Bilirubin Binding Capacity to Assess Bilirubin Load in Preterm Infants

NCT02691156 | Completed DMC

• 1 other identifier: IRB-31187
• Study Type: observational
• Target: 143
• Locations: 1 country
• Sites: 1

Brief Summary

Most preterm newborns are managed by phototherapy to reverse hyperbilirubinemia with the intent to prevent bilirubin neurotoxicity. A threshold-based relationship between a specific total bilirubin level and need for intervention has been elusive. This is most likely due to other biomarkers such as hemolysis, developmental maturation, concurrent illnesses, or even interventions, may impede bilirubin/albumin binding. The over-prescription of phototherapy has impacted clinical and family-centered care, and in the extreme preterm infants, it may have augmented their risk of mortality. Thus, the opportunity to individualize phototherapy in in order to reduce its use is unique. The investigators have assembled a transdisciplinary team to examine critical unanswered questions including the role of bilirubin binding capacity (BBC) of an individual during the first week of life in the context of clinical modifiers and antecedents for a domain of bilirubin-induced neurologic disorders, that includes neuro-anatomical, hearing, visual and developmental processing impairments. In this study, the investigator will evaluate two new innovative nanotechniques to quantify bilirubin load for the first time in the context of a clinical decision algorithm to identify those most at risk for any bilirubin-related neurotoxicity. The investigators anticipate that knowledge gained from this study will lead to ethically testable hypotheses to individualize the prescription of phototherapy.

Conditions

Bilirubin-induced Neurologic Dysfunction; Hyperbilirubinemia; Kernicterus; Infant, Premature; Infant, Low Birth Weight

Keywords

Hematofluorometer

Outcome Measures

Primary Outcomes (1)

• Age-specific gradations of BBC values for each week of GA and in order to characterize degree of disordered BBC.

  This aim addresses the hypothesis that there are functional degrees and extents of BBC that can be objectively graded to quantify insufficient BBC. These data will define BBC ranges to guide objective, accurate thresholds that identify what levels of TB compared to the BBC is "safe". Infants with insufficient (\>45% saturation) and near-normal (\<25% saturation) BBC will be identified as select cohorts and then further tested for BIND at term-equivalent age.

  postnatal age 0-7 days

Secondary Outcomes (1)

• Determinants of bilirubin load (using rates of bilirubin production) on BBC

  postnatal age 0-7 days

Other Outcomes (1)

• Infants most at-risk for BIND prior to discharge (up to 55 weeks) for subtle or direct evidence of NDI at term equivalent age.

  >=55 weeks PMA

Study Arms (1)

Premature Infants

Premature infants GA 24 to ≤34 wks at risk for hyperbilirubinemia will have BBC, ETCOc, and COHbc measured during 0-7 days of life.

Diagnostic Test: Bilirubin Binding Capacity; Diagnostic Test: End-tidal Carbon Monoxide; Diagnostic Test: Carboxyhemoglobin

Interventions

Bilirubin Binding Capacity DIAGNOSTIC_TEST

Research laboratory assay of bilirubin binding capacity

Also known as: BBC

Premature Infants

End-tidal Carbon Monoxide DIAGNOSTIC_TEST

Noninvasive bedside test to measure exhaled end-tidal carbon monoxide levels for the detection of hemolysis

Also known as: ETCOc

Premature Infants

Carboxyhemoglobin DIAGNOSTIC_TEST

Laboratory assay of carboxyhemoglobin levels for the detection of hemolysis

Also known as: COHbc

Premature Infants

Eligibility Criteria

• Age: 24 Weeks - 34 Weeks
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

Inpatient premature infants

You may qualify if:

• Patients (GA 24 to ≤34 wks)

You may not qualify if:

• Major life-threatening anomalies and diagnosed inborn errors of metabolic disorders
• Attending physician or parent refusal

Sponsors & Collaborators

• Stanford University: lead
• Smith-Kettlewell Eye Research Institute: collaborator

Study Sites (1)

Lucile-Packard Children's Hospital at Stanford

Stanford, California, 94305, United States

Location

Related Publications (26)

• Lamola AA, Bhutani VK, Du L, Castillo Cuadrado M, Chen L, Shen Z, Wong RJ, Stevenson DK. Neonatal bilirubin binding capacity discerns risk of neurological dysfunction. Pediatr Res. 2015 Feb;77(2):334-9. doi: 10.1038/pr.2014.191. Epub 2014 Nov 24.

