measurement of serum calcium

The calcium levels that result on our routine testing are total calcium levels. When we say total calcium, we are referring to the sum of all calcium content in the blood. In the blood, 45% of calcium is ionized, 40% is bound to albumin, and 15% is bound to anions such as sulfate, citrate, and phosphate. Ionized calcium is the only form which leads to the signs and symptoms of hypO- or hypErcalcemia and thus it is the only form which we care about. Total calcium levels are returned on routine testing and are the least expensive and thus we use them. When you get a calcium result that is below the lower limit of normal, it’s important to take into consideration albumin levels and acid-base status. Because 40% of calcium is albumin-bound, a decrease in albumin will cause a decrease in total calcium levels and can do so without lowering ionized calcium. In this case, the patient is perfectly fine. The accepted correction of total calcium for albumin is to add 0.8 mg/dL for each 1 g/dL albumin is below a level of 4.0 g/dL. For instance, if a patient has a total calcium level of 7.9 mg/dL, but an albumin level of 3.0 g/dL, then their corrected total calcium level would be 8.7 mg/dL. A different situation can occur during acid/base disorders. Even in the absence of a change in total calcium levels, alkalemia can cause more of the ionized calcium to bind to albumin, thus reducing ionized calcium levels and leading to symptomatic hypOcalcemia. Acidemia causes the opposite — it causes previously albumin-bound calcium to become ionized, thus increasing ionized calcium levels. It’s difficult to remember which was alkalemia pushes calcium, but use this mnemonic — we give bicarb to produce alkalosis and so remember that “bicarb binds calcium to albumin.” So how do we use all of this information? For routine clinic patients visits, get albumin levels and correct them for albumin, if the corrected albumin levels are not normal, then get an ionized calcium level to confirm hypocalcemia. Do the same for hospitalized patients, but if someone is sick with acid-base abnormalities and you are concerned about hypocalcemia — especially if they are getting lots of blood products (citrate in blood transfusions lowers ionized calcium, but keeps total calcium the same or even raises it), then check an ionized calcium to be sure. Bad things with hypocalcemia generally happen with ionized calcium levels < 1.0 mmol/L, so if you’re above this, then you’re ok.

Treat severe hypocalcemia

During your initial evaluation of hypocalcemia, make are sure that there is no life-threatening hypocalcemia. If patients have symptomatic hypocalcemia (seizures, tetany, carpopedal spasm, prolonged QTc) or ionized calcium <0.8 mmol/L, give IV calcium. Start with 1-2 grams calcium gluconate, over 10-20 minutes, which can be given via peripheral IV or central line. Calcium chloride can only be given through a central line and must never be given via PIV. Depending on the severity of the hypocalcemia, a constant infusion of calcium gluconate can be given. Make this by adding 11 grams calcium gluconate to enough D5W to make a final volume of 1000mL. After giving a bolus of 1-2 grams calcium gluconate over 10-20 minutes (as noted above), start the constant calcium gluconate infusion at a rate of 50mL/hr. Follow serial ionized calcium levels and titrate to a goal ionized calcium level of 1.00 mmol/L. Remember that hypomagnesemia can cause hypocalcemia. If hypomagnesemia is also present, give 2 grams magnesium sulfate IV over 10-20 minutes and follow this with 1 gram magnesium sulfate IV per hour and continue until the serum magnesium level is > 1.0 mg/dL. If the patient has mild, asymptomatic, hypocalcemia such as an ionized calcium >0.8mmol/L, a total corrected calcium of > 7.5mg/dL, then give calcium carbonate 500mg 4x daily. Depending on the particular cause of typical cause of hypocalcemia, there are specific treatments for hypocalcemia depending on the disease. Specific treatments for all of these etiologies is out of the scope of this overview.

Find the cause of hypocalcemia

In the absence of symptomatic hypocalcemia, the next step is to work up the hypocalcemia. If you have severe asymptomatic hypocalcemia, then you have about 30-60 minutes to get your lab tests drawn before starting IV calcium. Broadly speaking, etiologies of hypocalcemia are split into two main groups based on a high or low PTH. Past that one lab test, you have to look at the clinical picture of your patient and see if any of these clinical situations match them. After coming up with a differential diagnosis based on patient history, order PTH, serum magnesium, creatinine, phosphate, 25-OH-D, and 1.25-OH-D, ALP, amylase, and urinary calcium and magnesium excreteion as needed to confirm your suspicion for the etiology.

Evaluation of Hypercalcemia

The evaluation of hypercalcemia is almost diametrically opposed to that of hypocalcemia, firstly, you don’t have to have an ionized calcium for evaluation of this. You must correct the calcium for albumin though. Patients who are volume depleted may have hemoconcentration which will raise serum albumin levels and thus raise total calcium. The only exception to the rule that an increased total calcium level will follow ionized calcium levels is the etiology of pseudohypercalcemia in which calcium-binding paraproteins of multiple myeloma will cause an elevation in total calcium without an increase in ionized calcium. Remember that we only care about increases or decreases in ionized calcium levels. After you have corrected calcium for albumin, follow the following algorithm to find the diagnosis. Also, in contrast to hypocalcemia, history won’t help you tremendously, although a seasoned clinician will be able to spot nuances in calcium elevation. The only thing to add to the chart below is that if you have a patient that possibly looks like they have primary hyperparathyroidism (or FHH), make sure you measure urinary calcium excretion. Patients with FHH will have low urinary calcium excretion. You absolutely do not want to perform a parathyroidectomy in these patients since their parathyroid glands are not the problem.

Treatment of hypercalcemia.

The goals of treatment of hypercalcmia are to lower the serum calcium and also treat the underlying disease. So, when do you treat hypercalcmia? If patients have a corrected calcium of < 12 mg/dL, they probably don’t need urgent treatment,. Those with a corrected calcium of 12-14 mg/dL possibly need urgent treatment. Those with corrected calcium levels of > 14 mg/dL absolutely need treatment,

Let’s start with the treatment of severe (corrected calcium of >14 mg/dL). Hypercalcemia acts like a loop diuretic. Because of this, they are volume depleted and need IV fluids. Start normal saline at 250mL/hr and titrate to a UOP of 100-150mL/hr. Don’t start a loop diuretic in conjunction with the normal saline. That would be like having someone on lasix and bumex who is also volume depleted — not a good idea. This crazy regimen was actually used in the past, but they utilized regimens such as lasix 240mg IV Q8h and insane rates of normal saline administration. Needless to say they ensuing hypokalemia and hypomagnesemia were absolute nightmares to manage. We now have better medications for lowering calcium levels. In conjunction with normal saline, give calcitonin 4 units/kg. Give 4-8 units/kg calcitonin Q6-8h. These two treatments should be your first treatment.

The next question is — do we give bisphosphonates? Bisphosphonates reduce hypercalcemia associated with bone resorption. This means that they are not useful for hypercalcemia associated with things like granulomatous disease. To be fair, severe hypercalcemia is most likely associated with malignancy and bone issues, and so it would be a reasonably safe bet. If you do give a bisphosphonate, give zoledronic acid 4mg over 15 minutes. Bisphosphonates have potential nephrotoxicity. It is very risky to use these agents for patients with a serum Cr of > 4.5 mg/dL.

A couple of extra things. Glucocorticoids are used to treat hypercalcemia associated with granulomatous disorders. Also, if medical treatment fails for treatment of hypercalcemia, dialysis could be indicated.