Reducing bilirubin-induced neurological dysfunction (BIND) in premature newborns, additional use of bilirubin:albumin ratio in the treatment of hyperbilirubinemia

Neonatal jaundice due to unconjugated hyperbilirubinemia occurs is almost all
preterm infants and is potentially neurotoxic. Treatment is based on total
serum bilirubin (TSB), but is not evidence based. TSB is an unreliable
predictor of bilirubin induced neurological dysfunction (BIND). Free bilirubin,
i.e. not bound to albumin, is a better parameter for bilirubin neurotoxicity,
but measurements of free bilirubin concentrations are not available in clinical
practice. The bilirubin: albumin ratio is considered as a surrogate parameter
for free bilirubin. Low albumin levels (i.e. high B:A ratios) increase free
bilirubin levels and potentiate risk of BIND. The B:A ratio is thus an
interesting additional parameter in the management of hyperbilirubinemia in
preterm infants.

The research question of this study is whether BIND is reduced using B:A ratios
in addition to TSB versus TSB only as indicators for treatment of
hyperbilirubinemia in preterm infants.

Prospective, randomized controlled, open label, blinded outcome multicenter
study in tertiary neonatal intensive care units in the Netherlands

Hyperbilirubinemia is evaluated daily using the B:A ratio together with TSB
(study group) versus TSB only (control or care-as-usual group). Treatment
guidelines are based on B:A ratio and TSB (whichever comes first) versus only
TSB.

Daily blood examinations in the first 10 days of life will include measurements
of bilirubin and albumin levels. The estimated total bloodvolume for these
measurements is approximately 1.0 mL (10 x 100µL (about 10 µL plasma per
measurement)). Usually, these measurements do not require extra blood volume.
Sometimes, more blood is required (maximal 10 x 0.1 ml = 1.0 ml), but no extra
puncture will be necessary.
Residual blood samples will be stored for free bilirubin measurements: no extra
punctures will be done for this purpose.
Residual urine samples that are collected as part of the routine clinical
treatment, will be stored for lumirubine measurements.
It is a possibility that the childeren will be subjected to phototherapy or
exchange transfusion earlier than in the care-as-usual protocols. On the other
hand, earlier start of phototherapy may prevent exchange transfusions. The net
effect cannot be predicted.
A part of the studypopulation will be subjected to a more extended audiological
evaluation (ABR) than in the routine protocol (ALGO). The ABR and ALGO consist
of auditory stimuli via a headphone, registered by 3 (ABR) or 1 (ALGO)
head-electrodes.
A full developmental test is part of the studyprotocol. In general these tests
are part of the routine follow-up visits of NICU-graduates.
It is the intention to perform additional neurodevelopment assessments at later
ages (4-7years), but those are beyond the scope of this study protocol.