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.^3–5 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.^6–8 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

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

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,^1,3,5 but the presence of hypomagnesemia only weakly correlates with hypocalcemia in ICU patients.⁴

In many instances, the hypocalcemia of critical illness is multifactorial in etiology. Elderly patients are at increased risk for vitamin D deficiency due to malnutrition, poor absorption, and hepatic or renal dysfunction.³ Renal failure may precipitate hypocalcemia via decreased formation of calcitriol. Renal failure also can be associated with hyperphosphatemia, and phosphate anion can chelate ionized calcium.^1,3 The use of continuous renal replacement therapy in critically ill patients is associated with significant magnesium and calcium losses. These losses of divalent cations result in electrolyte replacement requirements that commonly exceed the calcium and magnesium supplementation provided in standard parenteral nutrition formulas.¹³ Other potential causes of ionized hypocalcemia in critically ill patients include alkalosis (increased binding of Ca²⁺ to albumin), medications (anticonvulsants, antibiotics, diphosphonates, and radiocontrast agents), massive blood transfusion, sepsis, and pancreatitis.^1,3–5 More recently, propofol—particularly when given in large doses—has been shown to reduce circulating calcium concentrations by elevating serum PTH levels, but the physiologic significance of this pharmacologic side effect is unclear.¹⁴

Ionized hypocalcemia (<1.0 mmol/L) is associated with prehospital hypotension and represents a better predictor of mortality in severely injured patients than base deficit.¹⁵ The exact reasons for the strong association between ionized hypocalcemia and mortality 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 Ca²⁺ chelation by citrate, which is used as an anticoagulant in banked blood.^16–18 The incidence of transfusion-related hypocalcemia is related to both the rate and volume of blood transfusion.^16,17 When blood transfusions are administered at a rate of 30 mL/kg/h (2 L/h in a 70-kg patient) and hemodynamic stability is maintained, ionized Ca²⁺ levels are preserved by physiologic compensatory mechanisms.¹⁸ Transient hypocalcemia may be observed with rapid transfusion and can be prolonged or exacerbated by hypothermia as well as renal or hepatic failure.^16–18 Consequently, ionized calcium should be monitored and replaced when clinically indicated during massive transfusion.

Hypocalcemia in Sepsis and Pancreatitis

Hypocalcemia is especially common in critically ill patients with systemic infection and pancreatitis.^1,3,4,7,11 Animal models of sepsis demonstrate reductions in serum calcium concentration following endotoxin infusion.^7,11,19,20 When septic patients with hypocalcemia were compared with nonseptic controls, increased TNF and interleukin (IL)-6 levels correlated with ionized hypocalcemia.²¹ Septic patients with hypocalcemia may demonstrate increased or decreased PTH levels, but urinary excretion of calcium and bone resorption appear to be preserved when compared to controls.^11,19 Procalcitonin levels appear to be increased during sepsis-induced hypocalcemia, but mature calcitonin only exerts a weak and transient effect on calcium levels.^21,22 Collectively, the results suggest that hypocalcemia during severe infection is multifactorial in etiology but that inflammatory cytokines, impaired activation of vitamin D, and elevated procalcitonin levels are contributory.

It remains unclear whether sepsis-induced hypocalcemia is pathologic or protective. Calcium administration in experimental sepsis has been shown to increase or have no effect on mortality.^19,20 In fact, a recent Cochrane review found no evidence that parenteral calcium supplementation influences the outcome of critically ill patients.²³ Similarly, investigations of the effects of Ca²⁺ blockade on septic mortality demonstrate conflicting results.^21–24 Therefore, although sepsis-induced hypocalcemia is commonly seen in critically ill patients, neither routine replacement of calcium nor the use of calcium channel blockers are supported by the existing literature. As with most situations, sepsis-induced hypocalcemia should be treated if patients are symptomatic.

Pancreatitis represents another inflammatory condition associated with hypocalcemia in critically ill patients.^1,3,24,25 Saponification of retroperitoneal fat contributes to the development of hypocalcemia in this patient population.^3,24,25 In experimental pancreatitis, injection of free fatty acids into the peritoneum induced hypocalcemia in rats.²⁴ However, the amount of calcium chelated is relatively small compared to available calcium stores for exchange from the bone reservoir. Interestingly, elevated levels of PTH seen in pancreatitis, like sepsis, do not result in normalized ionized calcium levels.^24–26 Resistance of bone and kidney to PTH may be a factor, but it is likely that inflammatory pathways identical to those in sepsis are responsible. In pancreatitis, as in sepsis, hypocalcemia is an indicator of disease severity. As with most clinical conditions, calcium replacement during pancreatitis should be reserved for the symptomatic or hemodynamically unstable patient.

