Clinical trial NCT01050660: Low Dose Parenteral Fat for Prevention of Parenteral Nutrition Associated Cholestasis in Preterm Neonates
Official title: Low Dose Parenteral Fat for Prevention of Parenteral Nutrition Associated Cholestasis in Preterm Neonates
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Parenteral Nutrition-Associated Liver Disease
Keywords: Parenteral nutrition associated liver disease
Direct bilirubin
Intravenous fat emulsion
Very low birth weight infants
PNAC
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: University of California, Los Angeles
name: Northwestern University Feinberg School of Medicine
First posted: 2010-01-15
Enrollment: 136
Sex: ALL
Minimum age (years): 12
Maximum age (years): 48
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The goal of the study is to determine if parenteral nutrition-associated cholestasis (PNAC) is related to the amount of parenteral (intravenous) fat administered to premature babies until full enteral nutrition is achieved.

Detailed description: In the neonatal intensive care unit, parenteral nutrition is widely used to provide protein, energy, vitamins and minerals to infants who cannot accept enteral feeds.

Intravenous fat emulsion is an important component of parenteral nutrition because of the important caloric supply that it brings, but also for the essential fatty acids (linoleic and linolenic acid) that it provides. Because intravenous fat emulsion is the only supply of essential fatty acids, at least until the enteral feeds are established, there is a minimum of fat that has to be administered with at least 0.25g/kg /day for preterm babies and 0.1g/kg/day for term infants (Lee EJ, 1993). The maximal dose of intravenous fat safe to administer is difficult to determine. Although in larger preterm infants intravenous fat is tolerated well based on measurement of serum triglycerides, there are still question regarding tolerance in extremely low birth weight infants.

Parenteral nutrition has been associated with the development of liver disease-parenteral nutrition associated liver disease (PNALD). PNALD can range from cholestasis and a transient elevation of liver enzymes to more severe forms including fibrosis, liver cirrhosis and hepatic failure. Cholestasis, defined as hyperbilirubinemia with a direct bilirubin above 2 mg/dL or more than 15% of total bilirubin, is a hepatocellular injury of the liver that manifests after the administration of parenteral nutrition for at least two weeks. The mechanism by which the liver injury occurs is unknown and probably multifactorial. Risk factors associated with the development of PNAC include: prematurity, low birth weight, absence of enteral feeds, bacterial sepsis, necrotizing enterocolitis, prolonged use of parenteral nutrition, and multiple surgical procedures on the gastro-intestinal tract. In addition, many of the nutrients contained in parenteral nutrition, have been linked with the development of cholestasis.

Specific factors associated with intravenous fat emulsions that have been related to PNAC include : phytosterols, the rate of administration of the intravenous emulsion, the total amount of fat administered and toxic metabolites of intravenous fat emulsions.

The total amount of lipids was found to be a risk factor for cholestasis in children on long-term parenteral nutrition and decreased amount of fat was recommended for the prevention of this hepatic complication (Colomb V, 2000). In the adult population parenteral lipid intake of less than 1gr/kg of body weight decreased the risk of cholestasis in parenteral nutrition treated patients (Cavicchi, 2000).

Current Nutritional Management for VLBW infants in the NBSCU:

The administration of parenteral nutrition to all the preterm babies with a gestational age less than or equal to 29 weeks' is standard practice in the NBSCU for infants not receiving full enteral nutrition. Fat, as an integral part of the intravenous alimentation, is started in the first day of life at a dose of 0.5 grams/kg/day of an 20% fat emulsion(eg, Lyposyn II, Abbott Laboratories Chicago, IL). The amount of fat is then gradually increased by 0.5-1 grams/kg/day to total amount of 3 grams/kg/day as tolerated. The tolerance is checked by measuring serum triglyceride level the morning after 3 grams/kg/day has been reached for the first time serum triglyceride level ≤200 mg/dl are accepted for infants ≤52 weeks postmenstrual age. If the serum triglyceride level is \>200 mg/dL, the intravenous fat emulsion is reduced for 24 hours, then the triglyceride level is checked again to ensure that it has dropped below 200 mg/dL. The fat emulsion is then restarted at 1-1.5 grams/kg/day and the serum triglyceride level is monitored as it is slowly increased.

