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Hypocalcemia and hypercalcemia
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 measured and from 15% to 50% when ionized calcium is measured. Hypercalcemia occurs less frequently, with a reported incidence of <15% in critically ill patients. Hypocalcemia is associated with injury severity and mortality in critically ill patients. , However, whether low serum calcium 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.
Calcium physiology and metabolism
Calcium is a divalent ion (Ca 2 + ) involved in critical biologic processes like muscle contraction, blood coagulation, neuronal conduction, hormone secretion, and the activity of various enzymes. Therefore it is not surprising that intracellular and extracellular calcium levels, like pH, are tightly regulated. A normal adult contains approximately 1–2 kg of total body calcium, which is primarily located in bone (99%) as hydroxyapatite. , , Skeletal stores of calcium represent an unlimited reservoir that is predominantly regulated by extracellular Ca 2 + , parathyroid hormone (PTH), and calcitonin. Extracellular concentrations of Ca 2 + are typically 1–10,000 times greater than cytoplasmic Ca 2 + levels. , Similarly, the majority of intracellular calcium (>90%) is found in subcellular organelles (e.g., mitochondria, microsomes, and endoplasmic or sarcoplasmic reticulum [ER/SR]) as opposed to in the cytoplasmic compartment. Ca 2 + -mediated cell signaling involves rapid changes in cytoplasmic Ca 2 + from both internal and external stores. , Cytoplasmic Ca 2 + influx occurs through cell membranes by receptor-activated, G-protein–linked channels and the release of internal Ca 2 + from ER/SR by second messengers. The efflux of cytoplasmic Ca 2 + involves the transport of Ca 2 + across the cell membrane and into the ER/SR via specific transporters. These tightly controlled pulsations of cytoplasmic Ca 2 + thus regulate signal strength and frequency for calcium-mediated cellular functions. Alterations in Ca 2 + signaling have been identified in myocytes, hepatocytes, neutrophils, and T lymphocytes during sepsis and may contribute to the development of organ dysfunction during catabolic illness (for a review see Ref. 7).
Extracellular calcium homeostasis is maintained by the coordinated actions of the gastrointestinal tract, kidneys, and bone. , Levels of extracellular Ca 2 + are detected by calcium-sensing receptors on parathyroid cells. In response to low serum Ca 2 + , the parathyroid glands secrete PTH, which reduces the renal reabsorption of phosphate, increases renal calcium reabsorption, and stimulates renal hydroxylation of vitamin D. , PTH and 1,25-dihydroxy vitamin D (calcitriol) promote the release of calcium from bone by activating osteoclasts. , 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. High circulating phosphate levels stimulate PTH secretion by lowering extracellular Ca 2 + . Magnesium is required for the release of PTH from parathyroid cells and may explain the occurrence 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 the urinary excretion of calcium, this hormone does not appear to play a major role in calcium homeostasis in humans. ,
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/L). 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 Ca 2 + . Increased free fatty acid levels caused by lipolysis or parenteral nutrition result in increased binding of calcium to albumin. Protein-bound calcium is also increased during alkalosis and reduced during acidosis. , Correcting total serum calcium for albumin and pH does not accurately estimate ionized Ca 2 + . , Therefore a direct measurement of ionized serum calcium has been found to be the most accurate way to determine the concentration of this cation, and hence this approach is indicated in critically ill patients.
Hypocalcemia in critically ill patients
Ionized hypocalcemia is frequently seen in critically ill patients with sepsis, pancreatitis, severe traumatic injuries, or after major surgery. The incidence of hypocalcemia ranges from 15% to 50%. The degree of hypocalcemia correlates with illness severity as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score and is associated with increased mortality in critically ill patients. In particular, the degree of systemic inflammation, as measured by cytokine, tumor necrosis factor (TNF)-alpha, and pro-calcitonin levels, appears to correlate with hypocalcemia in ICU patients. 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 Ca 2 + from bone ( Table 19.1 ).
TABLE 19.1
Causes of Hypocalcemia
From Zaloga GP. Hypocalcemia in critically ill patients. Crit Care Med. 1992;20(2):251–261.
| Impaired Parathyroid Hormone Secretion or Action |
|
| Impaired Vitamin D Synthesis or Action |
|
| Calcium Chelation/Precipitation |
|
| Decreased Bone Turnover |
|
Hypocalcemia in the ICU is rarely caused by primary hypoparathyroidism. However, sepsis and systemic inflammatory response syndrome (SIRS) is commonly associated with hypocalcemia, which is caused in part by the impaired secretion and action of PTH and the failure to synthesize calcitriol. , , Hypomagnesemia may contribute to hypocalcemia during critical illness via inhibitory effects on PTH secretion and target organ responsiveness. , , However, the presence of hypomagnesemia only weakly correlates with hypocalcemia in ICU patients.
In many instances, the hypocalcemia of critical illness is multifactorial in etiology. Elderly patients are at an increased risk for vitamin D deficiency because of malnutrition, poor intestinal absorption, and hepatic or renal dysfunction. In obese patients with previous gastric bypass, the intestinal absorption of calcium dramatically decreases despite reasonable vitamin D levels and recommended calcium intake. Renal failure may precipitate hypocalcemia via the decreased formation of calcitriol and hyperphosphatemia and the chelation of ionized calcium. , The use of continuous renal replacement therapy in critically ill patients is associated with significant magnesium and calcium losses. This results in electrolyte replacement requirements that often exceed the calcium and magnesium supplementation provided in standard parenteral nutrition formulas. Other potential causes of ionized hypocalcemia in critically ill patients include alkalosis (increased binding of Ca 2 + to albumin), medications (anticonvulsants, antibiotics, diphosphonates, and radiocontrast agents), massive blood transfusion, sepsis, and pancreatitis. , More recently, the infusion of high doses of propofol have been shown to reduce circulating calcium concentrations by elevating serum PTH levels, but the physiologic significance of this phenomenon is unclear. Ionized hypocalcemia (<1.0 mmol/L) is associated with prehospital hypotension and represents a better predictor of mortality in severely injured patients than does base deficit. The exact reasons for this observation are unclear but potentially relate to head injury and/or the presence of hemorrhagic shock. Injured patients receiving blood transfusions may develop hypocalcemia as a consequence of Ca 2 + chelation by citrate, which is used as an anticoagulant in banked blood. The incidence of transfusion-related hypocalcemia is related to both the rate and volume of blood transfusion. , When blood transfusions are administered at a rate of 30 mL/kg/h (e.g., 2 L/h in a 70-kg patient) and hemodynamic stability is maintained, ionized Ca 2 + levels are preserved by physiologic compensatory mechanisms. Transient hypocalcemia may be observed with rapid transfusion and can be prolonged or exacerbated by hypothermia, renal failure, or hepatic failure. Consequently, ionized calcium should be monitored and replaced when clinically indicated during massive transfusion. However, hypocalcemia tends to normalize within 4 days after ICU admission, and failure to normalize in severely hypocalcemic patients may be associated with increased mortality. Calcium replacement does not typically improve normalization or reduce mortality.
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