this slides are about calcium and its disorders in critical care unit.

1. CALCIUM [Ca++]
Dr AMIT PINJARI

2. calcium
 Most abundant macro (RDA > 100mg) mineral in human body
 Total body calcium 1-1.5kg
 About 99% of calcium is found in bones as carbonate or
phosphate of calcium
 0.5% in soft tissue
 0.1% in extracellular fluid (plasma)
 Normal serum Ca level = 8.6 to 10.2 mg/dl or 2.2-2.6 mmol/L

3. Plasma calcium
1. Ionized or free or unbound calcium
In blood, 40-50% of plasma calcium is free & is metabolically active
4.4-5.2 mg/dL, or 1.1-1.3 mmol/L (conversion factor 0.25)
2. Bound calcium
40% of plasma calcium is bound to protein mostly albumin
corrected Ca = measured Ca + 0.8(4 – measured albumin)
These two forms are diffusible from blood to tissues
3. Complexed calcium
10% of plasma calcium is complexed with anions including bicarbonate,
phosphate, lactate & citrate.

4. Calcium rich foods
Milk- 100 mg/dl
Egg, fish, cheese,
beans, lentils, nuts,
cabbage and
vegetables
Ragi- richest
Fruits- sitaphal,
dates, fig(Anjeer)
Adults = 500 mg/day
Children’s = 1200mg/day
Pregnancy & lactation =
1500 mg/day

5. Calcium absorption and metabolism
 Calcium is taken in the diet as calcium phosphate, carbonate & tartarate
 About 40% of dietary calcium is absorbed from the gut
1) first & second part of duodenum
active process, Requires a carrier protein(calbindin), helped by calcium-
dependent ATPase
1) Ileum
intracellular diffusion (simple diffusion)
 Both processes require 1, 25 DHCC (Calcitriol) which regulates the
synthesis of Ca-binding proteins & transport

6. Factors causing increased absorption
 Vitamin D: synthesis of carrier protein (Calbindin) facilitates absorption
 Parathyroid hormone (PTH): increases calcium transport from the intestinal cells by
enhancing 1α-hydroxylase activity
 Acidity: Ca-salts soluble in acidic solutions
 High protein diet:
 Amino acids: Lysine & arginine
 Sugars and organic acids: Organic acids produced by microbial fermentation of
sugars in the gut, increases the solubility of Ca-salts & increases their absorption
• Citric acid may also increase the absorption of calcium
 Lactose: enhance passive Ca uptake

7. Factors causing decreased absorption
 Phytic acid: Cereals contain phytic acid (maize, wheat, barley, rice etc)(Inositol
hexaphosphate) forms insoluble Ca-salts & decreases the absorption
 Oxalates: Present in some leafy vegetables, causes formation of insoluble
calcium oxalates
 Fibres: Excess of fibres in the diet interferes with the absorption
 Malabsorption syndromes: Causing formation of insoluble calcium salt of fatty acid
 Glucocorticoids: Diminishes intestinal transport of calcium
 Phosphate: High phosphate content will cause precipitation as calcium phosphate
 Magnesium: High content of Mg decreases the absorption
 alkaline medium: the absorption of calcium is lowered due to the
formation of insoluble tricalcium PO4

8.  Advanced age
 Estrogen deficiency
 Renal failure
 DM
 High fat diet

9. Biochemical functions
 Development of bones and teeth:
Osteoblasts induce bone deposition and osteoclasts produce demineralization
 Muscles: mediates excitation & contraction of muscles
decreases neuromuscular irritability.
 Nerve conduction
 Blood coagulation: factor IV in blood coagulation process
 Prothrombin contains γ-carboxyglutamate residues which are chelated by
Ca2+ during the thrombin formation
 Calcium is required for release of certain hormones from cells include
insulin, parathyroid hormone, calcitonin, vasopressin
 Second messenger: Calcium and cAMP are second messengers for hormones e.g.epinephrine in
liver glycogenolysis
 Myocardium: Ca2+ prolongs systole
In hypercalcemia, cardiac arrest is seen in systole

10.  Activation of enzymes:
Calmodulin is part of various regulatory kinases
• Enzymes activated by Ca2+ include pancreatic lipase, enzymes of
coagulation pathway, rennin, ATPase, SDH (succinate dehydrogenase).
 Secretory process : like exocytosis, endocytosis, cell motility.
 Wound healing, maintaining vascular permeability.

