AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hypocalcemia is a relatively frequently observed laboratory and clinical abnormality seen especially in neonates. Laboratory hypocalcemia is often asymptomatic, and its treatment in neonates is controversial. However, children with hypocalcemia in pediatric intensive care units (PICUs) have mortality rates higher than those of children with normal calcium levels. Hypocalcemia is defined as a total serum calcium concentration of less than 2.1 mmol/L (8.5 mg/dL) in children, less than 2 mmol/L (8 mg/dL) in term neonates, and less than 1.75 mmol/L (7 mg/dL) in preterm neonates.

Pathophysiology

Calcium is the most abundant mineral in the body. Of the body's total calcium, 99% is in bone, and serum levels constitute less than 1%. Various factors regulate the homeostasis of calcium and maintain serum calcium within a narrow range. These include parathormone (PTH), vitamin D, hepatic and renal function (for conversion of vitamin D to active metabolites), and serum phosphate and magnesium levels.

Although total serum calcium levels are often measured and reported, ionized calcium is the active and physiologically important component. Total calcium level includes both the ionized fraction and the bound fraction. The ionized calcium level is affected by the albumin level, blood pH, serum phosphate, serum magnesium, and serum bicarbonate, and it may be reduced by exogenous factors that may bind calcium, such as citrate from transfused blood or free fatty acids from total parenteral nutrition (TPN). At a physiologic pH of 7.4, 40% of total calcium is bound to albumin; 10% is complexed with bicarbonate, phosphate, or citrate; and the remaining 50% is free ionized calcium. The normal range for ionized calcium is 1-1.25 mmol/L (4-5 mg/dL).

The concentration of calcium in the serum is critical to many important biologic functions, including the following:

• Calcium messenger system by which extracellular messengers regulate cell function
• Activation of several cellular enzyme cascades
• Smooth muscle and myocardial contraction
• Nerve impulse conduction
• Secretory activity of exocrine glands

Hypocalcemia manifests as CNS irritability and poor muscular contractility. Low calcium levels decrease the threshold of excitation of neurons, causing them to have repetitive responses to a single stimulus. Because neuronal excitability occurs in both sensory and motor nerves, hypocalcemia produces a wide range of peripheral and CNS effects, including paresthesias, tetany (ie, contraction of hands, arms, feet, larynx, bronchioles), seizures, and even psychiatric changes in children. Tetany is not caused by increased excitability of the muscles. Muscle excitability is depressed because hypocalcemia impedes acetylcholine release at neuromuscular junctions and, therefore, inhibits muscle contraction. However, the increase in neuronal excitability overrides the inhibition of muscle contraction. Cardiac function may also be impaired because of poor muscle contractility.

Frequency

United States

The incidence of neonatal hypocalcemia varies in different studies. Hypocalcemia occurs in as many as 30% of infants with very low birth weight ( <1500 g) and in as many as 89% of infants whose gestational age at birth was less than 32 weeks. A high incidence is also reported in infants of mothers with diabetes mellitus (DM) and in infants with birth asphyxia.

International

No variation is reported across national boundaries. However, late-onset hypocalcemia is more common in infants in developing countries where babies are fed cow's milk or formulas containing high amounts of phosphate than in countries where infants are fed human milk or formulas containing low amounts of phosphate.

Mortality/Morbidity

Higher mortality rates have been reported in children with hypocalcemia than in normocalcemic children in PICU settings.

Sex

No sex-based variation in incidence is known.

Age

Most pediatric patients with hypocalcemia are newborns. In older children, hypocalcemia is usually associated with critical illness, acquired hypoparathyroidism, activating mutations of the calcium-sensing receptor, or defects in vitamin D supply or metabolism.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The history varies depending on the age of the patient.

• Newborns
• • Possibly no symptoms
  • Lethargy
  • Poor feeding
  • Vomiting
  • Abdominal distension
• Children
• • Seizures
  • Twitching
  • Cramping
  • Laryngospasm, a rare initial manifestation

Physical

• Lethargy
• Cyanosis
• Tremulousness
• Seizures
• Apnea
• Tetany and signs of nerve irritability, such as the Chvostek sign, carpopedal spasm, the Trousseau sign, and stridor
• Abdominal distension
• Prematurity, birth asphyxia, or congenital heart disease (features associated with infants of mothers with DM)

Causes

Overall, one of the most common causes of hypocalcemia is renal failure, which results in hypocalcemia because of inadequate 1-hydroxylation of 25-hydroxyvitamin D and hyperphosphatemia due to diminished glomerular filtration.

Although hypocalcemia is most commonly observed among neonates, it is frequently reported in older children and adolescents, especially in PICU settings. The causes of hypocalcemia can be classified by the child's age at presentation.

