Review Article
Calcium Abnormalities in Hospitalized Patients
Sarah French, MD, Jose Subauste, MD, and Stephen Geraci,
Abstract: Depending upon the method of measurement, hypocal-
cemia occurs in 15% to 88% and hypercalcemia occurs in 15% of
hospitalized patients. Ionized calcium should be measured in place
of total serum calcium to avoid errors related to hypoalbuminemia,
which is seen commonly in acutely ill patients. Symptomatic hypo-
calcemia requires prompt intravenous calcium administration.
Symptomatic hypercalcemia (most often caused by hyperparathy-
roidism or malignancy) warrants aggressive intravenous hydration to
correct volume depletion and, usually, additional therapy with
diuretics, bisphosphonates, calcitonin, or corticosteroids. Identica-
tion and treatment of the underlying cause of the calcium derange-
ment must be addressed after the acute electrolyte abnormality is
stabilized.
Key Words: acute illness, calcium, electrolyte disorder, hypercalce-
mia, hypocalcemia
A bnormalities in serum calcium are encountered fre-
quently in acutely ill patients. Hypocalcemia is found
in 15% to 88%1Y4 and hypercalcemia is found in approxi-
mately 15%5,6 of adult patients, depending on the method of
measurement (total serum vs ionized calcium) and patient
population (critically ill patients vs nonYintensive care unit
hospitalized patients).
Only 1% of total body calcium is exchangeable with ex-
tracellular uid, with the remainder residing in bone. Ap-
proximately half of extracellular calcium is ionized as the
physiologically active form, another 40% is bound to protein
(chiey albumin), and the remainder is complexed with anions
in calcium salts.7
Total serum calcium is affected by changes in plasma
protein concentrations because approximately 40% of cir-
culating calcium is bound to albumin.8 A correction of total
From the Division of Endocrinology, Metabolism, and Diabetes, and the De-
partment of Medicine, University of Mississippi School of Medicine,
Jackson; and the Medical Service, G.V. (Sonny) Montgomery Veterans
Affairs Medical Center, Jackson, Mississippi.
Reprint requests to Sarah French, MD, Division of Endocrinology, Metabo-
lism, and Diabetes, University of Mississippi Medical Center, 2500 N State
St, Jackson, MS 39216. Email: sfrench@umc.edu
The authors have no nancial relationships to disclose and no conicts of
interest to report.
Accepted October 14, 2011.
Copyright * 2012 by The Southern Medical Association
0038-4348/0Y2000/105-231
DOI: 10.1097/SMJ.0b013e31824e1737
Southern Medical Journal & Volume 105, Number 4, April 2012
Copyright 2012 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
MD
serum calcium for hypoalbuminemia may be estimated
(by adding 0.8 mg/dL [0.2 mmol/L] to the measured serum
calcium for each 1-g/dL decrease in albumin below the normal
value of 4.0 g/dL).8 When this correction was rst derived,
serum from general wards and outpatient settings were used
and patients perceived to have a high incidence of calcium
abnormalities, such as those with renal disease, were ex-
cluded.9 Subsequently, however, this correction has not proven
reliable because this value can differ signicantly from the
ionized calcium, leading to over- and underestimation of true
calcium status.7Y10 Direct measurement of serum ionized cal-
cium is therefore advisable in patients with abnormal albumin
concentrations.8,10 Many reports of calcium-related clinical
abnormalities have, however, cited total serum levels11Y13 or
corrected serum levels14,15 rather than ionized levels, which
introduces confusion when attempting to correlate clinical
ndings to measured levels.
Acid-base abnormalities alter both the ionization state of
calcium salts and the binding afnity of calcium ion to albu-
min. Ionized calcium concentrations are inversely related to
plasma pH16; however, pH-adjusted ionized calcium can differ
dramatically from directly measured ionized calcium and is not
recommended for use in the evaluation and treatment of
acutely ill patients.17
To address serum calcium abnormalities in hospital-
ized patients, we performed a literature search in PubMed using
the search terms hypocalcemia or hypercalcemia and man-
agement, limiting the search by publication date (1980Y
present), human subjects, English-language articles, adults,
clinical trials, randomized controlled trials, and review articles.
From this strategy, 450 articles were identied; with the
exclusion of case reports, case series, editorials, opinion
papers, and incompletely referenced reviews, 35 articles were
Key Points
& Symptomatic patients require prompt treatment, with the goal
of resolving clinically signicant manifestations of hypocal-
cemia and hypercalcemia.
& Various strategies of effective treatment are available for both
conditions.
& Identication and denitive treatment of the underlying con-
dition should always be addressed once the acute electrolyte
abnormality has been stabilized.
231
French et al & Calcium Abnormalities in Hospitalized Patients
selected. In addition, references used in identied articles
also were reviewed and additional relevant citations were in-
cluded in this review, resulting in the 89 publications that are
referenced.