  PMID: 25420178 BACKGROUND

• Practice parameter: management of hyperbilirubinemia in the healthy term newborn. American Academy of Pediatrics. Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Pediatrics. 1994 Oct;94(4 Pt 1):558-65. No abstract available.

  PMID: 7755691 BACKGROUND

• American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297-316. doi: 10.1542/peds.114.1.297.

  PMID: 15231951 BACKGROUND

• Bhutani VK, Johnson LH, Shapiro SM. Kernicterus in sick and preterm infants (1999-2002): a need for an effective preventive approach. Semin Perinatol. 2004 Oct;28(5):319-25. doi: 10.1053/j.semperi.2004.09.006.

  PMID: 15686262 BACKGROUND

• Bhutani VK, Vilms RJ, Hamerman-Johnson L. Universal bilirubin screening for severe neonatal hyperbilirubinemia. J Perinatol. 2010 Oct;30 Suppl:S6-15. doi: 10.1038/jp.2010.98.

  PMID: 20877410 BACKGROUND

• Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001 Feb 22;344(8):581-90. doi: 10.1056/NEJM200102223440807. No abstract available.

  PMID: 11207355 BACKGROUND

• Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM. Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol. 2009 Feb;29 Suppl 1:S25-45. doi: 10.1038/jp.2008.211.

  PMID: 19177057 BACKGROUND

• Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn. Pediatrics. 2006 Aug;118(2):805-7. doi: 10.1542/peds.2006-0675. No abstract available.

  PMID: 16882840 BACKGROUND

• Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed. 2003 Nov;88(6):F455-8. doi: 10.1136/fn.88.6.f455.

  PMID: 14602689 BACKGROUND

• Watchko JF, Oski FA. Kernicterus in preterm newborns: past, present, and future. Pediatrics. 1992 Nov;90(5):707-15.

  PMID: 1408544 BACKGROUND

• Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O'Shea TM, McDavid GE, Perritt RL, Van Meurs KP, Vohr BR, Grisby C, Yao Q, Pedroza C, Das A, Poole WK, Carlo WA, Duara S, Laptook AR, Salhab WA, Shankaran S, Poindexter BB, Fanaroff AA, Walsh MC, Rasmussen MR, Stoll BJ, Cotten CM, Donovan EF, Ehrenkranz RA, Guillet R, Higgins RD; NICHD Neonatal Research Network. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008 Oct 30;359(18):1885-96. doi: 10.1056/NEJMoa0803024.

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• O'Shea TM, Dillard RG, Klinepeter KL, Goldstein DJ. Serum bilirubin levels, intracranial hemorrhage, and the risk of developmental problems in very low birth weight neonates. Pediatrics. 1992 Dec;90(6):888-92.

  PMID: 1279513 BACKGROUND

• Oh W, Tyson JE, Fanaroff AA, Vohr BR, Perritt R, Stoll BJ, Ehrenkranz RA, Carlo WA, Shankaran S, Poole K, Wright LL; National Institute of Child Health and Human Development Neonatal Research Network. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics. 2003 Oct;112(4):773-9. doi: 10.1542/peds.112.4.773.

  PMID: 14523165 BACKGROUND

• Yeo KL, Perlman M, Hao Y, Mullaney P. Outcomes of extremely premature infants related to their peak serum bilirubin concentrations and exposure to phototherapy. Pediatrics. 1998 Dec;102(6):1426-31. doi: 10.1542/peds.102.6.1426.

  PMID: 9832580 BACKGROUND

• Johnson L, Bhutani VK. The clinical syndrome of bilirubin-induced neurologic dysfunction. Semin Perinatol. 2011 Jun;35(3):101-13. doi: 10.1053/j.semperi.2011.02.003.

