CHAPTER 125 
Electrolyte Disorders
Camiron L. Pfennig and Corey M. Slovis
Electrolyte abnormalities are common in emergency medicine
and can vary greatly in importance, severity, and symptoms.
Asymptomatic electrolyte abnormalities can usually be gradually
corrected, but those that cause alterations in consciousness or life-
threatening dysrhythmias require immediate therapy to avoid
permanent sequelae or death. In some cases, therapy for life-
threatening electrolyte disorders may even need to be initiated
before laboratory results become available.
HYPERKALEMIA
Principles of Disease
Hyperkalemia, defined as serum potassium level greater than
5.0 mEq/L, is the most dangerous acute electrolyte abnormality,
potentially leading to life-threatening arrhythmias and death.
Although hyperkalemia may have vague and varied symptoms, it
is usually totally asymptomatic, with cardiac arrest as its first
“symptom.”1 Thus the diagnosis of hyperkalemia depends on
paying specific attention to risk factors for impaired potassium
excretion, such as dehydration and renal failure, along with an
awareness of medications that cause potassium retention. Evalua-
tion of the electrocardiogram (ECG) of patients at risk for this
electrolyte disturbance is critical. Hyperkalemia can be rapidly
progressive, and lifesaving interventions must be instituted at the
earliest suspicion of toxicity.
Upwards of 98% of potassium in the body is contained intracel-
lularly, whereas less than 2% remains circulating in the blood.
Serum potassium concentration is normally between 3.5 and
5.0 mEq/L and is tightly regulated by the kidney. In the healthy
state, at least 90% of potassium excretion occurs through the
kidney; in the renally impaired state, the gastrointestinal tract may
account for roughly 25% of excretion. Hyperkalemia usually
develops from impaired renal excretion or increased release from
cells; however, in advanced chronic kidney disease or end-stage
renal disease, dietary intake of potassium may be a significant
factor in its development.2
Hyperkalemia causes cardiotoxicity by increasing the resting
membrane potential of the cardiac myocyte, causing “membrane
excitability” and conversely sluggish depolarization as well as
decreasing the duration of repolarization. At very high levels,
potassium causes the depolarization threshold to rise, leading to
overall depressed cardiac function. Nearly any cardiac arrhythmia
can be seen with hyperkalemia, including heart blocks, bradydys-
rhythmias, pseudoinfarction ST segment elevation, and the
classic “sine wave” pattern. As hyperkalemia advances, the end
1636
result is cardiac arrest, usually from disintegration into ventricular
fibrillation, pulseless electrical activity, or asystole. A serum potas-
sium level of 10.0 mEq/L is usually fatal, but decompensation and
death can occur at any level above 7 to 8 mEq/L.
The most common cause of hyperkalemia is spurious elevation
due to hemolysis during or after the blood draw. Thus an ECG
should be used to assess for true hyperkalemia while another
sample is analyzed. Most causes of true hyperkalemia are due to
release from cells or renal insufficiency. Renal failure is the most
common cause of confirmed hyperkalemia and is often com-
pounded by medications that further impair renal potassium
handling. Box 125-1 organizes the most common causes of hyper-
kalemia. The presence of one of these conditions may be the lone
historical clue in hyperkalemia.3
Clinical Features
Hyperkalemia remains a difficult clinical diagnosis to make on
clinical grounds alone. It is not uncommon for a patient with mild
to moderate hyperkalemia to be identified during routine blood
sampling for an unrelated condition. Patients with moderate to
severe hyperkalemia may have gastrointestinal effects such as
nausea, vomiting, and diarrhea often in association with their
underlying disease. Neuromuscular findings, including muscle
cramps, generalized weakness, paresthesias, tetany, and focal or
global paralysis, may be seen in patients with severe hyperkalemia.
The signs and symptoms of progressive muscle weakness, pares-
thesias, dyspnea, and depressed deep tendon reflexes are neither
sensitive nor specific, nor do they appear reliably with a particular
serum potassium level.3 Patients with severe hypokalemia may
present with hemodynamic instability and cardiac arrhythmias
requiring immediate intervention.
Diagnostic Strategies
The ECG is helpful in making the diagnosis of hyperkalemia and
can be used in unstable patients to initiate treatment (Figs. 125-1
to 125-3). Classic electrocardiographic changes—the peaked T
wave, flattened p wave with prolonged PR interval or a totally
absent P wave, wide QRS, and sine wave pattern, portending
imminent cardiac arrest—have been well described as appearing
sequentially with rising serum potassium levels.4,5 Peaked T waves
usually appear as serum potassium levels exceed 5.5 to 6.5 mEq/L;
P wave disappearance and PR prolongation are common with
levels above 6.5 to 7.5 mEq/L; and QRS prolongation is seen with
potassium levels above 7.0 to 8.0 mEq/L. Although these changes
may occur in only half the patients, recognition of these patterns

when they are present is vital to rapid diagnosis and initiation
of lifesaving treatment.6 A serum potassium level above 5.0 mEq/L
is diagnostic of hyperkalemia, but the value itself does not
always predict electrocardiographic changes or the degree of car-
diotoxicity. Subtle electrocardiographic changes consistent with
BOX 125-1 Five Most Common Causes of Hyperkalemia
Spurious elevation Hemolysis due to drawing or storing of the
laboratory sample or post–blood sampling
leak from markedly elevated white blood
cells, red blood cells, or platelets
Renal failure Acute or chronic
Acidosis Diabetic ketoacidosis, Addison’s disease,
adrenal insufficiency, type 4 renal tubular
acidosis
Cell death Rhabdomyolysis, tumor lysis syndrome,
massive hemolysis or transfusion, crush
injury, burn
Drugs Beta-blockers, acute digitalis overdose,
succinylcholine, angiotensin-converting
enzyme inhibitors, angiotension receptor
blockers, nonsteroidal anti-inflammatory
drugs, spironolactone, amiloride,
potassium supplementation
Chapter 125 / Electrolyte Disorders   1637
hyperkalemia should not be the sole reason to treat a stable patient
not likely to have an elevated potassium concentration until serum
levels have returned.3
Management
Patients with suspected or known hyperkalemia require intrave-
nous access and continuous cardiac monitoring. The treatment of
hyperkalemia is based on the clinical scenario combined with the
12-lead ECG and the laboratory potassium value. The treatment
strategy consists of three main steps: stabilization of the cardiac
membrane, shifting of potassium into the cells, and then removal
of potassium from the body. In patients who do not require urgent
treatment, lowering of total body potassium may be the only step
necessary. A variety of treatment options are considered for the
acute management of hyperkalemia, including calcium, insulin,
beta2-adrenergic agonists, sodium bicarbonate, resins, and dialysis
(Table 125-1).
Intravenous calcium is used to stabilize the cardiac membrane
by restoring the electrical gradient. Calcium increases the depo-
larization threshold and the calcium gradient across the cardiac
membrane, quieting myocyte excitability and increasing cardiac
conduction speed, thus narrowing the QRS. Calcium does not
decrease serum potassium levels, and its effect is rapid but tran-
sient. The dose is one ampule, or 10 mL of 10% calcium chloride

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

IV

Figure 125-1.  Hyperkalemia with

QRS widening merging into T wave,
absent P wave.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

VI

Figure 125-2.  Hyperkalemia in

the same patient as in Figure 125-1
V5 after potassium-lowering therapy
has begun. Tall peaked T waves,
150 Hz 25.0 mm/s 10.0 mm/mV 4 by 2.5s + 3 rhythm lds MAC5K 008B o 12SLTMv237 decreased P wave.
1638   PART III  ◆  Medicine and Surgery / Section Eleven • Metabolism and Endocrinology

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

VI

II

Figure 125-3.  The same patient V5

as in Figures 125-1 and 125-2 after
dialysis. The electrocardiogram is 150 Hz 25.0 mm/s 10.0 mm/mV 4 by 2.5s + 3 rhythm lds MAC5K 008B o 12SLTMv237
now normal.

prevent hypoglycemia, also shifts potassium into cells by stimula-

Table 125-1 Treatment of Hyperkalemia tion of the Na+,K+-ATPase pump. The onset of action is less than
15 minutes, and the effect is maximal between 30 and 60 minutes,
TREATMENT MEDICATION FEATURES
with a maximal drop of 0.6 mEq/L on average.
Stabilize Calcium chloride For wide QRS, restores Nebulized albuterol by face mask is effective in shifting potas-
cardiac (10 mL, maximum the electrical gradient; sium into cells by stimulation of the Na+,K+-ATPase pump.6 Nebu-
membrane 20 mL) or calcium does not decrease serum lized albuterol begins to take measurable effect after 15 minutes
gluconate (10-30 mL), potassium
and lowers the serum potassium level by 0.5 to 1 mEq/L, depend-
IV push
ing on the dose.7 The effective dose is at least four times higher
Shift potassium Insulin, 10 units, IV If severely acidotic than that typically used for bronchodilation.8 Mild tachycardia is
into cells push, combined with In conjunction with the main side effect but is generally well tolerated. The combina-
100 mL of 50% dextrose, nephrologist if dialysis
IV push dependent tion of nebulized albuterol and insulin with glucose appears to be
High-dose nebulized additive, lowering serum potassium by a mean of 1.2 mEq/L.9
albuterol by face mask Saline infusions also stimulate the Na+,K+-ATPase pump, and
(15-25 mg by continuous only a few hundred milliliters is required for beneficial effects.
inhalation) Saline infusions are given judiciously in anuric patients and
Bicarbonate 50-100 mL usually in consultation with the nephrologist. Sodium bicarbonate
Normal saline 100-
250 mL is effective only in hyperkalemic patients who are acidotic and has
no benefit when it is used for hyperkalemia in nonacidotic
Remove Hemodialysis Emergently in cardiac patients.10 Sodium bicarbonate buffers hydrogen ions extracellu-
potassium Normal saline and arrest, urgently in renal
from the body furosemide failure; may delay if renal
larly while shifting potassium intracellularly but should be reserved
Ion exchange resin function is normal for patients with confirmed acidosis. Although intravenous mag-
In patients with nesium also can drive potassium intracellularly, it should never be
rhabdomyolysis or used in hyperkalemia as most patients with elevated potassium
tumor lysis syndrome levels are also at risk for concomitant hypermagnesemia.
with intact urine output Potassium can best be removed from the body acutely by hemo-
Not effective acutely
dialysis. Hemodialysis effectively and reliably decreases serum
potassium levels by at least 1 mEq/L in the first hour and another
1 mEq/L during the next 2 hours.7,11 It is the only reliable method
solution. Some authors prefer calcium gluconate rather than of potassium removal that has been experimentally studied and
calcium chloride on the basis of the reduced risk of tissue necrosis should be instituted early in the treatment of life-threatening
should it extravasate at the injection site.4,5 More than 10 mL hyperkalemia in patients with renal failure. In patients with intact
of calcium gluconate will often be required as it contains only renal function, medical management alone is usually sufficient,
one third the calcium contained in calcium chloride. Calcium even in extreme cases, and hemodialysis may not be necessary
gluconate is also preferred in pediatric cases as well as in more unless multiple medical modalities fail. There are no randomized
chronic, less emergent hyperkalemic patients when a slow infusion trials addressing the use of diuretics such as furosemide in the
is desired. emergent management of hyperkalemia, but in cases such as rhab-
Potassium can be shifted intracellularly with beta2-agonists, domyolysis or tumor lysis syndrome, it may be appropriate to use
insulin, saline, and potentially sodium bicarbonate. Insulin is the a normal saline infusion supplemented by furosemide to enhance
most reliable agent to move potassium into cells, but beta2- diuresis and potassium excretion in the urine.
adrenergic receptor agonists also provide benefit in some patients. Cation exchange resins, such as sodium polystyrene sulfonate
Insulin, given intravenously in combination with glucose to (Kayexalate), have not been shown to decrease the serum

