OVERVIEW: What every practitioner needs to know
Are you sure your patient has hypocalcemia or hypercalcemia? What are the typical findings for this disease?
Calcium is an important divalent cation required for many enzymatic and cellular functions. It is a critical component of bone ossification, and as one would expect, about 99% of total body calcium resides in skeletal tissue. Of the fraction found in plasma, about 40% of it is bound to protein, and 10% is complexed with anions. The remaining serum calcium is ionized and unbound. While serum ionized calcium represents only a very small fraction of total body calcium, it is also the most physiologically important form of calcium circulating in the body. Depending on age, normal serum ionized calcium levels range between 0.95 and 1.5 mmol/L (3.7 and 6mg/dL).
Several organ systems can be impacted by derangements of calcium homeostasis. Among its many functions, calcium plays a key role in cardiac pacemaking, muscle contraction, neuronal function, vascular tone, and hemostasis. Derangements in calcium homeostasis can cause both acute findings related to changes in serum ionized calcium levels as well as chronic findings related to prolonged calcium imbalances.
Typical findings in mild to moderate hypocalcemia can include:
-Paresthesias, especially in the perioral area and distal extremities
In more severe cases of hypocalcemia, findings can include:
-Laryngospasm and stridor
-Altered mental status
-Decreased myocardial contractility
-Prolonged QT interval
-Nonspecific ST and T wave changes
With prolonged hypocalcemia, findings can include:
-Dry and coarse skin
-Alopecia and brittle hair
-Dental enamel hypoplasia
-Radiographic and clinical findings of Rickets (rachitic rosary, epiphyseal widening, genu varum, osteopenia)
On physical exam, there are two specific findings commonly reported with clinically significant hypocalcemia:
-Chvostek sign: facial muscle contraction with tapping of facial nerve below zygomatic arch.
-Trousseau sign: carpopedal spasms with compression of arms or legs by blood pressure cuff.
Typical findings in hypercalcemia can include:
-Altered mental status
In more severe cases of hypercalcemia, findings can include:
-Lethargy and coma
-QT interval shortening
With prolonged hypercalcemia, findings can include:
-Failure to thrive and anorexia
-Peptic ulcer disease
-Calcium deposition in soft tissues
What caused this disease to develop at this time?
Evaluation of abnormal calcium levels may take into consideration the age of the patient as well as how the homeostatic processes of the body regulating calcium may be affected. There are two general categories of processes that can lead to imbalances in calcium homeostasis.
First, extracellular calcium is very tightly regulated by a complex series of hormonal actions through Vitamin D and parathyroid hormone (PTH). Therefore, a failure in any component of this system can lead to derangements in calcium levels. Chronic or subacute calcium derangements are often caused by this process. Secondly, since a large amount of extracellular calcium is complexed with proteins or anions, conditions that affect protein binding and chelation can also affect unbounded calcium levels. Acute hypocalcemia is more likely to be caused by this type of process.
Causes of Hypocalcemia:
Transient conditions specific to the neonate:
-Early neonatal hypocalcemia: A condition developing in the first 4 days of life. The exact pathogenesis is debated in the medical literature, but is thought to be related to immature vitamin D pathways and peripheral resistance to parathyroid hormones. Risk factors for early neonatal hypocalcemia include prematurity, low birth weight and birth asphyxia. This process is typically transient and often does not cause clinical symptoms.
-Maternal diabetes mellitus: Generally occurs within the first 3 days after birth. Uncontrolled maternal hyperglycemia can lead to neonatal suppression of PTH with increased calcitonin activity. Nearly half of infants born to mothers with diabetes will have some degree of hypocalcemia, although good glycemic control during pregnancy does decrease the risk.
-Maternal hyperparathyroidism: Generally occurs within the first 3 days after birth. Hypercalcemia in mothers due to hyperparathyroidism results in neonatal suppression of PTH. After birth, the neonate can develop profound and clinically significant hypocalcemia that can last for several weeks.
-Transient late neonatal hypocalcemia: Typically occurs beyond 72hrs after birth. Is thought to be related to the immature response of the kidney to PTH in premature neonates.
