Plasma calcium concentration mg/dL meq/L mmolL % total Free ionized 5.0 2.5 1.25 50 Protein-bound 4.2 2.1 1.05 44 Complexed 0.8 0.4 0.2 6 Total 10 5.0 2.50 100 

Serum Ca corrections Correction of total serum Ca for serum albumin – add 0.8 meq/L for each 1 gm reduction in albumin Ionized Ca – can obtain if do not have a serum albumin measurement Gadolinium – certain gadolinium salts can dramatically transiently lower measured total serum Ca 

Hypocalcemia – effects of change in serum pH Alkalosis – decreases ionized Ca Acidosis – increases ionized Ca Clinical ramifications - if patient is acidotic and hypocalcemic treatment with NaHCO3 without addressing the hypocalcemia can further lower ionized Ca

Hypocalcemia – signs and symptoms Weakness Paresthesias Seizures Latent tetany – Trousseau, Chvostek signs Hypotension Long QT

Tests for latent tetany Chvostek sign - tap the skin over the facial nerve in front of the external auditory meatus, causes an ipsilateral contraction of the facial muscles, but up to 10% of population have a positive test Trousseau sign – inflate BP cuff on arm to 20 mmHg>systolic BP for 3-5 min & watch for carpopedal spasm, insensitive test

Mechanisms of hypocalcemia Reduced GI absorption – GI disease, hypoparathyroidism, vitamin D deficiency Renal loss – low Mg, genetic disorders, drugs (e.g. cisplatinum, cyclosporine, aminoglycosides, proton pump inhibitors) Redistribution of Ca into: bone (post parathyroidectomy) or abdominal cavity (pancreatitis) Binding by citrate (transfusions) or PO4 load (IV or enema)

Hypocalcemia in critical illness Mechanisms: low Mg renal failure blood transfusions (citrate) multiple mechanisms in gram negative sepsis including probable cytokine induction of hypoparathyroidism and vitamin D deficiency or resistance No proof correction of Ca affects course

Hypocalcemia – indications for IV Ca Patients who are severely symptomatic – tetany, carpopedal spasm, decreased cardiac function, or prolonged QT interval Asymptomatic patients with an acute decrease if corrected total serum Ca<7.5 mg/dl Not an indication - neuromuscular irritability such as paresthesias and corrected total serum Ca >7.5; initial treatment with oral Ca sufficient

Hypocalcemia treatment with bolus intravenous Ca Calcium gluconate – 10 mL of a 10% solution is 90 mg of elemental Ca Calcium chloride – 10 mL of a 10% solution is 270 mg of elemental Ca Tissue necrosis with extravasation – much more common with calcium chloride Code cart – contains Ca chloride Formation of insoluble Ca salts – occurs when HCO3 or PO4 is added to solution containing Ca Hyperkalemia with marked EKG changes (with no hypocalcemia) – affects conduction not serum [K+]

Hypocalcemia Rx with Ca infusion Since duration of action of IV Ca bolus is just 1-3 hours to maintain the serum Ca level may need to give IV infusion Add 11 amps of Ca gluconate to either D5W or NS to make a 1 L solution with a Ca concentration of 1 mg/ml Usual starting rate 1 ml/minute or 60 mg/hour of elemental Ca

Hypocalcemia with concurrent hypomagnesemia Often cannot correct the Ca unless the Mg is corrected Give 2 gm of Mg (16 meq) of MgSO4 as a 10% solution over 10 to 20 minutes Followed by 1 gm MgSO4 (8 meq) at 100 mL/hr Continue intravenous MgSO4 as long as Mg < 1 mg/dL Careful monitoring if patient has impaired renal function

Vitamin D nomenclature Vitamin D – cholecalciferol D3, ergocalciferol D2 25-hydroxy vitamin D - calcidiol D3, ercalcidiol D2 Vitamin D receptor agonist - calcitriol D3 (Rocaltrol), paricalcitol D2 (Zemplar) a synthetic analog, doxercalciferol D2 (Hectoral) a synthetic prohormone

