal tubular acidosis).
Mineralocorticoid deficiency also can result from a variety of rare inherited enzymatic
deficiencies [15] . Pseudohypoaldosteronism occurs when aldosterone levels are elevated
but without effect. Type 1 pseudohypoaldosteronism, characterized by salt wasting, is
believed to be caused by an aldosterone receptor defect, whereas type 2, which is
associated with hypertension, is believed to be caused by an abnormality in renal
chloride transport [15] .

Drugs
The most common cause of hyperkalemia is the use of K+ supplements or drugs that
interfere with K+ excretion (see Table 4 ) in combination with renal insufficiency.
Critically ill patients are especially likely to experience this combination of events, as
illustrated in Fig. 2 . In this example, a critically ill patient with severe congestive heart
failure developed life-threatening hyperkalemia on two occasions when renal function
declined. Both episodes were related to KCl administration, coupled with several other
drugs, discussed later, that impair K+ excretion.
K+-sparing diuretics
Spironolactone, amiloride, and triamterene inhibit renal K+ excretion and, with rare
exception, should not be used in patients with renal insufficiency. Fatal hyperkalemia
has been reported with all three drugs, and significant hyperkalemia occurs in 10–20%
of patients taking these medications [15] [23] [40] . Spironolactone, a competitive inhibitor of
aldosterone, is the most dangerous drug because its effects last for several days, even
after the drug is discontinued. The demonstration that this spironolactone improves
survival in congestive heart failure has led to a resurgence in its use, raising the specter
of more episodes of sustained hyperkalemia.

Angiotensin blockers
Angiotensin-converting enzyme (ACE) inhibitors reduce circulating aldosterone levels
and are associated with hyperkalemia in patients with renal insufficiency [6] [15] .
Hyperkalemia should be managed by reducing dietary K+ intake or by concomitantly
using loop diuretics. If these maneuvers are unsuccessful, withdrawal of the ACE
inhibitor promptly lowers serum [K+] and corrects the problem. Angiotensin receptor
blockers do not reduce aldosterone levels as much as ACE inhibitors and seem to be
less likely to cause hyperkalemia [6] . Nonetheless, serum [K+] should be monitored
regularly in patients receiving this class of drugs.

Nonsteroidal anti-inflammatory drugs

The drugs in this class (including the newer cyclooxygenase-2 [COX-2] inhibitors)
suppress renin and aldosterone secretion indirectly by inhibiting prostaglandin
synthesis. They reduce renal blood flow and glomerular filtration rate (GFR),
particularly in the setting of extracellular fluid (ECF) volume depletion or cardiac
failure. They impede K+ excretion as a result of both of these effects. Hyperkalemia is
typical when these drugs are associated with acute renal insufficiency, but hyperkalemia
also has been reported to occur without renal insufficiency [12] [15] .

Other drugs
Heparin inhibits aldosterone synthesis and can cause significant hyperkalemia in
patients with renal insufficiency. Hyperkalemia usually takes 5 to 10 days to develop
but can occur in a shorter interval of time [5] [15] . Cyclosporine and tacrolimus inhibit
renal K+ directly and also reduce GFR and aldosterone levels [7] [25] . Trimethoprim, a
commonly used antibiotic, inhibits collecting duct K+ secretion in a manner similar to
amiloride and can cause hyperkalemia in elderly individuals or in patients with renal
insufficiency [26] . Pentamidine also impairs renal K+ excretion and causes hyperkalemia
(see Table 4 ).

Impaired K+ entry into cells

Insulin deficiency and resistance
Insulin is a key regulator of transcellular K+ homeostasis (see Fig. 1 [Not Available]). A
reduction in circulating insulin levels increases serum [K+] levels, even in normal
individuals [14] . Insulin deficiency in diabetes mellitus impairs K+ movement into cells,
but also causes K+ depletion as a result of the osmotic diuresis associated with
hyperglycemia. As a result, serum [K+] may be low or normal despite insulin deficiency.
Patients with end-stage renal disease who are fasted or who have uncontrolled diabetes,
however, may develop severe hyperkalemia because they cannot excrete the K+ shifted
out of cells. Patients with type 2 diabetes with insulin resistance also manifest a defect
in K+ entry into cells but rarely have hyperkalemia unless they also have impaired renal
K+ excretion (see earlier in article).

Hypertonicity
An increase in extracellular fluid tonicity causes water to exit cells, and K+ is swept out
along with this fluid. Unless renal function is normal, the K+ that exits cells cannot be
excreted, and hyperkalemia occurs. The major clinical setting in which hypertonicity
develops is uncontrolled diabetes mellitus, but significant hyperkalemia occurs only
when renal insufficiency is also present, usually coupled with hyporenin
hypoaldosteronism [15] [21] .

Tissue breakdown
Massive tissue breakdown, such as that which occurs in rhabdomyolysis, burns, or
extensive trauma, causes the sudden release of large amounts of K+ into the ECF. If
renal function is normal, this excess K+ is excreted rapidly into the urine. In patients
with renal insufficiency, however, the newly released K+ can increase serum [K+]
markedly.

Familial hyperkalemic periodic paralysis

This rare autosomal-dominant hereditary disease, caused by a mutation in cell
membrane Na+ channels, causes paroxysmal shifts of K+ from cells to the extracellular
compartment [15] [31] . Clinical episodes are characterized by transient paralysis, usually
brought on by rest after exercise. Salbutamol (a β-adrenergic agonist) is useful in
aborting attacks, and for reasons that are unclear, acetazolamide is effective in reducing
the severity and frequency of attacks.