Conditions related to PTH:
PTH is produced by the chief cells of the parathyroid gland. PTH binds to receptors in both bone and kidney tissues, and leads to the release of phosphate and calcium from bone tissue, while promoting calcium reabsorption with phosphate excretion in the kidney. PTH also promotes the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D at the kidneys. Conditions listed below cause hypocalcemia via either low PTH levels or end-organ resistance to PTH effects:
Impaired secretion of parathyroid hormone: A variety of genetic, congenital and acquired conditions can result in decreased PTH production, and include:
Congenital agenesis of the parathyroid gland
Acute renal failure
PTH gene mutations
Autoimmune polyglandular syndrome type 1
Iatrogenic surgical destruction
Calcium-sensing receptor mutations
SIRS and cytokine release
End organ resistance to PTH (pseudohypoparathyroidism): Includes a set of genetic conditions with impaired response to PTH occurs in the bone and kidneys. The common features include hypocalcemia, hyperphosphatemia, and elevated PTH.
Conditions related to impaired Vitamin D function:
-1,25-dihydroxyvitamin D acts directly on nuclear receptors to increase absorption of calcium and phosphate in the intestine. It also acts in some part on the kidneys to decrease excretion of calcium and phosphate. Vitamin D is obtained in the body through both nutritional intake as well as production through sunlight driven processes in the skin. Vitamin D then undergoes conversion to 25-hydroxyvitamin D in the liver, and later conversion to 1,25-dihydroxyvitamin D in the kidneys.
-Inadequate intake or absorption of vitamin D: A variety of conditions carry an increased risk of impaired vitamin D intake or absorption. Infants who are exclusively breast-fed may not receive sufficient vitamin D intake. Patients who have undergone gastrectomy or small bowel surgery may not be able to properly absorb vitamin D. Celiac disease and Inflammatory bowel disease may also decrease vitamin D absorption. Patients with cystic fibrosis and resultant pancreatic insufficiency also have impaired absorption of fat-soluble vitamins.
-Increased catabolism: A variety of drugs can lead to the increased metabolism of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to inactive forms via the induced P-450 activity. These include phenobarbital, phenytoin, carbamazepine, isoniazid, theophylline and rifampin.
-Decreased hydroxylation of precursors: Both renal and liver disease can impair key metabolic pathways that lead to the final production of 1,25-dihydroxyvitamin D.
-Vitamin D resistance: There are a few genetic conditions that lead to impaired tissue response to 1,25-dihydroxyvitamin D. This condition manifests as that of classic type 1 vitamin D-dependant rickets, however, with elevated serum concentrations of 1,25-dihydroxyvitamin D.
Conditions related to protein binding or chelation:
-Hyperphosphatemia: Cellular destruction and release of phosphate can chelate circulating calcium and lead to clinically significant hypocalcemia. Conditions that can cause this process include tumor lysis syndrome, crush injuries, and rhabdomyolysis. Intravenous phosphate replacements may also lead to chelation of calcium.
-Blood transfusions: Citrate, a common preservative in blood products is known to chelate calcium. This is typically not clinically significant unless there has been exposure to large volumes of blood products.
-Pancreatitis: Free fatty acid release during pancreatitis can lead to calcium chelation.
-Alkalinization of blood: Increases calcium binding to protein.
Causes of Hypercalcemia:
Causes for hypercalcemia are more difficult to categorize by underlying mechanism but a variety of disease states can cause hypercalcemia:
-Transient neonatal hyperparathyroidism.
-Excessive calcium intake.
-Milk-alkali syndrome: Ingestion of high amounts of milk and antacids, or more recently calcium carbonate supplementations leads to a combination of hypercalcemia and metabolic alkalosis. The metabolic alkalosis exacerbates hypercalcemia by stimulating resorption of calcium at the kidneys.
-Hyperparathyroidism: Calcium-sensing receptor mutations; multiple endocrine neoplasias types 1 and 2a; Parathyroid adenoma; Lithium toxicity; Renal failure.
-Vitamin D intoxication.
-Hypercalcemia of malignancy: Several childhood malignancies and tumors can lead to this condition.
-Increased bone resorption: Thyrotoxicosis; Vitamin A intoxication; Primary and metastatic tumors; Immobilization.
-Subcutaneous fat necrosis.
-Sarcoidosis and other granulomatous diseases.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Evaluation of hypocalcemia and hypercalcemia should include analysis of total serum calcium and ionized calcium levels.
Ionized calcium is physiologically the most important form of calcium in the body.
Total serum calcium levels are affected by the levels of serum proteins that can bind calcium. The most important is albumin. Therefore a total calcium level may be low due to hypoalbuminemia, however the physiologically important ionized calcium level may be normal. Total serum calcium levels should be corrected based on the total albumin level. For every 1g/dL decrease in albumin, there will likely be a 0.8mg/dL decrease in total serum calcium.
