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Hypocalcemia

Updated : August 30, 2023





Background

Calcium metabolism disorders are commonly observed in clinical practice, and although hypercalcemia is more prevalent than hypocalcemia, the latter can be fatal if not identified and treated promptly. Calcium homeostasis is regulated by various hormones and factors, including vitamin D, PTH, FGF23, and calcitonin.

The calcium concentration in the blood is tightly controlled, with around 40% being ionized, 45% bound to plasma proteins, and 15% bound to small anions such as citrate and phosphate. While most cases of hypocalcemia are acquired, some are inherited. The clinical presentation can range from no symptoms to life-threatening conditions.

Epidemiology

The occurrence of hypocalcemia in the general population is not well documented in the literature. However, studies have reported varying prevalences of transient and permanent hypocalcemia following thyroidectomy, ranging from 6.9% and 33%, respectively.

Despite the lack of data on the general population, certain medical conditions have been identified as common causes of hypocalcemia. Renal failure, for instance, is the most frequently cited cause of hypocalcemia. Vitamin D deficiency, magnesium deficiency, and acute pancreatitis are also recognized causes of this condition.

Hypocalcemia can also result from various other factors, including hypoalbuminemia, which can reduce the total calcium level in the blood, and certain medications, such as loop diuretics, which can increase urinary calcium excretion. Also, inherited disorders such as familial hypocalciuric hypercalcemia and pseudohypoparathyroidism may result in hypocalcemia.

Anatomy

Pathophysiology

Calcium plays a crucial role in various bodily functions, including cell function, bone structure, nerve transmission, intracellular signaling, and blood coagulation. The gastrointestinal tract absorbs calcium, which is usually balanced by renal excretion. The levels of calcium in the body are tightly regulated by several hormones, including parathyroid hormone, vitamin D, calcitonin, and FGF23. The parathyroid hormone increases the levels of calcium in the blood.

It stimulates osteoclastic bone resorption, which releases calcium into the bloodstream. Additionally, it enhances calcium reabsorption in the distal tubules of the kidneys, increasing calcium levels in the blood. PTH also promotes the renal excretion of phosphate, which helps to balance the levels of calcium and phosphate in the body. Vitamin D also plays a critical role in maintaining calcium homeostasis by enhancing the production of 1,25-dihydroxy vitamin D in response to low calcium levels in the bloodstream.

Calcitonin is another hormone that plays a crucial role in calcium homeostasis. It lowers calcium levels in the bloodstream by inhibiting osteoclast activity, reducing bone resorption and releasing calcium into the bloodstream. FGF23 inhibits the conversion of vitamin D to its active form, 1,25-dihydroxy vitamin D. This action helps to reduce intestinal calcium absorption, which is important for preventing hypercalcemia.

Acid-base disturbances affect calcium homeostasis by altering the binding capacity of calcium to albumin and by affecting the exchange of hydrogen ions and calcium between the intracellular and extracellular space. Acidosis reduces calcium binding to albumin, increasing ionized calcium levels. Conversely, alkalosis increases calcium binding to albumin, decreasing ionized calcium levels.

Etiology

Hypocalcemia occurs when the calcium level in the blood is lower than normal. It can be caused by various factors, including pregnancy, which can increase the demand for calcium stores in the body. In addition, hypocalcemia may result from massive blood transfusions, as well as acute pancreatitis, which can disrupt the normal functioning of the parathyroid gland.

Other potential causes of hypocalcemia include acute hyperphosphatemia, a condition in which the level of phosphorus in the blood is elevated, as well as imbalances in other electrolytes, such as magnesium. For example, hypermagnesemia and hypomagnesemia can affect the body’s ability to regulate calcium levels.

Sepsis, a severe and potentially life-threatening condition caused by an infection, can also contribute to hypocalcemia. In addition, certain medications can impact calcium levels in the body. Drugs such as denosumab, bisphosphonates, cinacalcet, cisplatin, and foscarnet may all increase the risk of developing hypocalcemia.

Genetics

Prognostic Factors

Hypocalcemia has a good prognosis because it can be readily treated. However, in exceptional instances, patients undergoing total parathyroidectomy may need substantial calcium and vitamin D supplements to sustain normal calcium levels.

