Unbound Free Fatty Acids from Preterm Infants Treated with Intralipid Decouples Unbound from Total Bilirubin Potentially Making Phototherapy Ineffective

Abstract

Extremely low birth weight (ELBW; <1,000 g) infantshave poor outcomes, often compromised by bilirubin neurotoxicity. We measured unbound bilirubin (B_f) and unbound free fatty acid (FFA_u) levels in 5 ELBW infants in a trial examining the effects of pharmacologic ductal closure on infants treated with Intralipid infusion (3 g/kg/day). The levels for all infants (mean ± SD) were: total serum bilirubin (TSB) 4.6 ± 1.7 mg/dl, FFA_u 376 ± 496 n<smlcap>M</smlcap>, and B_f 42 ± 30 n<smlcap>M</smlcap>. Of the 3 infants who died, 2 had TSB <5.9 mg/dl but FFA_u >580 n<smlcap>M</smlcap> and B_f >75 n<smlcap>M</smlcap>. Multiple regression revealed a major effect on B_f levels due to FFA_u, indicating that Intralipid elevated levels of FFA_u and B_f. Indomethacin or ibuprofen reduced B_f levels, most likely by reducing FFA_u levels through lipase inhibition. Because displacement of B_f by FFA_u decouples B_f from TSB, phototherapy may not reduce the risk of bilirubin or FFA_u toxicity in Intralipid-treated ELBW infants.

Effects of Soybean Lipid Infusion on Unbound Free Fatty Acids and Unbound Bilirubin in Preterm Infants

“…(29) Our own previous study suggested that increases in FFAu and Bf can reach extreme and toxic levels, and that under such conditions phototherapy cannot reduce Bf sufficiently. (15) This investigation was not aimed at documenting the short or long-term toxicity of elevated Bf levels, thus auditory brainstem responses in the infants were not collected. (6) The standard of care in our neonatal intensive care unit is a hearing test by an automated auditory brainstem response test that provides only pass/fail data and infants who fail this screen are referred to the audiology program where the work-up may include a diagnostic auditory brainstem evoked response test.…”

“…The Bf probe (BL22P1B11-Rh) binds unconjugated bilirubin with high affinity (Kd=16 nM) but is poorly sensitive to FFA (Kd>3000 nM), conjugated bilirubin (Kd>300 nM), bilirubin photoisomers, bilirubin oxidation products, ibuprofen and indomethacin (17). FFAu concentrations were determined using the ADIFAB2 probe (15, 18). Fluorescence was assessed at two emission wavelengths: 457 and 550 nm for the FFAu probe and 525 and 580 nm for the Bf probe (excitation = 375 nm for both).…”

“…We have previously shown that both FFAu and Bf were highly elevated in extremely low birthweight infants treated with IL at 3 g/kg/day (15). In the present study, we hypothesized that 1) increasing doses of IL (from 1 to 3 g/kg/day) would be associated with increasing levels of FFAu and Bf, independent of TSB and 2) that phototherapy would be effective in lowering TSB but not Bf, particularly in extremely preterm (<28 weeks GA) infants during IL infusion.…”

Association of intralipid intake in extremely low birthweight infants with neurodevelopmental outcomes

“…The latter competes with the bilirubin binding sites of albumin, resulting in a higher unbound or free bilirubin (Bf). Hegyi et al recently showed that increasing doses of IL administration in VLBW infants is associated with increasing levels of unbound free fatty acid (FFAu) as well as Bf (4,5). Amin et al have previously shown similar results (6).…”

“…Hegyi et al. recently showed that increasing doses of IL administration in VLBW infants is associated with increasing levels of unbound free fatty acid (FFAu) as well as Bf . Amin et al.…”