potassium level within the first 4 hours of treatment and should
not be used in the acute management of hyperkalemia.12
Hyperkalemia is seen in diabetic ketoacidosis (DKA), although
most hyperkalemic patients with DKA are actually total body defi-
cient of potassium. In this insulin-deficient and acidotic state,
serum potassium levels rise because of cellular shifts. Simply treat-
ing the patient’s underlying DKA will also treat the hyperkalemia.
In fact, the mainstay of treatment of DKA—fluids and insulin—
closely mirrors the treatment of hyperkalemia itself.13
As hyperkalemia progresses, the end result will be cardiopulmo-
nary arrest due to ventricular fibrillation, pulseless electrical activ-
ity, or asystole. In a known or suspected hyperkalemic arrest, an
approach beginning with standard advanced cardiac life support
combined with the use of multiple potassium-lowering medica-
tions is rational.14,15 Epinephrine has been shown to lower potas-
sium by 0.25 mEq/L.16,17 Calcium chloride is given immediately by
intravenous push, followed by insulin and glucose. Bicarbonate
should be given by bolus dose if the patient is believed to be aci-
dotic. Emergent hemodialysis is recommended if it is readily avail-
able. Hemodialysis through central venous access can be used
during ongoing cardiopulmonary resuscitation to acutely lower
the serum potassium level and may result in return of spontane-
ous circulation with intact neurologic status despite prolonged
resuscitative efforts and failure of conventional medications and
defibrillation.18
HYPOKALEMIA
Principles of Disease
Hypokalemia is the most common electrolyte abnormality
encountered in clinical practice. When it is defined as a value of
less than 3.5 mEq/L, hypokalemia is found in more than 20% of
hospitalized patients and in 10 to 40% of patients treated with
thiazide diuretics in the outpatient setting.19 Although hypokale-
mia is usually asymptomatic, severe cardiac dysrhythmias and
rhabdomyolysis can occur secondary to potassium’s effect on the
heart and muscle.20 The five most common causes of hypokalemia
are renal losses, increased nonrenal losses, decreased potassium
intake, intracellular shift, and endocrine etiologies (Box 125-2).
Hypokalemia is often seen in association with hypomagnesemia,
and patients with low serum potassium levels should be assumed
to be hypomagnesemic also.20-22
Increased excretion of potassium, especially coupled with poor
intake, is the most common cause of hypokalemia, and patients
receiving diuretics represent the single most common patient
group encountered in clinical practice. Hypokalemia from thia-
zide diuretics occurs through increases in distal sodium delivery
in the nephron and by activation of the renin-angiotensin-
aldosterone system. Thiazide diuretics are more likely than loop
BOX 125-2 Five Most Common Causes of Hypokalemia
Renal losses Diuretic use, drugs, steroid use, metabolic
acidosis, hyperaldosteronism, renal
tubular acidosis, diabetic ketoacidosis,
alcohol consumption
Increased nonrenal Sweating, diarrhea, vomiting, laxative use
losses
Decreased intake Ethanol, malnutrition
Intracellular shift Hyperventilation, metabolic alkalosis, drugs
Endocrine Cushing’s disease, Bartter’s syndrome,
insulin therapy
Chapter 125 / Electrolyte Disorders   1639
or osmotic diuretics to cause hypokalemia, but both the thiazide
and loop diuretics block chloride-associated sodium and increase
delivery of sodium to the collecting tubules. Hypokalemia is a
common adverse effect of treatment with diuretics and may cause
fatal arrhythmias and increase the risk of digitalis toxicity.23 In
addition to diuretics, other drugs and disorders can cause signifi-
cant renal potassium losses, including hyperaldosteronism, steroid
excess, metabolic acidosis, DKA, renal tubular acidosis, and alcohol
consumption. Penicillin and its synthetic derivatives, when they
are given in large doses, promote renal potassium excretion by
increasing sodium delivery to the distal nephron.
Individuals with secondary hyperaldosteronism, whether it is
due to congestive heart failure (CHF), hepatic insufficiency, or
nephrotic syndrome, may also exhibit hypokalemia. Patients with
renal tubular acidosis can become hypokalemic because a defect
in the distal tubule leads to increased potassium excretion.
Administration of insulin may cause a reduction in serum
potassium because of insulin’s ability to stimulate the Na+,K+-
ATPase pump and move potassium intracellularly; hypokalemia
can be a dangerous complication with intentional overdoses of
insulin and during treatment of DKA. Although most patients
with DKA present with high-normal or mildly elevated serum
potassium levels, patients are usually 2 to 3 mEq/kg body weight
deficient in total body potassium.24 Failure to appreciate this
total body deficit—and to not begin potassium infusion once
significant hyperkalemia has been ruled out and intact renal
function confirmed—may lead to otherwise unexplained arrhyth-
mias or cardiac arrest in patients hours after their initial therapy
has begun.
Hypokalemia can also occur from gastrointestinal and dermal
losses. In diarrheal states, large quantities of potassium can be lost
as the volume of stool increases and secondary hyperaldosteron-
ism can occur. Although hypokalemia is often seen after pro-
tracted vomiting or nasogastric suctions, only 5 to 10 mEq/L of
potassium is lost in gastric fluid. The hypokalemia is secondary to
the resultant metabolic alkalosis, chloride losses, and hyperaldo-
steronism. Large doses of laxatives and repeated enemas cause
excessive potassium loss in the stool and can cause hypokalemia.
On occasion, excessive sweating can lead to hypokalemia from
losses of potassium through the skin. In addition, patients with
extensive burns can also suffer from hypokalemia because of sig-
nificant losses from the skin.
Dietary potassium deficiency should be considered in the
severely malnourished patient and the chronic alcoholic.25 When
poor potassium intake is combined with increased nonrenal
losses, severe hypokalemia can result. Hypokalemia can also result
from an acute shift of potassium from the extracellular compart-
ment into cells. This is most commonly seen in patients with
metabolic alkalosis, in patients with hyperventilation, and in those
patients taking medications such as beta-agonists or deconges-
tants. Beta receptor stimulation can lead to hypokalemia, espe-
cially in patients using repetitive and high doses of beta-agonists
for chronic obstructive pulmonary disease or asthma. Albuterol-
induced hypokalemia can occur even at normal therapeutic
doses.26 A standard dose of nebulized albuterol reduces serum
potassium by 0.2 to 0.4 mEq/L, and a second dose taken within 1
hour has the potential to reduce it by almost 1 mEq/L. Patients
with starvation or near-starvation may suffer from hypokalemia
when they are fed because insulin secretion and increased cellular
uptake can cause an acute intracellular migration of potassium.
Clinical Features
Hypokalemia is usually asymptomatic but can be manifested
with nonspecific complaints, including palpitations, skeletal
muscle weakness, easy fatigability, depression, and muscle pain.
1640   PART III  ◆  Medicine and Surgery / Section Eleven • Metabolism and Endocrinology
I aVR
II aVL
III aVF
Figure 125-4.  Hypokalemic
electrocardiographic changes,
including flattened T wave, VI
prolonged QT interval, nonspecific
ST changes, and prominent U wave
(arrow).
Although short periods of mild potassium depletion are typically
well tolerated in healthy individuals, severe potassium depletion
can result in serious cardiovascular instability, neurologic dys-
function, glucose intolerance, gastrointestinal symptoms, and
renal failure as well as affect the acid-base balance in the body.27
The likelihood of symptoms appears to correlate with the rapidity
of the decrease in serum potassium. In patients without underly-
ing heart disease, abnormalities in cardiac conduction are
extremely unusual, even when the serum potassium concentration
is below 3.0 mEq/L. Paresthesias, depressed deep tendon reflexes,
fasciculations, muscle weakness, and confusion can occur when
the serum potassium level is less than 2.5 mEq/L. However, in
patients with cardiac ischemia or heart failure, even mild to mod-
erate hypokalemia increases the likelihood of cardiac arrhythmias
secondary to potassium’s effect on the action potential. The
data linking hypokalemia with arrhythmias and cardiac arrest in
acute myocardial infarction are fairly strong, but the direct myo-
cardial stimulatory effects of increased circulating epinephrine is
a possible confounder.20 Hypokalemia is an independent risk
factor contributing to reduced survival of cardiac patients and
increased incidence of arrhythmic death. On the basis of available
evidence, it appears best to attempt to maintain a serum potas-
sium concentration above 4.5 mEq/L in patients having an acute
myocardial infarction. Hypokalemic patients can demonstrate
first- and second-degree heart block, atrial fibrillation, ventricular
fibrillation, and asystole. Hypokalemia can also promote meta-
bolic acidosis.
Hypokalemic periodic paralysis is a rare disorder characterized
by potentially fatal episodes of muscle weakness through the
involvement of the respiratory muscles. Life-threatening cardiac
arrhythmias are managed by restoration of serum potassium levels
into the normal range.28
Diagnostic Strategies
Hypokalemia is rarely suspected on the basis of clinical presenta-
tion, and the diagnosis is typically made by measurement of the
serum potassium concentration during routine laboratory study.
If there is any suspicion for hypokalemia or a patient presents
with generalized weakness, palpitations, or arrhythmias, an ECG
should be obtained. Just as a tall-peaked T wave is characteristic
of hyperkalemia, a flattened T wave can be seen in hypokalemia.
U waves, which are small deflections after the T wave, may also be
seen (Figs. 125-4 and 125-5). The real danger of hypokalemia is
V1 V4
V2 V5
V3 V6
ST
depression
Flat T wave
U wave
Prolonged Q-T interval
Hypokalemia
Figure 125-5.  Electrocardiographic changes in hypokalemia.
that it may also cause a prolonged QT interval. Once the QT
interval becomes longer than 500 milliseconds, the risk of malig-
nant ventricular arrhythmias and torsades de pointes increases
dramatically.28 Hypokalemia is also notorious for causing nonspe-
cific ST and T wave changes. In addition, prolonged potassium
depletion of even modest proportion can provoke or exacerbate
kidney injury or hypertension. A severe degree of hypokalemia
with paralysis is a potentially life-threatening medical emergency;
measurement of relative urinary potassium excretion and an
assessment of the acid-base status might help narrow the differ-
ential diagnosis in the emergency setting.
Management
Potassium is an intracellular cation, so a low serum potassium
level almost always reflects a significant total potassium deficit.
When treating hypokalemia, one should remember that each
0.3 mEq potassium drop below normal correlates with an approx-
imately 100 mEq total body deficit.29 Patients who have mild or
moderate hypokalemia are usually asymptomatic or present with
minor symptoms. These patients may only need oral potassium
replacement therapy if they do not have nausea or vomiting as the
cause of their hypokalemia. Oral replacement is available in liquid,
powder, and tablet form. Potassium chloride is the most com-
monly used supplementation, and 40 to 60 mEq orally every 2 to
4 hours is typically well tolerated. If the cause of hypokalemia is
not clear or the hypokalemia is severe and associated with
profound weakness, obtain a spot urine potassium level before
starting therapy to assess whether the patient’s kidneys are inap-
propriately wasting potassium from a renal or endocrine cause.
 Chapter 125 / Electrolyte Disorders   1641
Patients in whom severe hypokalemia is suspected should be
immediately placed on a cardiac monitor and intravenous access BOX 125-3 Three Types of Hypernatremia
secured.
Treatment of hypokalemia is essential in multiple populations Hypernatremia with Heatstroke
of patients. Hypokalemia is arrhythmogenic, especially in the set- dehydration and low Increased insensible losses: burns,
total body sodium sweating
tings of acute myocardial infarction, high catecholamine states,
Gastrointestinal loss: diarrhea,
and hypertrophied or dilated ventricles. Hypokalemia is an impor- protracted vomiting, continuous
tant independent risk factor for morbidity and mortality in gastrointestinal suction
patients with heart failure. Correction of serum potassium levels Osmotic diuresis: glucose, mannitol,
to between 4.0 and 5.0 mEq/L is important in these patients.30 enteral feeding
If intravenous infusion is necessary, potassium chloride at a rate Hypernatremia with low Diabetes insipidus
of 10 to 20 mEq/hr is considered safe. Potassium may burn total body water and Neurogenic
patients with small veins, so small amounts of lidocaine can be normal total body Elderly with “reset” osmostat
added to the intravenous solution. In the rare instance in which sodium Hypothalamic dysfunction
intravenous repletion is planned at more than 20 mEq/hr, closely Suprasellar or infrasellar tumors
Renal disease
monitor the patient with continuous cardiac monitoring and Drugs (amphotericin, phenytoin,
establish central line access. lithium, aminoglycosides,
Hypokalemia is associated with hypomagnesemia, and the methoxyflurane)
severity of the hypokalemia correlates with a similar degree of Sickle cell disease
hypomagnesemia.31 Magnesium replacement should usually Hypernatremia with Salt tablet ingestion
accompany potassium repletion. Unless the patient receives at increased total body Salt water ingestion92
least 0.5 g/hr of magnesium sulfate along with potassium replace- sodium Saline infusions
ment, potassium will not move intracellularly and the patient will Saline enemas
lose potassium through excretion.22 Correction of large potassium Intravenous sodium bicarbonate
deficits may require several days, and oral and intravenous replace- Poorly diluted interval feedings
Primary hyperaldosteronism
ment can occur simultaneously. Hemodialysis
Cushing’s syndrome
HYPERNATREMIA Conn’s syndrome

