Clinical trial NCT02370251
Conditions: Total Parenteral Nutrition-induced Cholestasis Cholestasis Short Bowel Syndrome Gastroschisis Intestinal Atresia Infant, Premature, Diseases Cholestasis of Parenteral Nutrition
Keywords: Fat Emulsions, Intravenous Parenteral-Nutrition-Associated Liver Disease Cholestasis Omegaven Fish Oil
Sponsor: University of Oklahoma
Start date: 2015-06-01; Completion date: 2019-09-27
Enrollment: 63 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-assignment study to evaluate whether Omegaven (IV fish oil) is effective at treating liver disease in children on long-term IV nutrition.

Detailed description:
Children up to 18 years of age, on parenteral nutrition, with a direct bilirubin level of 2 mg/dL or greater will be eligible to receive Omegaven at a maximum dose of 1 g/kg/day.

Up to 200 children will be eligible for enrollment.

Direct bilirubin levels and other labs will be monitored as well as growth parameters.

Arms: arm 1: Children will receive Omegaven at a maximum of 1 g/kg/day upon enrollment in this arm.
Interventions: intervention 1: Omegaven
Intervention descriptions: intervention 1: Once the direct bilirubin is 2 mg/dL or more x 2 weeks, Intralipid will be switched to Omegaven at 1 g/kg/day. The bilirubin level will be monitored to determine when resolution of cholestasis (DB \<2 mg/dL) occurs.

Protocol documents:
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February 19, 2018


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COMPASSIONATE USE PROTOCOL
Compassionate Use of Omegaven for the Treatment of 
Parenteral-Nutrition-Associated Liver Disease in Children
(IRB 5451)
Principal Investigator:
Kimberly Ernst, MD, MSMI; Pediatrics, Neonatology
Sub-Investigators:
Marilyn Steele, MD; Pediatrics, Gastroenterology
Safety Monitor:
Susan Bedwell, MS, APRN; Clinical Nurse Specialist
Inpatient Study Nurses:
Ashley Anderson; Neonatology
Erin Bohon; Neonatology
Outpatient Study Nurse:
Deidre Graham, RN; Gastroenterology
Data Manager:
Shannon Perkins; Neonatology
Regulatory Research:
Mike McCoy, APRN; Neonatology
Abstract
This is a single-group assignment, open-label protocol for the compassionate use of 
Omegaven® 10% in 200 children less than 6 years of age who are diagnosed with 
parenteral-nutrition-associated liver disease and have failed conventional lipid reduction 
strategies.  The primary objective is to safely provide Omegaven (fish oil lipid emulsion) 
to Oklahoma children who are dependent on parenteral nutrition and to determine the 
number of these children who have resolution of their cholestasis while on the emulsion.  
Omegaven at the FDA maximum dose of 1 g/kg/day will be used with informed consent 
after the failure of conventional therapies to prevent the progression of liver disease.  
Children will be eligible if they are dependent on parenteral nutrition and have a direct 
bilirubin level of ≥2 mg/dL on two consecutive tests at least 48 hours apart while on an 
average of <2 g/kg/day of parenteral lipids or ≥5 mg/dL on an average of 1 g/kg/day for 7 
days prior. Lab studies will be obtained to monitor safety and efficacy. Children will 
remain on Omegaven until their physician or guardian decides to no longer utilize the 
lipid emulsion.  Safety outcomes and the resolution of cholestasis will be monitored and 
reported to the FDA and IRB.


