Background Kernicterus can occur even with seemingly safe total bilirubin levels if the unbound bilirubin fraction (Bf) increases. This elevation can be caused by substances that displace bilirubin from albumin. Sulfisoxazole is a known displacer, and our previous research suggested that Intralipid might have a similar effect. Methods Our study aimed to compare the bilirubin-displacing effects of unbound free fatty acids (FFAu) from Intralipid with those of sulfisoxazole. We used a modified bilirubin fluorescence sensor to measure Bf in undiluted samples. Bilirubin–albumin complexes were created using human serum albumin (3 g/dL) and bilirubin (257 µmol/L), and FFAu was quantified with the ADIFAB2 sensor. Displacement studies involved titration with either sulfisoxazole or FFAu components of Intralipid, including oleate and linoleate. Results The baseline Bf was 0.017 µmol/L. Sulfisoxazole at 540 µmol/L raised Bf to 0.070 µmol/L. Comparable increases were observed with unbound oleate and linoleate at approximately 0.200 µmol/L and 1.800 µmol/L, respectively. Conclusions FFAu from Intralipid displaces bilirubin from albumin as effectively as sulfisoxazole at concentrations associated with kernicterus. These findings emphasize the potential neurotoxicity risk of Intralipid use in vulnerable infants and stress the importance of monitoring Bf and reassessing lipid therapy protocols in the NICU. Impact <UnorderedList Mark="Bullet"> <ItemContent> Unbound free fatty’ acids (FFAu) from Intralipid displace bilirubin from albumin as potently as sulfisoxazole, a known bilirubin-displacing drug, thereby elevating unbound bilirubin (Bf) to levels associated with kernicterus. This identifies Intralipid as a potential contributor to bilirubin neurotoxicity risk in preterm and sick newborns. </ItemContent> <ItemContent> Addition to literature: Provides direct quantitative evidence, using a bilirubin fluorescence sensor, that FFAu components of Intralipid (especially oleate and linoleate) displace bilirubin from albumin and extends prior suggestions and in vitro observations by showing equivalence to sulfisoxazole, the classic displacer historically linked to kernicterus. </ItemContent> <ItemContent> Impact: Raises clinical concern about the safety of Intralipid administration in vulnerable neonates, particularly preterm infants with impaired bilirubin clearance and reduced albumin binding capacity and suggests that lipid therapy protocols in the NICU may inadvertently increase kernicterus risk, calling for careful evaluation of dosing, timing, and monitoring. </ItemContent> </UnorderedList>

Unbound free fatty acids from intralipid displace bilirubin from albumin, comparable to sulfisoxazole

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2025年12月2日

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Thomas Hegyi,
Andrew Huber,
William Oh,
Alan Kleinfeld

摘要

Background

Kernicterus can occur even with seemingly safe total bilirubin levels if the unbound bilirubin fraction (Bf) increases. This elevation can be caused by substances that displace bilirubin from albumin. Sulfisoxazole is a known displacer, and our previous research suggested that Intralipid might have a similar effect.

Methods

Our study aimed to compare the bilirubin-displacing effects of unbound free fatty acids (FFAu) from Intralipid with those of sulfisoxazole. We used a modified bilirubin fluorescence sensor to measure Bf in undiluted samples. Bilirubin–albumin complexes were created using human serum albumin (3 g/dL) and bilirubin (257 µmol/L), and FFAu was quantified with the ADIFAB2 sensor. Displacement studies involved titration with either sulfisoxazole or FFAu components of Intralipid, including oleate and linoleate.

Results

The baseline Bf was 0.017 µmol/L. Sulfisoxazole at 540 µmol/L raised Bf to 0.070 µmol/L. Comparable increases were observed with unbound oleate and linoleate at approximately 0.200 µmol/L and 1.800 µmol/L, respectively.

Conclusions

FFAu from Intralipid displaces bilirubin from albumin as effectively as sulfisoxazole at concentrations associated with kernicterus. These findings emphasize the potential neurotoxicity risk of Intralipid use in vulnerable infants and stress the importance of monitoring Bf and reassessing lipid therapy protocols in the NICU.

Impact

Unbound free fatty’ acids (FFAu) from Intralipid displace bilirubin from albumin as potently as sulfisoxazole, a known bilirubin-displacing drug, thereby elevating unbound bilirubin (Bf) to levels associated with kernicterus. This identifies Intralipid as a potential contributor to bilirubin neurotoxicity risk in preterm and sick newborns.

Addition to literature: Provides direct quantitative evidence, using a bilirubin fluorescence sensor, that FFAu components of Intralipid (especially oleate and linoleate) displace bilirubin from albumin and extends prior suggestions and in vitro observations by showing equivalence to sulfisoxazole, the classic displacer historically linked to kernicterus.

Impact: Raises clinical concern about the safety of Intralipid administration in vulnerable neonates, particularly preterm infants with impaired bilirubin clearance and reduced albumin binding capacity and suggests that lipid therapy protocols in the NICU may inadvertently increase kernicterus risk, calling for careful evaluation of dosing, timing, and monitoring.