• Early neonatal hypocalcemia (within 48-72 h of birth)
• • Prematurity: Possible mechanisms include poor intake, decreased responsiveness to vitamin D, increased calcitonin, and hypoalbuminemia leading to decreased total but normal ionized calcium.
  • Birth asphyxia: Delayed introduction of feeds, increased calcitonin production, increased endogenous phosphate load, and alkali therapy all may contribute to hypocalcemia.
  • DM in the mother: Magnesium depletion in mothers with DM causes hypomagnesemic state in the fetus. This hypomagnesemia induces functional hypoparathyroidism and hypocalcemia in the infant. A high incidence of birth asphyxia and prematurity in infants of diabetic mothers are also contributing factors.
  • Intrauterine growth retardation (IUGR): Infants with IUGR may have hypocalcemia if they also are preterm or have had perinatal asphyxia.
• Late neonatal hypocalcemia (3-7 d after birth, though occasionally as late as 6 weeks of age)
• • Exogenous phosphate load: This is most commonly seen in developing countries. Hypocalcemia is caused by feeding with phosphate-rich formula or cow's milk. Whole cow's milk has 7 times the phosphate load of breast milk (956 vs 140 mg/L in breast milk).
  • Magnesium deficiency
  • Transient hypoparathyroidism of newborn
  • Hypoparathyroidism due to other causes
  • Recent data have suggested association with gentamicin use, especially with new every-24-hour dosing schedule.
• Hypocalcemia in infants and children
• • Hypoparathyroidism
    • Aplasia or hypoplasia - DiGeorge syndrome; velocardiofacial syndrome; gestational DM, fetal exposure to retinoic acid; complex of vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal abnormalities (VATER); and association of coloboma, heart defects, choanal atresia, renal abnormalities, growth retardation, male genital anomalies, and ear abnormalities (CHARGE)
    • PTH receptor defects - Pseudohypoparathyroidism
    • Autoimmune parathyroiditis
    • Infiltrative lesions - Hemosiderosis, Wilson disease, thalassemia
    • Activating mutations of the calcium-sensing receptor leading to inappropriately suppressed PTH secretion
    • Idiopathic causes
  • Abnormal vitamin D production or action
    • Vitamin D deficiency - Dietary insufficiency, maternal use of anticonvulsants
    • Acquired or inherited disorders of vitamin D metabolism
    • Resistance to actions of vitamin D
  • Hyperphosphatemia
    • Excessive phosphate intake because of improper formula
    • Excessive phosphate intake caused by inappropriate use of phosphate-containing enemas
    • Loading in TPN
    • Increased endogenous loading caused by anoxia, chemotherapy, or rhabdomyolysis
    • Renal failure
  • Others
    • Malabsorption syndromes
    • Alkalosis - Respiratory alkalosis caused by hyperventilation; metabolic alkalosis with the administration of bicarbonate, diuretics, or chelating agents, such as the high doses of citrates taken in during massive blood transfusions
    • Pancreatitis
    • Pseudohypocalcemia (ie, hypoalbuminemia)
    • Hungry bones syndrome - Rapid skeletal mineral deposition seen in infants with rickets or hypoparathyroidism after starting vitamin D therapy

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Anoxia
Intracranial bleeding
Narcotic withdrawal
Pseudohypoparathyroidism
Rickets, osteomalacia, or rachitis (ie, vitamin D deficiency)
Hyperphosphatemia
Hypoalbuminemia
Renal failure
Metabolic disease affecting vitamin D, seizures

