Introduction

Calcium is an essential cofactor for numerous enzymatic reactions and is an essential cation for muscle function. Hypocalcemia is a major, potentially life-threatening complication following thyroid and parathyroid surgery. Hypocalcemia is defined as total serum calcium levels below the normal range (generally 8.5 to 10.5 mg/dL). However, defining hypocalcemia by the total calcium value assumes that the several forms of circulating calcium are in the usual proportions. Under these circumstances, the physiologically active form of calcium, namely ionized calcium, is represented accurately by the total calcium measurement. The ionized calcium consists of approximately 50% of the total plasma calcium: 40% of plasma calcium is bound to plasma proteins, mostly albumin, and 10% is complexed with anions such as bicarbonate, sulfate, phosphate, lactate, and citrate. A reduced albumin concentration will lower the total calcium concentration without affecting the ionized calcium concentration and, thus, be associated with signs or symptoms of hypocalcemia. Under these circumstances, the total calcium measurement does not accurately reflect the ionized fraction and a correction factor is applied. For every g/dL the albumin is below a standardized value, 4 g/L, the total calcium is adjusted upward by 0.8 mg/dL. To circumvent this calculation, the ionized calcium can be measured directly, but it requires special handling and a calibrated ionized calcium electrode. Most laboratories are not equipped on a routine basis to measure the ionized calcium directly; thus the corrected calcium concentration is more frequently determined. Magnesium levels also play a critical role in this discussion because this cation is required for normal secretion of parathyroid hormone (PTH). When low, PTH secretion is inhibited. Such patients can present with the biochemical abnormalities of hypoparathyroidism, namely hypocalcemia and undetectable levels of PTH. In addition, hypomagnesemia is associated with peripheral resistance to renal and skeletal actions of PTH. Measuring serum magnesium levels and replacing magnesium to normal levels if low (greater than 1.7 mg/dL) is a critical component in the treatment of hypocalcemic patients.

Calcium levels are normally regulated by a feedback mechanism whereby PTH is secreted in response to low calcium levels, which stimulates the kidney to reabsorb calcium, activate vitamin D to promote intestinal absorption of dietary calcium, and stimulate bone resorption of calcium. Conversely, but much less important from a physiologic point of view, calcitonin is secreted by thyroid C cells in response to high calcium levels stimulating bone deposition of calcium and reduced gastrointestinal and kidney resorption of calcium. More important is the response of the parathyroid axis to hypercalcemia in which PTH is immediately inhibited and those physiologic properties are reversed.

The mechanism behind a transient postoperative hypocalcemia following parathyroidectomy is the dysregulation of the calcium feedback loop due to long-standing hyperparathyroidism that may not immediately recover. Postoperative hypocalcemia after parathyroid surgery is typically transient. More prolonged hypocalcemia after parathyroid surgery can be due to “hungry bone syndrome.” This syndrome describes a period of rapid skeletal calcium accrual in patients who have preexisting parathyroid bone disease. The hypocalcemia associated with the hungry bone syndrome lasts as long as it takes for the skeletal system to replenish itself with calcium. It can take several days or months.

In their review of 1112 bilateral neck dissections over a 17-year period, Allendorf et al. reported transient hypocalcemia in 1.8% of patients. More recent data from the Collaborative Endocrine Surgery Quality Improvement Program (CESQIP) estimates postoperative hypocalcemia in primary hyperparathyroidism to be 10.5% after recurrent parathyroid surgery but only 2.4% after the initial operation. At its extreme, postoperative hypocalcemia can be permanent due to removal of all parathyroid tissue and/or sacrifice of its vascular supply. Permanent hypoparathyroidism is said to occur in 1.6% of patients who undergo neck surgery. ^,

As thyroid surgery is a more common procedure, transient or permanent hypoparathyroidism occurs more often than after parathyroid surgery. The etiology of postoperative hypocalcemia following thyroidectomy is due to “stunning” or ischemia to all four parathyroid glands or inadvertent removal or devascularization, or failed autotransplantation of parathyroid glands. With specific reference to thyroid surgery, transient hypoparathyroidism occurs in approximately 23% to 38% of patients undergoing total thyroidectomy, with about 7% to 14% requiring a long-term calcium supplementation. Permanent hypoparathyroidism was reported to be between 0.12% and 5.8%. ^{, ,} Risk factors for postoperative hypocalcemia after thyroid surgery include surgery for Graves’ disease, lymphocytic thyroiditis (Hashimoto’s thyroiditis), bilateral neck dissections, repeat operations, and surgery for malignancy as well as surgeon’s expertise and experience. ^{, , , ,} The experience of the surgeon has the most important role in the success of the surgery and lowering the rate of hypoparathyroidism after thyroidectomy or parathyroidectomy. Studies by Sosa et al. and Aspinall et al. demonstrated that a high-volume surgeon is the one who performs more than 50 parathyroidectomies and thyroidectomies per year.