Principles of Disease
Hypernatremia is defined as a serum sodium concentration above
145 mEq/ L and is usually associated with a poor prognosis. It is BOX 125-4 More Common Causes of Diabetes Insipidus
uncommon in previously normal patients, and in adults it is
almost exclusively due to a total body water deficit.32 Most hyper- Central
Idiopathic
natremic patients have either an impaired sense of thirst or no Familial disease
access to water. Thus elders, infants, patients in coma or with Cancer
mental impairment, and those who are intubated and paralyzed Hypoxic encephalopathy
are at highest risk for this disorder.33,34 Hypernatremia can be Infiltrative disorders
divided into three physiologic pairings (Box 125-3). Diabetes Postsupraventricular tachycardia
insipidus, a condition that results in insufficient production of or Anorexia nervosa
lack of response to antidiuretic hormone, can lead to life- Nephrogenic
threatening hypernatremia35 (Box 125-4). Chronic renal insufficiency
Polycystic kidney disease
Clinical Features Lithium toxicity93
Hypercalcemia
Hypernatremia is a disease seen predominantly in elders, but it Hypokalemia
can also be seen in patients who depend on others to provide them Tubulointerstitial disease
with water, including infants, intubated patients, and persons with Hereditary
mental debilitation.36,37 In addition, patients will also have multi- Sickle cell disease
factorial causes leading to severe hypernatremia.38 Patients may
complain of polyuria or polydipsia or have obvious causes of
extrarenal fluid losses; others may have no complaints at all. A patient’s total body water is usually calculated by multiplying
Hypernatremia should be considered in any patient presenting the patient’s body weight in kilograms times 0.6. However, because
with altered mental status, especially individuals with severe of percentage body fat differences based on the age and sex of the
mental retardation, cerebral palsy, and head injury, as well as in patient, it is more accurate to use the correction factors listed in
bed-ridden patients who have no access to water. Table 125-2.

Diagnostic Strategies Management

In addition to routine serum chemistries, serum osmolarity and
urine sodium concentration and osmolality should be obtained.
The degree of hypernatremia almost always equals the total body
water deficit in adults. The patient’s total body water (TBW)
deficit can be estimated by the formula
TBW deficit = TBW × (serum Na + /140) − 1
The treatment of hypernatremia has three interdependent goals:
first, to quickly correct underlying shock, hypoperfusion, or sig-
nificant hypovolemia with normal saline; second, to treat the
underlying cause of hypernatremia, such as fever, vomiting, or
diabetes insipidus; and third, to carefully lower the serum sodium
level, usually by replacement of the body’s total water deficit.39
Until hypoperfusion and hypovolemia are corrected, homeostatic
1642   PART III  ◆  Medicine and Surgery / Section Eleven • Metabolism and Endocrinology

Table 125-2 Calculation of Body Water BOX 125-5 Causes of Hyponatremia

POPULATION TOTAL BODY WATER Pseudohyponatremia Hyperlipidemia
Children and adult men Body weight (kg) × 0.6 Hyperproteinemia (multiple
myeloma, macroglobulinemia)
Adult women Body weight (kg) × 0.5
Elderly men Body weight (kg) × 0.5 Dilutional Hyperglycemia*
Elderly women Body weight (kg) × 0.45 Hypovolemic Body fluid losses: sweating,
hyponatremia: decreased vomiting, diarrhea,
total body water and gastrointestinal suction
sodium, with a relatively Third spacing: bowel obstruction,
mechanisms for sodium balance will promote sodium resorption greater decrease in burns, pancreatitis,
to maintain intravascular volume, even at the expense of the sodium rhabdomyolysis
serum sodium concentration. Renal causes: diuretics,
mineralocorticoid deficiency,
The rate of correction in hypernatremia is extremely important
osmotic diuresis, renal tubular
to minimize morbidity and mortality. In adult patients who have acidosis, salt-wasting
had hypernatremia during a short time as a result of sodium nephropathies
loading, “rapid correction” at 1 to 2 mEq/hr lowering of serum
sodium appears relatively safe.39,40 However, most adult patients Hypervolemic Heart failure
have hypernatremia during days to weeks. In this group of patients, hyponatremia: increased Chronic renal failure
serum sodium concentration should be slowly corrected at no total body sodium with a Hepatic failure or cirrhosis
more than 0.5 mEq/hr or 10 to 12 mEq/day. relatively greater increase
Normal saline can typically be started for volume replacement in total body water
until the patient is hemodynamically stable and then changed to
Euvolemic hyponatremia: SIADH
half-normal saline at 100 mL/hr once vital signs have normalized. increased total body Drugs causing SIADH (diuretics,
The treatment of central diabetes insipidus with desmopressin water with nearly normal barbiturates, carbamazepine,
(DDAVP) is an effective means of improving polyuria and hyper- total body sodium chlorpropamide, clofibrate,
natremia; initial doses in the acute setting range from 1 to 2 µg.33 opioids, tolbutamide, vincristine)
Psychogenic polydipsia
Beer potomania
HYPONATREMIA Hypothyroidism
Adrenal insufficiency
Principles of Disease MDMA (ecstasy)
Accidental or intentional water
Hyponatremia, defined as serum sodium concentration of less
intoxication
than 135 mEq/L, is the second most common electrolyte abnor-
mality encountered in clinical practice.37 It is important to recog- *Hyperglycemia is referred by some as pseudohyponatremia, but hyperglycemia is
nize hyponatremia because of its potential morbidity and also actually a dilutional hyponatremia.
SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
because it can be a marker of underlying disease. The most
common causes of severe hyponatremia in adults are therapy with
thiazides, the postoperative state including transurethral prosta-
tectomy, the syndrome of inappropriate secretion of antidiuretic central pontine myelinolysis, although it is more accurately labeled
hormone (SIADH), polydipsia in psychiatric patients, and unin- the osmotic demyelinating syndrome.41
tentional water intoxication. Gastrointestinal fluid loss, ingestion Although hyponatremia has many causes, they fall into four
of overly dilute formula, accidental ingestion of excessive water, general categories: pseudohyponatremia, hyponatremia with
and receipt of multiple tap-water enemas are the main causes of dehydration and decreased extracellular volume, hyponatremia
severe hyponatremia in infants and children. Most patients pre- with increased extracellular volume, and euvolemic hyponatremia
senting to the emergency department (ED) with hyponatremia are with increased total body water (Box 125-5).
asymptomatic and do not require emergent therapy. If symptoms
are present, they are typically based on the degree of hyponatremia Pseudohyponatremia
and how acutely the hyponatremia developed. Symptoms range
from headache, nausea, and vomiting to confusion, seizures, and Pseudohyponatremia is a falsely low sodium reading caused by the
coma. There are two groups of hyponatremic patients that will presence of other osmolar particles in the serum. The phenome-
require treatment with either normal saline or hypertonic saline: non of pseudohyponatremia is explained by the increased percent-
(1) severe but asymptomatic hyponatremia with a sodium level of age of large molecular particles relative to sodium. These large
110 mEq/L or less and (2) acute symptomatic hyponatremia with molecules do not contribute to plasma osmolality, resulting in a
a sodium level below 120 mEq/L. state in which the relative sodium concentration is decreased but
Central nervous system (CNS) damage due to hyponatremia the overall osmolality remains unchanged. Severe hypertriglyceri-
may be caused by cerebral edema and increased intracranial pres- demia and hyperproteinemia are two common causes of this con-
sure, by osmotic fluid shifts during overly aggressive treatment, or dition.42 Blood draw or laboratory error should also be considered
by both. When they are subjected to a hyponatremic environment, a possible cause of a patient’s hyponatremia, especially if the blood
neurons become depleted of sodium and potassium in an attempt sample was drawn near an infusion site using 5% dextrose in water
to limit their own osmolarity to prevent intracellular fluid shifts (D5W) or 5% dextrose in half-normal saline or when a very abnor-
that would lead to cerebral edema. If fluid therapy raises extracel- mal sodium level is reported in an otherwise healthy patient.
lular sodium levels too quickly, fluids shift out of neurons and Hyperglycemia is sometimes considered a cause of pseudo-
diffuse demyelination may occur, leading to flaccid paralysis and hyponatremia; however, it actually causes a dilutional hyponatre-
often death due to a syndrome most commonly referred to as mia by pulling water into the vascular space by osmosis. Two