Measurement of vitamin D deficiency or insufficiency Vitamin D deficiency best determined by measuring 25-OH vitamin D even though the active form is 1,25 dihydroxy vitamin D This is because 1,25 dihydroxy vitamin D levels are often normal in vitamin D insufficiency because of a compensatory increase of PTH which then stimulates conversion of 25 to 1,25 dihydroxy vit D 25-hydroxy vitamin D levels are reported as a combination of D2 and D3 Vitamin D deficiency < 20 ng/ml Vitamin D insufficiency 20-30 ng/ml

Sources of vitamin D Very few foods contain vitamin D (livers of fatty fish are the exception) Synthesis in the skin of vitamin D3 during exposure to UV rays in sunlight is a major source This system is exceedingly efficient and brief casual exposure such as 10-15 minutes of the arms and face is equivalent to ingestion of 200 IU per day Disabled persons and elderly may have inadequate sun exposure Skin of those >70 does not convert vitamin D effectively At northern latitudes there is not enough radiation to convert vitamin D, particularly during the winter

Vitamin D deficiency Elderly – up to 74% deficient in vitamin D even if adequate intake; suggested guidelines in elderly 800-1000 IU/day NHANES study – 42% of African American women were deficient vs 4% Caucasian Response to bisphosphonates – may be blunted if vitamin D deficient

Hypocalcemia – rationale for Rx with calcitriol (Rocaltrol) PTH stimulates the conversion of 25-hydroxy vitamin D to 1-25 dihydroxy vitamin D So if give a patient with hypoparathyroidism vitamin D it would not be converted to the active form 1-25 dihydroxy vitamin D (calcitriol) Calcitriol must be given in this circumstance. Onset of action – much quicker in onset than vitamin D which may take several days Offset of action – much quicker than vitamin D, so if develop hypercalcemia of shorter duration Dosage - start with .25 ug bid, up to 2 ug per day Elevated urinary Ca and nephrolithiasis – can be induced by calcitriol even if no hypercalcemia

Ergocalciferol vs cholecalciferol Vitamin D2 – ergocalciferol (nephrologists use since listed in their guidelines) Vitamin D3 - cholecalciferol, longer half-life, greater activity

Vitamin D dosage in Rx of chronic hypocalcemia Simple dietary deficiency - can be corrected by the use of ergocalciferol 400-2000 IU/day However in conjunction with other hypocalcemic disorders (e.g., underlying impairments in vitamin D metabolism or renal insufficiency) larger doses may be needed e.g., a 6 to 8 week regimen of 50,000 units, dosed weekly Severe malnutrition or malabsorption – may require even higher doses

Oral calcium supplements Calcium carbonate - 40% elemental Ca (Oscal 250 or 500 mg Ca per tablet or Tums ES 400 mg Ca per tablet) Calcium acetate - 25% elemental Ca (Phoslo) Calcium Citrate 21% elemental Ca (Citracal) Dose – 1-2 gm of elemental calcium tid Should give apart from meals to enhance Ca absorption

Symptoms of severe phosphate depletion (< 1mg/dl) In general are due to inability to form ATP as well as impaired oxygen delivery due to a decrease in RBC 2,3 DPG: 1) muscle injury - rhabdomyolysis, impaired diaphragmatic function, CHF 2) neurologic - paresthesias, dysarthria, confusion, stupor, seizures, coma 3) hematologic (rare) – hemolysis, thrombocytopenia

Hypophosphatemia treatment Acute moderate hypophosphatemia (1-2.5 mg/dl) - is common in hospitalized patients, often due to transcellular shifts, if asymptomatic may require no treatment except correction of underlying cause Acute severe hypophosphatemia (< 1 mg/dl) - may require intravenous P if serious clinical manifestations

Intravenous phosphorus treatment for hypophosphatemia Total body P deficit – can not be easily determined but has been demonstrated that the dosage listed below can be given safely Infuse 0.08 to 0.16 mmol/kg in 500 mL of .45% NS over 6 hours and stop when P>1.5 mg/dl (so in a 100 kg patient this is 8-16 mm - order set in Cerner is for 10 mm) Duration of infusion – it may take 24-48 hours to replenish intracellular stores Hypocalcemia is the main risk (binding of serum Ca by the P) especially with prolonged infusions; hyperphosphatemia