11. Regulation of plasma calcium level
 • Dependent on the function of 3 main organs
• Bone
• Kidney
• Intestine
 • 3 main hormones
• Calcitriol
• Parathyroid hormone
• Calcitonin
 • Also by GH, glucocorticoids, estrogens, testosterone & thyroid

12. w
Cholecalciferol (D3)
Diet
Vit D3: fish,meat
Vit D2: supplements
25-OH cholecalciferol,
calcidiole
1,25 DOH cholecalciferol,
Calcitriole
D 25 hydroxylase
1 alpha hydroxylase
Subtypes: D1 to D5
D2: ergocalciferol, plants,fungus
D3 is 3 to 9 times potent

13. Regulation of plasma calcium level by Calcitriol
Bone:
 stimulates calcium uptake for deposition as calcium phosphate
 Calcitriol is essential for bone formation
 Calcitriol along with parathyroid hormone increases the mobilization of calcium and phosphate from th
bone
 Causes elevation in the plasma calcium and phosphate
Kidneys:
 Calcitriol minimizing the excretion of Ca2+ & phosphate by decreasing their
excretion & enhancing reabsorption
Intestine:
 increases the intestinal absorption of Ca2+ & phosphate
 Calcitriol binds with a cytosolic receptor to form a calcitriol-receptor complex which interacts with DNA
leading to the synthesis of a specific calcium binding protein
 • This protein increases calcium uptake by intestine

14. Regulation by parathyroid hormone (PTH)
Bone:
 PTH causes decalcification or demineralization of bone, a process carried out by osteoclasts With
help of pyrophosphatase & collagenase
 These enzymes result in bone resorption
 Demineralization ultimately leads to an increase in the blood Ca2+ level
kidney:
 PTH increases the Ca2+ reabsorption by kidney tubules
 It’s most rapid action of PTH to elevate blood Ca2+ levels
 PTH promotes the production of calcitriol (1,25 DHCC) in the kidney by stimulating 1- hydroxyaltion
of 25-hydroxycholecalciferol
Intestine:
 It increases the intestinal absorption of Ca2+ by promoting the synthesis of calcitriol

15. Calcitonin
 lt is secreted by parafollicular cells of thyroid gland
 The action of CT on calcium is antagonistic to that of PTH
Bone:
Calcitonin promotes calcification by increasing the activity of osteoblasts
 Calcitonin decreases bone resorption
Kidney:
 decreases reabsorption of ca++ in kidney
Intestine:
 Inhibits intestinal absorption of calcium

18. Disorders of calcium

19. Renal handling of calcium
Filtrable : free and complexed calcium
Non filtrable : bound (protein) (40%)
Despite the relatively small smount of
Ca++ delivered, the DCT is a major
regulatory site for Ca++ excretion. In
contrast to the PCT and TAL, DCT
reabsorbs predominately via an active,
transcellular route.
50% PTH
PTH

20. hypocalcemia
 Plasma [Ca2+] <8.5 mg/dL with normal albumin levels
 For each gram decrease of albumin from normal (i.e., 4.0 g/dL), [Ca2+] decreases by 0.8 mg/dL.
 hypoalbuminemia, total calcium is decreased
In such cases, the metabolically active ionized Ca2+ is normal & so there will be no deficiency
manifestations
 • Alkalosis and Acidosis:
Alkalosis favors binding of Ca2+ with proteins, with consequent lowering of ionized Ca2+
Total calcium is normal, but Ca2+ deficiency may be manifested
 • Acidosis favors ionization of Ca2+

21. causes
 Pseudohypocalcemia - MRI contrast interferes with lab value
 Low serum albumin
 Hypoparathyroidism
Genetic- parathyroid agenesis
Autoimmuno – activating mutation of CaSR
Acquired – surgery, infiltrative disease, irradiation
Hypomagnesemia – inhibits PTH
 Disturbance in vit D metabolism
malnutrition, intestinal sx, liver ds, renal failure, hyperphosphatemia, nephrotic syndrome
 Pancreatitis
 Sepsis and toxic shock syndrome
 Hungry bone syndrome – post parathyroid sx
 Cancer- increased metastatic osteoblastic activity

