Cholestasis
Conditions
Keywords
cholestasis, neonates, parenteral nutrition, gastrointestinal disorders
Brief summary
Neonates with congenital/acquired gastrointestinal disorders are at high risk for Parenteral Nutrition Associated Cholestasis (PNAC). Besides enteral nutrition, standard therapies to prevent and treat PNAC have been limited and marginal. Recently, the dose and composition of standard intravenous fat emulsions have implicated in the development and progression of PNAC. In this study, neonates with congenital/acquired gastrointestinal disorders will be randomized, in a unblinded fashion, to receive either the standard dose of an intravenous omega-6 fatty acid emulsion or a low dose of an intravenous omega-6 fatty acid emulsion throughout their course of PN or until hospital discharge, death or 100 days of life, whichever comes first. The primary outcome will be the presence of cholestasis.
Detailed description
Parenteral Nutrition (PN) acts as an intravenous source of both macronutrients and micronutrients when enteral feeds are not possible. Intravenous fat emulsions often supplement PN and provide a dense source of non-protein calories and essential fatty acids. Although PN is life-sustaining, it is associated with a myriad of life-threatening complications including Parenteral Nutrition Associated Cholestasis (PNAC). Children dependent on PN for an extended period of time are high risk for liver failure. The etiology of PNAC remains poorly understood. Neonates with congenital and acquired gastrointestinal disorders are at high risk for PNAC and its subsequent complications. Examples of these gastrointestinal disorders include gastroschisis, volvulus, atresias, dysmotility and malabsorption disorders, pseudo-obstruction, and Hirschsprung's disease. These disorders often render the gut non-functional for extended periods of time. As a result, these patients become PN-dependent and develop PNAC. Specific PN components have been implicated in the pathogenesis of PNAC. More recently, standard intravenous fat emulsions have been labeled as one of the main culprits contributing to PNAC. Standard intravenous fat emulsions are dosed as high as 4 g/kg/d and are derived from soybean and/or safflower oil, which are rich in omega-6 fatty acids and phytosterols and contain a paucity of omega-3 fatty acids. It is unclear if the dose or high omega-6 fatty acid:omega-3 fatty acid ratio and phytosterols is responsible for the development of PNAC. The primary specific aim of this study is to determine if PNAC is related to the amount of standard intravenous fat emulsion administered to neonates with congenital/acquired gastrointestinal disorders. The investigators hypothesize that the PNAC is unrelated to the dose of intravenous fat emulsions. To test this hypothesis, neonates with congenital/acquired gastrointestinal disorders will be randomized to low dose standard soybean based parenteral fat, 1 g/kg/d, or standard dose soybean parenteral fat, 3 g/kg/d. Secondary outcomes include: mortality rate, length of stay, and anthropometric measurements at 28 days of life and at the end of the hospital stay, which is expected to be an average of 5 weeks.
Interventions
DRUGIntralipid
The subject will receive 1 g/kg/d of the standard intravenous fat emulsion while receiving Parenteral Nutrition until discharge from the hospital, death or 100 days of life, whichever comes first.
Sponsors
St. Louis University
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Minutes to 5 Days
Healthy volunteers
No
Inclusion criteria
* congenital or acquired gastrointestinal disorder * age less than 5 days of life
Exclusion criteria
* congenital intrauterine infection know to be associated with liver involvement * known structural liver abnormalities * known genetic disorders (trisomy 21, 13, and 18) * inborn errors of metabolism * infants meeting the criteria for terminal illness (ph:6.8\>2 hours)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Cholestasis | prior to 100 days of life, hospital discharge, or death whichever comes first | Cholestasis will be defined by a direct bilirubin \> 2 mg/dL |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality Rate | at the end of the hospital stay which is expected to be an average of 5 weeks | death |
| Anthropometric Measurements | 28 days of age | Growth will be assessed by growth velocity at 28 days of age |
Countries
United States
Participant flow
Pre-assignment details
41 subjects were enrolled in the study. Only subjects who required \> 14 days of parenteral nutrition and who had an abdominal surgery were included in the final analysis.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Intravenous Fat Emulsion Subjects in this arm will receive approximately 1 g/kg/d IV of intravenous soybean oil (Intralipid).
Intralipid: The subject will receive 1 g/kg/d of the standard intravenous fat emulsion while receiving Parenteral Nutrition until discharge from the hospital, death or 100 days of life, whichever comes first. | 20 |
| Standard Dose Intravenous Fat Emulsion Subjects in this arm will receive approximately 3 g/kg/d IV of intravenous soybean oil (Intralipid).
Intralipid: The subject will receive 3 g/kg/d of the standard intravenous fat emulsion while receiving Parenteral Nutrition until discharge from the hospital, death or 100 days of life, whichever comes first. | 16 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Low Dose Intravenous Fat Emulsion | Total | Standard Dose Intravenous Fat Emulsion |
|---|---|---|---|
| Age, Continuous | 1.3 days STANDARD_DEVIATION 1.4 | 1.3 days STANDARD_DEVIATION 1.3 | 1.3 days STANDARD_DEVIATION 1.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 18 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 18 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 31 Participants | 14 Participants |
| Region of Enrollment United States | 20 participants | 36 participants | 16 participants |
| Sex: Female, Male Female | 12 Participants | 18 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 18 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 16 |
| serious Total, serious adverse events | 2 / 20 | 1 / 16 |
Outcome results
Primary
Presence of Cholestasis
Cholestasis will be defined by a direct bilirubin \> 2 mg/dL
Time frame: prior to 100 days of life, hospital discharge, or death whichever comes first
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Intravenous Fat Emulsion | Presence of Cholestasis | Presence of Cholestasis-Yes | 6 participants |
| Low Dose Intravenous Fat Emulsion | Presence of Cholestasis | Presence of Cholestasis-No | 14 participants |
| Standard Dose Intravenous Fat Emulsion | Presence of Cholestasis | Presence of Cholestasis-Yes | 6 participants |
| Standard Dose Intravenous Fat Emulsion | Presence of Cholestasis | Presence of Cholestasis-No | 10 participants |
Secondary
Anthropometric Measurements
Growth will be assessed by growth velocity at 28 days of age
Time frame: 28 days of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Intravenous Fat Emulsion | Anthropometric Measurements | 18 g/d | Standard Deviation 8 |
| Standard Dose Intravenous Fat Emulsion | Anthropometric Measurements | 24 g/d | Standard Deviation 16 |
Secondary
Anthropometric Measurements
Growth will be assessed by weight at the time of hospital discharge (approximately 5 weeks)
Time frame: approximately 5 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Intravenous Fat Emulsion | Anthropometric Measurements | 3.4 g | Standard Deviation 0.9 |
| Standard Dose Intravenous Fat Emulsion | Anthropometric Measurements | 3.5 g | Standard Deviation 0.7 |
Secondary
Mortality Rate
death
Time frame: at the end of the hospital stay which is expected to be an average of 5 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Intravenous Fat Emulsion | Mortality Rate | 0 participants |
| Standard Dose Intravenous Fat Emulsion | Mortality Rate | 0 participants |