Clinical Presentation

The classic symptom of hypocalcemia is neuromuscular irritability of both sensory and motor nerves. Hypocalcemia decreases the threshold for neuron firing, resulting in hyperexcitability and muscle spasm (tetany). Symptoms of neuronal hyperexcitability can range from relatively benign findings, such as paresthesia, numbness, tingling, and muscle spasms, to life-threatening tetany, namely cardiac bronchospasm, laryngospasm, and cardiac dysrhythmias. In order to prevent the development of life-threatening sequela of hypocalcemia, it is important to recognize and treat the milder and initial symptoms of hypocalcemia such as circumoral facial tingling and twitching, numbness, and tingling weakness of the hands and feet. If not corrected, these symptoms rapidly progress to muscle cramps and spasm in the extremities with lightheadedness, bradycardia, and seizures. Accompanying cognitive symptoms of confusion, anxiety, irritability, and hallucinations are also observed. Cardiovascular symptoms are also common in hypocalcemia, such as bradycardia, hypotension, and arrhythmias. Additional clinical presentations include seizures, papilledema, and psychiatric disturbances.

Physical Examination

Postoperative hypocalcemia can be detected on physical examination by seeing the manifestations of neuromuscular hyperexcitability, cardiovascular abnormalities, and psychiatric disturbances. Neuromuscular hyperexcitability often presents with the classic findings of Chvostek’s sign and Trousseau’s sign. Chvostek’s sign is performed by manually tapping the facial nerve about 2 cm anterior to the external auditory meatus. Ipsilateral twitching of the face results. Trousseau’s sign is elicited by inflating a blood pressure cuff slightly over the systolic pressure for 2 to 3 minutes. A positive result will be seen by carpal spasm, manifest by flexion of the wrist and metacarpophalangeal joints with adduction of thumb and fingers. Whereas Chvostek’s sign can be seen in as many as 10% of normocalcemic individuals, Trousseau’s sign is much more specific for hypocalcemia. Cardiovascular changes can be seen by hypotension and electrocardiographic (ECG) changes. The prolonged QT interval is the most classic sign by ECG but the ST segment can also be increased. Rarely, hypocalcemia can lead to torsades de pointes , a form of polymorphic ventricular tachycardia. Psychiatric disturbances can also be detected with irritability and depression. Rarely, psychosis is associated with hypocalcemia.

Diagnostic Tests

Although the history and physical examination can point toward postoperative hypocalcemia, the diagnosis is made mainly by detecting serum calcium levels that are below normal. Postoperative hypocalcemia can be diagnosed by serum calcium levels below 8.5 mg/dL; however, serum calcium levels must be interpreted appropriately. Serum calcium binds proteins within the blood, mainly albumin, and only ionized calcium within the blood contributes to physiologic activity. Serum calcium should be corrected for albumin levels with the formula: corrected calcium (Ca) = serum Ca level + [0.8 × (normal albumin – patient’s albumin)]. The normal albumin level is defaulted to 4 mg/dL Standard Units (40 g/L SI Units); therefore, the formula can be changed to that default value in the calculator: corrected Ca = serum Ca + 0.8 × (4 – serum albumin). Ionized calcium can be measured directly and is the most accurate level of calcium activity within the blood. Ionized calcium should be greater than 1.1 mmol/L (4.4 mg/dL). Hypocalcemia is often associated with hypomagnesemia, and magnesium levels should be checked and replaced to a level above 1.7 mEq/L. Measurement of serum PTH also should be included to confirm the diagnosis of acute postoperative hypoparathyroidism. The PTH level is actually a very important diagnostic element. If the patient is experiencing postoperative hypoparathyroidism, the PTH level will be low. If, however, the patient is experiencing the hungry bone syndrome (see earlier), their PTH level may actually be elevated, reflecting not hypoparathyroidism but a normal physiologic response to skeletal calcium demand.