Enteral nutrition is started initially as minimal enteral feedings, also called non-nutritive feedings, usually by 48±12 hours of age with about 12 ml/kg/day. The feedings are then advanced as tolerated with the goal to reach full enteral nutrition (\>120 ml/kg/day) between 14-21days of life. As the enteral volumes reach 1/3, 1/2, and 2/3 of the total daily fluid volume, the rate of administration of the lipid emulsion is decreased in steps (ie, from 2 grams/kg/day to 1.5 to 1.0) , until the intravenous fat emulsion is stopped.

As part of standard NBSCU management guidelines screening of liver function consists of measuring serum direct bilirubin level after the baby has been on TPN for 10 days to two weeks and then biweekly, if PN continues. In addition, if the direct bilirubin level is greater than 2.5mg/dL, then liver enzymes will be checked .

Study Procedure:

All preterm babies with a gestational age less than or equal to 29 weeks' born at YNHH who will receive intravenous fat emulsion as part of their nutrition management are eligible to participate in the study. The parents of these babies will be approached during the first 24 hours of life, regarding the possible participation in the study. After informed consent will be obtained, the subjects will be randomized by YNHH Investigator pharmacy to one of the two groups: intervention (restricted intravenous fat intake) and control (standard intravenous fat intake).

Therefore, the purpose of this study will be to determine if PNAC is related to the amount of parenteral fat administered to premature babies until full enteral nutrition is reached.

Eligibility criteria: Inclusion Criteria:

* Preterm infants less than or equal to 29 weeks' gestation
* Age less than 48 hours

Exclusion Criteria:

* Congenital intrauterine infection, known to be associated with liver involvement and cholestasis
* Known structural liver abnormalities that are associated with cholestasis
* Known genetic disorders: trisomy 21, trisomy 13 and trisomy 18
* Inborn errors of metabolism
* Infants meeting the criteria for terminal illness (eg, pH \< 6.8 \> 2 hours)
* Inability to obtain informed consent

Primary outcomes:
measure: The Presence of Cholestasis at Age of 28 Days or When Full Enteral Nutrition is Achieved, Whichever is Longer.
timeFrame: 28 days of age or when full enteral nutrition is acheived, whichever is longer
Secondary outcomes:
measure: Mortality Rate- Death Rate Before Discharge From the Hospital
timeFrame: Discharge from the Newborn ICU
measure: Incidence of Bronchopulmonary Dysplasia (BPD)
timeFrame: 36 weeks PMA or discharge home,whichever comes first
measure: Incidence of Necrotizing Enterocolitis (NEC)
timeFrame: At discharge from Newborn ICU
measure: Incidence of Retinopathy of Prematurity (ROP)
timeFrame: At discharge from Newborn ICU
measure: Late Onset Sepsis
timeFrame: At the discharge from Newborn ICU
measure: Length of Stay
timeFrame: At discharge from Newborn ICU/death
measure: Anthropometric Measurements(Body Weight)
timeFrame: At age of 28 days and at discharge
measure: Anthropometric Measurements(Length)
timeFrame: At age of 28 days and at discharge
measure: Anthropometric Measurements(Head Circumference)
timeFrame: At age of 28 days and at discharge
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
Study officials:
affiliation: Yale University
name: Richard A Ehrenkranz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee EJ, Simmer K, Gibson RA. Essential fatty acid deficiency in parenterally fed preterm infants. J Paediatr Child Health. 1993 Feb;29(1):51-5. doi: 10.1111/j.1440-1754.1993.tb00440.x.
citation: Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet JC, Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children. JPEN J Parenter Enteral Nutr. 2000 Nov-Dec;24(6):345-50. doi: 10.1177/0148607100024006345.
citation: Boyd GW. An investigation of the prolonged pressor response to renin in the nephrectomized rat. Clin Sci Mol Med Suppl. 1976 Dec;3:151s-153s. doi: 10.1042/cs051151s.