Hypercalcemia and Hypocalcemia

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17 Hypercalcemia and Hypocalcemia

Abnormal serum calcium concentration is a common finding in critically ill patients. The prevalence of hypocalcemia in intensive care unit (ICU) patients ranges from 70% to 90% when total serum calcium is used and from 15% to 50% when ionized calcium is measured.1 Hypercalcemia occurs less frequently, with a reported incidence of less than 15% in critically ill patients.2 Hypocalcemia is associated with injury severity and mortality in critically ill patients,1,35 but whether low serum calcium concentration is protective, harmful, or simply prognostic in critical illness is unclear. Therefore, in most instances, the management of hypocalcemia involves treating the underlying medical condition(s), except when patients are symptomatic or hemodynamically unstable. This chapter provides a brief overview of calcium physiology, the regulation of serum calcium concentration, potential etiologies and symptoms of hypocalcemia, conditions associated with hypocalcemia, and guidelines for treating hypo- and hypercalcemia in critically ill patients.

image Calcium Physiology and Metabolism

Calcium is a divalent ion (Ca2+) involved in critical biological processes like muscle contraction, blood coagulation, neuronal conduction, hormone secretion, and the activity of various enzymes.35 Therefore, it is not surprising that intra- and extracellular calcium levels, like pH, are tightly regulated. A normal adult contains approximately 1 to 2 kg of total body calcium, which is located primarily in bone (99%) as hydroxyapatite.1,3,5 Skeletal stores of calcium represent an unlimited reservoir that is regulated predominantly by extracellular Ca2+ concentration, parathyroid hormone (PTH), and calcitonin. Extracellular concentrations of Ca2+ are typically 10,000 times greater than cytoplasmic Ca2+ levels.1,3 Similarly, the majority of intracellular calcium (>90%) is found in subcellular organelles (mitochondria, microsomes, endoplasmic or sarcoplasmic reticulum) as opposed to the cytoplasmic compartment. Ca2+-mediated cell signaling involves rapid changes in cytoplasmic Ca2+ concentration, owing to release of the cation from both internal and external stores.6,7 Cytoplasmic Ca2+ influx occurs through the cell membranes by receptor-activated, G protein–linked channels and the release of internal Ca2+ from endoplasmic or sarcoplasmic reticulum (ER/SR) by second messengers.6 The efflux of cytoplasmic Ca2+ involves transport of Ca2+ across the cell membrane and into the ER/SR via specific transporters.68 These tightly controlled pulsations of cytoplasmic Ca2+ thus regulate signal strength and frequency for calcium-mediated cellular functions. Alterations in Ca2+ signaling have been identified in muscle, hepatocytes, neutrophils, and T lymphocytes during sepsis and may contribute to the development of organ dysfunction during catabolic illnesses (for review see Ref. 7).

Extracellular calcium homeostasis is maintained by the coordinated actions of the gastrointestinal tract, kidneys, and bone.1,3 Levels of extracellular Ca2+ are detected by calcium-sensing receptors on parathyroid cells.8 In response to low serum Ca2+ concentration, the parathyroid gland secretes PTH, which reduces renal reabsorption of phosphate, increases renal calcium reabsorption, and stimulates renal hydroxylation of vitamin D.1,3 PTH and 1,25-dihydroxy vitamin D (calcitriol) promote the release of calcium from bone by activating osteoclasts.1,3 Calcitriol also stimulates intestinal absorption of dietary calcium and regulates PTH secretion by inhibiting PTH gene transcription. PTH secretion is also influenced by serum phosphate concentration, which stimulates PTH secretion by lowering extracellular Ca2+ concentration. Magnesium is required for the release of PTH from parathyroid cells and may explain the development of hypocalcemia in patients with magnesium deficiency. Calcitonin is a calcium-regulating hormone secreted by the parafollicular C cells of the parathyroid gland during hypercalcemia. Although calcitonin inhibits bone resorption and stimulates urinary excretion of calcium, its does not appear to play a major role calcium homeostasis in humans.1,3

The normal concentration of ionized calcium in the extracellular space (plasma and interstitium) is 1.2 mmol/L and represents 50% of the total extracellular calcium. The remaining 40% is bound to plasma proteins, and 10% is combined with citrate, phosphate, or other anions. Total serum calcium normally ranges from 9.4 to 10.0 mg/dL (2.4 mmol). The distribution of ionized and bound calcium may be altered in critically ill patients. Chelating substances like citrate and phosphate may influence the abundance of ionized Ca2+. An increase in free fatty acids caused by lipolysis or parenteral nutrition results in increased binding of calcium to albumin.9 Protein-bound calcium is also increased during alkalosis and reduced during acidosis.1,3 Correcting total serum calcium for albumin and pH does not accurately estimate ionized Ca2+ concentration.10,11 Therefore, direct measurement of ionized serum calcium concentration is more accurate and is the recommended assay when caring for critically ill patients.12

image Hypocalcemia in Critically Ill Patients

Ionized hypocalcemia is frequently seen in critically ill patients with sepsis, acute pancreatitis, severe traumatic injuries, or following major surgery. The incidence of ionized hypocalcemia in ICU patients ranges from 15% to 50%.3 The degree of hypocalcemia correlates with illness severity as measured by the APACHE II score (Acute Physiology and Chronic Health Evaluation) and is associated with increased mortality in critically ill patients.4 In particular, the degree of systemic inflammation as measured by circulating cytokine (e.g., tumor necrosis factor [TNF]) or procalcitonin levels appears to correlate with the severity of hypocalcemia in ICU patients.11 Potential etiologies for the hypocalcemia of critical illness include impaired PTH secretion or action, vitamin D deficiency or resistance, calcium sequestration or chelation, or impaired mobilization of Ca2+ from bone (Table 17-1).

TABLE 17-1 Causes of Hypocalcemia

Impaired Parathyroid Hormone Secretion or Action

Impaired Vitamin D Synthesis or Action Calcium Chelation/Precipitation Decreased Bone Turnover

Data from Zaloga GP. Hypocalcemia in critically ill patients. Crit Care Med. 1992;20(2):251-262.

Hypocalcemia in the ICU is rarely caused by primary hypoparathyroidism. However, sepsis and systemic inflammatory response syndrome (SIRS) are commonly associated with hypocalcemia, which is caused in part by impaired secretion and action of PTH and failure to synthesize calcitriol.1,3,11 Hypomagnesemia may contribute to hypocalcemia during critical illness via inhibitory effects on PTH secretion and target organ responsiveness,1,3,

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