Subcutaneous Fat Necrosis after Moderate Hypothermia Therapeutic In Neonates

Brenda Strohm, RN, AnaHobson, BA , Peter Brocklehurst ,FRCOG, A David Edwards , DSc, and Denis Azzopardi , FRCPCH, on behalf of the UK TOBY Cooling register
BACKGROUND

Therapeutic moderate hypothermia in newborn infants with hypoxic-ischemic encephalopathy is quickly become standard clinical practice.Here we report 12cases of subcutaneous fat necrosis of the 1239 casesregistered with the national record of newborn infantswho were treated with moderate wholebodyhypothermia.All the infants suffered from perinatalasphyxia and hypoxicischemicencephalopathy. Moderate to severe hypercalcaemia was identified in 8 of 10 infants through themeasurement of blood calcium.In all cases, skinlesions appeared after completion of cooling treatment.Our data suggest that prolonged moderate hypothermiais an actual risk factor for subcutaneous fatnecrosis. Because the lesions often develop several days after birth, doctors need to recognize this condition as a possible complication in infants treatedwith moderate hypothermia after asphyxia. Blood calcium levels should be monitored in the affected infants.
METHOD

birth, so the lesions occurred after completion of coolingtreatment in all infants. The spread of lesions variedamong infants, but the common areas affected are the buttocks, back and arms. A photograph of the skin lesion from 1 of the case shown in Fig 1. In that infants, 9 days after onset of lesions, bleeding into the affected areas occurred, which required surgical evacuation of hematoma. This infant then requiredskindebridement and grafting. Blood calcium levels were measured in 10 infants,but the time and frequency measurement varied between cases, so it is not possible to provide a systematic count of temporary changes in blood calcium levels. The medianpeak blood calcium levels was 2.98 mmol/L(range: 1.5 to 5.1 mmol/L); the levels were 2.5 to 3 mmol/L in four infants and> 3 mmol/L in another four infants.One infant had characteristic skin lesions at17 days of age and then presented with vomiting at the age of 8 weeks, when the blood calcium level was found to be 3.37 mmol/L and renal ultrasound scan showednephrocalcinosis. Four infants received specifictherapy for hypercalcaemia which consists of feeding with low-calcium milk formula and diuretic therapy. All the infants survived.
CONCLUSIONS:

Twelve cases of subcutaneous fat necrosis in neonates treated with moderate whole body hypothermia (to a target rectal temperature of 33.5C for 72 hours) after birth asphyxia were identified of 1239 cases registered in the UK TOBY Cooling Registered from December2006 to August 2010. The infants median birth weight was 3700 grams (range: 2100 to 4260 g), and median gestation was 39.5 weeks (range: 38 to 41 weeks).All infants had clinical signs consistent with birth asphyxiaand encephalopathy as described in the register handbook (www.npeu.ox.ac.uk/tobyregister). The median 5-minute Apgar score was 5 (range: 2 to8), and median base deficit in the first arterial blood sample was 21 mmol/L (range: 13 to 25 mmol/L). Therapeutic hyporthermia was achieved withservo or manually controlled cooling mattresses;bag of ice was not used.
RESULTS

Subcutaneous fat necrosis is a rare condition that affects neonates and is characterized with redness andhardeningof subcutaneous tissue, sometimesaccompanied by hypercalcaemia. This condition usually resolves within a few days or weeks, but hypercalcaemia can be severe and require treatment with steroids, diuretics, or, pamidronat.3,4A single case of subcutaneous fat necrosis was reported ina randomized controlled trial of moderate hypothermia after perinatal asphyxia, and other cases after hypothermia therapy has recently been reported.
DISCUSSION:

Skin lesions weredescribed as reddish, hardening, andswollen, in some cases, the lesions were examined bydermatologists and confirmed to be characteristic ofsubcutaneous fat necrosis. The lesions were identified on average 6 days (range: 4 to 42 days) after

Our report highlights the importance of surveillance after such new therapies into routine clinical practice. The 12 cases of subcutaneous fat necrosis reported here represent the ~1% of infants who had been treated with moderate hypothermia and registeredin the UK TOBY Cooling Register.The

frequency of this subcutaneous fat necrosis in infants who are atcooling seems to be greater than previously reported after perinatal asphyxia, because the previous number is a rare anecdotal cases, but there are limited data in the literature, and the actual incidence of this complication after perinatal asphyxia isunknown. However, the frequency of subcutaneous fatnecrosisobserved in the UK TOBY Cooling Register indicates that a prolonged moderate hypothermia is an actual risk factor for subcutaneous fat necrosis, andparents should be informed about the complications that may occur if the whole body hypothermia therapy is offered. Because the lesions often develop several days after birth and sometimes after discharge from the hospital, physicians need to recognize this condition as a possible complication in infants who were treated with moderate hypothermia after asphyxia. The cause of subcutaneous fat necrosis is unknown. Previous cases have been associated with perinatal asphyxia, trauma, or severe hypothermia, including in infants who underwent cardiac surgery hypothermia, and cold has been known as a common factor.4 However, our patients were treated with milder levels of hypothermia than that previously associatedwith hypothermia.The possibility that mildhypothermia worsens skin perfusion that is already compromised by perinatal asphyxia, leading to fat necrosis.Histological examination of the subcutaneous lesion showed panniculitiswith mixed inflammatory infiltrate and giant cells with characteristic clefts,and necrosis of subcutaneous fat.6Subcutaneous fat necrosis must be distinguished from sclerema andscleroderma, which also causes redness, hardening,and swelling of the skin. Sclerema and scleroderma occursmainly at the first weekof age, usually in very sick newbornand more common in prematureinfants. Histopathology also differ in three conditions:scleremais characterized by thickening of connectivetissue with a thin inflammatory infiltrate of lymphocytes, histiocytes, and multinucleate giant cells, whereas edema is more prominent in scleroderma.7 Fat necrosis is not present in this condition, but ischaracteristic of necrosis subcutaneous fat. It is unknown why hypercalcemia occurs in some casesof subcutaneous fat necrosis, especially because renal function did not seem disturbed. It is known that hypercalcaemia may be caused by increased absorption of calcium as a result of production of 1,25dihydroxyvitamin D beyond the kidney that are not regulated, which may occur in another inflammatory disorders.8Altoughtblood biochemistry is checked regularly during treatment with moderate hypothermia, currently there has been no clue about how long the

levels of calcium should be monitored after rewarming.The findings of elevated levels of blood calcium in some of our patients, which is persistent over a period of prolonged in some patients, showed that the blood calcium levels should be monitored more closely after hypothermia therapy than currently practiced. It may beadvised to measure blood calcium levels at the time of hospital discharge in all infants who were treated with moderate whole body cooling and infants with subcutaneous fat necrosis to monitor blood calcium levels repeatedly until the skin lesions healed.