626921

research-article2016
PENXXX10.1177/0148607115626921Journal of Parenteral and Enteral NutritionDiamond et al

Original Communication
Journal of Parenteral and Enteral
Nutrition
Preventing the Progression of Intestinal FailureAssociated Volume 41 Number 5
July 2017 866877
Liver Disease in Infants Using a Composite Lipid Emulsion: 2016 American Society

A Pilot Randomized Controlled Trial of SMOFlipid for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607115626921
journals.sagepub.com/home/pen

Ivan R. Diamond, MD1; Robert C. Grant, MD1; Paul B. Pencharz, MD1;

Nicole de Silva, RN1; Brian M. Feldman, MD1; Peter Fitzgerald, MD2;
David Sigalet, MD3; Bryan Dicken, MD4; Justine Turner, MD4;
Valerie Marchand, MD5; Simon C. Ling, MD1; Aideen M. Moore, MD1;
Yaron Avitzur, MD1; and Paul W. Wales, MD1

Abstract
Background: To examine whether SMOFlipid prevents progression of intestinal failureassociated liver disease (IFALD) in parenteral
nutrition (PN)dependent infants with early IFALD (conjugated bilirubin 1750 mol/L, 1-3 mg/dL). Study Design: Pilot multicenter
blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they
achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin. Results: Twenty-four infants
(mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were
receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment (P = .99). At trial
conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, 59
mol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 mol/L than
those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral
tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes
between the groups. Conclusions: Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal
failure. This trial was registered at clinicaltrials.gov as NCT00793195. (JPEN J Parenter Enteral Nutr. 2017;41:866-877)

Keywords
intestinal failure; intestinal failure associated liver disease; -3 fatty acids; intravenous lipid emulsions; clinical trials

Clinical Relevancy Statement complication.14 While the development of IFALD is related to

-3 Lipid emulsions are thought to improve intestinal failure
associated liver disease (IFALD), but the true benefit is biased
by literature that has been dominated by level 3 evidence and
confounded by enteral feeding practices, lipid dose, and sepsis.
This multicenter randomized controlled trial (RCT) is the first
to assess liver function as the primary outcome using SMOFlipid
in early onset IFALD. The study was designed to control for
lipid dose, enteral feeding, and sepsis that have confounded pre-
vious literature. Given the current paucity of level 1 evidence,
this pilot RCT supporting the use of a composite lipid emulsion,
containing -3 lipids, provides information and data that have
utility for designing further trials and improving current access
to third-generation lipid emulsions across North America.
Introduction
Intestinal failureassociated liver disease (IFALD) is a choles-
tatic disorder that develops in up to 66% of children receiving
prolonged parenteral nutrition (PN), and historically, 10%50%
of children receiving prolonged PN have died of this
both components of the PN, as well as host factors such as sepsis
and prematurity, much recent focus has been on the role that
intravenous lipid emulsions (ILEs) play.58
Conventional ILEs that are composed of plant-based lip-
ids, primarily soy, are thought to be contributory to the
development of IFALD through a number of mechanisms,
including accumulation of phospholipids,9 excess phytoster-
ols,1013 predominance of -6 fatty acids (-6FAs) leading to
a proinflammatory state,1416 and also antioxidant imbalance
related to inadequate provision of -tocopherol.1719 Given
the role that ILEs are believed to play in the pathophysiology
of IFALD, there is much interest in alternate approaches to
lipid provision, namely, either restriction of the dose of con-
ventional lipid or provision of alternate lipid emulsions
based on fish oil.8 While clinical data support either
approach, limited randomized data exist on which to base
treatment recommendations.7,8,20
SMOFlipid (Fresenius Kabi, Bad Homburg, Germany) is a
composite emulsion lipid that contains soybean oil (30%),
medium-chain triglycerides (MCTs) (30%), olive oil (25%), and
fish oil (15%). By reducing exposure to conventional soy-based
Diamond et al 867

lipids as well as by adding -3 lipids, SMOFlipid may be benefi-
cial for the prevention of IFALD.21 We tested this hypothesis in
a pilot RCT that compared SMOFlipid with a conventional ILE
Intralipid (Fresenius Kabi). Although the study was designed as
a pilot to examine the feasibility of conducting a definitive trial,
this article presents the efficacy data from the trial.
Method
Trial Design
We performed a multicenter parallel-group randomized con-
trolled trial with 1:1 assignment comparing SMOFlipid with
Intralipid for the prevention of progression of IFALD in
infants. Given the limited experience with clinical trials in
neonates with IFALD, we designed the trial as a pilot study,
with the goal of examining the feasibility of performing a
clinical trial in this population and to obtain an estimate of
effect size for a definitive study. Planned enrollment was for
24 patients. Since the trial was designed as a pilot study, the
sample size was not based on an estimate of treatment effect
but rather to ensure good feasibility data. At the proposed
sample size, the trial had 80% power to detect a 60-point dif-
ference in serum conjugated bilirubin (CB). This difference
was felt to be a reasonable treatment effect for SMOFlipid
given our experience with Omegaven (Fresenius Kabi, Bad
Homburg, Germany) in those with advanced IFALD.8,22
The trial opened to enrollment at the Hospital for Sick
Children in January 2009. Enrollment was opened at the
Hamilton subsite in July 2009, Calgary subsite in September
2009, Edmonton subsite in November 2009, and Montreal
subsite in October 2010. Enrollment was to close 24 months
after the first site was opened or after 18 months if <16 valid
patients (ie, those who did not end early due to achievement
of full enteral tolerance) had been enrolled in the trial.
In June 2010, with 15 patients enrolled, an amendment was
made to continue the trial beyond this period. Although the trial
had not met its objective of 16 enrollments within 18 months, it
was felt that such a target could still be achieved within a rea-
sonable time period. The amendment included a provision to
analyze limited data, using blinded group assignments on
patients who were enrolled and had completed their participa-
tion in the study by June 30, 2010. This blinded analysis was
presented to the Data Safety Monitoring Board (DSMB) in
April 2011, which agreed to allow the trial to continue until the
entire target of 24 patients was met. The trial closed to enroll-
ment in September 2011, having met the target of 24 patients.
Participants
Recruitment and enrollment. Potential patients were identified
by examining the list of patients receiving PN weekly at each
institution for infants with hepatic dysfunction who obtained
>40% of their calories parenterally. Potential patients were
screened weekly until they became eligible or were clearly
ineligible. The clinical team caring for the patient made initial
contact, at which point a member of the research team met with
the family. Once consent was obtained, enrollment was com-
pleted by a member of the research team (physician or regis-
tered nurse), who notified the pharmacy of the enrollment by
submitting a PN order to the pharmacy for trial lipid.
Eligibility criteria. Detailed eligibility criteria are included in
Figure 1. The primary inclusion criteria were an infant (aged
<24 months) with short bowel syndrome or intestinal failure
who received substantial PN support (>40% total calories) and