Moreover, individuals who have had gastric bypass surgery often experience malabsorption and may also need significant calcium and vitamin D supplements to remedy hypocalcemia.

Clinical History

Clinical History

The severity of the symptoms depends on the degree and rate of development of the hypocalcemia and its chronicity. In some cases, patients with mild hypocalcemia may not experience any symptoms. A patient’s medical history may provide insight into the possible causes of hypocalcemia.

Some underlying medical conditions that can cause hypocalcemia include chronic kidney disease, hypoparathyroidism, vitamin D deficiency, malabsorption syndromes, and certain medications that can interfere with calcium absorption or metabolism.

Patients with hypocalcemia may experience a range of symptoms, including muscle cramps, twitching, spasms, numbness, tingling sensations in the fingers, toes, and face, fatigue, confusion, memory loss, depression, seizures, and even cardiac arrhythmias.

Physical Examination

Physical Examination

Hypocalcemia can present with various symptoms, including psychiatric manifestations such as depression, anxiety, or emotional lability. Additionally, hypocalcemia can cause Trousseau’s sign, Chvostek’s sign, which causes ipsilateral contraction of the facial muscles when the facial nerve is tapped in front of the ear.

Prolonged QTc interval can also occur in hypocalcemia and may lead to Torsades de pointes, which can be fatal, although extremely rare. It is essential to determine the underlying cause of hypocalcemia by conducting a thorough physical exam to identify potential risk factors such as a family history of similar problems, recent head and neck surgery, kidney disease, alcohol abuse (hypomagnesemia), and psychiatric history.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential Diagnoses

Acute renal failure

Hypomagnesemia

Hyperphosphatemia

Hypoparathyroidism

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

When patients have severe symptoms, experience acute hypocalcemia in a shorter period, or prolonged QTC intervals, intravenous (IV) calcium is recommended. Calcium gluconate, calcium chloride should be administered as a short infusion lasting 20 minutes. If hypocalcemia persists, a continuous infusion should be administered. Calcium gluconate is desired over calcium chloride because it has less potential to induce tissue necrosis if extravasation occurs.

It is important to avoid administering alkaline solutions such as phosphorus and bicarbonate-containing solutions through the same IV to control the precipitation of calcium salts. If patients show only mild symptoms like abnormal sensations (paresthesias) or no symptoms, they can be treated with oral calcium. The two commonly used forms of calcium are calcium carbonate and calcium citrate. The objective is administering elemental calcium daily, divided into two to three doses.

However, it is essential to note that calcium carbonate requires an acidic medium to be absorbed, so it should not be used in patients taking proton pump inhibitors (PPI). It is often advised to supplement calcium with vitamin D to improve absorption and counteract vitamin D deficiency, which is frequently associated with hypocalcemia in most clinical situations.

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Medication

 

calcium carbonate

500 - 1500

mg

Tablet

Orally 

twice a day



calcitriol 

Indicate for Chronic Renal Dialysis Associated Hypocalcemia:


Intravenous:
Initial dose:1-2mcg intravenous three times per a week
Adjust the dose every two to four weeks
Maintenance dose: 0.5-4mcg intravenous three times per a week

Oral
0.25mcg orally every day, increase the dose by 0.5-1mcg/day every 4-8 weeks



calcium gluconate 

For management of the mild Ca condition
1-3 gm each day orally in divided doses
1-2 gm intravenously for 2 hours
For the management of the severe Ca condition
Without tetany or seizures, 0.5 mg/kg/hr intravenously
Maintain the dose at 2 mg/kg/hr
Do not exceed more than 3-4 g intravenously for 4 hours