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Test of total and ionized serum calcium level
• • Measuring ionized calcium level is essential to differentiate true hypocalcemia from a mere decrease in total calcium concentration.
  • A decrease in total calcium can be associated with low serum albumin concentration and abnormal pH.
• Test of serum magnesium level
• • Serum magnesium may be low in patients with hypocalcemia.
  • Hypocalcemia may not respond to calcium therapy if hypomagnesemia is not corrected.
  • Severe hypomagnesemia (0.46 mmol/L) causes hypocalcemia by impairing the secretion and action of PTH.
• Test of serum electrolyte and glucose levels
  • Seizures and irritability in newborns and children can be associated with hypoglycemia and sodium abnormalities.
  • Low bicarbonate levels and acidosis may be associated with Fanconi syndrome and renal tubular acidosis.
• Test of phosphorus levels
• • Estimating the phosphate level is essential to establish the etiology of hypocalcemia.
  • Phosphate levels are increased in cases of exogenous and endogenous phosphate loading and renal failure.
  • Levels are usually high in hypoparathyroidism.
  • Levels are low in cases of vitamin D abnormalities and rickets.
• Test of PTH levels
• • Hormone studies are indicated if hypocalcemia persists in the presence of normal magnesium and normal or elevated phosphate levels.
  • Low PTH levels suggest hypoparathyroidism; serum calcium rises in response to PTH challenge.
  • On the converse, PTH levels are elevated in patients with vitamin D abnormalities and pseudohypoparathyroidism, and calcium levels do not rise in response to PTH challenge.
  • N-terminal fragment of PTH is the only biologically active fragment of PTH. It is difficult to measure because of its short half life of 2-5 minutes. Circulating PTH levels are determined by assaying for intact PTH peptide.
• Test of vitamin D metabolite (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) levels: These may be assessed, along with hormone concentrations, to eliminate uncommon causes of hypocalcemia (eg, malabsorption, disorders of vitamin D metabolism).
• Test for urine calcium, magnesium, phosphorus, and creatinine levels
  • These values should be assessed in patients with suspected renal tubular defects and renal failure.
  • Urine should also be evaluated for pH, glucose and protein.
  • In patients with renal defects, calcium excretion is high in presence of hypocalcemia.
  • A urine calcium-creatinine ratio of more than 0.3 on a spot sample in presence of hypocalcemia suggests inappropriate excretion.
• Test of serum alkaline phosphatase levels: Values are generally elevated in patients with rickets.

Imaging Studies

• Chest radiography: Evaluate for thymic shadow, which may be absent in patients with DiGeorge syndrome.
• Ankle and wrist radiography
• • Evaluate for evidence of rickets.
  • Changes appear at an early stage in the radius and ulna; the distal ends are widened, concave, and frayed.

Other Tests

• Electrocardiography
• • A prolonged QTc (>0.4 s), a prolonged ST segment, and T-wave abnormalities may be observed.
  • Measurements of specific intervals are of little value in predicting hypocalcemia.
• Malabsorption workup
• Total lymphocyte and T-cell subset analyses: Findings are decreased in patients with DiGeorge syndrome.
• Karyotyping to assess for 22q11 and 10p13 deletion.
• Maternal and family screening: This is helpful in familial forms of hypocalcemia, such as those caused by activating mutations of the calcium-sensing receptor.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• General medical care involves stabilization with management of the patient's airway and breathing if he or she presents with seizures.
• • Anticonvulsants are commonly administered before hypocalcemia is confirmed in a new patient.
  • Seizures usually do not respond to the usual antiseizure medications until calcium is administered intravenously.
• Treatment of an asymptomatic patient with hypocalcemia remains controversial, especially in neonates.
• • Some authorities suggest that treating such patients is unnecessary.
  • In contrast, most clinicians agree that hypocalcemia should be treated promptly in any symptomatic neonate or older child because of its serious implications for neuronal and cardiac function.
  • Intravenous treatment is usually indicated in patients having seizures, those who are critically ill, and those who are planning to have surgery.
  • Oral calcium therapy is used in asymptomatic patients and as follow-up to intravenous calcium therapy.
• In certain conditions like pancreatitis and rhabdomyolysis, full correction of hypocalcemia should be avoided. After the primary condition is resolved, these patients may develop hypercalcemia due to the release of complexed calcium.
• In cases with concurrent acidemia, hypocalcemia should be corrected first. Acidemia increases the ionized calcium levels by displacing calcium from albumin. If acidemia is corrected first, it decreases ionized calcium levels,

Consultations

• Pediatric endocrinologist
• Geneticist

Diet

A diet high in calcium and low in phosphate is required in most instances. Infants drinking regular cow's milk or evaporated milk must be given humanized infant formula instead. Patients with renal failure should be given a low-solute low-phosphate formula, such as Similac PM 60/40.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Calcium therapy is the mainstay of treatment for hypocalcemia. Therapy with intravenous calcium is the most effective and rapid means of elevating serum calcium concentration. After hypocalcemia is controlled, follow-up treatment with oral therapy can be given. However, in patients with asymptomatic hypocalcemia, therapy with oral calcium alone may be sufficient. Vitamin D, in one of its various forms, is also indicated depending on the metabolic abnormality present. However, the use of vitamin D formulations in newborns to prevent hypocalcemia has not been effective. The most important aspect of management is resolution of the primary cause (eg, hyperphosphatemia, hypomagnesemia).

Drug Category: Calcium compounds

Calcium is the most abundant mineral in the human body. It is essential for blood coagulation and the development and/or function of bone, teeth, nerves, and muscles. Calcium also functions as an enzymatic cofactor and affects endocrine secretory function. Supplements are used to increase serum calcium concentrations in patients with hypocalcemia. Oral preparations are prescribed to reduce phosphate absorption from the intestine in patients with hyperphosphatemia.