Phosphorus preparations Normal dietary P about 1000 mg 1 mmol P = 31 mg Neutraphos - 250 mg elemental P, K+ 7 meq, Na+ 7 meq Neutra-Phos potassium - 250 mg elemental P, K+ 14 meq Fleets Phospho-Soda – 815 mg P, Na+ 33 meq/ 5 mls Intravenous K+ phosphate – 1.5 meq KCl/mm PO4 Intravenous Na+ phosphate - 1.3 meq NaCl/mm PO4 Intravenous phosphate preparations recently not always available in hospital pharmacies

Hypomagnesemia - signs and symptoms Nonspecific symptoms – anorexia, nausea, apathy Hypocalcemia – tetany, seizures, positive Chvostek and Trousseau signs Hypokalemia – weakness, arrhythmias Increased susceptibility to ventricular arrhythmias during myocardial ischemia

Significance of low serum Mg in CV disease Mild hypomagnesemia is common with diuretics Predisposes to cardiac arrhythmias in the settings of acute ischemic event, CHF, cardiopulmonary bypass, torsades de pointes, or in ICU patients Myocardial infarction - with low Mg is increased risk of ventricular arrhythmias especially first 24 hours - which risk may be reduced by IV Mg Torsades de pointes – increased risk with low Mg especially if on class Ia or III antiarrhythmics

Plasma magnesium concentration mg/dL meq/L mmolL Free 1.3 1.1 0.55 Complexed 0.4 0.32 0.16 Protein-bound 0.4 0.32 0.16 Total 2.1 1.76 0.87 (1.9-2.3) (1.5-2.0) (0.7-1.0)

Hypomagnesemia treatment Severe symptomatic hypomagnesemia (tetany, hypocalcemia, arrhythmias): treat intravenously: e.g., 50 meq IV over 8 to 24 hours, to maintain Mg >1 mg/dl MgSO4 vial =1 gm MgSO4=96 mg elemental Mg=8 meq Asymptomatic hypomagnesemia: treat with oral agents

Oral magnesium preparations Normal daily dietary Mg intake 360 mg Mag-Ox 400 - 240 mg of elemental Mg per 400 mg tablet Uro-Mag – 84 mg per 140 mg tablet Sustained release (Slow-Mag) - 64 mg per tablet Typically 240 mg of elemental Mg is given for dietary deficiency, more severe deficiency may require up to 720 mg/day elemental Mg major side effect - diarrhea

Hypermagnesemia Urinary Mg excretion can increase more than fivefold in response to a Mg load thus hypermagnesemia is typically only seen in the setting of renal failure when a very large Mg load is given intravenous, oral, via enema

Hypermagnesemia - clinical manifestations Mg 4-6 meq/L – lethargy, drowsiness, diminished reflexes Mg 6-10 meq/L – somnolence, hypocalcemia, absent reflexes, low BP, bradycardia, EKG changes (with IV Mg in eclampsia usual level 5-7 meq/L) Mg >10 meq/L – muscle paralysis, complete heart block, cardiac arrest

Hypermagnesemia – signs and symptoms 3 types of symptoms are seen when Mg >4 meq/L : 1) neuromuscular effects (curare like) 2) cardiovascular effects (Ca and K channel blockade) 3) hypocalcemia (PTH suppression)

Hypermagnesemia – treatment of symptomatic patient If renal function is normal cessation of Mg allows prompt restoration of normal levels If renal function is impaired hemodialysis is effective in removing Mg In cases with severe symptoms 100-200 mg elemental Ca over 5-10 minutes is effective antagonist

Key points Main risk of IV Mg is giving to azotemia patients and development of hypermagnesemia Main risk of IV P is binding to serum Ca causing hypocalcemia, usually with prolonged infusions not adequately followed Main risk of IV Ca - infiltration of vein and tissue necrosis, especially with calcium chloride If hypocalcemia consider may also be low [Mg] If hypokalemia consider may also be low [Mg] Hypermagnesemia – inhibit effects with IV Ca