Prevention of Postoperative Hypocalcemia

Prevention of postoperative hypocalcemia starts with preoperative patient counseling. Patients should be taught to recognize early signs and symptoms of hypocalcemia. In addition, the importance of medical adherence and compliance to calcium supplementation postoperatively should be stressed to prevent severe hypocalcemia and its potential for life-threatening symptoms. Patients are instructed to begin calcium supplementation while in recovery on the day of surgery and to continue at regular intervals even during the night. They are advised to notify their surgical team once hypocalcemic symptoms begin so that dose adjustments of oral calcium supplementation can be implemented prior to the development of more severe symptoms. Patients that are high risk for hypocalcemia following parathyroidectomy or thyroidectomy should be monitored more cautiously, with repeat laboratory testing within a few days of discharge to ensure supplementation with calcium is appropriate to avoid either under- or overdosing.

The most effective way to treat postoperative hypocalcemia is through preventative measures with prophylactic supplementation of calcium preoperatively and postoperatively, and operative strategies to preserve the parathyroid glands. Preoperative vitamin D levels, which should always be measured, will dictate whether vitamin D repletion should be given prior to surgery. Most experts recommend 25-hydroxyvitamin D levels greater than 30 ng/mL in patients with metabolic bone diseases such as primary hyperparathyroidism. ^, This recommendation is eminently reasonable, although it has not been clearly shown that low vitamin D levels contribute to postoperative hypocalcemia. ^, A preoperative supplementation strategy to reduce postoperative hypocalcemia includes vitamin D optimization preoperatively by aggressively replacing vitamin D deficiency if the 25-hydroxyvitamin D level is less than 20 ng/mL with 50,000 IU of oral ergocalciferol once per week for 8 weeks. ^, Vitamin D levels of 20 to 30 ng/mL can be treated less aggressively with 1000 IU of ergocalciferol per day from either dietary or supplementary sources. ^,

Intraoperative strategies to avoid postoperative hypocalcemia include measuring PTH levels intraoperatively during parathyroidectomy, careful parathyroid gland preservation during a thyroidectomy, and parathyroid gland autotransplantation in the event that postoperative hypoparathyroidism is a concern (e.g., glands are incidentally removed, devascularized, and appeared to be nonviable). Parathyroid gland devascularization during thyroid surgery can lead to post-thyroidectomy hypoparathyroidism. Parathyroid preservation surgical techniques are used to decrease the incidence of post-thyroidectomy hypoparathyroidism, which include careful identification of parathyroid glands and meticulous dissection. Parathyroid autotransplantation can also be used to reconstitute parathyroid function after devascularization. Parathyroid autotransplantation involves implanting slices of viable parathyroid tissue into the ipsilateral sternocleidomastoid muscle, or subcutaneously into the muscle in the forearm. Fresh autografts or cryopreserved parathyroid tissue can be used for implantation, with the success rate being approximately 70% for cryopreserved tissue and 90% for fresh, autotransplanted tissue. ^, The parathyroid autotransplantation technique into the ipsilateral sternocleidomastoid muscle is performed as follows. The devascularized or accidently removed parathyroid gland is placed into a container with sterile normal saline solution until it is ready to be reimplanted. Then, the gland is crushed into small pieces with a scalpel. A pocket is created in the ipsilateral sternocleidomastoid muscle, ensuring there is no hematoma development, as this would impede the survival of the implanted parathyroid gland. Nonabsorbable nylon or an absorbable Vicryl (Ethicon Inc, NJ) suture is placed the same way so as to close the opening through both sides of the muscle pocket, and an air-node is created. The crushed fragments of the parathyroid gland are placed into the pocket and the air-node is tied down. A small, 5-mm, titanium clip is placed either on the node or on the end of the suture to mark the area of reimplantation in order to preserve the implant in case of future surgery in this area. Autotransplantation into the muscle or subcutaneous reimplantation into a forearm is performed for parathyroid hyperplasia. In the case of recurrence, the transplanted parathyroid gland can be easily removed from the arm under local anesthesia, avoiding re-exploration of the previously operated neck.