From 1Hospital for Sick Children, Toronto, Ontario, Canada; 2McMaster Childrens Hospital, Hamilton, Ontario, Canada; 3Alberta Childrens
Hospital, Calgary, Alberta, Canada; 4Stollery Childrens Hospital, Edmonton, Alberta, Canada; and 5CHU Sainte-Justine, Montreal, Quebec,
Canada.

Financial disclosure: The trial was funded by Fresenius Kabi, which also provided the SMOFlipid that was used in the study. The company
played no other role in the study and was not involved in the design of the study, data collection or analysis, or the preparation of the manuscript.
I. R. Diamond was supported by a fellowship award from the Canadian Institutes of Health Research, with additional support from the Surgeon
Scientist Training Program, Department of Surgery, University of Toronto. I. R. Diamond is also the recipient of a Graduate Studentship Award
from the Canadian Liver Foundation and the Chisholm Memorial Fellowship, Post Graduate Medical Education Office, the University of Toronto.
B. M. Feldman is supported by the Ho Family Chair in Autoimmune Disease. The remaining authors have no financial relationships relevant to
this article to disclose.

Conflicts of interest: P. W. Wales and J. Turner have received research funding support from Fresenius Kabi. The other authors have no conflicts of
interest to disclose.

Received for publication July 10, 2015; accepted for publication November 24, 2015.

This article originally appeared online on February 2, 2016.

Corresponding Author:
Paul W. Wales, MD, Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada.
Email: paul.wales@sickkids.ca
868 Journal of Parenteral and Enteral Nutrition 41(5)

Inclusion Criteria

1. 24 months of age at enrolment

2. Evidence of early hepatic dysfunction
Serum conjugated bilirubin 17 umol/L on 2 consecutive readings 7 days apart
i. No evidence of sepsis
ii. No prior administration of Omegaven**
3. 40% of total calories administered by PN
4. Meet one of the following diagnostic categories
a. Short Bowel Syndrome
i. Abdominal surgical procedure including gastroschisis/omphalocele closure by any means and percutaneous drainage
procedures within the past 6 months and has been receiving PN since surgery
b. Intestinal Failure
i. One of the following diagnoses for which the child is dependent on PN
1. Gastrointestinal Motility Disorder
2. Mucosal Enteropathy
5. Expectation of the treating physician that the patient will require PN for at least 3 weeks following enrollment**
6. Parents willing to participate including randomization

**Criteria 2-ii and 5 were added to the inclusion criteria 12 months after the trial opened.

Exclusion Criteria

1. Sepsis or Hemodynamic Instability of any cause.

2. Coagulopathy (Platelets 150 000, or INR 1.4)
3. Hypersensitivity to fish-, egg- or soy protein or to any of the active substances or excipients
4. Current enrolment in another clinical trial involving a surgical or pharmacologic intervention
5. Serum conjugated bilirubin > 50 umol/L
6. Hyperlipidemia
7. Treatment with intravenous N-Acetylcysteine or oral Ursodeoxycholic acid
8. Renal insufficiency
9. Disorders of Fluid Balance
10. Unstable medical conditions

Figure 1. Eligibility criteria. INR, international normalized ratio; PN, parenteral nutrition.

was demonstrating early hepatic dysfunction (CB: 1750 support pharmacist at the Hospital for Sick Children and the dis-
mol/L [13 mg/dL]) in the absence of sepsis. pensing pharmacist at the patients institution were aware of the
group assignment. Unblinding of participants and investigators
Intervention occurred only at the conclusion of the entire trial.