Hypocalcemic tetany- 100-300 mg elemental calcium, which is equivalent to 3 g calcium gluconate intravenously for 5-10 minutes, followed by continuous intravenous infusion at 0.5 mg/kg/hr
May increase to 2 mg/kg/hr
Monitor the levels of serum calcium every 4-6 hours to maintain the levels



calcium chloride 

Indicated for emergency treatment of hypocalcemia
500-1000 mg intravenously for 5-10 minutes
Repeat if required



calcium glubionate 

oral intake of 15 mL three times daily, preferably before meals
It is important to note that each 5 mL of the medication supplies 115 mg of elemental calcium
In addition to the calcium supplementation, treatment may also involve the oral administration of vitamin D



calcium glucoheptonate 

5-20 mL is slowly administered Intravenously once a day, which is less than 2 mL/min. The dose can be repeated for every 1-3 days as required or 2-5 mL is administered Intramuscularly once a day. The dose can be repeated for every 1-3 days as required



calcium levulinate 

Administration of phosphate & calcium carbonate:
In vivo data suggests taking oral tablets after meals for a duration of 1-5.5 hours or as advised by the medical practitioner
For adolescents & adults
The suggested dose is 800 mg to 1200 mg orally daily
For pregnancy & nursing women
The suggested dose is 1200 mg orally daily



chromium gluconate 

12-18 years: 10mmol given every 6 hours a day, then adjusted based on the response
5-12 years: 0.2mmol/kg given every 6 hours a day, then adjusted based on the response
1 month-5 years: 0.25mmol/kg given every 6 hours a day, then adjusted based on the response
Neonates: 0.25mmol/kg given every 6 hours a day, then adjusted based on the response



calcium lactate 

Before meals, take 325 to 650 mg orally two to three times a day



 

calcitriol 

Indicated for Chronic Renal Dialysis Associated Hypocalcemia:


0.25-2mcg/day orally every day



calcium gluconate 

For mild condition
In neonates- 500-1500 mg/kg orally divided every 4-6 hours each day
In infants and children- 500-725 mg/kg orally divided every 6-8 hours each day
For severe condition
In neonates, 200-800 mg/kg intravenously each day through continuous infusion or divided every 6 hours as intermittent infusions
For infants or children, 200-500 mg/kg intravenously each day through continuous infusion or divided every 6 hours as intermittent infusions
Hypocalcemic tetany
100-200 mg/kg intravenously every 10 minutes
It may be repeated 6 hours later or start over continuous infusion
Do not exceed 500 mg/kg each day



calcium chloride 

Indicated for the emergency treatment of hypocalcemia
For Infants: <75 mg of calcium chloride that includes 20 mg of elemental calcium intravenously
Repeat the dose as required
For children: 75-519 mg of calcium chloride that includes 20-140 mg elemental calcium intravenously
Repeat the dose as required



calcium glubionate 

Neonatal
Oral:
The recommended adequate intake (AI) for elemental calcium is 200 mg per day
It is important to note that individual requirements may differ based on factors such as prematurity, postnatal age, and other clinical consideration
Close monitoring of serum calcium concentrations is advised to determine the precise needs of each patient
The recommended dosage for elemental calcium is 50 to 150 mg/kg/day, administered in four to six doses divided
The daily dose should not exceed more than 1 grams
For calcium glubionate, the recommended dosage is 1200 mg/kg/day, also given in four to six dose divided
Dosing
Usual Oral
Adequate intake
for first to six months-Administer the dosage of 200 mg/day
for seven to twelve months- Administer the dosage of 260 mg/day
Recommended daily allowance
for Age one to three years- Administer the dosage of 700 mg/day
for Age four to eight years- Administer the dosage of 1000 mg/day
for Age nine to eighteen years- Administer the dosage of 1300 mg/day
Dietary supplement
Dosage based on product containing-(1.8 g calcium glubionate/5 mL) Infants (less than 12 months):
The recommended dosage for infants below the age of 12 months is one teaspoonful to be administered five times a day
It is permissible to mix the medication with juice or formula to facilitate administration
Children (less than four years)- The recommended dosage is two teaspoonfuls to be administered three times daily
Children (four years and older) and Adolescents:
The recommended dosage is one tablespoonful to be administered three times daily
Hypocalcemia Expressed in (mg) of elemental calcium:
Dosage Recommendation for Children:
The recommended dosage for children is 45 to 65 mg/kg/day, administered in four equally divided doses throughout the day
Expressed in (mg) of calcium glubionate
Dosage for infants and children should be administered at a range of 600 to 2000 mg/kg/day, divided into four equal doses
The daily dose should not exceed more than 9 grams
Daily maintenance calcium: (IV) For infants and children weighing less than 25 kg, The recommended dosage is 1 to 2 mEq/kg/day
In the case of children weighing between 25 and 45 kg, The dosage range is 0.5 to 1.5 mEq/kg/day
For children weighing over 45 kg and adults, the recommended dosage is either 10 to 20 mEq/kg/day or 0.2 to 0.3 mEq/kg/day