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Background and Significance
Humans cannot synthesize the precursors of ω-3 (α-linolenic acid) or ω-6 (linoleic acid) 
fatty acids and must obtain them from their diet.  In children who cannot tolerate full 
enteral feeds, the standard of care is to provide parenteral nutrition including IV lipids 
(fats).  The most commonly used IV product, introduced in 1961, is Intralipid 20%, a 
soybean oil-based lipid emulsion rich in omega-6 fatty acids (ω-6).  Omegaven 10% 
(Fresenius Kabi, Germany) was introduced in Europe in 2005.  Fish oil is rich in very 
long chain ω-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic 
acid (DHA), two conditionally-essential nutrients that have low rates of conversion from 
their precursor, α-linolenic acid.1,2,3
Lipid emulsions consisting primarily of omega-6 fatty acids have been linked to the 
development of liver damage when used for a prolonged length of time as an excess of 
omega-6 has been found to be pro-inflammatory. 1,2,3  Multiple studies have shown 
Omegaven useful for normalizing high direct bilirubin levels in comparison with 
Intralipid, as omega-3 is believed to attenuate the inflammatory response.1,2,3,4,5  
Unfortunately, those receiving Omegaven as a rescue therapy after receiving a course of 
Intralipid have histologic liver specimens with decreased inflammation6 but still 
demonstrate steatosis (fatty liver) and cirrhosis of the liver.7  In a 2012 study by Puder,8 
five groups of mice received different commercially-available lipid emulsions, including 
Intralipid and Omegaven. The only group to complete the study with normal liver 
histology had received Omegaven.
A retrospective cohort study that compared ω-3 to ω-6 lipid emulsions in 39 infants 
showed that it took 9.4 weeks in the ω-3 group versus 44.1 weeks in the ω-6 group to 
reverse cholestasis. Those in the ω-3 group also had lower mortality and liver transplant 
rates.9 Infants who started an ω-3 lipid emulsion with an initial direct bilirubin of <5 
mg/dL had a lower mortality rate (6%) versus those who started the therapy with a direct 
bilirubin of >10 mg/dL (35%).4  
One conventional therapy to prevent or treat cholestasis is lipid minimization, such that 
the IV lipid dose is reduced to levels below recommended intake amounts, compounding 
the growth failure inherent in infants with gastrointestinal disorders.  In those receiving 
Omegaven, their dose is limited by regulations to 1 g/kg/day, also below the 
recommended lipid intake.  Since fats have the highest caloric density of nutrients, 
maximizing intake is an important aspect of providing nutritional support.  The 
combination of maximum Omegaven dosing supplemented with lower doses of Intralipid 
could theoretically provide a more balanced intake of essential fatty acids as well as 
improved growth in this vulnerable population.


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Infants in our institution with severe PNALD were transferred outside of Oklahoma to 
centers approved to provide Omegave through “compassionate use” protocols as it is not 
available in the U.S. for routine use.  In 2014, The Children’s Hospital had approximately 
130 inpatient and 30 outpatient children between birth and 18 years of age with direct 
bilirubin levels above 4 mg/dL.10 Liver failure leads to approximately five liver 
transplants annually in Oklahoma children.  While not all of these are due to parenteral 
nutrition, the ability to prevent even one transplant yearly would result in a massive 
savings of healthcare dollars as well as improved quality of life for those affected.
This protocol will help delineate the safety and efficacy of Omegaven for use in the 
treatment of PNALD in children less than 6 years of age.  It has the potential to prevent 
or delay the need for liver transplantation in children who are exposed to long courses of 
intravenous nutrition while awaiting intestinal adaptation and growth and may provide a 
better alternative to our current sole use of ω-6 lipid emulsions associated with PNALD 
in children unable to achieve full enteral nutrition.  It will also demonstrate the essential 
fatty acid profiles of infants receiving Intralipid (ω-6) as a sole source versus Omegaven 
(ω-3) as a sole source versus the combination.
PRIMARY OBJECTIVES:
To safely provide Omegaven on a compassionate use basis to Oklahoma children 
who are dependent on parenteral nutrition and have failed conventional lipid 
reduction strategies.
To determine the number of these patients who have resolution of their cholestasis 
(direct bilirubin < 2 mg/dL) within 60 days of initiation of the emulsion.
SECONDARY OBJECTIVE:
To determine if the essential fatty acid profile differs between those receiving only 
Intralipid, only Omegaven, or a combination.
To determine if infants who receive Omegaven have different developmental 
outcomes than those on Intralipid.