Randomization and allocation concealment.Randomization
was done centrally by the research support pharmacy at the
Hospital for Sick Children. The randomization sequence was
developed by the research support pharmacy using a random-
number table prior to enrollment of the first patient. The
sequence was developed in blocks of variable size without
investigator input or knowledge.
Allocation concealment was achieved by the randomization
sequence only being known to the research support pharmacy
at the Hospital for Sick Children. The group assignment was
relayed to the dispensing pharmacist at the patients institution
only after enrollment had occurred. This was done immedi-
ately prior to dispensing the first dose of study medication.
Blinding. The study lipid was administered in a blinded manner,
by dispensing the trial lipids in identical containers (syringe or
infusion bag). All participants, treating clinicians, and investiga-
tors were blinded to the treatment assignment. Only the research
Duration of treatment. Participants received trial lipid for up
to 12 weeks. Patients also ended the trial if they achieved full
enteral tolerance (autonomy from PN) prior to this time point
or if they developed progressive liver disease defined by a
serum CB exceeding 100 mol/L for >14 days. Since duration
of PN is challenging to predict, we included a provision for
replacement of patients who discontinued PN prior to the sec-
ond week on the study due to achievement of full enteral toler-
ance but not for reasons of safety or efficacy. By design, these
patients were not to be included in the analysis of trial out-
comes or count toward recruitment targets.
Lipid dosing. The PN solution was formulated according to a
nomogram (Figure 2) that took into account the proportion of
caloric intake received parenterally. The feasibility of formu-
lating PN according to a nomogram was one of the objectives
of the pilot study. Based on initial experience, the nomogram
was modified 12 months into the study as indicated in Figure 2.
Diamond et al 869

PN Dosing Nomogram Initial Protocol

% of calories Lipid (g/kg/day) Protein (g/kg/day) Carbohydrate (g/ GIR* (mg/kg/min) PN Calorie
administered kg/day) Range** (kcal/kg/
by PN day)
80 100 % 2.5 3 34 15 20 10.4 13.9 88 114
60 80 % 2.5 3 2.5 3.5 9 15 6.3 10.4 66 95
50 60 % 23 2 2.5 7 11 4.9 7.6 52 77
40 50 % 1.5 2.5 1.5 2 69 4.2 6.3 41 69
30 40 % 1.0 2.5 1 1.5 57 3.5 4.9 31 55
20 30 % 0.7 2 0.7 1 34 2.1 2.8 20 38
10 20 % 0.3 1.5 0.5 1 12 0.7 1.4 8 28
< 10 % 01 0 1 01 0 0.7 0 17

PN Dosing Nomogram Revised January 2010

% of calories Lipid (g/kg/day) Protein (g/kg/day) Carbohydrate (g/ GIR* (mg/kg/min) PN Calorie
administered kg/day) Range** (kcal/kg/
by PN day)
80 100 % 23 34 10 20 6.9 13.9 64 111
60 80 % 23 2.5 3.5 8 16 5.6 11.1 55 95
50 60 % 23 2 2.5 6 12 4.2 8.3 46 78
40 50 % 1.5 2.5 1.5 2 5 10 3.5 6.9 37 65
30 40 % 1.0 2.5 1 1.5 48 2.8 5.6 27 56
20 30 % 0.7 2 0.7 1 26 1.4 4.2 16 42
10 20 % 0.3 1.5 0.5 1 14 0.7 2.8 8 31

< 10 % 01 0 1 02 0 1.4 0 20

Figure 2. Nomogram for dosing of parenteral nutrition (PN). *This value reflects the GIR for a 24-hour period based on the total
daily glucose intake. It does not reflect a maximum GIR in the setting of a PN cycle of < 24 hours. **Provided for reference only
with rounding to whole numbers. Lower limit calculated using the minimum macronutrient values and upper limit calculated using
the maximum values for each macronutrient. Caloric densities for the macronutrients used in the calculations were as follows: lipid =
9 kcal/g, protein = 4 kcal/g, carbohydrate = 3.4 kcal/g. GIR, glucose infusion rate.