Hypocalcemia
Clinical manifestations of hypocalcemia correlate with
both the magnitude and acuity of fall in serum levels.8 In
general, symptoms occur at an ionized calcium concentration of
2.8 mg/dL (0.7 mmol/L)7 and include circumoral paresthesias,
muscle cramps,8 muscle weakness, myalgias, dysphagia, irri-
tability, depression, and confusion. On physical examination,
hyperreexia and carpopedal spasms, as well as Trousseau
sign and Chvostek sign, may be present,7 although the latter
also may be seen in normocalcemic patients.8 Hypocalcemia
also has been correlated with hypotension, an increased need
for vasopressor support,18 and signicantly increased mortal-
ity.2,19,20 Although prolongation of the QT segment/interval
can occur,21 the signicance of this phenomenon is contro-
versial. It is unclear whether this is directly related to ven-
tricular arrhythmias or whether correction of the abnormalities
reduces the incidence of arrhythmias.22
Causes
The incidence of ionized hypocalcemia in seriously ill
hospitalized patients is 15% to 88%.2,4 Some mechanisms are
more typically seen at presentation, whereas others are more
likely to develop during the hospital course. Causes are listed
as follows:
Potential causes at presentation
Pancreatitis
Sepsis and septic shock
Severe burns
Hyperphosphatemia
Vitamin D deciency
Magnesium deciency
Milk-alkali syndrome
Bisphosphonates
Loop diuretics
Anticonvulsants: phenytoin, phenobarbital
Potential causes during hospital course
Multiple blood transfusions
Calcium chelation by drugs
Parathyroidectomy/hungry bone syndrome
Chemotherapy agents: cisplatin, cyclophosphamide
Antifungal agents: amphotericin B, ketoconazole
Antibiotics: dactinomycin, amikacin, gentamicin, tobramycin
Loop diuretics
Anticonvulsant drugs: phenytoin, phenobarbital
Rare causes
Congenital hypoparathyroidism
Hemochromatosis
Hypocalcemia in pancreatitis occurs as a result of bind-
ing of calcium to plasma free fatty acids.23 Hypoalbumine-
mia23 and hypomagnesemia,24 also associated with pancreatitis,
further decrease serum calcium levels. Hypomagnesemia, caused
232
Copyright 2012 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
by reduced absorption, poor dietary intake, or excessive renal
losses,25 frequently occurs with hypocalcemia. Hypomagnese-
mia decreases parathyroid hormone (PTH) secretion and induces
end-organ PTH resistance,26 making hypocalcemia refractory
to therapy until the magnesium deciency is corrected.25
Hyperphosphatemia, as occurs in tumor lysis syndrome
and rhabdomyolysis, leads to calcium phosphate salt forma-
tion, which decreases serum calcium.27 Acute renal failure
(glomerular ltration rate G30Y40 mL/min) can downregulate
the renal conversion of 25(OH)D3 to 1,25(OH)2D3 by 1>-
hydroxylase, reducing intestinal calcium absorption.28 Phos-
phate from exogenous sources such as phosphate-containing
enemas can have similar effects.27
Propofol and intravenous contrast dye may complex with
calcium, although whether this contributes to clinical hypo-
calcemia is disputed.29 Potassium ethylenediaminetetraacetic
acid can lead to factitious hypocalcemia and hypomagnesemia
through improper blood collection.30 Gadodiamide adminis-
tration, used in magnetic resonance imaging, can lead to
spurious hypocalcemia resulting from interference with col-
orimetric assay for serum calcium measurement.31
Heparin induces the production of free fatty acids, which
complex with calcium,32 and citrate from transfused blood
products20 or during anticoagulation in renal replacement
therapy33 and therapeutic plasma exchange34 can chelate cal-
cium, as can foscarnet35; all of these may lead to hypocalce-
mia. Administration of albumin, such as during therapeutic
plasma exchange,34 can cause transient hypocalcemia until a
new binding equilibrium state is achieved.4 Hypocalcemia
has been reported to occur with herbal preparations such as
Erycibe henryi Prain, used in Chinese medicine for pain re-
lief,36 and Yukmi-jihang-tang, used in Korean medicine for
inammatory conditions and osteoporosis.37
Some anticonvulsants, including phenytoin and pheno-
barbital, reduce 1,25(OH)2D3 by increasing vitamin D catab-
olism into inactive compounds.38 Malabsorption, primary
biliary cirrhosis,39 and chronic liver disease40 are additional
causes of vitamin D deciency contributing to hypocalcemia.
Decreased bone resorption and/or accelerated bone for-
mation may lead to hypocalcemia. The former can be caused
by bisphosphonates, chemotherapeutic agents (eg, cisplatin,
cyclophosphamide), calcitonin, and amphotericin B.7 Osteo-
blastic metastases of breast or prostate cancer and hungry
bone syndrome (following parathyroidectomy performed for
secondary or tertiary hyperparathyroidism) may lower serum
calcium levels signicantly as bone is formed and/or remin-
eralized.41 Rapid correction of uremic acidosis has been asso-
ciated with hypocalcemia42,43 by stopping bone demineralization
from the metabolic acidosis.42
Acute illness itself has been associated with hypocalce-
mia, independent of albumin, and increasing severity of illness
can lead to decreasing total and ionized calcium concentra-
tions.44 Calcitonin precursors frequently are elevated in acute
illness44,45 and may inversely correlate with ionized calcium
* 2012 Southern Medical Association

levels,38 although this correlation has not been found in other
studies.45,46
Treatment
Therapy is driven by the magnitude of deciency and its
clinical impact.7 In general, symptoms occur at ionized calcium
concentrations of 2.8 mg/dL (0.7 mmol/L)7 or total serum cal-
cium concentrations of 7.5 mg/dL (1.875 mmol/L).35 Short-
term therapy is directed at reversing clinical effects rather
than normalizing the serum calcium level per se.47 Manifes-
tations that warrant emergent therapies include seizures and
frank tetany.16 Patients should receive parenteral calcium until
clinical abnormalities resolve.7
Treatment recommendations are as follows:
& For severe symptomatic hypocalcemia (eg, seizure, tetany), ad-
minister 10 to 20 mL of 10% calcium gluconate or 10 mL of
10% calcium chloride intravenously for 10 minutes; repeat every
60 minutes until clinical manifestations resolve. Avoid administra-
tion of bicarbonate or phosphate during calcium administration.