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Lipid Emulsion Contents8
Intralipid (ω-6)
Omegaven (ω-3)
Fat content (per 10 ml)
2 grams
1 gram
α-Tocopherol (vit E)
38 mg/L
150-296 mg/L
Phytosterols
348 mg/L
0 mg/L
Linoleic acid (ω-6 precursor)
50 g/L
1-7 g/L
Arachidonic acid (ω-6)
0 g/L
1-4 g/L
α-Linolenic acid (ω-3 precursor)
9 g/L
<2 g/L
Eicosapentaenoic acid (EPA; ω-3)
0 g/L
13-28 g/L
Docosahexaenoic acid (DHA; ω-3)
0 g/L
14-31 g/L
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Preliminary Studies/Progress Report  
Dr. Kimberly Ernst, an associate professor at OU, has published several articles in the 
last 15 years specifically related to parenteral and enteral nutrition in extremely low birth 
weight infants. Her work is referenced in the 2009 “Nutritional Strategies for the Very 
Low Birthweight Infant.”  She provides annual nutrition training to the clinical nursing 
team dedicated to the treatment of extremely low birth weight infants.  As the Co-Chair 
of the NICU Nutritional Committee, she helped develop the first standardized parenteral 
nutrition solution started at OUMC NICU about 10 years ago.  In 2015, she helped to 
develop off-the-shelf parenteral solutions for improved safety, efficiency, and cost in the 
NICU.  She is the Leader of the NICU-GI Team, an interprofessional team providing 
comprehensive care to children with complex gastrointestinal disorders as they transition 
from the inpatient setting to home.  
In the summer of 2016, the FDA approved a newer generation lipid emulsion, SMOFlipid 
which contains a mixture of soybean oil, coconut oil (MCT), olive oil, and fish oil.12 
Many places around the country have already switched to using this blend instead of the 
pure soybean product, especially for children whose cholestasis has resolved and are on 
home parenteral nutrition.  Thus, at this time, clinical practice is likely to limit Omegaven 
use to a maximum of 3 years unless further evidence demonstrates it is superior to 
SMOFlipid.
In 2017, Dr Ernst published her findings in the Journal of Perinatology that 60% of 
infants on lipid minimization (~1 g/kg/day) with Intralipid (n=15) were found to have 
essential fatty acid deficiency while none of the infants on Omegaven (n=9) did. 
Furthermore, those who developed essential fatty acid deficiency (n=9) had a slower 
weight gain (19 g/kday) than those who did not (n=15) and gained 39 g/day.13
Research Design and Methods
Up to 200 children will be eligible for Omegaven use if they meet the following criteria: 
•
Live in or temporarily relocate to Oklahoma
•
Age up to 6 years, both sexes, all races
•
Have received at least 14 days of parenteral nutrition
•
Have a direct bilirubin level of ≥2 mg/dL for two consecutive samples at least 48 
hours apart and received parenteral lipids at a maximum dose of 28 g/kg over the 
two weeks prior OR have a direct bilirubin level of ≥5 mg/dL and received 
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Exclusion criteria for enrollment:
•
Known food allergy to fish
•
Known metabolic disorder of lipid metabolism
•
Active coagulopathies (active bleeding or requiring blood product treatment in the 
prior 48 hours)
•
Medical condition likely to result in death in the next 30 days
Baseline labs (Table 1) will be obtained within 48 hours prior to starting Omegaven.  An 
essential fatty acid profile will demonstrate the baseline profile on Intralipid.  An 
Omegaven infusion will be started at a dose of 1 g/kg/day after informed consent is 
obtained. This is the maximum dose allowed by the FDA. Monitoring studies will be 
obtained per Table 1.  Dosing modifications will be based on the parameters found on 
page 7 of the protocol.  After the first month of Omegaven therapy, routine study labs 
will be obtained as well as an essential fatty acid profile which will demonstrate the 
profile on Omegaven.  
Once the child’s direct bilirubin level has normalized (below 2 mg/dL) and they have 
received at least four weeks of Omegaven, additional parenteral lipids may be added or 
adjusted at the discretion of the physician.
Enrolled children will have full growth assessments (weight, length, FOC) and nutritional 
assessments at every patient encounter (typically this is daily in the hospital and at every 
GI clinic visit). Any surgical procedures, medications, hospital readmissions, and/or 
infections directly related to the use of parenteral nutrition will be documented as well as 
any laboratory, radiology, or pathology data obtained for this purpose while the patient is 
receiving Omegaven or within 30 days of stopping the lipid.