  PMID: 21641482 BACKGROUND

• Scheidt PC, Graubard BI, Nelson KB, Hirtz DG, Hoffman HJ, Gartner LM, Bryla DA. Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy. Pediatrics. 1991 Jun;87(6):797-805.

  PMID: 2034482 BACKGROUND

• Oh W, Stevenson DK, Tyson JE, Morris BH, Ahlfors CE, Bender GJ, Wong RJ, Perritt R, Vohr BR, Van Meurs KP, Vreman HJ, Das A, Phelps DL, O'Shea TM, Higgins RD; NICHD Neonatal Research Network Bethesda MD. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants. Acta Paediatr. 2010 May;99(5):673-678. doi: 10.1111/j.1651-2227.2010.01688.x. Epub 2010 Jan 25.

  PMID: 20105142 BACKGROUND

• Amin SB, Lamola AA. Newborn jaundice technologies: unbound bilirubin and bilirubin binding capacity in neonates. Semin Perinatol. 2011 Jun;35(3):134-40. doi: 10.1053/j.semperi.2011.02.007.

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• Cashore WJ, Oh W, Blumberg WE, Eisinger J, Lamola AA. Rapid fluorometric assay of bilirubin and bilirubin binding capacity in blood of jaundiced neonates: comparisons with other methods. Pediatrics. 1980 Sep;66(3):411-6.

  PMID: 7422430 BACKGROUND

• Lamola AA, Eisinger J, Blumberg WE, Patel SC, Flores J. Flurorometric study of the partition of bilirubin among blood components: basis for rapid microassays of bilirubin and bilirubin binding capacity in whole blood. Anal Biochem. 1979 Nov 15;100(1):25-42. doi: 10.1016/0003-2697(79)90105-2. No abstract available.

  PMID: 543536 BACKGROUND

• Hintz SR, Stevenson DK, Yao Q, Wong RJ, Das A, Van Meurs KP, Morris BH, Tyson JE, Oh W, Poole WK, Phelps DL, McDavid GE, Grisby C, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Is phototherapy exposure associated with better or worse outcomes in 501- to 1000-g-birth-weight infants? Acta Paediatr. 2011 Jul;100(7):960-5. doi: 10.1111/j.1651-2227.2011.02175.x. Epub 2011 Feb 25.

  PMID: 21272067 BACKGROUND

• Tyson JE, Pedroza C, Langer J, Green C, Morris B, Stevenson D, Van Meurs KP, Oh W, Phelps D, O'Shea M, McDavid GE, Grisby C, Higgins R; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns? J Perinatol. 2012 Sep;32(9):677-84. doi: 10.1038/jp.2012.64. Epub 2012 May 31.

  PMID: 22652561 BACKGROUND

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• Ahlfors CE, Wennberg RP, Ostrow JD, Tiribelli C. Unbound (free) bilirubin: improving the paradigm for evaluating neonatal jaundice. Clin Chem. 2009 Jul;55(7):1288-99. doi: 10.1373/clinchem.2008.121269. Epub 2009 May 7.

  PMID: 19423734 BACKGROUND

• Funato M, Tamai H, Shimada S, Nakamura H. Vigintiphobia, unbound bilirubin, and auditory brainstem responses. Pediatrics. 1994 Jan;93(1):50-3.

  PMID: 8265323 BACKGROUND

• Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R. Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics. 2001 Apr;107(4):664-70. doi: 10.1542/peds.107.4.664.

  PMID: 11335741 BACKGROUND

MeSH Terms

Conditions

Hyperbilirubinemia; Kernicterus; Premature Birth

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Erythroblastosis, Fetal; Hematologic Diseases; Hemic and Lymphatic Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Immune System Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Study Officials

• Vinod K Bhutani, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 16, 2016
• First Posted: February 25, 2016
• Study Start: February 1, 2016
• Primary Completion: August 31, 2018
• Study Completion: August 31, 2018
• Last Updated: October 1, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)