22. Causes
 Chronic respiratory alkalosis or metabolic alkalosis
 Rhabdomyolysis or Tumor lysis syndrome- hyperphosphatemia induced hypocalcemia
 Multiple blood transfusions- chelation of ca++ by citrate, EDTA
 DRUGS
• Anticonvulsants : ↑ metabolism of vit D3, ↓ Ca release from bone, ↓ ca absorption from intestine
• Bisphosphonates
• Denosumab
• Calcitonin
• Citrate
• Foscarnet, fluoride
• Antibiotics – consequence of hypomagnesemia (aminoglycosides, amphotericin B, pentamidine,
and foscarnet)
• Cinacalcet- inhibits PTH secretion
• Phosphate binders (calcium acetate)- bind phosphate in gut and ↓ ca absorption.
} Inhibits bone
resorption
} Chelates Ca

23. Clinical features
 Results from increased neuromuscular irritability/ excitability
 Weakness
 tingling, numbness (fingers and toes)
 Headache, seizure
 Muscle twitching and cramping
 Tetany (peripheral or laryngeal muscle)
 Altered sensorium
 Cataract, basal ganglia calcifications
 Ecg changes – prolonged QT (long ST) > torsades de pointes

24. vc ythgvgkbjhm BV√v1` v NH` J m.
bn B
Nonspecific, 25% of
normal adults
Insensitive, absent in 30% pt
of hypocalcemia

25. evaluation

27. management
If ECG changes or symptoms present, begin IV replacement:
a. Consider early initiation of hemodialysis when caused by hyperphosphatemia or hyperoxalemia
b. Bolus 2 g MgSO4 IV over 15 min if known hypomagnesemia or empirically if renal function is normal
c. Bolus 2 g calcium gluconate (20 mL or 2 ampules of 10% calcium gluconate; 1 g = 93 mg elemental
Ca2+) in 50–100 mL of 5% dextrose or saline IV over 10–15 min
d. Begin continuous Ca2+ infusion: Dilute 6 g of calcium gluconate (or 2 g, 20 mL, or 2 ampules of 10%
calcium chloridea ; 1 g = 272 mg elemental Ca2+) in 500 mL of 5% dextrose or saline and infuse at 0.5–1.5
mg elemental Ca2+/kg/hr

28.  e. Follow ionized [Ca2+] or corrected [Ca2+] Q 6 hours and continue infusion until [Ca2+]
normalizes
 f. Overlap with PO replacement
2. Dose 1–2 g elemental Ca2+ PO TID to QID, separate from meals
3. Can add 0.25–4 μg/d calcitriol AND/OR ergocalciferol especially in vitamin
D-deficient states
4. Can add salt restriction and hydrochlorothiazide if hypercalciuria occurs
Oral
preparations

29. precautions
 Solution may be diluted in NS, D5W (mix in up to 1000 mL),
 Do not mix in same bag or line with carbonates, and Ringer, to avoid precipitation
 May administer IV push at rate of 50-100 mg/min (0.5-1 mL/min);
 rapid IV administration may produce arrhythmias, hypotension, myocardial
infarction, or vasodilation
 central line

30. Hypercalcemia
 serum [Ca2+] >10.3 mg/dL in an individual with normal serum albumin
concentration or ionized calcium >5.2 mg/dL.
 • severe hypercalcemia is considered when serum [Ca2+] is above 14 mg/dL.