Management of enteral and parenteral feeds.We antici- Outcome Assessment

pated that, over the course of the trial, adjustments would be
made to the proportion of feeds received enterally and par-
enterally by each participant according to his or her clinical
needs. Choice of feeds, timing of the adjustment of the
enteral feeds, and ratio of enteral to parenteral feeds were to
be at the discretion of the treating physician. Initially, we
had provided a specific list of enteral feeds to choose from.
However, due to poor buy-in from the treating physicians,
this provision was removed from the protocol 12 months
into the study. The only enteral formula that was still not
allowed was enteral fish oil solution.
Efficacy outcomes.Most outcomes were assessed weekly
while the patient was on the trial. The primary end point for
analysis was CB the week that the child received his or her
last dose of trial lipid (at 12 weeks, at full enteral tolerance,
or on the development of progressive liver disease). In addi-
tion to the primary outcome, other data collected at baseline,
weekly while on the trial, and 4 weeks following trial com-
pletion (referred to as posttrial) included serum CB, serum
albumin, liver enzymes, parenteral intake, and enteral intake.
The following measurements were all obtained at the time
870 Journal of Parenteral and Enteral Nutrition 41(5)
the primary outcome was met and in addition as reported.
Weight, length, and head circumference were assessed at
baseline, week 6, and posttrial. A complete blood count was
done at weeks 0, 4, and 8 and posttrial. An international nor-
malized ratio, C-reactive protein, immunologic markers
(interleukins 1, 6, 8, 10, and 12; tumor necrosis factor ),
nephelometry, serum cholesterol, and serum triglycerides
were assessed at baseline, week 6, and posttrial. Red blood
cell phospholipid composition was assessed at baseline,
week 6, and posttrial.
Safety outcomes. Adverse events were handled according to
the principles of Good Clinical Practice (GCP) as adopted
by Health Canada.23 Adverse events were recorded irrespec-
tive of whether the adverse event was believed to be related
to the patients participation in the trial. All unexpected
adverse events were reported to the local Research Ethics
Board as well as to the DSMB.
The DSMB included a pediatric surgeon, a pediatrician
with expertise in nutrition and gastroenterology, and a bio-
statistician. All members of the DSMB were independent
from the trial to the extent that they were not investigators,
nor will they be included in any publications arising from
the trial. By protocol, the DSMB met to review the records
of the first 4 patients within 6 weeks of the 4th patients
posttrial assessment and again within 6 weeks of the 14th
patients posttrial assessment. No further scheduled meet-
ings were held, although a meeting could be called by any
DSMB member or one of the investigators. The DSMB
members were provided regularly with a listing of unex-
pected adverse events and serious adverse events.
Statistical Analysis
The primary end point for analysis was CB the week that the
child received his or her last dose of trial lipid (at 12 weeks,
at full enteral tolerance, or on the development of progressive
liver disease). The values for the SMOFlipid patients were
compared with the Intralipid patients at the time the primary
end point was met and at the completion of the posttrial
period (4 weeks following completion of trial lipid). Data are
presented as means and standard deviation (SD) to meet our
goal of obtaining an estimate of effect size. For a similar rea-
son, the a priori analysis plan included parametric analysis; t
tests were used for continuous data outcomes between groups
and Fisher exact tests were used for categorical data. Given
that the primary end point could occur in an individual patient
at a different time, a time-to-event analysis until 4 weeks
posttrial is also included, using the log-rank test, and Cox
proportional hazards regressions generated hazard ratios
(HRs). A P value of .05 was deemed statistically significant,
and a value of .1 was considered a trend. Analyses were per-
formed using R (The R Project for Statistical Computing,
Vienna, Austria).
Results
Recruitment and Participant Flow
Figure 3 lists the outcomes of all patients who were screened.
Of the 394 potential patients screened, 350 were not eligible.
Most of these (284; 81%) were excluded since their bilirubin
was not 1750 mol/L for at least 7 days while they were
receiving >40% of their calories parenterally. Twenty-two
potential patients were excluded because they were receiving
Omegaven, N-acetylcysteine, or ursodeoxycholic acid. Forty-
four potential patients were excluded because of a medical
contraindication; most of these potential patients were prema-
ture neonates who were excluded due to thrombocytopenia.
Of the 26 patients who were randomized, 17 were from the
Hospital for Sick Children, 5 from the Calgary subsite, 3 from
the Hamilton subsite, and 1 from the Edmonton subsite. No
patients were enrolled in Montreal. A total of 26 patients were
randomized to meet the final sample size of 24 as 2 patients
achieved full tolerance of enteral feeds prior to the second
week on trial. As per protocol, these patients were not consid-
ered valid participants, and their data were not included in the
analysis.
A total of 24 patients completed the trial: 11 in the
SMOFlipid group and 13 in the Intralipid group. All of these
patients were analyzed in the group to which they were
assigned. The mean duration on trial did not differ statistically
between those assigned to SMOFlipid (8 weeks; 95% confi-
dence interval [CI], 5.510.5 weeks) vs Intralipid (8 weeks;
95% CI, 5.710.7 weeks), P = .99.
Demographics
Table 1 provides the demographic characteristics of the partici-
pants at the time of recruitment. The mean age was approxi-
mately 6 weeks in both groups, and most participants had been
receiving PN for their entire life. At the time of trial enroll-
ment, patients in both groups were receiving 90% of their calo-
ries by PN. All but 1 of the patients had a surgical diagnosis
leading to their intestinal failure.
Outcomes
Hepatic and nutrition outcomes. Hepatic and nutrition outcomes
at baseline and at the time the primary outcome was achieved (the
primary endpoint) are shown in Table 2. The primary end point
was CB the week that the child received his or her last dose of
trial lipid (at 12 weeks, at full enteral tolerance, or on the develop-
ment of progressive liver disease). In the SMOFlipid group, 4
patients were studied to 12 weeks, 6 achieved full enteral toler-
ance, and 1 developed progressive liver disease. In the Intralipid
group, 6 patients were studied to 12 weeks, 6 achieved full enteral
tolerance, and 0 developed progressive liver disease. The 1
patient in the SMOFlipid group who met the definition for
Diamond et al 871

Figure 3. Patients screened and participant flow.

Table 1. Characteristics of Patients at Trial Entry.

Characteristic SMOFlipid (n = 11) Intralipid (n = 13)

Age, mean (range), wk 6.5 (4.38.7) 5.3 (3.57.2)
Gestational age, mean (range), wk 34.5 (32.436.7) 35.2 (33.237.1)
Birth weight, mean (range), kg 2.39 (1.942.84) 2.55 (2.132.98)
Weight at enrollment, mean (range), kg 3.24 (2.853.62) 3.21 (2.823.59)
Male sex, No. (%) 6 (55) 7 (54)
Etiology of intestinal failure, No. (%)
Small bowel atresia 5 (46) 3 (23)
Necrotizing enterocolitis 2 (18) 1 (8)
Gastroschisis 2 (18) 4 (31)
Motility disorder 1 (9) 2 (15)
Diaphragmatic hernia 1 (9) 0 (0)
Volvulus 0 (0) 1 (8)
Meconium ileus 0 (0) 1 (8)
Mucosal enteropathy 0 (0) 1 (8)
Weeks of PN prior to trial, mean (range) 5.5 (3.77.2) 4.4 (2.95.8)
No. (%) with ileocecal valve in situ 8 (73) 11 (85)
No. (%) with stoma 5 (46) 4 (31)
No. (%) with STEP procedure 1 (9) 1 (8)
Comorbidity, No. (%)
Neurological 4 (36) 4 (31)
Cardiac 2 (18) 3 (23)
Respiratory 2 (18) 1 (8)
Genitourinary 3 (27) 1 (8)
Hematologic 5 (46) 5 (39)
Musculoskeletal 0 (0) 1 (8)