different formulas based on the degree of a patient’s hyperglyce-
mia are currently used to correct serum sodium levels. One com-
monly used formula advocates the addition of 1.6 mEq/L to the
measured sodium for every 100 mg/dL of glucose above 100.
Another formula recommends use of 2.4 mEq as the correction
factor because glucose values above 400 mg/dL may lower sodium
values by 4 mEq/L per each 100 mg/dL of glucose rise.40
Hypovolemic Hyponatremia
Hypovolemic hyponatremia, or hyponatremia in association with
dehydration, occurs when there is decreased extracellular volume
combined with an even greater loss of sodium. Hyponatremia
secondary to body fluid losses must be differentiated from that
due to renal losses. Hyponatremia with dehydration due to body
fluid losses includes sweating, vomiting, diarrhea, and gastrointes-
tinal suction. Hypovolemic hyponatremia is also seen with “third
spacing” in bowel obstruction, burns, and intra-abdominal sepsis.
Hypovolemic hyponatremia due to renal causes includes diuretic
use, mineralocorticoid deficiency, renal tubular acidosis, and salt-
wasting nephropathy. Hypovolemic hyponatremia can be further
exacerbated when fluid losses are replaced with hypotonic saline.
Hypervolemic Hyponatremia
Hypervolemic hyponatremia, or hyponatremia with increased
extracellular volume, occurs when sodium and water are retained
but water retention exceeds sodium retention. Most of these
patients present with edema. Hyponatremia with increased total
body sodium occurs in patients with heart failure, chronic renal
failure, and hepatic failure. The fluid retention in these states is
secondary to renal hypoperfusion, resulting in increased aldoste-
rone secretion and a decrease in free water excretion.
Euvolemic Hyponatremia
The final category of hyponatremia is one in which patients are
euvolemic but have increased total body water. Causes of this type
of hyponatremia include SIADH, psychogenic polydipsia,43 beer
potomania, hypothyroidism, diuretic use in patients with mild
CHF, and accidental or intentional water intoxication. These
patients do not present with edema because most of the increased
body water is intracellular and not intravascular. Hyponatremia
without edema has also been described in patients after the use of
the recreational drug N-methyl-3,4-methylenedioxyamphetamine
(MDMA or ecstasy). MDMA-induced hyponatremia is multifac-
torial and is related to increased free water intake to avoid dehy-
dration and rhabdomyolysis, along with the tendency to be very
active while using the drug, leading to sweating and antidiuretic
hormone secretion.41 In addition, there are extensive case reports
of significant hyponatremia in endurance athletes.44
SIADH is an important cause of hyponatremia that occurs
when normal antidiuretic hormone secretion is lost and antidi-
uretic hormone is secreted independently of the body’s need to
conserve water. The process results from excess antidiuretic
hormone production that causes total body water to increase,
diluting the body’s sodium and causing the serum sodium to
decrease. Patients with SIADH have inappropriately concentrated
urine despite a low serum osmolality and normal circulating
blood volume. Patients with SIADH have excess total body water
but no signs of edema, ascites, or heart failure because most of the
increased body water is intracellular, not intravascular. The three
most common causes of SIADH are pulmonary lung masses and
infections, CNS disorders, and drugs (Box 125-6). Lung cancers
(especially small cell cancer), pneumonia, and tuberculosis can
lead to SIADH. CNS infections, masses, and psychosis can also
cause SIADH. A large number of medications are associated with
Chapter 125 / Electrolyte Disorders   1643
BOX 125-6 Three Most Common Causes of SIADH
Lung masses
Cancer (especially small cell)
Pneumonia
Tuberculosis
Abscess
Central nervous system disorders
Infection (meningitis, brain abscess)
Mass (subdural, postoperative, cerebrovascular accident)
Psychosis (with psychogenic polydipsia)
Drugs
Thiazide diuretics
Narcotics
Oral hypoglycemic agents
Barbiturates
Antineoplastics
SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
SIADH, the most common of which are thiazide diuretics, narcot-
ics, lithium, oral hypoglycemics, barbiturates, and antineoplastics.
The mainstay of treatment of most patients with SIADH and other
causes of euvolemic hyponatremia is free water restriction.
Diagnostic Strategies
A spot urinary sodium or urinary chloride level is useful to deter-
mine if hyponatremia of undetermined origin is renal in etiology.
Patients with hypovolemic hyponatremia due to nonrenal causes
typically have a low urinary sodium or chloride level (<20 mEq/L)
as they try to retain solute. Patients with hypovolemic hyponatre-
mia due to renal causes will have elevated urine sodium and chlo-
ride levels above 20 mEq/L as their kidneys cannot retain sodium
or chloride. Patients with euvolemic hyponatremia typically have
a urinary sodium concentration greater than 20 mEq/L secondary
to volume expansion caused by water retention. Patients with
hypervolemic hyponatremia secondary to CHF or cirrhosis have
urine sodium levels of less than 20 mEq/L because of renal hypo-
perfusion, whereas those with renal causes of hypervolemic hypo-
natremia or with SIADH have sodium levels in excess of 20 mEq/L
as their kidneys are not able to retain sodium. In interpreting
serum sodium levels, consider the possibility of sampling error if
the reported value does not seem consistent with the patient’s
presentation and confirm that a diuretic such as furosemide has
not been recently administered, which will increase urinary
sodium losses. It is also important to consider adrenal insuffi-
ciency when a dehydrated patient has both hyponatremia and
hyperkalemia.
Clinical Features
The signs and symptoms of hyponatremia increase as sodium
levels decline and also correlate with the rapidity with which
hyponatremia develops. Nonspecific signs of hyponatremia
include anorexia, nausea, vomiting, and generalized weakness.
Acutely hyponatremic patients whose sodium level drops below
120 mEq/L during 24 to 48 hours may present with severe neuro-
logic findings, including confusion, seizures, cerebral edema,
coma, and brainstem herniation. Determination of the hydration
status of the patient may help establish the etiology of the hypo-
natremia and help direct subsequent treatment. The diagnosis of
hypovolemic hyponatremia is more likely in the patient with
diminished skin turgor, increased capillary refill, dry mucous
membranes, and orthostasis. On the contrary, the patient with
jugular venous distention, peripheral edema, or pulmonary
1644   PART III  ◆  Medicine and Surgery / Section Eleven • Metabolism and Endocrinology
Table 125-3 Characteristics of Infusates
INFUSATE EXTRACELLULAR FLUID
INFUSATE SODIUM (mmol/L) DISTRIBUTION (%)
3% Hypertonic saline 513 100
0.9% Normal saline 154 100
solution
Lactated Ringer’s 130 97
solution
Half-normal saline 77 73
solution
0.2% Sodium chloride 34 55
+ 5% dextrose in water
5% Dextrose in water 0 45
congestion is much more likely to have hypervolemic hyponatre-
mia. Patients with SIADH will have no edema and have normal
skin turgor.
Management
Treatment of hyponatremia is guided by the patient’s clinical pre-
sentation, severity of symptoms, estimated duration of illness,
fluid status, and underlying cause of the sodium disturbance.
Typically, sodium should be corrected during a time course of 48
to 72 hours. Central pontine myelinolysis can occur with too rapid
correction of sodium.43 Most cases of central pontine myelinolysis
occur in the alcoholic, malnourished, and elder population,
although this devastating side effect can occur in healthy, young
patients as well. Patients with central pontine myelinolysis have a
flaccid paralysis, dysarthria, dysphagia, and hypotension. If a
patient have these symptoms during therapy, stop all sodium-
containing fluids and administer D5W immediately to lower
sodium values temporarily.44 Most patients presenting to the ED
with hyponatremia are stable and require no emergent therapy.
However, patients who have serum sodium levels of significantly
less than 120 mEq/L and those who have acute alterations in
mental status, seizures, or new focal findings due to hyponatremia
need immediate intervention. Table 125-3 presents the sodium
concentration of various infusates, and the following equation is
helpful to estimate the effect of 1 liter of any infusate on serum
sodium:
Change in serum Na + = infusate Na +
− serum Na + / total body water + 1
There is no consensus regarding the optimal treatment of
symptomatic hyponatremia. However, there is agreement that cor-
rection should occur at a sufficient pace and magnitude to reverse
the manifestations of hypotonicity but not be so rapid and large
as to pose a risk for development of osmotic demyelination. For
relatively asymptomatic patients with sodium values of 115 to
135 mEq/ L, free water restriction is typically the single most
important treatment.
In more severe cases when the sodium value is 120 mEq/L or
less and the patient has alterations in mental status, has focal find-
ings, or is seizing, hypertonic saline is indicated.45-47 Correction of
hyponatremia by 4 to 6 mEq/L within 6 hours, with bolus infu-
sions of 3% saline if necessary, is sufficient to manage the most
severe manifestations of hyponatremia.45
The serum sodium level should be below 120 mEq/L when
administration of hypertonic saline is being considered. It is rec-
ommended that critically ill hyponatremic patients with seizures,
focal findings, or coma receive 100 mL of 3% hypertonic saline
during 10 minutes. If a second bolus is required, an additional
100 mL of the 3% solution (513 mEq/L of sodium) may be
administered during the next 50 minutes. Increased neurologic
stability is highly likely once a symptomatic hyponatremic patient’s
serum sodium concentration has been raised by about 4 to 6 mEq
acutely by the hypertonic saline. To minimize the likelihood of
central pontine myelinolysis, it is essential that symptomatic
patients with severe hyponatremia not have serum sodium levels
rise by any more than a total of 10 to 12 mEq within the first 24
hours.46,47 Potassium deficits should be replaced aggressively in the
treatment of hyponatremic patients with a sodium disorder. If
patients are retaining volume and diuresis is not adequate, furo-
semide can be used; D5W is infused if the sodium level is rising
too quickly.46 Patients may be able to make full neurologic recover-
ies from central pontine myelinolysis with the reinduction of
hyponatremia in these extreme cases.44 Demeclocycline in a dosage
of 600 to 1200 mg daily is effective in patients with refractory
hyponatremia.48
Hypovolemic Hyponatremia
Treatment of hypovolemic hyponatremia begins with rehydration.
Hypotensive, dehydrated patients are volume resuscitated with
normal saline. Once the patient is hemodynamically stable, the
infusion rate is slowed. Typically, the normal saline is started
at 500 to 1000 mL/hr until the blood pressure is stable and
then slowed to 200 mL/hr with frequent sodium checks. If the
sodium value is below 120 mEq/L, the sodium concentration
should be allowed to rise only by an average of 0.5 mEq/hr or 10
to 12 mEq/day.47 It is essential to treat the underlying cause of
hyponatremia.
Hypervolemic Hyponatremia
Normal saline and hypertonic saline can cause pulmonary edema
in the hypervolemic hyponatremic patient. Restriction of fluid
and sodium is the preferred treatment of patients with hypervol-
emic hyponatremia, although loop diuretics can be used in severe
cases. Hemodialysis is an alternative in patients with renal impair-
ment and will be required in significantly hyponatremic renal
failure patients with volume overload. Patients with CHF will
usually benefit from diuretics that will increase water excretion
and cause vasodilation to improve cardiac output.49 In those
patients with liver failure, albumin is a consideration, along with
diuretics and possibly paracentesis to improve the underlying
pathologic process. Water restriction may make the largest impact
on the long-term care of these patients.
Euvolemic Hyponatremia
The mainstay of treatment of euvolemic hyponatremia is free
water restriction. As the hypo-osmolality in SIADH results from
a relative abundance of water in the intracellular and extracellular
volumes, maintained by a reduced ability to excrete water, the
restriction of free oral water intake is the first recommendation.
The use of water restriction is insufficient to treat acute severe
hyponatremia and is not recommended as a sole intervention in
severely symptomatic hyponatremia, in which a more rapid cor-
rection rate is necessary. The only definitive treatment of SIADH
is elimination of its underlying cause. Most cases of SIADH caused
by malignant disease resolve with effective antineoplastic therapy,
and most due to medication resolve promptly when the offending
agent is discontinued.50
In patients with SIADH, normal saline may cause the serum
sodium concentration to decrease even more as free water is
retained and hypertonic urine is excreted. If a patient is symptom-
atic because of a rapid decrease in serum sodium concentration,