& For moderate to severe hypocalcemia (ionized calcium G4 mg/dL
[G1 mmol/L]) without seizure or tetany, administer calcium glu-
conate 4 g intravenously for 4 hours.
& For mild hypocalcemia (ionized calcium 4Y5 mg/dL [1Y1.2 mmol/L]),
administer calcium gluconate 1 to 2 g intravenously for 2 hours.
& Repeat ionized calcium determinations 6 to 10 hours after com-
pleting parenteral calcium administration.
& Check for hypomagnesemia and correct if present.
& Consider continuous calcium infusion if hypocalcemia is caused
by an ongoing process such as pancreatitis or hungry bone
syndrome.
A 10-mL ampoule of 10% calcium gluconate contains
94 mg of elemental calcium, whereas 10 mL of 10% calcium
chloride contains 272 mg of (more bioavailable) elemental
calcium. Gluconate is preferred in general because it is less
phlebitic and less likely to cause tissue necrosis if extrava-
sated41,48; this risk is decreased if calcium is administered in
large veins or through a central venous catheter. Calcium should
be stopped if the patient complains of tenderness at the infusion
site.49 Cases of calcinosis cutis have been reported after cal-
cium chloride administration without extravasation.50Y52 The
use of calcium chloride should be reserved for life-threatening
situations.48
Intermittent intravenous infusions will normalize cal-
cium levels in most patients. One to two grams of calcium-
gluconate infused for 2 hours normalized ionized calcium
levels in 79% of patients in one series with mild hypocal-
cemia (ionized calcium 4Y4.5 mg/dL [1.0Y1.12 mmol/L])
when repeated determinations were made 6 to 8 hours
later.53 For patients with moderate to severe symptomatic
hypocalcemia (ionized calcium G4 mg/dL [G1 mmol/L]), 4 g
of calcium gluconate given in 4 hours increased serum ion-
ized calcium to 94 mg/dL (91 mmol/L) in 95% of patients
and to 94.5 mg/dL (91.12 mmol/L) in 70% of patients.
Mild hypercalcemia (ionized calcium 5.3Y5.5 mg/dL [1.34Y
Southern Medical Journal & Volume 105, Number 4, April 2012
Copyright 2012 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Review Article
1.38 mmol/L]) may occur, but it does not appear to result
in adverse events.54 Recommendations for monitoring calcium
levels to ensure efcacy of therapy range from 6 hours48 to
Q10 hours55 after completion of a parenteral calcium dose.
Calcium should be infused slowly (e0.8Y1.5 mEq/min)42 to
limit the risk of serious adverse cardiac effects, including
asystole.47
Patients receiving digoxin should be monitored closely
for acute digitalis toxicity precipitated by calcium replace-
ment.7 There are no cardiac arrhythmias indicative of digoxin
toxicity, but AV junctional block, especially higher degrees
and with accompanying atrial tachycardia, and frequent ven-
tricular premature beats of any morphology are seen most
commonly. Noncardiac manifestations are nonspecic in general
and include fatigue, anorexia, nausea, vomiting, headache, and
confusion. Visual complaints are uncommon but can include
halos around bright objects and changes in color perception.56
In patients with renal failure and appropriate indications,
hemodialysis with a high calcium bath can be used to nor-
malize calcium levels.41 If hypocalcemia is refractory to re-
placement, then serum magnesium should be measured and
hypomagnesemia corrected if present.25
In patients with hypocalcemia and hyperphosphatemia,
a phosphate binder should be administered to avoid soft-
tissue calcium phosphate precipitations. If possible, calcium
administration should be delayed until serum phosphorus
has fallen below 6 mg/dL (1.5 mmol/L).7
Although hypocalcemia is associated with increased
mortality,57 no randomized controlled clinical trials have
shown that correction of hypocalcemia improves survival,58 but
calcium administration in septic rat models has increased
mortality.59
Hypercalcemia
Total serum and ionized hypercalcemia occurs in 15%
of acutely ill patients.5,6 As with hypocalcemia, symptoms
of hypercalcemia in general correlate with the degree and
acuity of increase in serum concentration.41 Total serum cal-
cium 913 mg/dL (93 mmol/L) can cause cognitive dysfunc-
tion,7 but it can be difcult to differentiate this effect from
other causes of impairment in mental status during acute ill-
ness.41 Total serum calcium 913 mg/dL (93 mmol/L) can
cause obtundation, coma, acute renal failure, ventricular ar-
rhythmia, and death.48 Lower total serum calcium levels are, in
general, asymptomatic.7
Hypercalcemia can cause acute pancreatitis16 and
nephrogenic diabetes insipidus, leading to additional volume
depletion and further elevation of calcium concentration.41
Shortening of the QT interval has been observed,7 but the
clinical importance of this nding is unclear. Patients receiv-
ing digoxin should be monitored carefully because elevated
calcium levels may precipitate digitalis toxicity.16 Signs and
symptoms of digitalis toxicity are discussed earlier in the
article.
