Bilirubin Neurotoxicity (BN) and Neurodevelopmental Impairment (NDI) in Extremely Preterm (EP) Infants: Avoidable by Reducing the Usual Intravenous Lipid (UL) Administration

The purpose of this study is to evaluate the effect of usual versus reduced lipid intake on unbound bilirubin levels, brainstem auditory evoked responses, and neurodevelopmental outcome at 2 years in extremely preterm infants.

Study Overview

• Status: Active, not recruiting
• Conditions: Bilirubin Encephalopathy
• Intervention / Treatment: Drug: usual prescribed intralipid (UL) regimen; Drug: restricted prescribed intralipid (RL) regimen

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• no major congenital anomaly or overt nonbacterial infection
• mother has consented to inclusion of the infant for the Neonatal Research Network (NRN) Cycled Phototherapy Trial

Exclusion Criteria:

• has received Intralipid

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: usual prescribed intralipid (UL) regimen	Drug: usual prescribed intralipid (UL) regimen; Intralipid will be started at 1 g/kg/day and routinely advanced by 1 g/kg/day each day to a max of 3 g/kg/day as per usual clinical practice
Experimental: restricted prescribed intralipid (RL) regimen	Drug: restricted prescribed intralipid (RL) regimen; Intralipid will be started at 0.5 g/kg/day and routinely advanced by 0.5 g/kg/day each day to a max of 1.5 g/kg/day (half rate of usual clinical practice).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Unbound Bilirubin (UB) Concentration Greater Than 30 Nanomoles Per Liter (Nmol/L)		within first 14 days of life
Average Unbound Bilirubin (UB) Concentration	6 UB measurements will be taken per participant .Average of the 6 readings will be reported	within first 14 days of life
Brain Stem Auditory-evoked Response (BAER) V Latency	Brainstem auditory evoked response (BAER) testing is a procedure used to assess the auditory pathways of the brainstem and evaluate hearing ability. Wave latency, measured in milliseconds, is the measure of electric transmission of sound. If the wave latency is prolonged, this means that something is in the way of electric sound wave transmission, such as bilirubin which has an affinity for depositing in a specific area of the brainstem that wave V measures.	38 weeks post menstrual age(PMA)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight		36 weeks postmenstrual age
Peak Free Fatty Acid Uptake (FFAU)		within first 14 days of life
Peak UB Concentration		within first 14 days of life
Total Unbound Free Fatty Acids (FFA)	6 FFA measurements will be taken for each participant.Average of the 6 readings will be reported	within first 14 days of life
Peak Total Serum Bilirubin		within first 14 days of life
Number of Patients With Direct Bilirubin Greater Than 1.5 mg/dL		Before discharge (discharge is on average 3 months after birth)
Amount of Protein Given to Participant in Grams Per Kilograms on Day 14 of Life	Calculated as the mean daily protein intake in grams per kilogram of body weight on Day 14 of life.	Day 14 of life
Amount of Carbohydrates Given to Participant in Grams Per Kilograms on Day 14 of Life	Calculated as the mean daily carbohydrates intake in grams per kilogram of body weight on Day 14 of life.	Day 14 of life
Amount of Fats Given to Participant in Grams Per Kilograms on Day 14 of Life	Calculated as the mean daily fats intake in grams per kilogram of body weight on Day 14 of life.	Day 14 of Life
Weight z Score	Weight Z-scores were calculated using the PediTools Fenton Growth Curves Calculator (2013 version), based on the Fenton Preterm Growth Charts. The following thresholds were used for interpretation: Z-score ≤ -2: Growth failure (worse outcome) Z-score = 0: Population mean (appropriate outcome) Z-score 0 to <2: Appropriate growth (better outcome) Z-score ≥ 2: Excessive growth (worse outcome)	day 28
Weight		birth
Number of Patients With Bronchopulmonary Dysplasia		36 weeks post menstrual age
Number of Patients With Perinatal and Hospital Acquired Sepsis Episodes		birth until discharge ( discharge will be about 3 months post birth)
Number of Patients Who Died		24 months PMA
Number of Patients With Neurodevelopmental Impairment		24 months PMA
Number of Patients With Hearing Loss		24 months PMA
Number of Patients With Cerebral Palsy		24 months PMA
Serial FiO2 (Fraction of Inspired Oxygen)		Day 1 of life through day 14 of life
Ventilator Setting		Day 1 of life through day 14 of life

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Lindsay F Holzapfel, MD, MS, The University of Texas Health Science Center, Houston

Publications and helpful links

General Publications

• Holzapfel LF, Arnold C, Tyson JE, Shapiro SM, Reynolds EW, Pedroza C, Stephens EK, Kleinfeld A, Huber AH, Rysavy MA, Del Mar Romero Lopez M, Khan AM. Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial. BMC Pediatr. 2023 Jul 10;23(1):347. doi: 10.1186/s12887-023-04149-0.
• Holzapfel L, Arnold C, Tyson J, Shapiro S, Reynolds E, Pedroza C, Stephens E, Kleinfeld A, Huber A, Rysavy M, Khan A, Del Mar Romero Lopez M. Effect of Reduced Versus Usual Lipid Emulsion Dosing on Bilirubin Neurotoxicity and Neurodevelopmental Impairment in Extremely Preterm Infants: Study Protocol for a Randomized Controlled Trial. Res Sq [Preprint]. 2023 Mar 7:rs.3.rs-2566352. doi: 10.21203/rs.3.rs-2566352/v1.

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2021
• Primary Completion (Actual): March 14, 2024
• Study Completion (Estimated): June 14, 2026

Study Registration Dates

• First Submitted: October 6, 2020
• First Submitted That Met QC Criteria: October 6, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): November 28, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: preterm; bilirubin; lipid emulsions; unbound bilirubin; unbound free fatty acids
• Additional Relevant MeSH Terms: Urogenital Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Immune System Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Infant, Newborn, Diseases; Hyperbilirubinemia; Hematologic Diseases; Brain Diseases, Metabolic; Erythroblastosis, Fetal; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Hemic and Lymphatic Diseases; Premature Birth; Kernicterus; Health Care Quality, Access, and Evaluation; Therapeutics; Health Care Evaluation Mechanisms; Quality of Health Care; Epidemiologic Study Characteristics; Clinical Protocols
• Other Study ID Numbers: HSC-MS-20-0916; KL2TR003168 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No