BOX 125-7 Five Most Common Causes of Hypercalcemia
Malignant disease Ectopic secretions of parathyroid
hormone, multiple myeloma, cancer
metastatic to bone
Most common: breast, lung,
hematologic, kidney, prostate
Endocrine Hyperparathyroidism, multiple
endocrine neoplasias, hyperthyroidism,
pheochromocytoma, adrenal
insufficiency
Granulomatous Sarcoidosis, tuberculosis, histoplasmosis,
disease berylliosis, coccidioidomycosis
Pharmacologic agents Vitamins A and D, thiazide diuretics,
estrogens, milk-alkali syndrome
Miscellaneous Dehydration, prolonged immobilization,
iatrogenic, rhabdomyolysis, familial,
laboratory error
treatment with hypertonic saline is recommended. Demeclocy-
cline and lithium are rarely used in the treatment of SIADH
because of their many side effects and nephrotoxicity. Rapid cor-
rection of hyponatremia may occur during hemodialysis. To mini-
mize the risks of central pontine myelinolysis, hemodialysis is
reserved for patients with documented renal failure and used in a
very careful manner.50 Vaptans, which are oral agents that inhibit
the effects of vasopressin, have been studied for treatment of
patients with hyponatremia due to SIADH but need further evalu-
ation before becoming standard of care.46,51
HYPERCALCEMIA
Principles of Disease
Hypercalcemia is usually defined as a serum calcium level above
10.5 mg/dL; normal levels are usually defined as between 9 and
10.5 mg/dL. Hypercalcemia is considered mild if the total serum
calcium level is between 10.5 and 12 mg/dL; levels higher than
14 mg/dL can be life-threatening.
There are five major causes of hypercalcemia (Box 125-7).
Primary hyperparathyroidism is the most common cause of
hypercalcemia in outpatients, whereas malignant disease is the
most common cause in hospitalized patients. Mild hypercalcemia,
in an otherwise normal person, may be due to thiazide diuretics
with minimal dehydration. Other less common causes of elevated
calcium concentration are usually not considered until malignant
disease and parathyroid disease are ruled out. Malignancy-
associated hypercalcemia occurs in up to 10% of all patients with
advanced cancer and generally conveys a poor prognosis. Other
causes of hypercalcemia include granulomatous disease, such as
sarcoidosis and tuberculosis; medications and pharmacologic
agents; and a number of diverse conditions, such as rhabdomyoly-
sis and prolonged immobilization.
Clinical Features
Unfortunately, the clinical presentation of hypercalcemia is often
vague and nonspecific. Symptoms include nonfocal abdominal
pain, constipation, fatigue, diffuse body aches, anorexia, nausea,
and vomiting. Symptom severity depends on the degree of hyper-
calcemia, the rapidity of onset, and the patient’s baseline neuro-
logic and renal function.52 The diagnosis should be considered in
a large number of differential diagnoses. In addition, some patients
complain of polyuria or polydipsia. Neuropsychiatric disturbances
include anxiety, depression, confusion, and hallucinations. The
CNS manifestations that often predominate in more severe cases
Chapter 125 / Electrolyte Disorders   1645
include lethargy, altered mental status, seizures, and coma. Death
due to hypercalcemia is usually related to complications caused by
coma, dehydration, or electrolyte disturbances. Cardiac conduc-
tion abnormalities may occur; bradydysrhythmias are the most
common.53 Severe hypercalcemia has also been associated with
sinus arrest, atrioventricular block, atrial fibrillation, and ven-
tricular tachycardia.
Diagnostic Strategies
The diagnostic evaluation of a patient with suspected hypercalce-
mia begins with obtaining of electrolyte and renal function tests
and an ECG. Calcium is measured by determination of either a
total serum calcium level or an ionized calcium level. Ionized
calcium is the active form of the total calcium level. It is more
accurate in the diagnosis and treatment of hypocalcemia, but it
does need to be routinely evaluated in hypercalcemia.54 The serum
total calcium level represents both bound and unbound calcium
and thus should be corrected on the basis of the albumin concen-
tration. The adjustment to serum albumin is accomplished by
adding or subtracting 0.08 mg/dL to the measured total serum
calcium for every 1.0 g/L of albumin below or above 4 g/L albumin,
respectively.
A short QT interval can be seen in hypercalcemia and is con-
sidered a classic finding. However, although the incidence and
duration of QT shortening appear to be correlated with the degree
of hypercalcemia, it is not a reliable finding and is not routinely
seen in most patients (Fig. 125-6). ST segment elevation may be
the least well documented but most consistent electrocardio-
graphic finding, and hypercalcemia should be considered in the
differential diagnosis of ST segment elevation caused by condi-
tions other than myocardial infarction.55,56 In severe cases of
hypercalcemia, sinus bradycardia, bundle branch block, and high-
degree atrioventricular block may also been seen.
Management
Patients in hypercalcemic crisis are usually dehydrated, often
obtunded, and also predisposed to arrhythmias as a result of con-
comitant electrolyte disturbances; thus they require intravenous
access with a normal saline infusion and close monitoring. Normal
saline will inhibit proximal tubule reabsorption of calcium and
also correct the patient’s volume depletion. Normal saline is
infused “wide open” until blood pressure and perfusion are nor-
malized. After the initial bolus, the saline infusion is adjusted to a
rate of approximately 200 to 300 mL/hr, depending on the patient’s
age and renal function. Patients with underlying cardiac or renal
disease may require lower infusion rates that are carefully titrated.
Although the administration of higher volumes of saline may
further augment calcium excretion, it is much more likely to result
in increased morbidity and mortality from volume overload, pul-
monary edema, and myocardial ischemia. The routine use of furo-
semide in the management of hypercalcemia is no longer
recommended. Furosemide was once thought to block the distal
reabsorption of calcium, thus complementing saline’s proximal
tubule effects. However, no modern-day studies have shown furo-
semide to have significant calcium reabsorption blocking effects.
The use of furosemide is reserved to augment saline diuresis and
to avoid volume overload during the treatment of hypercalce-
mia.57 If it is given to patients who are not yet volume replete, this
loop diuretic may worsen the hypercalcemia because of its volume
depleting effects and also adversely affect the patient’s hemody-
namics and renal status. Once calcium excretion by saline infusion
has begun, other electrolyte values should be carefully monitored
with attention to serum potassium levels.
Osteoclast-inhibiting therapies for severe hypercalcemia are
generally considered in consultation with the patient’s primary
1646   PART III  ◆  Medicine and Surgery / Section Eleven • Metabolism and Endocrinology
I aVR
II
III
Figure 125-6.  Short QT interval
(arrow) in a patient with multiple
myeloma and a calcium level of II
14.2 mg/dL. (Courtesy Dr. Barton
Campbell.)
physician or oncologist. Drugs that inhibit osteoclast-mediated
bone resorption include the bisphosphonates, mithramycin, calci-
tonin, and glucocorticoids. Intravenous bisphosphonates are the
most extensively studied and most efficacious agents for the
treatment of malignancy-associated hypercalcemia.58 Their
calcium-lowering effect is achieved predominantly by inhibition
of osteoclast function and survival. Zoledronic acid is the bisphos-
phonate of choice in hypercalcemia of malignancy.59 The infusion
takes 15 minutes, and zoledronic acid may be more effective than
other bisphosphonates at keeping the calcium level down over
time. The use of intravenous bisphosphonates is restricted to the
treatment of acute hypercalcemia associated with serum calcium
concentrations above 15 mg/dL and rapid deterioration of CNS,
cardiac, gastrointestinal, and renal function.
In the rare case in which a patient has a life-threatening hyper-
calcemic arrhythmia or heart block, phosphates and hemodialysis
are considered.60,61 In cases of hypercalcemic crisis resulting
from primary hyperparathyroidism, urgent parathyroidectomy is
potentially curative.
HYPOCALCEMIA
Principles of Disease
Calcium regulation is critical for normal cell function, neural
transmission, membrane stability, bone structure, blood coagula-
tion, and intracellular signaling. Total body calcium is controlled
by a feedback system in which parathyroid hormone induces the
bone and the kidneys to increase serum calcium levels. Vitamin D
facilitates intestinal calcium absorption. Conversely, elevated
calcium levels normally inhibit parathyroid hormone release.
There are multiple causes of hypocalcemia, of which hypoalbu-
minemia is the most common (Box 125-8). Because calcium is
bound to albumin and other serum proteins, hypoalbuminemia
will cause a fall in the measured serum calcium by about 0.8 mg/
dL for every 1 g/dL reduction in serum albumin. The active form
of calcium is the ionized calcium, which is not affected by changes
in albumin.
Hypoparathyroidism is a common cause of hypocalcemia and
often develops because of surgery for head and neck cancers. It
develops in 1 to 2% of patients after total thyroidectomy. Patients
with vitamin D deficiency, including those with malabsorption
syndromes, liver disease, malnutrition, and very little sunlight
V1 V4
aVL V2 V5
aVF V3 V6
BOX 125-8 Most Common Causes of Hypocalcemia
Hypoalbuminemia
Hypoparathyroidism: inherited, postsurgical, autoimmune,
infiltrative
Vitamin D deficiency and vitamin D resistance: malabsorption
syndrome, liver disease, malnutrition, sepsis, anticonvulsants,
lack of sunlight exposure
Chronic renal failure
Hyperphosphatemia
Hypomagnesemia
Respiratory alkalosis
Severe pancreatitis
Drugs: bisphosphonates, phenytoin, phosphate, calcitonin
Tumor lysis syndrome
Rhabdomyolysis
exposure, are at high risk for development of hypocalcemia.62
Derangements in magnesium and phosphate can also lead to
hypocalcemia. Hyperphosphatemic patients often have hypocal-
cemia because of phosphate’s affinity to bind calcium, whereas
hypomagnesemia causes end-organ resistance to parathyroid
hormone and inhibits the hypocalcemic feedback loop. Patients
with sepsis demonstrate hypocalcemia usually associated with
hypoalbuminemia.
The most common causes of symptomatic hypocalcemia are
massive blood transfusions, toxins, pancreatitis, tumor lysis syn-
drome, and chronic malnutrition (Box 125-9). Patients receiving
massive blood transfusions are at risk for development of hypo-
calcemia because of citrate toxicity. Rapid blood transfusions and
radiocontrast dyes containing citrate should be monitored closely
in patients with hepatic failure, CHF, or other low-output states
to avoid hypocalcemia.63
Hypocalcemia in acute pancreatitis is caused primarily by pre-
cipitation of calcium soaps in the abdominal cavity, but glucagon-
stimulated calcitonin release and decreased parathyroid hormone
secretion may play a role. Toxic exposures to hydrofluoric acid and
ethylene glycol can cause profound hypocalcemia secondary to
their abilities to complex and chelate with calcium.
When patients are being treated for malignant neoplasms, they
are at risk for development of tumor lysis syndrome and multiple