Other studies that may be useful include:
Serum phosphorus level
Serum magnesium level
BUN and creatinine levels
Alkaline phosphatase level
1,25-dihydroxyvitamin D level
25-hydroxyvitamin D level
Spot urine calcium, phosphorus and creatinine levels
If you are able to confirm that the patient has hypocalcemia or hypercalcemia, what treatment should be initiated?
For symptomatic patients:
May administer 100-200mg/Kg of calcium gluconate up to 1-3g maximum in adults IV over 10-20 minutes.
For patients with central access and when there is evidence of liver dysfunction, may use calcium chloride 10-20mg/kg up to 1g in adults IV over 5-10 minutes.
Cardiorespiratory monitoring should be performed during intravenous replacement of calcium.
Continue to repeat as necessary to normalize ionized serum calcium. Repeat ionized serum calcium levels after each dose.
For refractory and symptomatic hypocalcemia, may initiate continuous infusion of calcium gluconate at 10-30mg/kg/hr.
For patients who are asymptomatic:
Significant hyperphosphatemia should be evaluated for and treated first as a combination of high calcium and phosphate levels may lead to soft tissue calcification. The product of serum calcium and serum phosphorus should be less than 80.
May begin enteral supplementation starting at 50mg/kg/dy of elemental calcium divided into 3 to 4 doses.
For all patients, evaluation and treatment of potential underlying causes should be done:
Correct any respiratory alkalosis
Evaluate and treat for hypomagnesemia
Evaluate for vitamin D deficiency and treat appropriately:
Children with nutritional rickets: 1000-5000 IU vitamin D daily.
If there is concern for poor medication compliance, may give one time dose of 600,000 IU vitamin D.
If there is concern for malabsorption, may consider 25,000-50,000 IU vitamin D daily.
For patients with rickets type 1, hypoparathyroidism, pseudohypoparathyroidism and renal failure, may give calcitriol (1,25 dihydroxyvitamin D) 0.01-0.08 micrograms/k/dy up to 0.25-1.0 micrograms/dy.
If hypercalcemia is mild (total serum calcium level <15mg/dl):
General management is limited to restricting calcium from diet and ensuring adequate hydration and voiding.
Total serum calcium levels that are greater than 15mg/dl can be a medical emergency with potential hemodynamic and neurologic compromise. Treatment should be initiated immediately.
Administer IV fluid boluses of isotonic fluids to restore intravascular volume.
Provide ongoing hydration with isotonic fluids (200-250ml/kg/dy) to ensure adequate urine output.
Administer lasix 1mg/kg (10-20mg max) every 6 hrs to help with renal calcium excretion.
For severe refractory hypercalcemia, calcitonin and bisphosphonate may be considered in consultation with an endocrinologist.
For severe cases refractory to medications, hemodialysis should be considered.
What are the adverse effects associated with each treatment option?
Both intravenous calcium chloride and calcium gluconate can cause extensive tissue necrosis if there is extravasation at the IV site. Ideally, calcium replacements should always be given centrally. Calcium gluconate should be used if replacements must be given peripherally.
Intravenous calcium replacements should be given slowly, since rapid infusions can cause bradycardia and asystole.
Volume overload and pulmonary edema may develop with overly aggressive fluid management.
Furosemide may cause substantial depletion of sodium, potassium and magnesium through renal loss. Furosemide can also lead to a metabolic alkalosis.
What is the evidence?
Aune, GJ, Custer, Rau. “Fluids and electrolytes”. (A brief practical approach to the identification and management of calcium disorders in children.)
Allen, DB, Hagen, SA, Carrel, AL, Furhman, Zimmerman. “Disorders of the Endocrine System Relevant to Pediatric Critical Illness”. 2006. (Includes a comprehensive differential diagnosis of the congenital and acquired causes of calcium disorders in children.)
Banasiak, KJ, Carpenter, TO, Nichols, DG. “Disorders of Calcium, Magnesium, and Phosphate”. (A general overview and comprehensive review of acute causes and management of calcium, magnesium, and phosphate in the acutely ill child.)
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has hypocalcemia or hypercalcemia? What are the typical findings for this disease?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- If you are able to confirm that the patient has hypocalcemia or hypercalcemia, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What is the evidence?