1. HYPOCALCEMIA Management in the Post-Op and Chronic Setting Donna Mojdami, PGY-2 Internal Medicine

2. Management of Hypocalcemia in the Post-operative Setting

3. Case One A 47 year old female with papillary thyroid cancer is POD #1 from a total thyroidectomy. Her serum calcium this morning was measured at 2.0 mmol/L with an albumin of 42 g/L. Except for some fatigue she denies any symptoms consistent with tetany nor displays any signs of hypocalcemia including Chvostek’s & Trousseau’s signs on exam.

4. Case One  Should this patient be treated for hypocalcemia? If so, how and for what period of time?  Should she have been treated prophylactically?  Is there any way for us to predict the development of hypocalcemia in this patient?  Would management of this patient be any different if she had received a parathyroidectomy for hyperparathyroidism?

5. Signs & Symptoms of Hypocalcemia

6. Paresthesias – circumoral, peripheral Increased neuromuscular irritability – tetany, muscular & abdo cramping, muscle weakness Laryngospasm Bronchospasm Altered CNS function – depression, seizures, altered mental status CHF

7. Chvostek’s Sign – contraction of ipsilateral facial muscles with the facial nerve is tapped just anterior to the ear. Contraction of the mouth alone occurs in 10-30% of normal individuals. Trousseau’s Sign – induction of carpopedal spasm by inflation of bp cuff above SBP for 3 min. Characterized by adduction of thumb, flexion of MCP joints, extension of interphalangeal joints, flexion of the wrist. More specific than Chvostek’s.

8. Calcium and Vitamin D Pharmacology Shoback, 2008. NEJM.

9. Calcium and Vitamin D Pharmacology  Vitamin D3 (cholecalciferol)  Some studies suggest it increases levels of 25OHD more efficiently than Vit D2  Vitamin D2 (ergocalciferol)  Not accurately measured in all Vit D assays  Least expensive  Calcitriol (1,25-dihydroxyvitamin D)  A vitamin D metabolite  Most useful in those with decreased synthesis calcitriol e.g. CKD  Expensive  Rapid onset of action with short half-life of 6hrs  When used as supplement, 25OHD levels do not indicate vit D status  Calcidiol (25-hydroxyvitamin D)  A Vitamin D metabolite  Most useful in pts with hepatic disease  More rapid onset of action and shorter half-life than vitamin D

10. Surgical Hypoparathyroidism  Hypoparathyroidism is a common complication following thyroid, parathyroid and radical neck surgery  May be transient lasting weeks to months, permanent and even intermittent  Can be the result of manipulation of blood supply, removal of one of more parathyroid glands, or decreased parathyroid reserve  Transient hypoparathyroidism occurs in 20% of surgeries for thyroid cancer  Permanent hypoparathyroidism occurs in 0.8 to 3% cases following total thyroidectomy

11. Is It Possible to Predict Post-Op Hypocalcemia? Noordzij et al. J. Am Coll Surgeons, 2007  Systematic review of 9 studies looking at post-op PTH to predict post-op symptomatic hypocalcemia  Accuracy of PTH (65% decrease compared to pre-op level) in predicting hypocalcemia best at 6hrs post op Sensitivity 96.4% and specificity 91.4%  Generally intra-op PTH less spec. & sens. than when checked 1-6hrs post-op  Not reflective of hypocalcemia over months or years

12. Complete Thyroidectomy  Hypoparathyroidism is the most common complication  Neither the ASO or Endocrine Society have specific practice guidelines for post-op calcium management  Common approach is to treat as needed based on serum calcium level  Alternatively, treat all regardless of bloodwork and taper off vitamin D and Ca over a few weeks

13. Post-Op Day Serum TestsTherapy Night of Surgery Calcium at 8pm Ca <1.8: calcitriol 0.5 µg TID x 3 days and calcium gluconate 3 g/L D5 1/2 normal saline IV at 100 mL/h Day 1Calcium & Phosphorus at 6am, if Ca<1.8, add Mg Ca <1.8: calcitriol 0.5 µg TID x 3 days and calcium gluconate 3 g/L D5 1/2 normal saline IV at 100 mL/h and calcium carbonate (2 gm elemental calcium) PO BID Ca 1.8-2: calcitriol 0.5 µg TID x 3 days and calcium carbonate (2 gm elemental calcium) PO BID Ca >2: calcium carbonate (1 gm elemental calcium) PO BID Mg <1: magnesium sulfate 4 gm in 100 mL normal saline IV at 33 mL/h and magnesium oxide 400 mg PO BID x 1 month Day 2-4If Day 1 Ca=<2, total Ca and Phosphorus Ca <1.8 and symptomatic: calcitriol 0.25 µg TID and calcium gluconate 3 g/L D5 1/2 normal saline IV at 100 mL/h and calcium carbonate (2 gm elemental calcium) PO BID Ca <1.8 and asymptomatic: calcitriol 0.25 µg TID and calcium carbonate (2 gm elemental calcium) PO BID Ca 1.8-2.1 or P1.45: calcitriol 0.25 µg daily and calcium carbonate (2 gm elemental calcium) PO BID Ca 2.1-2.35 and P1.45: Calcium carbonate (2 gm elemental calcium) PO BID Ca 2.35: no therapy UpToDate, 2009. Management of Hypocalcemia After Thyroid Surgery. Tuttle, M.