Five Most Common Symptomatic Causes of
Hypocalcemia Seen in the Emergency
BOX 125-9 Department
Hyperventilation Anxiety, sympathomimetics
Ethanol abuse, chronic Hypoalbuminemia
malnutrition
Massive blood transfusion More than 10 units
Toxins Hydrofluoric acid, ethylene glycol
Severe pancreatitis
secondary electrolyte abnormalities. Hypocalcemia has been
attributed to the precipitation of calcium phosphate salts. Finally,
one should expect to encounter hypocalcemia in malnourished
patients and chronic alcoholics who present to the ED, especially
alcoholics with hyperventilation due to alcohol withdrawal.
Clinical Features
Although there are many clinical manifestations of hypocalcemia,
neuromuscular and cardiovascular findings predominate. Severe,
symptomatic hypocalcemia may result in cardiovascular collapse,
hypotension, and dysrhythmias. Clinically evident hypocalcemia
generally is manifested in milder forms and is usually the result of
a chronic disease state. The patient may complain of muscle
cramping, perioral or finger paresthesias, shortness of breath sec-
ondary to bronchospasm, and tetanic contractions. More severe
symptoms include hypotension, QT prolongation, angina, and
CHF. Chronic hypocalcemia may be manifested with cataracts,
poor dentition, dry skin, coarse hair, and pruritus. Chvostek’s sign
may be present: when the examiner taps the facial nerve, facial or
eye muscle twitching will be elicited. Trousseau’s sign may also be
present: when the examiner inflates the blood pressure cuff to
20 mm Hg above the systolic blood pressure for 3 minutes, carpal
spasms will be induced because of local ulnar and median nerve
ischemia. Trousseau’s sign is relatively specific for hypocalcemia,
whereas Chvostek’s test is less diagnostic.
Diagnostic Strategies
Most cases of hypocalcemia are discovered by clinical suspicion
followed by appropriate laboratory testing. A serum calcium level
less than 8.5 mg/dL or an ionized calcium level less than 2.0 mEq/L
is considered diagnostic. Total serum calcium is approximately
50% free (ionized) and 50% bound, primarily to albumin; thus
the serum level must be “corrected” when hypoalbuminemia
exists. The ionized calcium level, which is not affected by the
albumin level, is more accurate. It is best to perform the whole
blood ionized calcium determination rapidly to avoid changes in
chelation and pH.64 In select cases, a parathyroid hormone level
may be sent to assist the admitting or consulting physician. Elec-
trocardiography and cardiac monitoring are recommended in
suspected hypocalcemia patients to evaluate the QT interval and
to provide continuous monitoring for potential dysrhythmias.
Management
Most asymptomatic patients and those with mild symptoms can
be treated with oral calcium supplementation, such as calcium
carbonate. Intravenous calcium is administered, either as calcium
chloride or calcium gluconate, to patients with moderate to severe
symptoms; 100 to 300 mg of elemental calcium given during 5 to
30 minutes will raise the ionized calcium level 0.5 to 1.5 mEq.
Calcium chloride contains 272 mg of elemental calcium but can
be caustic to veins and thus should be given only to critically ill
Chapter 125 / Electrolyte Disorders   1647
BOX 125-10 Five Most Common Causes of Hypermagnesemia
Iatrogenic Intravenous administration, dialysate
Oral administration Laxatives, antacids, vitamins, cathartics,
dialysate, parental
Impaired elimination: Bowel obstruction, chronic constipation
hypomotility
Impaired elimination: Anticholinergics, narcotics, lithium
medications therapy
Miscellaneous Hypothyroidism, tumor lysis syndrome,
adrenal insufficiency, milk-alkali
syndrome, near-drowning in Dead
Sea94
hypocalcemic patients who require calcium urgently. It is best
given through a central line. Calcium gluconate contains 92 mg of
elemental calcium. Although this is one-third the amount con-
tained in calcium chloride, it is safer to administer and can be
given peripherally.62 Most patients requiring intravenous calcium
should be admitted to the hospital for monitoring and treatment
of nausea, vomiting, hypertension, and bradycardia. Patients
taking digoxin have increased cardiac sensitivity to fluctuations in
serum calcium, so intravenous calcium administration is accom-
panied by continuous electrocardiographic monitoring.65
HYPERMAGNESEMIA
Principles of Disease
Hypermagnesemia is a relatively rare electrolyte abnormality
defined as a serum magnesium concentration above 2.2 mg/dL.
Hypermagnesemia is most often seen in patients with renal
insufficiency who cannot optimally regulate magnesium excre-
tion, especially as their magnesium load increases. There have
been reports of fatal and near-fatal cases involving hypermagne-
semia in patients receiving magnesium with unrecognized renal
failure.66 Hypermagnesemia can also be caused iatrogenically in
patients receiving intravenous magnesium for medical treatment
or in patients taking over-the-counter laxatives and antacids.67
Even though most patients at risk for hypermagnesemia have
underlying renal impairment, hypermagnesemia has been reported
in patients with normal renal function, especially in elders. Box
125-10 lists the most common causes of increased serum magne-
sium levels.
Iatrogenic hypermagnesemia most commonly occurs from
excessive intravenous infusions of magnesium in patients being
treated for preeclampsia or eclampsia, cardiac arrhythmias, or
asthma exacerbations. Magnesium administration during eclamp-
sia can also cause fetal hypermagnesemia as magnesium crosses
the placental barrier. Hypermagnesemia may also be seen in
patients with chronic renal failure on hemodialysis if the dialysate
solutions are not closely monitored for magnesium content.
In patients with normal renal function, large amounts of mag-
nesium can be excreted daily in the stool and urine. However, in
patients with impaired renal function, hypermagnesemia can be
seen even with therapeutic doses of magnesium-containing prod-
ucts. For example, a patient with renal insufficiency should not
use magnesium citrate for treatment of constipation. An adult
dose of 10 ounces of laxative syrup results in consumption of
approximately 2.0 g of elemental magnesium per single dose. A
healthy adult can excrete more than 6.0 g of magnesium daily, but
renally impaired patients may not be able to tolerate a single dose
of laxative syrup. Hypermagnesemia resulting from Epsom salt
gargles and salt enemas has been reported.68,69
1648   PART III  ◆  Medicine and Surgery / Section Eleven • Metabolism and Endocrinology
Table 125-4 Clinical Effects of Hypermagnesemia
EFFECT LEVEL (mg/dL)
Decreased deep tendon reflexes 4-5
Hypotension 5-7
Respiratory insufficiency 10
Heart block 10-15
Cardiac arrest 10-24
Decreased gastrointestinal elimination and increased gastroin-
testinal absorption of magnesium due to intestinal hypomotility
can also result in toxicity. Hypermagnesemia can be seen with
bowel obstruction, colitis, gastric dilation, and use of medications
that decrease motility, including narcotics and anticholinergics.
Other less common causes of hypermagnesemia include rhabdo-
myolysis, tumor lysis syndrome, adrenal insufficiency, hyperpara-
thyroidism, and hypothyroidism.
Clinical Features
Patients with hypermagnesemia may present with flushing, nausea,
vomiting, headache, and diminished deep tendon reflexes. Typi-
cally, symptoms begin to be manifested around magnesium levels
of 4 mg/dL (Table 125-4). Magnesium is a CNS and neuromus-
cular depressant and can cause cardiac instability. Magnesium acts
as a calcium channel blocker and also blocks potassium channels
needed for repolarization. As magnesium levels rise, hypotension
and electrocardiographic changes, including QRS widening and
QT and PR prolongation, begin to occur. When serum magnesium
levels rise above 7 mg/dL, patients can have signs and symptoms
of hypotension, respiratory insufficiency, and heart block. Cardiac
arrest and death have been reported in patients with serum mag-
nesium levels above 10 mg/dL.70 Finally, hypermagnesemia
causes suppression of parathyroid hormone secretion and can be
associated with hypocalcemia.
Diagnostic Strategies
Measured plasma magnesium levels often do not reflect total
magnesium content, making it difficult to consistently correlate
symptoms to specific magnesium levels. Although there is some
question of the role of measuring ionized magnesium in patients
with hypomagnesemia, only total body magnesium needs to be
followed in hypermagnesemic patients.71
Management
Management of hypermagnesemia is dictated by the neuromus-
cular, cardiovascular, and CNS changes that occur. Most stable
or asymptomatic hypermagnesemic patients can be treated
with cessation of their magnesium therapy. As symptoms become
more pronounced, intravenous isotonic fluids are administered to
dilute the extracellular magnesium. Diuretics can be used to
promote excretion of magnesium while more definitive treatment
is arranged.
In patients with higher levels of serum magnesium or more
severe symptoms, renal consultation should be initiated immedi-
ately to arrange for dialysis. Intravenous calcium therapy to reverse
magnesium toxicity should be reserved for patients with life-
threatening symptoms while dialysis is being arranged. Calcium
directly antagonizes the neuromuscular and cardiovascular effects
of magnesium and is recommended in hypotensive patients
BOX 125-11 Most Common Causes of Hypomagnesemia
Dietary
Gastrointestinal
Renal
Endocrine or metabolic
Drug induced
with respiratory depression and cardiac instability. In treating life-
threatening hypermagnesemia, initially administer 100 to 200 mg
of intravenous calcium as either calcium chloride or calcium glu-
conate (1-2 mL of 10% calcium chloride or 5 mL of 1% calcium
gluconate during 2-5 minutes) and then titrate to effect.72 One can
then consider a continuous infusion at 2 to 4 mg/kg/hr if it is
needed while dialysis is being arranged.
HYPOMAGNESEMIA
Principles of Disease
Hypomagnesemia is a common electrolyte abnormality that
often goes undetected. Normal serum magnesium levels range
from 1.5 to 3.0 mEq/L. Symptoms of hypomagnesemia typically
begin to be manifested at serum levels below 1.2 mEq/L, although
symptoms are often not well correlated with the patient’s serum
level. This is because most of the body’s magnesium is intracel-
lular, and thus a single blood sample with a low serum magnesium
level may not accurately reflect total body magnesium or the
extent of true hypomagnesemia. Magnesium exists in three states:
ionized magnesium, protein bound, and complexed to serum
anions. Even though studies show the importance of measuring
ionized calcium, most research shows that ionized magnesium can
be inferred from total magnesium. Currently, the clinical role of
measurement of ionized magnesium is unclear, and measurement
of ionized magnesium is not standard practice in the ED; there
may be a role for measurement of ionized magnesium in the
intensive care setting.73
There are many causes of hypomagnesemia (Box 125-11).
The following are the five most common ED presentations of
hypomagnesemia.
Patients Maintained with Diuretics.  Patients using either loop or
thiazide diuretics are at increased risk for hypomagnesemia. Both
types of diuretics can inhibit magnesium reabsorption. Con-
versely, potassium-sparing diuretics are also magnesium sparing
because they enhance magnesium reabsorption and decrease mag-
nesium excretion. The degree of hypomagnesemia induced by the
loop and thiazide diuretics is generally mild, partly because the
associated volume contraction will tend to increase proximal
sodium, water, and magnesium reabsorption.
Malnourished and Alcoholic Patients.  Healthy patients consume
enough magnesium in green vegetables, legumes, fruits, shellfish,
fresh meat, and cocoa on a regular basis to maintain normal total
body magnesium stores. However, hypomagnesemia is common
in patients with chronic protein-calorie malnutrition because of
an associated lack of essential minerals and vitamins including
magnesium. This is especially true in chronic alcoholics, who may
not eat foods rich in magnesium.74 Magnesium losses are further
increased in chronic alcoholics because of alcohol’s diuretic effects.
Hypomagnesemia may also be seen in patients with malabsorp-
tion disorders (celiac sprue and short bowel syndrome) and in
patients with increased magnesium excretion (chronic diarrhea or
inflammatory bowel conditions).
Patients with Hypokalemia.  Both potassium and magnesium are
critical to help stabilize the membrane potential, to decrease cell