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Table 1: Laboratory Monitoring
Baseline
Day 0
Weekly
Every 2 
Weeks
Monthly
After Last 
Omegaven Dose1
While DB ≥2 mg/dL
Direct bili
Day -1 to 0
±3 days
Continue weekly 
until normal
CBC/diff
± 3 days
±3 days
Within 7 days
AST/ALT/GGT
± 3 days
±3 days
Within 7 days
Triglycerides
Lipid panel
± 3 days
±3 days
PT/INR
± 3 days
±3 days
Within 14 days
EFAP
Day 0
±3 days
Within 30 ± 7 days
When DB <2 mg/dL
Direct bili
±3 days
CBC/diff
±3 days
Within 14 days
AST/ALT/GGT
±3 days
Within 14 days
Triglycerides
Lipid panel
±3 days
PT/INR
±3 days
Within 14 days
EFAP
±3 days
Within 30 ± 7 days
1If DB remains ≥2 mg/dL, monitoring will continue until child is off Omegaven for 4 
months.  When feasible, an EFAP will be obtained approximately 4 weeks after the 
parenteral nutrition use has ceased.
Dosing Modifications Based on Triglyceride Levels:
•
If triglyceride level ≤ 250 mg/dL, continue lipids at current dose.
•
If triglyceride level > 250 mg/dL, repeat specimen when off lipids for 4 hours. If 
repeat is ≤ 250 mg/dL, continue at current dose. If repeat is > 250 mg/dL, 
decrease dose by 25% and repeat within 24 hours.
•
If triglyceride level >500, stop lipids immediately with repeat level within 24 
hours. Restart lipids at the discretion of the physician.
Other Dosing Modifications:
•
For children unable to tolerate Omegaven due to a suspected allergy or toxicity or 
due to active bleeding believed to be caused or worsened by the lipid emulsion, 
the infusion may be decreased or stopped at the discretion of the child’s medical 
team with the reason documented.
•
The attending physician may choose to decrease or stop lipids at their discretion 
for any reason if they determine continuing may be detrimental to the patient with 


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the reason documented. 
•
If, for any reason, the supply of Omegaven is interrupted, the infant will receive 
the standard of care at an equivalent dose until Omegaven is available.
Outpatient Administration:
Children receiving Omegaven at the time of discharge must be seen within the first 
month in the OU Children’s GI Clinic as an outpatient once they are discharged from the 
hospital.  Further outpatient visits should occur no less frequently than every 2 months 
while on Omegaven.  Weight, length, and FOC will be obtained on all children less than 
2 years of age; weight and height should be obtained on all children over the age of 2 
years.  At each outpatient visit, enteral and parenteral nutrition volumes should be 
recorded.  Any surgical procedures, medications, hospital readmissions, and/or infections 
directly related to the use of parenteral nutrition should be documented as well as any 
laboratory, radiology, or pathology data obtained for this purpose.  Monitoring labs will 
be performed as per Table 1 as long as the child remains on Omegaven.
Children will be observed in the inpatient setting for a minimum of 48 hours after the 
initiation of Omegaven.  Children will be eligible for Omegaven administration for up to 
3 years. Two months before eligibility is lost via this IND, an individual IND will be 
submitted by the child’s physician to the FDA if they expect that the child will need to 
require ongoing therapy.  This can be completed via a new process as of January 2017 at: 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevel
opedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/UCM
490130.pdf
Option Care will be the outpatient provider for parenteral nutrition.  They are familiar 
with the procurement and use of Omegaven and have procedures in place for providing 
training to the families before hospital discharge regarding the administration of 
parenteral nutrition as well as the reporting of potential adverse events.  At the time of 
discharge, interested parties will be given information regarding potential AEs to be 
reported and how to directly contact the safety monitor and/or Dr Ernst.  The family, 
home health nurse, primary care physician, and GI physician will report any suspected 
AEs to Dr Ernst and/or Susan Bedwell (safety monitor).