PN, parenteral nutrition; STEP, serial transverse enteroplasty.

progressive liver disease experienced a septic episode at 6 weeks
with associated hepatic dysfunction, and the serum CB rose
acutely to 288 mol/L. This posed a challenge statistically, as this
value was a statistical outlier (Figure 4). Therefore, the analysis
was performed a number of ways. First, as per the analysis plan,
a t test was performed. In this analysis, there was no statistical
difference between the groups (P = .42). However, since it was
recognized that there was a statistical outlier influencing the
results, a nonparametric analysis was also performed using the
Wilcoxon rank sum test that demonstrated that the serum CB at
872 Journal of Parenteral and Enteral Nutrition 41(5)

Table 2. Hepatic and Nutrition Parameters at Trial Start and End.

SMOFlipid (n = 11) Intralipid (n = 13) Difference Between
SMOFlipid and P
Parameter Start End Start End Intralipid Value

Hepatic
Conjugated bilirubin,a mol/L 35 (2050) 22 (440) 36 (3240) 69 (4890) 47 (73 to 21) .001
Conjugated bilirubin,b mol/L 34 (2148) 46 (10 to 102) 36 (3240) 69 (4889) 23 (81 to 36) .42c
Unconjugated bilirubin, mol/L 23 (1134) 47.5 (32 to 127) 23 (1532) 38 (2155) 9 (71 to 89) .80
AST, U/L 58 (3582) 138 (92184) 66 (29102) 271 (98444) 133 (309 to 44) .13
ALT, U/L 51 (2378) 156 (71241) 51 (1192) 192 (88295) 36 (162 to 90) .56
ALP, U/L 304 (229380) 394 (290499) 339 (263414) 513 (426601) 119 (248 to 10) .07
GGT, U/L 196 (162231) 295 (190399) 151 (101200) 180 (131230) 114 (3226) .04
Serum albumin, g/L 27 (2429) 30 (2734) 28 (2530) 34 (3136) 3 (7 to 1) .12
INR, s 1.1 (11.2) 1.2 (11.3) 1.1 (11.2) 1.1 (11.2) 0.1 (0.1 to 0.2) .38
Nutrition
Proportion of calories parenterally 0.92 (0.811.03) 0.45 (0.140.77) 0.89 (0.790.98) 0.40 (0.20.59) 0.05 (0.3 to 0.41) .74
Weight, kg 3.2 (2.93.6) 4.5 (4.05.0) 3.2 (2.83.6) 4.3 (3.74.9) 0.2 (0.5 to 0.9) .51
Height, cm 50 (4952) 56 (5359) 50 (4952) 55 (5358) 0.5 (3 to 4) .78
Head circumference, cm 35 (3336) 38 (3639) 35 (3436) 38 (3740) 0.4 (2 to 2) .65

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; GGT, -glutamyl transferase; INR, international normalized ratio.
a
Does not include statistical outlier in the SMOFlipid group.
b
Includes statistical outlier in the SMOFlipid group.
c
The P value listed is for the t test; the corresponding nonparametric P value is .002.

trial completion remained significantly lower in the SMOFlipid

group (P = .02). Finally, to obtain an estimate of effect size, the
analysis was performed with the septic patient excluded. In this
analysis, the CB in the SMOFlipid group was 47 mol/L lower
than in the Intralipid group (P = .001). At 4 weeks, the patients
CB had declined to 90 mol/L. While this value was the highest
in the SMOFlipid group, it was no longer an outlier. At this time
point, the patients in the SMOFlipid group continued to exhibit a
lower CB than those in the Intralipid group, including all patients
with no exclusions (59 mol/L; P = .03). Patients who received
SMOFlipid were more likely to have a decrease in serum CB to 0
mol/L than those in the Intralipid group over the entire observa-
tion period (HR, 10.6; 95% CI, 1.386.9; P = .006).
At the time the primary end point was achieved, 3 (27%)
patients in the SMOFlipid group had a serum CB exceeding 50
mol/L, while 9 (69%) patients in the Intralipid group had a
bilirubin above this level (P = .04). Three (27%) patients in the
SMOFlipid group had a CB = 0, and 1 (9%) had a CB >100
mol/L (the patient with sepsis described above). There were 0
patients in the Intralipid group with a CB = 0 mol/L and 2
Figure 4. Box plots of the conjugated bilirubin in the final trial
(15%) with a CB >100 mol/L; these proportions were not sig-
week, demonstrating that 1 patient in the SMOFlipid group was a
nificantly different between groups. Posttrial, 1 (9%) patient in statistical outlier.
the SMOFlipid group and 6 (46%) patients in the Intralipid
group had a CB >50 mol/L (P = .08). At this time point, there
were 3 (23%) patients in the Intralipid group and no patients in statistically significant (P = .07). However, -glutamyl trans-
the SMOFlipid with a CB >100 mol/L (P = .22). ferase in the SMOFlipid group was significantly higher at
There was no significant difference in terms of unconju- trial completion (P = .04). There was no difference in these
gated bilirubin and transaminases between the groups at the cholestatic enzymes between the groups posttrial, but the
time the primary end point was achieved. Although alkaline patients in the SMOFlipid group had lower aspartate amino-
phosphatase was lower in the SMOFlipid group, it was not transferase levels (P = .02).
Diamond et al 873

A B

C D

Figure 5. (A) Conjugated bilirubin, (B) total caloric intake, (C) lipid intake, and (D) parenteral caloric intake throughout the trial.

