Hypocalcemia

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 have been reported to have a higher mortality rate in pediatric intensive care unit (PICU) settings than children with normal calcium levels. Hypocalcemia is defined as a total serum calcium concentration of less than 8.5 mg/dL in children, less than 8 mg/dL in term neonates, and less than 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 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 albumin level, blood pH, serum phosphate, serum magnesium, and serum bicarbonate and may be reduced by exogenous factors, such as citrate from transfused blood or free fatty acids from total parenteral nutrition (TPN), that may bind calcium. At physiologic pH of 7.40, 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 of ionized calcium is 4-5 mg/dL.

The concentration of calcium in the serum is critical to many important biological 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 actually is depressed because hypocalcemia impedes acetylcholine release at neuromuscular junctions and, thus, inhibits muscle contraction. However, the increase in neuronal excitability overrides the inhibition of muscle contraction. Cardiac function also may suffer because of poor muscle contractility.

Frequency:
 

• In the US: Incidence of neonatal hypocalcemia varies in different studies. Up to 30% of infants with very low birth weight (<1500 g) and up to 89% of infants whose gestational age at birth is less than 32 weeks have hypocalcemia. High incidence also is reported in infants of diabetic mothers and infants with birth asphyxia.

• Internationally: 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 less 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.

History: History is variable depending on the age of the patient.

• Newborns

• May be asymptomatic

• 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 Chvostek sign, carpopedal spasm, Trousseau sign, and stridor

• Abdominal distension

• Prematurity, birth asphyxia, or congenital heart disease (features associated with infants of diabetic mothers)

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 from diminished glomerular filtration.

Although hypocalcemia is observed most commonly among neonates, it is reported frequently 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 (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.

   

• Infant of diabetic mother: Functional hypoparathyroidism induced by magnesium deficiency plays a predominant role in addition to increased risk of prematurity and asphyxia.

   

• Intrauterine growth retardation (IUGR): Infants with IUGR may have hypocalcemia if they also are preterm or have had perinatal asphyxia.

• Late neonatal (3-7 d after birth)

• Exogenous phosphate load: Most commonly seen in developing countries, hypocalcemia is caused by feeding with phosphate-rich formula or cow's milk.

   

• Magnesium deficiency

   

• Transient hypoparathyroidism of newborn

   

• Hypoparathyroidism caused by other causes

• Infants and children

• Hypoparathyroidism

   

  • Aplasia or hypoplasia - DiGeorge syndrome, velocardiofacial syndrome, maternal diabetes mellitus or treatment with retinoic acid, VATER complex (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal abnormalities), CHARGE association (coloboma, heart defects, choanal atresia, renal abnormalities, growth retardation, male genital anomalies, ear abnormalities)

     

  • 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

• Abnormal vitamin D production or action

   

  • Vitamin D deficiency - Dietary, maternal anticonvulsants

     

  • Acquired or inherited disorders of vitamin D metabolism

     

  • Resistance to actions of vitamin D

• Hyperphosphatemia

   

  • Excessive phosphate intake because of wrong 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 administration of bicarbonate, diuretics, or chelating agents, such as the high doses of citrates taken in with massive blood transfusions

     

  • Pancreatitis

     

  • Pseudohypocalcemia (ie, hypoalbuminemia)

     

  • Hungry bones syndrome - Rapid skeletal mineral deposition seen in infants with rickets or hypoparathyroidism after starting

Lab Studies:
 

• Serum calcium, total and ionized

• Measurement of ionized calcium level is essential to differentiate true hypocalcemia from mere decrease in total calcium concentration.

• Decrease in total calcium can be associated with low serum albumin concentration and abnormal pH.

• Serum magnesium

• Serum magnesium may be low in patients with hypocalcemia.

• Hypocalcemia may not respond to calcium therapy if hypomagnesemia is not corrected.

• Serum electrolytes and glucose: Seizures and irritability in newborns and children could be associated with hypoglycemia and sodium abnormalities.

• Phosphorus

• Estimation of phosphate level is essential in establishing the etiology of hypocalcemia.

• Phosphate levels are higher 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.

• Parathormone studies

• 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.

• Conversely, in patients with vitamin D abnormalities and pseudohypoparathyroidism, PTH levels are elevated, and calcium levels do not rise in response to PTH challenge.

• Vitamin D metabolites (25-hydroxyvitamin D and 1,25- dihydroxyvitamin D): This study may be done along with hormone studies to rule out uncommon causes of hypocalcemia, such as malabsorption or disorders of vitamin D metabolism.

• Urine calcium, magnesium, phosphorus, and creatinine: These studies should be done in cases of suspected renal tubular defects and renal failure.

• Serum alkaline phosphatase generally is elevated in patients with rickets.

Imaging Studies:
 

• Chest x-ray: Check for thymic shadow, which may be absent in cases of DiGeorge syndrome.

• Ankle and wrist x-rays

• Evaluate for evidence of rickets.

• Changes appear at an early stage in radius and ulna; distal ends are widened, concave, and frayed.

Other Tests:
 

• Electrocardiogram

• Prolonged QTc (>0.4 s), prolonged ST segment, and T wave abnormalities may be observed.

• Measurement of specific intervals are of little value in predicting hypocalcemia.

• Malabsorption workup

• Total lymphocyte and T-cell subset counts: Findings are decreased in DiGeorge syndrome.

• 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

Medical Care:

• General medical care involves stabilization of patient with management of airway and breathing if the child or neonate presents with seizures. Anticonvulsants commonly are administered before confirmation of hypocalcemia 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 usually is indicated for patients having seizures, those who are critically ill, and those who are to have surgery. Oral calcium therapy is used for asymptomatic patients and as follow-up to intravenous calcium therapy.

Consultations:

• Pediatric endocrinologist

• Geneticist

MEDICATION

Calcium therapy is the mainstay of treatment for hypocalcemia. Intravenous calcium is the most effective and rapid means of elevating serum calcium concentration. Once hypocalcemia is controlled, follow-up treatment can be accomplished with oral therapy. However, in patients with asymptomatic hypocalcemia, oral calcium therapy may be sufficient. Vitamin D, in one of its various forms, also is 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 development and/or function of bone, teeth, nerves, muscles, and blood coagulation. 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. Increases calcium levels by promoting absorption of calcium in intestines and retention in kidneys.

Further Inpatient Care:
 

• Most babies with hypocalcemia are preterm and are in the neonatal intensive care unit (NICU) already.

• 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 underlying disease (eg, PTH concentration in hypoparathyroidism) is necessary.

• This monitoring is important because no definitive measures exist to determine whether an infant has a “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 typically is 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 significant sequelae.

• Late neonatal hypocalcemia secondary to exogenous phosphate load and magnesium deficiency also responds very 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 could be transient, last several weeks to months, or be permanent.

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 following 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.

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