mod 3: calcium disorders

total calcium

• normal range from 8.5-10.5 mg/dL

• measures calcium found in the extracellular fluid (ECF)

• affected by hypoalbuminemia

  • this is because if albumin is low, there are fewer binding sites for calcium

  • this means that the concentration of calcium will decrease, since the protein-bound concentrations are decreased

  • however, the free calcium (the active form) usually remains the same, since the body regulates these concentrations tightly (via PTH and vitamin D)

  • this matters because patients with low albumin can “look” hypocalcemic, if you only measure this specific concentration, but their free calcium may be normal—so they don’t actually have symptoms of hypocalcemia

  • this is why doctors often calculate “correct” calcium for albumin, or directly measure the free concentrations in these cases

ionized calcium

• refers to the free or ACTIVE form of calcium

• normal range from 4.5-5.5 mg/dL

• these concentrations are maintained by the body within a tight range (via PTH and vitamin D)

corrected calcium equation

• measured total Ca²⁺⁺ + 0.8(4 - serum albumin)

  • serum calcium in mg/dL

  • serum albumin in g/dL

• we would only use this if the serum albumin is less than 4

• avoid using in critically ill patients or in patients with severely low albumin → it would be more beneficial to measure the ionized calcium in that case

hypercalcemia

• total serum calcium > 10.5 mg/dL

• or, if the ionized calcium is over the normal range (4.5-5.5 mg/dL)

• remember, the lab value emergencies surround CALCIUM levels!

  • not phosphate or PTH levels!

mechanisms of hypercalcemia

1. increased bone resorption

   • PTH senses low calcium levels and causes increased osteoclast and osteoblast activity in the bone, leading to the breakdown of bone by osteoclasts

2. increased tubular reabsorption in the kidneys

   • increased renal calcium reabsorption and decreased renal phosphorous reabsorption

3. increased GI tract absorption

   • increased renal activation of vitamin D3 (calcitriol) causes increased intestinal calcium and phosphorous absorption/mobilization into the bloodstream

underlying causes of hypercalcemia

• cancers

• hyperparathyroidism

• medications

• granulomatous diseases

• endocrine diseases

• others

medications that can cause drug-induced hypercalcemia

• thiazides

• lithium

• vitamin D

• calcium

• vitamin A

• aluminum/magnesium antacids

• theophylline

• tamoxifen

• ganciclovir

presentation of mild-moderate hypercalcemia

• Ca²⁺⁺ < 13 mg/dL

• may be asymptomatic, or may have symptoms of fatigue or weakness

presentation of acute hypercalcemia

• often due to cancer

• anorexia

• N/V

• constipation

• polydipsia

• polyuria

• nocturia

presentation of hypercalcemia crisis

• Ca²⁺⁺ > 15 mg/dL

• patient may be unarousable

• AKI

• coma

• arrhythmia

• death

presentation of chronic hypercalcemia

• soft tissue calcification

• hypercalciuria

• interstitial nephrocalcinosis (calcium deposits within the kidney's interstitial tissue) leading to CKD

• nephrolithiasis

• increased calcium + increased phosphate + increased PTH = deposition

treatment for acute, asymptomatic hypercalcemia → serum calcium < 12 mg/dL

• they should be observed, and reversible causes should be corrected

treatment for acute, asymptomatic hypercalcemia → serum calcium > 12 mg/dL

• they should be administered:

  • saline rehydration

  • loop diuretic

  • calcitonin

  • corticosteroid

  • bisphosphonate

treatment for acute, symptomatic, life-threatening hypercalcemia → functioning kidneys

• these patients may present with complications such as ECG changes, tetany, or pancreatitis

• they should be administered:

  • saline rehydration

  • loop diuretic

  • hemodialysis (low calcium bath)

  • calcitonin

  • corticosteroid

• we also want to treat these patients rapidly with volume expansion (with normal saline)

  • hypercalcemic patients are often dehydrated

    • IV saline helps with rehydration, as well as increasing renal perfusion and consequently increasing GFR so more calcium is filtered out into the urine