At no time was there a statistical difference in terms of
nutrition parameters. Six patients in both the SMOFlipid and
Intralipid groups achieved full enteral tolerance at the primary
end point. Posttrial, there were 7 patients in the SMOFlipid
group and 6 in the Intralipid group with full enteral tolerance.
The time to achievement of full enteral tolerance did not differ
statistically between SMOFlipid and Intralipid in a time-to-
event analysis (HR, 1.3; 95% CI, 0.54.0; P = .59).
Figure 5 examines the relationship between serum CB, total
caloric intake, proportion of caloric intake parenterally, and
total lipid intake throughout the trial. This figure demonstrates
that total caloric intake, proportion of caloric intake parenter-
ally, and total lipid intake were similar throughout the trial for
those assigned to SMOFlipid and Intralipid, suggesting that
differences in these parameters do not account for the observa-
tion that patients who received SMOFlipid had a decline in
serum CB over the course of the study, whereas those receiving
Intralipid had an increase in serum CB.
Immunologic and lipid outcomes. Immunologic and lipid out-
comes at baseline and trial completion are included as supple-
mentary material (see Supplementary Table S1). The proportion
of -6:-3 fatty acids in the serum was lower in the SMOFli-
pid group (8:1) compared with the Intralipid group (14:1) at
trial completion (P = .05). However, this difference was no
longer evident posttrial. The patients who received SMOFlipid
also had statistically lower levels of linoleic acid and linoleic
acid and statistically higher levels of eicosapentaenoic acid,
docosahexaenoic acid, and oleic acid in their red blood cell
membranes while on the trial lipid, although none of these dif-
ferences persisted posttrial. There was no impact of the inter-
vention on triglycerides, cholesterol, or lipid clearance. There
was no statistical difference in terms of immunologic parame-
ters between the groups during or posttrial.
Adverse Events
Adverse events are provided in Supplementary Table S2. All
patients experienced at least 1 adverse event. The mean num-
ber of adverse events per patient was 12.4 in the SMOFlipid
group and 9.2 in Intralipid group (P = .30). There were no seri-
ous unexpected adverse events or any unexpected adverse drug
reactions as assessed by the DSMB. There were no deaths due
to liver disease during the trial, but 1 child who had received
874 Journal of Parenteral and Enteral Nutrition 41(5)
Intralipid died of progressive liver disease shortly after the trial
was completed. This death was reviewed by the DSMB as well
as the Research Ethics Boards at the Hospital for Sick Children
as well as the patients institution.
Discussion
IFALD is the greatest contributor to the morbidity experienced
by children with intestinal failure (IF).1,2,24 Historically, IFALD
was the primary cause of death of children with IF. While the
pathophysiology of IFALD is multifactorial, recently much
attention has been devoted to the critical role that -6FAs con-
taining ILEs play in the development of IFALD.3 Understanding
the role that ILEs play in the development of IFALD may allow
the use of targeted therapies.25,26 The 2 approaches that have
been advanced are that of lipid minimization and alternative
ILEs, including those containing -3 fatty acids (-3FAs).
Retrospective human studies and animal research have revealed
that decreasing or discontinuing parenteral soybean-based lipid
emulsions will reverse cholestasis and improve bile flow.10,2733
-3 Lipid emulsions are believed to improve hepatic function
via several mechanisms, including improved bile flow. Clearance
of lipid is improved and uptake by extrahepatic tissues is
increased through enhanced -oxidation. Added -3 polyunsat-
urated fatty acids (PUFAs) are metabolized into eicosanoids
with a less inflammatory profile and therefore may modulate the
immune system, with reduced hepatic inflammation and scar-
ring ultimately reducing the risk of cirrhosis and liver failure.7
An -6:-3 ratio <4:1 is believed to reduce inflammation, and
<2.5:1 has been shown to improve bile flow in animal models.
Current third-generation, -3containing lipid emulsions all
contain more -tocopherol than conventional soy-based lipids.
Preliminary studies in preterm piglets suggest this may be the
key factor in improving bile metabolism.19 The third-generation
lipids also contain less phytosterols than conventional lipids,
which can accumulate in the liver and also, based on animal
studies, appear to affect bile acid metabolism.13
Regardless of our incomplete understanding of the exact
mechanisms by which -3containing lipids can improve
IFALD, these therapies have been studied in children predomi-
nantly in uncontrolled settings and primarily in those having
advanced IFALD. A small trial has been conducted in IFALD
comparing 2 lipid emulsions, -3 (n = 9) and -6 (n = 7), at the
same dose but was confounded by enteral advancement, and
unfortunately, while there were differences in CB that favored
the -3 treatment, there was a high rate of resolution of IFALD
in both groups.34 A systematic review of the available literature
concluded that there was evidence that -3containing lipid
emulsions could reverse severe IFALD but that there were lim-
ited data for prevention.20 The review identified only 3 random-
ized trials and only 2 of good quality. The findings are also
supported by 1 recent RCT, which found equivalent efficacy
between -3 treatment and -6 dose restriction in preventing
early onset IFALD.29 In contrast, it appears that dose restriction
of conventional -6containing lipids can both prevent and
treat IFALD,28,35 but when used for prevention, there may be
potential for negative impact on normal growth and develop-
ment.28 Therefore, we have argued previously that there is
insufficient evidence to recommend these novel therapies in
children with early or no IFALD to prevent the progression to
advanced IFALD due to unproven efficacy in clinical trials, the
unknown long-term safety profile (coagulopathy, essential fatty
acid deficiency, neurocognitive outcome), and added cost.25,26
