Approach to management of Hypercalcemic emerggencies

Case based scenario of managing Hypercalcemic emergency

1. Management of Hypercalcemic Crisis

2. Hypercalcemia Definition :Total Serum Calcium(bound + ionized ) > 10.6 mg/dl or ionized calcium > 5.3 mg/dl.

3. Clinical manifestations Manifestations of hypercalcemia (S calcium > 12 mg/dl) Acute Chronic Gastrointestinal Anorexia Nausea, Vomiting Dyspepsia Constipation Pancreatitis Renal Polyuria Polydipsia Nephrolithiasis Nephrocalcinosis Neurological Depression Confusion Stupor, coma Weakness Cardiac Short Q-T interval bradycardia I degree AV block Hypertension

4. Hypercalcemic crisis Accepted definition Serum calcium > 14 mg/dl associated with rapid deterioration of the central nervous , cardiac, gastrointestinal and renal function (Ziegler R.. J Am Soc Nephrol 2001; 12: S3–9)

5. Etiology Etiology Primary Hyperparathyroidism (PHPT) in majority. Incidence 1.6-6 % Malignancy –advanced disease & poor prognosis Parathyroid adenoma-> 85 % Large Polyglandular Rarely ectopic Parathyroid carcinoma-4% Histopathology ( Microcystic pattern, Intracytoplasmic vacuole, necrosis, fibrosis)- SGPGIMS, Lucknow Decompensation could be triggered by immobilization, intercurrent illness, inadvertent Vit D supplementation, drugs (Thiazides, Lithium, antacids)

6. Literature review –Hypercalcemic crisis & PHPT Duration 1958-2011 n-=499 Mean age 43.94 y M=165,F=300 Mean S Calcium-18 mg/dl Symptoms- Frequent Nephrolithiasis Constipation Peptic Ulcers (non healing) Osteoporosis Less frequent Cardiac CNS changes Gurrado A et al Endokrynologia Polska 2012;63 ;494-502

7. Diagnostic tests Establish or refute the diagnosis of PHPT Elevated or inappropriately normal i PTH -PHPT Imaging USG Neck (High frequency 12/15 MHz transducers) Sestamibi Scan (dual phase) Assist in doing a focused parathyroidectomy

8. Management Medical management- bridge to parathyroidectomy Lowering calcium levels Correcting dehydration and enhancing renal excretion of calcium Decreasing Osteoclast mediated bone resorption

9. Therapy

10. Promoting calciuresis -Hydration Patients are dehydrated and have lost sodium (renal tubular absorption is suppressed by hypercalcemia IV fluid-0.9% Saline Initial rate 200-300 ml/h subsequently maintain urine output of 100-150 ml/h (≈ 3-4 L in first 24 h) Intravascular volume expansion increases GFR→ increases calcium filtration .Sodium promotes calciuresis at distal nephron Leads to 1.6-2.4 mg/dl reduction in serum calcium Caution-Poor cardiac reserve/impaired renal function Am J Med 2015;128 (3) : 239-244

11. Promoting calciuresis -Loop diuretics Block calcium re-absorption in the ascending loop of Henle Administer only after rehydration Furosemide 40-80 mg /day Combined with hydration reduce Serum Calcium by 4 mg/dl Useful in those with reduced cardiac function and mild renal impairment Am J Med 2015;128 (3) : 239-244

12. Inhibiting bone resorption- Bisphosphonates N Engl J Med 2002; 346:642

13. Bisphosphonates Effective in lowering calcium to near normal . Approved drugs for hypercalcemia - Pamidronate , Zoledronic acid Unless contraindicated should be considered first line therapy in conjunction with volume replacement Side effects -Flu like syndrome, hypophosphatemia, nephrotoxicity,hypocalcemia Mitigates postoperative hypocalcemia(‘hungry bone syndrome’)

14. Bisphosphonates Dose & administration Pamidronate Zoledronic acid Dose 60-90 mg 4mg Mode of administration IV infusion over 2 h Infusion over 15 min Efficacy - Considered better; achieves reduction in S Calcium earlier Dose modification * e GFR 30-60 ml/min e GFR < 30 ml/min No change Extend the infusion for 4-6 h Reduction in dose Not recommended * Kidney International (2008) 74, 1385–1393

15. C alcitonin Reduces o steoclastic action , promotes calciuresis , inhibits calcium absorption from intestine Not effective as monotherapy Used in conjunction with bisphosphonates as it has faster onset of action Calcitonin 4-8 mg IU/kg im or sc every 6-12 h.Peak decrease occurs in 2-6 h Down regulation of receptors in bone and kidney leads to tachyphylaxis . Side effects-Nausea, flushing, local site reaction ,hypersensitivity

16. Dialysis Patients with renal insufficiency Patients refractory to other therapy Either peritoneal dialysis or hemodialysis can be effective.

17. Glucocorticoids Utility in limited subset Suppresses growth of lymphoid neoplasia lymphoma and leukemia Suppresses 1 α hydroxylase in activated macrophage Vit D intoxication, granulomatous disorders Other actions- reduces bone resorption and increases renal excretion of Calcium Drug & dose-Hydrocortisone 200-300 mg iv over 24 h/Prednisolone 1-2 mg/kg for 3-5 days

18. Therapies-Comparative table Treatment Onset of action Duration of action Reduction in Serum Calcium Advantages Hydration with Saline Hours During infusion 1-3 mg/d; Corrects dehydration Infusion plus loop diuretics Hours During infusion 4 mg/dl Rapid onset Bisphosphonstes 1-2 days 10-14 days Returns to normal in majority High potency Calcitonon Hours 1-2 days - Rapid onset of action Dialysis Hours Till 24-48 h after 3-12 mg/dl Only effective modality for moderate to severe renal impairment

19. Therapies of hypercalcemia Serum Calcium (mg/dl) Therapy < 12mg/dl Rehydration 12-15mg/dl Rehydration +Bisphosphonates/Calcitonin >15 mg/dl Rehydration + Forced saline diuresis + Bisphosphonates/Calcitonin Dialysis if in renal failure Glucocorticoids (specific condition)

20. PHPT & Hypercalcemic crisis- SGPGIMS ,Lucknow

21. HIHC-SGPGIMS, Lucknow SGPGIMS, Lucknow (1989-2010) Number of patients 37 (Male-12.Female-25 Mean age 39 ± 15 Clinical presentation Bone pain, Fracture, proximal muscle weakness, Mental status changes, Pancreatitis significantly higher Serum Calcium (mg/dl) 15.14 ± 1.06 i PTH ( pg /ml) 890.33 ± 163.7 Treatment Saline , loop diuretics, Bisphosphonates Decrease in Serum Calcium 4.5 days Post operative hypocalcemia (symptomatic ) 12/37 Mortality 3/37 ( pancreatitis & sepsis/Cerebral mets /unknown)

22. Conclusion Hypercalcemic crisis is a rare endocrine emergency PHPT is the most common etiology H ydration and bisphosphonates are first line therapy Medical therapy is a bridge to definitive treatment i.e. Surgery Long term outcomes with combined therapy have shown excellent outcomes

23. THANK YOU

24. Newer therapies Cinacalcet 30 mg x bid oral titrated to 90 mg x QID daily for hypercalcemia due to parathyroid carcinoma Denusomab - Monoclonal antibody against RANKL Used in hypercalcemia of malignancy No role in hypercalcemic crisis