+ +
excitability, and for function of the Na ,K -ATPase pump. Approx-
imately 50% of patients with hypokalemia also have concomitant
magnesium deficiency. Increasing degrees of hypokalemia are cor-
related with an increasing likelihood of a magnesium deficit.21
Hypokalemic patients who are refractory to potassium replace-
ment are likely to also be hypomagnesemic.
Patients with Acute Coronary Artery Disease and Ventricular
Arrhythmias.  There appears to be a relationship between low
serum magnesium levels and the subsequent development of
coronary heart disease.75 Patients who have a myocardial infarc-
tion are more likely than controls to be hypomagnesemic. At
present, magnesium supplementation is recommended only for
those acute coronary syndrome patients who have evidence of
hypokalemia, prolonged QT, or known hypomagnesemia. Simi-
larly, patients with acute myocardial infarction who have mild
hypomagnesemia appear to have a twofold to threefold increase
in the frequency of ventricular arrhythmias in the first 24 hours
compared with those with normal magnesium levels.76 There is
controversy about whether magnesium should be administered
empirically after acute myocardial infarction.77 Dysrhythmia is the
most common cardiovascular manifestation of hypomagnesemia.
Magnesium affects the duration of phase 2 of the action potential,
and hypomagnesemia can prolong the QT interval. Magnesium
also has effects on phase 4, the resting membrane potential, when
it serves to keep the cell more negative by stimulating the sodium-
potassium pump. The exact mechanism underlying a possible
association between hypomagnesemia and arrhythmias is at
present unknown. Arrhythmias are likely to be due to concurrent
hypokalemia, hypomagnesemia, or both, resulting in a prolonged
QT interval and increases in spontaneous depolarization.
Patients Receiving Specific Medications.  In addition to diuretics,
many medications are associated with hypomagnesemia. Many
nephrotoxic drugs, including aminoglycosides, amphotericin B,
cisplatin, and pentamidine, can produce magnesium wasting. The
mechanism responsible for hypomagnesemia associated with
long-term proton pump inhibitor use is unknown; however, long-
term use of proton pump inhibitors may be associated with
changes in intestinal absorption of magnesium.78 Severe hypo-
magnesemia can also be seen in patients preparing for colonos-
copy with polyethylene glycol–based bowel preparations.
Clinical Features
Determination of the clinical consequences of isolated hypomag-
nesemia is often difficult because patients with hypomagnesemia
typically have hypokalemia, hypocalcemia, and hyponatremia.
However, many signs and symptoms are reported to correlate with
hypomagnesemia, including muscle cramping, diffuse weakness,
palpitations, vertigo, ataxia, depression, and seizures. The clinical
manifestations most likely seen in the ED typically involve the
neuromuscular and cardiovascular systems. Patients may present
with hyperactive deep tendon reflexes, muscle cramps, Trousseau’s
and Chvostek’s signs, and dysarthria and dysphagia from esopha-
geal dysmotility. Cardiac conduction abnormalities secondary to
magnesium depletion, and often coexisting hypokalemia, can
result in PR as well as QT interval prolongation. Dysrhythmias
including atrial fibrillation, multifocal atrial tachycardia, prema-
ture ventricular complexes, ventricular tachycardia, torsades de
pointes, and ventricular fibrillation are the most common cardio-
vascular manifestations of hypomagnesemia. Women with ade-
quate intakes of magnesium are less likely to be affected by
preeclampsia than are those with an inadequate intake.79
Diagnostic Strategies
Symptoms of hypomagnesemia begin to be manifested at serum
levels below 1.2 mEq/L, but symptoms do not always correlate
Chapter 125 / Electrolyte Disorders   1649
with the total serum magnesium level. Because most of the total
body magnesium is intracellular, the magnesium level alone does
not guide therapy. However, the possibility of hypomagnesemia is
considered in patients with malnourishment, significant or refrac-
tory hypokalemia, and ventricular arrhythmias. Electrocardio-
graphic findings in hypomagnesemia are nonspecific and may be
caused by both the hypomagnesemia and concomitant hypokale-
mia. Hypomagnesemia should be suspected whenever electrocar-
diographic findings of hypokalemia are noted, including PR and
QT interval prolongation, ST segment depression, flattening and
widening of the T waves, loss of voltage, and U waves.
Management
The route of magnesium repletion varies with the severity of the
clinical manifestations. Parenteral magnesium is recommended
for life-threatening conditions. In patients with normal renal
function, 1 to 2 g of magnesium sulfate is an appropriate loading
dose. A stable patient with hypomagnesemia can be treated with
a loading dose of 1 to 2 g of magnesium sulfate during 10 to 60
minutes, followed by a standard maintenance dose of 0.5 to 1 g/
hr until symptoms have resolved or a therapeutic effect is obtained.
However, patients in cardiac arrest should receive a bolus of 1 to
2 g magnesium sulfate by intravenous push.
Magnesium administration is strongly encouraged for patients
receiving intravenous potassium repletion. A dose of 0.5 g/hr is
safe in patients who are well hydrated and have normal renal func-
tion. There are potential adverse effects to rapid aggressive mag-
nesium replacement at more than 1 to 2 g/hr, including decreased
deep tendon reflexes, respiratory depression, and heart block.
Magnesium gluconate oral supplementation can be given if the
patient is only mildly hypomagnesemic and asymptomatic. When
preparing any patient for discharge, physicians can encourage life-
style changes, including adequate magnesium intake that may
benefit blood pressure control, promote weight loss, and improve
chronic disease risk.
HYPERPHOSPHATEMIA
Principles of Disease
Hyperphosphatemia is defined as a serum level above 2.5 mg/dL,
but it is usually clinically significant only when levels are greater
than 5 mg/dL. Although it is rare in the general population, hyper-
phosphatemia is extremely common in patients with renal insuf-
ficiency or renal failure.80 Almost all patients with renal failure
experience hyperphosphatemia at some time during the course of
their disease. Hyperphosphatemia can occur because of four
major pathways: decreased phosphate excretion, excessive phos-
phate intake, increased renal tubular reabsorption, and shift of
phosphate from intracellular to extracellular space. In addition,
physicians must be aware of spurious elevations in phosphate
(Box 125-12).
Decreased excretion of phosphate combined with excessive
intake is the most common mechanism for the development of
hyperphosphatemia. Excessive phosphate intake alone is an
uncommon cause of hyperphosphatemia in patients with normal
renal function. When patients have glomerular filtration rates
below 30 mL/min, the kidneys do not allow excretion of the full
amount of ingested phosphate to maintain homeostasis. Exoge-
nous phosphate, including intravenous or oral phosphate admin-
istration and phosphate enemas and laxatives can cause a large
burden on the kidneys if they do not have normal baseline
function.19
Hypoparathyroidism, vitamin D intoxication, and thyrotoxico-
sis increase renal phosphate reabsorption and may cause elevated
1650   PART III  ◆  Medicine and Surgery / Section Eleven • Metabolism and Endocrinology
Five Most Common Causes Five Most Common Causes of
BOX 125-12 of Hyperphosphatemia Hypophosphatemia in the Emergency
BOX 125-13 Department
Decreased phosphate Acute and chronic renal failure
excretion Decreased intake or Chronic alcoholism
Increased renal tubular Hypoparathyroidism increased absorptive states Home parenteral nutrition
reabsorption AIDS
Thyrotoxicosis Chemotherapy
Excess vitamin D administration Vomiting
Excessive phosphate intake Phosphate enemas or laxatives Malabsorption syndromes
Intravenous or oral phosphate Secretory diarrhea
administration Vitamin D deficiency
Shift of phosphate from Diabetic ketoacidosis Hyperventilatory states Sepsis
intracellular to extracellular Alcohol withdrawal
space Salicylate poisoning
Tumor lysis Neuroleptic malignant syndrome
Rhabdomyolysis Panic attacks
Spurious hyperphosphatemia Paraproteinemia Diabetic ketoacidosis
Hyperbilirubinemia Hepatic coma
Hemolysis Hormonal and endocrine Insulin loading