Intralipid, a soy-based lipid emulsion, has been the standard
lipid emulsion for parenterally supported patients for over 40
years. It provides energy and is a source of essential fatty acids.
Intralipid comprises predominantly -6 long-chain PUFAs and
is believed to contribute to IFALD due to its more inflamma-
tory cytokine profile, significant phytosterol content (that
inhibits bile acid excretion), and relatively low antioxidant
content (-tocopherol). It has an -6:-3 ratio of 8:1. It does
not provide any significant docosahexaenoic acid (DHA),
which is important especially in preterm infants for neurocog-
nitive development. The essential -3 PUFA in Intralipid,
linolenic acid, cannot be converted into DHA that is required
by neonates; therefore, the conventional lipid emulsion pro-
vided to neonates is DHA deficient.
Omegaven has been used in Canada since 2006, after Gura
etal36 first reported reversal of cholestasis in 2 patients. It is
available through compassionate release from Health Canada.
It is made of fish oil predominantly (-6:-3 = 1:7). It was
never designed as a source of sole parenteral lipid support. It
gained popularity for rescue therapy in children with advanced
IFALD who would otherwise die without liver transplantation.
With the reported success of Omegaven in several retrospec-
tive cohort studies, its use expanded, and it began to be used in
patients with lower risk disease. The literature unfortunately is
of poor quality due to the retrospective nature of study design
and the confounding of results by the effect of lipid dose
restriction, phytosterol restriction, enteral nutrition advance-
ment, and enhanced delivery of -tocopherol. SMOFlipid, a
third-generation product, is a composite lipid emulsion com-
posed of soybean oil, MCTs, olive oil, and fish oil. It has an
-6:-3 ratio of 2.5. It is designed as a balanced emulsion for
any patient requiring parenteral lipid support. It provides
essential fatty acids and also has a desirable immune profile
due to the added -3 PUFAs. SMOFlipid has been available in
Europe for several years and has been licensed for pediatric use
since 2009. It has been licensed in Canada since June 2013.
There have been 4 randomized trials, 3 in premature babies
that were short term (24 weeks) and evaluated safety as the
primary outcome. Most also demonstrated improved liver
function as a secondary outcome.3740
While the randomized controlled trial provides the best evi-
dence for the efficacy and safety of an intervention,41 these tri-
als may be challenging to perform in children with IF. First, IF
is a rare disease, and therefore trials will need to be performed
across multiple centers. Second, children with IF are a
Diamond et al 875
heterogeneous group of patients who typically have multiple
additional comorbidities, and the standardization of manage-
ment required in a clinical trial may be difficult to achieve.
Also, it is unclear if randomized studies would be acceptable to
the caregivers of these complex children. There is also little
evidence on which to base estimates of treatment efficacy with
the novel lipid-based approaches for use in sample size calcu-
lations. Finally, there is limited experience with clinical trials
in the IF population.42
Given the potential for challenges in performing such ran-
domized studies, we felt it prudent to evaluate the feasibility of
the randomized controlled design for the evaluation of a novel
lipid-based strategy for the prevention of advanced IFALD.
While recruitment was slower than anticipated, primarily due
to the delay in launching external sites and a number of refus-
als early in the trial, the overall design was assessed to be fea-
sible. One of the specific issues that we felt needed to be
addressed was the feasibility of standardizing the administra-
tion of PN for patients enrolled in the trial. We believed this
aspect of the design to be important to allow the groups to be
balanced from a nutrition perspective and facilitate optimal
assessment of efficacy of the therapy. We do acknowledge this
remains a limitation of conducting these trials and that our ini-
tial nomogram was adjusted during this trial with feedback
from investigational centers. The PN dosing nomogram was
the most common reason for deviations in the pilot study. The
outcome of the adjustments made was to substantially reduce
the incidence of such deviations over the course of the trial.
This will be critical in the design of future trials, and we con-
clude that it is feasible to standardize dosing of PN in the con-
text of a randomized controlled trial.
The objective of this study was to explore whether
SMOFlipid, a composite lipid emulsion, would reduce the risk
of IFALD progression in children receiving PN who were
exhibiting early hepatic dysfunction. Our results confirmed our
hypothesis that SMOFlipid, provided at conventional dosing,
lessens the risk of IFALD progression as quantified by serum
CB, our primary clinical outcome. Children who received
SMOFlipid had a higher level of the cholestatic marker
-glutamyltransferase (GGT) but a trend toward a lower alka-
line phosphatase (ALP). We do not have an explanation for this
dichotomy. We do not have histological samples to assess for
alterations in intrahepatic bile ducts. Another potential expla-
nation is a direct activation of GGT gene expression, without
underlying liver pathology. This issue should be explored in
future studies. We did not demonstrate a meaningful difference
in terms of immunologic outcomes. This may be related to the
fact that we measured serum cytokines, whereas tissue markers
may have been more sensitive, yet unfeasible to examine.
There were no differences in terms of nutrition or safety param-
eters between the groups.
There are a number of strengths to this study, the first ran-
domized blinded controlled trial of SMOFlipid for the preven-
tion of progression of early IFALD in children. While there
have been other randomized studies exploring SMOFlipid in
infants,3740 these were all short-term trials with safety as the
primary outcome. It also represents the longest intervention
studied with a treatment period of up to 12 weeks. The random-