233
French et al & Calcium Abnormalities in Hospitalized Patients
Causes
Hypercalcemia occurs when excess calcium, most often
released from bone or via enhanced intestinal absorption, cannot
be excreted by the kidney.60 The causes are as follows:
Potential causes at presentation
Primary hyperparathyroidism
Malignancy
Granulomatous disease
Thyrotoxicosis
Lithium
Tamoxifene
Thiazides
Potential causes during hospital course
Immobilization
Calcium administration
Rare causes (any setting)
Familial hypocalciuric hypercalcemia
Vitamin D toxicity
Similar to hypocalcemia, some disorders that increase serum
calcium are more likely to be encountered on initial patient pre-
sentation, whereas others develop more often during the hospital
course. As discussed above, ionized calcium is preferred to total
serum calcium for assessing hypercalcemia in acutely ill patients.
Primary hyperparathyroidism (approximately 50%) and
malignancy (30%Y40%) are the most common causes of hy-
percalcemia.7,61 Malignancies most often associated with hy-
percalcemia include squamous cell tumors (eg, carcinoma of
the lung), metastatic breast cancer, myeloma, and renal cell
carcinoma.41 Although metastases or invasion of bone can
result in calcium elevation, many tumors produce PTH-related
peptide (PTHrP), which activates PTH receptors; although it is
not detectable on PTH assays, specic PTHrP tests are avail-
able.62 PTHrP-mediated hypercalcemia also has been reported
in pheochromocytoma.63,64
Several other conditions may lead to hypercalcemia in
acutely ill hospitalized patients. Sarcoidosis, tuberculosis, and
other granulomatous diseases can cause hypercalcemia via en-
hanced conversion of 25(OH)D3 to 1,25(OH)2D3.65 Thyrotoxi-
cosis may elevate serum calcium through accelerated bone
resorption.66 Prolonged (several weeks or longer) immobilization
can lead to hypercalcemia5 through increased bone resorption.41
Hypercalcemia with adrenal insufciency has been reported,67,68
occurring possibly through increased bone resorption.68
Thiazide diuretics can increase serum calcium69 by re-
ducing urine calcium excretion.11 Lithium is associated with
hypercalcemia and hyperparathyroidism by its increasing
the calcium setpoint for PTH suppression; this may be re-
versible with discontinuation of the drug.70 Tamoxifen may
elevate calcium levels in patients with metastatic breast cancer
within weeks of initiation of therapy; levels generally nor-
malize with discontinuation of the drug.71 Toxic levels of
theophylline have been associated with hypercalcemia; hy-
percalcemia resolves when theophylline levels reach thera-
peutic or subtherapuetic levels.72
234
Copyright 2012 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Milk-alkali syndrome, caused by the ingestion of milk
and alkaline powders in the treatment of peptic ulcer disease,
was a common cause of hypercalcemia before the advent of
nonabsorbable antacids and histamine-2 blockers. By 1975,
milk-alkali syndrome accounted for G1% of cases of hyper-
calcemia.73 The increased use of calcium carbonate by certain
groups of patients, such as postmenopausal women for oste-
oporosis prevention and chronic renal failure patients for
phosphate binding, has lead to a reemergence of the syndrome,
with estimates of 12% to 16% of cases of hypercalcemia.73,74
The hallmarks of milk-alkali syndrome are hypercalcemia,
acute renal failure, and metabolic alkalosis. Traditional
milk-alkali syndrome is associated with increased serum
phosphorus levels resulting from the ingestion of phosphorus-
rich milk, whereas modern milk-alkali syndrome from cal-
cium carbonate supplementation typically presents with nor-
mal or low serum phosphorus values.74
Treatment
Recommendations for the treatment of symptomatic hy-
percalcemia are as follows:
& Isotonic saline infusion at 200 to 300 mL/hour to correct intra-
vascular volume depletion
& After adequate hydration, furosemide 20 to 100 mg to avoid vol-
ume overload and enhance urinary calcium excretion if estimated
glomerular ltration rate 930 mL/minute
& Zoledronic acid 4 mg as 15-minute infusion or pamidronate 60 to
90 mg as 1- to 2-hour infusion if hypercalcemia persists after
hydration
& Salmon calcitonin 4 IU/kg subcutaneously or intravenously every
12 hours (until bisphosphonates take effect)
& Hydrocortisone 200 to 300 mg intravenously or prednisone
20Y40 mg if hypercalcemia caused by malignancy or granulo-
matous disease
& Hemodialysis if calcium 918 to 20 mg/dL (94.5Y5.0 mmol/L),
patient with impaired renal function, or heart failure with volume
overload
In general, mild hypercalcemia (serum calcium G12 mg/dL
[G3 mmol/L]) corrects with hydration.7,47 Any medication that
can cause or worsen hypercalcemia should be discontinued.41
Total serum calcium levels 913 mg/dL (93 mmol/L)
warrant emergent treatment. Intravenous hydration is the cor-
nerstone of therapy and should be started with 0.9% NaCl at
200 to 300 mL/hour to correct the intravascular volume de-
pletion that is typically present.47 Furosemide does not reverse
hypercalcemia quickly, even at doses of 240 to 2400 mg, and
should only be used in the management of uid overload.75
Bisphosphonates are effective in treating hypercalcemia
of malignancy. In one report, single-dose infusions of 60 or
