1. Subcutaneous Fat Necrosis Hilary Rowe, BScPharm VIHA Pharmacy Resident 2009-10 Neonatal ICU Rotation June 9th, 2010

2. Outline • Objectives • Patient Case • Background • Clinical Question • Review of Evidence • Recommendation • Monitoring

3. Objectives • Review pathophysiology for subcutaneous fat necrosis and hypercalcemia • Be able to list: • 3 therapies used to treat hypercalcemia • The mg/kg dose of pamidronate used in neonates • The lab parameters to monitor & their normal ranges

4. Miss. Baby Girl B • ID: 5 week old girl wt 4,024 g • CC: Palpable fat necrosis, ↑ ionized Ca 1.55 mmol/L (started May 14th) • HPI: ↑ ionized calcium since 1 month of age

5. Subcutaneous Fat Necrosis

6. Miss. Baby Girl B • PMHx: Born at 365 by emergency cesarean section for fetal distress (↓HR) and prenatal diagnosis of gastroschisis • Resuscitated x 5 min • APGAR 1 at 1min, 1 at 5min, 3 at 10 min • Treated with therapeutic hypothermia (whole body) to reduce risk of brain injury • Gastroschisis- Repaired surgically at birth

7. Miss. Baby Girl B • Meds PTA: None • Allergies: NKA • SH: Mom 22 yo (G3P1A1) with 3 yo daughter • Discharge Plan: Unknown

8. Review of Systems

9. Review of Systems

10. Review of Systems

11. Review of Systems

12. Review of Systems

13. Review of Systems

14. Review of Systems

15. Review of Systems

16. Review of Systems

17. Medical Problems List • Gastroschisis- Repaired surgically at birth • Hypoxic-Ischemic Encephalopathy (HIE) • Subcutaneous Fat Necrosis (SCFN) • Hypercalcemia

18. DRP’s • BB is at risk of poor weight gain secondary to a poorly-functioning GI tract and requires daily assessment of her TPN • BB is at risk of rickets secondary to an interaction between Phenobarbital and Vitamin D (hyper-metabolism) and would benefit from reassessment of her vitamin D supplementation

19. DRP’s • BB is at risk of renal dysfunction and mortality secondary to high levels of serum ionized calcium despite current therapies and requires reassessment of her drug therapy

20. Subcutaneous Fat necrosis • Seen in 1st week of life in full term babies • Obstetric trauma, meconium aspiration, hypoxemia or hypothermia • Signs & Symptoms • Painful, firm, indurated, red nodules on buttocks, trunk, arms and cheeks • ↑ saturated fatty acids in subcutaneous tissue from defective neonatal fat metabolism, worsened by neonatal stress & fat necrosis from trauma during delivery

21. Subcutaneous Fat necrosis • The fat of neonates is made of saturated fatty acids with a relatively high melting point • Neonatal stress resulting in hypothermia may induce fat to undergo crystallization, causing necrosis • Hypercalcemia in SCFN may result in significant morbidity • Incidence of hypercalcemia complicating SCFN is not known

22. Hypercalcemia • Causes • Osteoclast activation and ↑ production of 1,25 dihydroxyvitamin D3 by macrophages increased bone turnover • Hypercalcemia is usually noticed 4-6 weeks after skin lesions

23. Hypercalcemia Hypercalcemia can cause • Metastatic calcifications in the heart, inferior vena cava & liver • Nephrocalcinosis and nephrolithiasis secondary to hypercalciuria occurs within 4-6 months of onset • Thrombocytopenia and hyperlipidemia • Death

24. SCFN & Hypercalcemia • SCFN is a self-limiting condition and needs no treatment except when associated with hypercalcemia • Requires: • Regular monitoring of serum calcium levels • Therapy: • ↓calcium and vitamin D in the diet • Hyperhydration ~200mL/kg/day • IV furosemide

25. NICU Discussion Rounds • Physician discussed that baby has ↑ calcium and that he has seen pamidronate used at other hospitals • Physician wanted to know • What dose to give • How often to give it • If there is evidence for this indication • What the safety risks are?

26. Clinical Question

27. Search Strategy • PubMed, Embase, Google • Search terms: • Subcutaneous fat necrosis • Hypercalcemia & gastroschisis • Hypercalcemia in neonates • Hypercalcemia treatment • Hypercalcemia and pamidronate • Found • Case reports

28. Alos et al. Horm Res 2006

29. Alos et al. Horm Res 2006 • 4 full-term newborns with SCFN & hypercalcemia • SCFN diagnosed on • Skin nodules (red or purple, indurated) • Serum ionized calcium (1.12-1.25 mmol/L) • Serum 25- hydroxy vitamin D (25-85 nmol/L) • 1, 25-dihydroxy vitamin D (41-145 pmol/L) • PTH (1.3-7.6 pmol/L) • Urinary Ca:Cr ratio (<2)