calcium glucoheptonate 

1-2.5 mL is administered Intravenously once a day



calcium lactate 

The recommended daily intake of elemental calcium is between 50 and 150 mg/kg divided into four to six doses, with a daily maximum of 1 g.
Calcium lactate dosage, measured in milligrammes (mg): Administer 400–500 mg/kg/day, divided every 4 to 6 hours.



calcium lactate 

Children
The elemental calcium dose, measured in mg: Administer 45 to 65 mg/kg per day, divided into four doses
Calcium lactate dose, measured in mg:
Infants: divided every four to six hours, administer 400 to 500 mg/kg each day.
Children: Administer 500 mg/kg/day, divided into 6-to-8-hour intervals; 9 g is the maximum daily dosage.



 

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References

Hypocalcemia

Updated : August 30, 2023




Calcium metabolism disorders are commonly observed in clinical practice, and although hypercalcemia is more prevalent than hypocalcemia, the latter can be fatal if not identified and treated promptly. Calcium homeostasis is regulated by various hormones and factors, including vitamin D, PTH, FGF23, and calcitonin.

The calcium concentration in the blood is tightly controlled, with around 40% being ionized, 45% bound to plasma proteins, and 15% bound to small anions such as citrate and phosphate. While most cases of hypocalcemia are acquired, some are inherited. The clinical presentation can range from no symptoms to life-threatening conditions.

The occurrence of hypocalcemia in the general population is not well documented in the literature. However, studies have reported varying prevalences of transient and permanent hypocalcemia following thyroidectomy, ranging from 6.9% and 33%, respectively.

Despite the lack of data on the general population, certain medical conditions have been identified as common causes of hypocalcemia. Renal failure, for instance, is the most frequently cited cause of hypocalcemia. Vitamin D deficiency, magnesium deficiency, and acute pancreatitis are also recognized causes of this condition.

Hypocalcemia can also result from various other factors, including hypoalbuminemia, which can reduce the total calcium level in the blood, and certain medications, such as loop diuretics, which can increase urinary calcium excretion. Also, inherited disorders such as familial hypocalciuric hypercalcemia and pseudohypoparathyroidism may result in hypocalcemia.

Calcium plays a crucial role in various bodily functions, including cell function, bone structure, nerve transmission, intracellular signaling, and blood coagulation. The gastrointestinal tract absorbs calcium, which is usually balanced by renal excretion. The levels of calcium in the body are tightly regulated by several hormones, including parathyroid hormone, vitamin D, calcitonin, and FGF23. The parathyroid hormone increases the levels of calcium in the blood.

It stimulates osteoclastic bone resorption, which releases calcium into the bloodstream. Additionally, it enhances calcium reabsorption in the distal tubules of the kidneys, increasing calcium levels in the blood. PTH also promotes the renal excretion of phosphate, which helps to balance the levels of calcium and phosphate in the body. Vitamin D also plays a critical role in maintaining calcium homeostasis by enhancing the production of 1,25-dihydroxy vitamin D in response to low calcium levels in the bloodstream.

Calcitonin is another hormone that plays a crucial role in calcium homeostasis. It lowers calcium levels in the bloodstream by inhibiting osteoclast activity, reducing bone resorption and releasing calcium into the bloodstream. FGF23 inhibits the conversion of vitamin D to its active form, 1,25-dihydroxy vitamin D. This action helps to reduce intestinal calcium absorption, which is important for preventing hypercalcemia.

Acid-base disturbances affect calcium homeostasis by altering the binding capacity of calcium to albumin and by affecting the exchange of hydrogen ions and calcium between the intracellular and extracellular space. Acidosis reduces calcium binding to albumin, increasing ionized calcium levels. Conversely, alkalosis increases calcium binding to albumin, decreasing ionized calcium levels.

