Bilirubin Binding Capacity to Assess Bilirubin Load in Preterm Infants

September 24, 2021 updated by: Stanford University
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The investigator intends to first collect simultaneous and comprehensive "acute phase" measurements of TB, BBC, ETCOc, and COHbc in MPT infants. The investigator will then seek to understand precisely the relationship between GA, TB, BBC, ETCOc, and COHbc levels and the domains of BIND. Third, The investigator will provide a comprehensive database that can be used to improve current neonatal BIND screening practices in the context of lowered and higher BBC. The investigator's working hypothesis is that exposures to modest TB levels in the presence of significantly diminished BBC in the developing neonate result in residual deficits of one or more neuroprocessing function (BIND) at TEA.

  1. Patients (GA 24 to <34 wks) will be enrolled. Subject exclusion criteria: Major life-threatening anomalies and diagnosed inborn errors of metabolic disorders; attending physician or parent refusal.

    Clinical data collection: After receiving written informed consent, the research team will complete clinical data forms for infant demographics. The data forms will be consistent with and abstracted from the medical record. No additional information will be collected for this exploratory study.

    Population: The entire cohort will compromise 60-80 patients. From this cohort, 12 at-risk infants with most impaired BBC and matched with those designated as low-risk will be re-recruited for the follow-up to identify any evidence of BIND in any or all 4 of the outcome variables.

    Laboratory data: Once inclusion criteria are met, routine neonatal laboratory tests will be as clinically ordered. Each infant will tested for BBC and ETCOc at least 2 intervals (maximum 4 over 12h-7d) during rates-of-rise and -decrease in TB. Subsequent laboratory and clinical data will be paired with research data for statistical analysis.

    The investigators will compare BIND outcomes at TEA to 3 mos-corrected age (<54 wks PMA) using a re-consented sample size: n=12 for those at high risk with decreased BBC versus a GA-matched controls at low risk (n=12).

  2. Measurements: 0.1-mL whole blood will be drawn in special heparinized tubes for COHbc determinations and anticoagulated blood set aside for the hematofluorometry.

Plasma for peroxidase UB assays will be stored and labeled without patient identifiers.

Frozen research samples will be transported to the Spectrum Child Health Research (SCHR) Lab for analyses. 1. BBC, TB, and UB will be measured directly: 1a. BBC, TB and UB in 50-μL whole blood using POC hematofluorometry; TB performed by the hospital-based clinical laboratory; and UB in plasma using the peroxidase method (Arrows device).

ETCOc will be determined for those breathing spontaneously.

c. Testing and techniques for outcome variables for select at-risk and matched control infants:

  1. Screening ABR: Two or more simultaneously channels will consist of the electrode pairs of: 1) contralateral to ipsilateral mastoid prominence; 2) vertex to ipsilateral mastoid; and 3) vertex to contralateral mastoid for better identification of waves. Insert tubephone earphone will be used to introduce an acoustic delay to distinguish CM response from artifact. Rarefaction clicks at 90, (75), 60, (45), and 30 dBnHL will be delivered monaurally to the right and left ears. RE and LE, ≥2 repetitions, ≥2,000 sweeps/repetition. Separate recording to rarefaction and condensation clicks will be obtained at 90 dB. The surface electrical activity will be amplified x10,000 and filtered from 30-3,000 Hz. Latencies and peak-to-trough amplitudes of waves and CM from the outer hair cells in the inner ear of the ABRs will be scored independently by "masked" interpreters (Drs. Oghalia and Popelka).

  2. Screening Visual Brainstem Responses after TEA (at 50-54 wks PMA): All infants in this subcohort will be evaluated using the sVEP technique described above.68 Electrodes are placed across the back of the visual cortex, midline and 2 cm to the left and right, with a reference lead at the occipital vertex. Thresholds and suprathreshold measurements will be compared with controls. Further, the infants in the bilirubin cohort can serve a case series with a dose response plot determined, comparing thresholds with TB levels. Bin averages for each type of vision can also be compared to the same for control infants to determine whether suprathreshold measures vary to any significant degree from controls (Fig. 3).

    Evidence from other studies of CNS damage suggests that lower signal amplitudes and thresholds correlate with CNS damage. Support for this sample size is based on practical considerations an ad hoc sample size calculation.

  3. Neuroimaging of the brain will be performed by conventional MRI at TEA; this is the routine near-term neuroimaging for preterm infants in our institution. MRI is performed in unsedated infants, using a 3-Tesla platform with sequences that include Sagittal T1 FLAIR, Axial DWI, T2 FRFSE, FLAIR, GRE, and SSFSE, and Coronal SSFSE and 3D SPGR over 30 min. Drs. Barnes and Hintz, who will be masked to the acute phase biomarkers data, will interpret imaging utilizing a central reader form that includes white matter scoring according to a widely used classification system, and data regarding location, number, size, and imaging characteristics of lesions. Dr. Bhutani will correlate these data to the acute biomarkers.

Study Type

Observational

Enrollment (Actual)

143

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Stanford, California, United States, 94305
        • Lucile-Packard Children's Hospital at Stanford

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 months to 7 months (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Inpatient premature infants

Description

Inclusion Criteria:

  • Patients (GA 24 to ≤34 wks)

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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
Research laboratory assay of bilirubin binding capacity
Other Names:
  • BBC
Diagnostic test: End-tidal Carbon Monoxide
Noninvasive bedside test to measure exhaled end-tidal carbon monoxide levels for the detection of hemolysis
Other Names:
  • ETCOc
Diagnostic test: Carboxyhemoglobin
Laboratory assay of carboxyhemoglobin levels for the detection of hemolysis
Other Names:
  • COHbc

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Age-specific gradations of BBC values for each week of GA and in order to characterize degree of disordered BBC.
Time Frame: postnatal age 0-7 days
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determinants of bilirubin load (using rates of bilirubin production) on BBC
Time Frame: postnatal age 0-7 days
This aim addresses the hypothesis that biochemical markers of bilirubin load, individually or collectively, related to excessive bilirubin production and insufficient BBC, define the mechanisms of bilirubin load for maturational age (both term PMA and GA). The studies are directed toward translating diverse components of bilirubin loads: serum albumin, BBC, and TB rate-of-rise and decrease. These data will integrate measurements of bilirubin load using established indices of bilirubin production that accurately characterize early signs of BIND at term equivalent age that may be associated with neuroanatomical changes, and NDI.
postnatal age 0-7 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Infants most at-risk for BIND prior to discharge (up to 55 weeks) for subtle or direct evidence of NDI at term equivalent age.
Time Frame: >=55 weeks PMA
This aim addresses the hypothesis that acute phenotypic measures of BIND at TEA are identified most in preterm infants who have insufficient BBC. These data will detect perturbations in any or all domains of visuo-oculomotor, auditory, neuroanatomical (MRI) and neurodevelopmental functions.
>=55 weeks PMA

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Stanford University

Collaborators

Smith-Kettlewell Eye Research Institute

Investigators

  • Principal Investigator: Vinod K Bhutani, MD, Stanford University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2016

Primary Completion (Actual)

August 31, 2018

Study Completion (Actual)

August 31, 2018

Study Registration Dates

First Submitted

February 16, 2016

First Submitted That Met QC Criteria

February 19, 2016

First Posted (Estimate)

February 25, 2016

Study Record Updates

Last Update Posted (Actual)

October 1, 2021

Last Update Submitted That Met QC Criteria

September 24, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-31187

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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