30. Alos et al. Horm Res 2006 Our Patient 35 1.55 5.06

31. Alos et al. Horm Res 2006 Case 1 • Born via cesarean for fetal distress • 1st developed haematuria & thrombocytopenia due to renal vein thrombosis • 2nd indurated SCFN lesion on back and shoulders • At 42 days-weight dropped from 90th to 10th percentile and baby developed renal failure

32. Alos et al. Horm Res 2006 • SrCr 107 umol/L (23-93) • Hypercalcemia iCa2+ 2.19 mmol/L • Ca:Cr 3.24 • Patient received hyperhydration, 6 doses of IV furosemide 1mg/kg and low Ca and Vitamin D in diet iCa2+ 2.3 mmol/L • Day 45, 46, 47 pamidronate 0.25mg/kg per dose • Day 54 iCa2+ normalized

33. Alos et al. Horm Res 2006 • At 3 mo no skin lesions, normal iCa2+, moderate nephrocalcinosis with normal renal function • At 18 mo growth in 75th percentile, bone age was identical to actual age, BMD Z score was 0SD • 3 years old growth curve was still 75th percentile, nephrocalcinosis disappeared on renal ultrasounds

34. Alos et al. Horm Res 2006 Case 2 • Born via cesarean for fetal distress • During 1st few days of life developed SCFN • Hypercalcemia discovered on day 6 • Vitamin D supplementation was stopped • Day 30 iCa2+ 1.58 mmol/L • Ca:Cr 6.5 • Hyperhydration and 4 doses of furosemide 1mg/kg

35. Alos et al. Horm Res 2006 • Pamidronate 0.25mg/kg on day 33 and 36 • Ca:Cr normalized day 38, iCa2+ normalized day 39 • Day 54 3rd dose of pamidronate given as iCa2+ ↑ to 1.45mmol/L & Ca:Cr 1.5

36. Alos et al. Horm Res 2006 • At 2 mo skin lesions almost gone, calcium continued to be normal, mild nephrocalcinosis on renal ultrasound • At 6 mo nephrocalcinosis had disappeared • At 2 years length 95th percentile, normal development, BMD Z score +1SD

37. Alos et al. Horm Res 2006 Case 3 • Delivered at term with meconium aspiration and transient thrombocytosis • Day 1 had SCFN (on cheeks had feeding difficulty) • 11th day hypercalcemia noted iCa2+ 1.64 • Fluid hydration, IV furosemide 1mg/kg x 1 dose, low calcium and vitamin D diet

38. Alos et al. Horm Res 2006 • Day 18 & 24 pamidronate 0.25mg/kg • Day 29 & 37 pamidronate 0.5mg/kg because of ↑ iCa2+ but normal Ca:Cr • At 3 mo all skin lesions gone • At 2 & 7 mo no nephrocalcinosis on renal ultrasound

39. Alos et al. Horm Res 2006 • Growth was at 50th percentile • BMD Z score at 7 mo was 0SD • At 7 & 13 mo motor development was normal

40. Alos et al. Horm Res 2006 Case 4 • Delivered at term with meconium aspiration • Mother had diabetes • 6th day SCFN-scalp and back • Day 12 hypercalcemia • Day 20 iCa2+ 1.49mmol/L • Ca:Cr 3.58

41. Alos et al. Horm Res 2006 • IV Hydration with no Furosemide • Day 26 pamidroante 0.25mg/kg + 2 doses pamidroante 0.5mg/kg days on 27 & 28 • Day 29 Ca:Cr normalized • Day 31 iCa2+ normalized • At 3 mo SCFN gone, iCa2+ 1.37 mmol/L, Ca: Cr 1.3 mmol/mol

42. Alos et al. Horm Res 2006 • At 3 & 9 mo no nephrocalcinosis • BMD Z score at 3 mo was 0SD • At 9 mo Length was on the 50th percentile

43. Alos et al. Horm Res 2006 • Furosemide & steroids can increase renal calcium excretion and the risk of nephrocalcinosis • Pamidronate inhibits bone resorption which results in ↓ serum calcium so it reduces the renal calcium load • it does not ↑ the risk of nephrocalcinosis

44. Alos et al. Horm Res 2006 Conclusion • 3-4 doses of pamidronate 0.25-0.5mg/kg is effective to reduce serum calcium • ? if used as 1st line it could ↓ the risk of nephrocalcinosis • commentary disagrees but pt was on steroid and furosemide 1st

45. Goals of Therapy Patient’s Family Goals • Discharge baby home with fewest complications Team Goals • ↓ the risk of nephrocalcinosis • Normalize serum iCa2+ • Resolve SCFN • Decrease morbidity & mortality • Minimize adverse drug events

46. Therapeutic Options • Limit Vitamin D • Limit Calcium intake • Hyperhydration 180mL/kg • IV Furosemide • Pamidronate 0.25-0.5mg/kg

47. Recommendation • Initiate pamidronate 1mg (0.25mg/kg) if ionized calcium level >1.4mmol/L • Monitor ionized calcium daily -Expect drop in calcium in 48-72 hours • Determine subsequent doses based on response (up to 4 doses)

48. Patients iCa2+ dropped to 1.38mmol/L so pamidronate was not initiated

50. Monitoring