14. Roh et al., 2006. Am. J. of Surgery  RCT of 90 patients undergoing total thyroidectomy  45 pts received oral calcium 1g tid and Vit D 0.5g bid on night of surgery and continued until POD 14  45 pts received supplementation only with symptomatic hypocalcemia  Symptomatic hypocalcemia developed in24% of pts without supplementation and 7% with supplementation (P<0.02)  Symptoms in the supplement group minimal and more severe in those not receiving therapy  No hypercalcemia nor PTH inhibition developed in the supplement group

15. Complete Thyroidectomy  Calcium and Vitamin D should be tapered over a 2 to 8 week period with regular measurement of serum PTH, calcium and phosphate  If unable to taper during this period of time, hypocalcemia likely to be permanent

16. Hungry Bone Syndrome  Severe and prolonged hypocalcemia often in the setting of post- parathyroidectomy for high PTH levels = Osteitis Fibrosa  High PTH levels drive the net efflux of calcium from bone  Abrupt withdrawal of PTH results in marked uptake of calcium, phosphate and magnesium  hypocalcemia, hypomagnesemia, hypophosphatemia

17. Hungry Bone Syndrome  Common occurrence in primary or secondary hyperparathyroidism due to CRF following parathyroidectomy  May also be seen in tx with calcimimetics in ESRD and described in some cases of thyroidectomy for hyperthyroidism

18. Are There Any RF’s for Developing Hungry Bone Syndrome?  Brasier & Nussbaum, 1988. Am. J. of Medicine.  215 pts evaluated for post-parathyroidectomy for primary hyperparathyroidism, of these 25 developed HBS  These pts were older by 10 years, had higher preop calcium levels, ALP & BUN, and had larger parathyroid adenomata

19. Hungry Bone Syndrome  Clinical picture mainly dominated by hypocalcemia  Serum calcium usually reaches its nadir at POD 2 to 4  Duration of hypocalcemia is variable and may last up to 3 months Brasier, AR, Nussbaum, SR, Am J Med 1988; 84:654

20. Hungry Bone Syndrome  Close monitoring and treatment needed as hypocalcemia may be catastrophic e.g. Tetany, seizures  Serum calcium should be measured 2 to 4 times per day for the first few post-op days  Oral calcium supplementation should begin as soon as patient able to swallow – 2-4g elemental calcium per day

21. Hungry Bone Syndrome  Vitamin D supplementation may also be of benefit  Clair et al., 1987. Nephron.  RCT, placebo-controlled of calcitriol max. 4 mcg/d in 14 hemodialysis pts post-parathyroidectomy  decrease in serum Ca much less in treatment arm  4 out of 7 pts in placebo arm developed severe hypocalcemia  Pts receiving calcitriol required less mean calcium supplements  Could results be applied to primary hyperparathyroidism?? HD pts are often Vit D deficient

22. Management of Chronic Hypocalcemia

23. Case Two A 23 year old male after presenting with perioral numbness and tingling in the fingers is discovered to have acquired autoimmune hypoparathyroidism with bloodwork showing a serum calcium of 1.9 mmol/L, albumin 45 g/L, low PTH, high phosphate and normal Mg and 25OHD levels.

24. Case Two  After acutely treating with calcium gluconate and calcitriol, what should be done in the chronic mgt of this patient?  If vitamin D supplementation is pursued, which form should be used in the chronic setting?  What are some of the adverse effects of calcium and vitamin D supplementation in this case?  Is there any role for replacing PTH?

25. Hypoparathyroidism  Hypoparathyroidism secondary to abnormal parathyroid gland function  Goal is to relieve symptoms and maintain serum Ca concentration within a low normal range 2.0 to 2.1  Typically achieved with 1 to 1.5g of elemental Ca per day  Vitamin D is the second pillar of tx e.g. Calcitriol at a starting dose of 0.25mcg bid increasing weekly to achieve satisfactory serum Ca

26. Hypoparathyroidism  Hypercalciuria is a side- effect of supplementation in the setting of hypoparathyroidism  Without the stimulatory effect of PTH on the kidneys, renal reabsorption of Ca does not occur  Therefore excretion of Ca greater than normal placing the pt at risk for nephrolithiasis, neprhocalcinosis and CKD