Prophylactic Postoperative Calcium and Vitamin D Replacement

It is much more difficult and takes longer to treat hypocalcemia symptoms than to prevent their development. Thus recent statements from the American Association of Clinical Endocrinologists and the American College of Endocrinology recommend routine, prophylactic treatment with oral calcium with or without calcitriol for all patients after a parathyroidectomy to prevent transient hypocalcemia. Oral calcium supplementation appears to be the most cost-effective approach. Calcium carbonate is the medication of choice, given as 500 to 1000 mg three times a day. This approach has been demonstrated to reduce postoperative hypocalcemia to approximately 10%. Our replacement protocol consists of oral calcium carbonate with vitamin D (OsCal, GSK, USA) starting with 500 to 1000 mg every 6 hours for the first week, then 500 to 1000 mg every 8 hours for the second week, then 500 to 1000 mg every 12 hours for the third week, and then 500 mg every 12 hours for the fourth week. We usually follow patients 2 weeks after the surgery with serum calcium and PTH levels. If the levels are within normal ranges, we stop calcium replacement earlier. Also, we modify our empiric replacement protocol based on intraoperative findings, such as the viability of the parathyroid glands during the thyroidectomy, or the number of parathyroid glands removed during the parathyroidectomy. We also decrease the dose of calcium in patients with impaired renal function and in elderly patients.

Another strategy is more objective and based on immediate postoperative PTH levels, within 1 hour of the surgery. If the PTH level is above 15 pg/mL (detected but at the lower limit of normal), the patient can be discharged home on prophylactic oral dose of 500 to 1000 mg of calcium three times a day. If the PTH level is less than 15 pg/mL, calcitriol at a dose of 0.5 to 1.0 μg per day should be started in addition to calcium. Magnesium supplementation should be considered if the serum magnesium level is below normal. It may take up to 72 hours for calcitriol to be effective. The patient can be observed in the hospital overnight, or, if reliable, compliant, and close by, they can be sent home with clear instructions on symptoms and when to call the doctor.

An alternative to calcium carbonate is calcium citrate (2000 to 6000 mg per day) administered orally in divided doses for those patients on proton pump inhibitors, elderly patients with achlorhydria, and those who had a gastric bypass. ^, Calcium carbonate requires an acidic environment for absorption, whereas calcium citrate does not. The advantage of calcium carbonate is that it is about 40% elemental calcium, whereas calcium citrate is only 21% elemental calcium. For enhanced absorption, both preparations of calcium should be taken with meals. It is important to administer oral calcium dosing separate from oral thyroid hormone replacement due to the binding of levothyroxine by calcium and inhibiting levothyroxine absorption. Levothyroxine should be taken 1 hour before or 3 hours after calcium is taken. In some patients who are very sensitive to fluctuations in the serum calcium, an “every 6 hours” or “every 8 hours” dosing regimen is preferred over a QID (four times a day) or TID (three times a day) in order to avoid the prolonged fasting period that occurs during sleep and which can result in morning hypocalcemia.

Measuring calcium levels postoperatively has been used to predict who can be safely discharged and who will require post-thyroidectomy calcium and vitamin D supplementation. If the serum calcium level is less than 8.5 mg/dL, or the ionized calcium level is less than 1.1 mmol/L, replacement should be considered. The pitfall with this protocol is in the timing of the measurement as studies have failed to demonstrate the reliability of the immediate postoperative calcium measurements to predict the development of hypoparathyroidism. Postoperatively, the decrease in serum calcium level can be delayed by as much as 48 to 72 hours and only materialize after the patient is home.

