USA Surgery Today

Calcium is the major constituent of bone and is thus the most abundant mineral in the body. Almost 99% of the body’s calcium is in the bone and therefore unavailable for biochemical interactions. The other 1% remains in flux with the mineralized fraction and is estimated by serum calcium levels. The nonosseous extracellular calcium is either bound to albumin (40%), complexed to small molecules such as sulfates and phosphates (10%), or free and ionized (50%). It is the free ionized form that is physiologically active and thus serum measurements of ionized calcium are most reflective of calcium balance. Hyperproteinemia and alkalosis result in an increased proportion of protein-bound albumin and a decrease in ionized calcium. Chelators such as the citrate used in exchange transfusions or with massive blood resuscitation after trauma bind free calcium as well. Conversely, hypoalbuminemia decreases serum measurements of total calcium due to a decrease in protein-bound calcium, whereas the ionized fraction often remains constant.

The gastrointestinal tract is responsible for the intake of calcium and is regulated directly by the activated form of vitamin D and indirectly by the parathyroid glands. When calcium stores are low, the parathyroids are stimulated to secrete parathyroid hormone (PTH). PTH increases hydroxylase activity in the kidney, which in turn converts the inactive form of vitamin D to the active form. PTH also stimulates osteoclasts in the bone to reabsorb calcium. Both vitamin D and PTH induce renal resorption of calcium in the proximal convoluted tubule (85%) coupled with sodium resorption, and in the distal tubule (15%), which is independent of sodium. Increased calcium absorption may be found in conditions associated with increased activated vitamin D levels, such as sarcoid, leukemia, and multiple myeloma. Calcium loss is mainly via the urine, and is increased by diuretic administration, growth hormone, thyroid hormone, and glucagon. As with most other electrolytes, high-output stomas or fistulae may result in a large calcium deficit.

Hypocalcemia is relatively common in the neonatal period and occurs at two predictable times in the first several days of life. The early period of risk is manifest in the first 24 to 48 hours, whereas the later period is around the end of the first week of postnatal life.

Early hypocalcemia is most common in premature neonates and is inversely proportional to birth weight and gestational age (58). It is associated with birth asphyxia, maternal diabetes, and maternal hyperparathyroidism. The DiGeorge syndrome, which is marked by absence of derivatives of the third and fourth pharyngeal pouches, results in hypoparathyroidism, hypocalcemia, and absent or abnormal thymus with consequent immunologic deficiency. Other conditions associated with hypocalcemia include phototherapy and maternal anticonvulsant use (59). Late hypocalcemia is less common and is associated with phosphate imbalance from the use of cow milk-derived formulas, early introduction of cereals, hypomagnesemia, intestinal malabsorption, and hypoparathyriodism (59).

Signs and symptoms associated with hypocalcemia may be mistaken for other common neonatal abnormalities and are often very subtle. The early signs are apnea, irritability, lethargy, feeding intolerance, or abdominal distention. Seizures, cyanosis, and hyperreflexia may occur later in the course. If hypocalcemic seizures occur, therapy should be initiated with 1 cc per kg of 10% calcium gluconate given over 10 minutes. Rapid calcium administration may induce arrhythmias and, therefore, cardiac monitoring is essential in the management of severe hypocalcemia. Once the seizures have subsided, maintenance doses of 200 to 500 mg per kg per day of calcium can be administered.

Hypercalcemia in infants and neonates is relatively rare. Often it is iatrogenic and diagnosed by routine chemistry evaluation. The most common cause of hypercalcemia is hypophosphatemia during inappropriate hyperalimentation administration or enteral feeding of human milk. Hypophosphatemia results in increased vitamin D production and subsequent calcium absorption, as well as bone resorption in order to increase serum phosphate levels. Overexposure to vitamin D, either in utero or postnatally, may also cause hypercalcemia, a syndrome known as hypervitaminosis D. Familial hypocalciuric hypercalcemia is an autosomally dominant disorder with variable penetrance that may be diagnosed as early as in the first day of life. It is usually diagnosed as part of screening after diagnosis of a family member with an elevated calcium level. Its pathophysiology is not well understood, but is dependent on intact parathyroid function (60). Hyperthyroid infants are also at risk for developing hypercalcemia either before or during thyroxine administration, perhaps due to calcitonin deficiency (61). Other causes in older children include bone tumors or metastases from other primary tumors.

Most neonates with hypercalcemia are asymptomatic, but if symptoms should be present urgent treatment may be required. Common manifestations of hypercalcemia are subtle and may be easily confused with other neonatal illness. They include lethargy, irritability, polyuria, emesis, dehydration, and failure to thrive. Treatment strategies are focused at the underlying cause, but adequate hydration with isotonic solution in 10 to 20 cc per kg boluses is recommended for symptomatic patients. This may be followed with a loop diuretic to stimulate calcium excretion in the urine. Care must be taken to avoid other electrolyte imbalances with this therapy, especially magnesium and potassium. Little information is available regarding hormonal or pharmacologic manipulation of hypercalcemia.

Magnesium is the fourth most abundant cation in the body and is the second most abundant intracellular cation. Tissue distribution of magnesium varies, but approximately 60% of the total body stores are found in bone, with 20% in muscle, and the rest in the intracellular space of other tissues. Extracellular magnesium concentration is maintained within a narrow range and is freely exchanged with that stored in the bone. Magnesium’s primary function is in cellular physiology, and it catalyzes enzymatic processes used in the transfer, storage, and production of energy. Most magnesium is absorbed in the upper gastrointestinal tract, and this is enhanced by vitamin D and PTH. PTH also stimulates magnesium resorption from the bone pool. Renal excretion is the method of maintaining magnesium balance. Only about 5% of filtered magnesium appears in the urine, the rest is reabsorbed in the proximal convoluted tubules and the ascending limb of the loop of Henle. Magnesium is competitive with calcium for transport and its resorption is induced by dehydration, calcitonin, and PTH. Increased urinary excretion is associated with volume overload, diuretics, hypercalcemia, and glucagon.

Hypomagnesemia is defined by serum concentrations of less than 1.5 mg per dL; however, tissue depletion may be present despite normal serum levels. Common symptoms include muscle irritability and weakness and are often difficult to distinguish from those of hypocalcemia, which regularly accompanies hypomagnesemia. Conditions leading to hypomagnesemia are dilution from the administration of resuscitative fluids, IUGR, intestinal malabsorption after small bowel resection, high-output fistulae and stomas, and a myriad of other disorders of PTH and phosphate balance. The treatment of choice is intravenous magnesium sulfate 0.2 to 0.4 mEq per kg per dose every 8 to 12 hours for 2 to 3 doses if symptomatic. Oral supplementation may be used in milder cases.

Hypermagnesemia is found in neonates after magnesium administration to their preeclamptic mothers. Otherwise, it is seen in patients with excessive administration in hyperalimentation or enterally. The renal excretion of magnesium is usually sufficient to handle any increased load; therefore, hypermagnesemia is much more common in patients with renal insufficiency. Most newborns are asymptomatic, but if symptoms are present these are usually hypotonia, hyporeflexia, respiratory depression, lethargy, and even coma. Neonates may present with failure to pass meconium due to hypermagnesemia after maternal administration. Clinical signs usually do not correlate with serum levels because they are a poor indicator of total body stores. The best therapy for hypermagnesium is calcium administration because it is a direct antagonist of magnesium. It may be given in the same dosages used for hypocalcemia. Loop diuretics with saline administration may provoke magnesium excretion in a similar fashion as calcium if symptoms are severe and refractory to calcium administration.