• with loop diuretic + hydration in combination → we want to drop the calcium 2-3 mg/dL over 1-2 days

treatment for acute, symptomatic, life-threatening hypercalcemia → severe kidney insufficiency

• these patients may present with complications such as EKG changes, neurological effects, tetany, or pancreatitis

• they should be administered:

  • hemodialysis (low to no calcium bath)

  • calcitonin

  • glucocorticoid

• we also want to treat these patients rapidly with volume expansion (with normal saline)

  • hypercalcemic patients are often dehydrated

    • IV saline helps with rehydration, as well as increasing renal perfusion and consequently increasing GFR so more calcium is filtered out into the urine

  • with loop diuretic + hydration in combination → we want to drop the calcium 2-3 mg/dL over 1-2 days

treatment for acute, symptomatic, NON-life-threatening hypercalcemia

• these patients may present with symptoms such as muscle weakness, fatigue, cognitive dysfunction, or abdominal pain

• they should be administered:

  • saline rehydration

  • loop diuretic

  • calcitonin

  • corticosteroid

  • bisphosphonate

secondary considerations for acute-onset hypercalcemia

• parathyroidectomy

• reducing tumor load

• discontinue offending medications

volume expansion with normal saline

• mechanistically works to increase natriuresis, as well as increasing urinary calcium excretion

  • in dehydration, kidneys reabsorb more sodium and water (and calcium tags along) → hydrating the pt can enhance calcium clearance as it follows Na+/water

  • may need to add electrolytes after initial hydration (especially if using a loop dieuretic):

    • potassium

    • magnesium

loop diuretics

• options:

  • furosemide

  • torsemide

  • bumetanide

  • ethacrynic acid

• MOA: blocks Ca²⁺ and Na⁺ reabsorption in the thick ascending limb, increasing urinary calcium excretion

• caution: do not dehydrate the patient → this can actually cause increased calcium reabsorption in the proximal tubule

  • dehydration = decrease plasma volume = lower GFR = lower clearance of calcium

  • give IV saline to hydrate the pt to enhance calcium excretion

• need to monitor fluid/hydration status, K+, and Mg++

calcitonin

• an alternative option to saline

• used for short-term

• rapid onset (1-2 hours)

• has an unpredictable degree of calcium reduction

• MOA: inhibits bone resorption, decreases tubular reabsorption of Ca⁺⁺, and increases urinary calcium excretion

• SQ or IM route

• ADRs: flushing, N/V, hypersensitivity (administer test dose), tachyphylaxis (effect wears off)

bisphosphonates

• options:

  • pamidronate

  • etidronate

  • zoledronate

  • ibandronate

• commonly used in hypercalcemia due to cancer

• MOA: blocks bone resorption

  • prevents hydrolysis of hydroxyapatite crystal (provides hardness to the bone) by phosphatases

  • prevents osteoclast precursors from binding to bone

• onset is somewhat slow → 2-7 days

  • may be given with calcitonin

• dosed q2-3 weeks

• generally given via IV route, but PO can be used for maintenance in some cases

• monitor SCr

• ADRs: fever

corticosteroids

• options:

  • prednisone (and others)

• slow-onset → 3-5 days

• MOA: decreases (dietary) calcium absorption and prevents calcitonin tachyphylaxis

  • they decrease calcium absorption by antagonizing vitamin D in the gut, reducing the transcription of calcium transporter proteins → decreased calcium mobilization

miscellaneous drugs used to treat hypercalcemia

• denosumab

• gallium nitrate

• mithramycin

• cinacalcet

hypocalcemia

• total calcium < 8.5 mg/dL

  • has a high prevalence in the ICU where patients have hypoalbuminemia

  • we would use the corrected calcium equation in this case

• ionized calcium < 4.5 mg/dL

• generally not a medical emergency in most cases

  • emergent treatment can be warranted if seizures or tetany occur

• generally, PTH is elevated as well,

  • exceptions: hypoparathyroidism or hypomagnesemia

common causes of hypocalcemia

• vitamin D deficiency

• hypomagenesemia

• hungry bone syndrome

• hypoparathyroidism

• medications

vitamin D deficiency

• the active form is essential for absorption of Ca++ and phosphorus in the gut

• can lead to chronic hypocalcemia

common causes of vitamin D deficiency 

• malnourished populations

• gastrointestinal disease or surgery

• CKD → inability to activate vitamin D (a metabolic function of the kidney)

hypomagnesemia

• can lead to:

  • impaired PTH secretion → it is required for exocytosis of PTH from the parathyroid

  • PTH resistance in target organs

  • severe, symptomatic hypocalcemia → even if calcium is low, the parathyroid can’t respond properly when it is severely low

• if present, patients will be unresponsive to calcium replacement → we must replenish this deficiency first!!

hungry bone syndrome

• this phenomenon follows a parathyroidectomy or thyroidectomy

  • especially in CKD patients who’ve had very high levels of PTH for a very long time, and suddenly they get surgery as treatment

  • so PTH levels go from very high to very low relatively quickly

  • in patients with chronically high PTH, their bones are in a state where resorption >>> formation, so the bones are basically depleted of minerals

  • when PTH sudden drops, osteoblasts aggressively deposit calcium into the bone matrix to restore density

  • essentially, the bones “suck up” all the calcium it can find, because they were in a chronic “loss” state

  • this can lead to very acute hypocalcemia

• treatment includes calcium replacement and frequent monitoring

  • monitor q6h x1-2 days post-surgery

drug-induced causes of hypocalcemia

• furosemide

• cinacalcet

• oral phosphorus

• denosumab

• calcitonin

• bisphosphonates

• mithramycin

• gallium nitrate

• pentamidine

• ketoconazole

• fluoride

• concentrated citrate

• phenobarbital

• phenytoin

• medications causes hypomagnesemia

clinical presentation of hypocalcemia

• varies based on acuity

• neuromuscular

  • parasthenia around mouth, cramping, tenancy, laryngeal spasms

• CNS

  • depression, anxiety, seizure, confusion, hallucination, memory loss

• dermatologic

  • alopecia, changes in nails

• cardiac

  • prolonged QT, CHF symptoms, arrhythmia, bradycardia, hypotension

• physical exam findings

  • positive Chvostek’s sign → facial twitching while tapping facial nerve

  • positive Trousseau’s sign → carpal spasm when BP cuff inflated > SBP for 3 minutes

treatment of hypocalcemia → hypomagenesemia

• magnesium replacement

treatment of hypocalcemia → hypoparathyroidism

• IV and oral calcium

• oral vitamin D

treatment of hypocalcemia → concurrent medications

• decrease doses or change therapy, if possible

treatment of hypocalcemia → vitamin D deficiency

• oral or IV vitamin D replacement

treatment of hypocalcemia → symptomatic, acute

• IV calcium chloride or gluconate bolus over 10 minutes

  • evaluate patient response to IV calcium as well as signs and symptoms

  • evaluate 10-12 hours after IV therapy or sooner for severe hypocalcemia

  • evaluate serum calcium every 24-48 hours initially during therapy, and then 1-2 times weekly

    • if patient is still symptomatic with calcium < 8.6 or ionized calcium < 4.4 → rebolus IV

treatment of hypocalcemia → Asymptomatic, acute

• consider IV calcium gluconate bolus at 1g/hour

  • evaluate patient response to IV calcium as well as signs and symptoms

  • evaluate 10-12 hours after IV therapy or sooner for severe hypocalcemia

  • evaluate serum calcium every 24-48 hours initially during therapy, and then 1-2 times weekly

    • if patient is still symptomatic with calcium < 8.6 or ionized calcium < 4.4 → rebolus IV or increase dose of oral product 

treatment of hypocalcemia → Asymptomatic, chronic

• oral calcium 1-3g/day