31. Causes
 A: increased Ca mobilization from bone
primary Hyperparathyroidism.
malignancy
MEN I & IIA
pseudohyperparathyroidism
renal failure
hyperthyroidism
immobilization
Addison disease
 B: due to decreased urinary excretion
thiazide diuretics – increased reabsorption in PCT
 Familial hypocalciuric hypercalcemia- mutation of ca sensing receptor (CaSR)
} 90%

32.  C: increased Ca absorption from GI tract
- granulomatous diseases – sarcoidosis, TB, histoplasmosis, coccidioidomycosis, leprosy, beryliosis,
silicone
-vit D intoxication
-milk alkali syndrome
 Medications
• Thiazide diuretics
• Lithium - ↑ PTH secretion
• Vit D - ↑ GI absorption of ca
• Vit A - ↑ bone resorption
• GH - unknown
• Estrogens/antiestrogens - ↑ bone resorption, ↓ sensitivity of PTH to ca
• Theophylline- beta agonist

33. Clinical features
 General: weakness, malaise, tiredness
 CNS: confusion, impaired memory, lethargy, stupor, coma, ms weakness, hypotonia
 CVS: short QT interval, arrhythmia, bundle branch blocks, HTN, J wave (Osborn’s wave)
 RENAL: dehydration, polyuria, polydipsia,nocturia (nephrogenic DI), nephrocalcinosis,
nephrolithiasis, AKI,CKD, tubulointerstitial disease.
 GI: nausea, vomiting, anorexia, wt loss, constipation, abdominal , pancreatitis.
 Skeletal: bone pain, arthritis, osteoporosis, osteitis fibrosa cystica
 Calcifications: band keratopathy, red eye syndrome, conjunctival and vascular calcifications

34. evaluation
PTHrP: parathyroid hormone related
peptide
FHH: Familial hypocalciuric
hypercalcemia
NSHPT: Neonatal severe
primary hyperparathyroidism
PHPT: primary hyperparathyroidism
HHM: Humoral hypercalcemia of
malignancy
LOH: Local osteolytic Hypercalcemia

36. Treatment of acute hypercalcemia
 Aim of therapy
 1. Hydration with normal saline and then administration of furosemide for volume
overload. Note that furosemide induced volume depletion may increase reabsorption of
Ca2+ by the proximal tubule
 2. Inhibition of bone resorption of Ca2+.
 3. Decrease intestinal absorption of Ca2+.
 4. Removal of Ca2+ by hemodialysis using a dialysate bath containing low Ca2+.
 General guidelines of therapy:
 1. Correct volume depletion FIRST, with isotonic normal saline
 2. If ECG changes or severe symptoms are present, begin the most rapidly acting
therapies in combination
 3. If rapid improvement is not seen (or anticipated due to the underlying condition),
consider adding the longer acting treatments (bisphosphonates) early since their effects
are delayed

37.  Calcium excretion
1..Isotonic saline Bolus: isotonic saline until euvolemic (may require up to 3–4 L), then adjust rate
to achieve urine output of 100–150 mL/hr
Onset at 2–4 hr Watch for signs of volume overload;
2..loop diuretics (frusemide)help with calcium excretion, but should be held until volume deficits have
first been corrected
 Decrease bone resorption
1.. Calcitonin
4–8 IU/kg IM or SC q6–12h Onset at 4–6 hr;
tachyphylaxis develops after 2–3 d
Lowers serum Ca2+ 1–2 mg/dL;
side effects include : flushing, nausea, and, rarely, allergic reactions

38. 2.. Bisphosphonates
Zoledronate 4 mg IV over 15 min OR pamidronate 60–90 mg IV over 2–4 hr
Onset at 2 d with peak effect at 4–6 d; lasts 2–4 wk
Decrease infusion rate of pamidronate or lower zoledronate dose in renal insufficiency
3..Denosunab - 60–120 mg SC
Onset within 3 days half-life of 25 days
Precautions: Watch for hypocalcemia, risk for infection
4..Gallium nitrate 100–200 mg/m2/d continuous infusion for up to 5 d
Onset after 2 d; lasts 1–2 wk
Significant risk of nephrotoxicity and is contraindicated if creatinine >2.5 mg/dL

39.  Decrease intestinal absorption
Glucocorticoids:
Prednisone 20–60 mg/d (or equivalent glucocorticoid dose)
Onset in 5–10 d Effective only in cases of granulomatous disease and hematologic
malignancies
 Haemodialysis
Variable based on starting [Ca2+] Immediate onset, lasting until dialysis completion Useful for
cases of severe hypercalcemia (>16 mg/dL) and when diuretic-resistant volume overload prohibits
saline administration

40. Thank you…