27. Hypoparathyroidism  Urinary calcium should be checked periodically and dose adjustments made to keep urinary calcium <300mg/d  Aim for serum Ca in the lower range of normal  If urinary calcium is starting to reach 250mg/d consider thiazide diuretics  Effects include enhancing proximal tubule passive reabsorption secondary to reduced volume and action at active reabsorption in the distal tubule

28. A Role for PTH Replacement  Several small trials have suggested that recombinant PTH (teriparatide) can maintain serum Ca within the normal range while reducing the level of urinary Ca excretion  Indicated in osteoporosis, but its use in hypoparathyroidism is off-label  May be an option in persistent hypocalcemia despite supplementation  Must insure that 1500 to 2000mg of Ca is also consumed daily  Limited by cost

29. A Role for PTH Replacement  Winer et al., 2003. J. Clin Endo & Met.  RCT, open label trial comparing PTH to calcitriol + calcium carbonate over a 3 year period  Both arms successfully maintained serum Ca at low- normal range and maintained bone  Treatment with PTH reduced urinary Ca – 5.8mmol/d vs. 8.2mmol/d (normal range 1.25-6.25mmol/d)

30. A Role for PTH Replacement  Winer et al., 1998. J. Clin Endo & Met.  Randomized, cross-over trial lasting 28 weeks in 17 subjects comparing once daily to twice daily PTH injection  Twice daily regimen maintained better serum Ca and Mg control and reduced variation in serum Ca at a lower total daily dose

31. Vitamin D Deficiency  Levels measured via 25OHD  As levels fall, Ca absorption decreases and PTH levels rise  No consensus on the optimal 25OHD concentration for skeletal health  Insufficiency 50 to 75nmol/L  Deficiency less than 50nmol/L

32. Vitamin D Deficiency  Nutritional Insufficiency  Vitamin D3 800-1000U daily as a starting point  This will increase 25OHD levels to 75nmol/L over a 3 month period  Nutritional Deficiency  Initial treatment with 50,000U of vit D2 or D3 weekly for 6-8 weeks then 800-1000U daily  Consider vitamin D metabolites for those with renal or liver disease or those with malabsorption unresponsive to supplementation  Preferred by some clinicians for its rapid onset and offset of action and ease of titration despite cost  Much greater doses ranging 10,000-50,000U may be required in malabsorptive states e.g. IBD  Maintain daily calcium intake of at least 1000mg/d

33. Vitamin D Treatment: Monitoring and Adverse Effects  25OHD levels should be monitored every 3 months  Vitamin D stored in adipose tissue making toxicity hard to predict and treat at times  First signs of toxicity are hypercalcemia and hypercalciuria typically occuring at 25OHD levels >220nmol/L

34. Hypo- and Hypermagnesemia  Hypomagnesemia  Commonly occurs with malabsorption, malnutrition, chronic alcoholism, cisplatin therapy  Hypomagnesemia interferes with the action of PTH at target organs (bone & kidneys) rendering a state of PTH resistance or decreasing PTH secretion  Resulting hypocalcemia can only be corrected with Mg supplementation In the form of magnesium chloride (Slow Mag) or magnesium lactate (Mag-Tab SR) 2 to 4 tablets sufficient for mild, asymptomatic cases may be increased to 6 to 8 tablets for severe cases Key is to avoid an abrupt elevation in serum Mg as this will promote urinary excretion

35. Hypo- and Hypermagnesemia  Hypermagnesemia  Often occurs in severe instances serum Mg >2.5mmol/L usually encountered with CKD or when given for pre- eclampsia  Mg activates parathyroid calcium-sensing receptors suppressing PTH secretion  Rarely develops into symptomatic hypocalcemia

36. Summary  Hypocalcemia may lead to serious complications if not treated effectively  In the post-op setting, there may be benefit to treating all patients prophylactically for hypocalcemia  A change in PTH level of 65% at 6hrs post-op may be helpful in predicting hypocalcemia and therefore an extended hospital stay  Patients following parathyroidectomy for hyperparathyroidism should be monitored closely for hungry bone syndrome  Oral calcium supplementation should be started as soon as possible in HBS, there may be a benefit in also starting calcitriol

37. Summary  In hypoparathyroidism Ca supplementation should be given to a target of low-normal serum calcium  If urinary calcium reaching 250mg/d consider thiazide diuretics  Small trials have shown PTH avoids hypercalciuria, however its use is off-label in hypoparathyroidism and it is costly  Most vitamin D deficiency and insufficiency can be treated with D2 or D3  Reserve vitamin D metabolites for renal and hepatic failure patients, however, many still use calcitriol given it’s quick onset and short half- life despite its cost  Hypocalcemia due to hypomagnesemia can only be corrected through Mg supplementation