Hyperlipidemia effects Glucose loading
Exogenous epinephrine
Hyperparathyroidism
Medications19,95 Diuretics
Chronic antacid ingestion
Steroids
phosphate levels. Hyperphosphatemia may also occur when there Phosphate binders
is a large shift of phosphate from the intracellular to the extracel- Xanthine derivatives
lular space and the kidney’s ability to excrete phosphate is over- Beta2-agonists
whelmed. This cause of hyperphosphatemia is seen in crush Disease states Trauma
Severe thermal burns
injuries and nontraumatic rhabdomyolysis, tumor lysis syndrome, Acute renal failure
and DKA. Gout
Hyperphosphatemia can be a spurious finding in cases of
hyperproteinemia, such as multiple myeloma, hyperlipidemia,
hemolysis, or hyperbilirubinemia. Drawing of a blood sample
from a line containing heparin is another cause of a falsely ele-
vated phosphate level.81
HYPOPHOSPHATEMIA
Clinical Features Principles of Disease
Patients with hyperphosphatemia may present with multiple com- Hypophosphatemia is defined as mild (2-2.5 mg/dL), moderate
plaints related to associated electrolyte abnormalities, particularly (1-2 mg/dL), or severe (<1 mg/dL). Mild to moderately severe
hypocalcemia. Hyperphosphatemia causes hypocalcemia by pre- hypophosphatemia is usually asymptomatic and like hypomagne-
cipitating calcium out of the blood and decreasing vitamin D semia often goes unrecognized. Although most patients remain
production. It is this secondary hypocalcemia that can cause asymptomatic, severe hypophosphatemia may result in potentially
muscle cramping, tetany, and seizures. Chronic hyperphosphate- life-threatening complications. Major clinical sequelae usually
mia can also lead to metastatic calcifications in joints, tissues, occur only in severe hypophosphatemia.
and arteries. Symptoms of hypophosphatemia typically begin to be mani-
fested at serum levels below 1.0 mg/dL. Acute hypophosphatemia
Management is most commonly due to a rapid intracellular shift, but there are
many other causes of clinical manifestations as well.86 Hyperven-
Dietary restriction alone may suffice for control of hyperphospha- tilation, glucose, insulin, volume, and resolving acidosis lead to
temia in persons with mild renal insufficiency, but it is inadequate hypophosphatemia by rapid intracellular shift. The many causes
for control in those with overt renal failure. Because most patients of hypophosphatemia include decreased phosphate intake or
presenting with severe hyperphosphatemia also have hypocalce- increased absorptive states, hyperventilatory states, hormonal and
mia, treatment focuses on the correction of both electrolytes. In endocrine effects, medications, and disease states (Box 125-13).
patients with normal renal function, phosphate excretion can be The ED patients most likely to have hypophosphatemia are those
increased by saline infusion coupled with loop diuretics. Hyper- who are malnourished with alcohol withdrawal, acute hyperven-
phosphatemia usually resolves in 6 to 12 hours in patients with tilation, or sepsis and patients with DKA or alcohol ketoacidosis
normal renal function.82 In patients with hyperphosphatemia with in whom reintroduction of insulin and glucose causes phosphate
renal failure, hemodialysis or peritoneal dialysis should be consid- uptake into cells.87,88
ered early in the management. Currently, phosphate control is
initiated only when hyperphosphatemia occurs, but a potentially Clinical Features
beneficial and simple approach may be to intervene earlier in
patients with chronic kidney disease.83 The optimal method for Mild to moderate hypophosphatemia is usually asymptomatic,
control of serum phosphate in patients undergoing dialysis is but major clinical manifestations can occur with severe hypophos-
unknown and may involve combinations of dietary modification phatemia. Hypophosphatemia can affect a variety of organ systems
and enhancement of phosphate clearance through longer dialysis and cause a wide variety of symptoms because phosphate is an
sessions.84,85 essential component to adenosine triphosphate (Box 125-14).
 Chapter 125 / Electrolyte Disorders   1651
89
period. For routine replacement, give 0.5 mL/hr K2PO4; this may
BOX 125-14 Clinical Manifestations of Hypophosphatemia be increased to 1 mL/hr in severe symptomatic patients.87 Each
milliliter of K2PO4 contains 3 mmol of phosphorus and 4.4 mEq
Central nervous system Irritability of potassium. Typical replacement therapy provides approxi-
Confusion mately 1 g of phosphorus per day. Monitoring of patients for the
Paresthesias
development of hypocalcemia, hyperkalemia, and hyperphospha-
Depression
Dysarthria temia is required while intravenous phosphate is administered,
Seizure especially in patients with renal insufficiency. Patients with DKA
Coma are initially hypophosphatemic. However, no studies have shown
Cardiovascular Cardiomyopathy significant benefit to routine phosphate therapy in DKA.91 Risks
Depressed myocardial contractility of routine treatment with phosphate include hyperphosphatemia,
Arrhythmias renal failure, hypocalcemia, and hypomagnesemia. In patients
Respiratory Acute respiratory failure with severe malnutrition or significant hypophosphatemia,
Depressed myocardial contractility replacement can be considered, but never administer more than
Gastrointestinal Ileus, dysphagia 60 mmol/day without reason.
Hematologic Depressed levels of
2,3-diphosphoglycerate and
adenosine triphosphate
Leukocyte dysfunction KEY CONCEPTS
Hemolysis
Platelet dysfunction ■ Asymptomatic electrolyte abnormalities can usually be
Renal Acute tubular necrosis corrected slowly, but those abnormalities that cause profound
Metabolic acidosis mental status changes or life-threatening arrhythmias require
Hypercalcemia immediate correction to avoid cardiac arrest or seizures.
Endocrine Insulin resistance ■ Intravenous calcium should be used only for hyperkalemic
Hyperparathyroidism emergencies, defined as the following: widening QRS; sine
wave; cardiac arrest believed to be due to hyperkalemia; or
rapidly evolving electrocardiographic changes, from normal to
development of tall peaked T waves and loss of the P wave.
Acute, rapid rises in serum potassium concentration are rare
Patients with hypophosphatemia may present with nonspecific but may be seen in tumor lysis syndrome, rhabdomyolysis, or
complaints including joint pain, myalgias, irritability, and depres- massive hemolysis.
sion. Severe hypophosphatemia can be manifested as seizures, ■ After the critical decision about administration of calcium has
arrhythmias, cardiomyopathy, insulin resistance, acute tubular been made, a beta2-agonist, insulin and glucose, normal
necrosis, rhabdomyolysis, and acute respiratory failure. saline, and bicarbonate (if the patient is acidotic) can be
given to shift potassium intracellularly.
■ In treatment of hypokalemia, it is critical that the physician
Management also replace magnesium sulfate, in addition to potassium, or
the patient will excrete most of the infused potassium in the
Therapy for hypophosphatemia is recommended as levels drop urine.
below 1.5 to 2.0 mg/dL, and therapy is essential as levels fall below ■ Low serum potassium levels reflect a much greater total
1.0 mg/dL. Because hypophosphatemia often is manifested with potassium deficit; correction of large deficits can require
hypokalemia, phosphate repletion is considered in conjunction several days.
with potassium administration. Oral phosphorous, 250 to 500 mg ■ Hypertonic saline should be reserved for severely
twice daily, can be given to stable or asymptomatic patients. Intra- hyponatremic patients (typically in the 100-110 mEq range)
venous preparations are available as sodium phosphate (Na2PO4 who present with coma, seizures, or focal neurologic deficits.
and NaPO4) or potassium phosphate (K2PO4 and KPO4), and rate Central pontine myelinolysis can occur if serum sodium
concentration is raised rapidly by more than 10 to  
of infusion and choice of initial dosage should be based on severity
12 mEq/day.
of hypophosphatemia and presence of symptoms. If the serum
phosphorus concentration is less than 1.5 mg/dL (0.48 mmol/L),
1.3 mmol/kg of elemental phosphorous (up to a maximum of The references for this chapter can be found online by
100 mmol) can be given in three or four divided doses in a 24-hour accessing the accompanying Expert Consult website.

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