90 mg of pamidronate normalized total serum calcium in
61% to 100% of patients, with a mean duration of effect of
13 days for 60 mg and 10 days for 90 mg.14 Pamidronate
should be administered with adequate hydration.76 Zoledronic
acid (4 mg) was superior to pamidronate 90 mg in normalizing
calcium levels in patients with hypercalcemia of malignancy
* 2012 Southern Medical Association

(88.4% vs 69.7%, P = 0.002) and demonstrated a median
duration of response of 32 days. Although the 4-mg dose of
zoledronic acid was as effective as 8 mg, 4 mg is recommended
as initial treatment, with the 8-mg dose reserved for patients
who require additional treatment.15 The dose of zoledronic
acid should be reduced when the estimated creatinine clear-
ance is 60 to 30 mL/min, and the drug is not recommended
when creatinine clearance is G30 mL/min. Consideration of a
reduced dose of pamidronate is recommended when creatinine
clearance is G30 mL/min.77 Renal impairment occurring
within several days after zoledronic acid administration and
hypomagnesemia are risk factors for the subsequent develop-
ment of symptomatic hypocalcemia.78
Higher rates of hypocalcemia are seen following bispho-
sphonate therapy when used in short-term treatment of con-
ditions such as hypercalcemia of malignancy. In one series,
42 of 120 patients (35%) developed hypocalcemia after zole-
dronic acid treatment, with 10 patients (8%) requiring intrave-
nous calcium supplementation for symptomatic hypocalcemia.78
In contrast, only 3 of 1065 patients (0.3%) developed hypo-
calcemia when bisphosphonates were used to treat osteopo-
rosis.79 Intravenous pamidronate, treating hypercalcemia of
malignancy, caused hypocalcemia in 2 of 17 patients treated
with 90 mg and in 1 of 15 patients treated with 30 mg.14 In
contrast, no hypocalcemia occurred in 129 postmenopausal
women taking 200 mg oral pamidronate for osteopenia or
osteoporosis.80
Salmon calcitonin reduces calcium levels within 2 hours
of administration,81 unlike bisphosphonates, which require
48 hours to achieve peak effect.75 The effectiveness of calci-
tonin may diminish with continuous administration.81 It is
generally well tolerated12 and can be used in patients with
congestive heart failure and azotemia where aggressive hy-
dration may not be feasible.81 Calcitonin has been used safely
in combination with bisphosphonates, with initial effect seen
within 24 hours and normalization within 4 days.13
Corticosteroids effectively treat hypercalcemia caused by
granulomatous diseases82 and hypercalcemia of malignancy83
by inhibiting the proliferation of inammatory cell activity
and decreasing levels of 1,25(OH)2D3.84 The onset of action
of hydrocortisone or prednisone is, in general, 3 to 5 days.7
Regimens recommended in the literature include prednisolone
25 mg orally three times daily for 8 days,83 prednisone 60 mg
orally once daily,85 and dexamethasone 40 mg orally once
daily.86
Although there are additional factors involved, nephrolo-
gy consultation should be obtained urgently to consider im-
mediate hemodialysis in hemodynamically stable patients when
total serum calcium concentration exceeds 18 to 20 mg/dL
(4.5Y5.0 mmol/L).7 Calcium-free hemodialysis decreases se-
rum calcium further than other treatment modalities,83 but
calcium rebound has been observed within 24 hours.87 Ad-
verse cardiovascular events during hemodialysis were com-
mon (35%) in one series of 33 patients,87 although these could
Southern Medical Journal & Volume 105, Number 4, April 2012
Copyright 2012 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Review Article
have been related to rapid removal of calcium from the serum
pool and inadequate hydration.88 Continuous venovenous
hemodialtration has been used in more hemodynamically
unstable patients and is more likely to lower serum calcium
concentrations.89
Conclusions
Derangements in serum calcium concentrations are en-
countered frequently in acutely ill patients, and ionized calcium
levels should be used in diagnosis. Pancreatitis, hyperpho-
sphatemia, drugs, osteoblastic metastases, hungry bone syn-
drome, and acute illness, independent of albumin, can lead to
hypocalcemia. Treatment should be driven by magnitude of ill-
ness and clinical manifestations, with calcium gluconate preferred
over calcium chloride for safety concerns. Patients with renal
failure may benet from hemodialysis with high calcium bath.
Primary hyperparathyroidism and malignancy are the
most common causes of hypercalcemia, and granulomatous
diseases and milk-alkali syndrome (from increased use of
calcium carbonate) also are encountered. Intravenous hydra-
tion is the cornerstone of therapy for hypercalcemia, with
blood diuretics used only if needed to prevent uid overload.
Bisphosphonates can be used in the treatment of hypercalce-
mia of malignancy, and corticosteroids can be effective in
granulomatous diseases or hematologic malignancies. Dialysis
may be considered in severe cases.
References
1. Chernow B, Zaloga G, McFadden E, et al. Hypocalcemia in critically ill
patients. Crit Care Med 1982;10:848Y851.
2. Zivin J, Gooley T, Zager RA, et al. Hypocalcemia: a pervasive met-
abolic abnormality in the critically ill. Am J Kidney Dis 2001;37:
689Y698.
3. Zaloga GP. Hypocalcemia in critically ill patients. Crit Care Med 1992;
20:251Y262.