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Data Collection:
The following data may be collected for protocol adherence and patient safety analysis.
•
Name
•
Medical record number
•
Date of birth
•
Dates of hospitalization and/or outpatient visits
•
Nutritional data (enteral and parenteral)
•
Growth data (weight, length/height, FOC)
•
Laboratory, microbiology, and pathology data
•
Medications, including Ursodiol, phenobarbital, and other enteral lipid products
•
Liver and/or intestinal transplant and other pertinent surgical procedures
•
Neurodevelopmental testing results
•
Mortality
•
Adverse event data
Termination and Completion
Termination of a patient’s participation will occur if the child develops a serious adverse 
event definitely caused by the lipid emulsion, if the child is diagnosed after enrollment 
with a fish allergy or a disorder of lipid metabolism, if the child is unable to tolerate the 
emulsion, if the child dies, if the child’s guardian decides to no longer participate, or if 
the attending physician feels it is in the child’s best interest.  In the event this occurs, the 
date of and reason for termination will be recorded.
Completion of the study occurs when any of the following are met: the child is no longer 
receiving parenteral nutrition and the direct bilirubin level is <2 mg/dL, the direct 
bilirubin is ≥2 mg/dL and it has been 4 months since the cessation of Omegaven, 
Omegaven has been used for 3 years, or the child reaches 6 years of age.  This does not 
preclude the patient from receiving the medication, but the patient’s current physician 
will need to apply for a treatment IND and assume monitoring of the patient.


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Data and Safety Monitoring Plan
All observed or volunteered adverse events (AE) will be investigated for seriousness and 
causality within 48 hrs of investigator awareness. AEs will be reported from enrollment 
through 30 calendar days after the last administration of Omegaven. A serious adverse 
event (SAE) includes any untoward medical occurrence that results in death, is life-
threatening, requires prolongation of existing hospitalization, or results in significant 
disability.
We will assess adverse events using the following scale (i.e. 3D):
0=No or mild complication
1=Moderate complication with no long-lasting effects
2=Severe, life-threatening, or disabling complication
3=Death
A=UNRELATED or UNLIKELY (clearly not related to the study or the 
relationship appears to be remote and other factors suggest an alternative etiology 
exists)
B=POSSIBLE (one or more factors suggest a possible relationship but other 
etiologies seem equally or more likely)
C=PROBABLE (relationship seems probable because of a clear temporal 
association with the interaction, lack of alternative explanations for the 
experience, or other factors)
D=DEFINITE (clearly related to the study procedure)
Per FDA requirements, any unexpected fatal or life-threatening suspected adverse 
reactions will be reported within 7 days after initial receipt of the information.  Any 
serious, unexpected suspected adverse reactions, findings from other clinical, animal, or 
in-vitro studies that suggest significant human risk, and a clinically important increase in 
the rate of a serious suspected adverse reaction will be reported to the FDA and all 
investigators within 15 days after determining that the information qualifies for reporting.  
Annual progress reports will be reported to the FDA within 60 days of the anniversary 
date that the IND becomes active (March 21, 2015).  All adverse events will be reported 
to the IRB and the FDA on an annual basis, at minimum, when the protocol goes through 
annual review.
The Principal Investigator will meet with a data safety monitor, Susan Bedwell, APRN 
(clinical nurse specialist), quarterly to review any AE that were observed or volunteered 
over the previous quarter.
IRB Information
1) Sources of research material
The EMR will be utilized for obtaining clinical data, study outcomes, and 


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information necessary for adverse event reporting.  Laboratory work will be done 
as part of routine care and FDA requirements for receiving the emulsion.
2) Recruitment and Consent
a.
Consent will occur either in the hospital setting at the patient’s bedside or in the 
outpatient clinic in a private room.
b. The consent and HIPAA forms will be printed in English and Spanish. Spanish-
speaking families will be consented using a Spanish-speaking interpreter provided 
by the hospital.  Families speaking languages will be informed via a language-
specific translator and will be asked to sign the English consent form.
c.
Parents/guardians will be provided the study forms, including the consent, with 
ample time to review the materials.
d. Families who would like to participate will need to be transferred to The 
Children’s Hospital at OUMC where the formal consent process will occur.  The 
study is listed on ClinicalTrials.gov where the public has access to information 
regarding the study.  It is possible that hospital social media or television 
advertisement may include information about this study.
3) Intravenous nutritional products carry the risk associated with parenteral 
administration, including line sepsis and extravasation.  In previous published studies, 
there have been no additional identified risks of adverse events associated with the 
administration of fish oil-based lipid over soybean oil-based lipid.
4) Data will be collected by the study personnel in a private and confidential manner 
using the password-protected EMR or on paper forms in the patient’s chart.  Any data 
collected for analysis will be kept in a password-protected database (REDCap) or 
Excel file on a secure server or in the locked offices of the investigators.
5) Children may have direct benefit from participating in this study because they have 
access to a nutritional treatment that is suggested to be beneficial in the treatment of 
PNALD without a higher risk of adverse effects than the standard treatment.  There 
may also be decreased sepsis and other adverse outcomes associated with 
inflammatory processes as well as the possibility of enhanced visual and 
neurodevelopmental outcomes with the inclusion of DHA in Omegaven.
6) Despite not being FDA-approved, Omegaven has been in use in the US for the last 
decade for “compassionate use” and is approved for use in other countries in Europe.  
Potential benefits include the possibility of preventing progressive liver damage 
associated with long-term ω-6-fatty acid lipid emulsions.
7) Several studies have shown the efficacy of Omegaven in resolving cholestasis 