Signs and Symptoms of Hypocalcemia

Hypocalcemia is frequently asymptomatic, and attributable signs or symptoms may be difficult to elucidate in critically ill patients. In general, the signs and symptoms of hypocalcemia correlate with both the magnitude and rapidity of onset of the condition. Neurologic (paresthesias, seizures, dementia) and cardiovascular (hypotension, impaired cardiac contractility, dysrhythmias) signs may be seen with ionized hypocalcemia (Ca²⁺ <1.0 mmol/L).^3,5 Neuromuscular symptoms of hypocalcemia include muscle spasms and tetany when severe. Psychiatric disturbances (dementia, psychosis, depression) also may be due to hypocalcemia.^3,5

Classic signs of hypocalcemia include the Chvostek and Trousseau signs, which test for latent tetany. The Chvostek sign is an involuntary twitching of facial muscles in response to light tapping of the facial nerve. It is nonspecific, present in 10% to 25% of normal adults, and may be completely absent in chronic hypocalcemia. Trousseau sign is carpopedal spasm induced by reduced blood flow to the hand in the presence of hypocalcemia; it is elicited by inflating a blood pressure (BP) cuff to a level 20 mm Hg higher than the systolic BP for 3 minutes. Trousseau sign is also nonspecific and may be absent in a third of patients with hypocalcemia.

Cardiac dysrhythmias such as ventricular tachycardia, prolonged QT interval, and heart block are more serious complications of hypocalcemia.^3,5 In addition, decreased cardiac output and hypotension, especially where refractory to inotropic agents and/or intravascular volume loading, should prompt calcium replacement when hypocalcemia is present.^3,5

Treatment of Hypocalcemia

Critical thresholds for calcium replacement vary, but severe ionized hypocalcemia below 0.8 mmol/L and symptomatic hypocalcemia should be treated in critically ill patients.^1,3,5 Calcium treatment of asymptomatic ionized hypocalcemia above 0.8 mmol/L is usually unnecessary and potentially may be harmful in conditions like sepsis and cellular hypoxia.^1,3,5,26

Treatment of hypocalcemia requires intravenous calcium replacement. The two solutions most commonly used are 10% calcium chloride and 10% calcium gluconate. Each solution contains 100 mg/mL of calcium salt and is provided in 10-mL ampules. 10% calcium chloride contains 27 mg of elemental calcium (1.36 mEq)/mL; 10% calcium gluconate contains 9 mg (0.46 mEq)/mL. Typically, 10 mL of 10% calcium gluconate solution is infused over 10 minutes. A total of 200 mg of elemental calcium may be necessary to raise the total serum calcium by 1 mg/dL. Since the effect of calcium infusion is usually brief, a continuous infusion may be necessary. Calcium chloride should not be infused peripherally if calcium gluconate is available, since the former can produce tissue necrosis and thrombophlebitis if extravasation occurs.

Hemodynamically unstable patients in the ICU who are hypocalcemic may show a transient increase in BP and/or cardiac output with calcium administration. This is probably due to increased cardiac performance.²⁶ However, in the presence of tissue hypoxia, calcium administration may aggravate the cellular injury.^9,22 Nonetheless, calcium administration is probably warranted in hypocalcemic, hemodynamically unstable patients, especially those requiring adrenergic support.

Hypercalcemia

Hypercalcemia is rare in critically ill patients, estimated to be present in between 1% and 15% of ICU patients.² Defined as an increase in serum calcium concentration to above 10.4 mg/dL (2.60 mmol/L), hypercalcemia usually is caused by excessive bone resorption. Hyperparathyroidism and humoral hypercalcemia of malignancy are the most common causes of hypercalcemia in hospitalized patients.^2,5,27 Less common causes of hypercalcemia include sarcoidosis, prolonged immobilization, and medications like thiazide diuretics.

Mild hypercalcemia is usually asymptomatic. However, patients with circulating Ca²⁺ levels above 12 mg/dL may manifest symptoms of confusion, delirium, psychosis, and coma.^2,5,27 Patients with hypercalcemia may also experience nausea, vomiting, constipation, abdominal pain, and ileus. Cardiovascular effects of hypercalcemia include hypotension, hypovolemia, and shortened QT interval. Profound skeletal muscle weakness may result. Seizures, however, are rare.

Treatment of hypercalcemia should be directed at the underlying medical condition. Saline infusion and diuresis is indicated in symptomatic patients and when the serum calcium level rises above 14 mg/dL (3.5 mmol/L). For patients with underlying malignancy, treatment with salmon calcitonin, pamidronate, or plicamycin may be necessary. These agents act to inhibit bone resorption. Hydrocortisone can also be used in combination with calcitonin to treat hypercalcemia associated with multiple myeloma.