ized design addresses many of the concerns with respect to the
literature in an area that has been patient to confounding related
to indication, as well as dosing, of lipid. Second, lipid dosing
was standardized for the trial. We believe that such standard-
ization is necessary to ensure that the treatment groups receive
equivalent nutrition intake allowing for unbiased assessment
of the treatment response. Finally, the range of lipid intake
used in the trial was within the range traditionally considered
appropriate for developing infants, and therefore, the strategy
employed allays our concerns with respect to impact of treat-
ment on growth and development. Finally, it is important to
recognize that this trial was designed as a pilot study, and while
this article primarily focused on the efficacy outcomes from
the pilot trial, it is important to note that our feasibility objec-
tive was met, which should facilitate future trials.
Despite the strengths of the trial, there are a number of limi-
tations. First is the fact that this was a pilot study, and while the
effect size demonstrated by the study is consistent with what
we hypothesized, the results need to be tempered by this fact.
The trial was never meant to be the definitive randomized trial,
rather to establish the feasibility of randomized trials in this
patient population and to provide data to facilitate the design of
these trials such as estimates of effect size. The impact of sam-
ple size was highlighted by the 1 patient who was a statistical
outlier, due to an episode of severe sepsis. In a larger trial, a
single patient would not likely have such an influential impact
on the results, and while we believe that we addressed the
impact of this patient statistically, this patient does weaken our
conclusion. Second, we adopted a very comprehensive
approach to screening patients for the trial and hence the large
number of patients whose bilirubin was not in range for the
study (1750 mol/L for at least 7 days). However, there were
44 patients who had another exclusion, typically sepsis or
thrombocytopenia, at the time that their CB was within range
(1750 mol/L) for the study. Most of the infants who were
excluded for this reason were preterm or low-birth-weight
infants. In designing future studies, it would be ideal to include
these infants, since they are known to be at significant risk of
progressive IFALD.2,4345 Thrombocytopenia should be recon-
sidered as an exclusion criterion as coagulopathy is largely a
consideration with an ILE that is exclusively composed of
-3FAs and not particularly germane to a composite emulsion
such as SMOFlipid.46 Finally, it is important to recognize that
while the results are consistent with the experience with -3
lipids in advanced IFALD, SMOFlipid is a composite emul-
sion, which has both reduced -6FAs and additional -3FAs,
and a positive result does not necessarily mean that the addi-
tion of -3FA is the reason for a beneficial effect. Therefore, in
concert with clinical trials, animal models are required to fur-
ther investigate ILEs of varying composition and their role in
876 Journal of Parenteral and Enteral Nutrition 41(5)
the management of IFALD. These studies will also allow
investigators to further delineate the mechanism of action of
these therapies.
Several important questions remain to be answered about
the use of lipid in children with PN-dependent intestinal fail-
ure.4749 Will a long-term reduction in soybean oil dose to 1 g/
kg/d result in adequate growth and neurological development,
and will essential fatty acid deficiency (EFAD) be prevented?
Is a fish oil emulsion more effective than an equivalently dosed
soybean oil emulsion at preventing IFALD, promoting neuro-
logical development, and what is the incidence of EFAD if the
low dose is given over a long duration? Is SMOFlipid, deliv-
ered at conventional lipid doses, effective at preventing the
development of IFALD while optimizing growth and develop-
ment over the long term? At this stage, it is unethical to design
a trial evaluating novel lipid strategies (dose restriction or fish
oil emulsions) in the setting of rescue therapy for children with
advanced IFALD. These children traditionally have a high
mortality and will die without transplantation. The focus of
future trials, therefore, should be on IFALD prevention with
short-term hepatic and longer term growth and developmental
outcomes. As evidence from clinical trials accumulates on the
efficacy of either novel lipid-based approach as a preventative
strategy, trials directly comparing these strategies should be
performed. In our recently published expert belief elicitation
study,50 there already appears to be evidence of equipoise in
terms of expert opinion on the relative efficacy of the alternate
approaches. This may provide justification for a trial that
would directly compare the -3FA approach to lipid minimiza-
tion. Obstacles to progress include lack of consensus on the
definition of cholestasis, determination of the most appropriate
study clinical end point,51 individual clinician bias and percep-
tion of advanced IFALD, and access to novel lipid products
and strategies outside a clinical trial (the backdoor).
Acknowledgments
We thank Mark Bedford (research pharmacy), Janice Bowers
(administrative support), and Eveline Lapidus-Kroll, Julia
Pemberton, Viona Lam, and Sandra Young (research coordinators).
Statement of Authorship
I. R. Diamond, P. B. Pencharz, B. M. Feldman, S. C. Ling, A. M.
Moore, Y. Avitzur, and P. W. Wales contributed to conception or
design of the research; I. R. Diamond, R. C. Grant, N. de Silva, P.
Fitzgerald, D. Sigalet, B. Dicken, J. Turner, V. Marchand, and P.
W. Wales contributed to acquisition, analysis, or interpretation of
the data; and I. R. Diamond, R. C. Grant, and P. W. Wales drafted
the manuscript. All authors critically revised the manuscript, gave
final approval, and agree to be accountable for all aspects of work
ensuring integrity and accuracy.
Supplementary Material
Supplementary Tables S1 and S2 are available with the article
online at http://journals.sagepub.com/home/pen.
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