Medical Management of Acute and Chronic Postoperative Hypocalcemia

Management of postoperative hypocalcemia, either from post-thyroidectomy or post-parathyroidectomy, focuses on calcium supplementation. The severity of the symptoms and the degree of hypocalcemia guide the aggressiveness and modality of calcium supplementation. Guidelines for the postoperative management of hypoparathyroidism recommend measuring PTH and calcium levels postoperatively, and supplementing with oral calcium (1 to 3 g daily of elemental calcium) if calcium levels are less than 7 mg/dL or ionized calcium levels less than 1.1 mmol/L, or if symptomatic with carpopedal spasm, perioral numbness, or positive Chvostek’s sign. If calcium levels remain below 7 mg/dL despite calcium supplementation, 0.5 μg of calcitriol twice daily can be added. Additional algorithms for measuring and treating postoperative hypocalcemia caused by postoperative hypoparathyroidism involve measuring PTH hormone and calcium levels to determine calcium dosage, calcitriol dosage, and adding intravenous calcium if severe symptoms are present. Supplementation can be escalated to include up to 6000 mg calcium per day, 2 μg/day calcitriol, or intravenous magnesium of 1 mg/kg per hour if patients remain symptomatic and hypocalcemic. In severe cases of hypocalcemia, refractory to oral supplementation or with severe symptoms, intravenous calcium should be administered as an initial bolus of 1 to 2 g of calcium in 50 mL of 5% dextrose infused over 20 minutes. If symptoms of severe hypocalcemia persist, an intravenous calcium infusion of a solution composed of 11 g of calcium gluconate added to normal saline or 5% dextrose water, to provide a final volume of 1000 mL, is administered at 50 mL/hour and adjusted to maintain the calcium level in the low normal range. The formula, however, is weight-based (15 mg calcium/kg weight). It is important to include continuous ECG monitoring during intravenous calcium replacement, as rapid replacement can elicit cardiac arrythmias. Patients should then be transitioned to oral calcium plus oral calcitriol to ensure calcium levels remain normal and symptoms do not recur. Magnesium levels should also be checked, especially in patients who are not responding to calcium supplementation. If the serum magnesium level is below 1.7 mEq/L, then 1 to 2 mg intravenous magnesium should be given in addition to calcium supplements.

In our outpatient protocol, we initiate calcitriol therapy at 0.25 μg once or twice a day for moderate, and 0.5 μg once or twice a day for severe hypocalcemia, or if 1-hour postoperative PTH level is less than 15 pg/mL. We recommend rechecking calcium and PTH levels in 2 to 3 days after the initiation of calcitriol therapy and then every 3 days thereafter to avoid an overdose and development of rebound hypercalcemia. A cautionary note to all providers is to be very cautious with administration of calcitriol in combination with calcium in patients with borderline renal function or the elderly. In these latter two situations, hypercalcemia can occur rather quickly.

Chronic Management of Hypocalcemia

Although most patients who develop postoperative hypocalcemia recover, some do not. In fact, the most common cause of permanent hypoparathyroidism is after neck surgery, occurring in about 75% of all patients with hypoparathyroidism. ^, Chronic hypoparathyroidism is defined as well-documented reductions in the corrected serum calcium and PTH concentrations over a 6-month period. This time point is useful because some patients who develop hypoparathyroidism after parathyroid surgery will regain parathyroid function within 6 months. Other causes of hypoparathyroidism are due to an autoimmune destruction of the parathyroid glands, to genetic etiologies (e.g., DiGeorge syndrome, autosomal dominant hypoparathyroidism), or very rarely to infiltration of the parathyroid glands with iron, copper, or metastatic cancer.

It has already been mentioned, but is worth repeating, that hypomagnesemia, of any etiology, can masquerade as hypoparathyroidism. It is always important to consider this possibility because it is reversible. When administered magnesium, these patients will demonstrate rapid increases in the circulating PTH level and eventual sensitivity to PTH. Although the secretory block is rapidly overcome by magnesium administration, patients will remain hypocalcemic until peripheral resistance to PTH is relieved, several days later. Measures taken to deal with acute hypocalcemia, thus, should be applied to patients with hypomagnesemia, when symptomatic, in the same manner as any other acutely symptomatic hypocalcemic state.

By far the most common cause of chronic hypocalcemia is hypoparathyroidism. It is true that other chronic conditions can be associated with chronic hypocalcemia such as gluten enteropathy and other malabsorption syndromes, such as bariatric surgery. Nutritional, severe vitamin D deficiency is virtually unheard of in the developed world, but it can also be associated with hypocalcemia.

The pathophysiology of chronic hypoparathyroidism is related to the lack of PTH’s actions on its target organs, the skeleton and the kidneys, and to its indirect gastrointestinal actions. Without PTH, the skeleton becomes inactive and no longer serves as a useful reservoir for calcium when there is need. Without PTH, the kidneys do not conserve filtered calcium and, thus, a relative hypercalciuria ensues. In addition, the renal tubules lose the phosphaturic actions of PTH, thus leading to hyperphosphatemia. Without PTH, the activation of vitamin D through the actions of PTH on the renal hydroxylase that converts 25-hydroxyvitamin D to 1,25-dihyroxyvitamin D is impaired. The deficiency in active vitamin D leads to malabsorption of calcium.