Hypocalcemia occurs when the calcium level in the blood is lower than normal. It can be caused by various factors, including pregnancy, which can increase the demand for calcium stores in the body. In addition, hypocalcemia may result from massive blood transfusions, as well as acute pancreatitis, which can disrupt the normal functioning of the parathyroid gland.

Other potential causes of hypocalcemia include acute hyperphosphatemia, a condition in which the level of phosphorus in the blood is elevated, as well as imbalances in other electrolytes, such as magnesium. For example, hypermagnesemia and hypomagnesemia can affect the body’s ability to regulate calcium levels.

Sepsis, a severe and potentially life-threatening condition caused by an infection, can also contribute to hypocalcemia. In addition, certain medications can impact calcium levels in the body. Drugs such as denosumab, bisphosphonates, cinacalcet, cisplatin, and foscarnet may all increase the risk of developing hypocalcemia.

Hypocalcemia has a good prognosis because it can be readily treated. However, in exceptional instances, patients undergoing total parathyroidectomy may need substantial calcium and vitamin D supplements to sustain normal calcium levels.

Moreover, individuals who have had gastric bypass surgery often experience malabsorption and may also need significant calcium and vitamin D supplements to remedy hypocalcemia.

Clinical History

The severity of the symptoms depends on the degree and rate of development of the hypocalcemia and its chronicity. In some cases, patients with mild hypocalcemia may not experience any symptoms. A patient’s medical history may provide insight into the possible causes of hypocalcemia.

Some underlying medical conditions that can cause hypocalcemia include chronic kidney disease, hypoparathyroidism, vitamin D deficiency, malabsorption syndromes, and certain medications that can interfere with calcium absorption or metabolism.

Patients with hypocalcemia may experience a range of symptoms, including muscle cramps, twitching, spasms, numbness, tingling sensations in the fingers, toes, and face, fatigue, confusion, memory loss, depression, seizures, and even cardiac arrhythmias.

Physical Examination

Hypocalcemia can present with various symptoms, including psychiatric manifestations such as depression, anxiety, or emotional lability. Additionally, hypocalcemia can cause Trousseau’s sign, Chvostek’s sign, which causes ipsilateral contraction of the facial muscles when the facial nerve is tapped in front of the ear.

Prolonged QTc interval can also occur in hypocalcemia and may lead to Torsades de pointes, which can be fatal, although extremely rare. It is essential to determine the underlying cause of hypocalcemia by conducting a thorough physical exam to identify potential risk factors such as a family history of similar problems, recent head and neck surgery, kidney disease, alcohol abuse (hypomagnesemia), and psychiatric history.

Differential Diagnoses

Acute renal failure

Hypomagnesemia

Hyperphosphatemia

Hypoparathyroidism

When patients have severe symptoms, experience acute hypocalcemia in a shorter period, or prolonged QTC intervals, intravenous (IV) calcium is recommended. Calcium gluconate, calcium chloride should be administered as a short infusion lasting 20 minutes. If hypocalcemia persists, a continuous infusion should be administered. Calcium gluconate is desired over calcium chloride because it has less potential to induce tissue necrosis if extravasation occurs.

It is important to avoid administering alkaline solutions such as phosphorus and bicarbonate-containing solutions through the same IV to control the precipitation of calcium salts. If patients show only mild symptoms like abnormal sensations (paresthesias) or no symptoms, they can be treated with oral calcium. The two commonly used forms of calcium are calcium carbonate and calcium citrate. The objective is administering elemental calcium daily, divided into two to three doses.

However, it is essential to note that calcium carbonate requires an acidic medium to be absorbed, so it should not be used in patients taking proton pump inhibitors (PPI). It is often advised to supplement calcium with vitamin D to improve absorption and counteract vitamin D deficiency, which is frequently associated with hypocalcemia in most clinical situations.

calcium carbonate

500 - 1500

mg

Tablet

Orally 

twice a day



calcitriol 

Indicate for Chronic Renal Dialysis Associated Hypocalcemia:


Intravenous:
Initial dose:1-2mcg intravenous three times per a week
Adjust the dose every two to four weeks
Maintenance dose: 0.5-4mcg intravenous three times per a week

Oral
0.25mcg orally every day, increase the dose by 0.5-1mcg/day every 4-8 weeks