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without any serious side effects reported.  Children in this study may benefit from 
receiving a medication that provides protection against developing liver damage that 
is associated with the current standard treatment.  The patient’s insurance will be 
billed for the lipid emulsion at reasonable cost of acquisition plus storage and 
dispensing costs and the hospital has agreed to pursue payment as they do for all 
other treatments, including the use of charity, etc.
Literature Cited
1. Calder PC. N-3 polyunsaturated fatty acids, inflammation, and inflammatory 
disease. Am J Clin Nutr 2006;83;1505S-19S.
2. Calder PC. Use of fish oil in parenteral nutrition: rationale and reality. Proc Nutr 
Soc 2006;65:264-77.
3. Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response 
of n-3 fatty acids in humans. Am J Clin Nutr 2006;83;1467S-76S.
4. Premkumar MH, Carter BA, Hawthorne KM, King K, Abrams SA. Fish oil-based 
lipid emulsions in the treatment of parenteral nutrition-associated liver disease: an 
ongoing positive experience. Adv Nutr 2014 Jan;5(1):65-70.
5. Lam HS, Tam YH, Poon TC, Cheung HM, Yu X, Chan BP, Lee KH, Lee BS, and 
Ng PC. A double-blind randomized controlled trial of fish oil-based versus soy-
based lipid preparations in the treatment of infants with parenteral nutrition-
associated cholestasis. Neonatology 2014. 105(4):290-6.
6. Matsumoto CS, Kaufman SS, Island ER, Kallakury B, Yazigi NA, Khan KM, and 
Fishbein TM. Hepatic explant pathology of pediatric intestinal transplant 
recipients previously treated with omega-3 fatty acid lipid emulsion. J Peds 2014 
Jul;165(1):59-64.
7. Mercer DF, Hobson BD, Fischer RT, Talmon GA, Perry DA, Gerhardt BK, Grant 
WJ, Botha JF, Langnas AN, and Quiros-Tejeira RE. Hepatic fibrosis persists and 
progresses despite biochemical improvement in children treated with intravenous 
fish oil emulsion. J Pediatr Gastroenterol Nutr 2013;56(4):364-9.
8. Meisel JA, Le HD, de Meijer VE, Nose V, Gura KM, Mulkern RV, Akhavan 
Sharif MR, and Puder M. Comparison of 5 intravenous lipid emulsions and their 
effects on hepatic steatosis in a murine model. J Ped Surg 2011;46(4):666-673.
9. Gura KM, Lee S, Valim C, Zhou J, Kim S, Modi B, Arsenault D, Strijbosch R, 
Lopes S, Duggan C, and Puder M. Safety and efficacy of a fish-oil-based fat 
emulsion in the treatment of parenteral nutrition-associated liver disease. 
Pediatrics 2008;121;678-86. DOI: 10.1542/peds.2007-2248
10. Ernst KD. Unpublished internal data from The University of Oklahoma Children’s 
Hospital. 2014.
11. Linus Pauling Institute Micronutrient Information Center.  
http://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids accessed 
8/11/2015.


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12. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207648lbl.pdf
13. Ernst KD. Essential Fatty Acid Deficiency During Parenteral Soybean Oil Lipid 
Minimization. J Perinatol, Mar 2017.