Metabolic acidosis
Metabolic acidosis has varying effects on transcellular K+ homeostasis depending on its
cause and duration [2] [15] [18] . Many forms of sustained metabolic acidosis are associated
with K+ depletion and hypokalemia [18] . The most common forms of acute metabolic
acidosis, diabetic ketoacidosis and lactic acidosis, are not associated with any shift of K+
out of cells [2] . Respiratory acidosis does not cause a notable shift of K+ out of cells;
thus, the finding of hyperkalemia in all these settings should not be ascribed
automatically to the acidosis, and other causes should be sought.

Drugs that Impair K+ Entry into Cells

β-Adrenergic blockers
As shown in Fig. 1 [Not Available], β2-adrenergic stimulation contributes to transcellular K+
homeostasis by promoting K+ entry into cells. The nonselective β-blockers (and the β1
specific agents at high doses) inhibit this effect and cause a small but significant
increase in serum [K+]. In patients with renal insufficiency, this effect may cause
notable hyperkalemia but rarely is severe enough to require discontinuation of the drug
[4] [15]
.

Digoxin
Digoxin is an inhibitor of cell membrane Na+/K+ ATPase, impairing K+ entry into cells,
but it does not cause significant hyperkalemia at therapeutic doses. Digoxin toxicity is
associated with hyperkalemia, which can be severe and difficult to manage. Mild
digoxin toxicity is often a contributing factor in inpatients with hyperkalemia [33] .
Other drugs
Succinylcholine blocks the normal re-entry of K+ into cells after depolarization and
causes a brief (<10 min) increase in serum [K+]. In patients with extensive trauma or
burns, however, the hyperkalemia can be more severe and long lasting [15] . The cationic
amino acids arginine and lysine shift K+ out of cells and can produce severe
hyperkalemia in patients with renal or hepatic insufficiency [10] [15] . Fluoride toxicity
increases cell membrane permeability, causing a shift of K+ out of cells and producing
hyperkalemia.

Treatment of hyperkalemia

Acute management
Regardless of the cause, therapy to lower serum [K+] should be initiated immediately
when it is greater than 6.5 mEq/L or if the ECG shows signs of conduction
abnormalities (see Fig. 3 [Not Available]). If the duration of hyperkalemia is unknown or is
likely to be short, therapy should be initiated at a Serum [K+] greater than 6.0 mEq/L.
Table 6 presents the approach to treatment. Intravenous calcium rapidly can reverse
cardiac conduction abnormalities when they are present and should be used without
delay in this setting. An exception to this rule is hyperkalemia caused by digoxin
toxicity, because acute hypercalcemia can potentiate the toxic effects of this drug. The
mainstay of the acute therapy of hyperkalemia is glucose and insulin administration,
which shifts K+ into cells within 10 to 20 minutes and lowers serum [K+] by 0.5 to 1.5
mEq/L. This effect is sustained for 2 to 3 hours. Inhaled albuterol is as effective if
intravenous access is a problem. Sodium bicarbonate is much less effective [8] and
should be given only as needed to treat concurrent metabolic acidosis.

Table 6.   Treatment of hyperkalemia

      a Intravenous calcium should not be given in the setting of digoxin toxicity.

Emergency Response time Duration

Cardiac conduction abnormal
Calcium gluconate or chloridea (10 mL of 10% solution) Immediate 15–30 min
+
[K ] >6.5 serum/mEq/L or rising
     Glucose (50 mL of 50% solution) plus regular insulin 10 10–20 min 2–3 h
U
     Albuterol 10–20 mg by inhaler over 10 min 20–30 min 2–3 h
−
NaHCO3 , only if metabolic acidosis present Delayed
     Kayexalate 15–30 g with sorbitol    
          By mouth 4–6 h —
          As retention enema 1h —
     Loop diuretic (intravenous) 1h —
     Hemodialysis 15–30 min —
   
Table 6.   Treatment of hyperkalemia
Long-term management
Dietary K+ restriction 2–3 g/d
Discontinue supplemental K+ (salt substitutes)
Discontinue drugs that interfere with K+ homeostasis (see [Tables 4 and 5])
Augment K+ excretion
     Loop, thiazide diuretics
     Fludrocortisone, if hypoaldosteronism present
Chronic kayexalate therapy

Measures also should be undertaken to remove K+ from the body as quickly as possible.
Loop diuretics are helpful if the patient has sufficient renal function, but in most
instances, other approaches are needed. Sodium polystyrene sulfonate (Kayexalate),
usually given with sorbitol, binds to K+ secreted into the colon; at equilibrium,
approximately 1 mEq of K+ is removed per gram of resin. When given by mouth,
Kayexalate has little effect for 4 to 6 hours because it must transit to the colon to be
effective. When given as a retention enema, it works within 1 hour. Unfortunately, the
combined use of sorbitol and Kayexalate can cause bowel necrosis when given by either
route in the postoperative or immunocompromised patient, and its use is contraindicated
in these settings [15] [19] . Hemodialysis removes 50 to 125 mEq of K+ rapidly and is used
when other interventions fail. Concurrent with initiating treatment for severe
hyperkalemia, its causes should be assessed and offending agents, such as KCl, K+-
sparing diuretics, and ACE inhibitors, should be removed.

Ongoing management
The mainstay of management for sustained hyperkalemia is to reduce dietary K+
intake. The goal of therapy is to maintain serum [K+] less than 6.0 mEq/L. In particular,
patients should be educated not to use any salt substitutes because most of them contain
KCl. Additional maneuvers include the use of loop diuretics to promote K+ excretion
and avoidance of drugs that interfere with normal K+ homeostasis. In patients with
hyporenin hypoaldosteronism who cannot be managed by these interventions, the oral
mineralocorticoid agent fludrocortisone is effective. If dietary and drug management
are ineffective, the cause is almost always dietary indiscretion. In such patients, the
daily use of oral K ayexalate is effective in reducing the incidence of severe
hyperkalemia.
References

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