4. Zaloga GP. Hypocalcemic crisis. Crit Care Clin 1991;7:191Y200.
5. Forser J, Querusio L, Burchard KW, et al. Hypercalcemia in critically
ill surgical patients. Ann Surg 1985;202:512Y518.
6. Martinez FJ, Lash RW. Endocrinologic and metabolic complications
in the intensive care unit. Clin Chest Med 1999;20:401Y421.
7. Weis-Guillet EM, Takala J, Jakob SM. Diagnosis and management of
electrolyte emergencies. Best Pract Res Clin Endocrinol Metab 2003;
17:623Y651.
8. Slomp J, van der Voort PH, Gerritsen RT, et al. Albumin-adjusted calcium
is not suitable for diagnosis of hyper- and hypocalcemia in the critically
ill. Crit Care Med 2003;31:1389Y1393.
9. Payne RB, Little AJ, Williams RB, et al. Interpretation of serum calcium
in patients with abnormal serum proteins. Br Med J 1973;4:643Y646.
10. Dickerson RN, Alexander KH, Minard G, et al. Accuracy of methods to
estimate ionized and corrected serum calcium concentrations in criti-
cally ill multiple trauma patients receiving specialized nutrition support.
JPEN J Parenter Enteral Nutr 2004;28:133Y141.
11. Wermers RA, Kearns AE, Jenkins GD, et al. Incidence and clinical
spectrum of thiazide-associated hypercalcemia. Am J Med 2007;120:
911.e9Ye15.
12. Wisneski LA, Croom WP, Silva OL, et al. Salmon calcitonin in hyper-
calcemia. Clin Pharmacol Ther 1978;24:219Y222.
235
French et al & Calcium Abnormalities in Hospitalized Patients
13. Sekine M, Takami H. Combination of calcitonin and pamidronate for emer-
gency treatment of malignant hypercalcemia. Oncol Rep 1998;5:197Y199.
14. Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous
therapy with pamidronate for the treatment of hypercalcemia of malig-
nancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993;95:
297Y304.
15. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to
pamidronate in the treatment of hypercalcemia of malignancy: a pooled
analysis of two randomized, controlled clinic trials. J Clin Oncol 2001;
19:558Y567.
16. Body JJ, Bouillon R. Emergencies of calcium homeostasis. Rev Endocr
Metab Disord 2003;4:167Y175.
17. Krahn J, Lou H. Ionized calcium: whole blood, plasma or serum? Clin Lab
2008;54:185Y189.
18. Desai TK, Carlson RW, Thill-Baharozian M, et al. A direct relationship
between ionized calcium and arterial pressure among patients in an in-
tensive care unit. Crit Care Med 1988;16:578Y582.
19. Desai TK, Carlson RW, Geheb MA. Prevalence and clinical implications
of hypocalcemia in acutely ill patients in a medical intensive care setting.
Am J Med 1988;84:209Y214.
20. Wilson RF, Binkley LE, Sabo FM, et al. Electrolyte and acid-base changes
with massive blood transfusions. Am Surg 1992;58:535Y544.
21. Benoit SR, Mendelsohn AB, Nourjah P, et al. Risk factors for prolonged
QTc among US adults: Third National Health and Nutrition Examination
Survey. Eur J Cardiovasc Prev Rehabil 2005;12:363.
22. Bayer R, Schwarzmaier J, Pernice R. Basic mechanisms underlying pre-
nylamine-induced torsade de pointes: differences between prenylamine
and fendiline due to basic actions of the isomers. Curr Med Res Opin
1988;11:254Y272.
23. Warshaw AL, Lee KH, Napier TW, et al. Depression of serum calcium by
increased plasma free fatty acids in the rat: a mechanism for hypocalcemia
in acute pancreatitis. Gastroenterology 1985;89:814Y820.
24. Imrie CW, Allam BF, Ferguson JC. Hypocalcaemia of acute pancreatits:
the effect of hypoalbuminaemia. Curr Med Res Opin 1976;4:101Y116.
25. Ryzen E, Rude RK. Low intracellular magnesium in patients with acute
pancreatitis and hypocalcemia. West J Med 1990;152:145Y148.
26. Graber ML. Magnesium deficiency: pathophysiologic and clinical over-
view. Am J Kidney Dis 1995;25:973.
27. Hsu HJ, Wu MS. Extreme hyperphosphatemia and hypocalcemic coma
associated with phosphate enema. Intern Med 2008;47:642Y646.
28. Bringhurst FR, Demay MB, Kronenburg HM. Hormones and disorders
of mineral metabolism, in Kronenburg HM (ed). Williams Textbook of
Endocrinology. Philadelphia, Saunders, 2008, ed 11, p 1246.
29. Sedlacek M, Schoolwerth AC, Remillard BD. Electrolyte disturbances in
the intensive care unit. Semin Dial 2006;19:496Y501.
30. Sharatt CL, Gilbert CJ, Cornes MC, et al. EDTA sample contamination
is common and often undetected, putting patients at unnecessary risk
of harm. Int J Clin Pract 2009;63:1126Y1127.
31. Williams SF, Meek SE, Moraghan TJ. Spurious hypocalcemia after
gadodiamide administration. Mayo Clin Proc 2005;80:1655Y1657.
