Subcutaneous Fat Necrosis

Hilary Rowe, BScPharm

VIHA Pharmacy Resident 2009-10

Neonatal ICU Rotation

June 9th, 2010

Outline

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

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

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

Subcutaneous Fat Necrosis

• 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

Miss. Baby Girl B

Miss. Baby Girl B

• Meds PTA: None• Allergies: NKA• SH: Mom 22 yo (G3P1A1) with 3 yo daughter • Discharge Plan: Unknown

Review of Systems

System Findings Medications

CNS •Activity-quiet & alert•Normal cry & good suck•Temp 371

•Previous seizures- started April 12th (last 19th) after hypothermia protocol ended

•Phenobarbital 25mg daily•Level 85umol/L (65-170umol/L)

HEENT •Unremarkable

Resp •RR 30 (normal 25-40)•Respirations clear and easy

Review of Systems

System Findings Medications

Cardio •HR 146 (normal 120-160)•No murmur•Palpable brachial and femoral pulses•No edema

GI •Gastroschisis- Repaired surgically at birth•No stool today•Passed gas and burped

Review of Systems

System Findings Medications

Liver April 18th•↑AST 40 (10-36)•↑ALT 157 (10-55)•↑Conj Bili 6 (0-4)

GU •SrCr 29•Urea 6•Output 5.6mL/kg/hr•Ca:Cr ratio ↑ 5.06 (<2)

Review of Systems

System Findings Medications

Heme •↓ RBC 3.9, ↓Hgb 99, ↑ Plt 554•TG ↑2.52 (0.3-1.9 mmol/L)

•Lipid 1.7g/kg/day

Fluids & Lytes

↓ Na 133, K+ 4.4, ↓Cl 94 •EBM 20mL/hr•Dextrose 3.71g/kg/day•Trophamine 1.1g/kg/day•Total Fluid Intake 160ml/kg/day

Review of Systems

Review of Systems

Review of Systems

System Findings Medications

Minerals •April 21st iCa2+1.33•May 14th iCa2+↑1.55

(normal 1.1-1.3 mmol/L)

•Limited Ca, hyperhydration (May 15-19)•Furosemide 4mg IV Q12h (May 18-22)

Skin •Intact, pink, skin with palpable fat necrosis

Musculoskeletal

•Normal tone & reflexes

Review of Systems

Review of Systems

Medical Problems List

• Gastroschisis- Repaired surgically at birth• Hypoxic-Ischemic Encephalopathy (HIE)• Subcutaneous Fat Necrosis (SCFN)• Hypercalcemia

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

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

DRP’s

• 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

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

Subcutaneous Fat necrosis

• 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

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

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

SCFN & Hypercalcemia

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?

Clinical Question

PIn a 5 week old baby with elevated ionized calcium and subcutaneous fat necrosis

I Pamidronate

CHyperhydration, IV Furosemide and limiting Vit D & Calcium

O

Reduce the ionized calcium

Reduce morbidity and mortality

Prevent complications in the heart, liver and kidneys

Search Strategy

• PubMed, Embase, Google• Search terms:

– Subcutaneous fat necrosis– Hypercalcemia & gastroschisis– Hypercalcemia in neonates– Hypercalcemia treatment– Hypercalcemia and pamidronate

• Found– Case reports

Alos et al. Horm Res 2006

Design Retrospective chart review 2001-2004

P •4 newborns with SCFN and hypercalcemia

I•Pamidronate 0.25-0.5mg/kg/dose infused over 4 hours

C •IV fluids, low calcium diet & Furosemide

O

•Prevent nephrocalcinosis (renal ultrasound)•Normalize hypercalcemia (iCa2+)•Bone density of lumbar spine (DXA)

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)

Alos et al. Horm Res 2006

Our Patient 35 1.55 5.06

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Alos et al. Horm Res 2006

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

Therapeutic Options

•Limit Vitamin D

•Limit Calcium intake

•Hyperhydration 180mL/kg

•IV Furosemide

•Pamidronate 0.25-0.5mg/kg

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)

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

Monitoring

Adverse Events

Monitor Who When How Long

Growth (percentile)

RN & Pharmacist

Daily While in hospital

Nephrocalcinosis via renal ultrasound

Physician At 3 mo Once

Monitoring

Efficacy

Monitor Who When How Long

iCa2+ Physician & Pharmacist

Daily X 7 days then weekly

Ca:Cr ratio Physician & Pharmacist

Weekly X 7 days then weekly

BMD Z score

Physician At 3 mo Once

Questions?

References

1. Alos N, Eugene D, Fillion M et al. Pamidronate: Treatment for severe hypercalcemia in neonatal subcutaneous fat necrosis. Horm Res 2006; 65: 289-94.

2. Vijayakumar M, Prahlad N, Nammalwar BR and Shanmughasundharam R. Subcutaneous fat necrosis with hypercalcemia. Indian Pediatrics April 17, 2006; 43: 360-63.