Drug Category: Vitamin D metabolites

The active forms of vitamin D regulate calcium absorption and its uses in the body. They increase calcium levels by promoting absorption of calcium in intestines and retention in kidneys.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Most babies with hypocalcemia are preterm and have already been admitted to the neonatal intensive care unit (NICU).
• Any newborn infant with hypocalcemia should be monitored in the NICU.
• Any child with symptomatic hypocalcemia should be admitted to the hospital unless the diagnosis is hyperventilation.

Further Outpatient Care

• Regular follow-up monitoring of serum calcium concentration and appropriate monitoring of the underlying disease (eg, PTH concentration in hypoparathyroidism) is necessary.
• This monitoring is important because no definitive measures exist to determine whether an infant has transient hypoparathyroidism that may last for several years or is at risk for recurrence of hypoparathyroidism and hypocalcemia; recurrence has been reported as late as adolescence.

In/Out Patient Meds

• Magnesium administration is necessary to correct any hypomagnesemia because hypocalcemia does not respond until the low magnesium level is corrected.
• Phosphate-lowering agents may be necessary if hypocalcemia is associated with hyperphosphatemia.

Deterrence/Prevention

• Late-onset hypocalcemia in neonates, which is typically caused by hyperphosphatemia, can be prevented by avoiding high-phosphate diets (eg, regular cow's milk). Ensuring adequate vitamin D stores in mothers during pregnancy also prevents late hypocalcemia.
• Feeding a low-phosphate diet such as human milk or Similac PM 60/40 formula may prevent hypocalcemia in hyperphosphatemic states, such as renal failure, hypoparathyroidism, and endogenous phosphate loading. Enhancing the calcium-phosphorus ratio to 4:1 in the diet (by adding calcium supplements to a low-phosphate diet) also reduces intestinal absorption of phosphate.

Prognosis

• Most cases of early neonatal hypocalcemia resolve within 48-72 hours without any clinically significant sequelae.
• Late neonatal hypocalcemia secondary to exogenous phosphate load and magnesium deficiency also responds well to phosphate restriction and magnesium repletion.
• When caused by hypoparathyroidism, hypocalcemia requires continued therapy with vitamin D metabolites and calcium salts. The period of therapy depends on the nature of the hypoparathyroidism, which can be transient, last several weeks to months, or be permanent.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Intravenous infusion with calcium-containing solutions can cause severe tissue necrosis. This can cause contractures and may require skin grafting. Integrity of the intravenous site should be ascertained before administering calcium through a peripheral vein.
• Necrosis of liver can occur after calcium infusion through an umbilical vein catheter placed in a branch of the portal vein. The position of all umbilical vein catheters must be confirmed radiologically before infusing calcium-containing solutions.
• Rapid infusion of calcium-containing solutions through arterial lines can cause arterial spasm and, if administered via an umbilical artery catheter, intestinal necrosis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Gertner JM. Disorders of calcium and phosphorus homeostasis. Pediatr Clin North Am. Dec 1990;37(6):1441-65. [Medline].
• Guise TA, Mundy GR. Clinical review 69: Evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab. May 1995;80(5):1473-8. [Medline].
• Jackson GL, Sendelbach DM, Stehel EK, et al. Association of hypocalcemia with a change in gentamicin administration in neonates. Pediatr Nephrol. Jul 2003;18(7):653-6. [Medline].
• Mimouni F, Tsang RC. Neonatal hypocalcemia: to treat or not to treat? (A review). J Am Coll Nutr. Oct 1994;13(5):408-15. [Medline].
• Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. N Engl J Med. Apr 13 1989;320(15):980-91. [Medline].
• Sanchez GJ, Venkataraman PS, Pryor RW, et al. Hypercalcitoninemia and hypocalcemia in acutely ill children: studies in serum calcium, blood ionized calcium, and calcium-regulating hormones. J Pediatr. Jun 1989;114(6):952-6. [Medline].
• Singh J, Moghal N, Pearce SH, Cheetham T. The investigation of hypocalcaemia and rickets. Arch Dis Child. May 2003;88(5):403-7. [Medline].
• Yamamoto M, Akatsu T, Nagase T, Ogata E. Comparison of hypocalcemic hypercalciuria between patients with idiopathic hypoparathyroidism and those with gain-of-function mutations in the calcium-sensing receptor: is it possible to differentiate the two disorders?. J Clin Endocrinol Metab. Dec 2000;85(12):4583-91. [Medline].

Article Last Updated: Sep 14, 2006