32. Nanji AA, Denegri JF. Hypomagnesemia associated with gentamicin
therapy. Drug Intell Clin Pharm 1984;18:596Y598.
33. Burry LD, Tung DD, Hallett D, et al. Regional citrate anticoagulation for
PrismaFlex continuous renal replacement therapy. Ann Pharmacother
2009;43:1419Y1425.
34. Kankirawatana S, Huang ST, Marques MB. Continuous infusion of calcium
gluconate in 5% albumin is safe and prevents most hypocalcemic reactions
during therapeutic plasma exchange. J Clin Apher 2007;22:265Y269.
35. Guillaume MP, Karmali R, Bergmann P, et al. Unusual prolonged hypo-
calcemia due to foscarnet in a patient with AIDS. Clin Infect Dis 1997;
25:932Y933.
36. Huang HH, Yen DH, Wu ML. Acute Erycibe henryi Prain (Ting Kung
Teng) poisoning. Clin Toxicol (Phila) 2006;44:71Y75.
37. Jin UH, Kim DI, Lee TK. Herbal formulation, Yukmi-jihang-tang-Jajage,
regulates bone resorption by inhibition of phosphorylation mediated by
236
Copyright 2012 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
tyrosine kinase Src and cyclooxygenase expression. J Ethnopharmacol
2006;106:333Y343.
38. Valsamis HA, Arora SK, Labban B. Antiepileptic drugs and bone me-
tabolism. Nutr Metab (Lond) 2006;3:36Y47.
39. Friedman HZ, Langman CB, Favus MJ. Vitamin D metabolism and os-
teomalacia in cystic fibrosis. Gastroenterology 1985;88:808Y813.
40. Wills MR, Savory J. Vitamin D metabolism and chronic liver disease.
Ann Clin Lab Sci 1984;14:189Y197.
41. Bushinsky DA, Monk R. Calcium. Lancet 1998;352:306Y311.
42. Movilli E, Zani R, Carli O. Direct effect of the correction of acidosis on
plasma parathyroid hormone concentrations, calcium and phosphate in
hemodialysis patients: a prospective study. Nephron 2001;87:257Y262.
43. Murros J, Luomanmaki K. A case of hypocalcemia, heart failure and ex-
ceptional repolarization disturbances. Acta Med Scand 1980;208:133Y136.
44. Muller B, Becker KL, Kranzlin M, et al. Disordered calcium homeostasis
of sepsis: association with calcitonin precursors. Eur J Clin Invest
2000;30:823Y831.
45. Lind L, Bucht E, Ljunghall S. Pronounced elevation in circulating cal-
citonin in critical care patients is related to the severity of illness and
survival. Intensive Care Med 1995;21:63Y66.
46. Ammori BJ, Becker KL, Kite P, et al. Calcitonin precursors in the pred-
ication of severity of acute pancreatitis on the day of admission. Br J Surg
2003;90:197Y204.
47. Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab
Clin North Am 1993;22:363Y375.
48. Kraft MD, Btaiche IF, Sacks GS, et al. Treatment of electrolyte disorders
in adult patients in the intensive care unit. Am J Health Syst Pharm
2005;62:1663Y1683.
49. Lin CY, Hsieh KC, Yeh MC, et al. Skin necrosis after intravenous calcium
chloride administration as a complication of parathyroidectomy for sec-
ondary hyperparathyroidism: report of four cases. Surg Today 2007;37:
778Y781.
50. Larralde M, Giachetti A, Kowalczuk A, et al. Calcinosis cutis following liver
transplantation in pediatric patient. Pediatr Dermatol 2003;20:225Y228.
51. Ehsani AH, Abedini R, Ghiasi M, et al. Calcinosis cutis complicating liver
transplantation. Dermatol Online J 2006;12:23.
52. Jucgla A, Sais G, Curco N, et al. Calcinosis cutis following liver trans-
plantation: a complication of intravenous calcium administration. Br J
Dermatol 1995;132:275Y278.
53. Dickerson RN, Morgan LG, Cauthen AD, et al. Treatment of acute hy-
pocalcemia in critically ill multiple-trauma patients. JPEN J Parenter
Enteral Nutr 2005;29:436Y441.
54. Dickerson RN, Morgan LM, Croce MA, et al. Treatment of moderate to
severe acute hypocalcemia in critically ill trauma patients. JPEN J Par-
enter Enteral Nutr 2007;31:228Y233.
55. Dickerson RN, Morgan LM, Croce MA, et al. Dose-dependent char-
acteristics of intravenous calcium therapy for hypocalcemic critically
ill trauma patients receiving specialized nutritional support. Nutrition
2007;23:9Y15.
56. Kelly RA, Smith TW. Recognition and management of digitalis toxicity.
Am J Cardiol 1992;68:108GY118G.
57. Egi M, Nichol A, Stachowski E, et al. Ionized calcium concentration and
outcome in critical illness. Crit Care Med 2011;39:314Y321.
58. Forsythe RM, Wessel CB, Billiar TR, et al. Parenteral calcium for intensive
care unit patients. Cochrane Database Syst Rev 2008;4:CD006163.
59. Zaloga GP, Sager A, Black KW, et al. Low dose calcium administration
increases mortality during septic peritonitis in rats. Circ Shock 1992;37:
226Y229.
60. Davis KD, Attie MF. Management of server hypercalcemia. Crit Care
Clin 1991;7:175Y190.
61. Moe SM. Disorders involving calcium, phosphorus, and magnesium.
Prim Care 2008;35:215Y217.
62. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of
a parathyroid-like protein in malignancy-associated hypercalcemia.
Ann Intern Med 1989;111:807Y812.
* 2012 Southern Medical Association

63. Bridgewater JA, Ratcliffe WA, Bundred NJ, et al. Malignant phaeochro-
mocytoma and hypercalcemia. Postgrad Med J 1993;69:77Y79.
64. Kimura S, Nishimura Y, Yamaguchi K, et al. A case of pheochromocytoma
producing parathyroid hormone-related protein and presenting with hy-
percalcemia. J Clin Endocrinol Metab 1990;70:1559Y1563.
65. Fuss M, Pepersack T, Gillet C, et al. Calcium and vitamin D metabolism
in granulomatous diseases. Clin Rheumatol 1992;11:28Y36.
66. Igbal AA, Burgess EH, Gallina DL, et al. Hypercalcemia in hyperthy-
roidism: patterns of serum calcium, parathyroid hormone, and 1,25-
dihydroxyvitamin D3 levels during management of thyrotoxicosis.
Endocr Pract 2003;9:517Y521.
67. Glemarec J, Varin S, Rodet D, et al. Hypercalcemia in a patient
with tuberculous adrenal insufficiency. Joint Bone Spine 2002;69:
88Y91.
68. Katahira M, Yamada T, Kawai M. A case of Cushing syndrome with both
secondary hypothyroidism and hypercalcemia due to postoperative adre-
nal insufficiency. Endocr J 2004;51:105Y113.
69. Agus ZS, Wasserstein A, Goldfarb S. Disorders of calcium and magne-
sium homeostasis. Am J Med 1982;72:473Y488.
70. Khandwala HM, Van Uum S. Reversible hypercalcemia and hyperpara-
thyroidism associated with lithium therapy: case report and review of
literature. Endocr Pract 2006;12:54Y58.
71. Arumugam GP, Sudravel S, Shanthi P, et al. Tamoxifen flare hypercal-
cemia: an additional support for gallium nitrate usage. J Bone Miner
Metab 2006;24:243Y247.
72. McPherson ML, Prince SR, Atamer ER, et al. Theophylline-induced
hypercalcemia. Ann Intern Med 1986;105:52Y54.
73. Beall DP, Henslee HB, Webb HR, et al. Milk-alkali syndrome: a historical
review and description of the modern version of the syndrome. Am J Med
Sci 2006;331:233Y234.
74. Waked A, Geara A, El-Imad B. Hypercalcemia, metabolic alkalosis and
renal failure secondary to calcium bicarbonate intake for osteoporosis
preventionVmodern milk alkali syndrome: a case report. Cases J
2009;2:6188.
75. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hy-
percalcemia: an unproven yet common practice. Ann Intern Med 2008;
149:259Y263.
Southern Medical Journal & Volume 105, Number 4, April 2012
Copyright 2012 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Review Article
76. Pamidronate disodium (adult dosing). Micromedex 2.0. Philadelphia,
Thompson Reuters.
77. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int
2008;74:1385Y1393.
78. Chennuru S, Koduri J, Baumann MA. Risk factors for symptomatic
hypocalcaemia complicating treatment with zoledronic acid. Intern Med J
2008;38:635Y637.
79. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and
clinical fractures and mortality after hip fracture. N Engl J Med 2007;
357:1799Y1809.
80. Roldan EJ, Kerzberg EM, Castelli G, et al. Effect of low doses of oral
pamidronate (APD) on the calcemia of osteopenic or osteoporotic
patients. Medicina (B Aires) 1996;56:133Y137.
81. Wisneski LA. Salmon calcitonin in the acute management of hypercal-
cemia. Calcif Tissue Int 1990;46:S26YS30.
82. Grutters JC, van den Bosch JM. Corticosteroid treatment in sarcoidosis.
Eur Respir J 2006;28:627Y636.
83. Kristensen B, Ejlertsen B, Holmegaard SN, et al. Prednisolone in the
treatment of severe malignant hypercalcemia in metastatic breast cancer:
a randomized study. J Intern Med 1992;232:237Y245.
84. Davidson TG. Conventional treatment of hypercalcemia of malignancy.
Am J Health Syst Pharm 2001;58(3 suppl):S8YS15.
85. Rubin MR, Bruce JN, Khandji AG, et al. Sarcoidosis with a pituitary
adenoma. Pituitary 2001;4:195Y202.
86. Robin J, Fintel B, Pikovskaya O, et al. Multiple myeloma presenting
with high-output heart failure and improving with anti-angiogenesis ther-
apy: two case reports and a review of literature. J Med Case Reports
2008;2:229.
87. Camus C, Charassee C, Jouannic-Montier I, et al. Calcium free hemodi-
alysis: experience in the treatment of 33 patients with severe hypercal-
cemia. Intensive Care Med 1996;22:116Y121.
88. Wang CC, Chen YC, Shiang JC, et al. Hypercalcemic crisis successfully
treated with prompt calcium-free hemodialysis. Am J Emerg Med 2009;
27:1174.e1Ye3.
89. Tan HK, Bellomo R, MPisi DA, et al. Ionized serum calcium levels
during acute renal failure: intermittent hemodialysis vs continuous
hemodiafiltration. Ren Fail 2002;24:19Y27.
237